CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added
Purpose
To determine whether addition of the angiotensin II receptor blocker candesartan is beneficial in patients with chronic heart failure (CHF) who are taking angiotensin converting enzyme (ACE) inhibitors
Reference
McMurray JJV, ?stergren J, Swedberg K, et al. for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–71.
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - TRIAL DESIGN -
Design
Multicenter, multinational, randomized, double-blind, placebo-controlled
Patients
2548 patients aged >18 years with symptomatic CHF (NYHA class II–IV), who had left ventricular ejection fraction <40% and were receiving ACE inhibitors
Follow up and primary endpoint
Primary endpoint: cardiovascular death or hospital admission for CHF. Median 41 months follow up.
Treatment
Placebo or candesartan titrated to 32 mg once daily
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - TRIAL DESIGN continued-
Age (years)a
Male
NYHA class:
Systolic BP (mmHg)a
Heart failure cause:
Ischemic
Idiopathic
Hypertensive
II
III
IV
History
MI
Diabetes mellitus
Hypertension
Medications
ACE inhibitor
Diuretic
Beta-blocker
Spironolactone
Aspirin
Baseline characteristics (%)
a
Mean
McMurray et al. Lancet 2003;362:767–71.
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - RESULTS -
Primary outcome of cardiovascular death or hospital admission for CHF significantly reduced in candesartan group compared with placebo (37.9 vs. 42.3%, hazard ratio 0.85, 95% CI 0.75–0.96, P=0.011): each component was reduced significantly
Secondary outcomes – composites of primary outcome and MI, nonfatal stroke and coronary revascularization – also significantly reduced
All-cause mortality not significantly reduced (30 vs. 32%, hazard ratio 0.89, 95% CI 0.77–1.02, P=0.086)
Benefits similar in patients taking beta-blockers and those who were not (P=0.14 for treatment interaction), and regardless of whether recommended dose of ACE inhibitor achieved (P=0.26)
Permanent discontinuation due to adverse event or laboratory abnormality more frequent with candesartan (24.2 vs. 18.3%, P=0.0003)
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - RESULTS continued -
Years after randomization
Proportion
with event
(%)
0
0
1.0
2.0
3.0
3.5
10
20
30
40
50
Cardiovascular death or hospital admission for CHF
McMurray et al. Lancet 2003;362:767–71.
Hazard ratio 0.85
(95% CI 0.75–0.96)
P = 0.011
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - RESULTS continued -
P
Cardiovascular death or
hospital admission for CHF
0.85 (0.75–0.96)
0.011
Primary and secondary outcomes
483
No.
(37.9)
(%)
Candesartan
(n=1276)
538
No.
(42.3)
Cardiovascular death, hospital
admission for CHF, or MI
0.85 (0.76–0.96)
0.010
495
(38.8)
550
(43.2)
Cardiovascular death, hospital
admission for CHF, MI,
or stroke
0.87 (0.77–0.98)
0.020
512
(40.1)
559
(43.9)
Cardiovascular death, hospital
admission for CHF, MI, stroke,
or coronary revascularization
0.87 (0.77–0.97)
0.015
548
(42.9)
596
(46.9)
(%)
Placebo
(n=1272)
Hazard ratio
(95% CI)
McMurray et al. Lancet 2003;362:767–71.
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - RESULTS continued -
Cardiovascular death or hospital admission for CHF in relation to
concomitant treatment at baseline
Candesartan
No. of
events/n
Candesartan
better
Placebo
better
Placebo
No. of
events/n
β-blocker
Yes
No
Recommended dose
of ACE inhibitor
Yes
No
All patients
223/702
260/574
232/643
251/633
483/1276
P for
treatment
interaction
0.14
0.26
274/711
264/561
275/648
263/624
538/1272
McMurray et al. Lancet 2003;362:767–71.
0.8
0.6
1.0
1.2
CHARM Added: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Added - SUMMARY -
In patients with symptomatic CHF who were taking ACE inhibitors, candesartan reduced:
Cardiovascular death and hospitalization for CHF
Secondary outcomes that combined these with MI, stroke and coronary revascularization procedures
Benefit was independent of concurrent beta-blocker therapy and ACE inhibitor dose