Review Article

Perioperative atrial fibrillation:

A systematic review of evolving
therapeutic options in pharmacologic
and procedural management
J. William Schleifer, Harish Ramakrishna1
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, 1Department of Anesthesiology, Mayo Clinic,
Phoenix, AZ 85054, USA

ABSTRACT Given the high incidence of atrial fibrillation (AF) in the surgical population and the associated morbidity,
physicians managing these complicated patients in the perioperative period need to be aware of the new
and emerging trends in its therapy. The cornerstones of AF management have always been rate/rhythm
control as well as anticoagulation. Restoration of sinus rhythm remains the fundamental philosophy as it
maintains the atrial contribution to cardiac output and improves ventricular function. The recent years have
seen a dramatic increase in the number of randomized AF trials that have made significant advances to
our understanding of both pharmacologic and procedural management, from the introduction of the new
generation of oral anticoagulants (NOAC’s) to catheter approaches for AF ablation. This paper will summarize
the newest data that will affect the perioperative management of these patients.
Received: 22‑08‑15
Accepted: 03‑09‑15 Key words: Atrial fibrillation; If oral anticoagulation; Novel anticoagulants; Pulmonary vein isolation

INTRODUCTION current guidelines,[1] (2) provided new data

to inform current practice where little data
Atrial fibrillation (AF), the most common atrial existed, (3) evaluated a new therapy, or
arrhythmia, ranges from being minimally (4) compared two or more treatments in a
symptomatic to cause debilitating symptoms. randomized, prospective fashion. The studies
It increases the risk of stroke so that most selected involve two areas relevant to the
patients require systemic anticoagulation. practicing anesthesiologist caring for patients
Several recent trials significantly expand our in the perioperative or intensive care setting:
understanding of treating AF with a catheter Anticoagulation management and ablation
or surgical ablation, preventing stroke procedural approach. These studies are
with device therapies or anticoagulants, discussed in detail below.
and managing complications of medical Address for correspondence: Dr. Harish Ramakrishna,
Access this article online and procedural therapies. The impact of Department of Anesthesiology, Mayo Clinic, 5777 East Mayo
Boulevard, Phoenix, AZ 85054, USA.
Website: www.annals.in these trials will likely affect periprocedural E‑mail: [email protected]
PMID:
***
anticoagulation management and
DOI:
intraprocedural management of patients This is an open access article distributed under the terms of the
Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0
10.4103/0971-9784.166466 treated for AF. License, which allows others to remix, tweak, and build upon the
Quick Response Code:
work non‑commercially, as long as the author is credited and the
new creations are licensed under the identical terms.
METHODS
For reprints contact: [email protected]
A MEDLINE search was performed for
Cite this article as: Schleifer JW, Ramakrishna H. Perioperative
studies published or reported in the past atrial fibrillation: A systematic review of evolving therapeutic
6 months regarding AF treatment. Studies options in pharmacologic and procedural management. Ann Card
Anaesth 2015;18:565-70.
were selected that either (1) challenged

