Guía - ESC - 2023 - Sobre - SCA Evidencia

2023 ESC Guidelines for the management of
acute coronary syndromes
Evidence tables
Developed by the task force on the management of acute coronary syndromes of the
European Society of Cardiology (ESC)
1
Recommendation Table 1 — Recommendations for clinical and diagnostic
tools for patients with suspected acute coronary syndrome
Acronym High-Sensitivity Troponin in the Evaluation of patients with

suspected Acute Coronary Syndrome (High-STEACS) trial
Reference Shah ASV, Anand A, Strachan FE, Ferry AV, Lee KK, Chapman AR,
Sandeman D, Stables CL, Adamson PD, Andrews JPM, Anwar MS,
Hung J, Moss AJ, O'Brien R, Berry C, Findlay I, Walker S, Cruickshank
A, Reid A, Gray A, Collinson PO, Apple FS, McAllister DA, Maguire D,
Fox KAA, Newby DE, Tuck C, Harkess R, Parker RA, Keerie C, Weir CJ,
Mills NL; High-STEACS Investigators. High-sensitivity troponin in the
evaluation of patients with suspected acute coronary syndrome: a
stepped-wedge, cluster-randomised controlled trial. Lancet. 2018 Sep
15;392(10151):919-928. doi: 10.1016/S0140-6736(18)31923-8. Epub
2018 Aug 28. PMID: 30170853.
Study Type Stepped-wedge, cluster-randomised controlled trial.
Details and Quality
Nº patients 48,282 (10 hospitals).

of Evidence
Intervention Implementation of an hs-cTnI assay (the unit of randomisation was

the hospital).
Main incl/excl Inclusion: suspected acute coronary syndrome and paired cardiac
criteria troponin measurements from the standard care and trial assays.
Exclusion: previous admission during the trial period or not resident
in Scotland.
Relevant The primary outcome was subsequent myocardial infarction or death
outcome(s) from cardiovascular causes at 1 year after initial presentation.
Outcomes were compared in patients reclassified by the high-
sensitivity assay before and after its implementation.
Key findings Twenty-one percent patients had cTnI concentrations greater than
Summary of Key findings
those of the 99th centile of the normal range of values, who were
identified by the contemporary assay or the high-sensitivity assay. In
patients reclassified with the use of the high-sensitivity assay (17%),
subsequent myocardial infarction or cardiovascular death within 1
year occurred in 15% patients in the validation phase and 12%
patients in the implementation phase (adjusted odds ratio for
implementation vs validation phase 1.10, 95% CI 0.75 to 1.61;
p=0.620).
Conclusion(s) Use of a high-sensitivity assay prompted reclassification of 17%s with
myocardial injury or infarction, but was not associated with a lower
subsequent incidence of myocardial infarction or cardiovascular
death at 1 year.
2
Acronym Advantageous Predictors of Acute Coronary Syndromes Evaluation
(APACE) Study
Reference Badertscher P, Boeddinghaus J, Twerenbold R, Nestelberger T, Wildi K,
Wussler D, Schwarz J, Puelacher C, Rubini Giménez M, Kozhuharov N,
du Fay de Lavallaz J, Cerminara SE, Potlukova E, Rentsch K, Miró Ò,
López B, Martin-Sanchez FJ, Morawiec B, Muzyk P, Keller DI, Reichlin T,
Mueller C; APACE Investigators. Direct Comparison of the 0/1h and
0/3h Algorithms for Early Rule-Out of Acute Myocardial Infarction.
Circulation. 2018 Jun 5;137(23):2536-2538. doi:
10.1161/CIRCULATIONAHA.118.034260. PMID: 29866778.
Study Type Diagnostic multicenter observational study.
Nº patients 2547 participants with hs-cTnT, and 2197 patients with hs-cTnI
Details and
Quality of
Evidence
Intervention 0/1h vs. the 0/3h algorithm.

Main incl/excl The study enrolled patients presenting with suspected AMI to the
criteria emergency department. Patients presenting with ST-segment–
elevation MI were excluded.
Relevant Negative predictive value (NPV) and the negative likelihood ratio (LR)
outcome(s) for the presence of AMI (final adjudication performed by 2
independent cardiologists using all information, including cardiac
imaging and serial hs-cTnT measurements). Efficacy was quantified by
the proportion of patients triaged toward rule-out.
Key findings AMI was the final adjudicated diagnosis in 15%.
Among patients with hs-cTnT, AMI was the final adjudicated diagnosis
in 15%. Comparisons (0/1h vs 0/3h algorithm):
- NPV, 99.8% (95% CI, 99.4–99.9) vs 99.7% (95% CI, 99.2–99.9)

- negative LR, 0.01 (95% CI, 0.00–0.03) vs. 0.02 (95% CI, 0.00–
0.05)
- Percentage of patients triaged toward rule rule-out (60% vs.
44%; P<0.001).
Among 2197 patients with hs-cTnI, AMI was the final diagnosis in 15%.
Comparisons (0/1h vs 0/3h algorithm):
- NPV, 99.6% (95% CI, 99.1–99.9%) vs 97.8% (95% CI, 96.7–98.5)
- negative LR, 0.02 (95% CI, 0.01–0.05) vs. 0.13 (95% CI, 0.09–
0.19)
- Percentage of patients triaged toward rule rule-out (52% vs.
51%; P=0.507).
Conclusion(s) The use of the 0/1h algorithm is safe compared to the use of the 0/3h
algorithm.
3
Acronym High-STEACS trial (High-Sensitivity Troponin in the Evaluation of
Patients With Acute Coronary Syndrome)
Reference Chapman AR, Anand A, Boeddinghaus J, Ferry AV, Sandeman D,
Adamson PD, Andrews J, Tan S, Cheng SF, D'Souza M, Orme K, Strachan
FE, Nestelberger T, Twerenbold R, Badertscher P, Reichlin T, Gray A,
Shah ASV, Mueller C, Newby DE, Mills NL. Comparison of the Efficacy
and Safety of Early Rule-Out Pathways for Acute Myocardial Infarction.
Circulation. 2017 Apr 25;135(17):1586-1596. doi:
10.1161/CIRCULATIONAHA.116.025021. Epub 2016 Dec 29. PMID:
28034899.
Study Type Prespecified analysis of the High-Sensitivity Troponin in the Evaluation
of Patients With Acute Coronary Syndrome (High-STEACS) trial
Nº patients 1218 participants
Details and Quality of Evidence
Intervention High-sensitivity cardiac troponin I measurement at presentation and 3

and 6 or 12 hours: European Society of Cardiology pathway (<99th
centile at presentation or at 3 hours if symptoms <6 hours) vs. a
pathway developed in the High-STEACS study population (<5 ng/L at
presentation or change <3 ng/L and <99th centile at 3 hours).
Main incl/excl Patients with suspected acute coronary syndrome were recruited from
criteria the emergency department of the Royal Infirmary of Edinburgh,
between June 1, 2013, and September 30, 2015. All patients in whom
the attending clinician requested cardiac troponin for suspected acute
coronary syndrome were eligible for inclusion. Patients with ST-
segment–elevation myocardial infarction, or those from outside the
hospital region were excluded to ensure complete follow-up.
Relevant The primary outcome was a comparison of the negative predictive
outcome(s) value of both pathways for index type 1 myocardial infarction or type 1
myocardial infarction or cardiac death at 30 days. We evaluated the
primary outcome in prespecified subgroups stratified by age, sex, time
of symptom onset, and known ischemic heart disease.
Key findings The primary outcome occurred in 15.7% patients:
- In those less than the 99th centile at presentation, the

European Society of Cardiology pathway ruled out myocardial
infarction in 28.1% and 78.9% at presentation and 3 hours,
respectively, missing 18 index and two 30-day events (negative
predictive value, 97.9%; 95% CI, 96.9–98.7).
- The High-STEACS pathway ruled out 40.7% and 74.2% at
presentation and 3 hours, missing 2 index and two 30-day
events (negative predictive value, 99.5%; 95% CI, 99.0–99.9;
P<0.001 for comparison).
Conclusion(s) The use of the High-STEACS pathway rules out myocardial infarction in
more patients at presentation and misses 5-fold fewer index
myocardial infarctions than the European Society of Cardiology
pathway.
4
Acronym The Rapid Assessment of Possible Acute Coronary Syndrome in the
Emergency Department With High-Sensitivity Troponin T Study
(RAPID-TnT)
Reference Chew DP, Lambrakis K, Blyth A, Seshadri A, Edmonds MJR, Briffa T,
Cullen LA, Quinn S, Karnon J, Chuang A, Nelson AJ, Wright D, Horsfall M,
Morton E, French JK, Papendick C. A Randomized Trial of a 1-Hour
Troponin T Protocol in Suspected Acute Coronary Syndromes: The
Rapid Assessment of Possible Acute Coronary Syndrome in the
Emergency Department With High-Sensitivity Troponin T Study (RAPID-
TnT). Circulation. 2019 Nov 5;140(19):1543-1556. doi:
10.1161/CIRCULATIONAHA.119.042891. Epub 2019 Sep 3. Erratum in:
Circulation. 2021 Jun 22;143(25):e1118. PMID: 31478763.
Study Type Investigador-initiated, prospective patient-level randomized
Details and Quality of
noninferiority trial
Evidence
Intervention Noninferiority assessment: 0/1-hour hs-cTnT protocol (reported to the

limit of detection, <5 ng/L) vs. masked hs-cTnT reported to ≤29 ng/L
evaluated at 0/3-hours (standard arm).
Main incl/excl Patients with suspected acute coronary syndrome presenting to the
criteria emergency department (ED).
Relevant The 30-day primary endpoint was all-cause death and myocardial
outcome(s) infarction. Noninferiority was defined as an absolute margin of 0.5%
determined by Poisson regression.

Key findings The primary outcome was met in 1.1% an 1.0% (incidence rate ratio =
1.06, 95% CI = 0.53–2.11, noninferiority P value=0.001, superiority P
value=0.744). Among patients discharged from ED, the 0/1-hour
protocol had a negative predictive value of 99.6% (95% CI, 99.0–99.9%)
for 30-day death or myocardial infarction.
Conclusion(s) The 0/1-hour hs-cTnT protocol was not inferior to standard care (0/1-
hour arm.
5
Reference Lopez-Ayala P, Nestelberger T, Boeddinghaus J, Koechlin L, Ratmann
PD, Strebel I, Gehrke J, Meier S, Walter J, Rubini Gimenez M, Mutschler
E, Miró Ò, López-Barbeito B, Martín-Sánchez FJ, Rodríguez-Adrada E,
Keller DI, Newby LK, Twerenbold R, Giannitsis E, Lindahl B, Mueller C;
APACE and TRAPID-AMI Investigators†. Novel Criteria for the Observe-
Zone of the ESC 0/1h-hs-cTnT Algorithm. Circulation. 2021 Sep
7;144(10):773-787. doi: 10.1161/CIRCULATIONAHA.120.052982. Epub
2021 Aug 11. Erratum in: Circulation. 2021 Dec 7;144(23):e488. PMID:
34376064.
Study Type Prospective international observational study
Nº patients 2076
Intervention 3h-hs-cTnT concentration and a 0/3h absolute change
Main incl/excl Adult patients presenting to the ED with symptoms suggestive of AMI.
criteria Patients were excluded if (1) they presented with ST-segment–
elevation myocardial infarction (MI); (2) the final diagnosis remained
unclear even after final adjudication and had at least 1 elevated hs-
cTnT concentration, thereby possibly indicating MI; (3) they presented
with chest pain onset and maximum >12 hours, (4) they had terminal
kidney failure requiring dialysis, and (5) they were missing 0h, 1h, or 3h
measurements of the hs-cTnT assay.
Relevant Diagnosis of AMI applying the fourth universal definition of myocardial
outcome(s) infarction, on the basis of complete cardiac workup, cardiac imaging,
and serial hs-cTnT
Key findings Novel derived 0/3h-criteria for the observe-zone patients ruled out
NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT

absolute change <4 ng/L, triaging 25% toward rule-out, resulting in a
sensitivity of 99.2% (95% CI, 96.0-99.9), missing 1 patient with NSTEMI.
A 0/3h-hs-cTnT absolute change ≥6 ng/L triaged 11.2% toward rule-in,
resulting in a specificity of 98% (95% CI, 96.2-98.9)
Taken together, these 0/3h-criteria reduced the number of patients in
the observe zone by 36%, and the number of type 1 myocardial
infarction by 50%.
Conclusion(s) A combination of a 3h-hs-cTnT concentration (<15 ng/L) and a 0/3h
absolute change (<4 ng/L) can be used to safely rule out NSTEMI in
patients remaining in the observe-zone of the ESC 0/1h-hs-cTnT-
algorithm.
6
Acronym Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto
Miocardico (GISSI)
Reference Effectiveness of intravenous thrombolytic treatment in acute
myocardial infarction. Gruppo Italiano per lo Studio della
Streptochinasi nell'Infarto Miocardico (GISSI). Lancet. 1986 Feb
22;1(8478):397-402. PMID: 2868337.
Study Type Unblinded randomised clinical trial
Nº patients 11712
Details and
Quality of
Evidence
Intervention Intravenous streptokinase (SK)

Main incl/excl Admitted within 12 h after the onset of symptoms and with no
criteria contraindications to SK were randomised to receive SK in addition to
usual treatment
Relevant 21-day all-cause mortaliy
outcome(s)
Key findings At 21 days overall hospital mortality was 10.7% in SK recipients versus
13% in controls (p = 0.0002, RR=0.81).
It was suggested that the extent of the beneficial effect was a
function of time from onset of pain to SK infusion (RRs 0.74, 0.80,
0.87, and 1.19 for the 0-3, 3-6, 6-9, and 9-12 h subgroups).
Conclusion(s) SK seems to be a safe drug for routine administration in acute
myocardial infarction.
7
Reference Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic
treatment in acute myocardial infarction: reappraisal of the golden
hour. Lancet. 1996 Sep 21;348(9030):771-5. doi: 10.1016/S0140-
6736(96)02514-7. PMID: 8813982.
Study Type Data tabulation from all randomised trials
Details and Quality
Nº patients 50,246 patients (22 studies)

of Evidence
Intervention Fibrinolytic therapy
Main incl/excl RCTs with at leas 100 patients between 1983 and 1993
criteria
Relevant Mortality
outcome(s)
Key findings Benefit of fibrinolytic therapy was:
- 65 (SD 14) lives saved per 1000 treated patients in the 0-1h interval
- 37 (SD 9) lives saved per 1000 treated patients in the 1-2 interval
- 26 (SD 6) lives saved per 1000 treated patients in the 2-3 interval
- 29 (SD 5) lives saved per 1000 treated patients in the 3-6 h interval
Proportional mortality reduction was significantly higher in patients

treated within 2 h compared to those treated later (44% [95% CI = 32
- 53] vs 20% [95% CI = 15 - 25]; p = 0.001).
Conclusion(s) The beneficial effect of fibrinolytic therapy is substantially higher in
patients presenting within 2 h after symptom onset compared to
those presenting later.
8
Recommendation Table 2 — Recommendations for non-invasive imaging in
the initial assessment of patients with suspected acute coronary syndrome
Acronym Rapid Assessment of Potential Ischaemic Heart Disease With CTCA

(RAPID-CTCA)
Reference Gray AJ, Roobottom C, Smith JE, Goodacre S, Oatey K, O'Brien R,
Storey RF, Curzen N, Keating L, Kardos A, Felmeden D, Lee RJ, Thokala
P, Lewis SC, Newby DE; RAPID-CTCA Investigators. Early computed
tomography coronary angiography in patients with suspected acute
coronary syndrome: randomised controlled trial. BMJ. 2021 Sep
29;374:n2106. doi: 10.1136/bmj.n2106. Erratum in: BMJ. 2022 Feb
21;376:o438. PMID: 34588162.
Study Type RCT
Details and Quality
Nº patients 1748 participants from 37 hospitals in the UK

of Evidence
Intervention Early CT coronary angiography and standard of care compared with

standard of care only.
Main incl/excl Adults with suspected or a provisional diagnosis of acute coronary
criteria syndrome and one or more of previous coronary heart disease, raised
levels of cardiac troponin, or abnormal electrocardiogram.
Relevant Primary endpoint was all cause death or subsequent type 1 or 4b
outcome(s) myocardial infarction at one year.
Key findings The primary endpoint occurred in5.8% participants randomised to CT
coronary angiography and 6.1% participants who received standard of
care only; adjusted HR 0.91 (95% confidence interval 0.62 to 1.35),
P=0.65.
Invasive coronary angiography was performed in 54.0% participants
randomised to CT coronary angiography and 60.8% participants who

received standard of care only; adjusted HR 0.81 (0.72 to 0.92),
P=0.001.
No overall differences in coronary revascularisation, use of drug
treatment for acute coronary syndrome, or subsequent preventive
treatments between the two groups.
Early CT coronary angiography was associated with a slightly longer
time in hospital; median increase 0.21 (95% confidence interval 0.05
to 0.40) days from a median hospital stay of 2.0 to 2.2 days.
Conclusion(s) In intermediate risk patients with acute chest pain and suspected
acute coronary syndrome, early CT coronary angiography did not alter
overall coronary therapeutic interventions or one year clinical
outcomes, but reduced rates of invasive angiography while modestly
increasing length of hospital stay.
9
Reference Nabi F, Kassi M, Muhyieddeen K, Chang SM, Xu J, Peterson LE, Wray
NP, Shirkey BA, Ashton CM, Mahmarian JJ. Optimizing Evaluation of
Patients with Low-to-Intermediate-Risk Acute Chest Pain: A
Randomized Study Comparing Stress Myocardial Perfusion
Tomography Incorporating Stress-Only Imaging Versus Cardiac CT. J
Nucl Med. 2016 Mar;57(3):378-84. doi: 10.2967/jnumed.115.166595.
Epub 2015 Dec 3. PMID: 26635341.
Study Type Single-center, prospective randomized observational study
Details and
Quality of
Evidence
Intervention CTA vs. SPECT

Main incl/excl Patients older than 18 y who were hospitalized under observational
criteria status awaiting SPECT for evaluation of acute chest pain between
February 2009 and August 2011. Patients were evaluated for
Relevant The primary endpoint was length of hospital stay, and secondary
outcome(s) endpoints were test feasibility, time to diagnosis, diagnostic accuracy,
radiation exposure, and overall cost
Key findings Of 2,994 patients screened, 56.9% were not candidates for CTA
because of prior cardiac disease (41%) or imaging contraindications
(16%).
Length of hospital stay (19.7 ± 27.8 vs. 23.5 ± 34.4 h) was significantly
shorter with CTA than with SPECT (P = 0.002).

Time to diagnosis (8.1 ± 8.5 vs. 9.4 ± 7.4 h) was significantly shorter
with CTA than with SPECT (P = 0.002).
There were no significant differences between CTA and SPECT
opmised with stress-only imaging in the following outcomes: time to
diagnosis (7.0 ± 6.2 vs. 6.8 ± 5.9 h, P = 0.20), length of stay (15.5 ± 17.2
vs. 16.7 ± 15.3 h, P = 0.36), and hospital costs ($4,242 ± $3,871 vs.
$4,364 ± 1781, P = 0.86). Compared with conventional SPECT, SPECT
with stress-only significantly reduced radiation exposure (5.5 ± 4.4 vs.
12.5 ± 2.7 mSv, P < 0.0001).
Conclusion(s) CTA reduced length of stay and time to diagnosis compared to stress
SPECT. Stress SPECT when optimized with stress-only imaging was
similar to CTA in length of hospital stay, time to diagnosis, and cost,
with less radiation exposure.
10
Recommendation Table 3 — Recommendations for the initial management of
patients with acute coronary syndrome
Acronym Determination of the Role of Oxygen in Suspected Acute Myocardial

Infarction (DETO2X-AMI) trial
Reference Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, Arefalk
G, Frick M, Alfredsson J, Nilsson L, Ravn-Fischer A, Omerovic E,
Kellerth T, Sparv D, Ekelund U, Linder R, Ekström M, Lauermann J,
Haaga U, Pernow J, Östlund O, Herlitz J, Svensson L; DETO2X–
SWEDEHEART Investigators. Oxygen Therapy in Suspected Acute
Myocardial Infarction. N Engl J Med. 2017 Sep 28;377(13):1240-1249.
doi: 10.1056/NEJMoa1706222. Epub 2017 Aug 28. PMID: 28844200.
Study Type Registry-based randomized clinical trial using nationwide Swedish
registries
Nº patients 6629 patients
Intervention supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered
through an open face mask) vs. ambient air

Main incl/excl Participants were required to be 30 years of age or older and to have
criteria symptoms suggestive of myocardial infarction for < 6 hours, an oxygen
saturation of 90% or higher on pulse oximetry, and either
electrocardiographic changes indicating ischemia or elevated cardiac
troponin levels on admission.
Patients who were receiving ongoing oxygen therapy, as well as those

who presented with a cardiac arrest or had a cardiac arrest between
presentation and enrollment were excluded. If supplemental oxygen
therapy had been administered for < 20 minutes before evaluation for
enrollment, a new evaluation was allowed after discontinuation of
oxygen delivery and 10 minutes of washout.
Relevant The primary endpoint was all-cause death within 1 year after
outcome(s) randomization
Key findings The primary endpoint (1-year all-cause death) occurred in 5.0% of
patients randomised to oxygen and in 5.1% of patients randomised to
ambient air (HR=0.97; 95% CI=0.79-1.21; P=0.80). Rehospitalization
with myocardial infarction within 1 year occurred in 3.8% assigned to
oxygen and in 3.3% assigned to ambient air (HR=1.13; 95% CI= 0.88-
1.46; P=0.33).
Conclusion(s) Routine use of supplemental oxygen in patients with suspected
myocardial infarction withoug hypoxemia has no impact on 1-year all-
cause mortality.
11
Acronym Effect of METOprolol in CARDioproteCtioN During an Acute
Myocardial InfarCtion (METOCARD-CNIC) trial
Reference Ibanez B, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L,
Mateos A, Fernández-Ortiz A, García-Ruiz JM, García-Álvarez A, Iñiguez
A, Jiménez-Borreguero J, López-Romero P, Fernández-Jiménez R,
Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vázquez JA,
Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Pérez de
Prado A, Fernández-Campos MJ, Casado I, García-Rubira JC, García-
Prieto J, Sanz-Rosa D, Cuellas C, Hernández-Antolín R, Albarrán A,
Fernández-Vázquez F, de la Torre-Hernández JM, Pocock S, Sanz G,
Fuster V. Effect of early metoprolol on infarct size in ST-segment-
elevation myocardial infarction patients undergoing primary
percutaneous coronary intervention: the Effect of Metoprolol in
Cardioprotection During an Acute Myocardial Infarction (METOCARD-
CNIC) trial. Circulation. 2013 Oct 1;128(14):1495-503. doi:
10.1161/CIRCULATIONAHA.113.003653. Epub 2013 Sep 3. PMID:
24002794.
Study Type Multicenter, randomized, parallel-group, single-blinded (to outcome
evaluators) clinical trial.
Nº patients
270 participants.
Intervention Intravenous metoprolol received up to three 5-mg boluses of
metoprolol tartrate 2 minutes apart.
Main incl/excl Patients were 18 to 80 years of age and showed symptoms consistent
criteria with STEMI for >30 minutes and ST elevation ≥2 mm in ≥2 contiguous
leads in V1 through V5 with an anticipated time of symptom onset to
reperfusion of ≤6 hours. The inclusion criterion was ≤4.5 hours from
symptom onset to randomization.
Exclusion criteria were Killip class III to IV acute myocardial infarction,
systolic blood pressure persistently <120 mm Hg, PR interval >240
milliseconds (or type II–III atrioventricular block), heart rate
persistently <60 bpm, or active treatment with any β-blocker agent.
Relevant The primary endpoint was infarct size on magnetic resonance imaging
outcome(s) performed 5 to 7 days after STEMI.
Key findings Mean ± SD infarct size by magnetic resonance imaging was smaller
after intravenous metoprolol compared with control (25.6 ± 15.3

versus 32.0 ± 22.2 g; adjusted difference, -6.52; 95% CI, -11.39 to -1.78;
P=0.012). Left ventricular ejection fraction was higher in the
intravenous metoprolol group (adjusted difference, 2.67%; 95% CI,
0.09-5.21; P=0.045). The composite of death, malignant ventricular
arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction
at 24 hours in the intravenous metoprolol and control groups was 7.1%
and 12.3%, respectively (P=0.21).
Conclusion(s) In STEMI patients with anterior Killip class ≤II whp underwent primary
PCI, early intravenous metoprolol before reperfusion reduced infarct
12
size and increased left ventricular ejection fraction withour excess of
adverse events during the first 24 hours after STEMI.
Acronym Early-Beta blocker Administration before reperfusion primary PCI in
patients with ST-elevation Myocardial Infarction (EARLY-BAMI)
Reference Roolvink V, Ibáñez B, Ottervanger JP, Pizarro G, van Royen N, Mateos
A, Dambrink JE, Escalera N, Lipsic E, Albarran A, Fernández-Ortiz A,
Fernández-Avilés F, Goicolea J, Botas J, Remkes W, Hernandez-Jaras V,
Kedhi E, Zamorano JL, Navarro F, Alfonso F, García-Lledó A, Alonso J,
van Leeuwen M, Nijveldt R, Postma S, Kolkman E, Gosselink M, de
Smet B, Rasoul S, Piek JJ, Fuster V, van 't Hof AWJ; EARLY-BAMI
Investigators. Early Intravenous Beta-Blockers in Patients With ST-
Segment Elevation Myocardial Infarction Before Primary Percutaneous
Coronary Intervention. J Am Coll Cardiol. 2016 Jun 14;67(23):2705-
2715. doi: 10.1016/j.jacc.2016.03.522. Epub 2016 Apr 3. PMID:
27050189.
Study Type Double-blind, placebo-controlled international multicenter study
Details and Quality
Nº patients 683 participants.

of Evidence
Intervention IV metoprolol (2 × 5-mg bolus).
Main incl/excl STEMI patients presenting <12 h from symptom onset in Killip class I
criteria to II without atrioventricular block.
Relevant Primary endpoint was myocardial infarct size as assessed by cardiac
outcome(s) magnetic resonance imaging (CMR) at 30 days. Secondary endpoints
were enzymatic infarct size and incidence of ventricular arrhythmias.
Key findings CMR was performed in 54.8% of patients. Infarct size (percent of left
ventricle) by CMR was 15.3 ± 11.0% and 14.9 ± 11.5% for metoprolol
and placebo groups, respectively (p = 0.616). Peak and area under the
creatine kinase curve did not differ between both groups. LV ejection
fraction by CMR was 51.0 ± 10.9% and 51.6 ± 10.8% in the metoprolol
group and the placebo group, respectively (p = 0.68). The incidence of
malignant arrhythmias was 3.6% and 6.9% in the metoprolol group
and the placebo, respectively (p = 0.050).
Conclusion(s) In a nonrestricted STEMI population, early intravenous metoprolol
before PPCI did not reduce myocardial infarct size.
13
Reference Chatterjee S, Chaudhuri D, Vedanthan R, Fuster V, Ibanez B, Bangalore
S, Mukherjee D. Early intravenous beta-blockers in patients with acute
coronary syndrome--a meta-analysis of randomized trials. Int J Cardiol.
2013 Sep 30;168(2):915-21. doi: 10.1016/j.ijcard.2012.10.050. Epub
2012 Nov 17. PMID: 23168009.
Study Type Meta-analysis (pooled treatment effects were estimated using relative
risk with Mantel-Haenszel risk ratio, using a random-effects model)

Nº patients Sixteen studies enrolling 73,396 participants met the inclusion ⁄
exclusion criteria.
Intervention Itravenous beta-blockers administered within 12 hours of presentation
of ACS
Main incl/excl It was searched the PubMed, EMBASE and the Cochrane Register for
criteria Controlled Clinical Trials for randomized clinical trials from 1965
through December, 2011, comparing intravenous beta-blockers
administered within 12 hours of presentation of ACS with standard
medical therapy and/or placebo.
Relevant The primary outcome assessed was the risk of short-term (in-hospital
outcome(s) mortality-with maximum follow up duration of 90 days) all-cause
mortality in the intervention group versus the comparator group. The
secondary outcomes assessed were ventricular tachyarrhythmias,
myocardial reinfarction, cardiogenic shock, and stroke.
Key findings In- hospital mortality was reduced 8% with intravenous beta-blockers,
RR=0.92 (95% CI, 0.86-1.00; p=0.04) when compared with controls, as
well as the risk of ventricular tachyarrhythmias (RR=0.61; 95 % CI 0.47-
0.79; p=0.0003) and myocardial reinfarction (RR=0.73, 95 % CI 0.59-
0.91; p=0.004) without increase in the risk of cardiogenic shock
(RR=1.02; 95% CI 0.77-1.35; p=0.91), or stroke (RR=0.58; 95 % CI 0.17-
1.98; p=0.38).
Conclusion(s) Intravenous beta-blockers within 12 hours of presentation of ACS are

associated with a significant reduction in the risk of inhospital
mortality, ventricular tachuarrhythmias and myocardial reinfarction.
14
Reference Pinto DS, Kirtane AJ, Nallamothu BK, Murphy SA, Cohen DJ, Laham RJ,
Cutlip DE, Bates ER, Frederick PD, Miller DP, Carrozza JP Jr, Antman EM,
Cannon CP, Gibson CM. Hospital delays in reperfusion for ST-elevation
myocardial infarction: implications when selecting a reperfusion
strategy. Circulation. 2006 Nov 7;114(19):2019-25. doi:
10.1161/CIRCULATIONAHA.106.638353. Epub 2006 Oct 30. PMID:
17075010.
Study Type Prospective observational study using 645 National Registry of
Myocardial Infarction (NRMI) hospitals
Nº patients 192,509 patients

Intervention door-to-balloon (DB) and door-to-needle (DN) times were calculated by
subtracting median DN time from median DB time at a hospital
Main incl/excl Patients with STEMI (ST-segment elevation and/or left bundle-branch
criteria block on initial ECG and <12 hours after onset of pain) who received
either fibrinolytic therapy or PPCI as initial reperfusion therapy were
eligible. Those transferred out of an NRMI hospital to a non-NRMI
hospital were excluded. Patients who had missing time-interval data
were also excluded. Inclusion in this analysis required a minimum
number of STEMI patients: at least 20 STEMI patients over the course
of the study, including at least 10 patients treated with PPCI and 10
with fibrinolytic therapy, were required.
Relevant Hypothesis #1: in clinical practice, longer DB-DN times would be
outcome(s) associated with higher mortality rates and reduced PPCI survival
advantage.
Hypohtesis #2: in addition to PPCI delays, patient risk factors would
significantly modulate the relative survival advantage of PPCI over

fibrinolysis.
Key findings Longer DB-DN times were associated with increased mortality
(P<0.0001).
The DB-DN time at which mortality rates with PPCI were no better than
that of fibrinolysis varied considerably depending on patient age,
symptom duration, and infarct location.
Conclusion(s) As DB-DN times increase, the mortality advantage of PPCI over

fibrinolysis declines, and this advantage varies considerably depending
on patient characteristics.
15
Reference Steg PG, Cambou JP, Goldstein P, Durand E, Sauval P, Kadri Z,
Blanchard D, Lablanche JM, Guéret P, Cottin Y, Juliard JM, Hanania G,
Vaur L, Danchin N; USIC 2000 Investigators. Bypassing the emergency
room reduces delays and mortality in ST elevation myocardial
infarction: the USIC 2000 registry. Heart. 2006 Oct;92(10):1378-83.
doi: 10.1136/hrt.2006.101972. Epub 2006 Aug 16. PMID: 16914481.
Study Type Nationwide observational registry of STEMI patients of 369 intensive
care units in France.
Intervention Initial management pathway: direct transfer to the coronary care unit
vs. catheterisation laboratory versus transfer via the emergency room.

Main incl/excl This analysis focused on patients with a confirmed diagnosis of STEMI
criteria who were admitted within 12 h of the onset of symptoms. Patients
who were transferred from another hospital were excluded.
All consecutive patients admitted to the participating centres from 1–
30 November 2000 were included in the registry if they had elevated
serum markers of myocardial necrosis higher than twice the upper
limit of normal for creatine kinase, creatine kinase‐MB or troponins,
and symptoms compatible with acute myocardial infarction for 30 min
and/or electrocardiographic changes on at least two contiguous leads
with pathological Q waves (⩾ 0.04 s) and/or persisting ST elevation or
depression > 0.1 mV, or a presumed new left bundle branch block on
the first ECG recorded.
Relevant Delays between symptom onset, admission and reperfusion therapy.
outcome(s) Mortality at five days and one year.
Key findings Bypassing the emergency room was associated with more frequent
use of reperfusion (61.7% vs. 53.1%; p = 0.001) and shorter delays
between symptom onset and admission (244 (interquartile range 158)
vs. 292 (172) min; p < 0.001), thrombolysis (204 (150) vs. 258 (240)
min; p < 0.01), hospital thrombolysis (228 (156) vs. 256 (227) min, p =
0.22), and primary percutaneous coronary intervention (294 (246) vs.
402 (312) min; p < 0.005).
5-day mortality rates were lower in patients who bypassed the
emergency room (4.9% vs. 8.6%; p = 0.01), regardless of the use and
type of reperfusion therapy. After adjusting for the TIMI risk score,
admission via the emergency room was an independent predictor of
5-day mortality (OR = 1.67, 95% CI = 1.01 to 2.75).
Conclusion(s) In this observational analysis, bypassing the emerngey room was

associated with more frequent and earlier use of reperfusion therapy,
and with a lower mortality compared with admission via the
emergency room.
16
Recommendation Table 4 — Recommendations for reperfusion therapy and
timing of invasive strategy
Reference Boersma E; Primary Coronary Angioplasty vs. Thrombolysis Group.
Does time matter? A pooled analysis of randomized clinical trials
comparing primary percutaneous coronary intervention and in-
hospital fibrinolysis in acute myocardial infarction patients. Eur Heart
J. 2006 Apr;27(7):779-88. doi: 10.1093/eurheartj/ehi810. Epub 2006
Mar 2. PMID: 16513663.
Study Type Pooled analysis of randomized clinical trials
Nº patients Twenty-five randomized trials (n = 7743). Of these, individual patient

data from 22 trials (n = 6763)
Evidence
Intervention PCI vs fibrinolysis

Main incl/excl Randomized trials testing the efficacy of PPCI vs. fibrinolysis were
criteria identified in journal articles and abstract listings published between
1990 and 2002.
Relevant Multi-level logistic regression was used to evaluate the relationship

outcome(s) among treatment, treatment delay, and 30-day mortality.
Key findings PPCI was associated with a significant 37% reduction in 30-day
mortality, adjusted OR, 0.63; 95% CI (0.42-0.84). There was no
heterogeneity in the treatment effect by presentation delay

(pBreslow-Day = 0.88), though the absolute mortality reduction by
PPCI widened over time (1.3% 0-1 h to 4.2% >6 h after symptom
onset). When the PCI-related delay was <35 min, the relative (67 vs.
28% pBreslow-Day = 0.004) and absolute (5.4 vs. 2.0%) mortality
reduction was significantly higher than those with longer delays.
Conclusion(s) PPCI was associated with significantly lower 30-day mortality relative
to fibrinolysis, regardless of treatment delay. Although logistic and
economic constraints challenge the feasibility of 'PPCI-for-all', the
benefit of timely treatment underscores the importance of a
comprehensive, unified approach to delivery of cardiac care in all AMI
patients.
17
Reference Keeley EC, Boura JA, Grines CL. Primary angioplasty versus
intravenous thrombolytic therapy for acute myocardial infarction: a
quantitative review of 23 randomised trials. Lancet. 2003 Jan
4;361(9351):13-20. doi: 10.1016/S0140-6736(03)12113-7. PMID:
12517460.
Study Type Quantitative review of 23 RCT
Nº patients 7739 patients.

Intervention primary PTCA vs. thrombolytic therapy.
Evidence
Main incl/excl A search of published work and identified 23 trials, assessing

criteria thrombolytic-eligible patients with ST-segment elevation AMI who
had been randomised to either primary PTCA or thrombolytic
therapy, and reported short-term and long-term clinical outcomes of
death, non-fatal reinfarction, and stroke.
Relevant Short-term and long-term clinical outcomes of death, non-fatal
outcome(s) reinfarction, and stroke. Subgroup analyses to assess the effect of
type of thrombolytic agent used and the strategy of emergent
hospital transfer for primary PTCA. All analyses were done with and
without inclusion of the SHOCK trial data.
Key findings Short-term death (7% vs. 9%; p=0.0002), was lower for PTCA than for
fibrinolytic gherapy. Death excluding the SHOCK trial data was 5% vs.
7% (p=0.0003). Other outcomes for the comparison between PTCA
and fibrinolysis were:
- non-fatal reinfarction (3% vs. 7%; p<0.0001),
- stroke (1% vs. 2%; p=0.0004),
- combined endpoint of death, non-fatal reinfarction, or stroke
(8% vs. 14%; p<0.0001).
The findings were consistent during long-term follow-up, and were
independent of both the type of thrombolytic agent used, and
whether or not the patient was transferred for primary PTCA.
Conclusion(s) Primary PTCA reduced clinical outcomes compared with thrombolytic
therapy in patients with STEMI.
18
Acronym Danish Multicenter Randomized Study on Fibrinolytic Therapy versus
Acute Coronary Angioplasty in Acute Myocardial Infarction
(DANAMI-2)
Reference Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H,
Thayssen P, Abildgaard U, Pedersen F, Madsen JK, Grande P, Villadsen
AB, Krusell LR, Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard
HK, Mortensen LS; DANAMI-2 Investigators. A comparison of coronary
angioplasty with fibrinolytic therapy in acute myocardial infarction. N
Engl J Med. 2003 Aug 21;349(8):733-42. doi: 10.1056/NEJMoa025142.
PMID: 12930925.
Study Type Multicentre, open label, randomized trial in Denmark

Intervention Tissue plasminogen activator (alteplase) and transfer to an
Evidence
interventional facility or primary PCI ± Platelet glycoprotein IIb/IIIa–

receptor blockers. Angioplasty of non–infarct-related arteries was not
performed.
Main incl/excl ST segment elevation myocardial infarction within 12 hours of
criteria symptom onset
Relevant Composite of death from any cause, clinical reinfarction, or disabling
outcome(s) stroke at 30 days. Procedure-related reinfarction was not included in
the primary end point.

Key findings The primary end point was reached in 8.5 %of the patients in the
angioplasty group, as compared with 14.2 % of those in the fibrinolysis
group (P=0.002), mainly driven by a reduction in the rate of
reinfarction (1.6 % in the angioplasty group vs. 6.3 % in the fibrinolysis
group, P<0.001)
Conclusion(s) A strategy for reperfusion involving the transfer of patients to an
invasive-treatment center for primary angioplasty is superior to on-
site fibrinolysis, provided that the transfer takes two hours or less.
19
Acronym Strategic Reperfusion Early after Myocardial Infarction (STREAM)
study
Reference Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert
Y, Sulimov V, Rosell Ortiz F, Ostojic M, Welsh RC, Carvalho AC, Nanas J,
Arntz HR, Halvorsen S, Huber K, Grajek S, Fresco C, Bluhmki E, Regelin
A, Vandenberghe K, Bogaerts K, Van de Werf F; STREAM Investigative
Team. Fibrinolysis or primary PCI in ST-segment elevation myocardial
infarction. N Engl J Med. 2013 Apr 11;368(15):1379-87. doi:
10.1056/NEJMoa1301092. Epub 2013 Mar 10. PMID: 23473396.
Study Type Randomised clinical trial
Intervention Primary PCI vs. fibrinolytic therapy with bolus tenecteplase (amended
to half dose in patients ≥75 years of age), clopidogrel, and enoxaparin
before transport to a PCI-capable hospital. Emergency coronary
angiography was performed if fibrinolysis failed; otherwise,
angiography was performed 6 to 24 hours after randomization.
Main incl/excl Patients who presented within 3 hours after the onset of symptoms,
criteria had evidence of acute STEMI on their qualifying electrocardiogram (at
least 2 mm in two contiguous peripheral or precordial leads), and
could not undergo primary PCI within 1 hour after the first medical
contact.
Patients with STEMI who were able to undergo primary PCI within 1
hour after the first medical contact were excluded.
Relevant The primary endpoint was a composite of death, shock, congestive
outcome(s) heart failure, or reinfarction up to 30 days.
Key findings The primary endpoint occurred in 12.4% in the fibrinolysis group and
in 14.3% in the primary PCI group (relative risk in the fibrinolysis

group, 0.86; with a 95% CI of 0.68-1.09; P=0.21). Emergency
angiography was required in 36.3% of patients in the fibrinolysis
group. There were more intracranial hemorrhages in the fibrinolysis
group than in the primary PCI group (1.0% vs. 0.2%, P=0.04; after
protocol amendment, 0.5% vs. 0.3%, P=0.45)
Conclusion(s) Prehospital fibrinolysis with timely coronary angiography resulted in
effective reperfusion in patients with early STEMI who could not
undergo primary PCI within 1 hour after the first medical contact.
However, fibrinolysis was associated with a slightly increased risk of
intracranial bleeding.
20
Acronym Rescue Angioplasty versus Conservative Treatment or Repeat
Thrombolysis (REACT) trial
Reference Gershlick AH, Stephens-Lloyd A, Hughes S, Abrams KR, Stevens SE,
Uren NG, de Belder A, Davis J, Pitt M, Banning A, Baumbach A, Shiu
MF, Schofield P, Dawkins KD, Henderson RA, Oldroyd KG, Wilcox R;
REACT Trial Investigators. Rescue angioplasty after failed thrombolytic
therapy for acute myocardial infarction. N Engl J Med. 2005 Dec
29;353(26):2758-68. doi: 10.1056/NEJMoa050849. PMID: 16382062.
Study Type Multicenter randomised clinical trial (UK)
Intervention Repeated thrombolysis vs. conservative treatment (141 patients) vs.

rescue PCI
Evidence
Main incl/excl Adults 21 to 85 years of age were eligible for inclusion if they had
criteria received athrombolytic therapy for myocardial infarction with ST-
segment elevation within 6 hours of the onset of chest pain and if
reperfusion had then failed to occur (less than 50% ST-segment
resolution lead with previous maximal ST-segment elevation) within
90 minutes after thrombolytic treatment.
Relevant The primary endpoint was a composite of death, reinfarction, stroke,
outcome(s) or severe heart failure within six months.
Key findings Rates of event-free survival were (overall P=0.004):
- among patients treated with rescue PCI, 84.6%,
- among those receiving conservative therapy, 70.1%
- among those undergoing repeated thrombolysis, 68.7%
The adjusted HR for the occurrence of the primary endpoint were:

- for repeated thrombolysis versus conservative therapy, HR=
1.09 (95% CI, 0.71 - 1.67; P=0.69),
- for rescue PCI versus repeated thrombolysis , HR= 0.43 (95%
CI, 0.26 - 0.72; P=0.001)
- for rescue PCI versus conservative therapy, HR= 0.47 (95% CI =
0.28 - 0.79; P=0.004).
There were no significant differences in mortality from all causes.
Conclusion(s) After failed thrombolytic therapy, survival was higher with rescue PCI
than with repeated thrombolysis or conservative treatment.
21
Acronym Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) Trial
Reference Schömig A, Mehilli J, Antoniucci D, Ndrepepa G, Markwardt C, Di Pede
F, Nekolla SG, Schlotterbeck K, Schühlen H, Pache J, Seyfarth M,
Martinoff S, Benzer W, Schmitt C, Dirschinger J, Schwaiger M, Kastrati
A; Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2)
Trial Investigators. Mechanical reperfusion in patients with acute
myocardial infarction presenting more than 12 hours from symptom
onset: a randomized controlled trial. JAMA. 2005 Jun 15;293(23):2865-
72. doi: 10.1001/jama.293.23.2865. PMID: 15956631.
Study Type International, multicenter, open-label, randomized controlled trial.
Details and Quality

of Evidence
Intervention Invasive strategy based predominantly on coronary stenting with

abciximab vs. conventional conservative treatment strategy.
Main incl/excl Patients aged 18 to 80 years without persistent symptoms admitted
criteria with the diagnosis of acute STEMI between 12 and 48 hours after
symptom onset.
Relevant The primary endpoint was final left ventricular infarct size according to
outcome(s) single-photon emission computed tomography study with technetium
Tc 99m sestamibi performed between 5 and 10 days after
randomization. The secondary endpoint was a composite of death,
recurrent MI, or stroke at 30 days.
Key findings The final left ventricular infarct size was 8% (interquartile range, 2.0%-
15.8%) and 13.0% (interquartile range, 3.0%-27.0%) in participants

assigned to the invasive group and to the conservative group,
respectively (P<0.001). The mean difference in final left ventricular
infarct size between the invasive and conservative groups was -6.8%
(95% CI, -10.2% to -3.5%).
The secondary endpointsof death, recurrent MI, or stroke at 30 days

occurred in 4.4% and 6.6% patients in the invasive group and the
conservative group, respectively (relative risk, 0.67; 95% CI, 0.27-1.62;
P = 0.37).
Conclusion(s) An invasive strategy based on coronary stenting with adjunctive use of
abciximab reduced final left ventricular infarct size in patients with
acute STEMI without persistent symptoms presenting 12 to 48 hours
after symptom onset.
22
Acronym Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial
Reference Ndrepepa G, Kastrati A, Mehilli J, Antoniucci D, Schömig A. Mechanical
reperfusion and long-term mortality in patients with acute myocardial
infarction presenting 12 to 48 hours from onset of symptoms. JAMA.
2009 Feb 4;301(5):487-8. doi: 10.1001/jama.2009.32. PMID:
19190313.
Study Type 4-year follow-up of the patients enrolled in the BRAVE-2 trial, which
was an international, multicenter, open-label, randomized controlled

study
Evidence

Intervention Invasive PCI strategy vs. conservative treatment strategy.
Main incl/excl Patients with STEMI who were assessed between 12 and 48 hours
criteria from symptom onset.
Relevant The primary end point was final infarct size measured by single-
outcome(s) photon emission computed tomography with technetium 99m
sestamibi 5 to 10 days after randomization. The present study focused
on the prespecified analysis of 4-year outcomes with mortality as the

primary outcome.
Key findings Death within 4 years occurred in 11.1% (95% CI = 7.3%-16.7%) in the
invasive group and 18.9; (95% CI = 13.9%-25.4%) in the conservative
group (unadjusted HR = 0.57; 95% CI = 0.33-0.99; P = 0.047; adjusted
HR, 0.55; 95% CI = 0.31-0.97; P =0.04)
Conclusion(s) In this follow-up study of the BRAVE-2 trial, an invasive PCI strategy
reduced mortality in patients with STEMI who were assessed between
12 and 48 hours from symptom onset, compared with a conservative
treatment strategy.
23
Reference Busk M, Kaltoft A, Nielsen SS, Bøttcher M, Rehling M, Thuesen L,
Bøtker HE, Lassen JF, Christiansen EH, Krusell LR, Andersen HR, Nielsen
TT, Kristensen SD. Infarct size and myocardial salvage after primary
angioplasty in patients presenting with symptoms for <12 h vs. 12-72
h. Eur Heart J. 2009 Jun;30(11):1322-30. doi:
10.1093/eurheartj/ehp113. Epub 2009 Apr 8. PMID: 19357105.
Study Type Observational study
Intervention Early presenters (<12 h) vs. late presenters (12-72 h) undergoing

primary angioplasty.
Main incl/excl All STEMI patients in a Danish region treated with primary angioplasty
criteria were included consecutively on weekdays. The patients were either
transported directly to the catheterization laboratory or transferred
from referral hospitals immediately when STEMI is diagnosed. From 1
May 2005 to 26 April 2007 the primary angioplasty service was
extended to include patients with symptoms for 12–72 h on admission
if they were eligible for inclusion in this study. Immediate transfer for
angioplasty was arranged for all patients independent of symptom
duration. Early presenters were included in two previously published,
randomized studies
Relevant Myocardial infarct size (FIS) and myocardial salvage i
outcome(s)
Key findings Outcomes for late presenters (n = 55) compared with early presenters
(n = 341):
- Median FIS: 14% (IQR 3-30) vs. 7% (IQR 2-18), P = 0.005.
- Salvage index: 53% (IQR 27-89) vs. 69% (IQR 45-91), P = 0.05
lower LVEF; 48% (IQR 44-58%) vs. 53% (IQR 47-59), P = 0.04
Conclusion(s) In patients with STEMI undergoing primary angioplasty, late
presenters compared with early presenters had larger median FIS,
lower salvage index, and lower LVEF.
24
Acronym Occluded Artery Trial (OAT) trial
Reference Hochman JS, Lamas GA, Buller CE, Dzavik V, Reynolds HR, Abramsky
SJ, Forman S, Ruzyllo W, Maggioni AP, White H, Sadowski Z, Carvalho
AC, Rankin JM, Renkin JP, Steg PG, Mascette AM, Sopko G, Pfisterer
ME, Leor J, Fridrich V, Mark DB, Knatterud GL; Occluded Artery Trial
Investigators. Coronary intervention for persistent occlusion after
myocardial infarction. N Engl J Med. 2006 Dec 7;355(23):2395-407.
doi: 10.1056/NEJMoa066139. Epub 2006 Nov 14. PMID: 17105759.
Study Type Multicentre, open label, randomized trial
Intervention PCI with stent placement and optimal medical therapy or optimal
medical therapy alone.
Evidence
Main incl/excl Total occlusion of the infarct-related artery with poor or absent
criteria antegrade flow, defined as a Thrombolysis in Myocardial Infarction
(TIMI) flow grade of 0 or 1, & criterion for increased risk: an ejection
fraction <50%, proximal occlusion of a major epicardial vessel with a
large risk region, or both (coronary angiography, performed 3 to 28
days after myocardial infarction)
Relevant Composite of death, myocardial reinfarction, or New York Heart
outcome(s) Association (NYHA) class IV heart failure.

