1. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative
Purpose
To determine whether the angiotensin II receptor blocker candesartan is beneficial in patients with chronic heart failure (CHF) who are intolerant to angiotensin converting enzyme (ACE) inhibitors
Reference
Granger CB, McMurray JJV, Yusuf S, et al. for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–6.

2. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - TRIAL DESIGN -
Design
Multicenter, multinational, randomized, double-blind, placebo-controlled
Patients
2028 patients aged >18 years with symptomatic CHF (NYHA class II–IV) and left ventricular ejection fraction <40%, who were not receiving ACE inhibitors because of previous intolerance due to cough (72%), hypotension (13%), renal dysfunction (12%), angioedema or anaphylaxis (4%), or other reasons
Follow up and primary endpoint
Primary endpoint: cardiovascular death or hospital admission for CHF. Median 33.7 months follow up.
Treatment
Placebo or candesartan titrated to 32 mg once daily

3. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - TRIAL DESIGN -
Baseline characteristics (%)
66.8
130.3 68 47 49 4 67 20 7
Placebo
(n=1015)
66.3
129.9 68 48 4 70 19 6
Candesartan
(n=1013) 61 55 23 59 40 74 12 10 4
Placebo
(n=1015) 62 55 25 57 43 70 14 13 4
Candesartan
(n=1013)
Age (years)a
History of MI
Male
Medications
Beta-blocker
NYHA class:
Spironolactone II
Aspirin
III
Lipid-lowering drug IV
Reason for
Systolic BP (mmHg)a
intolerance
Heart failure cause
Cough
Ischemic
Hypotension
Idiopathic
Renal dysfunction
Hypertensive
Angioedema/anaphylaxis
aMean
Granger et al. Lancet 2003;362:772–6.

4. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS -
Primary outcome of cardiovascular death or hospital admission for CHF significantly reduced in candesartan group compared with placebo (33.0 vs. 40.0%, hazard ratio 0.77, 95% CI 0.67–0.89, P=0.0004): each component was reduced but cardiovascular death nonsignificantly
Secondary outcomes – composites of primary outcome and MI, nonfatal stroke and coronary revascularization – also significantly reduced
All-cause mortality not significantly different (26.2 vs. 29.2%, hazard ratio 0.87, 95% CI 0.74–1.03, P=0.11)
Permanent discontinuation similar for candesartan and placebo (30 vs. 29%, P=0.53)

5. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS continued -
Cardiovascular death or hospital admission for CHF
Proportion 50
with event
(%) 40 30 20
Hazard ratio 0.77
(95% CI 0.67–0.89)
P = 10
Placebo
Candesartan 1 2 3
3.5
Years after randomization
Granger et al. Lancet 2003;362:772–6.

6. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - RESULTS continued -
Primary and secondary outcomes
Placebo
Candesartan
(n=1015)
(n=1013)
Hazard ratio P
(95% CI)
No.
(%)
No.
(%)
Cardiovascular death or
406
(40.0)
334
(33.0)
0.77 (0.67–0.89)
0.0004
hospital admission for CHF
Cardiovascular death
0.85 (0.71–1.02)
0.072
219
(21.6)
252
(24.8)
Hospital admission for CHF
0.68 (0.57–0.81)
<
0.0001
207
(20.4)
286
(28.2)
Cardiovascular death, hospital
admission for CHF, or MI
0.78 (0.68–0.90)
0.0007
353
(34.8)
420
(41.4)
Cardiovascular death, hospital
admission for CHF, MI,
or stroke
0.80 (0.69–0.91)
0.001
369
(36.4)
432
(42.6)
Cardiovascular death, hospital
admission for CHF, MI, stroke,
or coronary revascularization
0.81 (0.71–0.92)
0.002
396
(39.1)
456
(44.9)
Granger et al. Lancet 2003;362:772–6.

7. CHARM-Alternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity - Alternative - SUMMARY -
In patients with symptomatic CHF and intolerant to ACE inhibitors, candesartan reduced:
Cardiovascular death or hospitalization for CHF
Secondary outcomes that combined these with MI, stroke and coronary revascularization procedures
Despite prior intolerance to another inhibitor of the renin- angiotensin-aldosterone system, candesartan was well tolerated in this patient group