Jurnal Terapi
Jurnal Terapi
Jurnal Terapi
Impact of Candesartan on
Nonfatal Myocardial Infarction
and Cardiovascular Death
in Patients With Heart Failure
Catherine Demers, MD, MSc
John J. V. McMurray, MD
Karl Swedberg, MD, PhD
Marc A. Pfeffer, MD, PhD
Christopher B. Granger, MD
Bertil Olofsson, PhD
Robert S. McKelvie, MD, PhD
Jan stergren, MD, PhD
Eric L. Michelson, MD
Peter A. Johansson, MSc
Duolao Wang, PhD
Salim Yusuf, MBBS, DPhil
for the CHARM Investigators
NGIOTENSIN - CONVERTING
enzyme (ACE) inhibitors reduce cardiovascular death,
hospitalization for heart failure, and myocardial infarction (MI) in
patients with heart failure or left ventricular systolic dysfunction and in
high-risk patients with coronary artery disease or diabetes.1-9 This effect is
assumed to be due to the action of these
drugs to reduce angiotensin II production, although ACE inhibitors also prevent bradykinin breakdown, which may
have additional beneficial effects.10 This
raises the question of whether angiotensin II receptor blockers (ARBs) are
as protective as ACE inhibitors in preventing MI. Conversely, blockade of the
renin-angiotensin-aldosterone system
by ACE inhibitors may be incomplete,
especially during long-term treatment
in patients with an activated system; in
these patients, there is evidence of continued production of angiotensin II by
1794
Context Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of myocardial infarction (MI), but it is not known whether angiotensin receptor blockers have
the same effect.
Objective To assess the impact of the angiotensin receptor blocker candesartan on
MI and other coronary events in patients with heart failure.
Design, Setting, and Participants The Candesartan in Heart Failure: Assessment
of Reduction in Mortality and Morbidity (CHARM) program, a randomized, placebocontrolled study enrolling patients (mean age, 66 [SD, 11] years) with New York Heart
Association class II to IV symptoms who were randomly allocated to receive candesartan (target dose, 32 mg once daily) or matching placebo given in addition to optimal therapy for heart failure. Patients were enrolled from March 1999 through March
2001. Of 7599 patients allocated, 4004 (53%) had experienced a previous MI, and
1808 (24%) currently had angina. At baseline, 3125 (41%) were receiving an ACE
inhibitor; 4203 (55%), a -blocker; 3153 (42%), a lipid-lowering drug; 4246 (56%),
aspirin; and 6286 (83%), a diuretic.
Main Outcome Measure The primary outcome of the present analysis was the
composite of cardiovascular death or nonfatal MI in patients with heart failure receiving candesartan or placebo.
Results During the median follow-up of 37.7 months, the primary outcome of cardiovascular death or nonfatal MI was significantly reduced in the candesartan group
(775 patients [20.4%]) vs the placebo group (868 [22.9%]) (hazard ratio [HR], 0.87;
95% confidence interval [CI], 0.79-0.96; P=.004; number needed to treat [NNT], 40).
Nonfatal MI alone was also significantly reduced in the candesartan group (116 [3.1%])
vs the placebo group (148 [3.9%]) (HR, 0.77; 95% CI, 0.60-0.98; P=.03; NNT, 118).
The secondary outcome of fatal MI, sudden death, or nonfatal MI was significantly
reduced with candesartan (459 [12.1%]) vs placebo (522 [13.8%]) (HR, 0.86; 95%
CI, 0.75-0.97; P=.02; NNT, 59). Risk reductions in cardiovascular death or nonfatal
MI were similar across predetermined subgroups and the component CHARM trials.
There was no impact on hospitalizations for unstable angina or coronary revascularization procedures with candesartan.
Conclusion In patients with heart failure, candesartan significantly reduces the risk
of the composite outcome of cardiovascular death or nonfatal MI.
www.jama.com
JAMA. 2005;294:1794-1798
Patients with New York Heart Association functional class II to IV were eligible and were randomly allocated according to LVEF (40%, 40%) and
treatment with an ACE inhibitor. All patients received candesartan or matching placebo, starting at a dosage of 4 or
8 mg once daily, which was increased
as tolerated to the target of 32 mg once
daily. All sites received approval from
local ethics committees for the conduct of this trial, and all patients provided written informed consent.