Key findings The 4-year cumulative primary event rate was 17.2% in the PCI group
and 15.6% in the medical therapy group (HR 1.16; 95% CI, 0.92 to
1.45; P=0.20).
Conclusion(s) PCI did not reduce the occurrence of death, reinfarction, or heart
failure, and there was a trend toward excess reinfarction during 4
years of follow-up in stable patients with occlusion of the infarct-
related artery 3 to 28 days after myocardial infarction.
25
Acronym Primary Angioplasty After Transport of Patients from General
Community Hospitals to Catheterization Units With/Without
Emergency Thrombolysis Infusion 2 (PRAGUE-2) trial
Reference Widimský P, Budesínský T, Vorác D, Groch L, Zelízko M, Aschermann
M, Branny M, St'ásek J, Formánek P; 'PRAGUE' Study Group
Investigators. Long distance transport for primary angioplasty vs
immediate thrombolysis in acute myocardial infarction. Final results of
the randomized national multicentre trial--PRAGUE-2. Eur Heart J.
2003 Jan;24(1):94-104. doi: 10.1016/s0195-668x(02)00468-2. PMID:
12559941.
Study Type Multicentre, open label, randomized trial in the Czech Republic

Intervention Immediate transfert to Invasive treatment centre or streptokinase in
Evidence
the primary hospital (transport allowed for rescue PCI or for recurrent
ischaemia)
Main incl/excl ST-segment elevation myocardial infarction within 12 hours of
criteria symptom onset and who were treated with tenecteplase at centers
that did not have the capability of performing PCI
Relevant 30-day mortality
outcome(s)
Key findings 30-day mortality 6.0% in the primary PCI group vs 10.4% in the
streptokinase group (P<0.05). Patients randomized >3 h after the

onset of symptoms: 6.4% in the primary PCI group vs 15.3% in the
streptokinase group (P<0.02). Patients randomized within <3 h of
symptom onset had no difference in mortality whether treated by PCI
(7.3%) or TL (7.4%).
Conclusion(s) Long distance transport from a community hospital to a tertiary PCI
centre in the acute phase of AMI is safe.
This strategy markedly decreases mortality in patients presenting >3 h
after symptom onset. For patients presenting within <3 h of
symptoms, TL results are similar results to long distance transport for
PCI.
26
Acronym Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial
Reference Mehta SR, Granger CB, Boden WE, Steg PG, Bassand JP, Faxon DP,
Afzal R, Chrolavicius S, Jolly SS, Widimsky P, Avezum A, Rupprecht HJ,
Zhu J, Col J, Natarajan MK, Horsman C, Fox KA, Yusuf S; TIMACS
Investigators. Early versus delayed invasive intervention in acute
coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165-75.
doi: 10.1056/NEJMoa0807986. PMID: 19458363.
Study Type A multicenter, randomized, parallel-group, open label trial with
blinded adjudication of outcomes.
Intervention Early-intervention group: coronary angiography performed as rapidly

as possible and < 24 hours after randomization/ revascularization was
to occur as soon as possible after coronary angiography, or delayed-
intervention group: coronary angiography > 36 hours after
randomization/ revascularization could occur at any time after
coronary angiography.
Main incl/excl Patients with unstable angina or myocardial infarction without ST-
criteria segment elevation within 24 hours after the onset of symptoms and
≥2 criteria indicative of increased risk: an age of 60 years or older,
cardiac biomarkers above the upper limit of the normal range, or
results on electrocardiography that were compatible with ischemia
(i.e., ST-segment depression of ≥1 mm or transient ST-segment
elevation or T-wave inversion of >3 mm).
Relevant Composite of death, myocardial infarction, or stroke at 6 months.
outcome(s)
Key findings At 6 months, the primary outcome occurred in 9.6% of patients in the
early-intervention group vs. 11.3% in the delayed-intervention group
(HR in the early-intervention group, 0.85; 95% CI, 0.68 to 1.06;
P=0.15).
There was a relative reduction of 28% in the secondary outcome of

death, myocardial infarction, or refractory ischemia in the early-
intervention group (9.5%), as compared with the delayed-intervention
group (12.9%) (HR, 0.72; 95% CI, 0.58 to 0.89; P=0.003).
Conclusion(s) Early-intervention strategy did not differ from a delayed-intervention
strategy in preventing a composite outcome of death, myocardial
infarction, or stroke.
However, early intervention significantly reduced the risk of refractory

ischemia and appeared to be superior to a delayed strategy in high-
risk patients.
27
Acronym Very Early Versus Deferred Invasive Evaluation Using Computerized
Tomography (VERDICT) trial
Reference Kofoed KF, Kelbæk H, Hansen PR, Torp-Pedersen C, Høfsten D,
Kløvgaard L, Holmvang L, Helqvist S, Jørgensen E, Galatius S, Pedersen
F, Bang L, Saunamaki K, Clemmensen P, Linde JJ, Heitmann M,
Wendelboe Nielsen O, Raymond IE, Kristiansen OP, Svendsen IH, Bech
J, Dominguez Vall-Lamora MH, Kragelund C, Hansen TF, Dahlgaard
Hove J, Jørgensen T, Fornitz GG, Steffensen R, Jurlander B, Abdulla J,
Lyngbæk S, Elming H, Therkelsen SK, Abildgaard U, Jensen JS, Gislason
G, Køber LV, Engstrøm T. Early Versus Standard Care Invasive
Examination and Treatment of Patients With Non-ST-Segment
Elevation Acute Coronary Syndrome. Circulation. 2018 Dec
11;138(24):2741-2750. doi: 10.1161/CIRCULATIONAHA.118.037152.
Erratum in: Circulation. 2018 Dec 11;138(24):e750. PMID: 30565996.
Study Type A prospective, multicenter, open label, parallel group, randomized
controlled trial in Denmark

Evidence
Intervention Invasive coronary angiography (ICA) within 12 hours or standard

invasive care within 48 to 72 hours
Main incl/excl Patients with clinical suspicion of non-ST-segment elevation acute
criteria coronary syndrome and ECG changes indicating new ischemia or
elevated troponin, in whom ICA was clinically indicated and deemed
logistically feasible within 12 hours
Relevant A composite of all-cause death, nonfatal recurrent myocardial
outcome(s) infarction, hospital admission for refractory myocardial ischemia, or
hospital admission for heart failure.
Key findings Within a median follow-up time of 4.3 (interquartile range, 4.1–4.4)
years, the primary end point occurred in 27.5% of participants in the
very early ICA group and 29.5% in the standard care group (HR, 0.92;
95% CI, 0.78–1.08). Among patients with a GRACE risk score (Global
Registry of Acute Coronary Events) >140, a very early invasive
treatment strategy improved the primary outcome compared with the
standard invasive treatment (HR, 0.81; 95% CI, 0.67–1.01; P value for
interaction=0.023).
Among patients with significant coronary artery disease identified by

ICA, coronary revascularization was performed in 88.4% (very early ICA)
and 83.1% (standard invasive care).
Conclusion(s) A strategy of very early invasive coronary evaluation does not improve
overall long-term clinical outcome compared with an invasive strategy
conducted within 2 to 3 days in patients with non-ST-segment elevation
acute coronary syndrome. However, in patients with the highest risk,
very early invasive therapy improves long-term outcomes
28
Reference Jobs A, Mehta SR, Montalescot G, Vicaut E, Van't Hof AWJ, Badings
EA, Neumann FJ, Kastrati A, Sciahbasi A, Reuter PG, Lapostolle F,
Milosevic A, Stankovic G, Milasinovic D, Vonthein R, Desch S, Thiele H.
Optimal timing of an invasive strategy in patients with non-ST-
elevation acute coronary syndrome: a meta-analysis of randomised
trials. Lancet. 2017 Aug 19;390(10096):737-746. doi: 10.1016/S0140-
6736(17)31490-3. Epub 2017 Aug 1. PMID: 28778541.
Study Type Meta-analysis of randomised clinical trials.
Nº patients
5324 patients from 8 trials

Intervention Early vs. a delayed invasive strategy
Main incl/excl Randomised controlled trials comparing an early versus a delayed
criteria invasive strategy in patients presenting with NSTE-ACS were searched
in MEDLINE, Cochrane Central Register of Controlled Trials, and
Embase. Trials that reported all-cause mortality at least 30 days after
in-hospital randomisation and for which the trial investigators agreed
to collaborate (ie, providing individual patient data or standardised
tabulated data) were included. This meta-analysis was registered at
PROSPERO (CRD42015018988).
Relevant All-cause mortality at least 30 days after in-hospital randomisation

outcome(s)
Key findings There was no significant mortality reduction in the early invasive
group compared with the delayed invasive group (HR=0.81, 95% CI =

0.64-1.03; p=0.0879). In pre-specified analyses of high-risk patients, it
was found a lower mortality with an early invasive strategy in patients
with elevated cardiac biomarkers at baseline (HR = 0.761, 95% CI =
0.581-0.996), diabetes (0.67, 0.45-0.99), a GRACE risk score more
than 140 (0.70, 0.52-0.95), and aged 75 years older (0.65, 0.46-0.93),
although tests for interaction were inconclusive.
Conclusion(s) An early invasive strategy does not reduce mortality compared with a
delayed invasive strategy in all patients with NSTE-ACS. However, an
early invasive strategy might reduce mortality in high-risk patients.
29
Reference O'Donoghue M, Boden WE, Braunwald E, Cannon CP, Clayton TC, de
Winter RJ, Fox KA, Lagerqvist B, McCullough PA, Murphy SA, Spacek R,
Swahn E, Wallentin L, Windhausen F, Sabatine MS. Early invasive vs
conservative treatment strategies in women and men with unstable
angina and non-ST-segment elevation myocardial infarction: a meta-
analysis. JAMA. 2008 Jul 2;300(1):71-80. doi: 10.1001/jama.300.1.71.
PMID: 18594042.
Study Type Meta-analysis of randomized trials
Nº patients Data were combined across 8 trials (3075 women and 7075 men).
Intervention Invasive vs. conservative strategy
Main incl/excl Patients with with NSTE ACS.
criteria Trials were identified through a computerized literature search of the
MEDLINE and Cochrane databases (1970-April 2008) using the search
terms invasive strategy, conservative strategy, selective invasive
strategy, acute coronary syndromes, non-ST-elevation myocardial
infarction, and unstable angina. The study selection criterion was
randomized clinical trials comparing an invasive vs conservative
treatment strategy in patients with NSTE ACS.
Relevant The principal investigators for each trial provided the sex-specific
outcome(s) incidences of death, myocardial infarction (MI), and rehospitalization
with ACS through 12 months of follow-up.
Key findings In women, the composite of death, MI, or ACS occurred in 21.1% vs.
25.0% for invasive vs. conservative strategy, OR= 0.81 (95% CI = 0.65-
1.01). In men, the composite of death, MI, or ACS occurred in 21.2%
vs. 26.3% for invasive vs. conservative strategy, OR= 0.73 (95% CI =
0.55-0.98). There was no significant heterogeneity between sexes (P
for interaction = 0.26).
Conclusion(s) In NSTE ACS, an invasive strategy has a comparable benefit in men

and high-risk women for reducing the composite end point of death,
MI, or rehospitalization with ACS.
30
Reference Fanning JP, Nyong J, Scott IA, Aroney CN, Walters DL. Routine invasive
strategies versus selective invasive strategies for unstable angina and
non-ST elevation myocardial infarction in the stent era. Cochrane
Database Syst Rev. 2016 May 26;2016(5):CD004815. doi:
10.1002/14651858.CD004815.pub4. PMID: 27226069.
Study Type Systematic review and meta-analysis
Nº patients Eight RCTs with a total of 8915 participants (4545 invasive strategies,
4370 conservative strategies).
Intervention Routine invasive vs. a conservative or 'selective invasive' strategy for
the management of UA/NSTEMI in the stent era.
Main incl/excl There was a search in the following databases and additional resources
criteria up to 25 August 2015: the Cochrane Central Register of Controlled
Trials (CENTRAL) on the Cochrane Library, MEDLINE and EMBASE, with
no language restrictions. They included prospective randomised
controlled trials (RCTs) that compared invasive with conservative or

'selective invasive' strategies in participants with acute UA/NSTEMI.
Data collection and analysis: Two review authors screened the records
and extracted data in duplicate. Using intention-to-treat analysis with
random-effects models, we calculated summary estimates of the risk
ratio (RR) with 95% confidence intervals (CIs) for the primary endpoints
of all-cause death, fatal and non-fatal myocardial infarction (MI),
combined all-cause death or non-fatal MI, refractory angina and re-
hospitalisation. We performed further analysis of included studies
based on whether glycoprotein IIb/IIIa receptor antagonists were used
routinely. We assessed the heterogeneity of included trials using
Pearson χ² (Chi² test) and variance (I² statistic) analysis. Using the
Grading of Recommendations Assessment, Development and
Evaluation (GRADE) approach, we assessed the quality of the evidence
and the GRADE profiler (GRADEPRO) was used to import data from
Review Manager 5.3 (Review Manager) to create Summary of findings
(SoF) tables.
Relevant All-cause mortality, death or non-fatal MI, MI, refractory angina, re-
outcome(s) hospitalisation, procedure-related MI,
Key findings In the all-study analysis, there was no risk reductions in all-cause
mortality (RR 0.87, 95% CI 0.64 to 1.18) and death or non-fatal MI (RR
0.93, 95% CI 0.71 to 1.2) with invasive strategies compared to
conservative (selective invasive) strategies at six to 12 months follow-
up.
There was risk reduction in MI (RR 0.79, 95% CI 0.63 to 1.00),

refractory angina (RR 0.64, 95% CI 0.52 to 0.79) and re-hospitalisation
(RR 0.77, 95% CI 0.63 to 0.94) with routine invasive strategies
compared to conservative (selective invasive) strategies also at six to
12 months follow-up.
31
There was increased risks in bleeding (RR 1.73, 95% CI 1.30 to 2.31)
and procedure-related MI (RR 1.87, 95% CI 1.47 to 2.37) with routine
invasive strategies compared to conservative (selective invasive)
strategies.
Conclusion(s) This meta-analysis failed to show benefit with routine invasive
strategies for unstable angina and non-ST elevation MI compared to
conservative strategies in all-cause mortality and death or non-fatal MI
at six to 12 months.
32
Reference Elgendy IY, Mahmoud AN, Wen X, Bavry AA. Meta-Analysis of
Randomized Trials of Long-Term All-Cause Mortality in Patients With
Non-ST-Elevation Acute Coronary Syndrome Managed With Routine
Invasive Versus Selective Invasive Strategies. Am J Cardiol. 2017 Feb
15;119(4):560-564. doi: 10.1016/j.amjcard.2016.11.005. Epub 2016
Nov 16. PMID: 27939385.
Study Type Meta-analysis of randomised clinical trials
Details and Quality
Nº patients Eight trials with 6,657 patients

of Evidence
Intervention routine invasive strategy vs. selective invasive strategy

Main incl/excl Trials that compared a routine invasive strategy versus a selective
criteria invasive strategy in patients with NSTE-ACS and reported data on all-
cause mortality ≥1 year were included.
Relevant All-cause mortality
outcome(s)
Key findings
At a mean of 10.3 years, the risk of all-cause mortality was similar with
both strategies, 28.5% vs 28.5% (OR=1.00, 95% CI = 0.90 to 1.12, p =
0.97). This association was similar on subgroup analysis for follow-up
at 1 to ≤5 years (OR=0.89, 95% CI = 0.77 to 1.04, p = 0.15) and >5 years
(OR=1.02, 95% CI=0.90 to 1.14, p = 0.79
Conclusion(s) This meta-analysis did not show a difference in risk of all-cause

mortality betweeb routine invasive and selective invasive strategies in
patients with NSTE-ACS.
33
Recommendation Table 5 — Recommendations for antiplatelet and
anticoagulant therapy in acute coronary syndrome
Reference Antithrombotic Trialists' (ATT) Collaboration; Baigent C, Blackwell L,

Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C,
Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin
in the primary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant data from
randomised trials. Lancet. 2009 May 30;373(9678):1849-60. doi:
10.1016/S0140-6736(09)60503-1. PMID: 19482214.
Study Type Collaborative meta-analysis of individual participant data from
randomised trials.
Nº patients Six primary prevention trials (95,000 individuals at low average risk,
Evidence
660,000 person-years, 3554 serious vascular events) and 16

secondary prevention trials (17,000 individuals at high average risk,
43,000 person-years, 3306 serious vascular events).
Intervention Long-term aspirin.
Main incl/excl Primary and secondary prevention trials comparing long-term aspirin
criteria versus control.
Relevant Serious vascular events (myocardial infarction, stroke, or vascular
outcome(s) death) and major bleeds.
Key findings In the primary prevention trials, aspirin allocation yielded a 12%
proportional reduction in serious vascular events (0.51% aspirin vs.
0.57% control per year, p=0.0001), due mainly to a reduction of about
a fifth in non-fatal myocardial infarction (0.18% vs. 0.23% per year,
p<0.0001). The net effect on stroke was not significant (0.20% vs.
0.21% per year, p=0.4). Vascular mortality did not differ significantly
(0.19% vs. 0.19% per year, p=0.7). Aspirin allocation increased major
gastrointestinal and extracranial bleeds (0.10% vs. 0.07% per year,
p<0.0001), and the main risk factors for coronary disease were also
risk factors for bleeding.
In the secondary prevention trials, aspirin allocation yielded a greater

absolute reduction in serious vascular events (6.7% vs. 8.2% per year,
p<0.0001), with reductions of about a fifth in total stroke (2.08% vs.
2.54% per year, p=0.002) and in coronary events (4.3% vs. 5.3% per
year, p<0.0001). In both primary and secondary prevention trials, the
proportional reductions in the aggregate of all serious vascular events
seemed similar for men and women.
Conclusion(s) In the secondary prevention trials, aspirin allocation yielded a greater
absolute reduction in serious vascular events. There is less certainty
about its net benefit in primary prevention without previous disease.
34
Acronym Study of Platelet Inhibition and Patient Outcomes (PLATO) trial
Reference Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C,
Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene
A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A,
Thorsén M. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi:
10.1056/NEJMoa0904327. Epub 2009 Aug 30. PMID: 19717846.
Study Type Multicenter, randomized, double-blind clinical trial.
Intervention Ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) vs.
clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter)
Main incl/excl Patients were eligible for enrollment if they were hospitalized for an
criteria acute coronary syndrome, with or without ST-segment elevation, with
an onset of symptoms during the previous 24 hours.
- For patients who had NSTE-ACS, at least two of the following
three criteria had to be met: ST-segment changes on
electrocardiography, a positive test of a biomarker, or one of

several risk factors (age ≥60 years; previous myocardial
infarction or coronary-artery bypass grafting; coronary artery
disease with stenosis of ≥50% in at least two vessels; previous
ischemic stroke, transient ischemic attack, carotid stenosis of
at least 50%, or cerebral revascularization; diabetes mellitus;
peripheral arterial disease; or chronic renal dysfunction,
defined as a creatinine clearance of <60 ml per minute per
1.73 m2 of BSA).
- For patients who had STEMI, the following two inclusion
criteria had to be met: persistent ST-segment elevation of at
least 0.1 mV in at least two contiguous leads or a new left
bundle-branch block, and the intention to perform primary
PCI.
Major exclusion criteria were any contraindication against the use of
clopidogrel, fibrinolytic therapy within 24 hours before randomisation,
a need for oral anticoagulation therapy, an increased risk of
bradycardia, and concomitant therapy with a strong cytochrome P-
450 3A inhibitor or inducer.
Relevant The primary end point was a composite of death from vascular causes,
outcome(s) myocardial infarction, or stroke
Key findings At 12 months, the primary endpoint had occurred in 9.8% of patients
receiving ticagrelor as compared with 11.7% of those receiving
clopidogrel (HR=0.84; 95% CI, 0.77 - 0.92; P<0.001).
Significant differences in myocardial infarction rates (5.8% in the
ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death
from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone
(1.5% vs. 1.3%, P=0.22). The rate of all-cause death was not reduced
with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No
difference in the rates of major bleeding was found between the
ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively;
35
P=0.43), but ticagrelor was associated with a higher rate of major
bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%,
P=0.03), including more instances of fatal intracranial bleeding and
fewer of fatal bleeding of other types.
Conclusion(s) In patients with ACS, treatment with ticagrelor as compared with
clopidogrel reduced the rate of the primary endpint (a composite of
death from vascular causes, myocardial infarction, or stroke ) without
a significant increase in the rate of overall major bleeding but with an
increase in the rate of non-procedure-related bleeding.
36
Acronym Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial
Infarction (TRITON–TIMI) 38
Reference Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W,
Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA,
Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38
Investigators. Prasugrel versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. doi:
10.1056/NEJMoa0706482. Epub 2007 Nov 4. PMID: 17982182.
Study Type A multicenter, randomized, double-blind trial

Evidence
Intervention Aspirin (75-162mg) in combination with 60 mg of prasugrel or 300 mg

of clopidogrel
Main incl/excl Patients with acute coronary syndromes (representative of the entire
criteria spectrum of those syndromes) with scheduled percutaneous coronary
intervention
Relevant The primary endpoint was a composite of death from cardiovascular
outcome(s) causes, nonfatal myocardial infarction, or nonfatal stroke. The key
safety end point was major bleeding.
Key findings The primary efficacy end point occurred in 12.1% of patients receiving
clopidogrel vs. 9.9% of patients receiving prasugrel (HR, 0.81; 95% CI,
0.73 to 0.90; P<0.001).
Major bleeding was observed in 2.4% of patients receiving prasugrel
and in 1.8% of patients receiving clopidogrel (HR, 1.32; 95% CI, 1.03 to
1.68; P=0.03). Also greater in the prasugrel group was the rate of life-
threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal
bleeding (1.1% vs. 0.9%; HR, 1.25; P=0.23) and fatal bleeding (0.4% vs.
0.1%; P=0.002).
Conclusion(s) Prasugrel therapy was associated with significantly reduced rates of
ischemic events, but with an increased risk of major bleeding,
including fatal bleeding.
37
Acronym Percutaneous Coronary Intervention-Clopidogrel in Unstable angina
to prevent Recurrent Events (PCI-CURE) Study
Reference Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK,
Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA;
Clopidogrel in Unstable angina to prevent Recurrent Events trial
(CURE) Investigators. Effects of pretreatment with clopidogrel and
aspirin followed by long-term therapy in patients undergoing
percutaneous coronary intervention: the PCI-CURE study. Lancet.
2001 Aug 18;358(9281):527-33. doi: 10.1016/s0140-6736(01)05701-
4. PMID: 11520521.
Study Type Randomized, double-blind, placebo-controlled trial
Details and
Nº patients N=2658
Quality of
Evidence
Intervention Clopidogrel group or placebo in addition to aspirin for 3 to 12 months.

Main incl/excl Patients hospitalized within 24 hours after the onset of symptoms
criteria with acute coronary syndromes without ST-segment elevation and
treated with percutaneous coronary intervention
Relevant Composite of death from cardiovascular causes, nonfatal myocardial
outcome(s) infarction, or urgent target vessel revascularization
Key findings The primary outcome occurred in 4,5% patients in the clopidogrel
group vs. 6,4%

in the placebo group (relative risk 0.70 [95% CI 0.50–0.97], p=0,03).
Long-term administration of clopidogrel after PCI was associated with
a lower rate of cardiovascular death, myocardial infarction, or any
revascularisation (p=0,03), and of cardiovascular death or myocardial
infarction (p=0,047). There was no significant difference in major
bleeding between the groups (p=0,64).
Conclusion(s) In patients with acute coronary syndrome receiving aspirin, a strategy
of clopidogrel pretreatment followed by long-term therapy is
beneficial in reducing major cardiovascular events, compared with
placebo.
38
Acronym Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)
trial
Reference Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK;
Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial
Investigators. Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N Engl
J Med. 2001 Aug 16;345(7):494-502. doi: 10.1056/NEJMoa010746.
Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. Erratum in: N Engl
J Med 2001 Nov 15;345(20):1506. PMID: 11519503.
Study Type Randomized, double-blind, placebo-controlled trial
Details and Quality

of Evidence
Intervention Clopidogrel group or placebo in addition to aspirin for 3 to 12 months

Main incl/excl Patients hospitalized within 24 hours after the onset of symptoms
criteria with acute coronary syndromes without ST-segment elevation.
Relevant Composite of death from cardiovascular causes, nonfatal myocardial

outcome(s) infarction, or stroke
The first primary outcome or refractory ischemia.

Key findings The first primary outcome occurred in 9.3 % of the patients in the
clopidogrel group and 11.4 % of the patients in the placebo group
(relative risk with clopidogrel as compared with placebo, 0.80; 95 %

CI, 0.72 to 0.90; P<0.001). The second primary outcome occurred in
16.5 % of the patients in the clopidogrel group and 18.8 % of the
patients in the placebo group (relative risk, 0.86, P<0.001).
The percentages of patients with in-hospital refractory or severe
ischemia, heart failure, and revascularization procedures were also
significantly lower with clopidogrel. There were significantly more
patients with major bleeding in the clopidogrel group than in the
placebo group (3.7 % vs. 2.7 %; relative risk, 1.38; P=0.001), but there
were not significantly more patients with episodes of life-threatening
bleeding (2.1 % vs. 1.8 %, P=0.13) or hemorrhagic strokes.
Conclusion(s) Clopidogrel has beneficial effects in patients with acute coronary
syndromes without ST-segment elevation. However, the risk of major
bleeding is increased among patients treated with clopidogrel.
39
Acronym Intracoronary Stenting and Antithrombotic Regimen: Rapid Early
Action for Coronary Treatment (ISAR-REACT) 5 trial
Reference Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle
J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-
Flügel L, Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M,
Janisch M, Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Möllmann
H, Hochholzer W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S,
Strehle A, Leggewie S, Allali A, Ndrepepa G, Schühlen H, Angiolillo DJ,
Hamm CW, Hapfelmeier A, Tölg R, Trenk D, Schunkert H, Laugwitz KL,
Kastrati A; ISAR-REACT 5 Trial Investigators. Ticagrelor or Prasugrel in
Patients with Acute Coronary Syndromes. N Engl J Med. 2019 Oct
17;381(16):1524-1534. doi: 10.1056/NEJMoa1908973. Epub 2019 Sep
1. PMID: 31475799.
Study Type Multicenter, randomized, open-label trial

Intervention Ticagrelor (loading dose of 180 mg , maintenance dose of 90 mg twice
daily), or ticagrelor ( loading dose 60 mg, maintenance dose of 10 mg
once per day). A reduced maintenance dose of 5 mg daily was
recommended in patients who were 75 years of age or older and in
those who had a body weight of less than 60 kg.
Main incl/excl Patients with acute coronary syndromes (ST-segment elevation
criteria myocardial infarction [STEMI], non–ST-elevation myocardial infarction
[NSTEMI], or unstable angina) for which invasive evaluation was
planned (i.e., the patient was scheduled to undergo coronary
angiography).
Relevant The primary end point was the composite of death, myocardial
outcome(s) infarction, or stroke at 1 year.
A major secondary end point (the safety end point) was bleeding.
Key findings A primary end-point event occurred 9.3% in the ticagrelor group vs.
6.9% in the prasugrel group (HR, 1.36; 95% CI, 1.09 to 1.70; P=0.006).
Major bleeding (as defined by the Bleeding Academic Research
Consortium scale) was observed in 5.4% of patients in the ticagrelor
group and in 4.8% of patients in the prasugrel group (HR, 1.12; 95% CI,
0.83 to 1.51; P=0.46).
Conclusion(s) Among patients who presented with acute coronary syndromes with
or without ST-segment elevation, the incidence of death, myocardial
infarction, or stroke was significantly lower among those who received
prasugrel than among those who received ticagrelor, and the
incidence of major bleeding was not significantly different between
the two groups.
40
Acronym Ticagrelor or Prasugrel Versus Clopidogrel in Elderly Patients With
an Acute Coronary Syndrome and a High Bleeding Risk: Optimization
of Antiplatelet Treatment in High-risk Elderly (POPular AGE)
Reference Gimbel M, Qaderdan K, Willemsen L, Hermanides R, Bergmeijer T, de
Vrey E, Heestermans T, Tjon Joe Gin M, Waalewijn R, Hofma S, den
Hartog F, Jukema W, von Birgelen C, Voskuil M, Kelder J, Deneer V,
Ten Berg J. Clopidogrel versus ticagrelor or prasugrel in patients aged
70 years or older with non-ST-elevation acute coronary syndrome
(POPular AGE): the randomised, open-label, non-inferiority trial.
Lancet. 2020 Apr 25;395(10233):1374-1381. doi: 10.1016/S0140-
6736(20)30325-1. PMID: 32334703.
Study Type Open-label, randomised controlled trial in the Netherlands

Intervention Clopidogrel (loading dose of clopidogrel 300 mg or 600 mg,
Evidence
maintenance dose 75mg once daily) or either ticagrelor (loading dose

180 mg, maintenance dos 90mg twice daily) or prasugrel (loading
dose 60 mg, maintenance dose 10mg once daily) for the duration of
12 months
Main incl/excl Patients aged 70 years or older with non ST segment elevation
criteria myocardial infarction
Relevant Primary bleeding outcome: PLATelet inhibition and patient Outcomes
outcome(s) (PLATO; major or minor bleeding [superiority hypothesis]. Co-primary
net clinical benefit outcome consisted of all-cause death, myocardial
infarction, stroke, PLATO major and minor bleeding (non-inferiority

hypothesis, margin of 2%). Follow-up duration was 12 months.
Key findings Primary bleeding outcome was significantly lower in the clopidogrel
group 18% vs. ticagrelor group 24%; HR 0.71, 95% CI 0.54 to 0.94;
p=0.02 for superiority.
Co-primary net clinical benefit outcome was non-inferior for the use
of clopidogrel 28% vs ticagrelor 32%; absolute risk difference -4%,
95% CI -10.0 to 1.4; p=0.03 for non-inferiority).
Conclusion(s) Clopidogrel could be an alternative P2Y12 inhibitor especially for
elderly patients with a higher bleeding risk.
41
Acronym Cangrelor versus Standard Therapy to Achieve Optimal Management
of Platelet Inhibition (CHAMPION) PCI
Reference Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson
CM, Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS,
Goodman SG, Amine M, Angiolillo DJ, Becker RC, Chew DP, French WJ,
Leisch F, Parikh KH, Skerjanec S, Bhatt DL. Platelet inhibition with
cangrelor in patients undergoing PCI. N Engl J Med. 2009 Dec
10;361(24):2318-29. doi: 10.1056/NEJMoa0908628. PMID: 19915221.
Study Type Randomized, double-blind, double-dummy, active-control trial

Intervention Cangrelor
Evidence
Main incl/excl Patients with stable angina, unstable angina, or non–ST-segment–

criteria elevation myocardial infarction, and obstructive coronary artery
disease scheduled to undergo PCI.
Patients with ST-segment–elevation myocardial infarction for whom
primary PCI was planned (n=1000)
Relevant The primary efficacy end point was a composite of death from any
outcome(s) cause, myocardial infarction, or ischemia-driven revascularization at
48 hours.
Key findings The primary composite end point, which occurred in 7.5% of patients
in the cangrelor group vs. 7.1% of patients in the clopidogrel group
(odds ratio, 1.05; 95% CI, 0.88 to 1.24; P=0.59). Likewise, cangrelor
was not superior at 30 days.
The rate of major bleeding (according to Acute Catheterization and

Urgent Intervention Triage Strategy criteria) was higher with
cangrelor, a difference that approached statistical significance (3.6%
vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was
not the case with major bleeding (according to the Thrombolysis in
Myocardial Infarction criteria) or severe or life-threatening bleeding
(according to Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries criteria).
Conclusion(s) Cangrelor, when administered intravenously 30 minutes before PCI
and continued for 2 hours after PCI, was not superior to an oral
loading dose of 600 mg of clopidogrel, administered 30 minutes
before PCI, in reducing the composite end point of death from any
cause, myocardial infarction, or ischemia-driven revascularization at
48 hours.
42
of Platelet Inhibition (CHAMPION) PLATFORM trial
Reference Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot
G, Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV Jr,
Manoukian SV, Widimsky P, Chew DP, Cura F, Manukov I, Tousek F,
Jafar MZ, Arneja J, Skerjanec S, Harrington RA; CHAMPION PLATFORM
Investigators. Intravenous platelet blockade with cangrelor during PCI.
N Engl J Med. 2009 Dec 10;361(24):2330-41. doi:
10.1056/NEJMoa0908629. PMID: 19915222.
Study Type Multicenter double-blind, placebo-controlled, double-dummy trial
Nº patients 5362 of the 6400 patients planned
Intervention Enrollment was stopped when an interim analysis concluded that the
trial would be unlikely to show superiority for the primary end point.
Cangrelor (in a bolus of 30 μg per kilogram of body weight and an

infusion of 4 μg per kilogram per minute) or a placebo bolus and
infusion for the duration of the PCI procedure, with a minimum
infusion duration of 2 hours and a maximum of 4 hours.
Patients in the cangrelor group received 600 mg of clopidogrel after
the end of the cangrelor infusion, and those in the placebo group
received 600 mg of clopidogrel at the end of the procedure.
Main incl/excl Patients (clopidogrel naïve) to receive either cangrelor or placebo at
criteria the time of PCI, followed by 600 mg of clopidogrel.
Relevant The primary end point was a composite of death, myocardial
outcome(s)
infarction, or ischemia-driven revascularization at 48 hours.

Key findings The primary end point occurred in 7% of patients receiving cangrelor
vs 8.0% of patients receiving placebo (odds ratio in the cangrelor
group, 0.87; 95% CI, 0.71 to 1.07; P=0.17) (modified intention-to-treat
population adjusted for missing data). In the cangrelor group, as
compared with the placebo group, two prespecified secondary end
points were significantly reduced at 48 hours.
Conclusion(s) The use of periprocedural cangrelor during PCI was not superior to
placebo in reducing the primary end point.
43
of Platelet Inhibition (CHAMPION) PHOENIX
Reference Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW,
Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P,
Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P,
Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA;
CHAMPION PHOENIX Investigators. Effect of platelet inhibition with
cangrelor during PCI on ischemic events. N Engl J Med. 2013 Apr
4;368(14):1303-13. doi: 10.1056/NEJMoa1300815. Epub 2013 Mar 10.
PMID: 23473369.
Study Type Multicenter double-blind, placebo-controlled, double-dummy trial.

Intervention
Evidence
Cangrelor or clopidogrel (loading dose 300-600mg, maintenance dose

75mg) before PCI.
Main incl/excl Patients with coronary atherosclerosis who required PCI for stable
criteria angina, a non–ST-segment elevation acute coronary syndrome, or ST-
segment elevation myocardial infarction (STEMI) and who did not
receive pretreatment with platelet inhibitors.
Relevant The primary efficacy end point was a composite of death, myocardial
outcome(s) infarction, ischemia-driven revascularization, or stent thrombosis at
48 hours after randomization; the key secondary end point was stent
thrombosis at 48 hours. The primary safety end point was severe
bleeding at 48 hours.
Key findings The rate of the primary efficacy end point was 4.7% in the cangrelor
group and 5.9% in the clopidogrel group (adjusted odds ratio with
cangrelor, 0.78; 95% CI, 0.66 to 0.93; P=0.005). The rate of the
primary safety end point was 0.16% in the cangrelor group and 0.11%
in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22;
P=0.44). Stent thrombosis developed in 0.8% of the patients in the
cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62;
95% CI, 0.43 to 0.90; P=0.01).
Conclusion(s) Cangrelor significantly reduced the rate of ischemic events, including
stent thrombosis, during PCI, with no significant increase in severe
bleeding.
44
Reference Szummer K, Montez-Rath ME, Alfredsson J, Erlinge D, Lindahl B,
Hofmann R, Ravn-Fischer A, Svensson P, Jernberg T. Comparison
Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute
Coronary Syndrome: Insights From the SWEDEHEART Registry.
Circulation. 2020 Nov 3;142(18):1700-1708. doi:
10.1161/CIRCULATIONAHA.120.050645. Epub 2020 Sep 1. PMID:
32867508.
Study Type Nationwide prospective observational study
Nº patients 14 005 participants from the registry SWEDEHEART (Swedish Web-

System for Enhancement and Development of Evidence-Based Care in
Evidence
Heart Disease Evaluated According to Recommended Therapies).

Intervention Clopidogrel vs ticagrelor, in addition to aspirin
Main incl/excl Patients ≥80 years who were discharged alive with aspirin combined
criteria with either clopidogrel or ticagrelor after a MI between 2010 and 2017
registered in the national registry SWEDEHEART
Relevant The primary ischemic outcome (death, MI, or stroke), and bleeding
outcome(s) were obtained from national registries at 1 year.
Key findings In patients ≥80 years, the incidence of the primary ischemic outcome
was similar for ticagrelor- and clopidogrel-treated patients (HR = 0.97,

95% CI = 0.88-1.06). Ticagrelor was associated with a 17% and 48%
higher risk of death (HR = 1.17, 95% CI = 1.03-1.32) and bleeding (HR =
1.48, 95% CI = 1.25-1.76), but a lower risk of MI (HR = 0.80, 95% CI =
0.70-0.92) and stroke (HR = 0.72, 95% CI = 0.56-0.93).
Conclusion(s) In this observation study evaluating patients ≥80 years, there were no
differences in the primary ischemic outcome (death, MI, or stroke)
between ticagrerlor and clopidogrel. Nevertheless, ticagrelor use
among elderly patients with MI was associated with higher risk of
bleeding and death compared with clopidogrel.
45
Reference Steg PG, Bhatt DL, Hamm CW, Stone GW, Gibson CM, Mahaffey KW,
Leonardi S, Liu T, Skerjanec S, Day JR, Iwaoka RS, Stuckey TD, Gogia
HS, Gruberg L, French WJ, White HD, Harrington RA; CHAMPION
Investigators. Effect of cangrelor on periprocedural outcomes in
percutaneous coronary interventions: a pooled analysis of patient-
level data. Lancet. 2013 Dec 14;382(9909):1981-92. doi:
10.1016/S0140-6736(13)61615-3. Epub 2013 Sep 3. PMID: 24011551.
Study Type Pooled analysis of data from three large, double-blind, randomised
trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-
PHOENIX)
Intervention Cangrelor
Main incl/excl Three large, double-blind, randomised trials (CHAMPION-PCI,
criteria CHAMPION-PLATFORM, and CHAMPION-PHOENIX) comparing
cangrelor with control (clopidogrel or placebo) for prevention of
thrombotic complications during and after PCI were used to pool
patient-level. Trial participants were patients undergoing PCI for ST-
elevation myocardial infarction (11.6%), non-ST-elevation acute
coronary syndromes (57.4%), and stable coronary artery disease
(31.0%).
Relevant The prespecified primary efficacy composite was death, myocardial
outcome(s) infarction, ischaemia-driven revascularisation, or stent thrombosis at
48 h. The primary safety outcome was non-coronary artery bypass
graft-related GUSTO (Global Use of Strategies to Open Occluded
Coronary Arteries) severe or life-threatening bleeding at 48 h.
Key findings The primary outcome occurred in 3.8% and 4.7% for cangrelor and
control patients respectively (OR = 0.81, 95% CI 0.71-0.91, p=0.0007).

Cangrelor also reduced stent thrombosis by 41% (0.5% vs 0.8%, OR
0.59, 95% CI 0.43-0.80, p=0.0008), and the odds of the secondary
triple composite (all-cause death, myocardial infarction, or ischaemia-
driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95%
CI 0.71-0.92, p=0.0014). These benefits were maintained at 30 days.
The primary safety outcome occurred in 0.2% patients in both groups,
without significant differences. Cangrelor increased GUSTO mild
bleeding (16.8% vs 13.0%, p<0.0001).
Conclusion(s) Compared with control (clopidogrel or placebo), cangrelor reduced

PCI periprocedural thrombotic complications, at the expense of
increased bleeding.
46
Acronym Administration of Ticagrelor in the Cath Lab or in the Ambulance for
New ST Elevation Myocardial Infarction to Open the Coronary Artery
(ATLANTIC) study
Reference Montalescot G, van 't Hof AW, Lapostolle F, Silvain J, Lassen JF,
Bolognese L, Cantor WJ, Cequier A, Chettibi M, Goodman SG,
Hammett CJ, Huber K, Janzon M, Merkely B, Storey RF, Zeymer U,
Stibbe O, Ecollan P, Heutz WM, Swahn E, Collet JP, Willems FF,
Baradat C, Licour M, Tsatsaris A, Vicaut E, Hamm CW; ATLANTIC
Investigators. Prehospital ticagrelor in ST-segment elevation
myocardial infarction. N Engl J Med. 2014 Sep 11;371(11):1016-27.
doi: 10.1056/NEJMoa1407024. Epub 2014 Sep 1. PMID: 25175921.
Study Type A phase 4, international, randomized, double-blind study
Details and Quality

of Evidence
Intervention Prehospital (in the ambulance) or in-hospital (in the catheterization

laboratory) treatment with ticagrelor (180-mg loading dose), in
addition to aspirin and standard care.
Main incl/excl Patients with ST segment elevation myocardial infarction with a time
criteria to the first balloon inflation of less than 120 minutes.
Relevant The coprimary end points were the proportion of patients who did not
outcome(s) have a 70% or greater resolution of ST-segment elevation before
percutaneous coronary intervention (PCI) and the proportion of
patients who did not have Thrombolysis in Myocardial Infarction flow
grade 3 in the infarct-related artery at initial angiography.
Key findings The median time from randomization to angiography was 48 minutes,
and the median time difference between the two treatment strategies
was 31 minutes. The two coprimary end points did not differ
significantly between the prehospital and in-hospital groups. The
absence of ST-segment elevation resolution of 70% or greater after
PCI (a secondary end point) was reported for 42.5% and 47.5% of the
patients, respectively.
Rates of major bleeding events were low and virtually identical in the
two groups.
Conclusion(s) Prehospital administration of ticagrelor in patients with acute STEMI
appeared to be safe but did not improve pre-PCI coronary
reperfusion.
47
Acronym Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation
Acute Coronary Syndrome (EARLY ACS) trial
Reference Giugliano RP, White JA, Bode C, Armstrong PW, Montalescot G, Lewis
BS, van 't Hof A, Berdan LG, Lee KL, Strony JT, Hildemann S, Veltri E,
Van de Werf F, Braunwald E, Harrington RA, Califf RM, Newby LK;
EARLY ACS Investigators. Early versus delayed, provisional eptifibatide
in acute coronary syndromes. N Engl J Med. 2009 May
21;360(21):2176-90. doi: 10.1056/NEJMoa0901316. Epub 2009 Mar
30. PMID: 19332455.
Study Type A prospective, open-label, randomized, multicenter trial
Nº patients
9492 participants
Intervention Early eptifibatide (two boluses, each containing 180 μg per kilogram of
Evidence
body weight, administered 10 minutes apart, and a standard infusion

≥12 hours before angiography) or a matching placebo infusion with
provisional use of eptifibatide after angiography (delayed
eptifibatide).
Main incl/excl Patients with acute coronary syndromes without ST-segment
criteria elevation assigned to an invasive strategy.
Relevant The primary efficacy end point was a composite of death, myocardial
outcome(s) infarction, recurrent ischemia requiring urgent revascularization, or
the occurrence of a thrombotic complication during percutaneous
coronary intervention that required bolus therapy opposite to the
initial study-group assignment (“thrombotic bailout”) at 96 hours. The
key secondary end point was a composite of death or myocardial
infarction within the first 30 days.
Key safety end points were bleeding and the need for transfusion
within the first 120 hours after randomization.
Key findings The primary end point occurred in 9.3% of patients in the early-
eptifibatide group vs. 10.0% in the delayed-eptifibatide group (odds
ratio, 0.92; 95% CI, 0.80 to 1.06; P=0.23).
At 30 days, the rate of death or myocardial infarction was 11.2% in the
early-eptifibatide group, vs. 12.3% in the delayed-eptifibatide group
(odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08).
Patients in the early-eptifibatide group had significantly higher rates
of bleeding and red-cell transfusion.
Conclusion(s) Eptifibatide 12 hours or more before angiography was not superior to
the provisional use of eptifibatide after angiography. The early use of
eptifibatide was associated with an increased risk of non–life-
threatening bleeding and need for transfusion.
48
Acronym Comparison of Prasugrel at the Time of Percutaneous Coronary
Intervention (PCI) or as Pretreatment at the Time of Diagnosis in
Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) trial
Reference Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay
JF, ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P,
Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G,
Visconti LO, Vicaut E, Widimsky P; ACCOAST Investigators.
Pretreatment with prasugrel in non-ST-segment elevation acute
coronary syndromes. N Engl J Med. 2013 Sep 12;369(11):999-1010.
Study Type A phase 3, randomized, double-blind, event-driven study.
Details and Quality

of Evidence
Intervention Pretreatment with prasugrel (pretreatment group, loading dose 30mg

pre PCI, and 30mg at the time of PCI) or matching placebo (control
group, prasugrel 60mg loading dose after diagnostic angiogram).
Main incl/excl Patients with a non ST segment elevation acute coronary syndrome
criteria with elevated troponin levels.
Relevant The primary efficacy end point was a composite of death from
outcome(s) cardiovascular causes, myocardial infarction, stroke, urgent
revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy
(glycoprotein IIb/IIIa bailout) through day 7
Key findings The rate of the primary efficacy end point through day 7, did not differ
significantly between the two groups (HR, 1.02; 95% CI, 0.84 to 1.25;
P=0.81).
The rate of the key safety end point of all Thrombolysis in Myocardial
Infarction (TIMI) major bleeding episodes, whether related or not
related to coronary-artery bypass grafting (CABG), through day 7 was
increased with pretreatment (HR, 1.90; 95% CI, 1.19 to 3.02; P=0.006).
The rates of TIMI major bleeding and life-threatening bleeding not
related to CABG were increased by a factor of 3 and 6, respectively.
All the results were confirmed at 30 days and in prespecified
subgroups.
Conclusion(s) Among patients with NSTE acute coronary syndromes who were
scheduled to undergo catheterization, pretreatment with prasugrel
did not reduce the rate of major ischemic events up to 30 days but
increased the rate of major bleeding complications.
49
Acronym Clopidogrel for the Reduction of Events During Observation (CREDO)
trial
Reference Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C,
Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events
During Observation. Early and sustained dual oral antiplatelet therapy
following percutaneous coronary intervention: a randomized
controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. doi:
10.1001/jama.288.19.2411. Erratum in: JAMA. 2003 Feb
26;289(8):987. PMID: 12435254.
Study Type A prospective, a randomized, double-blind, placebo-controlled trial

Intervention 300-mg clopidogrel loading dose or placebo 3 to 24 hours before PCI.
Evidence
Main incl/excl Patients with symptomatic coronary artery disease with objective
criteria evidence of ischemia referred for PCI, or thought to be at high
likelihood for requiring PCI with either stent placement with or
without conventional balloon angioplasty or another revascularization
device.
Relevant One-year incidence of the composite of death, myocardial infarction
outcome(s) (MI), or stroke in the intent-to-treat population;
28-day incidence of the composite of death, MI, or urgent target
vessel revascularization in the per-protocol population.

Key findings At 1 year, long-term clopidogrel therapy was associated with a 26.9%
relative reduction in the primary endpoint (95% CI, 3.9%-44.4%; P =
.02; absolute reduction, 3%). At 28 days clopidogrel pretreatment did
not significantly reduce the co-primary endpoint (reduction, 18.5%;
95% CI, −14.2% to 41.8%; P = 0.23).
Conclusion(s) Following PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A loading dose of
clopidogrel given at least 3 hours before the procedure did not reduce
events at 28 days.
50
Acronym Clopidogrel and the Optimization of Gastrointestinal Events Trial
(COGENT) trial
Reference Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook
TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon
CP; COGENT Investigators. Clopidogrel with or without omeprazole in
coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909-17.
doi: 10.1056/NEJMoa1007964. Epub 2010 Oct 6. PMID: 20925534.
Study Type A multicenter, randomized, double-blind, double-dummy, placebo
controlled, parallel group study.

Nº patients 3873 of the 5000patients planned
Intervention The trial was terminated prematurely when the sponsor lost financing.
A fixed-dose combination of clopidogrel (75 mg) and omeprazole (20

mg), or clopidogrel alone
Main incl/excl The use of clopidogrel therapy with concomitant aspirin was
criteria anticipated for at least the next 12 months, including patients
presenting with an acute coronary syndrome or undergoing
placement of a coronary stent.
Relevant The primary gastrointestinal end point was a composite of overt or
outcome(s) occult bleeding, symptomatic gastroduodenal ulcers or erosions,
obstruction, or perforation.
The primary cardiovascular end point was a composite of death from
cardiovascular causes, nonfatal myocardial infarction,
revascularization, or stroke.
Key findings In all, the gastrointestinal event rate was 1.1% with omeprazole and
2.9% with placebo at 180 days (HR, 0.34, 95% CI, 0.18 to 0.63;
P<0.001).
The rate of overt upper gastrointestinal bleeding was also reduced
with omeprazole as compared with placebo (HR, 0.13; 95% CI, 0.03 to
0.56; P=0.001).
The cardiovascular event rates was 4.9% with omeprazole and 5.7%
with placebo (HR, 0.99; 95% CI, 0.68 to 1.44; P=0.96).
Conclusion(s) Among patients receiving aspirin and clopidogrel, prophylactic use of
a PPI reduced the rate of upper gastrointestinal bleeding. There was
no apparent cardiovascular interaction between clopidogrel and
omeprazole.
51
Reference Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu WH, Lau GK, Wong
WM, Yuen MF, Chan AO, Lai CL, Wong J. Lansoprazole for the
prevention of recurrences of ulcer complications from long-term low-
dose aspirin use. N Engl J Med. 2002 Jun 27;346(26):2033-8. doi:
10.1056/NEJMoa012877. PMID: 12087138.

Intervention 30 mg of lansoprazole daily vs. placebo, in addition to 100 mg of
Evidence
aspirin daily, for 12 months.