© 2015 Annals of Cardiac Anaesthesia | Published by Wolters Kluwer ‑ Medknow 565

 Schleifer and Ramakrishna: Recent advances in atrial fibrillation

Stroke prevention and anticoagulation management uninterrupted anticoagulation based on the patient’s
Antithrombotic therapy in low risk patients stroke risk according to the CHA2DS2‑VASc score in all
Whether AF is paroxysmal, persistent, or permanent; patients diagnosed with AF, even if they spontaneously
whether it is rate‑controlled or ablated, stroke convert to sinus rhythm. Martin et al. performed a trial
prevention with antithrombotic therapy is usually to determine whether or not anticoagulation based
required. The CHA2DS2‑VASc (congestive heart failure, on the rhythm the patient was actually in could be
hypertension, age ≥75 for 2 points, diabetes mellitus, performed using already implanted cardiac devices
stroke for 2 points, vascular disease, age 65–74, and via remote monitoring.[3] In the intervention group,
sex category with 1 point for females) scoring system oral anticoagulation with warfarin or a non‑Vitamin
has been validated as an estimator of clinical risk K‑antagonist oral anticoagulant (NOAC) was initiated
of stroke, with each point being roughly equivalent immediately once rapid atrial tachyarrhythmias were
to 1% risk per year. Patients with a score  ≥2 benefit detected, and discontinued if the patient was free of
from anticoagulation, and aspirin is recommended for atrial tachyarrhythmias for  >30  days for a CHADS2
lower‑risk patients without contraindications.[1] score of 1–2 or  >90  days for a CHADS2 score  >2
if they had no history of thromboembolism. The
Lip et al. studied a cohort of 39,400 patients in the 1357 patients in the intervention group were compared
Danish National Patient Register with nonvalvular to 1361 patients randomized to usual care and analyzed
AF and a CHA2DS2‑VASc score of 0 or 1.[2] Diagnosis both by intention‑to‑treat and per protocol. The primary
codes were used to identify patients with AF, exclude outcomes of stroke, systemic thromboembolism, and
patients with valvular heart disease, calculate the stroke bleeding were not significantly different in either
risk with the CHA2DS2‑VASc score, and determine the arm after 5430 patient‑years of follow‑up. Comparing
outcomes of bleeding, stroke, thromboembolism, and intervention and control groups, annual ischemic
intracranial hemorrhage. Patients with a CHA2DS2‑VASc stroke rates were 0.7% and 1.6%; thromboembolism
score of 0–1 for males and 0–2 for females were divided rates were 1.0% and 1.6%, and major bleeding
into groups based on whether oral anticoagulation, rates were 1.6% and 1.2%, respectively. Stroke and
aspirin, or no antithrombotic therapy was prescribed thromboembolic events were not temporally related to
within 1 year of AF diagnosis. Based on this treatment, the development of atrial tachyarrhythmias. This study
the results were analyzed by intention‑to‑treat. Mean is a well‑done randomized assessment of whether or
follow‑up was 5.2 years; 23,572 patients were untreated. not patients would benefit from a rhythm‑determined
In patients with no risk factors besides female sex, the anticoagulation strategy. However, the findings of
annual rate of stroke was 0.47% in untreated patients, (1) no significant clinical benefit, (2) no reduction in
compared to 0.71% in patients treated with aspirin and bleeding, and (3) no temporal association between
0.76% in patients treated with warfarin. The annual rhythm events and thromboembolic events indicate
bleeding rate was 0.97% in untreated patients, 1.29% in that anticoagulation should be continued without
patients on aspirin, and 1.42% in patients on warfarin. significant interruption in patients with AF as directed
The patients with 1 risk factor besides female sex had by the CHA2DS2‑VASc score, regardless of spontaneous
stroke rates of 1.24% if untreated, 1.22% on aspirin, and conversion to sinus rhythm.
1.08% on warfarin; bleeding rates were 1.97% with no
treatment, 2.21% on aspirin, and 2.32% on warfarin, Periprocedural anticoagulation “bridging”
by intention‑to‑treat analysis. Additionally, there was When surgeries are necessary for patients with AF, oral
a reduction in death in the patients with 1 risk factor anticoagulation is often suspended so that patients more
taking warfarin (hazard ratio 0.86). This study provides easily achieve hemostasis. While the anticoagulation
compelling evidence that aspirin is not effective stroke effects are normalizing, patients may be maintained
prevention in AF; it only increases bleeding risk. on either unfractionated or low‑molecular‑weight
Anticoagulation for patients with an additional stroke heparin for “bridging.” Steinberg et al., analyzed a
risk factor besides sex is reasonable, weighed against registry of patients with AF, the Outcomes Registry
the patient’s individual bleeding risk. for Better Informed Treatment of Atrial Fibrillation to
assess for outcomes related to temporary interruption
Rhythm‑determined versus risk‑determined anticoagulation of anticoagulation and compare patients who were
Patients frequently ask whether they can stop bridged with unfractionated or low‑molecular weight
anticoagulation if they spontaneously convert back to heparin to those who were not bridged.[4] The registry
sinus rhythm. Current recommendations are to continue included 10,132 patients, among whom there were

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 Schleifer and Ramakrishna: Recent advances in atrial fibrillation

