CHARMAlternative: Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity A

1
CHARM-AlternativeCandesartan 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-enzy
  me inhibitors the CHARM-Alternative trial.
  Lancet 20033627726.

2
CHARM-AlternativeCandesartan 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 gt18 years with symptomatic
  CHF (NYHA class IIIV) and left ventricular
  ejection fraction lt40, 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-AlternativeCandesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Alternative- TRIAL DESIGN -
Baseline characteristics ()

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
Granger et al. Lancet 20033627726.
aMean
4
CHARM-AlternativeCandesartan 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 0.670.89,
  P0.0004) 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
  0.741.03, P0.11)
• Permanent discontinuation similar for candesartan
  and placebo (30 vs. 29, P0.53)

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
10
0
0
1
2
3
3.5
Years after randomization
Granger et al. Lancet 20033627726.
6
CHARM-Alternative Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Alternative- RESULTS continued -
Primary and secondary outcomes
Candesartan
Placebo
Hazard ratio
P
(n1013)
(n1015)
(95 CI)
No.
()
No.
()
Cardiovascular death or
0.77 (0.670.89)
0.0004
334
(33.0)
406
(40.0)
hospital admission for CHF
Granger et al. Lancet 20033627726.
7
CHARM-AlternativeCandesartan in Heart failure
Assessment ofReduction 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