Main incl/excl Patients who had ulcer complications after using low-dose aspirin
criteria continuously for more than one month and who had H. pylori
infection.
Relevant The primary endpoint was the recurrence of ulcer complications.

outcome(s)
Key findings During a median follow-up of 12 months, 14.8% and 1.6% patients in
the placebo group and the lansoprazole group, respectively, had a

recurrence of ulcer complications (adjusted hazard ratio, 9.6; 95 % CI
= 1.2 - 76.1). Patients in the lansoprazole group were significantly less
likely to have a recurrence of ulcer complications than patients in the
placebo group (P=0.008). There was no significant difference in
mortality between the two groups.
Conclusion(s) In patients who had ulcer complications related to the long-term use
of low-dose aspirin, treatment with lansoprazole in addition to the
eradication of H. pylori infection significantly reduced the rate of
recurrence of ulcer complications.
52
Reference Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S.
Unfractionated heparin and low-molecular-weight heparin in acute
coronary syndrome without ST elevation: a meta-analysis. Lancet.
2000 Jun 3;355(9219):1936-42. doi: 10.1016/S0140-6736(00)02324-2.
Erratum in: Lancet 2000 Aug 12;356(9229):600. PMID: 10859038.
Study Type Meta-analysis
Nº patients 12 trials, involving a total of 17157 patients

Intervention unfractionated heparin or LMWH vs. placebo or untreated control
Evidence
Main incl/excl Randomised trials comparing unfractionated heparin or LMWH with

criteria placebo or untreated control, or comparing unfractionated heparin
with LMWH, for the short-term and long-term management of
patients with acute coronary syndrome without ST elevation, were
identified by electronic and manual searches and through contact
with experts and industry representatives.
Relevant Composite of myocardial infarction or death, and major bleeding
outcome(s)
Key findings Summary ORs for myocardial infarction or death during short-term
(up to 7 days):
- Unfractionated heparin or LMWH compared with placebo or
untreated control: OR = 0.53 (95% CI = 0.38-0.73; p=0.0001)
or 29 events prevented per 1000 patients treated;
- LMWH compared with unfractionated heparin: OR = 0.88

(0.69-1.12; p=0.34);
Summary ORs for myocardial infarction or death during long-term up
to 3 months):
- LMWH compared with placebo or untreated control. OR =
0.98 (0.81-1.17; p=0.80)
LMWH was associated with a significantly increased risk of major

bleeding. OR=2.26, (95% CI = 1.63-3.14, p<0.0001).
Conclusion(s) In aspirin-treated patients with acute coronary syndrome without ST
elevation, short-term unfractionated heparin or LMWH reduced the
risk of myocardial infarction or death. There was no difference in
efficacy between LMWH and unfractionated heparin. Long-term
LMWH has not been proven to confer benefit after the first 7 days
53
Acronym Fondaparinux Trial With Unfractionated Heprin During
Revascularization in Acute Coronary Syndromes/Organization to
Assess Strategies in Acute Ischemic Syndromes (FUTURA)/OASIS-8
trial
Reference FUTURA/OASIS-8 Trial Group; Steg PG, Jolly SS, Mehta SR, Afzal R,
Xavier D, Rupprecht HJ, López-Sendón JL, Budaj A, Diaz R, Avezum A,
Widimsky P, Rao SV, Chrolavicius S, Meeks B, Joyner C, Pogue J, Yusuf
S. Low-dose vs standard-dose unfractionated heparin for
percutaneous coronary intervention in acute coronary syndromes
treated with fondaparinux: the FUTURA/OASIS-8 randomized trial.
JAMA. 2010 Sep 22;304(12):1339-49. doi: 10.1001/jama.2010.1320.
Epub 2010 Aug 31. PMID: 20805623.
Study Type Double-blind randomized parallel-group trial conducted in 179
hospitals in 18 countries
Nº patients 2026 patients undergoing PCI within 72 hours, nested within a cohort
of 3235 high-risk patients with non-ST-segment elevation acute
coronary syndromes initially treated with fondaparinux enrolled

Intervention Low-dose unfractionated heparin, 50 U/kg, regardless of use of
glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors vs. standard-dose
unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors),
adjusted by blinded activated clotting time (ACT).
Main incl/excl Patients with all of the following criteria were eligible if they had
criteria history consistent with new, or worsening ischemia, within 48 hours
of the most recent symptoms;, had planned coronary angiography,
with PCI if indicated, within 72 hours; and at least 2 of the following
criteria: aged 60 years or older, troponin T or I or creatine kinase MB
above the upper limit of normal; electrocardiograph changes
compatible with ischemia, ie, ST depression of 1 mm or greater in 2
contiguous leads, T-wave inversion more than 3 mm, or any dynamic
ST shifts.
Relevant Composite of major bleeding, minor bleeding, or major vascular
outcome(s) access-site complications up to 48 hours after PCI. Key secondary
outcomes include composite of major bleeding at 48 hours with
death, myocardial infarction, or target vessel revascularization within
day 30.
Key findings The primary outcome occurred in 4.7% and 5.8% of those in the low-
dose group and the standard-dose group, respectively (OR= 0.80; 95%
CI= 0.54-1.19; P = 0.27).
The rates of major bleeding were not different but the rates of minor
bleeding were lower with 0.7% and 1.7% in the low-dose group and
the standard-dose group, respectively (OR= 0.40; 95% CI= 0.16-0.97; P
= 0.04).
The rates for death, myocardial infarction, or target vessel
revascularization was 4.5% for the low-dose group vs 2.9% for the
standard-dose group (OR= 1.58; 95% CI= 0.98-2.53; P = 0.06).
54
Conclusion(s) Low-dose compared with standard-dose unfractionated heparin did
not reduce major peri-PCI bleeding and vascular access-site
complications.
55
Reference Silvain J, Beygui F, Barthélémy O, Pollack C Jr, Cohen M, Zeymer U,
Huber K, Goldstein P, Cayla G, Collet JP, Vicaut E, Montalescot G.
Efficacy and safety of enoxaparin versus unfractionated heparin
during percutaneous coronary intervention: systematic review and
meta-analysis. BMJ. 2012 Feb 3;344:e553. doi: 10.1136/bmj.e553.
PMID: 22306479.
Study Type Systematic review and meta-analysis.
Nº patients 23 trials representing 30,966 patients were identified, including
10,243 patients (33.1%) undergoing primary PCI for STEMI, 8750
(28.2%) undergoing secondary PCI after fibrinolysis, and 11,973
(38.7%) with NSTE-ACS or stable patients scheduled for PCI.
Intervention Enoxaparin vs. unfractionated heparin during percutaneous coronary
intervention.
Main incl/excl The meta-analysis included cohort studies and clinical trials that
criteria compared the efficacy and safety of enoxaparin with unfractionated
heparin among patients undergoing primary, secondary (post-
fibrinolysis), or scheduled percutaneous coronary intervention
according to a predefined protocol. The analysis was restricted to
trials that met all of the following inclusion criteria: patients with
coronary heart disease undergoing percutaneous coronary
intervention, considering the whole study population or at least a
predominant subset of this population; a control group using
unfractionated heparin for comparison with enoxaparin; and
publications reporting data at least on mortality and major bleeding.
To focus on the direct comparison of enoxaparin with unfractionated
heparin, studies that used a low molecular weight heparin other than
enoxaparin were excluded, with the exception of one study in which
other low molecular weight heparins were used in a few of the
patients.
Relevant Mortality (efficacy endpoint) and major bleeding (safety endpoint)
outcome(s) outcomes.
Key findings Enoxaparin was associated with significant reductions in death
(RR=0.66, 95% CI=0.57 to 0.76; P<0.001), the composite of death or

myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications
of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction
in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In
patients who underwent primary PCI, the reduction in death (0.52,
0.42 to 0.64; P<0.001) was particularly significant and associated with
a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).
Conclusion(s) This meta-analysis suggests that enoxaparin reduced mortality and
bleeding outcomes during PCI and particularly in patients undergoing
primary PCI for ST elevation myocardial infarction, as compared with
unfractionated heparin.
56
Acronym Acute Myocardial Infarction Treated with Primary Angioplasty and
Intravenous Enoxaparin or Unfractionated Heparin to Lower
Ischemic and Bleeding Events at Short- and Long-term Follow-up
(ATOLL) study
Reference Montalescot G, Zeymer U, Silvain J, Boulanger B, Cohen M, Goldstein
P, Ecollan P, Combes X, Huber K, Pollack C Jr, Bénezet JF, Stibbe O,
Filippi E, Teiger E, Cayla G, Elhadad S, Adnet F, Chouihed T, Gallula S,
Greffet A, Aout M, Collet JP, Vicaut E; ATOLL Investigators.
Intravenous enoxaparin or unfractionated heparin in primary
percutaneous coronary intervention for ST-elevation myocardial
infarction: the international randomised open-label ATOLL trial.
Lancet. 2011 Aug 20;378(9792):693-703. doi: 10.1016/S0140-
6736(11)60876-3. PMID: 21856483.
Study Type International, randomised open-label trial.

Intervention intravenous bolus of 0·5 mg/kg of enoxaparin vs. unfractionated
heparin before primary PCI.
Main incl/excl Patients presenting with ST-elevation myocardial infarction.
criteria Wherever possible, medical teams travelling in mobile intensive care
units (ambulances) selected, randomly assigned (using an interactive
voice response system at the central randomisation centre), and
treated patients. Patients who had received any anticoagulant before
randomisation were excluded. Patients and caregivers were not
masked to treatment allocation.
Relevant The primary endpoint was 30-day incidence of death, complication of
outcome(s) myocardial infarction, procedure failure, or major bleeding. The main
secondary endpoint was the composite of death, recurrent acute
coronary syndrome, or urgent revascularisation.
Key findings The primary endpoint occurred in 28% and 34% patients after
anticoagulation with enoxaparin and patients on unfractionated
heparin. Relative risk= 0.83, 95% CI=0.68-1.01, p=0.06).
The incidence of death (enoxaparin, 4% vs. heparin, 6% patients;

p=0.08), complication of myocardial infarction (4% vs. 6%; p=0.21),
procedure failure (26% vs. 28%; p=0.61), and major bleeding (5%
vs.5%; p=0.79) did not differ between groups.
Enoxaparin resulted in a significantly reduced rate of the main

secondary endpoint (7% vs 11% patients; relative risk =0.59, 95%
CI=0.38-0.91, p=0.015).
Conclusion(s) Intravenous enoxaparin compared with unfractionated heparin did
not significantly reduced the primary outcome (30-day incidence of
death, complication of myocardial infarction, procedure failure, or
major bleeding). Nevertheless, it reduced the secondary outcome
(composite of death, recurrent acute coronary syndrome, or urgent
revascularisation).
57
Acronym Minimizing Adverse Hemorrhagic Events by Transradial Access Site
and Systemic Implementation of Angiox (MATRIX)
Reference Valgimigli M, Frigoli E, Leonardi S, Rothenbühler M, Gagnor A, Calabrò
P, Garducci S, Rubartelli P, Briguori C, Andò G, Repetto A, Limbruno U,
Garbo R, Sganzerla P, Russo F, Lupi A, Cortese B, Ausiello A, Ierna S,
Esposito G, Presbitero P, Santarelli A, Sardella G, Varbella F, Tresoldi S,
de Cesare N, Rigattieri S, Zingarelli A, Tosi P, van 't Hof A, Boccuzzi G,
Omerovic E, Sabaté M, Heg D, Jüni P, Vranckx P; MATRIX Investigators.
Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N
Engl J Med. 2015 Sep 10;373(11):997-1009. doi:
10.1056/NEJMoa1507854. Epub 2015 Sep 1. PMID: 26324049.
Study Type MATRIX was a program of three randomized, multicenter, open-label
superiority trials involving patients with an acute coronary syndrome.
The first trial compared transradial access with transfemoral access in
8404 patients. In this study, they report the two other, nested trials,
which were conducted as additional randomized comparisons in
subgroups of patients.
Nº patients
7213 participants
Intervention In acute coronary syndrome for whom PCI was anticipated to receive
either bivalirudin or unfractionated heparin, patients in the bivalirudin
group were subsequently randomly assigned to receive or not to
receive a post-PCI bivalirudin infusion.
Main incl/excl Patients with NSTE-ACS were eligible if they had a history consistent
criteria with new or worsening cardiac ischemia, occurring while they were at
rest or with minimal activity within 7 days before randomization, and
met at least two high-risk criteria among the following: an age of 60
years or older, an elevation in cardiac biomarkers, or
electrocardiographic changes compatible with ischemia; and if they
were considered to be candidates for PCI after completion of coronary
angiography. Patients with STEMI were eligible if they presented
within 12 hours after the onset of symptoms or between 12 and 24
hours after symptom onset if there was evidence of continuing
ischemia or previous fibrinolytic treatment.
Relevant Primary outcomes for the comparison between bivalirudin and
outcome(s) heparin were the occurrence of MACE (a composite of death,
myocardial infarction, or stroke) and net adverse clinical events (a
composite of major bleeding or a major adverse cardiovascular event).

The primary outcome for the comparison of a post-PCI bivalirudin
infusion with no post-PCI infusion was a composite of urgent target-
vessel revascularization, definite stent thrombosis, or net adverse
clinical events.
Key findings The rate of MACE was not significantly lower with bivalirudin than
with heparin (10.3% and 10.9%, respectively; relative risk = 0.94; 95%
CI = 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical
events (11.2% and 12.4%, respectively; relative risk = 0.89; 95% CI =
0.78 to 1.03; P=0.12).
58
Post-PCI bivalirudin infusion, as compared with no infusion, did not
significantly decrease the rate of urgent target-vessel
revascularization, definite stent thrombosis, or net adverse clinical
events (11.0% and 11.9%, respectively; relative risk = 0.91; 95% CI =
0.74 to 1.11; P=0.34).
Conclusion(s) In patients with an acute coronary syndrome, there were no

differences in the rates of major adverse cardiovascular events and
net adverse clinical events between lower with bivalirudin and
unfractionated heparin. The rate of the composite of urgent target-
vessel revascularization, definite stent thrombosis, or net adverse
clinical events did not differ between post-PCI bivalirudin infusion and
no post-PCI infusion.
59
Acronym Acute Catheterization and Urgent Intervention Triage Strategy
(ACUITY) trial
Reference Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW,
White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier
AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH,
Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM; ACUITY
Investigators. Bivalirudin for patients with acute coronary syndromes.
N Engl J Med. 2006 Nov 23;355(21):2203-16. doi:
10.1056/NEJMoa062437. PMID: 17124018.
Study Type A prospective, open-label, randomized, multicenter trial
Details and Quality

of Evidence
Intervention Heparin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin plus a

glycoprotein IIb/IIIa inhibitor, or bivalirudin alone
Main incl/excl Patients with moderate- or high-risk acute coronary syndromes who
criteria were undergoing an early invasive strategy.
Relevant The primary end points were a composite ischemia end point (death,
outcome(s) myocardial infarction, or unplanned revascularization for ischemia),
major bleeding, and the net clinical outcome, defined as the
combination of composite ischemia or major bleeding.
Key findings Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with
heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with
noninferior 30-day rates of the composite ischemia end point (7.7%

vs. 7.3%, respectively), major bleeding (5.3% vs. 5.7%), and the net
clinical outcome end point (11.8% vs. 11.7%). Bivalirudin alone, as
compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was
associated with a noninferior rate of the composite ischemia end
point (7.8% vs. 7.3%, respectively; P=0.32; relative risk, 1.08; 95%
confidence interval [CI], 0.93 to 1.24) and significantly reduced rates
of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI,
0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%;
P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97).
Conclusion(s) In patients treated with glycoprotein IIb/IIIa inhibitors, bivalirudin was
associated with rates of ischemia and bleeding that were similar to
those with heparin. Bivalirudin alone was associated with similar rates
of ischemia and significantly lower rates of bleeding.
60
Acronym Ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial
Reference van 't Hof AW, Ernst N, de Boer MJ, de Winter R, Boersma E, Bunt T,
Petronio S, Marcel Gosselink AT, Jap W, Hollak F, Hoorntje JC,
Suryapranata H, Dambrink JH, Zijlstra F; On-TIME study group.
Facilitation of primary coronary angioplasty by early start of a
glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in
myocardial infarction evaluation (On-TIME) trial. Eur Heart J. 2004
May;25(10):837-46. doi: 10.1016/j.ehj.2004.04.003. PMID: 15140531.
Study Type Multicenter, double-blind, randomized controlled trial

Intervention Early, pre-hospital initiation of Tirofiban (Early) or to initiation in the
Evidence
catheterisation laboratory (Late).

Main incl/excl Patients with ST segment elevation myocardial infarction with the
criteria intention to perform primary percutaneous coronary intervention
Relevant The primary end-point was TIMI flow grade 3 of the infarct-related
outcome(s) vessel (IRV) at initial angiography.
Key findings At initial angiography, TIMI 3 flow was present in 19% the Early group
and in 15% in the Late group (⁠P=0.22P=0.22⁠).

The combined incidence of TIMI 2 or 3 flow was present in 43% in the
Early group and in 34% in the Late group, respectively (⁠P=0.04P=0.04⁠).
Thrombus or a fresh occlusion was present in 60% and 73% in the
Early and Late group, respectively (⁠P=0.002P=0.002⁠).
However, at one-year follow-up, the combined incidence of death or
recurrent MI was not different between the groups (7.0% vs.
.0%, P=0.99P=0.99⁠).
Conclusion(s) Early initiation of Tirofiban did not improve initial TIMI 3 flow of the
infarct related artery significantly.
61
Acronym VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in ST-Segment
and Non–ST-Segment Elevation Myocardial Infarction in Patients on
Modern Antiplatelet Therapy in the Swedish Web System for
Enhancement and Development of Evidence-based Care in Heart
Disease Evaluated according to Recommended Therapies Registry
Trial)
Reference Erlinge D, Omerovic E, Fröbert O, Linder R, Danielewicz M, Hamid M,
Swahn E, Henareh L, Wagner H, Hårdhammar P, Sjögren I, Stewart J,
Grimfjärd P, Jensen J, Aasa M, Robertsson L, Lindroos P, Haupt J,
Wikström H, Ulvenstam A, Bhiladvala P, Lindvall B, Lundin A, Tödt T,
Ioanes D, Råmunddal T, Kellerth T, Zagozdzon L, Götberg M,
Andersson J, Angerås O, Östlund O, Lagerqvist B, Held C, Wallentin L,
Scherstén F, Eriksson P, Koul S, James S. Bivalirudin versus Heparin
Monotherapy in Myocardial Infarction. N Engl J Med. 2017 Sep
21;377(12):1132-1142. doi: 10.1056/NEJMoa1706443. Epub 2017 Aug
27. PMID: 28844201.
Study Type Multicenter, randomized, registry-based, open-label clinical trial.
Nº patients
6006 patients (3005 with STEMI and 3001 with NSTEMI)

Intervention Bivalirudin or heparin during PCI, which was performed predominantly
Evidence
with the use of radial-artery access.

Main incl/excl Patients with either ST-segment elevation myocardial infarction
criteria (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and
receiving treatment with a potent P2Y12 inhibitor (ticagrelor,
prasugrel, or cangrelor) without the planned use of glycoprotein
IIb/IIIa inhibitors
Relevant The primary endpoint was a composite of death from any cause,
outcome(s) myocardial infarction, or major bleeding during 180 days of follow-up.
Key findings At 180 days, a primary endpoint event had occurred in 12.3% and
12.8% of the patients in the bivalirudin group and in the heparin group
(HR= 0.96; 95% CI = 0.83 to 1.10; P=0.54). The results were consistent
between patients with STEMI and those with NSTEMI and across other
major subgroups.
Conclusion(s) Among patients undergoing PCI for myocardial infarction, the rate of
the composite of death from any cause, myocardial infarction, or
major bleeding was not different among those who received
bivalirudin than among those who received heparin monotherapy.
62
Acronym Randomized Evaluation of Dual Antithrombotic Therapy with
Dabigatran versus Triple Therapy with Warfarin in Patients with
Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary
Intervention (RE-DUAL PCI) trial
Reference Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, Maeng M,
Merkely B, Zeymer U, Gropper S, Nordaby M, Kleine E, Harper R,
Manassie J, Januzzi JL, Ten Berg JM, Steg PG, Hohnloser SH; RE-DUAL
PCI Steering Committee and Investigators. Dual Antithrombotic
Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med.
2017 Oct 19;377(16):1513-1524. doi: 10.1056/NEJMoa1708454. Epub
2017 Aug 27. PMID: 28844193.
Study Type Randomised, multicentre, open-label, non-inferiority trial with
masked outcome evaluation
Nº patients
2725 participants
Intervention Dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor
(clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-
therapy groups) or warfarin plus a P2Y12 inhibitor (clopidogrel or
ticagrelor) and aspirin (for 1-3 months)
Main incl/excl Men and women who were at least 18 years of age were eligible for
criteria inclusion in the trial if they had nonvalvular atrial fibrillation and had
successfully undergone PCI with a bare-metal or drug-eluting stent
within the previous 120 hours. Key exclusion criteria were the
presence of bioprosthetic or mechanical heart valves, severe renal
insufficiency (creatinine clearance, <30 ml per minute), or other major
coexisting conditions.
Relevant Time to first occurrence of major or clinically relevant nonmajor
outcome(s) bleeding (CRnM) as defined by the International Society on
Thrombosis and Haemostasis (ISTH M or CRnM).

Key findings At 14 months (mean) ISTH Major or CRnM was 15.4% in the 110-mg
dual-therapy group (DAT) vs. 26.9% in the triple-therapy group
(TAT)(HR, 0.52; 95% CI, 0.42 to 0.63; P<0.001 for noninferiority;
P<0.001 for superiority) and 20.2% in the 150-mg DAT vs. as compared
with 25.7% in the corresponding TAT (HR, 0.72; 95% CI, 0.58 to 0.88;
P<0.001 for noninferiority).
Conclusion(s) The risk of bleeding was lower among those who received dual
therapy with dabigatran and a P2Y12 inhibitor than among those who
received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin.
63
Acronym An OPen-label, Randomized, Controlled, Multicenter Study ExplorIng
TwO TreatmeNt StratEgiEs (Rivaroxaban or Dose-Adjusted Oral
Vitamin K Antagonist Plus Dual Antiplatelet Therapy Followed by
Rivaroxaban Plus Low-dose Acetylsalicylic Acid) in Subjects With
Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention
(PIONEER AF-PCI)
Reference Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P,
Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y,
Lip GY, Cohen M, Husted S, Peterson ED, Fox KA. Prevention of
Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J
Med. 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594.
Epub 2016 Nov 14. PMID: 27959713.
Study Type International, multicenter, randomized, open-label trial.

Intervention Rivaroxaban 15 mg once daily plus a P2Y12 inhibitor for 12 months
(group 1), rivaroxaban 2.5 mg twice daily plus DAPT for 1, 6, or 12
months (group 2), or a dose-adjusted vitamin K antagonist (VKA) (once
daily) plus DAPT for 1, 6, or 12 months (group 3).
Main incl/excl Inclusion criteria:
criteria Systemic anticoagulation for atrial fibrillation and PCI with stenting
Key exclusion criteria: patients requiring oral anticoagulation for

established indications beyond atrial fibrillation, heart failure,
mechanical valves, pulmonary embolism or deep vein thrombosis
Relevant A composite of major bleeding or minor bleeding according to
outcome(s) Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding
requiring medical attention
Key findings Clinically significant bleeding were lower in the two groups receiving
rivaroxaban than in the group receiving standard therapy (16.8% in
group 1, 18.0% in group 2, and 26.7% in group 3; Hazard ratio (HR) for
group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76;
P<0.001; HR for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80;
P<0.001).
Conclusion(s) The administration of either low-dose rivaroxaban plus a P2Y12
inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1,
6, or 12 months was associated with a lower rate of clinically
significant bleeding than was standard therapy with a vitamin K
antagonist plus DAPT for 1, 6, or 12 months.
64
Acronym Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to
Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin
vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute
Coronary Syndrome and/or Percutaneous Coronary Intervention
(AUGUSTUS)
Reference Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R,
Goodman SG, Windecker S, Darius H, Li J, Averkov O, Bahit MC,
Berwanger O, Budaj A, Hijazi Z, Parkhomenko A, Sinnaeve P, Storey RF,
Thiele H, Vinereanu D, Granger CB, Alexander JH; AUGUSTUS
Investigators. Antithrombotic Therapy after Acute Coronary Syndrome
or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-
1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID:
30883055.
Study Type Prospective, multicenter, two-by-two factorial, randomized clinical
trial: open label (Apixaban vs. VKA), blinded (aspirin vs. placebo)
Nº patients 4614 participants from 33 countries

Intervention Apixaban 5mg twice daily vs dose adjusted VKA and Aspirin vs Aspirin-
Placebo
Main incl/excl Inclusion criteria:
criteria Patients with atrial fibrillation who had an acute coronary syndrome
or had undergone PCI and were planning to take a P2Y12 inhibitor to
receive apixaban or a vitamin K antagonist and to receive aspirin or
matching placebo for 6 months.

Relevant The primary safety outcome was clinically significant bleeding (a
outcome(s) composite of major bleeding or minor bleeding according to
Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding
requiring medical attention).

Key findings At 6 months ISTH Major or CRnM occurred in 10.5% of patients
receiving apixaban, vs. in 14.7% of those receiving VKA (HR ratio, 0.69;
95% CI, 0.58 to 0.81; P<0.001 for both noninferiority and superiority),
and in 16.1% of the patients receiving aspirin, vs. 9.0% of those
receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001).
Conclusion(s) An antithrombotic regimen that included apixaban and a P2Y(12)
inhibitor, without aspirin, resulted in less bleeding and fewer
hospitalizations without significant differences in the incidence of
ischemic events than regimens that included a vitamin K antagonist
and a P2Y(12) inhibitor, aspirin, or both.
65
Acronym Edoxaban Treatment vs Vitamin K Antagonist in Patients With Atrial
Fibrillation Undergoing Percutaneous Coronary Intervention
(ENTRUST-AF PCI)
Reference Vranckx P, Valgimigli M, Eckardt L, Tijssen J, Lewalter T, Gargiulo G,
Batushkin V, Campo G, Lysak Z, Vakaliuk I, Milewski K, Laeis P, Reimitz
PE, Smolnik R, Zierhut W, Goette A. Edoxaban-based versus vitamin K
antagonist-based antithrombotic regimen after successful coronary
stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a
randomised, open-label, phase 3b trial. Lancet. 2019 Oct
12;394(10206):1335-1343. doi: 10.1016/S0140-6736(19)31872-0.
Epub 2019 Sep 3. PMID: 31492505.
Study Type Randomised, multicentre, open-label, non-inferiority trial with
masked outcome evaluation

Intervention Edoxaban 60 mg once daily plus a P2Y12 inhibitor or VKA in
combination with a P2Y12 inhibitor and aspirin (100 mg once daily for
1-12months)
Main incl/excl Patients had atrial fibrillation requiring oral anticoagulation, were
criteria aged at least 18 years, and had a successful PCI for stable coronary
artery disease or acute coronary syndrome.
Patients with non-valvular atrial fibrillation not secondary to a
reversible disorder were included and patients with mechanical heart
valves, moderate-to-severe mitral stenosis, end-stage renal disease,
and other major comorbidities were excluded.
Relevant The primary endpoint was a composite of major or clinically relevant
outcome(s) non-major (CRNM) bleeding within 12 months.
Summary of Key
Key findings At 12 months ISTH Major or CRnM occurred 20.7% per year in the
findings
edoxaban-based regimen vs. 25.6% per year in the VKA-based

regimen; HR 0.83; 95% CI, 0.65–1.05; P=0.0010 for non-inferiority,
margin HR=1.20; P=0.1154 for superiority
Conclusion(s) The edoxaban-based regimen was non-inferior, but not superior, for
bleeding as compared to VKA-based regimen
66
Reference Gargiulo G, Goette A, Tijssen J, Eckardt L, Lewalter T, Vranckx P,
Valgimigli M. Safety and efficacy outcomes of double vs. triple
antithrombotic therapy in patients with atrial fibrillation following
percutaneous coronary intervention: a systematic review and meta-
analysis of non-vitamin K antagonist oral anticoagulant-based
randomized clinical trials. Eur Heart J. 2019 Dec 7;40(46):3757-3767.
doi: 10.1093/eurheartj/ehz732. PMID: 31651946.
Study Type Systematic review and meta-analysis of randomised clinical trials
Nº patients Four trials encompassing 10 234 patients (DAT = 5496 vs. TAT = 4738)
were included.
Intervention double vs. triple antithrombotic therapy (DAT vs. TAT) in patients with
atrial fibrillation (AF) and acute coronary syndrome or who underwent
percutaneous coronary intervention (PCI).
Main incl/excl A systematic review and meta-analysis was performed using PubMed
criteria to search for non-vitamin K antagonist oral anticoagulant (NOAC)-
based randomized clinical trials comparing DAT vs. TAT in AF patients
undergoing PCI.
Relevant The primary safety endpoint was ISTH major or clinically relevant non-
outcome(s) major bleeding.
Key findings The primary safety endpoint was significantly lower with DAT
compared with TAT (RR= 0.66, 95% CI= 0.56-0.78; P < 0.0001), which
was consistent across all available bleeding definitions. There was a
significant increase of stent thrombosis (RR= 1.59, 95% CI= 1.01-2.50;
P = 0.04) and a trend towards higher risk of myocardial infarction with
DAT. There were no significant differences in all-cause and
cardiovascular death, stroke and major adverse cardiovascular events.
Conclusion(s) Compared with TAT, DAT is associated with a reduction of the primary
safety endpoint (ISTH major or clinically relevant non-major
bleeding.), though it is also associated with a higher risk of stent
thrombosis.
67
Acronym Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to
Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin
vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute
Coronary Syndrome and/or Percutaneous Coronary Intervention
(AUGUSTUS)
Reference Windecker S, Lopes RD, Massaro T, Jones-Burton C, Granger CB,
Aronson R, Heizer G, Goodman SG, Darius H, Jones WS, Aschermann M,
Brieger D, Cura F, Engstrøm T, Fridrich V, Halvorsen S, Huber K, Kang HJ,
Leiva-Pons JL, Lewis BS, Malaga G, Meneveau N, Merkely B, Milicic D,
Morais J, Potpara TS, Raev D, Sabaté M, de Waha-Thiele S, Welsh RC,
Xavier D, Mehran R, Alexander JH; AUGUSTUS Investigators.
Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute
Coronary Syndrome Treated Medically or With Percutaneous Coronary
Intervention or Undergoing Elective Percutaneous Coronary
Intervention: Insights From the AUGUSTUS Trial. Circulation. 2019 Dec
Epub 2019 Sep 26. PMID: 31557056.
Study Type Substudy of the AUGUSTUS trial
Intervention Apixaban with vitamin K antagonists vs. aspirin with placebo in 3

prespecified subgroups: patients with ACS treated medically, patients
with ACS treated with PCI, and those undergoing elective PCI.
Main incl/excl Inclusion criteria if the AUGUSTUS trial:
criteria Patients with atrial fibrillation who had an acute coronary syndrome or
had undergone PCI and were planning to take a P2Y12 inhibitor to
receive apixaban or a vitamin K antagonist and to receive aspirin or
matching placebo for 6 months.

Relevant Bleeding, death and hospitalization, as well as death and ischemic
outcome(s) events.
Key findings Apixaban compared with vitamin K antagonist reduced International
Society on Thrombosis and Haemostasis major or clinically relevant
nonmajor bleeding in patients with ACS treated medically (HR= 0.44,

95% CI= 0.28-0.68), patients with ACS treated with PCI (HR= 0.68, 95%
CI= 0.52-0.89), and patients undergoing elective PCI (HR= 0.82, 95% CI=
0.64-1.04; Pinteraction=0.052) and reduced death or hospitalization in the
ACS treated medically (HR= 0.71, 95% CI= 0.54-0.92), ACS treated with
PCI (HR= 0.88, 95% CI= 0.74-1.06), and elective PCI (HR= 0.87, 95% CI=
0.72-1.04; Pinteraction=0.345) groups. Compared with vitamin K
antagonists, apixaban resulted in a similar effect on death and ischemic
events in the ACS treated medically, ACS treated with PCI, and elective
PCI groups (Pinteraction=0.356). Aspirin had a higher rate of bleeding than
did placebo in patients with ACS treated medically (HR= 1.49, 95% CI=
0.98-2.26), those with ACS treated with PCI (HR= 2.02, 95% CI= 1.53-
68
2.67]), and those undergoing elective PCI (HR= 1.91, 95% CI= 1.48-2.47;
Pinteraction=0.479). For the same comparison, there was no difference in
outcomes among the 3 groups for the composite of death or
hospitalization (Pinteraction=0.787) and death and ischemic events
(Pinteraction=0.710).
Conclusion(s) In this prespecified subgroup analyses, apixaban and a P2Y12 inhibitor
without aspirin provides superior safety and similar efficacy in patients
with AF who have ACS, whether managed medically or with PCI, and
those undergoing elective PCI compared with regimens that include
vitamin K antagonists, aspirin, or both.
69
Acronym Bivalirudin With Prolonged Full Dose Infusion Versus Heparin Alone
During Emergency PCI (BRIGHT-4)
Reference Li Y, Liang Z, Qin L, Wang M, Wang X, Zhang H, Liu Y, Li Y, Jia Z, Liu L,
Zhang H, Luo J, Dong S, Guo J, Zhu H, Li S, Zheng H, Liu L, Wu Y, Zhong
Y, Qiu M, Han Y, Stone GW. Bivalirudin plus a high-dose infusion versus
heparin monotherapy in patients with ST-segment elevation
myocardial infarction undergoing primary percutaneous coronary
intervention: a randomised trial. Lancet. 2022 Nov
26;400(10366):1847-1857. doi: 10.1016/S0140-6736(22)01999-7. Epub
2022 Nov 6. PMID: 36351459.
Study Type Investigator-initiated, open-label, randomised controlled trial
conducted at 87 clinical Chinese hospitals

Intervention
Evidence
Bivalirudin with a post-PCI high-dose infusion for 2–4 h vs.

unfractionated heparin monotherapy
Main incl/excl Patients with STEMI undergoing primary PCI within 48 h of symptom
criteria onset who had not received previous fibrinolytic therapy,
anticoagulants, or glycoprotein IIb/IIIa inhibitors. Radial artery access
was used in 93.1% 6008 patients.
Relevant The primary endpoint was a composite of all-cause mortality or
outcome(s) Bleeding Academic Research Consortium (BARC) types 3–5 bleeding at
30 days.
Key findings The primary endpoint occurred in 4.39% and 3.06% in the heparin
group and the bivalirudin group, respectively (difference=1.33%, 95%

CI=0.38–2.29%; HR=0.69, 95%=CI 0.53–0.91; p=0.0070). All-cause
mortality within 30 days occurred in 3.92%) and 2.96% in heparin-
assigned and bivalirudin-assigned patients, respectively (HR=0.75; 95%
CI=0.57–0.99; p=0.0420), and BARC types 3–5 bleeding occurred in
0.80% and 0.17% in heparin-assigned and bivalirudin-assigned patients
(HR=0.21; 95% CI=0.08–0.54; p=0.0014).
Conclusion(s) In patients with STEMI undergoing primary PCI (93% with radial artery
access), anticoagulation with bivalirudin plus a post-PCI high-dose
infusion for 2–4 h significantly reduced the 30-day composite rate of
all-cause mortality or BARC types 3–5 major bleeding compared with
heparin monotherapy
70
Recommendation Table 6 — Recommendations for alternative
antithrombotic therapy regimens
Acronym Atrial Fibrillation and Ischemic Events with Rivaroxaban in

Patients with Stable Coronary Artery Disease (AFIRE) trial
Reference Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M,
Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa
H; AFIRE Investigators. Antithrombotic Therapy for Atrial
Fibrillation with Stable Coronary Disease. N Engl J Med. 2019 Sep
19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143. Epub 2019
Sep 2. Erratum in: N Engl J Med. 2021 Oct 21;385(17):1632.
PMID: 31475793.
Study Type Multicenter, randomized, open-label, paralell-group trial conducted in
Japan
Nº patients 2236
Intervention Monotherapy with rivaroxaban (10 mg once daily for patients with a
creatinine clearance of 15 to 49 ml per minute or 15 mg once daily for

patients with a creatinine clearance of ≥50 ml per minute) or
combination therapy with rivaroxaban at the previously stated doses
plus an antiplatelet agent (either aspirin or a P2Y12 inhibitor,
according to the discretion of the treating physician).
Main incl/excl Inclusion: Men and women who were 20 years of age or older and had
criteria received a diagnosis of atrial fibrillation and stable coronary artery
disease: i.e., a history of PCI with or without stenting, at least 1 year
before enrollment; a history of angiographically confirmed coronary
artery disease (with stenosis of ≥50%) not requiring revascularization;
or a history of coronary-artery bypass grafting (CABG) at least 1 year
before enrollment.
Key exclusion criteria were a history of stent thrombosis, coexisting
active tumor, and poorly controlled hypertension
Relevant The primary efficacy end point was the composite of stroke, systemic
outcome(s) embolism, myocardial infarction, unstable angina requiring
revascularization, or death from any cause.
The primary safety end point was major bleeding, as defined

according to the criteria of the International Society on Thrombosis
and Hemostasis (ISTH)
Key findings The trial was stopped early because of increased mortality in the
combination therapy group
Rivaroxaban monotherapy was non-inferior to combination therapy

for the primary efficacy end point, with event rates of 4.14% vs. 5.75%
per patient year, respectively (HR, 0.72; 95% CI, 0.55 to 0.95; P<0.001
for noninferiority)
71
Rivaroxaban monotherapy was superior to combination therapy for
the primary safety end point, with event rates of 1.62% vs. 2.76% per
patient-year, respectively (HR 0.59; 95% CI, 0.39 to 0.89; P=0.01 for
superiority).
All-cause death: 1.9%/patient-year of the rivaroxaban monotherapy

group compared with 3.4%/patient-year of the
rivaroxaban/antiplatelet therapy group (p < 0.05) Cardiovascular
death: 1.2%/patient-year of the rivaroxaban monotherapy group
compared with 2.0%/patient-year of the rivaroxaban/antiplatelet
therapy group (p < 0.05)
Conclusion(s) Rivaroxaban monotherapy was noninferior to combination therapy for
efficacy and superior for safety in patients with atrial fibrillation and
stable coronary artery disease.
72
Acronym Dual Antiplatelet Therapy (DAPT) study
Reference Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG,
Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr,
Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt
KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study
Investigators. Twelve or 30 months of dual antiplatelet therapy after
drug-eluting stents. N Engl J Med. 2014 Dec 4;371(23):2155-66. doi:
Study Type A prospective, multicenter, randomized, double-blind trial
Intervention Patients were enrolled within 72 hours after placement of a stent and
were given open-label aspirin and thienopyridine for 12 months.
At 12 months, patients who had not had a major adverse
cardiovascular or cerebrovascular event, repeat revascularization, or
moderate or severe bleeding and had been adherent to
thienopyridine therapy (defined as having taken 80 to 120% of the
drug without an interruption of longer than 14 days) were eligible for
randomization:
continued thienopyridine therapy or to placebo for an additional 18
months (months 12 to 30 after enrollment).
Main incl/excl Patients who were candidates for dual antiplatelet therapy after
criteria treatment with FDA-approved drug-eluting or bare-metal stents.
Relevant The coprimary efficacy end points were the cumulative incidence of
outcome(s) definite or probable stent thrombosis (as assessed according to the
Academic Research Consortium definitions)
and major adverse cardiovascular and cerebrovascular events (a
composite of death, myocardial infarction, or stroke) during the
period from 12 to 30 months.
The primary safety end point was moderate or severe GUSTO
bleeding.
Key findings Continued treatment with thienopyridine, as compared with placebo,

reduced the rates of stent thrombosis (0.4% vs. 1.4%; HR, 0.29 [95%
CI, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and
cerebrovascular events (4.3% vs. 5.9%; HR, 0.71 [95% CI, 0.59 to 0.85];
P<0.001).
The rate of moderate or severe bleeding was increased with
continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001).
An elevated risk of stent thrombosis and myocardial infarction was
observed in both groups during the 3 months after discontinuation of
thienopyridine treatment.
Conclusion(s) Dual antiplatelet therapy beyond 1 year after placement of a drug-
eluting stent, as compared with aspirin therapy alone, significantly
reduced the risks of stent thrombosis and major adverse
cardiovascular and cerebrovascular events but was associated with an
increased risk of bleeding.
73
Acronym Prevention of Cardiovascular Events in Patients with Prior Heart
Attack Using Ticagrelor Compared to Placebo on a Background of
Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54)
trial
Reference Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC,
Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T,
Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss
RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS;
PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term
use of ticagrelor in patients with prior myocardial infarction. N Engl J
Med. 2015 May 7;372(19):1791-800. doi: 10.1056/NEJMoa1500857.
Epub 2015 Mar 14. PMID: 25773268.
Study Type Multicenter, randomized, double-blind, placebo-controlled clinical
trial
Nº patients N: 21162
Intervention Ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg
twice daily, or placebo.
Main incl/excl Patients with a spontaneous myocardial infarction 1-3 years before
criteria enrollment, and had one of the following additional high-risk features:
age of 65 years or older, diabetes mellitus requiring medication, a
second prior spontaneous myocardial infarction, multivessel coronary
artery disease, or chronic renal dysfunction, defined as an estimated
creatinine clearance of less than 60 ml per minute.
Relevant The primary efficacy end point was the composite of cardiovascular
outcome(s) death, myocardial infarction, or stroke. The primary safety end point
was Thrombolysis in Myocardial Infarction (TIMI) major bleeding.
Key findings The two ticagrelor doses each reduced, as compared with placebo:
the rate of the primary efficacy end point, with Kaplan–Meier rates at
3 years of 7.85% in the group that received 90 mg of ticagrelor twice

daily, 7.77% in the group that received 60 mg of ticagrelor twice daily,
and 9.04% in the placebo group (HR for 90 mg of ticagrelor vs.
placebo, 0.85; 95% CI, 0.75 to 0.96; P=0.008; HR for 60 mg of
ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004).
Rates of TIMI major bleeding were higher with ticagrelor (2.60% with
90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for
each dose vs. placebo).
Conclusion(s) In patients with a myocardial infarction more than 1 year previously,
treatment with ticagrelor significantly reduced the risk of
cardiovascular death, myocardial infarction, or stroke and increased
the risk of major bleeding.
74
Acronym Cardiovascular Outcomes for People Using Anticoagulation
Strategies (COMPASS)
Reference Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F,
Metsarinne K, O'Donnell M, Dans AL, Ha JW, Parkhomenko AN,
Avezum AA, Lonn E, Lisheng L, Torp-Pedersen C, Widimsky P, Maggioni
AP, Felix C, Keltai K, Hori M, Yusoff K, Guzik TJ, Bhatt DL, Branch KRH,
Cook Bruns N, Berkowitz SD, Anand SS, Varigos JD, Fox KAA, Yusuf S;
COMPASS investigators. Rivaroxaban with or without aspirin in
patients with stable coronary artery disease: an international,
randomised, double-blind, placebo-controlled trial. Lancet. 2018 Jan
20;391(10117):205-218. doi: 10.1016/S0140-6736(17)32458-3. Epub
2017 Nov 10. Erratum in: Lancet. 2017 Dec 21;: PMID: 29132879.
Study Type An international, multicentre, double-blind, placebo controlled,
double-dummy, randomized trial using a 3-by-2 partial factorial design
Intervention After a 14-day run in phase to identify participants who were unwilling
or unable to adhere to the trial regimen.
Rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), or
rivaroxaban (5 mg twice daily) with an aspirin-matched placebo once
daily, or aspirin (100 mg once daily) with a rivaroxaban-matched

placebo twice daily. Patients who were eligible for the proton-pump
inhibitor randomization were also randomly assigned in a 1:1 ratio to
receive pantoprazole (40 mg once daily) or matched placebo.
Main incl/excl Patients with a diagnosis of coronary artery disease: myocardial
criteria infarction within 20 years, multi-vessel coronary artery disease,
history of stable or unstable angina, previous multi-vessel
percutaneous coronary intervention, or previous multi-vessel
coronary artery bypass graft surgery. Patients also needed to be aged
at least 65 years, to have documented atherosclerosis or
revascularisation in an additional vascular bed (carotid or peripheral),
or needed to have at least two of the following risk factors: current
smoker or quit within 1 year of randomisation, diabetes mellitus,
estimated glomerular filtration rate (eGFR) of less than 60 mL/min,
heart failure, or non-lacunar ischemic stroke at least 1 month before
randomisation.
Relevant The primary outcome of the COMPASS trial was the occurrence of
outcome(s) myocardial infarction, stroke, or cardiovascular death.
Key findings The primary outcome occurred in [4%] in the rivaroxaban-plus-aspirin

group e vs 6% in the aspirin alone group, HR 0.74, 95% CI 0.65–0.86,
p<0.0001). Treatment with rivaroxaban alone did not significantly
improve the primary outcome when compared with treatment with
aspirin alone ( [5%] vs [6%]; HR 0.89, 95% CI 0.78–1.02, p=0.094).
Combined rivaroxaban plus aspirin treatment resulted in more major
bleeds than treatment with aspirin alone: 3% vs 2%; HR 1.66, 95% CI
1.37–2.03, p<0.0001), and more bleeds were seen in the rivaroxaban
alone group than in the aspirin alone group: 3% vs 2%; HR 1.51, 95%
CI 1.23–1.84, p<0.0001). Rivaroxaban plus aspirin reduced mortality
75
when compared with aspirin alone: 3% vs 4%; HR 0.77, 95% CI 0.65–
0.90, p=0.0012).
Conclusion(s) Addition of rivaroxaban to aspirin has the potential to substantially
reduce morbidity and mortality from coronary artery disease
76
Acronym Cardiovascular Outcomes for People Using Anticoagulation
Strategies (COMPASS)
Reference Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG,
Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P,
Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu
J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK,
Fox KAA, Parkhomenko AN, Ertl G, Störk S, Keltai M, Ryden L,
Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik
TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C,
Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E,
Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or
without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017
Oct 5;377(14):1319-1330. doi: 10.1056/NEJMoa1709118. Epub 2017
Aug 27. PMID: 28844192.
Study Type An international, multicentre, double-blind, placebo controlled,
double-dummy, randomized trial using a 3-by-2 partial factorial design
Intervention After a 14-day run in phase to identify participants who were unwilling
or unable to adhere to the trial regimen.

Rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), or
rivaroxaban (5 mg twice daily) with an aspirin-matched placebo once
daily, or aspirin (100 mg once daily) with a rivaroxaban-matched
placebo twice daily. Patients who were eligible for the proton-pump
inhibitor randomization were also randomly assigned in a 1:1 ratio to
receive pantoprazole (40 mg once daily) or matched placebo.
Main incl/excl Patients with a history of stable atherosclerotic vascular disease.
criteria Patients with coronary artery disease who were younger than 65 years
of age were also required to have documentation of atherosclerosis
involving at least two vascular beds or to have at least two additional
risk factors (current smoking, diabetes mellitus, an estimated
glomerular filtration rate [GFR] <60 ml per minute, heart failure, or
nonlacunar ischemic stroke ≥1 month earlier).
Relevant The primary outcome was a composite of cardiovascular death,
outcome(s) stroke, or myocardial infarction.
Key findings The study was stopped prematurely for superiority of the rivaroxaban-
plus-aspirin group after a mean follow-up of 23 months.

The primary outcome occurred in 4.1% of patients in the rivaroxaban-
plus-aspirin group vs. 5.4% in the aspirin alone group; HR, 0.76; 95%
CI, 0.66 to 0.86; P<0.001; z=−4.126), major bleeding events occurred
in 3.1% the rivaroxaban-plus-aspirin group vs. 1.9% in the aspirin
alone group; HR, 1.70; 95% CI, 1.40 to 2.05; P<0.001. There were 3.4%
deaths in the rivaroxaban-plus-aspirin group as compared with 4.1% in
the aspirin-alone group (HR, 0.82; 95% CI, 0.71 to 0.96; P=0.01;
threshold P value for significance, 0.0025).
The primary outcome did not occur in significantly fewer patients in
the rivaroxaban-alone group than in the aspirin-alone group, but
77
major bleeding events occurred in more patients in the rivaroxaban-
alone group.
Conclusion(s) Rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular
outcomes and more major bleeding events than those assigned to
aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in
better cardiovascular outcomes than aspirin alone and resulted in
more major bleeding events.
78
Acronym Study of Platelet Inhibition and Patient Outcomes (PLATO)
Reference Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C,
Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene
A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A,
Thorsén M. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi:
Study Type A multicenter, randomized, double-blind trial
Intervention Aspirin (50-100mg) in combination with Ticagrelor was given in a
loading dose of 180 mg followed by a dose of 90 mg twice daily, or
clopidogrel 300-mg loading dose followed by a dose of 75 mg daily.
Main incl/excl Patients with an acute coronary syndrome, with or without ST-
criteria segment elevation, with an onset of symptoms during the previous 24
hours.
For patients who had an acute coronary syndrome without ST-
segment elevation, at least two of the following three criteria had to
be met: ST-segment changes on electrocardiography, indicating
ischemia; a positive test of a biomarker, indicating myocardial
necrosis; or one of several risk factors (age ≥60 years; previous
myocardial infarction or coronary-artery bypass grafting [CABG];
coronary artery disease with stenosis of ≥50% in at least two vessels;
previous ischemic stroke, transient ischemic attack, carotid stenosis of
at least 50%, or cerebral revascularization; diabetes mellitus;
peripheral arterial disease; or chronic renal dysfunction, defined as a
creatinine clearance of <60 ml per minute per 1.73 m2 of body-surface
area).
Relevant The primary end point was a composite of death from vascular causes,
outcome(s) myocardial infarction, or stroke.
Key findings The primary end point occurred in 9.8% of patients receiving
ticagrelor as compared with 11.7% of those receiving clopidogrel (HR,
0.84; 95% CI, 0.77 to 0.92; P<0.001).
The rate of death from any cause was reduced with ticagrelor (4.5%,
vs. 5.9% with clopidogrel; P<0.001).
No significant difference in the rates of major bleeding was found
between the ticagrelor and clopidogrel groups (11.6% and 11.2%,
respectively; P=0.43), but ticagrelor was associated with a higher rate
of major bleeding not related to coronary-artery bypass grafting (4.5%
vs. 3.8%, P=0.03), including more instances of fatal intracranial
bleeding and fewer of fatal bleeding of other types.
Conclusion(s) Ticagrelor as compared with clopidogrel significantly reduced the rate
of death from vascular causes, myocardial infarction, or stroke
without an increase in the rate of overall major bleeding but with an
increase in the rate of non–procedure-related bleeding
79
Acronym Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated
With Pharmacological Thrombolysis (TREAT)
Reference Berwanger O, Lopes RD, Moia DDF, Fonseca FA, Jiang L, Goodman SG,
Nicholls SJ, Parkhomenko A, Averkov O, Tajer C, Malaga G, Saraiva JFK,
Guimaraes HP, de Barros E Silva PGM, Damiani LP, Santos RHN, Paisani
DM, Miranda TA, Valeis N, Piegas LS, Granger CB, White HD, Nicolau
JC. Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With
Fibrinolysis: TREAT Trial. J Am Coll Cardiol. 2019 Jun 11;73(22):2819-
2828. doi: 10.1016/j.jacc.2019.03.011. Epub 2019 Mar 18. PMID:
30898608.
Study Type International, multicenter, randomized, open-label with blinded
endpoint adjudication trial

Evidence
Intervention Ticagrelor with a loading dose of 180 mg or clopidogrel (with a loading

dose of 300 to 600 mg) as early as possible after the index event and
not >24 h post-event.
Main incl/excl Patients with ST segment elevation myocardial infarction < 24 h of the
criteria onset of symptoms, <75 years of age, and following fibrinolytic
therapy
Relevant 1st Composite of cardiovascular mortality, myocardial infarction, or
outcome(s) stroke, at 12 months.
2nd composite: The same composite outcome with the addition of
severe recurrent ischemia, transient ischemic attack, at 12 months.

Key findings 1st composite occurred in 6.7% receiving ticagrelor and 7.3% receiving
clopidogrel (HR: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53).
2nd composite occurred in 8.0% treated with ticagrelor and 9.1%
receiving clopidogrel (HR: 0.88; 95% CI: 0.71 to 1.09; p = 0.25).
The rates of major, fatal, and intracranial bleeding were similar
between the ticagrelor and clopidogrel groups.
Conclusion(s) Among patients age <75 years with STEMI and treated with
fibrinolysis, administration of ticagrelor did not significantly reduce
the frequency of cardiovascular events when compared with
clopidogrel.
80
Acronym Ticagrelor in CABG (TiCAB) trial
Reference Schunkert H, Boening A, von Scheidt M, Lanig C, Gusmini F, de Waha
A, Kuna C, Fach A, Grothusen C, Oberhoffer M, Knosalla C, Walther T,
Danner BC, Misfeld M, Zeymer U, Wimmer-Greinecker G, Siepe M,
Grubitzsch H, Joost A, Schaefer A, Conradi L, Cremer J, Hamm C, Lange
R, Radke PW, Schulz R, Laufer G, Grieshaber P, Pader P, Attmann T,
Schmoeckel M, Meyer A, Ziegelhöffer T, Hambrecht R, Kastrati A,
Sandner SE. Randomized trial of ticagrelor vs. aspirin in patients after
coronary artery bypass grafting: the TiCAB trial. Eur Heart J. 2019 Aug
1;40(29):2432-2440. doi: 10.1093/eurheartj/ehz185. PMID: 31145798.
Study Type Investigator-initiated randomized, double-blind, parallel grouped, and
placebo-controlled phase III trial.
Nº patients 1859 out of 3850 planned patients.