2803 interruptions of oral anticoagulation. Bridging enlargement.[6] The primary modifiable variables that
anticoagulation was used in 665 interruptions, 73% affected hematoma enlargement included the degree that
of which were with low‑molecular‑weight heparin. anticoagulation was reversed, the time from symptoms
Bridging anticoagulation was not used in 2138 for that reversal to take place and the systolic blood
interruptions. The mean CHA2DS2‑VASc score was pressure. Receiver operating characteristic analysis
higher in bridged patients (4.25 vs. 4.03), and bridged demonstrated that the optimal international normalized
patients were more likely to have heart failure, ratio (INR) to reverse anticoagulation to was 1.3, and
prior stroke, and valvular heart disease, particularly should be reversed within 4 h of symptom onset.
mechanical prosthetic valves (9.6% of bridged patients). A  systolic blood pressure  >160  mmHg significantly
Major bleeding events were more frequent in bridged increased the risk of hematoma enlargement. In
patients (3.6% vs. 1.2%, odds ratio 3.84). Thrombotic 172 patients, oral anticoagulation was restarted after a
events were also more common in bridged patients (0.8% mean of 31 days. Patients, where anticoagulation was not
vs. 0.6%), with a 0.6% occurrence of stroke in bridged restarted, had a 3‑fold higher risk of subsequent ischemic
patients compared to a 0.3% occurrence of stroke in cerebrovascular and cardiovascular complications
patients who were not bridged. This registry provides compared to those who restarted anticoagulation (15.2%
data that bridging anticoagulation during periprocedural vs. 5.0%), and hemorrhagic complications were not
interruptions of oral anticoagulation does not reduce significantly different (6.6% vs. 8.1%). Additionally,
thrombotic complications in most patients with AF, mortality was significantly less in the group that
and significantly increases the risk of major bleeding. restarted anticoagulation, but this group was younger
The registry does not provide sufficient data on patients and had a less neurologic disability compared to the
with mechanical valves, prior thromboembolic disease, group that did not restart anticoagulation. This study
and prior strokes, and anticoagulation bridging should will impact the clinical decisions that must be made
probably be used for these patients. in patients presenting with intracerebral hemorrhage
from oral anticoagulation therapy. It places a priority
Dabigatran anticoagulation reversal on anticoagulation reversal and blood pressure
A major disadvantage of the NOACs has been the management and gives targets for the clinician to
lack of reversibility in the event of bleeding. Pollack achieve. The resumption of anticoagulation after a
et al., report clinical experience with a monoclonal potentially devastating intracerebral hemorrhage will
antibody fragment idarucizumab for reversing one remain a difficult decision, but this study indicates
of the NOACs, dabigatran. [5] In 51 patients with that anticoagulation likely can be safely resumed after
serious bleeding and 39 patients requiring an urgent a few weeks.
procedure, idarucizumab successfully restored normal
hemostasis in all patients on dabigatran. All patients Left atrial appendage exclusion
had confirmed abnormalities in coagulation studies that One exciting option for patients with devastating bleeds
were normalized by monoclonal antibody within 4 h. is a nonpharmacologic treatment, the newly‑approved
Despite the effective reversal of anticoagulation, there Watchman device (Boston Scientific, Marlborough,
were 18 deaths and 3 thrombotic events in the group of MA, USA). While other devices have been developed,
patients with serious bleeding. This study raises hope the Watchman is the only such device approved in the
that soon reversal agents for NOACs will be available. United States. This device is a nitinol framework that
However, it also highlights the fact that serious bleeding is delivered percutaneously via trans‑septal puncture
still can be fatal, despite reversal of anticoagulation. to the left atrial appendage under echocardiographic
and fluoroscopic guidance. After full endothelialization
Anticoagulation‑associated intracerebral hemorrhage in a few months, antithrombotic therapy is no longer
There is no more dreaded complication of chronic required for stroke prevention. Reddy et al. studied
anticoagulation than intracerebral hemorrhage. 707 patients randomized in a 2:1 unblinded fashion to
What is particularly perplexing is the management Watchman device or anticoagulation with warfarin.[7]
of patients with intracerebral hemorrhage who have Follow‑up has continued in this study now for 4 years.
a strong indication for anticoagulation. Kuramatsu The mean CHADS2 score was 2.2–2.3, and baseline
et al., studied 1322 patients across Germany with characteristics, including duration of AF, were not
anticoagulation‑associated intracerebral hemorrhage, different between the groups. In the warfarin group,
identified patients where the hematoma enlarged, the mean time in therapeutic range was 70%, indicating
and then attempted to find risk factors leading to good adherence to therapy. The Watchman device was