Statistical Analyses
After the initial dose-titration period, follow-up visits occurred every 4 months,
METHODS
The design and primary results of
CHARM have been published and are
summarized here. 12,13 In brief, the
CHARM program consisted of 3 component trials that compared the effects
of adding candesartan or placebo to optimal background therapy in consenting patients with heart failure and either
preserved left ventricular ejection fraction (LVEF) (CHARM-Preserved) or reduced LVEF (CHARM-Added, enrolling patients treated with an ACE
inhibitor, and CHARM-Alternative, enrolling those not receiving an ACE inhibitor because of documented intolerance). Patients were enrolled from
March 1999 through March 2001.
Study Population
COMMENT
In the CHARM program, the addition
of the ARB candesartan to conventional therapies for heart failure resulted in a significant reduction in the
combined outcome of cardiovascular
death or nonfatal MI in patients with
symptomatic heart failure. These findings were consistent across all subgroups examined, including patients
treated with other therapies proven to
be effective in reducing the risk of MI
or reinfarction. The prevention of MI
broadens the potential benefit of candesartan in this patient population.
Candesartan
(n = 3803)
775 (20.4)
116 (3.1)
691 (18.2)
459 (12.1)
Placebo
(n = 3796)
868 (22.9)
148 (3.9)
769 (20.3)
522 (13.8)
HR (95% CI)
0.87 (0.79-0.96)
0.77 (0.60-0.98)
0.88 (0.79-0.97)
0.86 (0.75-0.97)
P
Value
.004
.03
.01
.02
NNT
40
118
48
59
360 (9.5)
394 (10.4)
0.89 (0.77-1.03)
.11
NA
394 (10.4)
236 (6.2)
397 (10.5)
241 (6.4)
0.97 (0.84-1.11)
0.96 (0.80-1.14)
.60
.60
NA
NA
Abbreviations: CI, confidence interval; HR, hazard ratio; NA, not applicable; NNT, number needed to treat.
*Percutaneous coronary intervention or coronary artery bypass graft surgery.
Nonfatal MI
6
25
20
Placebo
15
Candesartan
10
5
P = .004
Cumulative Events, %
Cumulative Events, %
30
5
4
Placebo
Candesartan
2
1
P = .03
0
Year
No. at Risk
Placebo
3796
Candesartan 3803
1796
3413
3521
3101
3206
Year
2088 722
2163 744
3796
3803
3413
3521
3101
3206
2088 722
2163 744
alone. Neither trial showed superiority of the ARB over captopril, with respect to the primary end point of allcause mortality. In OPTIMAAL, the risk
of fatal or nonfatal reinfarction was
comparable in patients treated with losartan and captopril (relative risk, 1.03;
95% confidence interval, 0.89-1.18;
P =.72).18 In VALIANT, the number of
patients who experienced an MI was
similar in the groups treated with valsartan (3-year Kaplan-Meier rate,
Candesartan
Placebo
Age, y
<65
231/1614
260/1642
<65 to <75
279/1337
310/1270
75
265/852
298/884
Sex
Male
569/2617
623/2582
Female
206/1186
245/1214
Trial
Alternative
245/1013
275/1015
Added
319/1276
372/1272
Preserved
211/1514
221/1509
LVEF, %
40
564/2286
647/2292
>40
211/1516
221/1504
Diabetes
No
481/2715
545/2721
Yes
294/1088
323/1075
IHD Etiology
No
237/1449
275/1469
Yes
538/2354
593/2327
Previous Revascularization
No
538/2529
594/2486
Yes
237/1274
274/1310
SBP, mm Hg
120
335/1402
353/1356
>120
440/2401
515/2439
ACE Inhibitors
No
405/2230
447/2244
Yes
370/1573
421/1552
ACE Inhibitors (Recommended Dose)
No
592/2996
658/3004
Yes
183/807
210/792
-Blockers
No
417/1701
465/1695
Yes
358/2102
403/2101
Spironolactone
No
610/3160
681/3167
Yes
165/643
187/629
Lipid-Lowering
No
506/2225
563/2221
Yes
269/1578
305/1575
Aspirin
No
355/1698
400/1655
Yes
420/2105
468/2141
Overall
775/3803
Favors
Placebo
P Value for
Heterogeneity
.78
.58
.53
.34
.78
.78
.88
.54
.57
.66
.83
.41
.83
.36
868/3796
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Hazard Ratio
Values in the candesartan column may not sum to total values due to missing data for some patients. Error
bars indicate 95% confidence intervals. ACE indicates angiotensin-converting enzyme; IHD, ischemic heart
disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; SBP, systolic blood pressure.
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