Evidence
The trial was prematurely halted because of slow recruitment

Intervention Ticagrelor 90 mg twice daily or 100 mg aspirin (1:1) once daily
Main incl/excl Patients with an acute coronary syndrome or stable coronary artery
criteria disease [including three-vessel coronary disease or left main stenosis
or two-vessel disease with impaired left ventricular function (<50%)]
who were scheduled for CABG.
Relevant The primary endpoint was a composite of cardiovascular death,
outcome(s) myocardial infarction (MI), repeat revascularization, and stroke 12
months after CABG
The main safety endpoint was BARC ≥4 for periprocedural and

hospital stay-related bleedings and BARC ≥3 for post-discharge
bleedings
Key findings 12 months after CABG, the primary endpoint occurred in 9.7% in the
ticagrelor group and in 8.2% in the aspirin group [HR 1.19; 95% CI
0.87–1.62; P = 0.28]. The main safety endpoint was also not
significantly different (ticagrelor 3.7% vs. aspirin 3.2%, hazard ratio
1.17, CI 0.71–1.92; P = 0.53).
Conclusion(s) In this prematurely terminated and thus underpowered randomized
trial of ticagrelor vs. aspirin in patients after CABG no significant
differences in major cardiovascular events or major bleeding could be
demonstrated.
81
Acronym Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent
EveNTs/Optimal Antiplatelet Strategy for InterventionS (CURRENT-
OASIS 7)
Reference Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB,
Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG,
Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani
AE, White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S; CURRENT-OASIS
7 trial investigators. Double-dose versus standard-dose clopidogrel
and high-dose versus low-dose aspirin in individuals undergoing
percutaneous coronary intervention for acute coronary syndromes
(CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010 Oct
9;376(9748):1233-43. doi: 10.1016/S0140-6736(10)61088-4. PMID:
20817281.
Study Type International, multicenter 2×2 factorial trial
Nº patients
25086 participants
Intervention Double-dose clopidogrel ( 600 mg loading dose on day 1 followed by
150 mg once daily on days 2–7), or standard-dose clopidogrel ( 300
mg loading dose on day 1 followed by 75 mg once daily on days 2–7).
On days 8–30, both groups received 75 mg once daily.
On days 2–30, patients randomly allocated low-dose aspirin : 75–100
mg daily, or high-dose aspirin: 300–325 mg daily.
Main incl/excl Patients with acute coronary syndromes (with or without ST-segment
criteria elevation) and either electrocardiographic evidence of ischaemia or
raised biomarkers, and coronary angiography with intent to undergo
PCI as early as possible, but no later than 72 h after randomisation.
Relevant The primary outcome was cardiovascular death, myocardial infarction,
outcome(s) or stroke at 30 days.
Key findings Compared with the standard dose, double-dose clopidogrel reduced
the rate of the primary outcome 3,9% vs 4,5%; adjusted HR 0.86, 95%
CI 0.74–0.99, p=0.039
High-dose and low-dose aspirin did not differ for the primary outcome
4,1% vs 4,2%; 0.98, 0.84–1.13, p=0.76.
Major bleeding was more common with double-dose than with
standard-dose clopidogrel 1,6% vs 1,1%; 1,41, 1,09–1,83, p=0.009)
and did not differ between high-dose and low-dose aspirin
1,5% vs 1,3%; 1,18, 0.92–1.53, p=0.20.
Conclusion(s) A double-dose clopidogrel regimen can be considered for all patients
with acute coronary syndromes treated with an early invasive strategy
and intended early PCI.
82
Acronym timing of platelet inhibition after acute coronary syndrome (TOPIC)
Reference Cuisset T, Deharo P, Quilici J, Johnson TW, Deffarges S, Bassez C,
Bonnet G, Fourcade L, Mouret JP, Lambert M, Verdier V, Morange PE,
Alessi MC, Bonnet JL. Benefit of switching dual antiplatelet therapy
after acute coronary syndrome: the TOPIC (timing of platelet
inhibition after acute coronary syndrome) randomized study. Eur
Heart J. 2017 Nov 1;38(41):3070-3078. doi:
10.1093/eurheartj/ehx175. PMID: 28510646.
Study Type Open-label, single centre, randomized, controlled trial
Intervention One month after the ACS, Aspirin 75 mg plus clopidogrel 75 mg

(switched DAPT), or continuation of aspirin plus continuation of
Evidence
newer P2Y12 blocker (unchanged DAPT with same treatment than

before randomization).
Main incl/excl Admission for an acute coronary syndrome ACS requiring
criteria percutaneous coronary intervention (PCI) < 72 h, treatment with
aspirin and a newer P2Y12 blocker at discharge, no major adverse
event one month after the ACS.
Relevant The primary outcome was a composite of cardiovascular death,
outcome(s) urgent revascularization, stroke and bleeding as defined by the
Bleeding Academic Research Consortium (BARC) classification ≥2 at 1
year post ACS.

Key findings The primary endpoint occurred in 13.4% patients in the switched
DAPT group vs. 26.3% patients in the unchanged DAPT (HR 95%CI 0.48
(0.34–0.68), P < 0.01).
No significant differences were reported on ischaemic endpoints,
while BARC ≥ 2 bleeding occurred in 13 (4.0%) patients in the
switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR
95%CI 0.30 (0.18–0.50), P < 0.01).
Conclusion(s) A switched DAPT is superior to an unchanged DAPT strategy to
prevent bleeding complications without increase in ischaemic events
following ACS.
83
Acronym Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet
Treatment For Acute Coronary Syndromes Trial (TROPICAL-ACS)
Reference Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, Orban
M, Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Dézsi CA, Holdt L,
Felix SB, Parma R, Klopotowski M, Schwinger RHG, Rieber J, Huber K,
Neumann FJ, Koltowski L, Mehilli J, Huczek Z, Massberg S; TROPICAL-
ACS Investigators. Guided de-escalation of antiplatelet treatment in
patients with acute coronary syndrome undergoing percutaneous
coronary intervention (TROPICAL-ACS): a randomised, open-label,
multicentre trial. Lancet. 2017 Oct 14;390(10104):1747-1757. doi:
10.1016/S0140-6736(17)32155-4. Epub 2017 Aug 28. PMID:
28855078.
Study Type International, multicenter, investigator-initiated, randomised, open-
label, assessor-blinded, trial

Intervention Prasugrel for 12 months (control group), or a step-down regimen (1
Evidence
week prasugrel followed by 1 week clopidogrel and Platelet Function

Test-guided maintenance therapy with clopidogrel or prasugrel from
day 14 after hospital discharge; guided de-escalation group)
Main incl/excl Patients with biomarker-positive acute coronary syndrome with
criteria successful percutaneous coronary intervention (PCI) and a planned
duration of dual antiplatelet treatment of 12 months
Relevant The primary endpoint was net clinical benefit (cardiovascular death,
outcome(s) myocardial infarction, stroke or bleeding grade 2 or higher according
to Bleeding Academic Research Consortium [BARC]) criteria) 1 year
after randomisation (non-inferiority hypothesis; margin of 30%).

Key findings The primary endpoint occurred in 7% in the guided de-escalation
group and in 9%in the control group (pnon-inferiority=0.0004; HR 0.81
[95% CI 0.62–1.06], psuperiority=0.12). MACCE (cardiovascular death,
myocardial infarction, or stroke): 3% in the de-escalation group vs. 3%
in the control group; pnon-inferiority=0.0115). BARC 2 or higher bleeding
events: 5% in the de-escalation group vs. 6% in the control group (HR
0.82 [95% CI 0.59–1.13]; p=0.23).
Conclusion(s) Guided de-escalation of antiplatelet treatment was non-inferior to
standard treatment with prasugrel at 1 year after PCI in terms of net
clinical benefit.
84
Acronym Tailored Antiplatelet Therapy Following PCI (TAILOR-PCI)
Reference Pereira NL, Farkouh ME, So D, Lennon R, Geller N, Mathew V, Bell M,
Bae JH, Jeong MH, Chavez I, Gordon P, Abbott JD, Cagin C, Baudhuin L,
Fu YP, Goodman SG, Hasan A, Iturriaga E, Lerman A, Sidhu M, Tanguay
JF, Wang L, Weinshilboum R, Welsh R, Rosenberg Y, Bailey K, Rihal C.
Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs
Conventional Clopidogrel Therapy on Ischemic Outcomes After
Percutaneous Coronary Intervention: The TAILOR-PCI Randomized
Clinical Trial. JAMA. 2020 Aug 25;324(8):761-771. doi:
10.1001/jama.2020.12443. PMID: 32840598.
Study Type Open-label randomized clinical trial
Intervention A genotype-guided therapy group using point-of-care genotyping, or

conventional therapy group without prospective genotyping.
In the genotype-guided group, those identified as
having CYP2C19*2 or *3 LOF alleles (CYP2C19 LOF carriers) were
prescribed ticagrelor for maintenance therapy, and noncarriers or
those with inconclusive results were prescribed clopidogrel;
In the conventional therapy group all patients were prescribed
clopidogrel according to drug label instructions. Prasugrel was
recommended as an alternative for patients who did not tolerate
ticagrelor. All patients received aspirin (81 mg).
Main incl/excl Patients undergoing PCI for acute coronary syndromes (ACS) or stable
criteria coronary artery disease (CAD).
Relevant The primary end point was a composite of cardiovascular death,
outcome(s) myocardial infarction, stroke, stent thrombosis, and severe recurrent
ischemia at 12 months.
Key findings The primary end point occurred in 4% of CYP2C19 LOF carriers in the
genotype-guided therapy group and 5.9% in the conventional therapy
group at 12 months HR, 0.66 [95% CI, 0.43-1.02]; P = .06). Among all
randomized patients, the primary end point occurred in 0.4% in the
genotype-guided group vs. 5.3% in the conventional group (HR, 0.84
[95% CI, 0.65-1.07]; P = .16).
Conclusion(s) Among patients with CYP2C19 loss-of-function alleles who underwent
PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared
with conventional clopidogrel therapy, did not significantly reduce
ischemic events
85
Acronym Cost-effectiveness of Genotype Guided Treatment With Antiplatelet
Drugs in STEMI Patients: Optimization of Treatment (POPular
Genetics)
Reference Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, van 't Hof
AWJ, van der Harst P, Barbato E, Morisco C, Tjon Joe Gin RM,
Asselbergs FW, Mosterd A, Herrman JR, Dewilde WJM, Janssen PWA,
Kelder JC, Postma MJ, de Boer A, Boersma C, Deneer VHM, Ten Berg
JM. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary
PCI. N Engl J Med. 2019 Oct 24;381(17):1621-1631. doi:
Study Type A randomized, open-label, assessor-blinded trial
Intervention P2Y12 inhibitor on the basis of early CYP2C19 genetic testing

(genotype-guided group), or standard treatment with either ticagrelor
Evidence
or prasugrel (standard-treatment group) for 12 months. In the

genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-
function alleles received ticagrelor or prasugrel, and noncarriers
received clopidogrel.
Main incl/excl Patients undergoing primary PCI with stent implantation
criteria
Relevant The two primary outcomes were net adverse clinical events: death
outcome(s) from any cause, myocardial infarction, definite stent thrombosis,
stroke, or major bleeding defined according to Platelet Inhibition and
Patient Outcomes (PLATO) criteria — at 12 months (primary combined
outcome; tested for noninferiority, with a noninferiority margin of 2
percentage points for the absolute difference)
PLATO major or minor bleeding at 12 months (primary bleeding

outcome).
Key findings The primary combined outcome occurred in 5.1% in the genotype-
guided group vs. 5.9% in the standard-treatment group (absolute
difference, −0.7 percentage points; 95% CI, −2.0 to 0.7; P<0.001 for
noninferiority).
The primary bleeding outcome occurred in 9.8% in the genotype-
guided group and in 12.5% in the standard-treatment group (hazard
ratio, 0.78; 95% CI, 0.61 to 0.98; P=0.04).
Conclusion(s) CYP2C19 genotype–guided strategy for selection of oral P2Y12 inhibitor
therapy was noninferior to standard treatment with ticagrelor or
prasugrel at 12 months with respect to thrombotic events and
resulted in a lower incidence of bleeding.
86
Acronym TicAgrelor Versus CLOpidogrel in Stabilized Patients With Acute
Myocardial Infarction (TALOS-AMI) trial
Reference Kim CJ, Park MW, Kim MC, Choo EH, Hwang BH, Lee KY, Choi YS, Kim
HY, Yoo KD, Jeon DS, Shin ES, Jeong YH, Seung KB, Jeong MH, Yim HW,
Ahn Y, Chang K; TALOS-AMI investigators. Unguided de-escalation
from ticagrelor to clopidogrel in stabilised patients with acute
myocardial infarction undergoing percutaneous coronary intervention
(TALOS-AMI): an investigator-initiated, open-label, multicentre, non-
inferiority, randomised trial. Lancet. 2021 Oct 9;398(10308):1305-
1316. doi: 10.1016/S0140-6736(21)01445-8. PMID: 34627490.
Study Type Open-label, assessor-masked, multicentre, non-inferiority,
randomised trial in South Korea

Evidence
Intervention Unguided de-escalation (clopidogrel, without a loading dose, plus

aspirin), or active control (ticagrelor plus aspirin) group.
Main incl/excl Patients with acute myocardial infarction who had no major
criteria ischaemic or bleeding events and tolerated aspirin plus ticagrelor
therapy during the first month after an index PCI
outcome(s) myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to
Bleeding Academic Research Consortium (BARC) criteria from 1 to 12
months.
Key findings At 12 months, the primary endpoints occurred in 4,6% in the de-
escalation group vs. 8.2% in patients in the active control group (pnon-
inferiority<0.001; HR 0.55 [95% CI 0.40–0.76], psuperiority=0.0001). There
was no significant difference in MACCE ( cardiovascular death,
myocardial infarction, or stroke): 2,1% in the de-escalation vs. 3,1%
the active control group (3.1%; HR 0.69; 95% CI 0.42–1.14, p=0.15).
Composite of BARC 2, 3, or 5 bleeding: 3.0% in the de-escalation
group vs 5.6% in the active control group, HR 0.52; 95% CI 0.35–0.77,
p=0.0012.
Conclusion(s) A uniform unguided de-escalation antiplatelet strategy switching from
ticagrelor to clopidogrel was superior to the ticagrelor-based DAPT
strategy at preventing net adverse clinical events, including the
thrombotic composite and clinically relevant bleeding.
87
Acronym Dual antiplatelet therapy after drug-eluting stent implantation in ST-
elevation myocardial infarction (DAPT-STEMI)
Reference Kedhi E, Fabris E, van der Ent M, Buszman P, von Birgelen C, Roolvink
V, Zurakowski A, Schotborgh CE, Hoorntje JCA, Eek CH, Cook S, Togni
M, Meuwissen M, van Royen N, van Vliet R, Wedel H, Delewi R,
Zijlstra F. Six months versus 12 months dual antiplatelet therapy after
drug-eluting stent implantation in ST-elevation myocardial infarction
(DAPT-STEMI): randomised, multicentre, non-inferiority trial. BMJ.
2018 Oct 2;363:k3793. doi: 10.1136/bmj.k3793. PMID: 30279197.
Study Type Prospective, randomised, multicentred, open label, non-inferiority
trial
Evidence
Intervention Single antiplatelet therapy (SAPT) (ie, aspirin only) or to DAPT for an
additional six months.
Main incl/excl Patients with STEMI aged 18 to 85 that underwent a primary PCI with
criteria the implantation of second generation drug-eluting stents were
eligible if they were event-free at six months after primary PCI.
Relevant The primary endpoint was a composite of all cause mortality, any
outcome(s) myocardial infarction, any revascularisation, stroke, and thrombolysis
in myocardial infarction major bleeding at 18 months after
randomisation.
Key findings The primary endpoint occurred in 4.8% and 6.6% of patients receiving
SAPT versus those receiving DAPT (HR= 0.73, 95% CI = 0.41 to 1.27,
P=0.26). Non-inferiority was met (P=0.004 for non-inferiority), as the
upper 95% confidence interval of 1.27 was smaller than the
prespecified non-inferiority margin of 1.66.
Conclusion(s) DAPT to six months was non-inferior to DAPT for 12 months in

patients with event-free STEMI at six months after primary PCI with
second generation drug-eluting stents.
88
Acronym Smart Angioplasty Research Team: Comparison Between P2Y12
Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients
Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-
CHOICE) trial
Reference Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, Im ES, Jeong JO,
Cho BR, Oh SK, Yun KH, Cho DK, Lee JY, Koh YY, Bae JW, Choi JW, Lee
WS, Yoon HJ, Lee SU, Cho JH, Choi WG, Rha SW, Lee JM, Park TK, Yang
JH, Choi JH, Choi SH, Lee SH, Gwon HC; SMART-CHOICE Investigators.
Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy
on Cardiovascular Events in Patients Undergoing Percutaneous
Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial.
JAMA. 2019 Jun 25;321(24):2428-2437. doi: 10.1001/jama.2019.8146.
Erratum in: JAMA. 2019 Oct 1;322(13):1316. PMID: 31237645.
Study Type Investigator-initiated, multicenter, open-label, noninferiority,
randomized study in Korea.

Evidence
Intervention P2Y12 inhibitor monotherapy group (aspirin plus a P2Y12 inhibitor for
3 months and thereafter a P2Y12 inhibitor alone) or to the DAPT
group (aspirin plus a P2Y12 inhibitor for at least 12 months)
Main incl/excl Patients following percutaneous coronary intervention with drug
criteria eluting stent implantation
Relevant The primary end point was major adverse cardiac and cerebrovascular
outcome(s) events (a composite of all-cause death, myocardial infarction, or
stroke) at 12 months after the index procedure. The noninferiority
margin was 1.8%.

Key findings At 12 months, the primary outcome occurred in 2.9% of patients in
the P2Y12 inhibitor monotherapy group and 2.5% in patients in the
DAPT group (difference, 0.4% [1-sided 95% CI, –∞% to 1.3%]; P = .007
for noninferiority).
The rate of bleeding was significantly lower in the P2Y12 inhibitor
monotherapy group than in the DAPT group (2.0% vs 3.4%; HR, 0.58;
95% CI, 0.36-0.92; P = .02).
Conclusion(s) P2Y12 inhibitor monotherapy after a short duration of DAPT resulted
in a noninferior rate of major cardiovascular events compared with
prolonged DAPT
89
Reference Valgimigli M, Gragnano F, Branca M, Franzone A, Baber U, Jang Y,
Kimura T, Hahn JY, Zhao Q, Windecker S, Gibson CM, Kim BK,
Watanabe H, Song YB, Zhu Y, Vranckx P, Mehta S, Hong SJ, Ando K,
Gwon HC, Serruys PW, Dangas GD, McFadden EP, Angiolillo DJ, Heg D,
Jüni P, Mehran R. P2Y12 inhibitor monotherapy or dual antiplatelet
therapy after coronary revascularisation: individual patient level
meta-analysis of randomised controlled trials. BMJ. 2021 Jun
16;373:n1332. doi: 10.1136/bmj.n1332. Erratum in: BMJ. 2022 Jan
27;376:o239. PMID: 34135011.
Study Type Individual patient level meta-analysis of six randomized controlled
trials
Nº patients 24 096 patients.
Evidence
Intervention P2Y12 monotherapy vs. DAPT after percutaneous or surgical

revascularization for stable or unstable coronary artery disease.
Main incl/excl Trials recruiting patients with a concomitant indication for oral
criteria anticoagulation were excluded.
Relevant The pre-specified primary efficacy endpoint was the composite of all
outcome(s) cause death, myocardial infarction, and stroke throughout the
duration of the randomized comparison of protocol mandated P2Y12
inhibitor monotherapy versus DAPT. The key safety endpoint was
Bleeding Academic Research Consortium (BARC) type 3 or type 5
bleeding.
Key findings The primary outcome occurred in 2.95% and 3.27% patients with
P2Y12 inhibitor monotherapy and DAPT in the per protocol
population, respectively (HR=0.93, 95% CI = 0.79 to 1.09; P=0.005 for
non-inferiority; P=0.38 for superiority) and in 2.94%and 3.36% with
P2Y12 inhibitor monotherapy and with DAPT in the intention to treat
population, respectively (HR=0.90, 95% CI = 0.77 to 1.05; P=0.18 for
superiority).
The risk of bleeding was lower with P2Y12 inhibitor monotherapy
than with DAPT (0.89% vs. 1.83%; HR= 0.49, 95% CI = 0.39 to 0.63;
P<0.001).
Conclusion(s) In patients following coronary revascularisation, P2Y12 inhibitor

monotherapy was associated with a similar risk of death, myocardial
infarction, or stroke, and a lower bleeding risk compared with DAPT.
90
Acronym Ticagrelor Monotherapy After 3 Months in the Patients Treated With
New Generation Sirolimus-eluting Stent for Acute Coronary
Syndrome (TICO)
Reference Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S,
Jeon DW, Yoo SY, Cho DK, Hong BK, Kwon H, Ahn CM, Shin DH, Nam
CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y; TICO Investigators. Effect
of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major
Bleeding and Cardiovascular Events in Patients With Acute Coronary
Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020 Jun
16;323(23):2407-2416. doi: 10.1001/jama.2020.7580. PMID:
32543684.
Study Type An investigator-initiated, multicenter, randomized, unblinded trial in
South Korea

Evidence
Intervention Ticagrelor monotherapy after 3-month DAPT, or ticagrelor-based 12-

month DAPT
Main incl/excl Patients following successful PCI with ultrathin bioresorbable polymer
criteria sirolimus-eluting stents (Orsiro; Biotronik AG) for ACS (ST-elevation
myocardial infarction, non-ST-elevation myocardial infarction, or
unstable angina)
Relevant The primary outcome was a 1-year net adverse clinical event, defined
outcome(s) as a composite of major bleeding and adverse cardiac and
cerebrovascular events (death, myocardial infarction, stent
thrombosis, stroke, or target-vessel revascularization).
Key findings The primary outcome occurred in 3.9% of patients receiving ticagrelor
monotherapy after 3-month DAPT and in 5.9% of patients receiving
ticagrelor-based 12-month DAPT (absolute difference, −1.98% [95%
CI, −3.50% to −0.45%]; HR, 0.66 [95% CI, 0.48 to 0.92]; P = .01). Major
bleeding occurred in 1.7% of patients with ticagrelor monotherapy

after 3-month DAPT and in 3.0% of patients with ticagrelor-based 12-
month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02). The incidence of
major adverse cardiac and cerebrovascular events was not
significantly different between the ticagrelor monotherapy after 3-
month DAPT group (2.3%) vs the ticagrelor-based 12-month DAPT
group (3.4%) (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09).
Conclusion(s) Ticagrelor monotherapy after 3 months of dual antiplatelet therapy,
compared with ticagrelor-based 12-month dual antiplatelet therapy,
resulted in a modest but statistically significant reduction in a
composite outcome of major bleeding and cardiovascular events at 1
year.
The lower than expected event rates should be considered in

interpreting the trial.
91
Acronym Harmonizing Optimal Strategy for Treatment of coronary artery
stenosis-Extended Antiplatelet Monotherapy (HOST-EXAM)
Reference Koo BK, Kang J, Park KW, Rhee TM, Yang HM, Won KB, Rha SW, Bae
JW, Lee NH, Hur SH, Yoon J, Park TH, Kim BS, Lim SW, Cho YH, Jeon
DW, Kim SH, Han JK, Shin ES, Kim HS; HOST-EXAM investigators.
Aspirin versus clopidogrel for chronic maintenance monotherapy after
percutaneous coronary intervention (HOST-EXAM): an investigator-
initiated, prospective, randomised, open-label, multicentre trial.
Lancet. 2021 Jun 26;397(10293):2487-2496. doi: 10.1016/S0140-
6736(21)01063-1. Epub 2021 May 16. PMID: 34010616.
Study Type Investigator-initiated, prospective, randomised, open-label,
Details and Quality
multicentre trial in South Korea.

of Evidence

Intervention Clopidogrel 75 mg once daily or aspirin 100 mg once daily.
Main incl/excl Patients following percutaneous coronary intervention with drug
criteria eluting stents, and maintained DAPT, and without any clinical events
within 6–18 months.
Relevant The primary endpoint was a composite of all-cause death, non-fatal
outcome(s) myocardial infarction, stroke, readmission due to acute coronary
syndrome, and Bleeding Academic Research Consortium (BARC)

bleeding type 3 or greater.
Key findings During 24-month follow-up, the primary outcome occurred in 5,7% of
patients in the clopidogrel group and 7,7% in the aspirin group (HR
0.73 [95% CI 0.59–0.90]; p=0.0035).
Conclusion(s) In patients requiring indefinite antiplatelet monotherapy after
percutaneous coronary intervention, clopidogrel monotherapy was
superior to aspirin monotherapy in preventing future adverse clinical
events.
92
Reference Chiarito M, Sanz-Sánchez J, Cannata F, Cao D, Sturla M, Panico C,
Godino C, Regazzoli D, Reimers B, De Caterina R, Condorelli G,
Ferrante G, Stefanini GG. Monotherapy with a P2Y12 inhibitor or
aspirin for secondary prevention in patients with established
atherosclerosis: a systematic review and meta-analysis. Lancet. 2020
May 9;395(10235):1487-1495. doi: 10.1016/S0140-6736(20)30315-9.
PMID: 32386592.
Study Type Systematic review and meta-analysis of RCTs.
Nº patients
Nine RCTs were included in this study, which recruited 4 108 patients
(21043 allocated to a P2Y12 inhibitor, and 21065 to aspirin).
Intervention P2Y12 inhibitor vs. aspirin monotherapy
Main incl/excl On Dec 18, 2019, the search was undertaken in PubMed, Embase,
criteria BioMedCentral, Google Scholar, and the Cochrane Central Register of
Controlled Trials. Additionally, the authors reviewed references from
identified articles and searched abstracts from 2017 to 2019
presented at relevant scientific meetings. Randomised trials
comparing P2Y12 inhibitor with aspirin monotherapy for secondary
prevention in patients with cerebrovascular, coronary, or peripheral
artery disease were evaluated for inclusion.
Relevant Co-primary endpoints were myocardial infarction and stroke. Key
outcome(s) secondary endpoints were all-cause death and vascular death.
Key findings Compared with those who received aspirin, patients who received a
P2Y12 inhibitor had lower risk of myocardial infarction (OR=0.81, 95%

CI=0.66-0.99). Risks of stroke (OR=0.93, 95% CI=0.82-1.06), all-cause
death (OR=0.98, 95 CI%=0.89-1.08), and vascular death (OR=0.97, 95%
CI=0.86-1.09) did not differ between patients who received a P2Y12
inhibitor and those who received aspirin. The risk of major bleeding
did not differ between groups (OR=0.90, 95% CI=0.74-1.10).
Conclusion(s) Compared with aspirin monotherapy, P2Y12 inhibitor monotherapy is
associated with a borderline risk reduction for myocardial infarction
and a comparable risk of stroke in the setting of secondary
prevention.
93
Acronym A Clinical Study Comparing Two Forms of Anti-platelet Therapy After
Stent Implantation (GLOBAL LEADERS)
Reference Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, van Es GA,
McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E,
Möllmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A,
Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW,
Windecker S; GLOBAL LEADERS Investigators. Ticagrelor plus aspirin
for 1 month, followed by ticagrelor monotherapy for 23 months vs
aspirin plus clopidogrel or ticagrelor for 12 months, followed by
aspirin monotherapy for 12 months after implantation of a drug-
eluting stent: a multicentre, open-label, randomised superiority trial.
Lancet. 2018 Sep 15;392(10151):940-949. doi: 10.1016/S0140-
6736(18)31858-0. Epub 2018 Aug 27. PMID: 30166073.
Study Type International, multicenter, open-label, randomised superiority trial
Intervention 75–100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month,
followed by 23 months of ticagrelor monotherapy, or standard dual
antiplatelet therapy with 75–100 mg aspirin daily plus either 75 mg
clopidogrel daily (for patients with stable coronary artery disease) or
90 mg ticagrelor twice daily (for patients with acute coronary
syndromes) for 12 months, followed by aspirin monotherapy for 12
months.
Main incl/excl Patients scheduled to undergo percutaneous coronary intervention
criteria for stable coronary artery disease or acute coronary syndromes who
required dual antiplatelet therapy, unless oral anticoagulation was
indicated.
Relevant The primary endpoint at 2 years was a composite of all-cause
outcome(s) mortality or non-fatal centrally adjudicated new Q-wave myocardial
infarction ( assessed by a core lab in a blinded manner).
Key findings At 2 years, the primary endpoint occurred in 3,81% participants in the
experimental group vs. 4.37% of patients in the control group (rate

ratio 0.87 [95% CI 0.75–1.01]; p=0.073]).
Grade 3 or 5 bleeding occurred in 2.04% in the experimental group vs
2.12% in the control group ( rate ratio 0.97 [95% CI 0.78–1.20];
p=0.77).
Conclusion(s) Ticagrelor in combination with aspirin for 1 month followed by
ticagrelor alone for 23 months was not superior to 12 months of
standard dual antiplatelet therapy followed by 12 months of aspirin
alone in the prevention of all-cause mortality or new Q-wave
myocardial infarction 2 years after percutaneous coronary
intervention.
94
Acronym Short and Optimal Duration of Dual Antiplatelet Therapy After
Everolimus-Eluting Cobalt-Chromium Stent (STOPDAPT) trial
Reference Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T,
Ohya M, Suwa S, Takagi K, Nanasato M, Hata Y, Yagi M, Suematsu N,
Yokomatsu T, Takamisawa I, Doi M, Noda T, Okayama H, Seino Y, Tada
T, Sakamoto H, Hibi K, Abe M, Kawai K, Nakao K, Ando K, Tanabe K,
Ikari Y, Hanaoka KI, Morino Y, Kozuma K, Kadota K, Furukawa Y,
Nakagawa Y, Kimura T; STOPDAPT-2 Investigators. Effect of 1-Month
Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual
Antiplatelet Therapy on Cardiovascular and Bleeding Events in
Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial.
JAMA. 2019 Jun 25;321(24):2414-2427. doi: 10.1001/jama.2019.8145.
PMID: 31237644.
Study Type A multicenter, open-label, adjudicator-blinded randomized clinical
trial in Japan
Intervention 1 month of DAPT either aspirin, 81 to 200 mg/d, and clopidogrel, 75
mg/d, or aspirin, 81 to 200 mg/d, and prasugrel, 3.75 mg/d, at the
discretion of the attending physician, or 12 months of DAPT after

CoCr-EES implantation.
At 1 month, patients in the experimental group were to stop aspirin
and receive clopidogrel monotherapy for up to 5 years, while patients
in the control group were to receive DAPT with aspirin and clopidogrel
for up to 12 months. For patients who had received prasugrel,
prasugrel was switched to clopidogrel at 1 month in both groups. At
12 months (between 335 and 394 days), patients in the control group
were to stop clopidogrel and receive aspirin monotherapy for up to 5
years.
Main incl/excl Patients following successful PCI with CoCr-EES (Xience Series, Abbott
criteria Vascular) without concomitant use of other types of drug-eluting
stent or in-hospital major complications other than periprocedural
MI.
Relevant The primary end point was a composite of cardiovascular and
outcome(s) bleeding events (cardiovascular death, MI, definite stent thrombosis,
ischemic or hemorrhagic stroke, or Thrombolysis in Myocardial

Infarction [TIMI] major or minor bleeding).
Key findings The 1-year cumulative incidence of a composite end point consisting
of cardiovascular death, myocardial infarction, ischemic or
hemorrhagic stroke, definite stent thrombosis, and major bleeding
was 2.4% in the 1-month DAPT group and 3.7% in the 12-month DAPT
group, a difference that met the noninferiority margin of a hazard
ratio of 0.5, as well as superiority.
Conclusion(s) 1 month of DAPT followed by clopidogrel monotherapy provided
benefit compared with 12 months of DAPT
95
Acronym Ticagrelor Monotherapy After 3 Months in the Patients Treated With
New Generation Sirolimus-eluting Stent for Acute Coronary
Syndrome (TICO)
Reference Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S,
Jeon DW, Yoo SY, Cho DK, Hong BK, Kwon H, Ahn CM, Shin DH, Nam
CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y; TICO Investigators. Effect
of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major
Bleeding and Cardiovascular Events in Patients With Acute Coronary
Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020 Jun
16;323(23):2407-2416. doi: 10.1001/jama.2020.7580. PMID:
32543684.
Study Type Investigator-initiated, multicenter, randomized, unblinded trial
conducted at 38 centers in South Korea

Intervention Ticagrelor monotherapy (90 mg twice daily) after 3-month DAPT vs.
Evidence
ticagrelor-based 12-month DAPT

Main incl/excl Patients with ACS treated with drug-eluting stents.
criteria Key exclusion criteria included increased risk of bleeding due to prior
hemorrhagic stroke, traumatic brain injury or brain surgery within the
past 6 months, internal bleeding within the past 6 weeks, need of oral
anticoagulation therapy, and anemia (hemoglobin ≤8 g/dL).
Relevant The primary outcome was a 1-year net adverse clinical event, defined
outcome(s) as a composite of major bleeding and adverse cardiac and
cerebrovascular events (death, myocardial infarction, stent
thrombosis, stroke, or target-vessel revascularization).

Key findings The primary outcome occurred in 3.9% and 5.9% patients receiving
ticagrelor monotherapy after 3-month DAPT and those receiving
ticagrelor-based 12-month DAPT. The absolute difference was -1.98%
(95% CI= -3.50% to -0.45%), and the hazard ratio was 0.66 (95% CI=
0.48 to 0.92; P = 0.01).
Conclusion(s) Among patients with acute coronary syndromes treated with drug-
eluting stents, ticagrelor monotherapy after 3 months of dual
antiplatelet therapy, compared with ticagrelor-based 12-month dual
antiplatelet therapy, reduced the composite outcome of major
bleeding and cardiovascular events at 1 year.
96
Acronym Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary
Intervention (TWILIGHT) trial
Reference Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha
JY, Collier T, Dangas G, Dudek D, Džavík V, Escaned J, Gil R, Gurbel P,
Hamm CW, Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff
M, Kunadian V, Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd
K, Sardella G, Sartori S, Shlofmitz R, Steg PG, Weisz G, Witzenbichler B,
Han YL, Pocock S, Gibson CM. Ticagrelor with or without Aspirin in
High-Risk Patients after PCI. N Engl J Med. 2019 Nov 21;381(21):2032-
2042. doi: 10.1056/NEJMoa1908419. Epub 2019 Sep 26. PMID:
31556978.
Study Type International, multicenter, randomised superiority trial.
Nº patients 9006 enrolled, 7119 randomized after 3 months.
Intervention 3 months after the index PCI: ticagrelor (90 mg twice daily) and
enteric-coated aspirin (81 to 100 mg daily). At 3 months: aspirin or
matching placebo for an additional 12 months along with continuation
of open-label ticagrelor treatment.
Main incl/excl Patients with at least one additional clinical feature and one
criteria angiographic feature associated with a high risk of ischemic or
bleeding event , and who underwent successful PCI with at least one
locally approved drug-eluting stent , and whom the treating clinician
intended to discharge with a regimen of ticagrelor plus aspirin.
At 3 months after hospital discharge, no major bleeding event or no

ischemic event.
Relevant The primary end point was the first occurrence of BARC type 2, 3, or 5
outcome(s) bleeding between randomization and 1 year in a time-to-event
analysis.
The key secondary end point was the first occurrence of death from
any cause, nonfatal myocardial infarction, or nonfatal stroke in a time-
to-event analysis.
Key findings Between randomization and 1 year, the incidence of the primary end
point was 4.0% in the ticagrelor plus placebo group vs. 7.1% in the
ticagrelor plus aspirin group (HR, 0.56; 95% CI, 0.45 to 0.68; P<0.001).
BARC type 3 or 5 bleeding occurred in 1.0% in the ticagrelor plus
placebo group vs. 2.0% in the ticagrelor plus aspirin group; HR, 0.49;
95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal
myocardial infarction, or nonfatal stroke was 3.9% in both groups
(difference, −0.06 percentage points; 95% CI, −0.97 to 0.84; hazard
ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).
Conclusion(s) Among high-risk patients who underwent PCI and completed 3
months of dual antiplatelet therapy, ticagrelor monotherapy was
associated with a lower incidence of clinically relevant bleeding than
ticagrelor plus aspirin, with no higher risk of death, myocardial
97
Reference Giacoppo D, Matsuda Y, Fovino LN, D'Amico G, Gargiulo G, Byrne RA,
Capodanno D, Valgimigli M, Mehran R, Tarantini G. Short dual
antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs.
prolonged dual antiplatelet therapy after percutaneous coronary
intervention with second-generation drug-eluting stents: a systematic
review and meta-analysis of randomized clinical trials. Eur Heart J.
2021 Jan 21;42(4):308-319. doi: 10.1093/eurheartj/ehaa739. PMID:
33284979.
Study Type Systematic review and meta-analysis of randomized clinical trials
Nº patients
Five randomized clinical trials (32 145 patients)

Intervention Short dual antiplatelet therapy (DAPT) followed by single antiplatelet
Evidence
therapy (SAPT) with a P2Y12 receptor inhibitor vs. prolonged DAPT

Main incl/excl Multiple electronic databases, including PubMed, Scopus, Web of
criteria Sciences, Ovid, and ScienceDirect, were searched to identify
randomized clinical trials comparing ≤3 months of DAPT followed by
P2Y12 inhibitor SAPT vs. 12 months of DAPT after PCI with second-
generation DES implantation.
Relevant The primary and co-primary outcomes of interest were major bleeding
outcome(s) and stent thrombosis 1 year after randomization.
Key findings Major bleeding was significantly lower in the patients assigned to
short DAPT followed by P2Y12 inhibitor SAPT compared with those

assigned to 12-month DAPT (HR=0.63, 95%=0.45-0.86, P = 0.004). No
significant differences between groups were observed in terms of
stent thrombosis (HR=1.19, 95% CI= 0.86-1.65, P = 0.302) and the
secondary endpoints of all-cause death (HR= 0.85, 95% CI= 0.70-1.03),
myocardial infarction (HR=1.05, 95% CI=0.89-1.23), and stroke
(HR=1.08, 95% CI=0.68-1.74).
Conclusion(s) In patients with a second-generation DES, 1-3 months of DAPT
followed by P2Y12 inhibitor SAPT was associated with lower major
bleeding and similar stent thrombosis, compared with prolonged
DAPT.
98
Acronym Management of High Bleeding Risk Patients Post Bioresorbable
Polymer Coated Stent Implantation with an Abbreviated versus
Standard DAPT Regimen (MASTER DAPT) trial
Reference Valgimigli M, Frigoli E, Heg D, Tijssen J, Jüni P, Vranckx P, Ozaki Y,
Morice MC, Chevalier B, Onuma Y, Windecker S, Tonino PAL, Roffi M,
Lesiak M, Mahfoud F, Bartunek J, Hildick-Smith D, Colombo A,
Stanković G, Iñiguez A, Schultz C, Kornowski R, Ong PJL, Alasnag M,
Rodriguez AE, Moschovitis A, Laanmets P, Donahue M, Leonardi S,
Smits PC; MASTER DAPT Investigators. Dual Antiplatelet Therapy after
PCI in Patients at High Bleeding Risk. N Engl J Med. 2021 Oct
28;385(18):1643-1655. doi: 10.1056/NEJMoa2108749. Epub 2021 Aug
28. PMID: 34449185.
Study Type An investigator-initiated, multicenter, randomized, open-label,
noninferiority trial with sequential superiority testing.

Intervention Abbreviated-therapy group: DAPT 1 month after the index procedure
and continued single antiplatelet therapy until the completion of the
trial (patients on oral anticoagulation: single antiplatelet therapy up
to 6 months after the index procedure), or Standard-therapy group:
DAPT for at least 6 months after the index procedure ( patients on
OAC: at least 3 months DAPT after the index procedure) with the
continuation of single antiplatelet therapy thereafter. Single
antiplatelet therapy consisted of aspirin or a P2Y12 inhibitor.
Main incl/excl Patients with an acute or chronic coronary syndrome; and successful
criteria PCI for one or more coronary-artery stenoses with implantation of a
biodegradable-polymer sirolimus-eluting stent, and at high bleeding
risk. In addition, patients had to be free from adverse cardiovascular
events during the first month after the index PCI.
Relevant The three ranked primary outcomes were: net adverse clinical events
outcome(s) (death from any cause, myocardial infarction, stroke, or major
bleeding), major adverse cardiac or cerebral events (death from any
cause, myocardial infarction, or stroke), and major or clinically
relevant nonmajor bleeding; at 335 days. The first two outcomes were
assessed for noninferiority in the per-protocol population, and the
third outcome for superiority in the intention-to-treat population.
Key findings Net adverse clinical events occurred in 7.5% in the abbreviated-
therapy group vs. in 7.7% in the standard-therapy group (difference,
−0.23 percentage points; 95% CI, −1.80 to 1.33; P<0.001 for
noninferiority).
MACCE: 6.1% of patients in the abbreviated-therapy group vs. 5.9% in
the standard-therapy group (difference, 0.11 percentage points; 95%
CI, −1.29 to 1.51; P=0.001 for noninferiority). Major or clinically
relevant nonmajor bleeding: 6.5% of patients in the abbreviated-
therapy group vs. 9.4% in the standard-therapy group (difference,
99
−2.82 percentage points; 95% CI, −4.40 to −1.24; P<0.001 for
superiority).
Conclusion(s) One month of dual antiplatelet therapy was noninferior to the
continuation of therapy for at least 2 additional months with regard to
the occurrence of net adverse clinical events and major adverse
cardiac or cerebral events; abbreviated therapy also resulted in a
lower incidence of major or clinically relevant nonmajor
bleeding. Rates of net adverse clinical outcomes and major adverse
cardiac and cerebral events did not differ with abbreviated APT in
patients with high bleeding risk with or without an OAC indication and
resulted in lower bleeding rates in patients without an OAC indication.
100
Acronym What is the Optimal antiplatElet and anticoagulant therapy in
patients with oral anticoagulation and coronary StenTing (WOEST)
study
Reference Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman
JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van
't Hof AW, ten Berg JM; WOEST study investigators. Use of clopidogrel
with or without aspirin in patients taking oral anticoagulant therapy
and undergoing percutaneous coronary intervention: an open-label,
randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.
doi: 10.1016/S0140-6736(12)62177-1. Epub 2013 Feb 13. PMID:
23415013.
Study Type International, open-label, multicentre, randomised, controlled trial
Intervention DAT vs TAT. Maintenance dose of 75 mg clopidogrel per day for at

least 5 days, a loading dose of 300 mg at least 24 h before PCI, or a
loading dose of 600 mg at least 4 h before PCI.
All patients received 75 mg clopidogrel daily, and those in the triple-
therapy group were also given 80–100 mg aspirin daily; a 320 mg
loading dose was also given to patients who had not been taking
aspirin before the study. During the intervention, oral anticoagulants
were continued where possible, with a target international
normalisation ratio of 2.0.
Main incl/excl Inclusion: adults receiving oral anticoagulants and undergoing PCI
criteria
Relevant Any bleeding event
outcome(s)
Summary of Key
Key findings At 12 months,bleeding was seen in 19.4% of patients receiving double

findings
therapy (DAT) and in 44.4% receiving triple therapy (TAT)(hazard ratio

[HR] 0.36, 95% CI 0.26–0.50, p<0.0001).
Conclusion(s) Use of clopiogrel without aspirin was associated with a significant
reduction in bleeding complications and no increase in the rate of
thrombotic events.
101
Recommendation Table 7 — Recommendations for fibrinolytic therapy
Acronym Comparison of Angioplasty and Prehospital Thrombolysis in Acute

Myocardial Infarction (CAPTIM) study
Reference Bonnefoy E, Lapostolle F, Leizorovicz A, Steg G, McFadden EP, Dubien
PY, Cattan S, Boullenger E, Machecourt J, Lacroute JM, Cassagnes J,
Dissait F, Touboul P; Comparison of Angioplasty and Prehospital
Thromboysis in Acute Myocardial Infarction study group. Primary
angioplasty versus prehospital fibrinolysis in acute myocardial
infarction: a randomised study. Lancet. 2002 Sep 14;360(9336):825-9.
doi: 10.1016/S0140-6736(02)09963-4. PMID: 12243916.
Study Type Multicentre, open label, randomized trial in France
Nº patients
834 participants
Intervention Prehospital recombinant tissue plasminogen activator (rtPA) with
Evidence
transfer to an interventional facility or primary PCI

Main incl/excl ST segment elevation myocardial infarction within 6 hours of
criteria symptom onset
Patients were not eligible if the duration of transfer to the hospital

was expected to exceed 1 hour.
Relevant Composite of death, non-fatal reinfarction, and non-fatal disabling
outcome(s) stroke at 30 days
Key findings The median delay between onset of symptoms and treatment was
130 min in the prehospital-fibrinolysis group and 190 min (time to
first balloon inflation) in the primary-angioplasty group. Rescue

angioplasty was done in 26% of the patients in the fibrinolysis group.
The rate of the primary endpoint was 8,2% in the prehospital-
fibrinolysis group and 6,2% in the primary-angioplasty group (risk
difference 1,96, 95% CI−1.53 to 5.46). 3.8% patients assigned
prehospital fibrinolysis and 4.8% assigned primary angioplasty died
(p=0.61).
Conclusion(s) A strategy of primary angioplasty was not better than a strategy of
prehospital fibrinolysis (with transfer to an interventional facility for
possible rescue angioplasty) in patients presenting with early
102
Acronym Assessment of the Safety and Efficacy of a New Thrombolytic
(ASSENT-2) trial
Reference Assessment of the Safety and Efficacy of a New Thrombolytic
(ASSENT-2) Investigators; Van De Werf F, Adgey J, Ardissino D,
Armstrong PW, Aylward P, Barbash G, Betriu A, Binbrek AS, Califf R,
Diaz R, Fanebust R, Fox K, Granger C, Heikkilä J, Husted S, Jansky P,
Langer A, Lupi E, Maseri A, Meyer J, Mlczoch J, Mocceti D, Myburgh D,
Oto A, Paolasso E, Pehrsson K, Seabra-Gomes R, Soares-Piegas L,
Sùgrue D, Tendera M, Topol E, Toutouzas P, Vahanian A, Verheugt F,
Wallentin L, White H. Single-bolus tenecteplase compared with front-
loaded alteplase in acute myocardial infarction: the ASSENT-2 double-
blind randomised trial. Lancet. 1999 Aug 28;354(9180):716-22. doi:
10.1016/s0140-6736(99)07403-6. PMID: 10475182.
Study Type Double-blind, randomised, controlled trial
Details and Quality
Nº patients 16,949 participants

of Evidence
Intervention Rapid infusion of alteplase (< or = 100 mg) vs. single-bolus injection of
tenecteplase (30-50 mg according to bodyweight).
Main incl/excl Patients with acute myocardial infarction of less than 6 h duration. All
criteria patients received aspirin and heparin (target activated partial
thromboplastin time 50-75 s).
Relevant The primary outcome was equivalence in all-cause mortality at 30
outcome(s) days.
Key findings Covariate-adjusted 30-day mortality rates were 6.18%and 6.15% for
tenecteplase and alteplase, respectively. The 95% one-sided upper
boundaries of the absolute and relative differences in 30-day
mortality were 0.61% and 10.00%, respectively, which met the
prespecified criteria of equivalence.
Conclusion(s) Tenecteplase and alteplase showed similar efficacy for 30-day
mortality.
103
Acronym ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)
Reference Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS;
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial)
collaborative group. Addition of clopidogrel to aspirin in 45,852
patients with acute myocardial infarction: randomised placebo-
controlled trial. Lancet. 2005 Nov 5;366(9497):1607-21. doi:
10.1016/S0140-6736(05)67660-X. PMID: 16271642.
Study Type Randomised placebo-controlled trial
Details and Quality
Nº patients 45,852 patients admitted to 1250 hospitals

of Evidence
Intervention Clopidogrel 75 mg daily vs. matching placebo, in addition to aspirin

162 mg daily.
Main incl/excl Patients admitted within 24 h of suspected acute MI onset.
criteria Patients scheduled for primary PCI were excluded.
Relevant The two prespecified co-primary outcomes were: (1) the composite of
outcome(s)
death, reinfarction, or stroke; and (2) death from any cause during
the scheduled treatment period.
Key findings Patients who received clopidogrel had less death, reinfarction, or
stroke (9.2% clopidogrel vs. 10.1% placebo; p=0.002), corresponding
to 9 fewer events per 1000 patients treated for about 2 weeks.
There was also a difference in all-cause moretality (7.5% vs. 8.1%;
p=0.03).
Conclusion(s) In patients with acute MI, adding clopidogrel 75 mg daily to aspirin
reduced mortality and major vascular events in hospital.
104
Acronym Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–
Thrombolysis in Myocardial Infarction (TIMI) 28 study; (CLARITY-
TIMI 28)
Reference Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot
G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH,
Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to
aspirin and fibrinolytic therapy for myocardial infarction with ST-
segment elevation. N Engl J Med. 2005 Mar 24;352(12):1179-89. doi:

Intervention Clopidogrel (300-mg loading dose, followed by 75 mg once daily)
Evidence
Main incl/excl Patients 18 to 75 years of age, who presented within 12 hours after
criteria the onset of an ST-elevation myocardial infarction. Patients received a
fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed
according to body weight) and were scheduled to undergo
angiography 48 to 192 hours after the start of study medication.
Relevant The primary efficacy endpoint was a composite of an occluded infarct-
outcome(s) related artery (defined by a Thrombolysis in Myocardial Infarction
flow grade of 0 or 1) on angiography or death or recurrent myocardial
infarction before angiography.
Key findings Telephone follow-up was performed at 30 days. The rates of the
primary efficacy end point were 21.7% and 15.0% in the placebo
group and the clopidogrel group, respectively; representing an
absolute reduction of 6.7% in the rate and a 36% reduction in the
odds of the endpoint with clopidogrel therapy (95% CI = 24 – 47%;
P<0.001).
Conclusion(s) In patients 75 years of age or younger who have myocardial infarction
with ST-segment elevation and who receive aspirin and a standard
fibrinolytic regimen, the addition of clopidogrel improved the
composite endpoint of patency rate of the infarct-related artery or
recurrent myocardial infarction
105
Acronym Assessment of the Safety and Efficacy of a New Thrombolytic
Regimen (ASSENT)-3
Reference Assessment of the Safety and Efficacy of a New Thrombolytic
Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase
in combination with enoxaparin, abciximab, or unfractionated
heparin: the ASSENT-3 randomised trial in acute myocardial
infarction. Lancet. 2001 Aug 25;358(9282):605-13. doi:
10.1016/S0140-6736(01)05775-0. PMID: 11530146.
Nº patients
6095 patients
Intervention Full-dose tenecteplase and enoxaparin for a maximum of 7 days
Evidence
(enoxaparin group) vs. half-dose tenecteplase with weight-adjusted

low-dose unfractionated heparin and a 12-h infusion of abciximab
(abciximab group) vs. full-dose tenecteplase with weight-adjusted
unfractionated heparin for 48 h (unfractionated heparin group).
Main incl/excl Patients with acute myocardial infarction of less than 6 h.
criteria
Relevant The primary endpoints were the composites of 30-day mortality, in-
outcome(s) hospital reinfarction, or in-hospital refractory ischaemia (efficacy
endpoint), and the above endpoint plus in-hospital intracranial
haemorrhage or in-hospital major bleeding complications (efficacy
plus safety endpoint).
Key findings There were significantly fewer efficacy endpoints in the enoxaparin
and abciximab groups than in the unfractionated heparin group:

11.4% vs. 15.4%; relative risk 0.74 (95% CI 0.63-0.87, p=0.0002) for
enoxaparin, and 11.1% vs. 15.4%; relative risk 0.72 (95 % CI 0.61-0.84,
p<0.0001) for abciximab.
Percentages and estimates of the safety endpoint were on the same
direction: 13.7% vs. 17.0%; relative risk 0.81 (95% CI 0.70-0.93,
p=0.0037) for enoxaparin, and 14.2% vs. 17.0%; relative risk 0.84 (95
% CI 0.72-0.96, p=0.01416) for abciximab.
Conclusion(s) Compared with unfractionated heparin, tenecteplase plus enoxaparin
or abciximab regimens reduced the frequency of the efficacy
endpoint (composite of 30-day mortality, in-hospital reinfarction, or
in-hospital refractory ischaemia), and the efficacy plus safety
endpoint (efficacy ednpoint in-hospital intracranial haemorrhage or
in-hospital major bleeding complications at 30 days).
106
Acronym Organization for the Assessment of Strategies for Ischemic
Syndromes (OASIS-6) trial
Reference Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj
A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA; OASIS-6 Trial
Group. Effects of fondaparinux on mortality and reinfarction in
patients with acute ST-segment elevation myocardial infarction: the
OASIS-6 randomized trial. JAMA. 2006 Apr 5;295(13):1519-30. doi:
10.1001/jama.295.13.joc60038. Epub 2006 Mar 14. PMID: 16537725.
Study Type Randomized, double-blind trial involving 447 centers from 41
countries (September 2003-January 2006).