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 Schleifer and Ramakrishna: Recent advances in atrial fibrillation

successfully implanted in 88%. The adverse effects safety endpoints were compared. The results are
from the Watchman device implantation were primarily unpublished at this time, but 12‑month follow‑up
periprocedural: 4.8% risk of serious pericardial data on 315 patients were presented at the 2015 Heart
effusion, 1.1% risk of periprocedural ischemic stroke, Rhythm Society meeting, showing noninferiority
and 0.6% risk of device embolization. The cumulative between the two approaches. With a single procedure,
risk of ischemic stroke was 1.5/100 patient‑years with 64–65% of patients were free of AF at 6 months, and
the Watchman device and 2.2/100 patient‑years with with an additional procedure for patients who had
warfarin. The cumulative risk of hemorrhagic stroke recurrence, the rate of freedom from AF at 12 months
with the Watchman device was 0.2/100 patient‑years improved to 72–74% without antiarrhythmics.
and 1.1/100 patient‑years with warfarin. Cardiovascular Cryoablation has a 5.8% risk of phrenic nerve injury,
and cerebrovascular mortality was significantly lower in which in most cases is asymptomatic and improves with
the Watchman group, 3.7% versus 9%. The combined time. Additionally, likely because of the larger sheath
primary efficacy endpoint not only met criteria for required, cryoablation has a higher risk of vascular
noninferiority, but also superiority. complications (5% vs. 3% in radiofrequency ablation,
a difference not statistically significant). Both of these
The Watchman device is currently approved for patients complications have significant anesthetic implications.
who can be anticoagulated but also have “an appropriate There appears to be no statistically significant difference
reason” for seeking nonpharmacologic stroke prevention. in other complication rates, including pericardial
This and future devices will hopefully further reduce effusion, tamponade, atrioesophageal fistula, and
cerebrovascular complications from AF. pulmonary vein stenosis. While cryoablation cases
tend to be shorter and require less fluoroscopic time,
Ablation techniques the mean total radiation dose is actually higher than in
Many ablation techniques have been developed for AF. radiofrequency ablation cases.
Recent studies have attempted to compare approaches.
In this section, the ablation approaches will be briefly Paroxysmal atrial fibrillation: Visually‑guided laser balloon
described, along with the studies of their efficacy. catheter ablation
Another balloon‑based ablation technology has been
Paroxysmal atrial fibrillation: Radiofrequency ablation developed, in this case, utilizing an endoscopic
versus cryoablation for pulmonary vein isolation system through a transparent balloon to allow direct
Paroxysmal AF is predominantly mediated by premature visualization of the pulmonary vein ostium. The
beats and tachycardia arising from the pulmonary ablation is then performed with laser energy. This
veins. The primary approaches to isolate, or make an system has not yet been approved for use in the United
electrical barrier between the pulmonary vein and States. Dukkipati et al. report their investigational
the left atrial myocardium, are with radiofrequency experience with this method of ablation.[9] While acute
energy to cauterize the tissue, or with cryoenergy to isolation occurred in 97% of veins attempted, only 61%
freeze the tissue to form a scar that will not conduct the of patients had freedom from AF after 12 months. The
action potential. Radiofrequency ablation is delivered 3.5% occurrence of pericardial tamponade and 6% risk
point‑by‑point, one lesion at a time until a circular lesion of temporary phrenic nerve palsy are similar to other
surrounds each pulmonary vein. Cryoenergy is delivered methods. There is the possibility that with increased
via a balloon that is inflated within each pulmonary operator experience with this system that the procedural
vein ostium, checked for completeness of occlusion outcomes would improve.
by contrast injection within the pulmonary vein, and
then cooled to less than −50°C for approximately 3 min Paroxysmal and persistent atrial fibrillation: Anatomic
per application. Both approaches require transeptal versus electrogram‑guided ablation strategy
puncture for left atrial access. Both approaches require There is considerable debate regarding whether AF
general anesthesia and controlled ventilation along with ablation should be anatomically guided (for example,
complete patient immobility. ablating circumferentially around each pulmonary
vein) or electrically guided (ablating sources or triggers
Luik et al. are comparing cryoablation to radiofrequency of fibrillation). Atienza et al., compared patients with
ablation for pulmonary vein isolation (PVI) to paroxysmal or persistent AF randomized to PVI only or
treat paroxysmal AF in the Freeze study.[8] Patients high‑frequency source ablation.[10] High‑frequency atrial
were randomized 1:1 to each arm and efficacy and electrograms were identified with a computer‑based