Nº patients 12 092 patients
Evidence
Intervention Fondaparinux 2.5 mg once daily for up to 8 days

Main incl/excl Patients with STEMI were included. Those with contraindications to
criteria anticoagulation, including those at high risk of bleeding, receiving oral
anticoagulants, or with creatinine levels greater than 265.2 mg/dL (3.0
mmol/L), were excluded.
Relevant Composite of death or reinfarction at 30 days (primary).
outcome(s)
Summary of Key
Key findings Death or reinfarction at 30 days was significantly reduced from 11.2%
findings
in the control group to 9.7% in the fondaparinux group (hazard ratio

0.86; 95% CI, 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95%
CI, 0.4%-2.6%).
Conclusion(s) In patients with STEMI, fondaparinux significantly reduced the
composite of mortality or reinfarction.
107
Acronym Rescue Angioplasty versus Conservative Treatment or Repeat
Thrombolysis (REACT) trial
Reference Gershlick AH, Stephens-Lloyd A, Hughes S, Abrams KR, Stevens SE,
Uren NG, de Belder A, Davis J, Pitt M, Banning A, Baumbach A, Shiu
MF, Schofield P, Dawkins KD, Henderson RA, Oldroyd KG, Wilcox R;
REACT Trial Investigators. Rescue angioplasty after failed thrombolytic
therapy for acute myocardial infarction. N Engl J Med. 2005 Dec
29;353(26):2758-68. doi: 10.1056/NEJMoa050849. PMID: 16382062.
Study Type Single-country, multicenter ramdomised clinical trial
Details and Quality

of Evidence
Intervention Repeated thrombolysis vs. conservative treatment (141 patients) vs.

rescue PCI.
Main incl/excl Adults 21 to 85 years of age with ST-segment elevation myocardial
criteria infarction in whom reperfusion failed to occur (less than 50% ST-
segment resolution) within 90 minutes after thrombolytic treatment.
Relevant The primary endpoint was a composite of death, reinfarction, stroke,
outcome(s) or severe heart failure within six months.
Key findings The rates of event-free survival were 84.6%, 70.1% and 68.7% among
patients treated with rescue PCI, those receiving conservative therapy
and those undergoing repeated thrombolysis, respectively (overall

P=0.004). The adjusted hazard ratio for the occurrence of the primary
end point for repeated thrombolysis versus conservative therapy was
1.09 (95 % CI, 0.71 to 1.67; P=0.69), as compared with adjusted hazard
ratios of 0.43 (95 % CI, 0.26 to 0.72; P=0.001) for rescue PCI versus
repeated thrombolysis and 0.47 (95 % CI, 0.28 to 0.79; P=0.004) for
rescue PCI versus conservative therapy. There were no significant
differences in mortality from all causes.
Conclusion(s) The primary endpoint (a composite of death, reinfarction, stroke, or
severe heart failure within six months) after failed thrombolytic
therapy was significantly reduced with rescue PCI than with repeated
thrombolysis or conservative treatment.
108
Acronym Trial of Routine Angioplasty and Stenting after Fibrinolysis to
Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-
AMI)
Reference Cantor WJ, Fitchett D, Borgundvaag B, Ducas J, Heffernan M, Cohen
EA, Morrison LJ, Langer A, Dzavik V, Mehta SR, Lazzam C, Schwartz B,
Casanova A, Goodman SG; TRANSFER-AMI Trial Investigators. Routine
early angioplasty after fibrinolysis for acute myocardial infarction. N
Engl J Med. 2009 Jun 25;360(26):2705-18. doi:
10.1056/NEJMoa0808276. PMID: 19553646.
Study Type Randomized, nonblinded trial performed at 52 sites in three provinces
(Ontario, Manitoba, and Quebec) in Canada.
Intervention Standard treatment (including rescue PCI, if required, or delayed
angiography) vs. a strategy of immediate transfer to another hospital
and PCI within 6 hours after fibrinolysis
Main incl/excl Patients with myocardial infarction with ST-segment elevation who
criteria presented within 12 hours after the onset of symptoms to
participating centers that did not have the capability of performing PCI
and who were treated with tenecteplase were eligible either if they
had ST-segment elevation of 2 mm or more in two anterior leads or if
they had ST-segment elevation of 1 mm or more in two inferior leads
and at least one of the following high-risk characteristics: systolic
blood pressure of less than 100 mm Hg, heart rate of more than 100
bpm, Killip class II or III, ST-segment depression of 2 mm or more in
the anterior leads, or ST-segment elevation of 1 mm or more in right-
sided lead V4 (V4R), which is indicative of right ventricular
involvement.
Key exclusion criteria included cardiogenic shock before
randomisation, PCI within the previous month, previous coronary-
artery bypass surgery, and the availability of primary PCI with an
anticipated door-to-balloon time of less than 60 minutes.
Relevant The primary endpoint was the composite of death, reinfarction,
outcome(s) recurrent ischemia, new or worsening congestive heart failure, or
cardiogenic shock within 30 days.
Key findings Cardiac catheterization was performed in 88.7% of the patients
assigned to standard treatment a median of 32.5 hours after

randomization, and in 98.5% of the patients assigned to routine early
PCI a median of 2.8 hours after randomization. At 30 days, the primary
endpoint occurred in 11.0% and 17.2% of the patients who were
assigned to routine early PCI and in those assigned to standard
treatment, respectively (relative risk with early PCI, 0.64; 95% CI, 0.47
to 0.87; P=0.004).
Conclusion(s) Among high-risk patients who had a myocardial infarction with ST-
segment elevation and who were treated with fibrinolysis, transfer for
PCI within 6 hours after fibrinolysis was associated with significantly
fewer ischemic complications than was standard treatment
109
Reference Borgia F, Goodman SG, Halvorsen S, Cantor WJ, Piscione F, Le May
MR, Fernández-Avilés F, Sánchez PL, Dimopoulos K, Scheller B,
Armstrong PW, Di Mario C. Early routine percutaneous coronary
intervention after fibrinolysis vs. standard therapy in ST-segment
elevation myocardial infarction: a meta-analysis. Eur Heart J. 2010
Sep;31(17):2156-69. doi: 10.1093/eurheartj/ehq204. Epub 2010 Jul 2.
PMID: 20601393.
Study Type Meta-analysis of randomized controlled trials
Nº patients 2961 patients from 7 randomised trials
Intervention early PCI after fibrinolysis vs. standard therapy
Main incl/excl A comprehensive literature search on MEDLINE and Cochrane Library
criteria electronic database was conducted to identify all published RCTs
performed between 1999 and 2010 comparing early PCI, performed
within 24 h from fibrin-specific lytic therapy, to the standard strategy

in STEMI patients presenting in non-PCI centres. The search was
performed for the following keywords: ‘early PCI’, ‘immediate PCI’,
‘thrombolysis’, ‘fibrinolysis’, ‘PCI’, ‘angioplasty’, ‘invasive strategy
post-thrombolysis’, ‘early PCI post-thrombolysis’ and was restricted to
English language and peer-reviewed journals. Reference lists of
identified studies were reviewed to ensure that potential eligible trials
were not excluded from the search.
Exclusion criteria: studies that utilized non fibrin-specific agents,
studies on facilitated angioplasty, and balloon-PTCA trials. Trials
included were those designed to investigate the benefits and
feasibility of a routine invasive strategy with immediate transfer for
early PCI after successful fibrinolysis in patients in whom primary PCI
is not readily available, and therefore trials on facilitated PCI were
excluded.
Relevant 30-day: (i) all-cause mortality, (ii) reinfarction, (iii) death or
outcome(s) reinfarction, (iv) recurrent ischemia, (v) major bleeding, and (vi)
stroke.
Key findings There were 3.8% and 3.3% deaths in the standard conservative group
and the early invasive group, respectively, without significant
differences between the two strategies (OR = 0.87; 95% CI = 0.59–

1.30; P = 0.51). Early PCI after successful fibrinolysis reduced the rate
of reinfarction (OR = 0.55, 95% CI = 0.36-0.82; P = 0.003), the
combined endpoint death or reinfarction (OR = 0.65, 95% CI = 0.49-
0.88; P = 0.004) and recurrent ischaemia (OR = 0.25, 95% CI = 0.13-
0.49; P < 0.001) at 30-day follow-up. These advantages were achieved
without a significant increase in major bleeding (OR= 0.93, 95% CI=
0.67-1.34; P = 0.70) or stroke (OR = 0.63, 95% CI = 0.31-1.26; P = 0.21).
Conclusion(s) Early routine PCI after fibrinolysis in STEMI patients significantly
reduced reinfarction and recurrent ischaemia at 1 month, with no
significant impact on all-cause mortality and adverse bleeding events
compared to standard therapy.
110
Reference Madan M, Halvorsen S, Di Mario C, Tan M, Westerhout CM, Cantor
WJ, Le May MR, Borgia F, Piscione F, Scheller B, Armstrong PW,
Fernandez-Aviles F, Sanchez PL, Graham JJ, Yan AT, Goodman SG.
Relationship between time to invasive assessment and clinical
outcomes of patients undergoing an early invasive strategy after
fibrinolysis for ST-segment elevation myocardial infarction: a patient-
level analysis of the randomized early routine invasive clinical trials.
JACC Cardiovasc Interv. 2015 Jan;8(1 Pt B):166-174. doi:
10.1016/j.jcin.2014.09.005. Epub 2014 Oct 31. PMID: 25616922.
Study Type Patient-level meta-analysis from 6 randomized trials
Intervention Early angiography after fibrinolysis.
Main incl/excl The study population was the early invasive cohort from the below list
criteria of studies (i.e., STEMI patients undergoing fibrinolysis and randomized
to early angiography). Furthermore, the patients included in this
analysis were those STEMI patients from trials in which the median
time from fibrinolysis to angiography was <12 h.
Randomized trials conforming the collaborative patient-pooled

database: CAPITAL AMI (Combined Angioplasty and Pharmacological
Intervention Versus Thrombolysis Alone in Acute Myocardial
Infarction) study (N = 170), SIAM III (Southwest German Interventional
Study in Acute Myocardial Infarction) (N = 197), WEST (Which Early ST-
Elevation Myocardial Infarction Therapy) study (N = 221), NORDISTEMI
(NORwegian study on DIstrict treatment of ST-Elevation Myocardial
Infarction) (N = 266), CARESS-in-AMI (Combined Abciximab Reteplase
Stent Study in Acute Myocardial Infarction) study (N = 597), and the
TRANSFER-AMI (Trial of Routine Angioplasty and Stenting after
Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) (N
= 1,059).The GRACIA-1 study was not included in the present analysis
because the invasive approach was undertaken up to 24 h post-
fibrinolysis (median time from fibrinolysis to angiography of 17 h)
Relevant The primary endpoint was 30-day death or reinfarction. The key
outcome(s) secondary endpoint was in-hospital major bleeding. The relationship
between fibrinolysis to angiography time and symptom onset to
angiography time with outcomes was studied using 2- and 4-h

intervals, respectively, and in multivariable models.
Key findings The median fibrinolysis to angiography time was 165 min, and the
median symptom onset to angiography time was 5.33 h. The primary
and key secondary endpoints occurred in 5.7% and 4.7%, respectively.
Early angiography (<2 h) after fibrinolysis was not associated with
increased bleeding. Recurrent ischemia increased with increasing
fibrinolysis to angiography time (3.7% to 7.9%, p for trend = 0.02). 30-
day and 1-year death/reinfarction and 30-day recurrent ischemia
increased significantly with increasing symptom onset to angiography
time.
111
Conclusion(s) Very early angiography (<2 h) after fibrinolysis was not associated with
an increased risk of 30-day death/reinfarction or in-hospital major
bleeding, and angiography within 4 h after fibrinolysis was associated
with reduced 30-day recurrent ischemia. A shorter symptom onset to
angiography time (<4 h) was associated with reduced 30-day and 1-
year death/reinfarction and 30-day recurrent ischemia.
112
Recommendation Table 8 — Recommendations for cardiac arrest and out-of-
hospital cardiac arrest
Reference Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut
JF, Carli P. Immediate coronary angiography in survivors of out-of-
hospital cardiac arrest. N Engl J Med. 1997 Jun 5;336(23):1629-33. doi:
10.1056/NEJM199706053362302. PMID: 9171064.
Study Type Prospective observational study
Nº patients
84 participants
Intervention Coronary angiography
Evidence
Main incl/excl Survivors of out-of-hospital cardiac arrest between the ages of 30 and
criteria 75 years. Successfully resuscitated patients were included if they were
between 30 and 75 years of age, if the sudden cardiac arrest occurred
within six hours of the onset of symptoms in patients who were
previously leading a normal life, and if there was no obvious
noncardiac cause of cardiac arrest.
Relevant Prevalence of coronary artery disease and acute coronary-artery
outcome(s) occlusion, and the potential influence of primary angioplasty on
survival during hospitalization.
Key findings Sixty of the 84 patients had clinically significant coronary disease on
angiography, 40 of whom had coronary-artery occlusion (48%).
Angioplasty was attempted in 37 patients and was technically
successful in 28. The in-hospital survival rate was 38%. Multivariate
logistic-regression analysis revealed that successful angioplasty was
associated with survival (odds ratio = 5.2; 95 % CI, 1.1 to 24.5; P =
0.04).
Conclusion(s) Acute coronary-artery occlusion is frequent in survivors of out-of-
hospital cardiac arrest. In this observational study, accurate diagnosis
by immediate coronary angiography improved survival after
adjustment for confounding.
113
Acronym Coronary Angiography after Cardiac Arrest (COACT) trial
Reference Lemkes JS, Janssens GN, van der Hoeven NW, Jewbali LSD, Dubois EA,
Meuwissen M, Rijpstra TA, Bosker HA, Blans MJ, Bleeker GB, Baak R,
Vlachojannis GJ, Eikemans BJW, van der Harst P, van der Horst ICC,
Voskuil M, van der Heijden JJ, Beishuizen A, Stoel M, Camaro C, van
der Hoeven H, Henriques JP, Vlaar APJ, Vink MA, van den Bogaard B,
Heestermans TACM, de Ruijter W, Delnoij TSR, Crijns HJGM, Jessurun
GAJ, Oemrawsingh PV, Gosselink MTM, Plomp K, Magro M, Elbers
PWG, van de Ven PM, Oudemans-van Straaten HM, van Royen N.
Coronary Angiography after Cardiac Arrest without ST-Segment
Elevation. N Engl J Med. 2019 Apr 11;380(15):1397-1407. doi:
Study Type Investigator-initiated, randomized, open-label, multicenter trial
Nº patients
552 participants
Intervention immediate coronary angiography vs. coronary angiography that was
Evidence
delayed until after neurologic recovery

Main incl/excl Patients were eligible for the trial if they had had an out-of-hospital
criteria cardiac arrest with an initial shockable rhythm and were unconscious
after the return of spontaneous circulation. Patients were excluded if
they had signs of STEMI on ECG in the emergency department, shock,
or an obvious noncoronary cause of the arrest.
Relevant The primary endpoint was survival at 90 days. Secondary endpoints
outcome(s) included survival at 90 days with good cerebral performance or mild
or moderate disability, myocardial injury, duration of catecholamine
support, markers of shock, recurrence of ventricular tachycardia,
duration of mechanical ventilation, major bleeding, occurrence of

acute kidney injury, need for renal-replacement therapy, time to
target temperature, and neurologic status at discharge from the
intensive care unit.
Key findings At 90 days, 64.5% and 67.2% in the immediate angiography group and
the delayed angiography group, respectively, were alive (odds ratio =
0.89; 95% CI = 0.62 to 1.27; P=0.51).
Conclusion(s) Among patients who had been successfully resuscitated after out-of-
hospital cardiac arrest and had no signs of STEMI, a strategy of
immediate angiography did not increased survival compared with a
strategy of delayed angiography.
114
Acronym Immediate Unselected Coronary Angiography Versus Delayed Triage
in Survivors of Out-of-hospital Cardiac Arrest Without ST-segment
Elevation (TOMAHAWK)
Reference Desch S, Freund A, Akin I, Behnes M, Preusch MR, Zelniker TA, Skurk C,
Landmesser U, Graf T, Eitel I, Fuernau G, Haake H, Nordbeck P,
Hammer F, Felix SB, Hassager C, Engstrøm T, Fichtlscherer S, Ledwoch
J, Lenk K, Joner M, Steiner S, Liebetrau C, Voigt I, Zeymer U, Brand M,
Schmitz R, Horstkotte J, Jacobshagen C, Pöss J, Abdel-Wahab M, Lurz
P, Jobs A, de Waha-Thiele S, Olbrich D, Sandig F, König IR, Brett S, Vens
M, Klinge K, Thiele H; TOMAHAWK Investigators. Angiography after
Out-of-Hospital Cardiac Arrest without ST-Segment Elevation. N Engl J
Med. 2021 Dec 30;385(27):2544-2553. doi: 10.1056/NEJMoa2101909.
Epub 2021 Aug 29. PMID: 34459570.
Study Type Investigator-initiated, randomized, international, multicenter, open-
label trial

Evidence
Intervention Immediate coronary angiography (immediate-angiography group) vs.

initial intensive care assessment with delayed or selective angiography
(delayed-angiography group).
Main incl/excl Patients with successfully resuscitated out-of-hospital cardiac arrest of
criteria possible coronary origin. All the patients had no evidence of ST-
segment elevation on postresuscitation electrocardiography.
Relevant The primary endpoint was death from any cause at 30 days.
outcome(s) Secondary endpoints included a composite of death from any cause or
severe neurologic deficit at 30 days.
Key findings At 30 days, 54.0% and 56.0% in the immediate-angiography group and
the delayed-angiography group, respectively, had died (HR = 1.28;
95% CI = 1.00 to 1.63; P = 0.06). The composite of death or severe
neurologic deficit occurred more frequently in the immediate-
angiography group (64.3%) than in the delayed-angiography group
(55.6%), for a relative risk of 1.16 (95% CI, 1.00 to 1.34).
Conclusion(s) Among patients with resuscitated out-of-hospital cardiac arrest

without ST-segment elevation, immediate angiography provided no
benefit over a delayed or selective strategy in terms of 30-day
mortality.
115
Acronym Target Temperature Management 33°C versus 36°C after Out-of-
Hospital Cardiac Arrest (TTM) trial
Reference Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C,
Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P,
Wanscher M, Wise MP, Åneman A, Al-Subaie N, Boesgaard S, Bro-
Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP,
Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M,
Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial
Investigators. Targeted temperature management at 33°C versus 36°C
after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. doi:
Study Type Randomized clinical trial recruiting patients in 36 intensive care units
in Europe and Australia

Intervention Targeted temperature management at either 33°C vs. 36°C.
Main incl/excl Patients 18 years of age or older who were unconscious (a score of <8
criteria on the Glasgow Coma Scale) on admission to the hospital after out-of-
hospital cardiac arrest of presumed cardiac cause, irrespective of the
initial rhythm. Patients had > 20 consecutive minutes of spontaneous
circulation after resuscitation.
The main exclusion criteria were an interval from the return of
spontaneous circulation to screening > 240 minutes, unwitnessed
arrest with asystole as the initial rhythm, suspected or known acute
intracranial hemorrhage or stroke, and a body temperature < 30°C.
Relevant The primary endpoint was all-cause mortality through the end of the
outcome(s) trial. Secondary outcomes included a composite of poor neurologic
function or death at 180 days, as evaluated with the Cerebral
Performance Category (CPC) scale and the modified Rankin scale.
Key findings At the end of the trial, 50% and 48% of the patients in the 33°C group
and the patients in the 36°C group, respectively, had died (hazard
ratio with a temperature of 33°C, 1.06; 95% CI, 0.89 to 1.28; P=0.51).
At the 180-day follow-up, 54% and 52% of the patients in the 33°C
group and the patients in the 36°C group, respectively, had died or
had poor neurologic function according to the CPC (risk ratio, 1.02;
95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin
scale, the comparable rate was 52% in both groups (risk ratio, 1.01;
95% CI, 0.89 to 1.14; P=0.87).
Conclusion(s) In unconscious survivors of out-of-hospital cardiac arrest of presumed
cardiac cause, hypothermia at a targeted temperature of 33°C did not
improve all-cause mortality as compared with a targeted temperature
of 36°C.
116
Acronym Targeted Hypothermia Versus Targeted Normothermia After Out-of-
hospital Cardiac Arrest (TTM-2)
Reference Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullén S,
Rylander C, Wise MP, Oddo M, Cariou A, Bělohlávek J, Hovdenes J,
Saxena M, Kirkegaard H, Young PJ, Pelosi P, Storm C, Taccone FS,
Joannidis M, Callaway C, Eastwood GM, Morgan MPG, Nordberg P,
Erlinge D, Nichol AD, Chew MS, Hollenberg J, Thomas M, Bewley J,
Sweet K, Grejs AM, Christensen S, Haenggi M, Levis A, Lundin A,
Düring J, Schmidbauer S, Keeble TR, Karamasis GV, Schrag C, Faessler
E, Smid O, Otáhal M, Maggiorini M, Wendel Garcia PD, Jaubert P, Cole
JM, Solar M, Borgquist O, Leithner C, Abed-Maillard S, Navarra L,
Annborn M, Undén J, Brunetti I, Awad A, McGuigan P, Bjørkholt Olsen
R, Cassina T, Vignon P, Langeland H, Lange T, Friberg H, Nielsen N;
TTM2 Trial Investigators. Hypothermia versus Normothermia after
Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun
17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591. PMID:
34133859.
Study Type Investigator-initiated superiority trial
Intervention Targeted hypothermia at 33°C, followed by controlled rewarming, or
targeted normothermia with early treatment of fever (body

temperature, ≥37.8°C).
Main incl/excl Patients ≥18 years of age who had been admitted to the hospital after
criteria out-of-hospital cardiac arrest of a presumed cardiac or unknown
cause, irrespective of the initial rhythm. All the patients were
unconscious and not able to obey verbal commands and did not have
a verbal response to pain. They had more than 20 consecutive
minutes of spontaneous circulation after resuscitation.
The main exclusion criteria were an interval from return of
spontaneous circulation to screening of more than 180 minutes,
unwitnessed cardiac arrest with asystole as the initial rhythm, and
limitations in care.
Relevant The primary outcome was death from any cause at 6 months.
outcome(s) Secondary outcomes included functional outcome at 6 months as
assessed with the modified Rankin scale.
Key findings At 6 months, 50% and 48% in the hypothermia group and the
normothermia group, respectively, had died (relative risk with
hypothermia, 1.04; 95% CI, 0.94 to 1.14; P = 0.37).
Among the 1747 patients in whom the functional outcome was
assessed, moderately severe disability or worse (modified Rankin scale
score ≥4) was found in 55% and 55% in the hypothermia group and
the normothermia group, respectively (relative risk with hypothermia,
1.00; 95% CI, 0.92 to 1.09).
Conclusion(s) In patients with coma after out-of-hospital cardiac arrest, targeted
hypothermia did not reduce the incidence of death by 6 months than
targeted normothermia.
117
Recommendation Table 9 — Recommendations for cardiogenic shock
Acronym Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock
(CULPRIT-SHOCK) trial
Reference Thiele H, Akin I, Sandri M, Fuernau G, de Waha S, Meyer-Saraei R,
Nordbeck P, Geisler T, Landmesser U, Skurk C, Fach A, Lapp H, Piek JJ,
Noc M, Goslar T, Felix SB, Maier LS, Stepinska J, Oldroyd K, Serpytis P,
Montalescot G, Barthelemy O, Huber K, Windecker S, Savonitto S,
Torremante P, Vrints C, Schneider S, Desch S, Zeymer U; CULPRIT-
SHOCK Investigators. PCI Strategies in Patients with Acute Myocardial
Infarction and Cardiogenic Shock. N Engl J Med. 2017 Dec
21;377(25):2419-2432. doi: 10.1056/NEJMoa1710261. Epub 2017 Oct
30. PMID: 29083953.
Study Type Investigator-initiated, randomized, open-label, multicenter trial
Nº patients 706
Intervention PCI of the culprit lesion only, with the option of staged
revascularization of nonculprit lesions, vs. immediate multivessel PCI.

Main incl/excl Patients had acute myocardial infarction with cardiogenic shock, with
criteria planned early revascularization by means of PCI, multivessel coronary
artery disease, and an identifiable culprit lesion.
Exclusion criteria were resuscitation for longer than 30 minutes, no
intrinsic heart action, an assumed severe deficit in cerebral function
with fixed dilated pupils, an indication for primary urgent coronary-
artery bypass grafting, single-vessel coronary artery disease, a
mechanical cause of cardiogenic shock, the onset of shock more than
12 hours before randomization, an age of more than 90 years, shock
with a noncardiogenic cause, massive pulmonary embolism, known
severe renal insufficiency, and other severe concomitant disease
associated with a life expectancy of < 6 months.
Relevant The primary endpoint was a composite of death or severe renal failure
outcome(s) leading to renal-replacement therapy within 30 days after
randomization. Safety end points included bleeding and stroke
Key findings At 30 days, the composite primary endpoint of death or renal-
replacement therapy had occurred in 45.9% and 55.4% in the culprit-

lesion-only PCI group and the multivessel PCI group, respectively
(relative risk, 0.83; 95% CI, 0.71 to 0.96; P=0.01). Consistent findings
were observed for the individual components of the composite:
- Relative risk of death, 0.84 (95% CI, 0.72 to 0.98; P=0.03),
- Relative risk of of renal-replacement therapy, 0.71 (95% CI, 0.49 to
1.03; P=0.07).
Conclusion(s) Among patients who had multivessel coronary artery disease and
acute myocardial infarction with cardiogenic shock, the 30-day risk of
a composite of death or severe renal failure leading to renal-
replacement therapy was lower among those who initially underwent
118
PCI of the culprit lesion only than among those who underwent
immediate multivessel PCI.
Acronym Should We Emergently Revascularize Occluded Coronaries for
Cardiogenic Shock (SHOCK) trial
Reference Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD,
Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early
revascularization in acute myocardial infarction complicated by
cardiogenic shock. SHOCK Investigators. Should We Emergently
Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J
Med. 1999 Aug 26;341(9):625-34. doi:
10.1056/NEJM199908263410901. PMID: 10460813.
Intervention Emergency revascularization vs. initial medical stabilization

Main incl/excl Patients had ST-segment elevation, a Q-wave infarction, a new left
criteria bundle-branch block, or a posterior infarction with anterior ST-
segment depression, complicated by shock due predominantly to left
ventricular dysfunction. Cardiogenic shock was confirmed by both
clinical and hemodynamic criteria. The onset of shock had to be within
36 hours of infarction, and randomization had to occur as soon as
possible and no more than 12 hours after the diagnosis of shock. The
exclusion criteria were severe systemic illness, mechanical or other
cause of shock, severe valvular disease, dilated cardiomyopathy, the
inability of care givers to gain access for catheterization, and
unsuitability for revascularization.
Relevant The primary endpoint was mortality from all causes at 30 days. Six-
outcome(s) month survival was a secondary endpoint.
Key findings 97% of the patients assigned to revascularization underwent early
coronary angiography, and 87 % underwent revascularization; whereas
only 2.7% of the patients assigned to medical therapy crossedover to

early revascularization without clinical indication.
All-cause mortality at 30 days did not differ significantly between the
revascularization and medical-therapy groups (46.7% and 56.0%,
respectively; difference, -9.3 percent; 95 % CI for the difference, -20.5
to 1.9 percent; P=0.11). However, six-month mortality was lower in the
revascularization group than in the medical-therapy group (50.3% vs.
63.1%, P=0.027).
Conclusion(s) In patients with cardiogenic shock, emergency revascularization did

not significantly reduce all-cause mortality at 30 days. However, after
six months there was a significant survival benefit.
119
Acronym Should We Emergently Revascularize Occluded Coronaries for
Cardiogenic Shock (SHOCK) trial
Reference White HD, Assmann SF, Sanborn TA, Jacobs AK, Webb JG, Sleeper LA,
Wong CK, Stewart JT, Aylward PE, Wong SC, Hochman JS. Comparison
of percutaneous coronary intervention and coronary artery bypass
grafting after acute myocardial infarction complicated by cardiogenic
shock: results from the Should We Emergently Revascularize Occluded
Coronaries for Cardiogenic Shock (SHOCK) trial. Circulation. 2005 Sep
PMID: 16186436.
Study Type Secondary analysis aimed to compare the effects of PCI and CABG on
Details and Quality
30-day and 1-year survival in the SHOCK trial.

of Evidence
Nº patients Of the 302 patients from the trial cohort, 128 had emergency
revascularization.
Intervention Coronary artery bypass grafting vs. percutaneous coronary intervention
Main incl/excl Described in the previous table (criteria for SHOCK trial)
criteria
Relevant 30-day and 1-year survival in the SHOCK trial.
outcome(s)
Key findings Eighty-one patients (63.3%) had PCI, and 47 (36.7%) had CABG. The
median time from randomization to intervention was 0.9 hours for PCI
and 2.7 hours for CABG. There were more patients with diabetes
(48.9% vs. 26.9%; P=0.02), 3-vessel disease (80.4% vs. 60.3%; P=0.03),
and left main coronary disease (41.3% vs. 13.0%; P=0.001) in the CABG
group.
At 30 days, the survival rates were 55.6% and 57.4% in the PCI group
and the CABG group, respectively (P=0.86). At 1 year, the survival rates
were 51.9% and 46.8%, respectively (P=0.71).
Conclusion(s) Among SHOCK trial patients randomized to emergency

revascularization, survival rates were similar between those patients
receiving CABG and those receiving PCI. Since the mode of
revascularization was not randomised, differences were found in
baseline characteristics between groups.
120
Acronym Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial
Reference Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J,
Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I,
Hambrecht R, Fuhrmann J, Böhm M, Ebelt H, Schneider S, Schuler G,
Werdan K; IABP-SHOCK II Trial Investigators. Intraaortic balloon
support for myocardial infarction with cardiogenic shock. N Engl J
Med. 2012 Oct 4;367(14):1287-96. doi: 10.1056/NEJMoa1208410.
Epub 2012 Aug 26. PMID: 22920912.
Study Type Randomised, prospective, open-label, multicenter trial
Intervention Intraaortic balloon counterpulsation (IABP group) vs. no intraaortic
balloon counterpulsation (control group).
Main incl/excl Patients with cardiogenic shock complicating acute myocardial
criteria infarction. All patients were expected to undergo early

revascularization (by means of percutaneous coronary intervention or
bypass surgery).
Patients were not excluded if they had undergone resuscitation for

more than 30 minutes; had no intrinsic heart action; were in a coma
with fixed dilatation of pupils that was not induced by drugs; had a
mechanical cause of cardiogenic shock; had onset of shock more than
12 hours before screening; had a massive pulmonary embolism,
severe peripheral arterial disease precluding insertion of an intraaortic
balloon pump, or aortic regurgitation greater than grade II in severity;
were older than 90 years of age; were in shock as a result of a
condition other than acute myocardial infarction; or had a severe
concomitant disease associated with a life expectancy of less than 6
months.
Relevant The primary efficacy endpoint was 30-day all-cause mortality. Safety
outcome(s) assessments included major bleeding, peripheral ischemic
complications, sepsis, and stroke.
Key findings At 30 days, 39.7% and 41.3% patients in the IABP group and the
control group, respectively, had died (relative risk with IABP, 0.96;
95% CI, 0.79 to 1.17; P=0.69).
The IABP group and the control group did not differ significantly with
respect to the rates of major bleeding (3.3% and 4.4%, respectively;
P=0.51), peripheral ischemic complications (4.3% and 3.4%, P=0.53),
sepsis (15.7% and 20.5%, P=0.15), and stroke (0.7% and 1.7%, P=0.28).
Conclusion(s) In patients with cardiogenic shock complicating acute myocardial

infarction for whom an early revascularization strategy was planned,
the use of intraaortic balloon counterpulsation did not significantly
reduce the primary endpoint of 30-day mortality.
121
Acronym Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II)
trial
Reference Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J,
de Waha A, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S,
Eitel I, Hambrecht R, Lauer B, Böhm M, Ebelt H, Schneider S, Werdan
K, Schuler G; Intraaortic Balloon Pump in cardiogenic shock II (IABP-
SHOCK II) trial investigators. Intra-aortic balloon counterpulsation in
acute myocardial infarction complicated by cardiogenic shock (IABP-
SHOCK II): final 12 month results of a randomised, open-label trial.
Lancet. 2013 Nov 16;382(9905):1638-45. doi: 10.1016/S0140-
6736(13)61783-3. Epub 2013 Sep 3. PMID: 24011548.
Study Type Long-term follow-up of a randomised, prospective, open-label,
multicenter trial (secondary publication)
Nº patients Of the original sample size of 600 participants, 595 patients
completed 12 month follow-up or had an event
Intervention Intraaortic balloon counterpulsation (IABP group) vs. no intraaortic
balloon counterpulsation (control group).
Main incl/excl Patients with cardiogenic shock complicating acute myocardial

criteria infarction. All patients were expected to undergo early
revascularization (by means of percutaneous coronary intervention or
bypass surgery).
Patients were not excluded if they had undergone resuscitation for

more than 30 minutes; had no intrinsic heart action; were in a coma
with fixed dilatation of pupils that was not induced by drugs; had a
mechanical cause of cardiogenic shock; had onset of shock more than
12 hours before screening; had a massive pulmonary embolism,
severe peripheral arterial disease precluding insertion of an
intraaortic balloon pump, or aortic regurgitation greater than grade II
in severity; were older than 90 years of age; were in shock as a result
of a condition other than acute myocardial infarction; or had a severe
concomitant disease associated with a life expectancy of less than 6
months.
Relevant The primary efficacy endpoint of the primary publication was 30 day
outcome(s) all-cause mortality. In this study, it was evaluated 6 and 12 month
follow-up, in addition to quality-of-life assessment for all survivors
with the Euroqol-5D questionnaire. A masked central committee

adjudicated clinical outcomes. Patients and investigators were not
masked to treatment allocation.
Key findings Death within 12 months occurred in 52% and 51% in the IABP group
and the control group, respectively (relative risk [RR] 1.01, 95% CI
0.86-1.18, p=0.91). For survivors, quality-of-life measures including
mobility, self-care, usual activities, pain or discomfort, and anxiety or
depression did not differ significantly between study arms.
Conclusion(s) In patients undergoing early revascularisation for myocardial
infarction complicated by cardiogenic shock, IABP did not reduce 12
month all-cause mortality, and did not improve quality of life.
122
Recommendation Table 10 — Recommendations for in-hospital management
Reference Melberg T, Jørgensen M, Ørn S, Solli T, Edland U, Dickstein K. Safety

and health status following early discharge in patients with acute
myocardial infarction treated with primary PCI: a randomized trial. Eur
J Prev Cardiol. 2015 Nov;22(11):1427-34. doi:
10.1177/2047487314559276. Epub 2014 Nov 14. PMID: 25398704.
Study Type Single-center randomised clinical trial.

Intervention discharge ≤3 days or usual care
Main incl/excl All surviving PPCI patients at a single teaching hospital were
criteria considered eligible if the Zwolle risk score ≤3.
Exclusion criteria were: need for artificial respiration therapy or
intraaortic counterpulsation pump, re-infarction, post AMI ischaemia,
need for urgent repeat invasive procedures, non-cardiac complication
(bleeding, stroke, renal failure) or concomitant diseases likely to
increase length of hospital stay, refusal of early discharge or study
inclusion by the patient or caring physician, and impossible early
discharge due to social, nursing or family reasons.
Relevant Health status and all readmissions up to 30 days follow-up were
outcome(s) tracked.
Key findings Of 425 consecutive PPCI patients, 215 (50.6%) were.
During the 30-day follow-up there were no deaths, and similar
readmission rate (3.7% vs. 2.8%, p = 0.69 in the early vs. usual
discharge group, respectively). There was no difference in the 30 days
health status measurements.
Conclusion(s) Discharging low-risk PPCI patients (according to a Zwolle risk score ≤3)
within three days seems feasible and safe.
123
Recommendation Table 11 — Recommendations for technical aspects of
invasive strategies
Acronym Phase IIIb Study Minimizing Adverse Haemmhorragic Events by

TRansradial Access Site and Systemic Implementation of angioX
(MATRIX)
Reference Valgimigli M, Gagnor A, Calabró P, Frigoli E, Leonardi S, Zaro T,
Rubartelli P, Briguori C, Andò G, Repetto A, Limbruno U, Cortese B,
Sganzerla P, Lupi A, Galli M, Colangelo S, Ierna S, Ausiello A,
Presbitero P, Sardella G, Varbella F, Esposito G, Santarelli A, Tresoldi
S, Nazzaro M, Zingarelli A, de Cesare N, Rigattieri S, Tosi P, Palmieri C,
Brugaletta S, Rao SV, Heg D, Rothenbühler M, Vranckx P, Jüni P;
MATRIX Investigators. Radial versus femoral access in patients with
acute coronary syndromes undergoing invasive management: a
randomised multicentre trial. Lancet. 2015 Jun 20;385(9986):2465-76.
doi: 10.1016/S0140-6736(15)60292-6. Epub 2015 Mar 16. PMID:
25791214.
Study Type Randomised, multicentre, superiority trial
Details and Quality
of Evidence

Intervention Transradial vs. transfemoral access
Main incl/excl Patients with acute coronary syndrome with or without ST-segment
criteria elevation myocardial infarction who were about to undergo coronary
angiography and percutaneous coronary intervention.
Relevant The 30-day coprimary outcomes were major adverse cardiovascular
outcome(s) events, defined as death, myocardial infarction, or stroke, and net
adverse clinical events, defined as major adverse cardiovascular
events or Bleeding Academic Research Consortium (BARC) major
bleeding unrelated to coronary artery bypass graft surgery.
Key findings Major adverse cardiovascular events occurred in 8.8% and 10.3%
patients with radial and femoral access, respectively (rate ratio [RR]
0.85, 95% CI 0.74-0.99; p=0.0307), non-significant at α of 0.025.
Net adverse clinical events occurred in 9.8% and 11.7% in patients

with radial and femoral access (0.83, 95% CI 0.73-0.96; p=0.0092). The
difference was driven by BARC major bleeding unrelated to CABG
(1.6% vs 2.3%, RR 0.67, 95% CI 0.49-0.92; p=0.013) and all-cause
mortality (1.6% vs 2.2%, RR 0.72, 95% CI 0.53-0.99; p=0.045).
Conclusion(s) In patients with acute coronary syndrome undergoing invasive

management, radial as compared with femoral access did not reduce
major adverse cardiovascular event at a pre-spefified α of 0.025.
However, it reduced net adverse clinical events, through a reduction
in major bleeding and all-cause mortality.
124
Acronym clinical Evaluation of the Xience-V stent in Acute Myocardial
INfArcTION (EXAMINATION)
Reference Sabaté M, Brugaletta S, Cequier A, Iñiguez A, Serra A, Jiménez-
Quevedo P, Mainar V, Campo G, Tespili M, den Heijer P, Bethencourt
A, Vazquez N, van Es GA, Backx B, Valgimigli M, Serruys PW. Clinical
outcomes in patients with ST-segment elevation myocardial infarction
treated with everolimus-eluting stents versus bare-metal stents
(EXAMINATION): 5-year results of a randomised trial. Lancet. 2016 Jan
23;387(10016):357-366. doi: 10.1016/S0140-6736(15)00548-6. Epub
2015 Oct 29. PMID: 26520230.
Study Type Multicentre, multinational, prospective, randomised, two-arm,
singleblind, controlled trial conducted in Italy, Spain, and the
Netherlands.
Intervention everolimus-eluting stents (EES) vs. bare-metal stents (BMS)

Main incl/excl The inclusion criteria were any adult presenting with ST elevation
criteria myocardial infarction and meeting the following electrocardiograph
(ECG) criteria: at least 1 mm in two or more standard leads, at least 2
mm in two or more contiguous precordial leads, or new left bundle-
branch block within the first 48 h after onset of symptoms that
required emergency PCI, and a vessel size of 2·25–4·00 mm without
other anatomical restrictions.
Exclusion criteria were age younger than 18 years, pregnancy, chronic
treatment with anti-vitamin K agents, ST-elevation myocardial
infarction secondary to stent thrombosis, and known intolerance to
aspirin, clopidogrel, heparin, stainless steel, everolimus, or contrast
material.
Relevant At 5 years, it was assessed the combined patient-oriented outcome of
outcome(s) all-cause death, any myocardial infarction, or any revascularisation.

Key findings The patient-oriented endpoint occurred in 21% and 26% patients in
the EES group and the BMS group (HR = 0.80, 95% CI = 0.65-0.98;
p=0.033). This difference was mainly driven by a reduced rate of all-
cause mortality (9% vs. 12%; HR = 0.72, 95% CI = 0.52-0.10; p=0.047).
Conclusion(s) In patients with ST-segment elevation myocardial infarction, those
receiving EES reduced the pecentage of patient-oriented outcomes
compared with patients receiving BMS.
125
Acronym Norwegian Coronary Stent Trial (NORSTENT)
Reference Bønaa KH, Mannsverk J, Wiseth R, Aaberge L, Myreng Y, Nygård O,
Nilsen DW, Kløw NE, Uchto M, Trovik T, Bendz B, Stavnes S,
Bjørnerheim R, Larsen AI, Slette M, Steigen T, Jakobsen OJ, Bleie Ø,
Fossum E, Hanssen TA, Dahl-Eriksen Ø, Njølstad I, Rasmussen K,
Wilsgaard T, Nordrehaug JE; NORSTENT Investigators. Drug-Eluting or
Bare-Metal Stents for Coronary Artery Disease. N Engl J Med. 2016
Sep 29;375(13):1242-52. doi: 10.1056/NEJMoa1607991. Epub 2016
Aug 29. PMID: 27572953.
Study Type Multicenter, randomized trial conducted at all eight centers in Norway
that perform PCI.
Nº patients 9013 patients who had stable or unstable coronary artery disease to
undergo PCI
Intervention implantation of contemporary drug-eluting stents vs. bare-metal
stents
Main incl/excl Men and women who were at least 18 years of age and who
criteria presented with stable angina or an acute coronary syndrome, had
lesions in native coronary arteries or coronary-artery grafts (all of
which were amenable for implantation of either drug-eluting stents or
bare-metal stents), had a Norwegian national identification number
and were able to communicate in Norwegian.
Patients were excluded if they had previously been treated with a
coronary stent, had a bifurcation lesion requiring treatment with a
two-stent technique, had a serious medical condition other than
coronary artery disease with a life expectancy of less than 5 years,
were participating in another randomized trial, had intolerable side
effects to any drug in use during PCI or contraindications to long-term
dual-antiplatelet therapy or had been prescribed warfarin, or were
not able to follow the trial protocol.
Relevant The primary outcome was a composite of death from any cause and
outcome(s) nonfatal spontaneous myocardial infarction after a median of 5 years
of follow-up. Secondary outcomes included repeat revascularization,
stent thrombosis, and quality of life.
Key findings At 6 years, the rates of the primary outcome were 16.6% and 17.1% in
the group receiving drug-eluting stents and the group receiving bare-
metal stents, respectively (HR = 0.98; 95% CI = 0.88 to 1.09; P=0.66).
There were no significant between-group differences in the
components of the primary outcome. The 6-year rates of any repeat
revascularization were 16.5% and 19.8% in the group receiving drug-
eluting stents and the group receiving bare-metal stents, respectively
(HR = 0.76; 95% CI = 0.69 to 0.85; P<0.001); the rates of definite stent
thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-
life measures did not differ significantly between the two groups.
Conclusion(s) In patients undergoing PCI, there were no significant differences
between those receiving drug-eluting stents and those receiving bare-
metal stents in the composite outcome of death from any cause and
nonfatal spontaneous myocardial infarction.
126
Acronym Comparison of Biolimus Eluted From an Erodible Stent Coating With
Bare Metal Stents in Acute ST-Elevation Myocardial Infarction
(COMFORTABLE AMI) trial
Reference Räber L, Yamaji K, Kelbæk H, Engstrøm T, Baumbach A, Roffi M, von
Birgelen C, Taniwaki M, Moschovitis A, Zaugg S, Ostojic M, Pedrazzini
G, Karagiannis-Voules DA, Lüscher TF, Kornowski R, Tüller D, Vukcevic
V, Heg D, Windecker S. Five-year clinical outcomes and intracoronary
imaging findings of the COMFORTABLE AMI trial: randomized
comparison of biodegradable polymer-based biolimus-eluting stents
with bare-metal stents in patients with acute ST-segment elevation
myocardial infarction. Eur Heart J. 2019 Jun 21;40(24):1909-1919. doi:
10.1093/eurheartj/ehz074. PMID: 30851032.
Study Type Multicentre, randomized, assessor-blinded, superiority trial.
Details and
Quality of
Evidence
Intervention biolimus-eluting stents (BESs) with biodegradable polymer as

compared with bare-metal stent (BMS)
Main incl/excl 1161 patients presenting with STEMI and undergoing primary PCI
criteria between 19 September 2009 and 25 January 2011 in 11 centres
Relevant The prespecified primary endpoint was the composite of MACE
outcome(s) including cardiac death, target vessel-related reinfarction, and
ischaemia-driven TLR within 12 months.

Key findings At 5 years, BES reduced the risk of MACE (HR = 0.56, 95% CI = 0.39-
0.79, P = 0.001), driven by lower risks for target vessel-related
reinfarction (HR = 0.44, 95% CI = 0.22-0.87, P = 0.02) and ischaemia-
driven target lesion revascularization (HR = 0.41, 95% CI = 0.25-0.66, P
< 0.001).
Conclusion(s) Compared with BMS, the implantation of biodegradable polymer-
coated BES resulted in a lower 5-year rate of MACE in patients with
STEMI undergoing primary PCI.
127
Acronym Impact of Intravascular Ultrasound Guidance on Outcomes of Xience
Prime Stents in Long Lesions (IVUS-XPL) trial
Reference Hong SJ, Kim BK, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Kang TS,
Kang WC, Her AY, Kim YH, Hur SH, Hong BK, Kwon H, Jang Y, Hong MK;
IVUS-XPL Investigators. Effect of Intravascular Ultrasound-Guided vs
Angiography-Guided Everolimus-Eluting Stent Implantation: The IVUS-
XPL Randomized Clinical Trial. JAMA. 2015 Nov 24;314(20):2155-63.
doi: 10.1001/jama.2015.15454. Erratum in: JAMA. 2016 Feb
2;315(5):518. Kim, Yonghoon [corrected to Kim, Yong Hoon]. PMID:
26556051.
Study Type Randomized, multicenter trial
Details and
Quality of
Evidence
Intervention IVUS-guided vs. angiography-guided everolimus-eluting stent

implantation.
Main incl/excl Patients with long coronary lesions (implanted stent ≥28 mm in
criteria length) in Korea.
Relevant Primary outcome measure was the composite of major adverse
outcome(s) cardiac events, including cardiac death, target lesion-related
myocardial infarction, or ischemia-driven target lesion
revascularization at 1 year.
Key findings MACE at 1 year occurred in 2.9% and 5.8% undergoing IVUS-guided
and angiography-guided stent implantation, respectively (absolute
difference, -2.97% [95% CI, -5.14% to -0.79%]) (HR 0.48 [95% CI, 0.28
to 0.83], P = 0.007). The difference was driven by a lower risk of
ischemia-driven target lesion revascularization (2.5% vs 5.0% in
patients undergoing IVUS-guided and angiography-guided,
respectively (HR, 0.51 [95% CI, 0.28 to 0.91], P = 0.02). For cardiac
death, there were 0.4% and 0.5% patients in the IVUS-guided group
and the angiography-guided group, respectively (HR, 0.60 [95% CI,
0.14 to 2.52], P = 0.48). Target lesion-related myocardial infarction
occurred in 0.1% patients in the angiography-guided stent
implantation group (P = 0.32).
Conclusion(s) Among patients requiring long coronary stent implantation, the use of
IVUS-guided everolimus-eluting stent implantation, compared with
MACE at 1 year. These differences can be mostly explained due to
lower risk of target lesion revascularization.
128
Acronym Intravascular Ultrasound Guided Drug Eluting Stents Implantation in
"All-Comers" Coronary Lesions (ULTIMATE)
Reference Zhang J, Gao X, Kan J, Ge Z, Han L, Lu S, Tian N, Lin S, Lu Q, Wu X, Li Q,
Liu Z, Chen Y, Qian X, Wang J, Chai D, Chen C, Li X, Gogas BD, Pan T,
Shan S, Ye F, Chen SL. Intravascular Ultrasound Versus Angiography-
Guided Drug-Eluting Stent Implantation: The ULTIMATE Trial. J Am Coll
Cardiol. 2018 Dec 18;72(24):3126-3137. doi:
10.1016/j.jacc.2018.09.013. Epub 2018 Sep 24. PMID: 30261237.
Study Type Multicenter, prospective, randomized study
Intervention IVUS guidance over angiography guidance during DES implantation.
Main incl/excl All-comer patients who required DES implantation.
criteria
They were patients who had silent ischemia, stable or unstable angina,
or myocardial infarction (MI) (including both ST-segment elevation
and non–ST-segment elevation MI) >24 h from the onset of chest pain
to admission, and a de novo coronary lesion eligible for DES
implantation.
Patients were excluded if they had: 1) comorbidity with a life

expectancy <12 months; 2) intolerant of antithrombotic therapy; 3)
significant anemia, thrombocytopenia, or leucopenia; 4) history of
major hemorrhage (intracranial, gastrointestinal, and so on); 5)
chronic total occlusion lesion in either the left anterior descending
coronary artery, or left circumflex artery or right coronary artery not
recanalized; and 6) severe calcification needing rotational
atherectomy.
Relevant The primary endpoint was target-vessel failure (TVF) at 12 months,
outcome(s) including cardiac death, target-vessel myocardial infarction, and
clinically driven target-vessel revascularization (TVR). The procedure
was defined as a success if all IVUS-defined optimal criteria were met.
Key findings At 12 months follow-up, TVFs occurred in 2.9% and 5.4% in the IVUS
group and the angiography group, respectively (HR = 0.53; 95% CI =
0.31 to 0.90; p = 0.019).
In the IVUS group, TVF was recorded in 1.6% and 4.4% of patients
with successful procedures and patients who failed to achieve all
optimal criteria, respectively (HR = 0.35; 95% CI = 0.14 to 0.90; p =
0.029).
The HR for clinically driven target-lesion revascularization or definite
stent thrombosis was 0.41 (95% CI = 0.19 to 0.88; p = 0.018).
Conclusion(s) IVUS-guided DES implantation significantly improved the primary
outcome in all-comers, compared with angiography guidance
129
Acronym Does Optical Coherence Tomography Optimize Results of Stenting
(DOCTORS Study)
Reference Meneveau N, Souteyrand G, Motreff P, Caussin C, Amabile N, Ohlmann
P, Morel O, Lefrançois Y, Descotes-Genon V, Silvain J, Braik N, Chopard
R, Chatot M, Ecarnot F, Tauzin H, Van Belle E, Belle L, Schiele F. Optical
Coherence Tomography to Optimize Results of Percutaneous Coronary
Intervention in Patients with Non-ST-Elevation Acute Coronary
Syndrome: Results of the Multicenter, Randomized DOCTORS Study
(Does Optical Coherence Tomography Optimize Results of Stenting).
Circulation. 2016 Sep 27;134(13):906-17. doi:
10.1161/CIRCULATIONAHA.116.024393. Epub 2016 Aug 29. PMID:
27573032.
Study Type Multicenter, randomized study
Nº patients OCT-guided PCI (use of OCT pre- and post-PCI; OCT-guided group) vs.
fluoroscopy-guided PCI (angiography-guided group).

Intervention 240 participants
Main incl/excl Patients with non-ST-segment elevation acute coronary syndromes,
criteria aged 18 to 80 years inclusive.
Exclusion criteria were: Left main disease; in-stent restenosis; presence
of coronary artery bypass grafts; cardiogenic shock or severe
hemodynamic instability; severely calcified or tortuous arteries;
persistent ST-segment elevation; 1 or more other lesions considered
angiographically significant, or nonsignificant diffuse disease, located
on the target vessel; severe renal insufficiency (estimated glomerular
filtration rate (eGFR) ≤30 mL/min); bacteremia or septicemia; severe
coagulation disorders; pregnancy.
Relevant The primary endpoint was the functional result of PCI assessed by the
outcome(s) measure of post PCI fractional flow reserve. Secondary endpoints
included procedural complications and type 4a periprocedural
Key findings The primary end point was improved in the OCT-guided group, with a
significantly higher fractional flow reserve value (0.94±0.04 vs.
0.92±0.05, P=0.005) compared with the angiography-guided group.
There was no significant difference in the rate of type 4a myocardial
infarction (33% vs. 40%, P=0.28). The rates of procedural complications
(5.8%) and acute kidney injury (1.6%) were identical in each
Conclusion(s) In patients with non-ST-segment elevation acute coronary syndromes,
OCT-guided PCI is associated with higher postprocedure fractional flow
reserve than PCI guided by angiography alone, and did not increase
periprocedural complications, and type 4a myocardial infarction.
130
Acronym Controlled Abciximab and Device Investigation to Lower Late
Angioplasty Complications (CADILLAC)
Reference Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi
G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ; Controlled
Abciximab and Device Investigation to Lower Late Angioplasty
Complications (CADILLAC) Investigators. Comparison of angioplasty
with stenting, with or without abciximab, in acute myocardial
infarction. N Engl J Med. 2002 Mar 28;346(13):957-66. doi:
10.1056/NEJMoa013404. PMID: 11919304.
Study Type Multicenter, prospective, randomized trial using a 2-by-2 factorial
design
Intervention PTCA alone vs. PTCA plus abciximab therapy vs. stenting alone with
the MultiLink stent vs. stenting plus abciximab therapy.
Main incl/excl Patients with acute myocardial infarction.
criteria Patients were excluded if they were in cardiogenic; had a history of
bleeding diathesis or allergy to the study drug; had undergone major
surgery within the preceding six weeks; had had gastrointestinal or
genitourinary bleeding within the preceding six months; had had a
cerebrovascular event within the preceding two years or had any
permanent residual neurologic defect; had a history of leukopenia,
thrombocytopenia, or hepatic or renal dysfunction; had recently
received a thrombolytic agent; or had a noncardiac illness associated
with a life expectancy of less than one year.
Relevant The primary endpoint was a composite of death, reinfarction,
outcome(s) disabling stroke, and ischemia-driven revascularization of the target
vessel.
Key findings At six months, the primary endpoint occurred in:
- 20.0% of patients after PTCA
- 16.5% after PTCA plus abciximab

- 11.5% after stenting,
- 10.2% after stenting plus abciximab (P<0.001).
There were no significant differences among the groups in the rates of
death, stroke, or reinfarction; the difference in the incidence of the
primary endpoint was mostly driven by the differences in the rates of
target-vessel revascularization (ranging from 15.7% after PTCA to
5.2% after stenting plus abciximab, P<0.001).
Conclusion(s) Stent implantation (with or without abciximab therapy) was effective
in reducing the composite of death, reinfarction, disabling stroke, and
ischemia-driven revascularization of the target vessel, though this was
mainly drive by one of the individual components of the composite
(target-vessel revascularization).
131
Acronym Deferred versus conventional stent implantation in patients with ST-
segment elevation myocardial infarction (DANAMI 3-DEFER)
Reference Kelbæk H, Høfsten DE, Køber L, Helqvist S, Kløvgaard L, Holmvang L,
Jørgensen E, Pedersen F, Saunamäki K, De Backer O, Bang LE, Kofoed
KF, Lønborg J, Ahtarovski K, Vejlstrup N, Bøtker HE, Terkelsen CJ,
Christiansen EH, Ravkilde J, Tilsted HH, Villadsen AB, Aarøe J, Jensen
SE, Raungaard B, Jensen LO, Clemmensen P, Grande P, Madsen JK,
Torp-Pedersen C, Engstrøm T. Deferred versus conventional stent
implantation in patients with ST-segment elevation myocardial
infarction (DANAMI 3-DEFER): an open-label, randomised controlled
trial. Lancet. 2016 May 28;387(10034):2199-206. doi: 10.1016/S0140-
6736(16)30072-1. Epub 2016 Apr 3. PMID: 27053444.
Study Type Open-label, randomised controlled trial at four primary PCI centres in
Denmark.

Intervention Standard primary PCI with immediate stent implantation or deferred
Evidence
stent implantation 48 h after the index procedure if a stabilised flow

could be obtained in the infarct-related artery.
Main incl/excl Eligible patients (aged >18 years) had acute onset symptoms lasting
criteria 12 h or less, and ST-segment elevation of 0·1 mV or more in at least
two or more contiguous electrocardiographic leads or newly
developed left bundle branch block.
Relevant The primary endpoint was a composite of all-cause mortality, hospital
outcome(s) admission for heart failure, recurrent infarction, and any unplanned
revascularisation of the target vessel within 2 years' follow-up.

Key findings After a median follow-up time was 42 months, the primary endpoint
occurred in 18% vs. 17% patients who had standard PCI vs. patients
who had deferred stent implantation (HR = 0.99, 95% CI = 0.76-1.29;
p=0.92).
Conclusion(s) In patients with STEMI, routine deferred stent implantation did not
reduce the occurrence of death, heart failure, myocardial infarction,
or repeat revascularisation compared with conventional PCI.
132
Acronym Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone
in Patients with STEMI (TOTAL)
Reference Jolly SS, Cairns JA, Yusuf S, Meeks B, Pogue J, Rokoss MJ, Kedev S,
Thabane L, Stankovic G, Moreno R, Gershlick A, Chowdhary S, Lavi S,
Niemelä K, Steg PG, Bernat I, Xu Y, Cantor WJ, Overgaard CB, Naber
CK, Cheema AN, Welsh RC, Bertrand OF, Avezum A, Bhindi R, Pancholy
S, Rao SV, Natarajan MK, ten Berg JM, Shestakovska O, Gao P,
Widimsky P, Džavík V; TOTAL Investigators. Randomized trial of
primary PCI with or without routine manual thrombectomy. N Engl J
Med. 2015 Apr 9;372(15):1389-98. doi: 10.1056/NEJMoa1415098.
Epub 2015 Mar 16. PMID: 25853743.
Study Type International, investigator-initiated, multicenter, prospective,
randomized trial
Evidence
Intervention Strategy of routine upfront manual thrombectomy vs. PCI alone

Main incl/excl Patients with STEMI who were referred for primary PCI within 12
criteria hours after the onset of symptoms were eligible to participate in the
trial. Patients who had undergone previous coronary-artery bypass
grafting or those who had received fibrinolytic therapy were not
eligible.
Relevant The primary outcome was a composite of death from cardiovascular
outcome(s) causes, recurrent myocardial infarction, cardiogenic shock, or NYHA
class IV heart failure within 180 days. The key safety outcome was
stroke within 30 days.
Key findings The primary outcome occurred in 6.9% and 7.0% in the thrombectomy
group and the PCI-alone group, respectively (HR in the thrombectomy
group = 0.99; 95% CI = 0.85 to 1.15; P=0.86).
Stroke within 30 days occurred in 0.7% and 0.3% in the thrombectomy
group and the PCI-alone group (HR = 2.06; 95% CI = 1.13 to 3.75;
P=0.02).
Conclusion(s) In patients with STEMI who were undergoing primary PCI, routine
manual thrombectomy, as compared with PCI alone, did not reduce
the risk of cardiovascular death, recurrent myocardial infarction,
cardiogenic shock, or NYHA class IV heart failure within 180 days but
was associated with an increased rate of stroke within 30 days.
133
Acronym Thrombus Aspiration in ST-Elevation Myocardial Infarction in
Scandinavia (TASTE) trial
Reference Fröbert O, Lagerqvist B, Olivecrona GK, Omerovic E, Gudnason T,
Maeng M, Aasa M, Angerås O, Calais F, Danielewicz M, Erlinge D,
Hellsten L, Jensen U, Johansson AC, Kåregren A, Nilsson J, Robertson L,
Sandhall L, Sjögren I, Ostlund O, Harnek J, James SK; TASTE Trial.
Thrombus aspiration during ST-segment elevation myocardial
infarction. N Engl J Med. 2013 Oct 24;369(17):1587-97. doi:
10.1056/NEJMoa1308789. Epub 2013 Aug 31. Erratum in: N Engl J
Med. 2014 Aug 21;371(8):786. PMID: 23991656.
Study Type Multicenter, prospective, randomized, controlled, open-label clinical
trial

Intervention Manual thrombus aspiration followed by PCI vs. to PCI only.
Evidence
Main incl/excl Patients with STEMI undergoing PCI. The major exclusion criterion was
criteria the need for emergency coronary-artery bypass grafting.
Trial participants recruited from the national comprehensive Swedish
Coronary Angiography and Angioplasty Registry (SCAAR), which is part
of the Internet-based SWEDEHEART.
Relevant The primary end point was all-cause mortality at 30 days, evaluated
outcome(s) through national registries.
Key findings All-cause death within 30 days occurred in 2.8% and 3.0% of the
patients in the thrombus-aspiration group and the PCI-only group,
respectively (HR = 0.94; 95% CI = 0.72 to 1.22; P=0.63).
The rates of hospitalization for recurrent myocardial infarction at 30
days were 0.5% and 0.9% in the two groups, respectively (HR = 0.61;
95% CI = 0.34 to 1.07; P=0.09), and the rates of stent thrombosis were
0.2% and 0.5%, respectively (HR = 0.47; 95% CI, 0.20 to 1.02; P=0.06).
Conclusion(s) Routine thrombus aspiration before PCI as compared with PCI alone
did not reduce 30-day mortality among patients with STEMI.
134
Recommendation Table 12 — Recommendations for management of patients
with multivessel disease
Reference Sabatine MS, Bergmark BA, Murphy SA, O'Gara PT, Smith PK, Serruys
PW, Kappetein AP, Park SJ, Park DW, Christiansen EH, Holm NR,
Nielsen PH, Stone GW, Sabik JF, Braunwald E. Percutaneous coronary
intervention with drug-eluting stents versus coronary artery bypass
grafting in left main coronary artery disease: an individual patient
data meta-analysis. Lancet. 2021 Dec 18;398(10318):2247-2257. doi:
10.1016/S0140-6736(21)02334-5. Epub 2021 Nov 15. Erratum in:
Lancet. 2022 Apr 23;399(10335):1606. Erratum in: Lancet. 2022 Oct
15;400(10360):1304. PMID: 34793745.
Study Type Individual patient data meta-analysis (one-stage approach)
Nº patients 1599 publications, of which four RCTs-SYNTAX, PRECOMBAT, NOBLE,
and EXCEL met the inclusion criteria to be included in this meta-

analysis. 4394 patients were evaluated in this meta-analysis
Intervention PCI vs. CABG
Main incl/excl A searched MEDLINE, Embase, and the Cochrane database using the
criteria search terms "left main", "percutaneous coronary intervention" or
"stent", and "coronary artery bypass graft*" was used to identify
randomised controlled trials (RCTs) published in English between
database inception and Aug 31, 2021, comparing PCI with drug-
eluting stents with CABG in patients with left main coronary artery
disease that had at least 5 years of patient follow-up for all-cause
mortality.
Relevant The primary endpoint was 5-year all-cause mortality. Secondary
outcome(s) endpoints were cardiovascular death, spontaneous myocardial
infarction, procedural myocardial infarction, stroke, and repeat
revascularisation.
Key findings The Kaplan-Meier estimate of 5-year all-cause death was 11.2% (95%
CI 9.9-12.6 and 10.2% (9.0-11.6) for PCI and CABG, respectively (HR =
1.10, 95% CI = 0.91-1.32; p=0.33). In Bayesian analyses, there was an
85·7% probability that death at 5 years was greater with PCI than with
CABG, though this difference was more likely than not less than 1·0%
(<0·2% per year).
Conclusion(s) Among patients with left main coronary artery disease and, there was
no statistically significant difference in 5-year all-cause death between
PCI and CABG, although a Bayesian approach suggested a difference
probably exists (more likely than not <0·2% per year) favouring CABG.
135
Acronym Complete versus Culprit-Only Revascularization Strategies to Treat
Multivessel Disease after Early PCI for STEMI (COMPLETE) trial
Reference Mehta SR, Wood DA, Storey RF, Mehran R, Bainey KR, Nguyen H,
Meeks B, Di Pasquale G, López-Sendón J, Faxon DP, Mauri L, Rao SV,
Feldman L, Steg PG, Avezum Á, Sheth T, Pinilla-Echeverri N, Moreno R,
Campo G, Wrigley B, Kedev S, Sutton A, Oliver R, Rodés-Cabau J,
Stanković G, Welsh R, Lavi S, Cantor WJ, Wang J, Nakamya J,
Bangdiwala SI, Cairns JA; COMPLETE Trial Steering Committee and
Investigators. Complete Revascularization with Multivessel PCI for
Myocardial Infarction. N Engl J Med. 2019 Oct 10;381(15):1411-1421.
Study Type Multinational, randomized trial.
Nº patients 4041 patients from 140 centers in 31 countries
Intervention Strategy of complete revascularization (consisting of PCI of all suitable
nonculprit lesions) vs. strategy of no further revascularization
Main incl/excl Patients with STEMI and multivessel coronary artery disease who had
criteria undergone successful culprit-lesion PCI, and could undergo

randomization within 72 hours after successful culprit-lesion PCI. E
Multivessel coronary artery disease, defined as the presence of at

least one angiographically significant non–infarct-related (nonculprit)
lesion that was amenable to successful treatment with PCI and was
located in a vessel with a diameter of at least 2.5 mm that was not
stented as part of the index culprit-lesion PCI. Nonculprit lesions were
deemed angiographically significant if they were associated with at
least 70% stenosis of the vessel diameter on visual estimation or with
50 to 69% stenosis accompanied by a FFR measurement of ≤0.80.
The main exclusion criteria were an intention before randomization to

revascularize a nonculprit lesion, a planned surgical revascularization,
or previous coronary-artery bypass grafting surgery.
Relevant The first coprimary outcome was the composite of cardiovascular
outcome(s) death or myocardial infarction; the second coprimary outcome was
the composite of cardiovascular death, myocardial infarction, or
ischemia-driven revascularization.
Key findings At a median follow-up of 3 years, the first coprimary outcome had
occurred in 7.8% and 10.5% patients in the complete-revascularization
group and the culprit-lesion-only PCI group, respectively (HR = 0.74;
95% CI = 0.60 to 0.91; P=0.004). The second coprimary outcome had
occurred in 8.9% and 16.7% patients in the complete-revascularization
group and the culprit-lesion-only PCI group, respectively (HR =0.51;
95% CI = 0.43 to 0.61; P<0.001).
Conclusion(s) Among patients with STEMI and multivessel coronary artery disease,
complete revascularization reduced the risk of cardiovascular death or
myocardial infarction, as well as the risk of cardiovascular death,
myocardial infarction, or ischemia-driven revascularization, compared
with a culprit-lesion-only PCI.
136
Acronym Flow Evaluation to Guide Revascularization in Multivessel ST-
Elevation Myocardial Infarction (FLOWER-MI) trial
Reference Puymirat E, Cayla G, Simon T, Steg PG, Montalescot G, Durand-Zaleski
I, le Bras A, Gallet R, Khalife K, Morelle JF, Motreff P, Lemesle G,
Dillinger JG, Lhermusier T, Silvain J, Roule V, Labèque JN, Rangé G,
Ducrocq G, Cottin Y, Blanchard D, Charles Nelson A, De Bruyne B,
Chatellier G, Danchin N; FLOWER-MI Study Investigators. Multivessel
PCI Guided by FFR or Angiography for Myocardial Infarction. N Engl J
Med. 2021 Jul 22;385(4):297-308. doi: 10.1056/NEJMoa2104650.
Epub 2021 May 16. PMID: 33999545.
Study Type Investigator-initiated, randomized, open-label, multicenter trial with
blinded end-point evaluation conducted in 41 sites in France

Intervention Complete revascularization guided by either FFR or angiography.
Main incl/excl Adult patients (≥18 years of age) with STEMI who had undergone
criteria successful PCI of an infarct-related artery (primary PCI, rescue PCI, or
pharmacoinvasive PCI) and had multivessel disease were candidates
for enrollment.
Key exclusion criteria were single-vessel disease, hemodynamic
instability (i.e., cardiogenic shock), previous CABG surgery, coronary-
artery calcification or chronic total occlusion, failed culprit-lesion PCI,
and referral for CABG.
Relevant The primary outcome was a composite of death from any cause,
outcome(s) nonfatal myocardial infarction, or unplanned hospitalization leading to
urgent revascularization at 1 year.
Key findings During follow-up, a primary outcome event occurred in 5.5% and 4.2%
patients in the FFR-guided group and the angiography-guided group

(HR = 1.32; 95% CI = 0.78 to 2.23; P=0.31).
Death occurred in 1.5% and 1.7% patients in the FFR-guided group and
the angiography-guided group; nonfatal myocardial infarction in 3.1%
and 1.7%, respectively; and unplanned hospitalization leading to
urgent revascularization in 2.6% and 1.9%, respectively.
Conclusion(s) In patients with STEMI with mutlivessel disease undergoing complete

revascularization, an FFR-guided strategy did notreduced the risk of
death, myocardial infarction, or urgent revascularization at 1 year,
compared with an angiography-guided strategy.
137
Acronym Comparison Between FFR Guided Revascularization Versus
Conventional Strategy in Acute STEMI Patients With MVD
(CompareAcute)
Reference Smits PC, Abdel-Wahab M, Neumann FJ, Boxma-de Klerk BM, Lunde K,
Schotborgh CE, Piroth Z, Horak D, Wlodarczak A, Ong PJ, Hambrecht R,
Angerås O, Richardt G, Omerovic E; Compare-Acute Investigators.
Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial
Infarction. N Engl J Med. 2017 Mar 30;376(13):1234-1244. doi:
Study Type Investigator-initiated, prospective, multicenter, randomised trial.

Intervention Fractional flow reserve (FFR)-guided, complete revascularization vs.
with infarct-related, coronary-artery-only revascularization in patients
with STEMI.
Main incl/excl Patients with STEMI and multivessel disease who had undergone
criteria primary PCI of an infarct-related coronary artery. The most important
criteria for study exclusion were left main coronary artery disease,
chronic total occlusion, severe stenosis, with a TIMI flow grade of 2 or
less in the non–infarct-related coronary artery, a suboptimal result or
complications after treatment of an infarct-related coronary artery,
severe valve dysfunction, and Killip class III or IV.
Relevant The primary endpoint was a composite of death from any cause,
outcome(s) nonfatal myocardial infarction, revascularization, and cerebrovascular
events at 12 months. Clinically indicated elective revascularizations
performed within 45 days after primary PCI were not counted as
events in the group receiving PCI for an infarct-related coronary artery
only.
Key findings The primary outcome occurred in 23 (7.8%) and 121 (20.5%) patients
in the complete-revascularization group and the infarct-artery-only
group that did not receive complete revascularization, respectively

(HR= 0.35; 95% CI= 0.22 to 0.55; P<0.001).
Percentages of individual components of the primary endpoint:
- death (1.4% vs. 1.7%)
- myocardial infarction (2.4% vs. 4.7%)
- revascularization (6.1% vs. 17.5%)
- cerebrovascular events (0 vs. 0.7%)
Conclusion(s) In patients with STEMI and multivessel disease who underwent

primary PCI of an infarct-related artery, the addition of FFR-guided
complete revascularization of non–infarct-related arteries in the acute
setting resulted in a reduction of the composite cardiovascular
outcome compared with the treatment of the infarct-related artery
only. This finding was mainly driven by a reduction in subsequent
revascularizations.
138
Acronym Complete revascularisation versus treatment of the culprit lesion
only in patients with ST-segment elevation myocardial infarction and
multivessel disease (DANAMI-3—PRIMULTI)
Reference Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang
L, Jørgensen E, Pedersen F, Saunamäki K, Clemmensen P, De Backer O,
Ravkilde J, Tilsted HH, Villadsen AB, Aarøe J, Jensen SE, Raungaard B,
Køber L; DANAMI-3—PRIMULTI Investigators. Complete
revascularisation versus treatment of the culprit lesion only in patients
with ST-segment elevation myocardial infarction and multivessel
disease (DANAMI-3—PRIMULTI): an open-label, randomised
controlled trial. Lancet. 2015 Aug 15;386(9994):665-71. doi:
10.1016/s0140-6736(15)60648-1. PMID: 26347918.
Study Type Open-label, randomised controlled trial at two university hospitals in
Denmark.
Evidence
Intervention no further invasive treatment vs. complete FFR-guided

revascularisation before discharge.
Main incl/excl Patients presenting with STEMI who had one or more clinically
criteria significant coronary stenosis in addition to the lesion in the infarct-
related artery.
Relevant The primary endpoint was a composite of all-cause mortality, non-
outcome(s) fatal reinfarction, and ischaemia-driven revascularisation of lesions in
non-infarct-related arteries.
Key findings After a median follow-up of 27 months (range 12–44 months), the
primary endpoint was met in 22% and patients who had PCI of the
infarct-related artery only and 13% who had complete
revascularisation (HR= 0.56, 95% CI=0.38–0.83; p=0.004). The hazard

ratios for the individual components of the composite endpoint were:
- For all-cause mortality, HR=1.40 (95% CI=0.63–3.00; p=0.43)
- For non-fatal reinfarction, HR=0.94 (95% CI=0.47–1.90;
p=0.87)
- For revascularisation of non-infarct-related lesions, HR=0.31
(95% CI=0.18–0.53; p<0.0001)
Conclusion(s) In patients with STEMI and multivessel disease, complete
revascularisation guided by FFR measurements reduced the risk of the
composite of all-cause mortality, non-fatal reinfarction, or ischaemia-
driven revascularisation of lesions in non-infarct-related arteries
compared with no further invasive intervention after primary PCI. This
effect is mostly driven by fewer repeat revascularisations.
139
Acronym Complete Versus Lesion-Only Primary PCI trial (CvLPRIT)
Reference Gershlick AH, Khan JN, Kelly DJ, Greenwood JP, Sasikaran T, Curzen N,
Blackman DJ, Dalby M, Fairbrother KL, Banya W, Wang D, Flather M,
Hetherington SL, Kelion AD, Talwar S, Gunning M, Hall R, Swanton H,
McCann GP. Randomized trial of complete versus lesion-only
revascularization in patients undergoing primary percutaneous
coronary intervention for STEMI and multivessel disease: the CvLPRIT
trial. J Am Coll Cardiol. 2015 Mar 17;65(10):963-72. doi:
10.1016/j.jacc.2014.12.038. PMID: 25766941.
Study Type Multicenter, randomized, open-label trial conducted in the UK.
Details and Quality

of Evidence
Intervention Complete revascularization at index admission vs. treatment of the

infarct-related artery only.
Main incl/excl Patients with multivessel disease while undergoing primary
criteria percutaneous coronary intervention for ST-segment elevation
Relevant The primary endpoint was a composite of all-cause death, recurrent
outcome(s) myocardial infarction, heart failure, and ischemia-driven
revascularization within 12 months.
Key findings The primary endpoint occurred in 10.0% and 21.2% of the complete
revascularization group versus and the IRA-only revascularization

group, respectively (HR= 0.45; 95% CI=0.24 to 0.84; p=0.009). The
hazard ratios of the individual components of the primary endpoint
were:
- All-cause mortality, HR=0.32 (95%CI=0.06–1.60), p=0.14
- Recurrent MI, HR=0.48 (95%CI=0.09–2.62), p=0.39
- Heart failure, HR=0.43 (95%CI=0.13–1.39), p=0.14
- Repeat revascularization, HR=0.55 (95%CI=0.22–1.39), p=0.20
Conclusion(s) In patients presenting for primary PCI with multivessel disease, index
admission complete revascularization significantly reduced the rate of
the composite primary endpoint at 12 months compared with treating
only the infarct-related artery.
140
Acronym Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial
Reference Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry
C, Oldroyd KG; PRAMI Investigators. Randomized trial of preventive
angioplasty in myocardial infarction. N Engl J Med. 2013 Sep
19;369(12):1115-23. doi: 10.1056/NEJMoa1305520. Epub 2013 Sep 1.
PMID: 23991625.
Study Type Single-blind, randomized clinical trial conducted in the UK.
Intervention Preventive PCI (PCI in noninfarct coronary arteries with major

stenoses) vs. no preventive PCI.
Evidence
Main incl/excl Patients of any age with acute STEMI and multivessel coronary disease
criteria detected at the time of emergency PCI. Patients were ineligible if they
were in cardiogenic shock, had undergone previous CABG, had a
noninfarct-artery stenosis of 50% or more in the left main stem or the
ostia of both the left anterior descending and circumflex arteries, or if
the only noninfarct stenosis was a chronic total occlusion.
Relevant The primary outcome was a composite of death from cardiac causes,
outcome(s) nonfatal myocardial infarction, or refractory angina.
Key findings During a mean follow-up of 23 months, the primary outcome occurred
in 21/234 and patients assigned to preventive PCI and in 53/231
patients assigned to no preventive PCI (infarct-artery-only PCI), HR in
the preventive-PCI group= 0.35; 95% CI=0.21 to 0.58; p<0.001. Hazard
ratios for the three components of the primary outcome were:

- For death from cardiac causes, HR=0.34 (95% CI= 0.11 to
1.08).
- For nonfatal myocardial infarction, HR=0.32 (95% CI= 0.13 to
0.75).
- For refractory angina, HR=0.35 (95% CI= 0.18 to 0.69).
Conclusion(s) In patients with STEMI and multivessel coronary artery disease

undergoing infarct-artery PCI, preventive PCI in noninfarct coronary
arteries with major stenoses significantly reduced the risk of the
composite of death from cardiac causes, nonfatal myocardial
infarction, or refractory angina, as compared with PCI limited to the
infarct artery.
141
Acronym Fractional flow reserve versus angiography in guiding management
to optimize outcomes in non–ST-elevation myocardial infarction
(FAMOUS-NSTEMI)
Reference Layland J, Oldroyd KG, Curzen N, Sood A, Balachandran K, Das R,
Junejo S, Ahmed N, Lee MM, Shaukat A, O'Donnell A, Nam J, Briggs A,
Henderson R, McConnachie A, Berry C; FAMOUS–NSTEMI
investigators. Fractional flow reserve vs. angiography in guiding
management to optimize outcomes in non-ST-segment elevation
myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI
randomized trial. Eur Heart J. 2015 Jan 7;36(2):100-11. doi:
10.1093/eurheartj/ehu338. Epub 2014 Sep 1. PMID: 25179764.
Study Type Prospective, multicentre, parallel group, randomized, controlled trial
Details and Quality
in six UK hospitals
of Evidence
Nº patients 350 participants recruited from October 2011 to May 2013.

Intervention fractional flow reserve (FFR)-guided management vs. angiography-
guided standard care.
Main incl/excl NSTEMI patients with ≥1 coronary stenosis ≥30% of the lumen
criteria diameter assessed visually (threshold for FFR measurement)
Relevant The primary outcome was the between-group difference in the
outcome(s) proportion of patients allocated to medical management. The final
treatment decision was made by the clinicians in the cardiac catheter
laboratory during the index procedure or shortly afterwards if a
multidisciplinary heart team review was indicated.
Key findings For the primary outcome, the proportion of patients treated initially
by medical therapy was higher in the FFR-guided group than in the
angiography-guided group (22.7% vs. 13.2%). Estimated difference of
9.5% (95% CI = 1.4%, 17.7%), P = 0.022. Fractional flow reserve
disclosure resulted in a change in treatment between medical therapy,
PCI or CABG in 21.6% patients. At 12 months, revascularization
remained lower in the FFR-guided group [79.0 vs. 86.8%, P = 0.054].
There were no statistically significant differences in health outcomes
and quality of life between the groups.
Conclusion(s) In NSTEMI patients, FFR-guided management was associated with
higher rates of of patients treated initially by medical therapy
compared with angiography-guided management.
142
Recommendation Table 13 — Recommendations for myocardial infarction
with non-obstructive coronary arteries and ischaemia with non-obstructive
coronary arteries
Acronym Heart Attack Research Program- Imaging Study (HARP)

Reference Reynolds HR, Maehara A, Kwong RY, Sedlak T, Saw J, Smilowitz NR,
Mahmud E, Wei J, Marzo K, Matsumura M, Seno A, Hausvater A,
Giesler C, Jhalani N, Toma C, Har B, Thomas D, Mehta LS, Trost J, Mehta
PK, Ahmed B, Bainey KR, Xia Y, Shah B, Attubato M, Bangalore S,
Razzouk L, Ali ZA, Merz NB, Park K, Hada E, Zhong H, Hochman JS.
Coronary Optical Coherence Tomography and Cardiac Magnetic
Resonance Imaging to Determine Underlying Causes of Myocardial
Infarction With Nonobstructive Coronary Arteries in Women.
Circulation. 2021 Feb 16;143(7):624-640. doi:
10.1161/CIRCULATIONAHA.120.052008. Epub 2020 Nov 14. PMID:
33191769.
Study Type Prospective, multicenter, international, observational study
Nº patients Among 301 women enrolled at 16 sites, 170 were diagnosed with
MINOCA, of whom 145 had adequate OCT image quality for analysis;
116 of these underwent CMR.
Intervention Coronary OCT and CMR imaging to assess mechanisms of MINOCA.
Main incl/excl Women with a clinical diagnosis of myocardial infarction. If invasive
criteria coronary angiography revealed <50% stenosis in all major arteries,
multivessel OCT was performed, followed by CMR (cine imaging, late
gadolinium enhancement, and T2-weighted imaging and T1 mapping).
Angiography, OCT, and CMR were evaluated at blinded, independent
core laboratories. Culprit lesions identified by OCT were classified as
definite or possible. The CMR core laboratory identified ischemia-
related and nonischemic myocardial injury. Imaging results were
combined to determine the mechanism of MINOCA, when possible.
Relevant Mechanism of MINOCA
outcome(s)
Key findings A definite or possible culprit lesion was identified by OCT in 46.2% of
participants, most commonly plaque rupture, intraplaque cavity, or
layered plaque. CMR was abnormal in 74.1% of participants. An

ischemic pattern of CMR abnormalities (infarction or myocardial edema
in a coronary territory) was present in 53.4% of participants undergoing
CMR. A nonischemic pattern of CMR abnormalities (myocarditis,
takotsubo syndrome, or nonischemic cardiomyopathy) was present in
20.7%.
A cause of MINOCA was identified in 84.5% of the women with
multimodality imaging, higher than with OCT alone (P<0.001) or CMR
alone (P=0.001). An ischemic cause was identified in 63.8% of women
with MINOCA, a nonischemic cause was identified in 20.7% of the
women, and no mechanism was identified in 15.5%.
143
Conclusion(s) Multimodality imaging with coronary OCT and CMR identified potential
mechanisms in 84.5% of women with a diagnosis of MINOCA.
Acronym CORonary MICrovascular Angina (CorMicA)
Reference Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S,
Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R,
McDade R, Yii E, Sidik N, McCartney P, Corcoran D, Collison D, Rush C,
McConnachie A, Touyz RM, Oldroyd KG, Berry C. Stratified Medical
Therapy Using Invasive Coronary Function Testing in Angina: The
CorMicA Trial. J Am Coll Cardiol. 2018 Dec 11;72(23 Pt A):2841-2855.
doi: 10.1016/j.jacc.2018.09.006. Epub 2018 Sep 25. PMID: 30266608.
Study Type Randomized, controlled, blinded clinical trial
Nº patients
391 patients enrolled between November 25, 2016, and November 12,
2017.
Intervention
Evidence
Interventional diagnostic procedure (IDP) linked to stratified medicine.

The IDP consisted of guidewire-based assessment of coronary flow
reserve, index of microcirculatory resistance, fractional flow reserve,
followed by vasoreactivity testing with acetylcholine.
Main incl/excl Patients with angina symptoms and/or signs of ischemia but no
criteria obstructive coronary artery disease (INOCA)
Relevant The primary endpoint was the mean difference in angina severity at 6
outcome(s) months (assessed by the Seattle Angina Questionnaire summary
score).
Key findings The intervention resulted in a mean improvement of 11.7 U in the

Seattle Angina Questionnaire summary score at 6 months (95% CI: 5.0
to 18.4; p = 0.001). In addition, the intervention led to improvements
in the mean quality-of-life score (EQ-5D index 0.10 U; 95% CI: 0.01 to
0.18; p = 0.024) and visual analogue score (14.5 U; 95% CI: 7.8 to 21.3;
p < 0.001). No differences in major adverse cardiac events at the 6-
month follow-up were reported (2.6% controls vs. 2.6% intervention;
p = 1.00).
Conclusion(s) Interventional diagnostic procedure (IDP) linked to stratified medicine
improved angina in patients with INOCA.
144
Recommendation Table 14 — Recommendations for acute coronary
syndrome complications
Reference Jordaens L, Trouerbach J, Calle P, Tavernier R, Derycke E, Vertongen P,

Bergez B, Vandekerckhove Y. Conversion of atrial fibrillation to sinus
rhythm and rate control by digoxin in comparison to placebo. Eur Heart
J. 1997 Apr;18(4):643-8. doi:
10.1093/oxfordjournals.eurheartj.a015310. PMID: 9129896.
Study Type Randomized, double-blind study
Intervention digoxin 1.25 mg administered intravenously
Evidence
Main incl/excl Symptomatic patients with recent onset (< 1 week) atrial fibrillation.
criteria The ventricular rate had to be more than 100 bpm on the first
recording. Patients were excluded if treatment with cardiac glycosides
had been given within the last week, or if antiarrhythmic drugs had
already been used in the last 72 h.
Relevant The primary endpoint was conversion to sinus rhythm within 12 h of
outcome(s) treatment initiation. Other endpoints: average ventricular rates (1 min
intervals), beginning 10 min after the initiation of therapy, rates
immediately before and after conversion, rates before conversion.

Key findings Conversion occurred in 9/19 patients on digoxin and in 8/20 on placebo
(p>0.05). Heart rate during atrial fibrillation decreased after 30 min for
converters and non-converters (P < 0.05). For all patients on digoxin,
heart rate after 30 min was lower compared to baseline (P < 0.002) and
to placebo (P < 0.02). Persistent, stable slowing occurred only in 3/10
non-converters on digoxin (P < 0.05), and two patients developed
bradyarrhythmias.
Conclusion(s) Intravenous digoxin offers no substantial advantages over placebo in
recent onset atrial fibrillation with respect to conversion, and provides
weak rate control.
145
Cardiac Arrhythmia Suppression Trial
Reference Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker
AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and
morbidity in patients receiving encainide, flecainide, or placebo. The
Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar
21;324(12):781-8. doi: 10.1056/NEJM199103213241201. PMID:
1900101.
Intervention Active drug (either encainde or flecainide) vs. placebo

Main incl/excl Patients were eligible for enrollment six days to two years after
criteria myocardial infarction if they had an average of six or more ventricular
premature depolarizations per hour on ambulatory
electrocardiographic monitoring of at least 18 hours' duration, and no
runs of ventricular tachycardia of 15 or more beats at a rate of ≥120
beats per minute. Patients were required to have an ejection fraction
of 0.55 or less if recruited within 90 days of the myocardial infarction,
or 0.40 or less if recruited 90 days or more after the myocardial
infarction.
Flecainide was not given to patients with an ejection fraction below
0.30, to avoid potential aggravation of left ventricular dysfunction
Relevant The primary endpoint of the trial was death or cardiac arrest with
outcome(s)
resuscitation, either of which was due to arrhythmia.

Key findings After a mean follow-up of 10 months, 59 died of arrhythmia (43
receiving active drug vs. 16 receiving placebo; P = 0.0004), 22 died of
nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving
placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs. 5
receiving placebo).
Conclusion(s) There was an excess of deaths due to arrhythmia and deaths due to
shock after acute recurrent myocardial infarction in patients treated
with encainide or flecainide.
146
Reference Hine LK, Laird N, Hewitt P, Chalmers TC. Meta-analytic evidence
against prophylactic use of lidocaine in acute myocardial infarction.
Arch Intern Med. 1989 Dec;149(12):2694-8. PMID: 2688587.
Study Type Meta-analysis of 14 RCTs of to detect any mortality effect.
Nº patients 7656 participants from six prehospital-phase RCTs, and 1407 patients
from eight hospital-phase RCTs
Intervention lidocaine prophylaxis during AMI
Main incl/excl A literature search was conducted by weekly reviews of Current
criteria Contents: Clinical Practice, a MEDLINE search from 1966 through
1987, and supplementary hand searches of references in reviews and
published RCTs.
Inclusion criteria:
(1) RCTs evaluating the use of prophylactic lidocaine in patients with
suspected or proved AMI; (2) enrollment within 72 hours of
symptoms; and (3) lidocaine dosing in a fashion consistent with
current medical practice (bolus ≥50 mg followed by continuous
infusion of ≥1.0 mg/min for at least 24 hours; or bolus of at least 300
mg without subsequent infusion).
Relevant All-cause mortality.
outcome(s)
Key findings
The prehospital-phase RCTs showed no meaningful mortality effect

(risk difference, 0.0184; 95% confidence interval, -0.048 to +0.012).
The hospital-phase RCTs showed a statistically significant increase in
mortality during the treatment period for lidocaine recipients (risk
difference, 0.029; 95% confidence interval, +0.004 to +0.055).
Conclusion(s) Lidocaine administered to monitored patients during the prehospital

phase of AMI did not reduce mortality, whereas lidocaine
administered in the hospital phase of monitored, uncomplicated AMI
increased mortality.
147
Acronym Intravenous Amiodarone Multicenter Trial
Reference Levine JH, Massumi A, Scheinman MM, Winkle RA, Platia EV, Chilson
DA, Gomes A, Woosley RL. Intravenous amiodarone for recurrent
sustained hypotensive ventricular tachyarrhythmias. Intravenous
Amiodarone Multicenter Trial Group. J Am Coll Cardiol. 1996
Jan;27(1):67-75. doi: 10.1016/0735-1097(95)00427-0. PMID:
8522712.
Study Type Prospective, controlled, randomized, double-blind, dose-range study
Intervention amiodarone: 525 mg/24h vs. 1,050 mg/24h vs. 2,100 mg/24h, by
continuous infusion over 24 h

Main incl/excl Patients with recurrent hypotensive ventricular tachyarrhythmias
criteria refractory to lidocaine, procainamide and bretylium.
Patients were ex cluded if they were in cardiogenic shock (unrelated
to their arrhythmia) or had significant hepatic dysfunction, chronic
pulmonary disease, acute pulmonary edema or respiratory failure.
Patients were also excluded if they had a history of torsade de
pointes, congenital QT prolongation, sick sinus syndrome, sinus
arrest, symptomatic bradycardia, sinoatrial block or second-degree or
higher atrioventricular block (unless they had a pacemaker). All
patients had systolic blood pressure >90 mm Hg (except during
ventricular tachycardia or fibrillation), heart rate >50 beats/rain, QT
interval <0.55 s and arterial pH >7.25.
Relevant The primary endpoint was the proportion of patients who survived
outcome(s) with a successful response defined as no further episodes of
hemodynamically destabilizing ventricular tachycardia or ventricular
fibrillation and no adverse experiences requiring discontinuation of

the drug during hours 6 to 24 of the double-blind period
Key findings There was a numerical trend observed in the primary endpoint
response rate, with increased response at higher doses (41%, 45%
and 53% for the low, medium and high dose groups, respectively),
without reaching statistical significance (p = 0.298).
Conclusion(s) There is no evidence of a dose-response to intravenous amiodarone
with respect to the proportion of patients who survived with a
successful response, defined as no further episodes of ventricular
tachycardia or fibrillation (primary endpoint) and no adverse drug
effects during hours 6 to 24, or with respect to mortality.
148
Acronym Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)
trial
Reference Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert
JP, Higgins SL, Brown MW, Andrews ML; Multicenter Automatic
Defibrillator Implantation Trial II Investigators. Prophylactic
implantation of a defibrillator in patients with myocardial infarction
and reduced ejection fraction. N Engl J Med. 2002 Mar
21;346(12):877-83. doi: 10.1056/NEJMoa013474. Epub 2002 Mar 19.
PMID: 11907286.

Intervention Implantable defibrillator vs. conventional medical therapy
Main incl/excl Patients had had a myocardial infarction one month or more before
criteria entry, as documented by the finding of an abnormal Q wave on
electrocardiography, elevated cardiac-enzyme levels on laboratory
testing during hospitalization for suspected myocardial infarction, a
fixed defect on thallium scanning, or localized akinesis on
ventriculography with evidence of obstructive coronary disease on
angiography, and an ejection fraction of ≤30% within three months
before entry, as assessed by angiography, radionuclide scanning, or
echocardiography.
Relevant The primary endpoint was all-cause mortality.
Summary of Key
outcome(s)
Key findings During an average follow-up of 20 months, the mortality rates were
findings
19.8% and 14.2% in the conventional-therapy group and the

defibrillator group (HR= 0.69; 95% CI = 0.51 - 0.93; P=0.016).
Conclusion(s) In patients with a prior myocardial infarction and LVEF≤30%,
prophylactic implantation of a defibrillator improved survival.
149
Acronym Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
Reference Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski
M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing
N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden
Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators.
Amiodarone or an implantable cardioverter-defibrillator for
congestive heart failure. N Engl J Med. 2005 Jan 20;352(3):225-37. doi:
10.1056/NEJMoa043399. Erratum in: N Engl J Med. 2005 May
19;352(20):2146. PMID: 15659722.

Intervention Conventional therapy for CHF plus placebo vs. conventional therapy
Evidence
plus amiodarone vs. conventional therapy plus a conservatively

programmed, shock-only, single-lead ICD.
Placebo and amiodarone were administered in a double-blind fashion.
Main incl/excl Patients with NYHA class II or III CHF and LVEF ≤35%
criteria
Relevant The primary endpoint was all-cause death.
outcome(s)
Key findings The median follow-up was 45.5 months. There were 29%, 28% and
22% deaths in the placebo group, the amiodarone group, and the ICD
group, respectively. As compared with placebo, the risk of death was:
For amiodarona: HR = 1.06; (97.5% CI = 0.86-1.30; P=0.53)
For ICD therapy: HR = 0.77 (97.5% CI = 0.62 - 0.96; P=0.007).
Conclusion(s) In patients with NYHA class II or III CHF and LVEF 35%, amiodarone has
no favorable effect on survival, whereas single-lead, shock-only ICD
therapy reduced all-cause mortality by 23 percent.
150
Recommendation Table 15 — Recommendations for acute coronary
syndrome co-morbid conditions
Reference Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N,
Ree M, Shah AI, Burchette RJ. Sodium bicarbonate vs sodium chloride
for the prevention of contrast medium-induced nephropathy in
patients undergoing coronary angiography: a randomized trial. JAMA.
2008 Sep 3;300(9):1038-46. doi: 10.1001/jama.300.9.1038. PMID:
18768415.
Study Type Single-center, andomized, controlled, single-blind trial

Intervention Sodium chloride vs. sodium bicarbonate, administered at the same
rate (3 mL/kg for 1 hour before coronary angiography, decreased to
1.5 mL/kg per hour during the procedure and for 4 hours after the
completion of the procedure).
Main incl/excl Patients with stable renal disease who were undergoing coronary
criteria angiography. Included patients were 18 years or older and had an
estimated glomerular filtration rate of 60 mL/min per 1.73 m2 or less
and 1 or more of diabetes mellitus, history of congestive heart failure,
hypertension, or age older than 75 years.
Relevant The primary endpoint was a 25% or greater decrease in the estimated
outcome(s) glomerular filtration rate on days 1 through 4 after contrast exposure.
Key findings The primary end point was met in 13.3% and 14.6% of the sodium
bicarbonate group and the sodium chloride group (relative risk = 0.94;
95% CI = 0.55-1.60; P=0.82). In patients randomized to receive sodium
bicarbonate vs sodium chloride, there were no differences in the

following rates at 30 days (p>0.10 for all):
- death (1.7% vs 1.7%)
- dialysis (0.6% vs 1.1%)
- myocardial infarction (0.6% vs 0%)
- cerebrovascular events (,0% vs 2.2%)
There were no differences at 30 days to 6 months (0.6% vs 2.3%, 0.6%
vs 1.1%, 0.6% vs 2.3%, and 0.6% vs 1.7%, respectively) (P > .10 for all).
Conclusion(s) Hydration with sodium bicarbonate is not superior to hydration with
sodium chloride for preventing contrast medium-induced
nephropathy in patients with moderate to severe chronic kidney
disease who are undergoing coronary angiography.
151
Acronym Prevention of Contrast Renal Injury with Different Hydration
Strategies (POSEIDON) trial
Reference Brar SS, Aharonian V, Mansukhani P, Moore N, Shen AY, Jorgensen M,
Dua A, Short L, Kane K. Haemodynamic-guided fluid administration
for the prevention of contrast-induced acute kidney injury: the
POSEIDON randomised controlled trial. Lancet. 2014 May
24;383(9931):1814-23. doi: 10.1016/S0140-6736(14)60689-9. PMID:
24856027.
Study Type Randomised, parallel-group, comparator-controlled, single-blind
phase 3 trial
Intervention
Evidence
Fluid protocol based on the left ventricular end-diastolic pressure for

the prevention of contrast-induced acute kidney injury.
Main incl/excl Patients undergoing cardiac catheterisation, with an estimated
criteria glomerular filtration rate of 60 mL/min per 1.73 m2 or less and one or
more of several risk factors (diabetes mellitus, history of congestive
heart failure, hypertension, or age older than 75 years).
Relevant The primary outcome was the occurrence of contrast-induced acute
outcome(s)
kidney injury, which was defined as a > 25% or > 0.5 mg/dL increase in
serum creatinine concentration.
Key findings Contrast-induced acute kidney injury occurred less often in patients in
the left ventricular end-diastolic pressure-guided group than in the
control group (6.7% vs. 16.3%; relative risk 0.41, 95% CI 0.22-0.79;
p=0.005).
Conclusion(s) Compared with the control group, left ventricular end-diastolic
pressure-guided fluid administration prevented contrast-induced
acute kidney injury in patients undergoing cardiac catheterisation.
152
Acronym A MAstricht Contrast-Induced Nephropathy Guideline (AMACING)
trial
Reference Nijssen EC, Rennenberg RJ, Nelemans PJ, Essers BA, Janssen MM,
Vermeeren MA, Ommen VV, Wildberger JE. Prophylactic hydration to
protect renal function from intravascular iodinated contrast material
in patients at high risk of contrast-induced nephropathy (AMACING):
a prospective, randomised, phase 3, controlled, open-label, non-
inferiority trial. Lancet. 2017 Apr 1;389(10076):1312-1322. doi:
10.1016/S0140-6736(17)30057-0. Epub 2017 Feb 21. PMID:
28233565.
Study Type Prospective, randomised, phase 3, parallel-group, open-label, non-
inferiority trial
Intervention Intravenous hydration vs. no prophylaxis
Main incl/excl Patients aged 18 years and older, referred for an elective procedure
criteria requiring intravascular iodinated contrast material and with an
estimated glomerular filtration rate between 45 and 59 mL per
min/1.73 m2 combined with either diabetes, or at least two
predefined risk factors (age >75 years; anaemia; cardiovascular
disease; non-steroidal anti-inflammatory drug or diuretic nephrotoxic
medication); or eGFR between 30 and 45 mL per min/1.73 m2 ; or
multiple myeloma or lymphoplasmacytic lymphoma with small chain
proteinuria.
Exclusion criteria were eGFR lower than 30 mL per min/1.73 m2, renal
replacement therapy, emergency procedures, intensive care patients,
known inability to plan primary endpoint data collection, no referral
for prophylactic hydration, participation in another randomised trial,
and isolation (infection control).
Relevant The primary outcome was incidence of contrast-induced
outcome(s) nephropathy, defined as an increase in serum creatinine from
baseline of more than 25% or 44 μmol/L within 2-6 days of contrast
exposure, and cost-effectiveness of no prophylaxis compared with

intravenous hydration in the prevention of contrast-induced
nephropathy.
Key findings Contrast-induced nephropathy was reported in 2.6% and 2.7% of non-
hydrated patients and hydrated patients, respectively. The absolute
difference (no hydration vs hydration) was -0.10% (one-sided 95% CI -
2.25 to 2.06; one-tailed p=0.47). No hydration was cost-saving relative
to hydration.
Conclusion(s) No prophylaxis was non-inferior and cost-saving in preventing
contrast-induced nephropathy compared with intravenous hydration.
153
Acronym Normoglycemia in Intensive Care Evaluation–Survival Using Glucose
Algorithm Regulation (NICE-SUGAR) trial
Reference Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R,
Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK,
McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J,
Robinson BG, Ronco JJ. Intensive versus conventional glucose control
in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97.
doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24. PMID: 19318384.
Study Type Parallel-group, randomized, controlled trial conducted in 38 academic
tertiary care hospitals and 4 community hospitals.

Intervention Glucose control with one of two target ranges: the intensive (i.e.,
Evidence
tight) control target of 81 to 108 mg/dL (4.5 to 6.0 mmol/L) vs. a

conventional-control target of 180 mg/dL or less (10.0 mmol/L or
less).
Main incl/excl Adult medical and surgical patients admitted to the ICUs. Eligible
criteria patients were those expected to require treatment in the ICU on 3 or
more consecutive days.
Relevant The primary end point was death from any cause within 90 days after
outcome(s) randomization.
Key findings A total of 27.5% vs 24.9% in the intensive-control group and the
conventional-control group died (odds ratio for intensive control,
1.14; 95% CI = 1.02 - 1.28; P=0.02). The treatment effect did not differ
significantly between surgical patients and medical patients (odds
ratio for death in the intensive-control group were 1.31 and 1.07,
respectively; P=0.10).
Conclusion(s) Intensive glucose control increased mortality among adults in the ICU:
a blood glucose target of 180 mg/dL or less resulted in lower mortality
than did a target of 81 to 108 mg/dL.
154
Reference Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP,
Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA,
McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary
and secondary prevention of cardiovascular and renal outcomes in
type 2 diabetes: a systematic review and meta-analysis of
cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-39.
doi: 10.1016/S0140-6736(18)32590-X. Epub 2018 Nov 10. Erratum in:
Lancet. 2019 Jan 5;393(10166):30. PMID: 30424892.
Study Type Systematic review and meta-analysis of cardiovascular outcome trials
Details and Quality
Nº patients 34 322 patients (data from 3 trials)

of Evidence
Intervention SGLT2 inhibitors

Main incl/excl Randomised, placebo-controlled, cardiovascular outcome trials of
criteria SGLT2i in patients with type 2 diabetes published up to Sept 24, 2018.
These trials should report efficacy outcomes,such as major adverse
cardiovascular events
Relevant Efficacy outcomes included major adverse cardiovascular events
outcome(s) (myocardial infarction, stroke, or cardiovascular death), the
composite of cardiovascular death or hospitalisation for heart failure,
and progression of renal disease
Key findings SGLT2i reduced major adverse cardiovascular events by 11%
(HR=0.89, 95% CI = 0.83-0.96], p=0.0014), with benefit only seen in
patients with atherosclerotic cardiovascular disease (HR=0.86, 95% CI
= 0.80-0.93) and not in those without HR=1.00, 95% CI = 0.87-1.16, p
for interaction=0.0501).
SGLT2i reduced the risk of cardiovascular death or hospitalisation for

heart failure by 23% (HR = 0.77, 95% CI = 0.71-0.84, p<0.0001), with a
similar benefit in patients with and without atherosclerotic
cardiovascular disease and with and without a history of heart failure.
SGLT2i reduced the risk of progression of renal disease by 45% (HR =

0.55, 95% CI = 0.48-0.64], p<0.0001), with a similar benefit in those
with and without atherosclerotic cardiovascular disease.
Conclusion(s) SGLT2i reduces major adverse cardiovascular events, though this
seems to be confined to patients with established atherosclerotic
cardiovascular disease. There were no significan interaction in the
reduction of reducing hospitalisation for heart failure and progression
of renal disease.
155
Acronym Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney
Disease (DAPA-CKD) trial
Reference Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene
T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström
CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees
and Investigators. Dapagliflozin in Patients with Chronic Kidney
Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi:
Study Type Randomized, double-blind, placebo-controlled, multicenter clinical
trial
Intervention Dapagliflozin (10 mg once daily)

Main incl/excl Adults with or without type 2 diabetes who had an estimated
criteria glomerular filtration rate (GFR) of 25 to 75 ml/min/1.73 m2 of body-
surface area and a urinary albumin-to-creatinine ratio (with albumin
measured in milligrams and creatinine measured in grams) of 200 to
5000. They were receiving a stable dose of an ACE inhibitor or ARB for
at least 4 weeks before screening.
Key exclusion criteria were a documented diagnosis of type 1
diabetes, polycystic kidney disease, lupus nephritis, or antineutrophil
cytoplasmic antibody–associated vasculitis. Those who had received
immunotherapy for primary or secondary kidney disease within 6
months before enrollment were also excluded.
Relevant The primary outcome was a composite of a sustained decline in the
outcome(s) estimated GFR of at least 50%, end-stage kidney disease, or death
from renal or cardiovascular causes.
Key findings The trial was stop early for efficacy. Over a median of 2.4 years, the
primary outcome event occurred in 9.2% and 14.4% in the

dapagliflozin group and the placebo group, respectively (HR = 0.61;
95% CI = 0.51 - 0.72; P<0.001). The number needed to treat to prevent
one primary outcome event was 19 (95% CI, 15 to 27). The effects of
dapagliflozin were similar in participants with type 2 diabetes and in
those without type 2 diabetes.
Conclusion(s) Among patients with chronic kidney disease, regardless of the
presence or absence of type 2 diabetes, the risk of a composite of a
sustained decline in the estimated GFR of at least 50%, end-stage
kidney disease, or death from renal or cardiovascular causes was
significantly lower with dapagliflozin than with placebo.
156
Reference McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN,
Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm
M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J,
Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA,
Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M,
Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS,
Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees
and Investigators. Dapagliflozin in Patients with Heart Failure and
Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-
2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19. PMID:
31535829.
Study Type Randomised placebo-controlled trial
Intervention Dapagliflozin (at a dose of 10 mg once daily)
Main incl/excl Patients with New York Heart Association class II, III, or IV heart failure
criteria and an ejection fraction of 40% or less. High levels of NT-ProBNP were
required.
Patients were required to receive standard heart-failure device
therapy (an implantable cardioverter–defibrillator, cardiac
resynchronization therapy, or both) and standard drug therapy
Exclusion criteria included recent treatment with or unacceptable side

effects associated with an SGLT2 inhibitor, type 1 diabetes mellitus,
symptoms of hypotension or a systolic blood pressure < 95 mm Hg,
and an estimated glomerular filtration rate < 30 ml per minute per
1.73 m2 of body-surface area (or rapidly declining renal function).
Relevant The primary endpoint was a composite of worsening heart failure
outcome(s) (hospitalisation or an urgent visit resulting in intravenous therapy for
heart failure) or cardiovascular death.