568 Annals of Cardiac Anaesthesia  |  Oct-Dec-2015 | Vol 18 | Issue 4

 Schleifer and Ramakrishna: Recent advances in atrial fibrillation

algorithm. Of 232 patients randomized, 49% had mortality, antiarrhythmic use, or stroke rate in either
paroxysmal, and 51% had persistent AF. The difference in group. Implantation of a permanent pacemaker was
success between the two approaches was not significant. significantly higher in the ablation group at 21%, in
The percent of patients free from AF or atrial tachycardia contrast to 8% in the control group.
at 6 months was 69% in paroxysmal AF patients receiving
PVI only; 65% in patients receiving high‑frequency There are many valid ways to ablate AF, with different
source ablation only. In patients with persistent AF, catheter types, different lesion sets, and different
56–59% of patients were free of recurrent AF after a single ablation strategies all being investigated. While the
procedure, with no significant difference between groups. noninferiority of each approach has been demonstrated,
There were fewer procedural complications in patients no superior approach has been proven. In fact, recent
with high‑frequency source ablation compared to PVI, trials raise the question of whether there is any
likely related to the smaller ablation lesions required for additional benefit for creating lesions beyond PVI
high‑frequency source ablation. While the noninferiority during initial procedures. The trials discussed above are
threshold was not reached for single procedures, after a significant step toward understanding the individual
redo procedures were allowed, high‑frequency source benefits of each approach. The goal of further research
ablation was non inferior to PVI. remains to improve efficacy, reduce complications and
fluoroscopy, and procedure times.
Persistent atrial fibrillation: Catheter ablation approaches
Additional atrial ablation lines or other attempts at Clinical implications for perioperative management and
modifying the atrial substrate are often performed in summary
patients with persistent AF. Verma et al., randomized Treatment of AF requires a multi‑disciplinary approach.
patients with persistent AF in a 1:4:4 fashion to PVI Recent trials advance our understanding beyond the
alone, PVI with complex fractionated atrial electrogram most recent guideline statements. The findings above
ablation or PVI with empiric mitral valve isthmus line may be challenged by other trials, but for now, we have
and roof line.[11] There were no significant differences evidence to conclude:
in freedom from atrial arrhythmias or complications in • Aspirin does not significantly reduce stroke in low
either group, but a trend toward fewer atrial arrhythmias risk patients with AF; it only increases bleeding risk;
in the PVI only group. When the ablation with linear • Anticoagulation based on stroke risk assessed by
lines group was compared pairwise with the PVI only the CHA 2DS2‑VASc score should be continued
group, there were significantly fewer recurrences of AF indefinitely, despite spontaneous conversion to
in the PVI only group. The smaller number of patients sinus rhythm;
randomized to pulmonary isolation alone may have • “Bridging” anticoagulation when oral anticoagulation
underpowered this study, but these findings are worth is interrupted is unnecessary except in patients with
confirming since they run counter to current practice. prior thromboembolic disease and mechanical
valves;
Persistent atrial fibrillation: Surgical ablation approaches • Effective reversal agents for NOACs are on the verge
Procedural treatment for AF began in the operating room of becoming available;
with the development of the Cox‑Maze procedure, where • Evidence now informs the management of
sources of AF were isolated by atriotomy scars (“cut and anticoagulation‑associated intracerebral
sew”). Gillinov et al., recently investigated different hemorrhage, with the following therapeutic targets:
methods of surgical ablation of AF in 260 patients • Reversal of anticoagulation  (INR  ≤1.3)
undergoing mitral valve surgery who had persistent within 4 h of symptom onset;
AF.[12] Patients were randomized 1:1 to surgical ablation • Reduction of systolic blood pressure to
or no ablation, and then the patients undergoing surgical <160 mmHg;
ablation were randomized to a biatrial maze procedure • Restarting oral anticoagulation after about
or PVI alone with conduction block confirmed 1 month, which does not increase the risk
intraoperatively. There was a significant difference in of repeat hemorrhage and reduces the risk
freedom from AF, which was 29.4% in the control group of ischemic stroke significantly;
and 63.2% in the ablation group. Freedom from AF was • Patients with an appropriate reason to discontinue
not significantly greater in the group undergoing biatrial anticoagulation can be considered for the
maze procedure (66%) compared to those undergoing newly‑approved Watchman left atrial appendage
PVI only (61%). There was no significant difference in closure device;