Key findings During a median of 18.2 months, the primary outcome occurred in
16.3% and 21.2% in the dapagliflozin group and the placebo group
(HR= 0.74; 95% CI=0.65 - 0.85; P<0.001). Findings in patients with
diabetes were similar to those in patients without diabetes.
Conclusion(s) In patients with heart failure and a reduced ejection fraction, receiving
recommended therapy for heart failure, dapagliflozin reduced the risk
of orsening heart failure or death from cardiovascular causes
compared with placebo. The findings were consistent regardless of
the presence or absence of diabetes.
157
Acronym Empagliflozin Outcome Trial in Patients with Chronic Heart Failure
and a Reduced Ejection Fraction (EMPEROR-Reduced)
Reference Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi
J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J,
Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E,
Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S,
Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I,
Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei
S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators.
Cardiovascular and Renal Outcomes with Empagliflozin in Heart
Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi:
Study Type Double-blind randomised controlled trial
Intervention Empagliflozin (10 mg once daily)

Main incl/excl Adults (≥18 years of age) who had chronic heart failure (functional
criteria class II, III, or IV) with a left ventricular ejection fraction of 40% or less
were eligible to participate in the trial. All the patients were receiving
appropriate treatments for heart failure, including diuretics, inhibitors
of the renin–angiotensin system and neprilysin, beta-blockers,
mineralocorticoid receptor antagonists, and, when indicated, cardiac
devices.
The number of patients who had an ejection fraction of more than

30% were limited by requiring a history of hospitalization for heart
failure within the previous 12 months, or high levels of NT-proBNP.
Relevant The primary outcome was a composite of cardiovascular death or
outcome(s) hospitalization for worsening heart failure.
Key findings During a median of 16 months, the primary outcome event occurred
in 19.4% and 24.7% in the empagliflozin group and the placebo group
(hazard ratio for cardiovascular death or hospitalization for heart
failure was 0.75, with a 95% confidence interval of 0.65 to 0.86;
P<0.001). The effect of empagliflozin on the primary outcome was
consistent in patients regardless of the presence or absence of
diabetes.
Conclusion(s) In patients receiving recommended therapy for heart failure,
empagliflozin reduced the risk of cardiovascular death or
hospitalization for heart failure compared with placebo. The findings
were consistent regardless of the presence or absence of diabetes.
158
Recommendation Table 16 — Recommendations for long-term management
Reference Anderson L, Thompson DR, Oldridge N, Zwisler AD, Rees K, Martin N,
Taylor RS. Exercise-based cardiac rehabilitation for coronary heart
disease. Cochrane Database Syst Rev. 2016 Jan 5;2016(1):CD001800.
doi: 10.1002/14651858.CD001800.pub3. Update in: Cochrane
Database Syst Rev. 2021 Nov 6;11:CD001800. PMID: 26730878.
Study Type Cochrane systematic review and metanalysis
Details and Quality
of Evidence
Nº patients 14,486 patients from 62 trials

Intervention Cardiac rehabilitation
Main incl/excl criteria RCTs of exercise-based CR with ≥6 months’ follow-up, compared
with a no exercise control in patients with CHD
Relevant outcome(s) At least one of: mortality, MI, revascularizations, hospitalizations,
health-related quality of life (HRQL), or costs.
Summary of Key
Key findings EBCR significantly reduced cardiovascular mortality (RR: 0.74) and
findings
risk of hospitalizations (RR:0.82). CR did not reduce total mortality,

risk of MI/ CABG/PCI.
Conclusion(s) EBCR reduces the risk of cardiovascular mortality but not total
mortality. CR reduces the risk of hospitalization but not the risk of MI
or revascularization
159
Reference Salzwedel A, Jensen K, Rauch B, Doherty P, Metzendorf MI,
Hackbusch M, Völler H, Schmid JP, Davos CH. Effectiveness of
comprehensive cardiac rehabilitation in coronary artery disease
patients treated according to contemporary evidence based
medicine: Update of the Cardiac Rehabilitation Outcome Study
(CROS-II). Eur J Prev Cardiol. 2020 Nov;27(16):1756-1774. doi:
10.1177/2047487320905719. Epub 2020 Feb 23. PMID: 32089005.
Study Type Systematic review and metanalysis
Details and Quality
of Evidence

Main incl/excl criteria RCTs, pCCS and rCCS of comprehensive CR versus usual care, with ≥6
months’ follow-up in patients with CHD.
Relevant outcome(s) All-cause mortality
Key findings
Summary of
Key findings CR significantly reduced total mortality after ACS (HR:0.37), CABG
(HR 0.62) and in mixed populations (HR 0.52).
Conclusion(s) Comprehensive CR participation after ACS and after CABG reduced
total mortality.
160
Reference Santiago de Araújo Pio C, Marzolini S, Pakosh M, Grace SL. Effect of
Cardiac Rehabilitation Dose on Mortality and Morbidity: A
Systematic Review and Meta-regression Analysis. Mayo Clin Proc.
2017 Nov;92(11):1644-1659. doi: 10.1016/j.mayocp.2017.07.019.
Epub 2017 Nov 1. PMID: 29101934.
Details and Quality
of Evidence

Main incl/excl criteria Randomized or non-randomized studies, with comprehensive CR and
a control/comparison group in patients with MI, HF and other
diagnoses or procedures.
Relevant outcome(s) Effect of CR dose on mortality and morbidity.
Key findings
Key findings
Summary of
CR dose was significantly associated with less PCI (RR:0.65). No dose-

response association was found for cardiovascular mortality and
other outcomes.
Conclusion(s) A minimum of 36 comprehensive CR sessions may be needed to
reduce PCI.
161
Reference van Halewijn G, Deckers J, Tay HY, van Domburg R, Kotseva K, Wood
D. Lessons from contemporary trials of cardiovascular prevention
and rehabilitation: A systematic review and meta-analysis. Int J
Cardiol. 2017 Apr 1;232:294-303. doi: 10.1016/j.ijcard.2016.12.125.
Epub 2016 Dec 23. PMID: 28094128.
Details and Quality
of Evidence
Nº patients 7691 patients from 18 trials

Main incl/excl criteria RCTs of cardiovascular prevention and rehabilitation with ≥6 months’
follow-up in patients with CHD mainly, or PAD/stroke.
Relevant outcome(s) All-cause and cardiovascular mortality
Key findings CR did not reduce all-cause mortality, but it significantly reduced
cardiovascular mortality by 58%, MI by 30% and cerebrovascular
events by 60%. Programmes managing ≥6 risk factors reduced all-
cause mortality (RR 0.63) as well those that prescribed and
monitored cardioprotective medications for BP and lipids (RR 0.35).
Conclusion(s) Comprehensive prevention and rehabilitation programmes reduce
all-cause mortality. In addition, they not only reduce cardiovascular
mortality and myocardial infarction but also cerebrovascular events.
162
Reference Ji H, Fang L, Yuan L, Zhang Q. Effects of Exercise-Based Cardiac
Rehabilitation in Patients with Acute Coronary Syndrome: A Meta-
Analysis. Med Sci Monit. 2019 Jul 7;25:5015-5027. doi:
10.12659/MSM.917362. PMID: 31280281.
Evidence
Nº patients 55 035 patients from 25 trials

Main incl/excl criteria RCTs, pCCS and rCCS of exercise-based CR versus usual care, with ≥6
months’ follow-up in patients with ACS.
Relevant outcome(s) Cardiovascular/cardiac mortality, MACE.
Key findings
Key findings
Summary of
Exercise-based cardiac rehabilitation (EBCR) significantly reduced

cardiovascular mortality (HR:0.47), cardiac death rate (RR:0.40). The
risk of MACE in the cardiac rehabilitation group (RR:0.49).
Conclusion(s) EBCR is associated with reductions in cardiac mortality and MACE
after ACS.
163
Reference Candelaria D, Randall S, Ladak L, Gallagher R. Health-related quality
of life and exercise-based cardiac rehabilitation in contemporary
acute coronary syndrome patients: a systematic review and meta-
analysis. Qual Life Res. 2020 Mar;29(3):579-592. doi:
10.1007/s11136-019-02338-y. Epub 2019 Nov 5. PMID: 31691204.
Details and Quality
of Evidence
Nº patients 1739 patients from 14 studies

Main incl/excl criteria RCTs comparing exercise-based CR to a no-exercise control in ACS

patients with a follow-up ≥6 months.
Relevant outcome(s) Health-related quality of life (HRQoL) outcomes.
Key findings EBCR significantly improved physical performance and general health
Summary of Key
(SF-36) at 6 months, and in physical functioning at 12months.

findings
Statistically significant and sustained improvements were also found

in social and physical functioning.
Conclusion(s) EBCR achieves clinically meaningful improvements in physical
performance, general health, and physical functioning in the short
and long term in ACS patients
164
Reference Huang R, Palmer SC, Cao Y, Zhang H, Sun Y, Su W, Liang L, Wang S,
Wang Y, Xu Y, Melgiri ND, Jiang L, Strippoli GFM, Li X. Cardiac
Rehabilitation Programs for Chronic Heart Disease: A Bayesian
Network Meta-analysis. Can J Cardiol. 2021 Jan;37(1):162-171. doi:
10.1016/j.cjca.2020.02.072. Epub 2020 Feb 19. PMID: 32485140.
Study Type Bayesian Network Meta-analysis.
Details and Quality
of Evidence

Intervention Exercise-based cardiac rehabilitation (EBCR)
Main incl/excl criteria RCTs comparing exercise-based CR to a no-exercise control in CHD

patients with a follow-up ≥6 months.
Relevant outcome(s) All-cause mortality, cardiovascular mortality, MACE.
Key findings Compared with standard care, EBCR significantly reduced

cardiovascular mortality (OR:0.70), MACE (OR:0.57), MI (OR:0.71),
all-cause hospitalization (OR:0.74), cardiovascular hospitalization
(OR:0.69). Exercise-only CR was associated with lower cardiovascular
hospitalization risk relative to CR without exercise (OR:0.68).
Conclusion(s) CR significantly reduces cardiovascular mortality, MACE and
hospitalizations in CHD patients. CR programs containing exercise
might provide broader benefits compared with those without
exercise.
165
Reference Dibben G, Faulkner J, Oldridge N, Rees K, Thompson DR, Zwisler AD,
Taylor RS. Exercise-based cardiac rehabilitation for coronary heart
disease. Cochrane Database Syst Rev. 2021 Nov 6;11(11):CD001800.
doi: 10.1002/14651858.CD001800.pub4. PMID: 34741536.
Study Type Cochrane systematic review and metanalysis
Details and
Nº patients
Quality of
23430 patients from 85 trials

Evidence
Intervention Exercise-based cardiac rehabilitation (EBCR)
Main incl/excl RCTs of exercise-based CR with ≥6 months’ follow-up, compared with a

criteria no exercise control in patients with CHD
Relevant Mortality, morbidity and health-related quality of life (HRQoL).
outcome(s)
Key findings At short-term (6-12 months) follow-up, EBCR slightly reduced all-cause
mortality (RR:0.87), significantly reduced MI (RR:0.72) and all-cause

hospitalizations (RR:0.58) EBCR likely results in little to no difference in
risk of cardiovascular mortality CABG and PCI. At medium-term and
long-term follow-up, a significant reduction in cardiovascular mortality
(RRs: 0.77 and 0.58) and MI (RR: 0.67) was found.
Conclusion(s) EBCR provides important benefits to people with CHD, including
reduced risk of MI, a small reduction in all-cause mortality, and a large
reduction in all-cause hospitalization and improved HRQoL up to 12
months. Over longer-term follow-up, benefits may include reductions
in cardiovascular mortality and MI.
166
Acronym CORonary Diet Intervention With Olive Oil and Cardiovascular
PREVention (CORDIOPREV)
Reference Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, Quintana-Navarro GM,
Fuentes F, Garcia-Rios A, Ortiz-Morales AM, Gonzalez-Requero AI,
Perez-Caballero AI, Yubero-Serrano EM, Rangel-Zuñiga OA, Camargo
A, Rodriguez-Cantalejo F, Lopez-Segura F, Badimon L, Ordovas JM,
Perez-Jimenez F, Perez-Martinez P, Lopez-Miranda J; CORDIOPREV
Investigators. Long-term secondary prevention of cardiovascular
disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a
randomised controlled trial. Lancet. 2022 May 14;399(10338):1876-
1885. doi: 10.1016/S0140-6736(22)00122-2. Epub 2022 May 4. PMID:
35525255.
Study Type Single-centre, randomised clinical trial
Details and
Quality of
Evidence

Intervention Mediterranean diet vs. a low-fat diet intervention
Main incl/excl Patients with established coronary heart disease (aged 20-75 years)
criteria
Relevant The primary outcome was a composite of major cardiovascular
outcome(s) events, including myocardial infarction, revascularisation, ischaemic
stroke, peripheral artery disease, and cardiovascular death.
Key findings For the primary endpoint, crude rate per 1000 person-years: 28.1
(95% CI: 27.9-28.3) vs 37.7 (95% CI: 37.5-37.9) in the Mediterranean
diet group and the low-fat group, respectively (log-rank p=0.039).
Multivariable-adjusted hazard ratios (HRs) of the different models

ranged from 0.719 (95% CI: 0.541-0.957) to 0.753 (95% CI: 0.568-
0.998) in favour of the Mediterranean diet.
Conclusion(s) In secondary prevention, the Mediterranean diet was more effective

than the low-fat diet in preventing major cardiovascular events.
167
Reference Critchley JA, Capewell S. Mortality risk reduction associated with
smoking cessation in patients with coronary heart disease: a
systematic review. JAMA. 2003 Jul 2;290(1):86-97. doi:
10.1001/jama.290.1.86. PMID: 12837716.
Study Type Systematic review
Details and Quality
of Evidence
Nº patients 12 603 adult smokers from 20 studies

Intervention Smoke cessation
Main incl/excl Prospective cohort studies on patients with CHD
criteria All-cause mortality reported
At least 2 years of follow-up
Summary of Key
outcome(s)
Key findings 36% reduction in crude relative risk (RR) of mortality for patients with
findings
CHD who quit compared with those who continued smoking (RR, 0.64
(0.58-0.71).
Conclusion(s) Quitting smoking is associated with a substantial reduction in risk of
all-cause mortality among patients with CHD.
168
Prevención con Dieta Mediterránea (PREDIMED)
Reference Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-
Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM,
Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA,
Fitó M, Gea A, Hernán MA, Martínez-González MA; PREDIMED Study
Investigators. Primary Prevention of Cardiovascular Disease with a
Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts.
N Engl J Med. 2018 Jun 21;378(25):e34. doi:
10.1056/NEJMoa1800389. Epub 2018 Jun 13. PMID: 29897866.
Study Type Randomised clinical trial conducted in Spains
Details and Quality
Nº patients 7447 adult subjects

of Evidence
randomized to Mediterranean diet supplemented with olive oil,

Mediterranean diet supplemented with nuts, or control low-fat diet
Intervention Mediterranean diet with olive, Mediterranean diet with nuts
Main incl/excl 55-80 years
criteria At high CVD risk
Relevant Major CV event (MI, stroke, or CV death).
Summary of Key
outcome(s)
Key findings HR 0.69 (95% CI = 0.53-0.91) for a Mediterranean diet with olive oil
findings
and 0.72 (95% CI = 0.54-0.95) for a Mediterranean diet with nuts, as

compared with the control diet
Conclusion(s) Following a Mediterranean diet enriched with olive oil or nuts can
reduce the risk of future CV events
169
Reference Becerra-Tomás N, Blanco Mejía S, Viguiliouk E, Khan T, Kendall CWC,
Kahleova H, Rahelić D, Sievenpiper JL, Salas-Salvadó J. Mediterranean
diet, cardiovascular disease and mortality in diabetes: A systematic
review and meta-analysis of prospective cohort studies and
randomized clinical trials. Crit Rev Food Sci Nutr. 2020;60(7):1207-
1227. doi: 10.1080/10408398.2019.1565281. Epub 2019 Jan 24.
PMID: 30676058.
Nº patients 3 RCTs and 38 cohort studies on the Mediterranean diet. Total

Evidence
number of subjects not reported but was approximately 9000 in RCTs

and 1 500 000 in cohort studies
Intervention Mediterranean diet
Main incl/excl Studies should include subjects with type 1 or 2 diabetes and have
criteria incidence of or mortality from CVD, CHD, MI, and stroke as outcome
Relevant CVD and MI incidence
outcome(s)
Summary of Key
Key findings From RCTs: RR for CVD incidence was 0.62 (0.50-0.78) and MI
findings
incidence was 0.65 (0.49-0.88). Data from cohort studies showed

lower RR for all outcomes in when comparing high vs low adherence
to the Mediterranean diet
Conclusion(s) Mediterranean diet has a beneficial role on CVD prevention in
populations inclusive of individuals with diabetes.
170
Reference Wood AM, Kaptoge S, Butterworth AS, Willeit P, Warnakula S, Bolton
T, Paige E, Paul DS, Sweeting M, Burgess S, Bell S, Astle W, Stevens D,
Koulman A, Selmer RM, Verschuren WMM, Sato S, Njølstad I,
Woodward M, Salomaa V, Nordestgaard BG, Yeap BB, Fletcher A,
Melander O, Kuller LH, Balkau B, Marmot M, Koenig W, Casiglia E,
Cooper C, Arndt V, Franco OH, Wennberg P, Gallacher J, de la Cámara
AG, Völzke H, Dahm CC, Dale CE, Bergmann MM, Crespo CJ, van der
Schouw YT, Kaaks R, Simons LA, Lagiou P, Schoufour JD, Boer JMA,
Key TJ, Rodriguez B, Moreno-Iribas C, Davidson KW, Taylor JO,
Sacerdote C, Wallace RB, Quiros JR, Tumino R, Blazer DG 2nd,
Linneberg A, Daimon M, Panico S, Howard B, Skeie G, Strandberg T,
Weiderpass E, Nietert PJ, Psaty BM, Kromhout D, Salamanca-
Fernandez E, Kiechl S, Krumholz HM, Grioni S, Palli D, Huerta JM, Price
J, Sundström J, Arriola L, Arima H, Travis RC, Panagiotakos DB,
Karakatsani A, Trichopoulou A, Kühn T, Grobbee DE, Barrett-Connor E,
van Schoor N, Boeing H, Overvad K, Kauhanen J, Wareham N,
Langenberg C, Forouhi N, Wennberg M, Després JP, Cushman M,
Cooper JA, Rodriguez CJ, Sakurai M, Shaw JE, Knuiman M, Voortman
T, Meisinger C, Tjønneland A, Brenner H, Palmieri L, Dallongeville J,
Brunner EJ, Assmann G, Trevisan M, Gillum RF, Ford I, Sattar N, Lazo
M, Thompson SG, Ferrari P, Leon DA, Smith GD, Peto R, Jackson R,
Banks E, Di Angelantonio E, Danesh J; Emerging Risk Factors
Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group. Risk
thresholds for alcohol consumption: combined analysis of individual-
participant data for 599 912 current drinkers in 83 prospective
studies. Lancet. 2018 Apr 14;391(10129):1513-1523. doi:
10.1016/S0140-6736(18)30134-X. Erratum in: Lancet. 2018 Jun
2;391(10136):2212. PMID: 29676281.
Study Type Meta-analysis of cohort studies
Details and Quality
of Evidence
Nº patients 599 912 adult subjects from 83 prospective studies

Intervention Alcohol consumption
Main incl/excl Current drinkers free from CVD at baseline with information recorded
criteria about alcohol amount and baseline characteristics
At least 1 year of follow-up
Relevant All-cause mortality, total CVD, and several CVD subtypes
outcome(s)
Key findings Alcohol consumption was roughly linearly associated with a higher
risk of all outcomes except for MI which there was a log-linear
negative association.
Conclusion(s) The threshold for lowest risk of all-cause mortality was about 100
g/week. For CVD subtypes other than MI there were no clear risk
thresholds below which lower alcohol consumption stopped being
associated with lower disease risk.
171
Reference Liu Y, Lee DC, Li Y, Zhu W, Zhang R, Sui X, Lavie CJ, Blair SN.
Associations of Resistance Exercise with Cardiovascular Disease
Morbidity and Mortality. Med Sci Sports Exerc. 2019 Mar;51(3):499-
508. doi: 10.1249/MSS.0000000000001822. PMID: 30376511.
Study Type Single-centre prospective cohort study
Nº patients 12 591 adult subjects

Evidence
Intervention Resistance exercise (self-reported medical history questionnaire)
Main incl/excl Participants who received at least two clinical examinations 1987-
criteria 2006.
Subjects with CVD at baseline were excluded
Relevant Major CV events (fatal and non-fatal)
outcome(s)
Summary of Key
Key findings Compared with no resistance exercise (RE), weekly RE frequencies of

findings
one, two, three times or total amount of 1-59 min were associated
with approximately 40%-70% decreased risk of total CVD events,
independent of aerobic exercise (AE) (all P values <0.05).
Conclusion(s) Even one time or less than 1 h.wk of RE, independent of AE, is
associated with reduced risks of CVD and all-cause mortality.
172
Reference Ekelund U, Tarp J, Steene-Johannessen J, Hansen BH, Jefferis B,
Fagerland MW, Whincup P, Diaz KM, Hooker SP, Chernofsky A, Larson
MG, Spartano N, Vasan RS, Dohrn IM, Hagströmer M, Edwardson C,
Yates T, Shiroma E, Anderssen SA, Lee IM. Dose-response associations
between accelerometry measured physical activity and sedentary
time and all cause mortality: systematic review and harmonised
meta-analysis. BMJ. 2019 Aug 21;366:l4570. doi: 10.1136/bmj.l4570.
PMID: 31434697.
Details and Quality
Nº patients 36 383 adult subjects from 8 prospective cohort studies

of Evidence
Intervention Physical activity assessed by accelerometry

Main incl/excl Prospective cohort studies assessing physical activity and sedentary
criteria time by accelerometry and associations with all cause mortality and
reported effect estimates as hazard ratios, odds ratios, or relative
risks with 95% confidence intervals
outcome(s)
Key findings Any physical activity, regardless of intensity, was associated with
lower risk of mortality, with a non-linear dose-response.
For sedentary time, HRs were 1.00 (referent; least sedentary), 1.28
(95% CI = 1.09-1.51), 1.71 (95% CI = 1.36-2.15), and 2.63 (95% CI =
1.94-3.56).
Conclusion(s) Higher levels of total physical activity, at any intensity, and less time
spent sedentary, are associated with substantially reduced risk for
premature mortality
173
Reference Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter
DA. Sedentary time and its association with risk for disease incidence,
mortality, and hospitalization in adults: a systematic review and
meta-analysis. Ann Intern Med. 2015 Jan 20;162(2):123-32. doi:
10.7326/M14-1651. Erratum in: Ann Intern Med. 2015 Sep
1;163(5):400. PMID: 25599350.
Details and Quality
Nº patients 829 917 adult subjects from 41 studies

of Evidence
Intervention Physical activity
Main incl/excl Studies assessing sedentary behavior as a distinct predictor variable,

criteria independent of physical activity and correlated to at least 1 health
outcome
Relevant All-cause mortality and CVD
Summary of Key
outcome(s)
Key findings Significant HR associations were found with all-cause mortality 1.24
findings
(1.09-1.41), CVD mortality 1.18 (1.11-1.26), and CVD incidence 1.14

(1.00 to 1.73).
Conclusion(s) Prolonged sedentary time was independently associated with
deleterious health outcomes regardless of physical activity.
174
Reference Patterson R, McNamara E, Tainio M, de Sá TH, Smith AD, Sharp SJ,
Edwards P, Woodcock J, Brage S, Wijndaele K. Sedentary behaviour
and risk of all-cause, cardiovascular and cancer mortality, and
incident type 2 diabetes: a systematic review and dose response
meta-analysis. Eur J Epidemiol. 2018 Sep;33(9):811-829. doi:
10.1007/s10654-018-0380-1. Epub 2018 Mar 28. PMID: 29589226.
Details and Quality
of Evidence
Nº patients 1 331 468 adult subjects from 34 studies

Intervention Sedentary time
Main incl/excl Prospective cohort studies on healthy subjects, where sedentary time
criteria was objectively measured or self-reported
Relevant All-cause mortality, CVD mortality, incident CVD.
outcome(s)
Summary of Key
Key findings For total sedentary behaviour, the PA-adjusted relationship was non-
findings
linear for all-cause mortality (RR per 1 h/day: were 1.01 (1.00-1.01) ≤
8 h/day; 1.04 (1.03-1.05) > 8 h/day of exposure), and for CVD
mortality (1.01 (0.99-1.02) ≤ 6 h/day; 1.04 (1.03-1.04) > 6 h/day).
Conclusion(s) Independent of PA, total sitting and TV viewing time are associated
with greater risk for several major chronic disease outcomes.
175
Acronym Lung Health Study (LHS)
Reference Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett
JE; Lung Health Study Research Group. The effects of a smoking
cessation intervention on 14.5-year mortality: a randomized clinical
trial. Ann Intern Med. 2005 Feb 15;142(4):233-9. doi: 10.7326/0003-
4819-142-4-200502150-00005. PMID: 15710956.
Study Type Randomized clinical trial involving 10 clinical centers in the United
States and Canada

Nº patients 5887
Evidence
Intervention 10-week smoking cessation program that included a strong physician

message and 12 group sessions using behavior modification and
nicotine gum, plus either ipratropium or a placebo inhaler
Main incl/excl Middle-aged volunteers with asymptomatic airway obstruction.
criteria
outcome(s)
Key findings At 5 years, 21.7% vs 5.4% of participants had stopped smoking in the
intervention and the usual care arms, respectively.
After up to 14.5 years of follow-up, all-cause mortality was

significantly lower in the special intervention group than in the usual
care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-
years; P = 0.03). The HR for mortality in the usual care group
compared with the special intervention group was 1.18 (95% CI, 1.02
to 1.37).
Conclusion(s) Smoking cessation intervention programs can have a substantial
effect on subsequent mortality, even when successful in a minority of
participants.
176
Reference Saeidifard F, Medina-Inojosa JR, West CP, Olson TP, Somers VK,
Bonikowske AR, Prokop LJ, Vinciguerra M, Lopez-Jimenez F. The
association of resistance training with mortality: A systematic review
and meta-analysis. Eur J Prev Cardiol. 2019 Oct;26(15):1647-1665. doi:
10.1177/2047487319850718. Epub 2019 May 19. PMID: 31104484.
Details and Quality
of Evidence
Nº patients 370 256 adult subjects from 1 RCT and 10 cohort studies
Intervention Resistance training

Main incl/excl Subjects from the general population
criteria
Relevant Total mortality and CVD events
outcome(s)
Key findings Compared with no exercise, resistance training alone was associated
with 21% lower all-cause mortality. HR=0.79 (95%CI = 0.69-0.91)
Compared with no exercise, resistance training combined with aerobic

exercise was associated with 40% lower all-cause mortality. HR=0.60
(95%CI= 0.49-0.72).
Conclusion(s) Resistance training is associated with lower mortality and appears to
have an additive effect when combined with aerobic exercise.
177
Reference Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Nicotine
replacement therapy versus control for smoking cessation. Cochrane
10.1002/14651858.CD000146.pub5. PMID: 29852054.
Details and
Quality of
Evidence
Nº patients 64,640 participants from 133 studies

Intervention Smoking cessation
Main incl/excl Randomized trials People motivated to quit comparing NRT to placebo
criteria or no treatment
Relevant The relative effectiveness of NRT appears largely independent of
outcome(s)
Key findings
Summary of
intensity of additional support provided to the individual

Key findings NRTs increase rate of quitting by 50%-60% regardless to setting
Conclusion(s) All licensed forms of NRT (gum, transdermal patch nasal spray inhaler
& sub lingual tablets) can help people make a quit attempt to increase
their success of stopping smoking
178
Reference Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, Lindson N.
Antidepressants for smoking cessation. Cochrane Database Syst Rev.
2020 Apr 22;4(4):CD000031. doi: 10.1002/14651858.CD000031.pub5.
PMID: 32319681.
Study Type Meta-analysis
Nº patients 115 studies, with sub analysis largest group 17,866 participants
Intervention Smoking cessation
Evidence
Main incl/excl (RCTs) comparing antidepressant medications with placebo or no

criteria treatment, an alternative pharmacotherapy, or the same medication
used in a different way
Excluded: excluded trials with less than six months follow-up

Relevant Use of Bupropion resulted in more trial dropouts due to AE
outcome(s) bupropion resulted in inferior smoking cessation rates compared to
Summary of Key
varenicline
findings
Key findings Bupropion increased long term smoking cessation rates

Nortriptyline aids smoking cessation
Conclusion(s) Evidence suggests that bupropion may be as successful as NRT and
nortriptyline in helping people to quit smoking, but that it is less
effective than varenicline
179
Reference Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T.
Nicotine receptor partial agonists for smoking cessation. Cochrane
10.1002/14651858.CD006103.pub7. PMID: 27158893.
Nº patients 25,290 participants, 11,801 of whom used varenicline.
27 trials that tested varenicline.

8 trials compared varenicline with NRT.
5 of these trials also included a bupropion treatment arm.
9 studies tested variations in varenicline dosage, and 13 tested usages
in disease‐specific subgroups of patients.
Intervention Varenicline
Main incl/excl Included randomised controlled trials which compared the treatment
criteria drug with placebo.
Included comparisons with bupropion and nicotine patches where
available.
Excluded trials which did not report a minimum follow-up period of six
months from start of treatment.
Relevant Dianicline failed to find evidence that it was effective.
outcome(s) Varenicline beyond the 12‐week standard regimen found the drug to
be well‐tolerated during long‐term use
Key findings Cytisine stopped smoking compared with placebo at longest follow‐up,
(low‐quality evidence).
Cytisine compared with NRT found a benefit for cytisine at six months
Conclusion(s) Cytisine increases the chances of quitting.
Varenicline at standard dose increased the chances of successful long‐
term smoking cessation.
Lower dose regimens also conferred benefits for cessation, while
reducing the incidence of adverse events.
More participants quit successfully with varenicline than with
bupropion or with NRT.
180
Reference Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, Hartmann-Boyce
J. Different doses, durations and modes of delivery of nicotine
replacement therapy for smoking cessation. Cochrane Database Syst
Rev. 2019 Apr 18;4(4):CD013308. doi: 10.1002/14651858.CD013308.
PMID: 30997928.
Study Type Meta analysis
Nº patients 63 trials with 41,509 participants

Intervention Nicotine replacement therapy
Evidence
Main incl/excl Randomized trials in people motivated to quit, comparing one type of
criteria NRT use with another.
Excluded trials that did not assess cessation as an outcome, with
follow-up less than six months, and with additional intervention
components not matched between arms.
Relevant Combination NRT (fast-acting form + patch) results in higher long-term
outcome(s) quit rates than single form.
Moderate evidence that 42/44 mg are as effective as 21/22 mg (24-

hour) patches &
21 mg are more effective than 14 mg (24-hour) patches.
4 mg gum to 2 mg gum found a benefit of the higher dose. However,
that only smokers who are highly dependent may benefit.
Key findings No evidence of an effect on cardiac AEs, SAEs or withdrawals.
Conclusion(s) Using combination NRT versus single-form NRT, and 4 mg versus 2 mg
nicotine gum, can increase the chances of successfully stopping
smoking.
181
Reference Woolf KJ, Zabad MN, Post JM, McNitt S, Williams GC, Bisognano JD.
Effect of nicotine replacement therapy on cardiovascular outcomes
after acute coronary syndromes. Am J Cardiol. 2012 Oct 1;110(7):968-
70. doi: 10.1016/j.amjcard.2012.05.028. Epub 2012 Jun 20. PMID:
22727182.
Study Type Retrospective analysis
Details and Quality

of Evidence
Intervention Nicotine replacement therapy

Main incl/excl All patients who were current tobacco users who presented with an
criteria ACS and underwent cardiac catheterization.
Excluded were patients who died during the index hospitalization and
the patients who were current users of NRT on admission.
Relevant More patients in the NRT group underwent percutaneous intervention,
outcome(s) and this group had a greater cardiovascular medication rate.
Summary of Key
However were not statistically sig.

findings
Key findings No differences were seen in the individual 1-year end points of death,
MI, repeat revascularization or rehospitalization for angina, congestive
heart failure, or arrhythmia.
Conclusion(s) NRT use after ACS was not associated with an increased risk of adverse
cardiovascular events.
182
Reference Suissa K, Larivière J, Eisenberg MJ, Eberg M, Gore GC, Grad R, Joseph L,
Reynier PM, Filion KB. Efficacy and Safety of Smoking Cessation
Interventions in Patients With Cardiovascular Disease: A Network
Meta-Analysis of Randomized Controlled Trials. Circ Cardiovasc Qual
Outcomes. 2017 Jan;10(1):e002458. doi:
10.1161/CIRCOUTCOMES.115.002458. PMID: 28093398.
Study Type Meta-Analysis
Details and Quality
Nº patients Seven pharmacotherapy randomized controlled trials (n=2809)

of Evidence
17 behavioral intervention randomized controlled trials (n=4666)

Intervention Smoking Cessation Interventions
Main incl/excl RCTs evaluating the efficacy of smoking cessation pharmacotherapies
criteria and behavioral therapies in CVD patients
Relevant The evidence about nicotine replacement therapies was inconclusive.
outcome(s)
Summary of Key
Telephone therapy and individual counseling were both efficacious.

findings
Key findings Varenicline is the most efficacious smoking cessation therapy in

patients with CVD who are motivated to quit smoking, although more
safety data are needed.
Conclusion(s) Varenicline and bupropion, as well as individual and telephone
counselling, are efficacious for smoking cessation in CVD patients.
183
Acronym EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients
With Acute Coronary Syndromes (EVOPACS)
Reference Koskinas KC, Windecker S, Pedrazzini G, Mueller C, Cook S, Matter CM,
Muller O, Häner J, Gencer B, Crljenica C, Amini P, Deckarm O, Iglesias
JF, Räber L, Heg D, Mach F. Evolocumab for Early Reduction of LDL
Cholesterol Levels in Patients With Acute Coronary Syndromes
(EVOPACS). J Am Coll Cardiol. 2019 Nov 19;74(20):2452-2462. doi:
10.1016/j.jacc.2019.08.010. Epub 2019 Aug 31. PMID: 31479722.
Study Type Investigator-initiated, randomized, double-blind, placebo-controlled
trial
Nº patients 308 adult subjects randomly assigned 1:1 to receive subcutaneous
Evidence
evolocumab 420 mg or matching placebo, administered in-hospital and

after 4 weeks, on top of atorvastatin 40 mg.
Intervention Evolocumab
Main incl/excl Patients hospitalized for ACS with elevated LDL-C levels (≥1.8 mmol/l
criteria on high-intensity statin for at least 4 weeks; ≥2.3 mmol/l on low- or
moderate-intensity statin; or ≥3.2 mmol/l on no stable dose of statin)
Relevant Primary endpoint percentage change in calculated LDL-C from baseline
outcome(s) to 8 weeks.
Safety.
Key findings Mean LDL-C levels decreased from 3.61 to 0.79 mmol/l at week 8 in
the evolocumab group, and from 3.42 to 2.06 mmol/l in the placebo
group; the difference in mean percentage change from baseline was -
40.7% (95% confidence interval: -45.2 to -36.2; p < 0.001). LDL-C levels
<1.8 mmol/l were achieved at week 8 by 95.7% of patients in the
evolocumab group versus 37.6% in the placebo group. Adverse events
and centrally adjudicated cardiovascular events were similar in both
groups.
Conclusion(s) In the very high-risk setting of ACS, evolocumab added to high-
intensity statin therapy was well tolerated and resulted in substantial
reduction in LDL-C levels, rendering >95% of patients within currently
recommended target levels.
184
Acronym Further Cardiovascular Outcomes Research with PCSK9 Inhibition in
Subjects with Elevated Risk (FOURIER)
Reference Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD,
Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS,
Pedersen TR; FOURIER Steering Committee and Investigators.
Evolocumab and Clinical Outcomes in Patients with Cardiovascular
Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi:
Study Type Randomized, double-blind, placebo-controlled, multinational clinical
trial conducted in 49 countries
Intervention Evolocumab (either 140 mg every 2 weeks or 420 mg monthly)

Main incl/excl Patients between 40 and 85 years of age who had clinically evident
criteria atherosclerotic cardiovascular disease, defined as a history of
myocardial infarction, nonhemorrhagic stroke, or symptomatic
peripheral artery disease, as well as additional characteristics that
placed them at higher cardiovascular risk. Patients had to have a
fasting LDL cholesterol level of 70 mg/dL (1.8 mmol/L) or higher or a
non–high-density lipoprotein (HDL) cholesterol level of 100 mg/dL (2.6
mmol/L) or higher while they were taking an optimized regimen of
lipid-lowering therapy (defined as preferably a high-intensity statin
but must have been at least atorvastatin at a dose of 20 mg daily or its
equivalent, with or without ezetimibe).
Relevant The primary efficacy endpoint was the composite of cardiovascular
outcome(s) death, myocardial infarction, stroke, hospitalization for unstable
angina, or coronary revascularization. The key secondary efficacy end
point was the composite of cardiovascular death, myocardial
Key findings The median duration of follow-up was 2.2 years.
At 48 weeks, LDL cholesterol levels were reduced from a median
baseline value of 92 mg/dL (2.4 mmol/L) to 30 mg/dL (0.78 mmol/L)
(P<0.001).
Relative to placebo, evolocumab treatment significantly reduced the
risk of the primary endpoint (9.8% vs. 11.3%; HR= 0.85; 95%CI = 0.79 -
0.92; P<0.001) and the key secondary endpoint (5.9% vs. 7.4%; HR=
0.80; 95% CI = 0.73 - 0.88; P<0.001).
Conclusion(s) Evolocumab on a background of statin therapy lowered LDL
cholesterol levels to a median of 30 mg/dL (0.78 mmol/L) and reduced
the risk of cardiovascular events.
185
Acronym Evaluation of Cardiovascular Outcomes After an Acute Coronary
Syndrome During Treatment With Alirocumab (ODYSSEY
OUTCOMES)
Reference Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg
JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G,
Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ,
Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES
Committees and Investigators. Alirocumab and Cardiovascular
Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov
29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov
7. PMID: 30403574.
Study Type Multicenter, randomized, double-blind, placebo-controlled trial
Intervention Alirocumab subcutaneously at a dose of 75 mg every 2 weeks. The
dose was adjusted under blinded conditions to target an LDL

cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol/L).
Main incl/excl Patients were 40 years of age or older, had been hospitalized with an
criteria acute coronary syndrome (myocardial infarction or unstable angina) 1
to 12 months before randomization, and had an LDL cholesterol level
of at least 70 mg/dL (1.8 mmol/L), a non−high-density lipoprotein
(HDL) cholesterol level of at least 100 mg/dL, or an apolipoprotein B
level of at least 80 mg/dL. All qualifying lipid levels were measured
after a minimum of 2 weeks of stable treatment with atorvastatin at a
dose of 40 to 80 mg once daily, rosuvastatin at a dose of 20 to 40 mg
once daily, or the maximum tolerated dose of one of these statins
(including no statin in the case of documented unacceptable side
effects).
Relevant The primary endpoint was a composite of death from coronary heart
outcome(s) disease, nonfatal myocardial infarction, fatal or nonfatal ischemic
stroke, or unstable angina requiring hospitalization.
Key findings The median duration of follow-up was 2.8 years.
The composite primary end-point event occurred in 9.5% vs. 11.1% in

the alirocumab group and the placebo group, respectively (HR= 0.85;
95% CI = 0.78 - 0.93; P<0.001).
There were also less deaths in the alirocumab arm: 3.5% vs 4.1% (HR=
0.85; 95% CI = 0.73 - 0.98).
Conclusion(s) Among patients who had a previous acute coronary syndrome and
who were receiving high-intensity statin therapy, the risk of the
composite of death from coronary heart disease, nonfatal myocardial
infarction, fatal or nonfatal ischemic stroke, or unstable angina
requiring hospitalization was lower among those who received
alirocumab than among those who received placebo.
186
Acronym Improved Reduction of Outcomes: Vytorin Efficacy International
Trial (IMPROVE-IT)
Reference Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P,
Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W,
De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM,
Musliner TA, Braunwald E, Califf RM; IMPROVE-IT Investigators.
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
N Engl J Med. 2015 Jun 18;372(25):2387-97. doi:
10.1056/NEJMoa1410489. Epub 2015 Jun 3. PMID: 26039521.
Study Type Double-blind, randomized controlled trial
Intervention The combination of simvastatin (40 mg) and ezetimibe (10 mg)
(simvastatin–ezetimibe) was compared with simvastatin (40 mg) and
Evidence
placebo (simvastatin monotherapy).

Main incl/excl Patients who had been hospitalized for an acute coronary syndrome
criteria within the preceding 10 days and had LDL cholesterol levels of 50 to
100 mg/dL (1.3 to 2.6 mmo/L) if they were receiving lipid-lowering
therapy or 50 to 125 mg/dL (1.3 to 3.2 mmo/L) if they were not
receiving lipid-lowering therapy
outcome(s) nonfatal myocardial infarction, unstable angina requiring
rehospitalization, coronary revascularization (≥30 days after
randomization), or nonfatal stroke.
Key findings The median follow-up was 6 years.

The median time-weighted average LDL cholesterol level during the
study was 53.7 mg/dL (1.4 mmol/L) in the simvastatin–ezetimibe
group, as compared with 69.5 mg/dL (1.8 mmol/L) in the simvastatin-
monotherapy group (P<0.001).
The event rate for the primary endpoint at 7 years was 32.7% and
34.7% in the simvastatin–ezetimibe group and the simvastatin-
monotherapy group, respectively (absolute risk difference, 2.0
percentage points; HR= 0.936; 95% CI= 0.89 - 0.99; P=0.016).
Conclusion(s) Relative to simvastatin alone, the combination of ezetimibe and
simvastatin resulted in incremental lowering of LDL cholesterol levels
and improved cardiovascular outcomes
187
Acronym Further Cardiovascular Outcomes Research With PCSK9 Inhibition in
Subjects With Elevated Risk (FOURIER) trial
Reference Gencer B, Mach F, Murphy SA, De Ferrari GM, Huber K, Lewis BS,
Ferreira J, Kurtz CE, Wang H, Honarpour N, Keech AC, Sever PS,
Pedersen TR, Sabatine MS, Giugliano RP. Efficacy of Evolocumab on
Cardiovascular Outcomes in Patients With Recent Myocardial
Infarction: A Prespecified Secondary Analysis From the FOURIER Trial.
JAMA Cardiol. 2020 Aug 1;5(8):952-957. doi:
10.1001/jamacardio.2020.0882. Erratum in: JAMA Cardiol. 2021 Aug
1;6(8):980. PMID: 32432684.
Study Type Prespecified secondary analysis of the FOURIER trial
Details and Quality
of Evidence

Intervention Evolocumab
Main incl/excl Patients with prior MI treated with a statin.
criteria Per protocol, patients with MI within 4 weeks prior to randomization
were excluded from the FOURIER trial.
Relevant The primary composite end point was cardiovascular death, MI,
outcome(s) stroke, hospitalization for unstable angina, or coronary
revascularization. The key secondary composite end point was
cardiovascular death, MI, or stroke.
Key findings Patients having a recent MI (within 12 months of randomization)
:5711.
Patients having or a remote MI (more than 12 months prior to
randomization): 16609.
In the placebo arm, the 3-year rate for the primary endpoint was
17.2% vs 14.4% in patients with recent MI compared with those with
remote MI (adjusted HR, 1.45; 95% CI, 1.29-1.64; P < 0.001). Similarly,
the 3-year rate for the key secondary endpoint was also higher in
those with recent MI (10.9% vs 9.5%; adjusted HR, 1.45; 95% CI, 1.24-
1.69; P < .001).
In patients with a recent MI, evolocumab reduced the risk of the

primary and key secondary end points by 19% (HR=0.81; 95% CI =
0.70-0.93) and 25% (HR=0.75; 95% CI= 0.62-0.91), respectively.
In patients with a remote MI, evolocumab reduced the risk of the

primary and key secondary end points by 8% (HR= 0.92; 95% CI= 0.84-
1.01; P for interaction = 0.13) and 15% (HR=0.85; 95% CI=0.76-0.96; P
for interaction = 0.24), respectively.
For the primary endpoint, the absolute risk reductions over 3 years
with evolocumab were 3.7% vs 1.1% in those with recent MI vs. those
with remote MI, whereas for the secondary endpoint they were 3.2%
vs 1.3%, respectively.
188
Conclusion(s) Patients with a recent MI were at higher risk of cardiovascular events
and tended to experience greater absolute risk reductions with
evolocumab than those with remote MIs.
189
Acronym Carvedilol Post- Infarct Survival Control in LV Dysfunction
(CAPRICORN) study
Reference Dargie HJ. Effect of carvedilol on outcome after myocardial infarction
in patients with left-ventricular dysfunction: the CAPRICORN
randomised trial. Lancet. 2001 May 5;357(9266):1385-90. doi:
10.1016/s0140-6736(00)04560-8. PMID: 11356434.
Study Type Multicentre, double-blind, randomised controlled trial involving 17
countries
Intervention Carvedilol 6.25 mg, progressively increased to a maximum of 25 mg
twice daily during the next 4–6 weeks
Main incl/excl Eligible patients were aged 18 years or older with a stable, definite
criteria myocardial infarction occurring 3–21 days before randomisation.

Other inclusion criteria were: left-ventricular ejection fraction of 40%
or less, or wallmotion-score index of 1.3 or less; and receipt of
concurrent treatment with ACE inhibitors for at least 48 h and stable
dose for more than 24 h unless there was proven intolerance of ACE
inhibitors.
Patients who had heart failure appropriately treated with diuretics
and ACE inhibitors during the acute phase were included, but those
who continued to require intravenous diuretics or inotropes, or who
had uncontrolled heart failure were excluded.
Other exclusion criteria: unstable angina, hypotension, uncontrolled
hypertension, bradycardia, and unstable insulin-dependent diabetes
mellitus. Patients with a continuing indication for β-blockers for any
clinical indication other than heart failure were excluded, as were
those requiring ongoing therapy with inhaled β2-agonists or steroids.
Relevant The original primary endpoint was all-cause mortality, but, during a
outcome(s) masked analysis, the DSMB noted that overall mortality was lower
than had been predicted. The steering committee therefore decided
to adopt co-primary endpoints of all-cause mortality (the original
primary endpoint), together with all-cause mortality or cardiovascular

hospital admissions (the first prespecified secondary endpoint).
Key findings There was no difference between the carvedilol and placebo groups
in the percentage of patients with the primary endpoint (35%
vs 37%), with a HR of 0.92 (95% CI = 0.80–1.07, p=0.296).
Nevertheless, all-cause mortality was lower in the carvedilol
group than in the placebo group (12% vs 15%), with a HR of
0.77 (95% CI=0.60–0.98], p=0.031primar).
Conclusion(s) In patients treated long-term after an acute myocardial infarction
complicated by left-ventricular systolic dysfunction, carvedilol did not
reduce the primary endpoint, but reduced the frequency of all-cause
mortality.
190
Reference Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade
after myocardial infarction: systematic review and meta regression
analysis. BMJ. 1999 Jun 26;318(7200):1730-7. doi:
10.1136/bmj.318.7200.1730. PMID: 10381708.
Study Type Systematic review of randomised controlled trials
Details and
Quality of
Evidence
Nº patients 54 234 patients

Intervention Beta blockers
Main incl/excl Patients with acute or past myocardial infarction
criteria
Relevant All cause mortality and non-fatal reinfarction
outcome(s)
Key findings There was a 23% reduction in the odds of death in long term trials
(95% CI: 15% to 31%), but only a 4% reduction in the odds of death in
short term trials (95% CI: -8% to 15%). Meta regression in long term
trials did not identify a significant reduction in effectiveness in drugs
with cardioselectivity but did identify a near significant trend towards
decreased benefit in drugs with intrinsic sympathomimetic activity.
In long term trials, the number needed to treat for 2 years to avoid a
death was 42.
Conclusion(s) Efficacy was shown for beta blockers in long-term secondary
prevention, but not in the short-term.
191
Acronym Carvedilol Post-Intervention Long-Term Administration in Large-scale
Randomized Controlled Trial (CAPITAL-RCT)
Reference Watanabe H, Ozasa N, Morimoto T, Shiomi H, Bingyuan B, Suwa S,
Nakagawa Y, Izumi C, Kadota K, Ikeguchi S, Hibi K, Furukawa Y, Kaji S,
Suzuki T, Akao M, Inada T, Hayashi Y, Nanasato M, Okutsu M,
Kametani R, Sone T, Sugimura Y, Kawai K, Abe M, Kaneko H, Nakamura
S, Kimura T; CAPITAL-RCT investigators. Long-term use of carvedilol in
patients with ST-segment elevation myocardial infarction treated with
primary percutaneous coronary intervention. PLoS One. 2018 Aug
28;13(8):e0199347. doi: 10.1371/journal.pone.0199347. PMID:
30153268.
Study Type Multi-center, open-label, randomized controlled trial.
Details and
Quality of
Nº patients
Evidence
801 patients
Intervention Carvedilol started within 7 days after primary PCI
Main incl/excl STEMI patients with successful primary PCI within 24 hours from the
criteria onset and with left ventricular ejection fraction (LVEF) ≥40%
Relevant The primary endpoint was a composite of all-cause death, myocardial
outcome(s) infarction, hospitalization for heart failure, and hospitalization for
acute coronary syndrome.
Key findings The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to
6.3±4.3 mg at 1-year. During median follow-up of 3.9 years, the
cumulative 3-year incidences of both the primary endpoint was not
significantly different between the carvedilol and no beta-blocker
groups (6.8% and 7.9%, P = 0.20). There was no significant difference
in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P =
0.06).
Conclusion(s) Long-term carvedilol therapy added on the contemporary evidence-
based medications did not seem beneficial in STEMI patients treated
with primary PCI.
192
Reference Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, Ruddox V, Munkhaugen
J, Atar D, Otterstad JE. Effect of oral β-blocker treatment on mortality
in contemporary post-myocardial infarction patients: a systematic
review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2019
Jan 1;5(1):12-20. doi: 10.1093/ehjcvp/pvy034. PMID: 30192930.
Study Type Metaanalysis of 16 observational studies
Nº patients 164408 patients with acute MI

Intervention Oral beta blockers versus No beta blockers
Evidence
Main incl/excl All study types and sizes published between 1 January 2000 and 30
criteria October 2017 concerning patients following AMI were eligible for
inclusion. Studies where none or only a minority of patients had a
history of HF, were in Killip class ≥III or had LVEF <40% at baseline,
were included. Studies that did not provide estimates between the β-
blocker group and the no β-blocker group were excluded.
outcome(s)
Key findings The pooled estimate showed that β-blocker treatment (median follow-
up time of 2.7 years) was associated with a 26% reduction in all-cause
mortality with a rate ratio of 0.74, 95% CI = 0.64-0.85, with moderate
heterogeneity (I2 = 67.4%). There was described a presence of
publication bias, or small study effect, and when controlling for bias by
the trim and fill simulation method, the effect disappeared (adjusted
rate ratio of 0.90, 95% CI 0.77-1.04.
Conclusion(s) There is no association between β-blockers and all-cause mortality.
193
Reference Maqsood MH, Alam M, Atar D, Birnbaum Y. Efficacy of Long-Term Oral
Beta-Blocker Therapy in Patients Who Underwent Percutaneous
Coronary Intervention for ST-Segment Elevation Myocardial Infarction
With Preserved Left Ventricular Ejection Fraction: A Systematic Review
and Meta-analysis. J Cardiovasc Pharmacol. 2021 Jan 1;77(1):87-93.
doi: 10.1097/FJC.0000000000000922. PMID: 33136764.
Study Type Metaanalysis of 1 RCT and 11 observational studies
Details and
Quality of
Nº patients
Evidence
32108 patients
Intervention Long-term oral beta-blocker therapy
Main incl/excl Patients with preserved LVEF who underwent percutaneous coronary
criteria intervention (PCI) for STEMI.
Relevant The outcomes of interest were all-cause mortality and major adverse
outcome(s) cardiac event (MACE).
Key findings For unadjusted all-cause mortality, the OR was 0.58 (95% CI: 0.42-
0.79), whereas for adjusted all-cause mortality, the OR was 0.64 (95%
CI: 0.48-0.87). The odds of dying were significantly lower in patients on
the long-term beta-blocker therapy group.
For unadjusted MACE, the odds ratio was not reduced with beta-
blocker therapy in these patients (OR = 0.87, 95% CI: 0.70-1.08).
Conclusion(s) Patients with preserved LVEF after STEMI treated with PCI on long-
term oral beta-blocker therapy have a significant reduction in risk of
all-cause mortality, without an effect on MACE rates.
194
Acronym Microalbuminuria, cardiovascular, and renal outcomes (MICRO
HOPE), a substudy of the Heart Outcomes Prevention Evaluation
(HOPE)
Reference Effects of ramipril on cardiovascular and microvascular outcomes in
people with diabetes mellitus: results of the HOPE study and MICRO-
HOPE substudy. Heart Outcomes Prevention Evaluation Study
Investigators. Lancet. 2000 Jan 22;355(9200):253-9. Erratum in:
Lancet 2000 Sep 2;356(9232):860. PMID: 10675071.
Study Type Randomised clinical trial with two-by-two factorial design
Nº patients 3577
Intervention Ramipril (10 mg/day) or placebo, and vitamin E or placebo, according

to a two-by-two factorial design.
Main incl/excl People with diabetes included in the HOPE study, aged 55 years or
criteria older, who had a previous cardiovascular event or at least one other
cardiovascular risk factor, no clinical proteinuria, heart failure, or low
ejection fraction, and who were not taking ACE inhibitors.
Key exclusion criteria were dipstick-positive proteinuria or established
diabetic nephropathy, other severe renal disease, hyperkalaemia,
congestive heart failure, low ejection fraction (< 0.4), uncontrolled
hypertension, recent myocardial infarction or stroke (< 4 weeks), and
use of or hypersensitivity to vitamin E or ACE inhibitors.
Relevant The combined primary outcome was myocardial infarction, stroke, or
outcome(s) cardiovascular death. Overt nephropathy was a main outcome in a
substudy.
Key findings The study was stopped 6 months early (after 4.5 years) by the
independent DSMB for efficacy. Ramipril lowered the risk of the
combined primary outcome by 25% (95% Cl 12–36, p=0.0004),
myocardial infarction by 22% (95% 6–36), stroke by 33% (95% 10–50),
cardiovascular death by 37% (95% 21–51), total mortality by 24%
(95% 8–37), revascularisation by 17% (95% 2–30), and overt
nephropathy by 24% (95% 3–40, p=0.027).
Conclusion(s) Ramipril was beneficial for cardiovascular events and overt
nephropathy in people with diabetes. The cardiovascular benefit was
greater than that attributable to the decrease in blood pressure.
195
Acronym EUropean trial on Reduction Of cardiac events with Perindopril in
patients with stable coronary. Artery disease (EUROPA) study
Reference Fox KM; EURopean trial On reduction of cardiac events with
Perindopril in stable coronary Artery disease Investigators. Efficacy of
perindopril in reduction of cardiovascular events among patients with
stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial (the EUROPA study). Lancet. 2003 Sep
6;362(9386):782-8. doi: 10.1016/s0140-6736(03)14286-9. PMID:
13678872.
Study Type Double-blind, placebo-controlled, multicentre randomised clinical
trial
Nº patients 13655 were registered, 12218 were randomised
Intervention Perindopril 8 mg once daily (after a run-in period of 4 weeks, in which
all patients received perindopril)

Main incl/excl Men and women aged at least 18 years without clinical evidence of
criteria heart failure and with evidence of coronary heart disease,
documented by previous myocardial infarction (>3 months before
screening), percutaneous or surgical coronary revascularisation (>6
months before screening), or angiographic evidence of at least 70%
narrowing of one or more major coronary arteries. Men could also be
recruited if they had a history of chest pain and a positive
electrocardiogram, echo, or nuclear stress test.
Exclusion criteria included: clinical evidence of heart failure, planned
revascularisation, hypotension, uncontrolled hypertension, recent
use of ACE inhibitors or angiotensin-receptor blockers, renal
insufficiency, and serum potassium higher than 5.5 mmol/L.
Relevant The primary endpoint was cardiovascular death, myocardial
outcome(s) infarction, or cardiac arrest.
Summary of Key
Key findings Placebo and perindopril patients experienced the primary endpoint in
findings
10% and 8%, respectively, which yields a 20% relative risk reduction
(95% CI = 9-29, p=0.0003) with perindopril. These benefits were
consistent in all predefined subgroups and secondary endpoints.
Conclusion(s) Patients with stable coronary heart disease without apparent heart
failure, perindopril improved clinical outcomes.
196
Acronym Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy
and Survival Study (EPHESUS)
Reference Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman
R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study Investigators.
Eplerenone, a selective aldosterone blocker, in patients with left
ventricular dysfunction after myocardial infarction. N Engl J Med. 2003
Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar
31. Erratum in: N Engl J Med. 2003 May 29;348(22):2271. PMID:
12668699.
Study Type Randomised clinical trial conducted in 37 countries
Nº patients 6642
Intervention Eplerenone (25 mg per day) for four weeks, after which the dose of
was increased to a maximum of 50 mg per day
Main incl/excl Patients with acute myocardial infarction complicated by left
criteria ventricular dysfunction and heart failure. In patients with diabetes
who met the criteria for left ventricular dysfunction after acute
myocardial infarction, symptoms of heart failure did not have to be
demonstrated.
Important criteria for exclusion were the use of potassium-sparing

diuretics, a serum creatinine concentration of more than 2.5 mg/dL,
and a serum potassium concentration of > 5.0 mmol/L before
randomization.
Relevant The primary end points were death from any cause and death from
outcome(s) cardiovascular causes or hospitalization for heart failure, acute
myocardial infarction, stroke, or ventricular arrhythmia
Key findings During a mean follow-up of 16 months, the relative risk to die of
patients receiving eplereneno relative to those receiving placebo was

0.85 (95CI= 0.75 - 0.96; P=0.008). For cardiovascular death, the
relative risk was 0.83 (95% CI= 0.72 - 0.94; P=0.005). The rate of death
from cardiovascular causes or hospitalization for cardiovascular
events was reduced by eplerenone (relative risk = 0.87; 95% CI = 0.79 -
0.95; P=0.002), as was the secondary endpoint of death from any
cause or any hospitalization (relative risk = 0.92; 95% CI = 0.86 - 0.98;
P=0.02).
Conclusion(s) Eplerenone, on top of optimal medical therapy, reduces morbidity and
mortality among patients with acute myocardial infarction
complicated by left ventricular dysfunction and heart failure.
197
Acronym Secondary Prevention of Cardiovascular Disease in the Elderly
(SECURE) trial
Reference Castellano JM, Pocock SJ, Bhatt DL, Quesada AJ, Owen R, Fernandez-
Ortiz A, Sanchez PL, Marin Ortuño F, Vazquez Rodriguez JM, Domingo-
Fernández A, Lozano I, Roncaglioni MC, Baviera M, Foresta A, Ojeda-
Fernandez L, Colivicchi F, Di Fusco SA, Doehner W, Meyer A, Schiele F,
Ecarnot F, Linhart A, Lubanda JC, Barczi G, Merkely B, Ponikowski P,
Kasprzak M, Fernandez Alvira JM, Andres V, Bueno H, Collier T, Van de
Werf F, Perel P, Rodriguez-Manero M, Alonso Garcia A, Proietti M,
Schoos MM, Simon T, Fernandez Ferro J, Lopez N, Beghi E, Bejot Y,
Vivas D, Cordero A, Ibañez B, Fuster V; SECURE Investigators. Polypill
Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022
Sep 15;387(11):967-977. doi: 10.1056/NEJMoa2208275. Epub 2022
Aug 26. PMID: 36018037.
Study Type Randomized, controlled clinical trial.
Intervention Polypill-based strategy, consisting of aspirin (100 mg), ramipril (2.5, 5,

or 10 mg), and atorvastatin (20 or 40 mg).
Evidence
Main incl/excl Patients with type 1 myocardial infarction within the previous 6
criteria months. All the patients were either older than 75 years of age or at
least 65 years of age with at least one of the following risk factors:
diabetes mellitus, mild or moderate kidney dysfunction, previous
myocardial infarction, previous coronary revascularization or
coronary-artery bypass grafting, or previous stroke.
Relevant The primary composite outcome was cardiovascular death, nonfatal
outcome(s) type 1 myocardial infarction, nonfatal ischemic stroke, or urgent
revascularization. The key secondary end point was a composite of
cardiovascular death, nonfatal type 1 myocardial infarction, or

nonfatal ischemic stroke.
Key findings After a median of 36 months, the primary-outcome event occurred in
9.5% in the polypill group and in 12.7% in the usual-care group (HR=
0.76; 95% CI = 0.60 - 0.96; P=0.02). The key secondary-outcome event
occurred in 8.2% in the polypill group and in 11.7% in the usual-care
group (HR= 0.70; 95% CI=0.54 - 0.90; P=0.005).
Conclusion(s) Within 6 months after myocardial infarction, a polypill-based strategy
resulted in a significantly lower risk of major adverse cardiovascular
events than usual care.
198
Reference Yedlapati SH, Khan SU, Talluri S, Lone AN, Khan MZ, Khan MS, Navar
AM, Gulati M, Johnson H, Baum S, Michos ED. Effects of Influenza
Vaccine on Mortality and Cardiovascular Outcomes in Patients With
Cardiovascular Disease: A Systematic Review and Meta-Analysis. J Am
Heart Assoc. 2021 Mar 16;10(6):e019636. doi:
10.1161/JAHA.120.019636. Epub 2021 Mar 13. PMID: 33719496.
Nº patients
Details and
Influenza Vaccination
Quality of
Evidence
Intervention A total of 16 studies (n=237 058) including 4 randomized controlled

trials (n=1667)
Main incl/excl Studies must have at least 50% of patients with established CVD
criteria Follow-up duration of at least 12 months
Relevant All-cause mortality, CV mortality, MI, heart failure, MACE.
outcome(s)
Key findings Influenza vaccine was associated with a lower risk of all-cause mortality
(RR, 0.75 (0.60–0.93) [P=0.01]), CV mortality (0.82 (0.80–0.84)
[P<0.001]), and MACE (0.87 (0.80–0.94) [P<0.001]) compared with
control. The use of the influenza vaccine was not associated with a
statistically significant reduction of MI (0.73 (0.49–1.09) [P=0.12])
Conclusion(s) Data from both randomized controlled trials and observational studies
support the use of the influenza vaccine in adults with CVD to reduce
mortality and CV events.
199
Acronym Flu Vaccination Acute Coronary Syndromes (FLUVACS) study
Reference Gurfinkel EP, Leon de la Fuente R, Mendiz O, Mautner B. Flu
vaccination in acute coronary syndromes and planned percutaneous
coronary interventions (FLUVACS) Study. Eur Heart J. 2004
Jan;25(1):25-31. doi: 10.1016/j.ehj.2003.10.018. PMID: 14683739.
Study Type Randomized controlled study

Intervention Influenza vaccination
Evidence
Main incl/excl Inclusion:

criteria AMI (200) or PCI (101)
Exclusion:
No enrolment during spring summertime
Relevant Primary outcome at one year:
outcome(s) CV deaths
Secondary MACE:
Composite of CV death, MI, and re-hospitalization for severe recurrent
ischaemia
Key findings CV death for vaccination versus placebo: 6% versus 17% (HR 0.34 (0.17-
0.71) p=0.002)
MACE: 22% vs 37% (HR 0.59 (0.40-0.86, p=0.004)
Conclusion(s) Influenza vaccination may reduce the risk of death and ischaemic
events in patients suffering from infarction and post-angioplasty during
flu season
200
Reference Phrommintikul A, Kuanprasert S, Wongcharoen W, Kanjanavanit R,
Chaiwarith R, Sukonthasarn A. Influenza vaccination reduces
cardiovascular events in patients with acute coronary syndrome. Eur
Heart J. 2011 Jul;32(14):1730-5. doi: 10.1093/eurheartj/ehr004. Epub
2011 Feb 2. PMID: 21289042.
Study Type Randomized open with blinded endpoint (PROBE) study

Intervention Influenza vaccination
Evidence
Main incl/excl Inclusion

criteria
Recent (<8week) ACS
age >50y
Exclusion: Previous influenza vaccination
Severe renal/hepatic failure
Relevant MACE, including death, hospitalization for ACS, hospitalization for heart
Summary of Key
outcome(s) failure, hospitalization for stroke between randomization and 12

months.
findings
Key findings MACE for vaccination versus placebo :9.5% vs 19.3%. (HR 0.70 (0.57-
0.86) p = 0.004).
CV death: 2.3% vs 5.5% (HR 0.39 (0.14-1.12) p=0.088)
Conclusion(s) The influenza vaccine reduced MACE in patients with ACS.
201
Acronym Influenza Vaccination After Myocardial Infarction (IAMI trial)
Reference Fröbert O, Götberg M, Erlinge D, Akhtar Z, Christiansen EH, MacIntyre
CR, Oldroyd KG, Motovska Z, Erglis A, Moer R, Hlinomaz O, Jakobsen L,
Engstrøm T, Jensen LO, Fallesen CO, Jensen SE, Angerås O, Calais F,
Kåregren A, Lauermann J, Mokhtari A, Nilsson J, Persson J, Stalby P,
Islam AKMM, Rahman A, Malik F, Choudhury S, Collier T, Pocock SJ,
Pernow J. Influenza Vaccination After Myocardial Infarction: A
Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.
Circulation. 2021 Nov 2;144(18):1476-1484. doi:
10.1161/CIRCULATIONAHA.121.057042. Epub 2021 Aug 30. PMID:
34459211.
Study Type Randomized, double-blind trial

Intervention influenza vaccination
Evidence
Main incl/excl Inclusion:

criteria STEMI or non-STEMI
Stable CAD (if >75y old)
Exclusion:
previous influenza vaccination,
age<18y
Relevant Composite of all-cause death, MI, or stent thrombosis at 12 months
outcome(s)
Key findings The primary outcome for vaccination versus placebo was: 5.3% vs 7.2%
(HR 0.72 (0.52-0.99) p=0.040).
All-cause death: 2.9% and 4.9% (HR 0.59 (0.39-0.89) p=0.010), CV death
2.7% and 4.5%, (HR, 0.59 (0.39-0.90) p=0.014), and MI 2.0% and 2.4%
(HR 0.86 (0.50-1.46) p=0.57)
Conclusion(s) Influenza vaccination early after an MI or in high-risk CAD resulted in a
lower risk of a composite of all-cause death, MI, or stent thrombosis, as
well as a lower risk of all-cause death and CV death at 12 months
compared with placebo
202
Acronym Low-dose colchicine for secondary prevention of
cardiovascular disease (LoDoCo2)
Reference Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ,
The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P,
Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J,
Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG,
Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ,
Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL; LoDoCo2 Trial
Investigators. Colchicine in Patients with Chronic Coronary Disease. N
Engl J Med. 2020 Nov 5;383(19):1838-1847. doi:

Details and Quality
Nº patients 5522 patients with coronary disease

of Evidence
Intervention 0.5 mg of colcichine once daily or placebo

Main incl/excl 35-82 years of age
criteria Evidence of CHD on invasive angiography or CR
Clinically stable for at least 6 months
No renal or heart failure
Relevant Primary outcome : Composite of CV death, MI, stroke, or coronary
outcome(s) revascularization
Key findings After a median follow-up of 28.6 months, the HR for primary outcome
was 0.69 (0.57-0.83), p<0.001. The incidence of death from non-CV
causes was higher in the colchicine group (incidence, 0.7 vs. 0.5 events
per 100 person-years; HR 1.51 (0.99-2.31).
Conclusion(s) The risk of cardiovascular events was significantly lower among those
who received 0.5 mg of colchicine once daily than among those who
received placebo.
203
Acronym Colchicine Cardiovascular Outcomes Trial (COLCOT)
Reference Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto
FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, López-Sendón J, Ostadal P,
Koenig W, Angoulvant D, Grégoire JC, Lavoie MA, Dubé MP, Rhainds
D, Provencher M, Blondeau L, Orfanos A, L'Allier PL, Guertin MC,
Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial
Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi:
Details and
Quality of
Evidence
Nº patients 4745 patients recruited within 30 days after an MI

Intervention 0,5 mg colcichine once daily or placebo
Main incl/excl Adult patients with MI within 30 days. No renal or heart failure or
criteria other severe illness.
Relevant Primary outcome : composite of death from cardiovascular causes,
outcome(s) resuscitated cardiac arrest, myocardial infarction, stroke, or urgent

hospitalization for angina leading to coronary revascularization.
Key findings After a median follow-up of 22.6 months the HR for the primary
outcome was 0.77 (0.61-0.96) p=0.02. Patients in the intervention
group had a higher rate of diarrea and pneumonia.
Conclusion(s) Among patients with a recent myocardial infarction, colchicine at a
dose of 0.5 mg daily led to a significantly lower risk of ischemic
cardiovascular events than placebo.
204
Recommendation Table 17 — Recommendations for patient perspectives in
acute coronary syndrome care
Reference van Oosterhout REM, de Boer AR, Maas AHEM, Rutten FH, Bots ML,
Peters SAE. Sex Differences in Symptom Presentation in Acute
Coronary Syndromes: A Systematic Review and Meta-analysis. J Am
Heart Assoc. 2020 May 5;9(9):e014733. doi:
10.1161/JAHA.119.014733. Epub 2020 May 4. PMID: 32363989.
Study Type A Systematic Review and Meta‐analysis
Nº patients Twenty‐seven studies
Including >1 million patients
Intervention Assessed the extent of sex differences in symptom presentation in

patients with confirmed ACS.
Main incl/excl All studies that reported on symptom presentation in both women
criteria and men with confirmed ACS
Excluded if they reported on patients with other cardiac conditions or

if specific symptoms were required for inclusion in the study
Relevant Demonstrated that sex differences in symptoms for patients with
outcome(s) established ACS have been evident since the early 2000s and hardly
changed over time since then
Women with ACS are less likely to report chest pain and more likely to
report a variety of symptoms than men with ACS
Key findings Both sexes presented most often with chest pain
Compared with men, women with ACS had higher odds of presenting
with pain between the shoulder blades
nausea or vomiting
shortness of breath
Conclusion(s) Women with ACS do have different symptoms at presentation than
men with ACS, but there is also considerable overlap
Symptoms should no longer be labeled as “atypical” or “typical.”
205
Reference Ferry AV, Anand A, Strachan FE, Mooney L, Stewart SD, Marshall L,
Chapman AR, Lee KK, Jones S, Orme K, Shah ASV, Mills NL. Presenting
Symptoms in Men and Women Diagnosed With Myocardial
Infarction Using Sex-Specific Criteria. J Am Heart Assoc. 2019 Sep
3;8(17):e012307. doi: 10.1161/JAHA.119.012307. Epub 2019 Aug 20.
PMID: 31431112.
Study Type Sub study of
High-STEACS trial(Randomised)
Nº patients 1941 patients 39% women
Intervention Prospectively evaluate the frequency and predictive value of patient-

reported symptoms in men and women with suspected acute
coronary syndrome and to determine whether symptoms differ
when the diagnosis of myocardial infarction is based on sex-specific
criteri
Main incl/excl criteria Included: suspected acute coronary syndrome
Excluded: patients with ST‐segment elevation myocardial infarction,

those who were unable to provide consent, or those with previous
involvement in the trial.
Relevant outcome(s) A term such as chest discomfort may be translated into the absence
of chest pain.
Women with type 1 myocardial infarction reported more typical

symptoms than did men.
Key findings 93% of women with myocardial infarction presented with chest pain,
these symptoms occurred as additional symptoms and not primary
presenting symptoms.
Conclusion(s) Women more frequently describe pain of a typical nature than do
men, and typical symptoms are more predictive of a diagnosis of
myocardial infarction in women than in men.
206
Reference Hirpa M, Woreta T, Addis H, Kebede S. What matters to patients? A
timely question for value-based care. PLoS One. 2020 Jul
9;15(7):e0227845. doi: 10.1371/journal.pone.0227845. PMID:
32644993.
Study Type Survey at 2 sites one city
Nº patients 226
Intervention
Evidence
To assess patients' priorities for a range of attributes in ambulatory

care consultations across five key health service delivery domains
and determine potential associations between patient priorities and
certain demographic profiles.
Main incl/excl criteria Consecutive patients were surveyed prior to seeing their physician in
clinic.
Relevant outcome(s) Shared decision making SDM (understanding importance of
diagnostic tests and understanding indication and side effects of
medications) is important to patients.
Key findings Patients have priorities on qualities they value across key health
service domains.
Multiple factors including patient demographics can be predictors of

these priorities.
Conclusion(s) Delivery of effective and quality medical care requires understanding
of what most matters to patients.
Deciphering the multiple factors that may affect patient priorities for
what they value is a real challenge.
207
Reference Poitras ME, Maltais ME, Bestard-Denommé L, Stewart M, Fortin M.
What are the effective elements in patient-centered and
multimorbidity care? A scoping review. BMC Health Serv Res. 2018
Jun 14;18(1):446. doi: 10.1186/s12913-018-3213-8. PMID:
29898713.
Study Type Scoping review.
Nº patients Four systematic reviews and 98 original studies

Intervention
Evidence
To determine the particular elements of patient-centered

interventions and interventions for persons with multimorbidity that
are associated with positive health-related outcomes for patients
Main incl/excl criteria Inclusion:
Studies with interventions for persons with multimorbidity or
patient-centered care in primary care.
Excluded: were studies that not heath related outcomes
Relevant outcome(s) Providing patient-oriented approaches, self-management support
interventions (e.g. Providing educational resources and skills have

the potential to result in positive impacts for patients with chronic
diseases
Key findings Providing a patient-centered approach was one of the most
important interventions in terms of positive health-related outcomes
for patients with chronic diseases
Conclusion(s) Clinicians must consider every component of patient-centered-care

that will engage patients.
208
Reference Wolf A, Vella R, Fors A. The impact of person-centred care on
patients' care experiences in relation to educational level after acute
coronary syndrome: secondary outcome analysis of a randomised
controlled trial. Eur J Cardiovasc Nurs. 2019 Apr;18(4):299-308. doi:
10.1177/1474515118821242. Epub 2019 Jan 17. PMID: 30652920.
Study Type Randomized controlled trial
Nº patients 252 patients aged less than 75 years
Intervention To evaluate the effects of person-centred care on patients'

experiences of care, and also in relation to educational level, after an
acute coronary syndrome
Main incl/excl criteria Patients admitted and diagnosed with ACS
less than 75 years
Exclusion criteria: currently listed at a private primary care centre or

a primary care centre in another region; having no permanent
address; being planned for heart surgery participation in a conflicting
study; cognitive impairment; current drug or alcohol abuse or
expected survival less than one year
Relevant outcome(s) Family members play a vital role in cardiac care, particularly in
healthy lifestyle changes on which they are likely to exert greater
influence than healthcare professionals
Spouses may have a higher symptom burden than patients from

feelings of anxiety, depression and having lower levels of perceived
control
Therefor after a cardiac event it is important to include the
perspective of next of kin
Key findings The effect of PCC was especially prominent in patients with a low
educational level, who were also more involved in care decisions
Conclusion(s) A person-centred care approach after an event of acute coronary
syndrome improves patients' care experiences for information,
shared documentation and involvement of family and friends.
209
Reference Hochhalter AK, Song J, Rush J, Sklar L, Stevens A. Making the Most of
Your Healthcare intervention for older adults with multiple chronic
illnesses. Patient Educ Couns. 2010 Nov;81(2):207-13. doi:
10.1016/j.pec.2010.01.018. Epub 2010 Mar 11. PMID: 20223617.
Study Type Randomized single center
Intervention Testing the efficacy of a patient engagement intervention for older
adults with multiple chronic illnesses
Main incl/excl criteria Inclusion: 65 years of age or older and had been treated for at least
two of seven qualifying chronic illnesses, including ( arthritis, lung
disease, heart disease, diabetes, hypertension, depression, and
osteoporosis
Exclusion: Participants diagnosed with dementia, receiving hospice
care, unable to travel to the clinic for a workshop or living outside of
the recruitment area
Relevant outcome(s) Patient-directed skills training interventions may be a successful way
to support clinicians' and others' efforts to encourage older patients
Summary of Key
to be actively involved in their care.

findings
Key findings After a 2-hour workshop patients showed a statistically significant

improvement in self-efficacy for self-management.
Conclusion(s) Education and contact to the patient before and after a medical
encounter showed promise for improving quality of life and/or
health.
210
Reference Hess EP, Knoedler MA, Shah ND, Kline JA, Breslin M, Branda ME,
Pencille LJ, Asplin BR, Nestler DM, Sadosty AT, Stiell IG, Ting HH,
Montori VM. The chest pain choice decision aid: a randomized trial.
Circ Cardiovasc Qual Outcomes. 2012 May;5(3):251-9. doi:
10.1161/CIRCOUTCOMES.111.964791. Epub 2012 Apr 10. PMID:
22496116.
Study Type Randomised trial
Intervention Assessment of whether patient preferences were driving the decision
to obtain stress testing.

Main incl/excl criteria Eligible clinicians included physicians caring for patients with chest
pain.
Eligible patients included adults aged >17 years who presented to
the ED with primary symptoms of nontraumatic chest pain(at low
risk for ACS)
and who were being considered for admission to the ED observation
unit for monitoring and cardiac stress testing within 24 hours.
Excluded:
Known CAD,LLBB,hx MI
cocaine use within the previous 72 hours by clinician history, or
pregnancy
Relevant outcome(s) The decision aid to include plain language, avoided use of medical
jargon, used a large font size and clear style, and presented risk
information as natural frequencies and in graphic format
presenting information in this way decreases cognitive load and
facilitates knowledge transfer in patients with limited health literacy
Key findings Chest Pain Choice decision aid increased patient knowledge,
decreased patients' decisional conflict related to feeling uninformed,

did not significantly affect physician trust, and increased patient
engagement in decision making
Patient-centered approaches to decision making may improve

healthcare delivery for patients with potential acute cardiovascular
conditions.
Conclusion(s) Use of a decision aid in patients with chest pain increased knowledge
and engagement in decision making and decreased the rate of
observation unit admission for stress testing.
Patient-centered approaches to decision making may improve
healthcare delivery for patients with potential acute cardiovascular
conditions.
211
Reference Hess EP, Hollander JE, Schaffer JT, Kline JA, Torres CA, Diercks DB,
Jones R, Owen KP, Meisel ZF, Demers M, Leblanc A, Shah ND,
Inselman J, Herrin J, Castaneda-Guarderas A, Montori VM. Shared
decision making in patients with low risk chest pain: prospective
randomized pragmatic trial. BMJ. 2016 Dec 5;355:i6165. doi:
10.1136/bmj.i6165. PMID: 27919865.
Study Type Multicenter pragmatic parallel randomized controlled trial
Nº patients 898 adults (aged >17 years) with a primary complaint of chest pain
who were being considered for admission to an observation unit for
cardiac testing (451 were allocated to the decision aid and 447 to
usual care), and 361 emergency clinicians .
Intervention To compare the effectiveness of shared decision making with usual
care in choice of admission for observation and further cardiac
testing or for referral for outpatient evaluation in patients with

possible acute coronary syndrome.
Main incl/excl criteria Eligible clinicians included all emergency physicians, nurse
practitioners, and physician assistants caring for patients with chest
pain
Eligible patients included adults (aged >17 years) presenting to the
emergency department with a chief complaint of chest pain who
were being considered by the treating clinician for admission to the
observation unit for cardiac stress testing or CCTA. Patients were
excluded if they had ischemic changes on the initial ECG (eg, ST
segment depression, T wave inversion, or new left bundle branch
block), had an initial cardiac troponin level more than the 99th
centile, had known coronary artery disease, had used cocaine in the
past 72 hours
had a prior plan for cardiac intervention or admission, had barriers to
outpatient follow-up, were prisoners, were pregnant, were hearing
or visually impaired, or were otherwise unable to use the decision
aid.
Relevant outcome(s) When risk estimates from validated prediction models are shared
with patients, and patients are invited to apply their informed values
and preferences to decisions, rates of admission and testing did not

increase.
Key findings Patients can be effectively educated and engaged in the emergency
care setting in decisions about testing and follow-up.
Conclusion(s) Use of a decision aid in patients at low risk for acute coronary
syndrome increased patient knowledge about their risk, increased
engagement, and safely decreased the rate of admission to an
observation unit for cardiac testing.
212
Reference Olsson A, Ring C, Josefsson J, Eriksson A, Rylance R, Fröbert O, James
S, Sparv D, Erlinge D. Patient experience of the informed consent
process during acute myocardial infarction: a sub-study of the
VALIDATE-SWEDEHEART trial. Trials. 2020 Mar 6;21(1):246. doi:
10.1186/s13063-020-4147-0. PMID: 32143733.
Study Type A sub-study of the VALIDATE-SWEDEHEART randomized, controlled
trial
Nº patients 414 patients who participated

From a sub-study of the VALIDATE-SWEDEHEART trial
Intervention To assess the patient experience of informed consent (IC) during

acute myocardial infarction (AMI) in a sub-study of the VALIDATE-
SWEDEHEART trial
Main incl/excl criteria Inclusion:

Patients admitted to the hospital with a diagnosis of STEMI or non-
ST-segment elevation myocardial infarction (NSTEMI) for whom
urgent PCI was planned
Relevant outcome(s) 85% expressed a positive opinion about being asked to participate in
a study
Key findings 88% did not wish to have received more comprehensive study
information during the initial oral IC
Sixty-eight percent wanted to be consulted before study inclusion
Conclusion(s) It is reasonable to ask patients for verbal IC in the acute phase of

AMI.
Most patients felt positively about being asked to participate and
had knowledge of being enrolled in a scientific study.
Patients objected to providing IC after randomization and treatment
213
Reference Dickert NW, Wendler D, Devireddy CM, Goldkind SF, Ko YA, Speight
CD, Kim SY. Understanding preferences regarding consent for
pragmatic trials in acute care. Clin Trials. 2018 Dec;15(6):567-578.
doi: 10.1177/1740774518801007. Epub 2018 Oct 3. PMID:
30280582.
Study Type A randomized, experimental study part of the HEAT-PPCI trial.

Evidence
Survey was run on two consecutive weeks
Intervention assess preferences of the general public regarding consent for a

pragmatic trial in ST-elevation myocardial infarction
Main incl/excl criteria Participants from the HEAT PPCI trial
Relevant outcome(s) 60.0% brief verbal consent to written consent
Even among respondents stating they would be unlikely to enroll in

the trial if asked, more respondents (50.6%) preferred brief verbal
consent
Key findings The finding that individuals were more likely to support alternatives
to written consent when asked for a personal preference rather than
as a "committee member" suggests that conservative institutional
approaches to consent could hinder implementation of more
patient-centered approaches
Conclusion(s) Respondents generally supported prospective involvement in
enrollment decisions in the setting of acute myocardial infarction
and were particularly supportive of brief verbal consent.
214
Reference Dickert NW, Scicluna VM, Adeoye O, Angiolillo DJ, Blankenship JC,
Devireddy CM, Frankel MR, Goldkind SF, Kumar G, Ko YA, Mitchell
AR, Nogueria RG, Parker RM, Patel MR, Riedford M, Silbergleit R,
Speight CD, Spokoyny I, Weinfurt KP, Pentz RD. Emergency Consent:
Patients' and Surrogates' Perspectives on Consent for Clinical Trials
in Acute Stroke and Myocardial Infarction. J Am Heart Assoc. 2019
Jan 22;8(2):e010905. doi: 10.1161/JAHA.118.010905. PMID:
30663498.
Study Type cross‐sectional interview study
Nº patients 176 (84 stroke, 92 AMI) completed interviews.
Intervention To capture experiences of patients and decision makers for patients

enrolled in acute stroke and AMI trials where clinical treatment and
enrollment decisions must happen very quickly
Main incl/excl criteria Included trials involved randomization and required enrollment in
the acute phase (<24 hours from presentation
Excluded:
Patients did not speak English
Relevant outcome(s) Patients and surrogates of patients enrolled in a range of acute

stroke and acute MI trials, the large majority of respondents felt that
they had been treated respectfully during the enrollment decision
and were glad that they had been asked for consent prospectively
Key findings Understanding of the trial was relatively poor, many respondents did
not recall substantial contact after initial enrollment occurred, and
the views of consent forms were mixed
Conclusion(s) Consent that incorporates highly simplified consent language,

targeting of the most essential elements of informed consent,
explicit attention to postenrollment contact, and recognition of the
nature of decision making on the part of investigators and IRBs may
help to maximize respect for participants while facilitating important
studies
215
Reference Dickert NW, Hendershot KA, Speight CD, Fehr AE. Patients' views of
consent in clinical trials for acute myocardial infarction: impact of
trial design. J Med Ethics. 2017 Aug;43(8):524-529. doi:
10.1136/medethics-2016-103866. Epub 2016 Dec 30. PMID:
28039285.
Study Type Qualitative Structured interviews
Nº patients 30 patients with AMI
Intervention Explore views of patients with a primary AMI diagnosis regarding

consent for key trial types
Main incl/excl criteria Inclusion: admitting diagnosis AMI, age >18 and angiography during
admission (with or without intervention). Non-English-speaking
patients were excluded due to the interactive nature of interviews.
Interviewers were instructed to exclude individuals unable to engage
in discussion.
Relevant outcome(s) Desire to participate in trials was affected by trial type
Clinical trials are difficult to explain, and it is not likely that actual
enrolees understand these considerations more fully
Key findings There is a need to develop and evaluate context-sensitive

approaches to consent in AMI trials that account for both the acuity
of the situation and trial characteristics
Conclusion(s) Patients prefer prospective involvement in enrolment decisions to

enrolment without consent across trial types
216
Reference Astin F, Stephenson J, Probyn J, Holt J, Marshall K, Conway D.
Cardiologists' and patients' views about the informed consent
process and their understanding of the anticipated treatment
benefits of coronary angioplasty: A survey study. Eur J Cardiovasc
Nurs. 2020 Mar;19(3):260-268. doi: 10.1177/1474515119879050.
Epub 2019 Nov 27. PMID: 31775522.
Study Type A cross-sectional survey
Nº patients A self-report questionnaire was distributed to two groups; 400

patients in recruited from 10 centres.
England treated with either elective or acute PCI (acute/urgent cases

but not primary PCI), and a non-probability sample of 400 UK
cardiologists involved in taking PCI informed consent
Intervention To assess cardiologists' and patients' views about the informed

consent process and anticipated treatment benefits
Main incl/excl criteria The anonymous electronic questionnaire was distributed by email to
all medically qualified members of the BCIS.
All adults undergoing elective or urgent PCI, who were able to read
English, and willing to give their consent to participate were included
Excluded:
primary PCI patients were excluded
Relevant outcome(s) A majority of patients depended on their doctor to make the
decision for them
Approximately half of the respondents agreed that most patients do
not usually understand or remember the information provided

during the informed consent process.
Key findings Redesign of the patient pathway is recommended to allow protected
time for health professionals to engage in discussions with patients
and those close to them, using evidence-based approaches such as
‘teach back’ and decision support to improve patient
comprehension.
Conclusion(s) The PCI informed consent process requires improvement to ensure
that patients are more involved and accurately understand
treatment benefits to make an informed decision
217
Reference Scott JT, Thompson DR. Assessing the information needs of post-
myocardial infarction patients: a systematic review. Patient Educ
Couns. 2003 Jun;50(2):167-77. doi: 10.1016/s0738-3991(02)00126-x.
PMID: 12781932.
Nº patients 14 published studies

Evidence
Intervention Examining information needs of post-myocardial infarction patients

and their families
Main incl/excl criteria Studies examining information needs of post-myocardial infarction

patients and their families
Relevant outcome(s) Patients preferred physicians over nurses as information givers

Key findings
Key findings
Summary of
Information about miscellaneous items, diet, psychological factors,

and the CCU, although ranked lower, were still rated important
Conclusion(s) Information about risk factors ranked as the most important
category overall, followed by information on cardiac anatomy and
physiology, medications, and physical activity
218
Reference Ha Dinh TT, Bonner A, Clark R, Ramsbotham J, Hines S. The
effectiveness of the teach-back method on adherence and self-
management in health education for people with chronic disease: a
systematic review. JBI Database System Rev Implement Rep. 2016
Jan;14(1):210-47. doi: 10.11124/jbisrir-2016-2296. PMID: 26878928.
Nº patients 21 articles retrieved in full, 12 used the teach-back method
Intervention Examined the evidence on using the teach-back method in health

education programs for improving adherence and self-management
Evidence
of people with chronic disease.

Main incl/excl criteria Adults aged 18 years and over with one or more than one chronic
disease
Studies using all types of interventions which included the teach-
back method in an education program for people with chronic
diseases
Relevant outcome(s) Four studies confirmed improved disease-specific knowledge in
intervention participants
Summary of Key
Key findings One study showed a statistically significant improvement in

findings
adherence to medication and diet among type 2 diabetics patients

Conclusion(s) Evidence from the systematic review supports the use of the teach-
back method in educating people with chronic disease to maximize
their disease understanding and promote knowledge, adherence,
self-efficacy and self-care skills
219
Reference Klingbeil C, Gibson C. The Teach Back Project: A System-wide
Evidence Based Practice Implementation. J Pediatr Nurs. 2018 Sep-
Oct;42:81-85. doi: 10.1016/j.pedn.2018.06.002. Epub 2018 Jul 21.
PMID: 30219303.
Study Type Evidence-based practice project
Nº patients 300 multidisciplinary team members (including acute care,

emergency room, and surgical nurses, dieticians, respiratory care
Evidence
practitioners and occupational and physical therapists)

Intervention Examined the impact of a brief educational intervention for a
multidisciplinary staff on knowledge of health literacy and the use of
teach-back during patient-education
Main incl/excl criteria Clinical staff working at a 290 bed Magnet® designated Midwest
pediatric healthcare organization
Relevant outcome(s) Clarifications are often about medications and skill-based treatments
Key findings Both nurses and non-nurses demonstrated increased knowledge of

the teach-back process and reported high rates of clarifying
information and correcting misunderstandings when using teach
back with patients and families
Conclusion(s) Teach-back is a valuable strategy that can improve the safety and
quality of health care and supports the National Action Plan to
Improve Health Literacy.
220
Reference Prochnow JA, Meiers SJ, Scheckel MM. Improving Patient and
Caregiver New Medication Education Using an Innovative Teach-back
Toolkit. J Nurs Care Qual. 2019 Apr/Jun;34(2):101-106. doi:
10.1097/NCQ.0000000000000342. PMID: 30198943.
Study Type Quality improvement project
Nº patients
Using the Always Use Teach-back! innovative toolkit,
RNs (n = 25) were observed in patient/caregiver education and

surveyed in confidence/con-viction in the teach-back method before
and after education.
Patients' (n = 74) and caregivers' (n = 33) knowledge was assessed.
Intervention Teach-back method
Main incl/excl criteria RNs on the demonstration unit
The caregiver sample included English-speaking patients and care-

givers, 18 years and older, who were discharged home with at least 1
new medication
Relevant outcome(s) RNs reported significant increases in conviction in the importance of
Summary of Key
& confidence in using, and frequency in using teach-back

Key findings With teach-back, both patients and caregivers recalled the purpose
findings
and side effects of new medications
Conclusion(s) The teach-back method strengthened safe nursing practice and

enhanced quality in new medication education
221
Reference Hedegaard U, Kjeldsen LJ, Pottegård A, Henriksen JE, Lambrechtsen J,
Hangaard J, Hallas J. Improving Medication Adherence in Patients
with Hypertension: A Randomized Trial. Am J Med. 2015
Dec;128(12):1351-61. doi: 10.1016/j.amjmed.2015.08.011. Epub
2015 Aug 21. PMID: 26302142.
Study Type A Randomized Trial
Nº patients Patients (n = 532) were recruited from 3 hospital outpatient clinics
Intervention Investigating the effectiveness of a multifaceted pharmacist

intervention in a hospital setting to improve medication adherence
in hypertensive patients
Main incl/excl criteria Patients with hypertension were included from December 2012 to
July 2013 from one cardiology and two endocrinology outpatient
clinics
Patients were excluded if they lived in a care home, received dose-
dispensed medicine from a pharmacy, had medicine dispensed by a
home nurse, had terminal illness, had conditions that precluded
patient interview, e.g. dementia or lived outside the Region of
Southern Denmark
Relevant outcome(s) At 12 months, the intervention group were nonadherent compared
with the control group
Key findings The intervention had no significant impact on blood pressure and
secondary clinical outcomes.
Conclusion(s) A multifaceted pharmacist intervention in a hospital setting led to a

sustained improvement in medication adherence for patients with
hypertension
222
Reference Ceccarini M, Manzoni GM, Castelnuovo G. Assessing depression in
cardiac patients: what measures should be considered? Depress Res
Treat. 2014;2014:148256. doi: 10.1155/2014/148256. Epub 2014 Feb
6. PMID: 24649359.
Study Type Review
Nº patients Analysis of eight well established depression assessment tools
Intervention Review the fundamental steps that have most commonly been used
Evidence
to evaluate depression in cardiac hospitalised patients
Main incl/excl criteria Depression assessment tools taken into consideration by Italian,
American, and European recommendations on cardiac patients
depression screening
Relevant outcome(s) Patients and professionals often underestimate or misjudge

depressive symptomatology as cardiac symptoms; hence, quick,
reliable, and early mood changes assessments are warranted
Key findings It is highly recommended to promptly assess depression in heart

disease patients as it represents a crucial risk factor which may result
in premature deaths following acute cardiac events and a more
severe psychopathology, even in cases of subsequent nonfatal
cardiac events.
Conclusion(s) Cardiac patients often display depressive symptoms of some sort
following an acute heart event or a cardiac surgery
223
Reference Moser DK. "The rust of life": impact of anxiety on cardiac patients.
Am J Crit Care. 2007 Jul;16(4):361-9. PMID: 17595368.
Study Type Prospective, comparative, cross-cultural study
from the original study
A five-country comparison of anxiety early after acute myocardial
infarction
Intervention 1) examination and comparison of the intensity of anxiety in
international samples of various critically, acutely, and chronically ill
cardiac patients; (2) determination of differences between men and

women in the expression of anxiety; (3) investigation of factors
predictive of anxiety levels, including perceived control; (4) studies
of healthcare providers' knowledge of anxiety assessment and
providers' practices in assessing and managing anxiety; and (5)
determination of the impact of anxiety on clinical outcomes in
cardiac patients
Main incl/excl criteria Eligibility: (1) documented AMI by elevated cardiac isoenzymes and
typical ECG changes; (2) onset of AMI outside of the hospital or other
institutional setting, such as an extended care facility; (3)
hemodynamic stability and absence of pain at the time of interview;
and (4) intact cognitive function that allowed the participant to
answer questions concerning their emotional status
Exclusion:
Participants with life-threatening or debilitating co-morbidities
Relevant outcome(s) Anxiety is common, even more so than depression, among persons
with chronic cardiovascular disease and among those coping with
recovery from acute cardiac events or interventions
Anxiety after AMI is associated with increased risk of in-hospital

complications such as potentially lethal dysrhythmias, continued
ischemia, and reinfarction
Key findings The impact of psychological risk factors on morbidity and mortality is
at least equal to the impact of demographics or clinical risk factors
Conclusion(s) Given the negative impact of anxiety in cardiac patients, it is
essential that clinicians accurately determine which patients have
anxiety and then effectively manage that anxiety.
224
Reference Bauer LK, Caro MA, Beach SR, Mastromauro CA, Lenihan E, Januzzi JL,
Huffman JC. Effects of depression and anxiety improvement on
adherence to medication and health behaviors in recently
hospitalized cardiac patients. Am J Cardiol. 2012 May 1;109(9):1266-
71. doi: 10.1016/j.amjcard.2011.12.017. Epub 2012 Feb 9. PMID:
22325974.
Study Type A sub-study from the Randomized controlled trial
A Collaborative Care Program to Improve Depression Treatment in
Cardiac Patients

Intervention Assessed the association between improvements in
depression/anxiety and self-reported adherence to health behaviors
in depressed cardiac patients in the 6 months after cardiac
hospitalization
Main incl/excl criteria Inclusion Criteria:
Inpatient admission for cardiac diagnosis
Positive depression evaluation (PHQ-2>2, PHQ-9>9)
Ability to provide informed consent
Exclusion Criteria:
Active suicidal ideation
Bipolar disorder, psychotic disorder, active substance use disorder
Relevant outcome(s) Patients with anxiety may be highly anxious about (and focused on)
health concerns, leading to greater vigilance regarding

recommendations about their health.
Key findings Depression is associated with impaired subsequent adherence
behavior (e.g., medication adherence, heart-healthy diet) in cardiac
patients
Conclusion(s) Improvement of depression symptoms (whether spontaneously or by
treatment) appears to lead to improved adherence in patients with a
broad range of cardiac diagnoses
225
Reference Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C,
Beekman A. Depression and the risk for cardiovascular diseases:
systematic review and meta analysis. Int J Geriatr Psychiatry. 2007
Jul;22(7):613-26. doi: 10.1002/gps.1723. PMID: 17236251.
Study Type Meta-analyses and meta-regression analyses
Nº patients 28 studies
Intervention To estimate the risk of depression as an independent risk factor for

various cardiovascular diseases (CVD) and explore the effects of
heterogeneity and methodological quality
Main incl/excl criteria Studies eligible for inclusion had to meet the following selection
criteria:
Reporting on adult or elderly patients with depressive symptoms or
disorders as exposure variable and CVDs (fatal or non-fatal) as
outcome variable;
Based on community-dwelling or general practice samples;
Designed as a longitudinal case-control or cohort study.
Relevant outcome(s) Depression seems to be an independent risk factor for the onset of a
wide range of CVDs, although this evidence is related to a high level
Summary of Key
of heterogeneity
findings
Key findings Clinically diagnosed major depression showed

The greatest risk for the development of CVD, which equals the risk
of smoking
Conclusion(s) Depression is associated with the development of various CVDs in
community-dwelling and general practice populations.
226

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2023 ESC Guidelines for the management of

acute coronary syndromes

Acronym High-Sensitivity Troponin in the Evaluation of patients with

Nº patients 48,282 (10 hospitals).

Intervention Implementation of an hs-cTnI assay (the unit of randomisation was

Intervention 0/1h vs. the 0/3h algorithm.

- NPV, 99.8% (95% CI, 99.4–99.9) vs 99.7% (95% CI, 99.2–99.9)

Intervention High-sensitivity cardiac troponin I measurement at presentation and 3

- In those less than the 99th centile at presentation, the

Intervention Noninferiority assessment: 0/1-hour hs-cTnT protocol (reported to the

determined by Poisson regression.

NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT

Intervention Intravenous streptokinase (SK)

Nº patients 50,246 patients (22 studies)

Intervention Fibrinolytic therapy

Proportional mortality reduction was significantly higher in patients

Acronym Rapid Assessment of Potential Ischaemic Heart Disease With CTCA

Nº patients 1748 participants from 37 hospitals in the UK

Intervention Early CT coronary angiography and standard of care compared with

randomised to CT coronary angiography and 60.8% participants who

Intervention CTA vs. SPECT

shorter with CTA than with SPECT (P = 0.002).

Acronym Determination of the Role of Oxygen in Suspected Acute Myocardial

through an open face mask) vs. ambient air

Patients who were receiving ongoing oxygen therapy, as well as those

after intravenous metoprolol compared with control (25.6 ± 15.3

Nº patients 683 participants.

Intervention IV metoprolol (2 × 5-mg bolus).

risk with Mantel-Haenszel risk ratio, using a random-effects model)

Conclusion(s) Intravenous beta-blockers within 12 hours of presentation of ACS are

Nº patients 192,509 patients

significantly modulate the relative survival advantage of PPCI over

Conclusion(s) As DB-DN times increase, the mortality advantage of PPCI over

vs. catheterisation laboratory versus transfer via the emergency room.

Conclusion(s) In this observational analysis, bypassing the emerngey room was

Nº patients Twenty-five randomized trials (n = 7743). Of these, individual patient

Intervention PCI vs fibrinolysis

Relevant Multi-level logistic regression was used to evaluate the relationship

heterogeneity in the treatment effect by presentation delay

Nº patients 7739 patients.

Main incl/excl A search of published work and identified 23 trials, assessing

Nº patients 4278 participants

interventional facility or primary PCI ± Platelet glycoprotein IIb/IIIa–

the primary end point.

in 14.3% in the primary PCI group (relative risk in the fibrinolysis

Intervention Repeated thrombolysis vs. conservative treatment (141 patients) vs.

- among those undergoing repeated thrombolysis, 68.7%

The adjusted HR for the occurrence of the primary endpoint were:

Nº patients 365 participants.

Intervention Invasive strategy based predominantly on coronary stenting with

15.8%) and 13.0% (interquartile range, 3.0%-27.0%) in participants

The secondary endpointsof death, recurrent MI, or stroke at 30 days

was an international, multicenter, open-label, randomized controlled

Nº patients 365 participants

on the prespecified analysis of 4-year outcomes with mortality as the

Intervention Early presenters (<12 h) vs. late presenters (12-72 h) undergoing

outcome(s) Association (NYHA) class IV heart failure.

Nº patients 4853 participants

streptokinase group (P<0.05). Patients randomized >3 h after the