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 Schleifer and Ramakrishna: Recent advances in atrial fibrillation

• Efficacy of radiofrequency ablation and cryoablation CHA2DS2‑VASc score. J Am Coll Cardiol 2015;65:1385‑94.
are about equal; cryoablation has a higher rate of 3. Martin DT, Bersohn MM, Waldo AL, Wathen MS,
temporary phrenic nerve palsy and vascular access Choucair WK, Lip GY, et al. Randomized trial of atrial
arrhythmia monitoring to guide anticoagulation in
complications; patients with implanted defibrillator and cardiac
• Efficacy of a visually‑guided laser balloon is similar resynchronization devices. Eur Heart J 2015;36:1660‑8.
to other methods, despite little experience in this 4. Steinberg BA, Peterson ED, Kim S, Thomas L, Gersh BJ,
technique; Fonarow GC, et al. Use and outcomes associated with
bridging during anticoagulation interruptions in patients
• While there are fewer complications with with atrial fibrillation: Findings from the Outcomes
high‑frequency source ablation, it has less Registry for Better Informed Treatment of Atrial
effectiveness as a single procedure than PVI alone; Fibrillation (ORBIT‑AF). Circulation 2015;131:488‑94.
• In both catheter ablation and surgical treatment of 5. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P,
Bernstein RA, et al. Idarucizumab for dabigatran reversal.
persistent AF, there appears to be little additional
N Engl J Med 2015;373:511‑20.
benefit for additional ablation lesions, whether 6. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J,
linear or targeted at complex fractionated atrial Endres M, Sobesky J, et al. Anticoagulant reversal, blood
electrograms; pressure levels, and anticoagulant resumption in patients
• Surgical treatment of AF during mitral valve with anticoagulation‑related intracerebral hemorrhage.
JAMA 2015;313:824‑36.
surgery significantly reduces the risk of recurrent 7. Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M,
AF but increases the risk of requiring a permanent Neuzil P, et al. Percutaneous left atrial appendage closure
pacemaker. vs. warfarin for atrial fibrillation: A randomized clinical
trial. JAMA 2014;312:1988‑98.
With the advances in stroke prevention, anticoagulation 8. Luik A, Merkel M, Hoeren D, Riexinger T, Kieser M,
Schmitt C. Rationale and design of the FreezeAF trial:
management, and ablation techniques seen in the past A randomized controlled noninferiority trial comparing
few months, optimizing AF treatment for individual isolation of the pulmonary veins with the cryoballoon
patients is becoming increasingly possible. catheter versus open irrigated radiofrequency ablation
in patients with paroxysmal atrial fibrillation. Am Heart
J 2010;159:555‑60.e1.
Financial support and sponsorship 9. Dukkipati SR, Woollett I, McElderry HT, Böhmer MC,
Nil. Doshi SK, Gerstenfeld EP, et al. Pulmonary vein isolation
using the visually guided laser balloon: Results of
Conflicts of interest the U.S. feasibility study. J Cardiovasc Electrophysiol
2015;26:944-9.
There are no conflicts of interest.
10. Atienza F, Almendral J, Ormaetxe JM, Moya A,
Martínez‑Alday JD, Hernández‑Madrid A, et al. Comparison
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