Candesartan in Heart Failure—Alternative Trial - CHARM Alternative Trial

Description:

The goal of the CHARM Alternative Trial was to assess the effect of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in patients with symptomatic heart failure (HF), left ventricular ejection fraction (LVEF) ≤40%, and angiotensin-converting enzyme (ACE) inhibitor intolerance.

Hypothesis:

In patients with symptomatic HF, LVEF ≤40%, and ACE inhibitor intolerance, treatment with an angiotensin II receptor antagonist will lead to decreased mortality and hospitalizations.

Study Design

Study Design:

Patients Enrolled: 2,028
Mean Follow Up: Minimum 2 years; median 34 months
Mean Patient Age: Mean age 67 years
Female: 32%
Mean Ejection Fraction: Mean LVEF 30% overall

Patient Populations:

Age >18 years with symptomatic CHF corresponding to New York Heart Association (NYHA) class II-IV for ≥4 weeks prior to randomization

Study on ACE-I intolerant patients:
LVEF ≤40% and no current therapy with ACE inhibitors because of intolerance due to angioedema, anaphylaxis, cough, symptomatic hypotension, renal dysfunction, and/or other adverse event

Exclusions:

Serum creatinine ≥3 mg/dl; current serum potassium ≥5.5 mEQ/l, history of marked ACE inhibitor-induced hyperkalemia (serum K+ .5.9 mEQ/l), or life-threatening adverse event; known bilateral renal artery stenosis; current symptomatic hypotension; persistent systolic or diastolic hypertension; stroke, acute MI, or open heart surgery within the last four weeks; previous or planned heart transplant within the next six months; or life expectancy <2 years

Primary Endpoints:

Combined endpoint of CV mortality or CHF hospitalization

Secondary Endpoints:

1) Combined endpoint of CV mortality, nonfatal MI, and hospitalization for management for CHF; 2) Combined all-cause hospitalization and all-cause mortality; 3) The effect of candesartan on all-cause hospitalization, all-cause mortality, CV mortality, nonfatal MI, and hospitalization for management of CHF individually; 4) Resource utilization, safety, and tolerability; or 5) New diabetes

Drug/Procedures Used:

CHARM consists of three independent, parallel, placebo-controlled studies in patients with symptomatic HF. In the CHARM Alternative component trial, patients had LVEF ≤40% and were ACE inhibitor intolerant (n=2,028). Patients were randomized to candesartan (4 or 8 mg/day, titrated to target dose of 32 mg; n=1,013) or placebo (n=1,015) and followed for a minimum of two years.

Principal Findings:

The most frequently reported reason for ACE inhibitor intolerance was cough (70% in the candesartan arm and 74% in the placebo arm). The primary endpoint of cardiovascular (CV) mortality or chronic heart failure (CHF) hospitalization was lower in the candesartan arm compared with placebo (33.0% vs. 40.0%, hazard ratio [HR] 0.77, p=0.0004).

Among the individual components, HF hospitalizations occurred less frequently in the candesartan arm (HR 0.68, p<0.0001), but CV mortality was only nonsignificantly reduced (HR 0.85, p=0.072).

The secondary composite endpoint of CV death, HF hospitalization, or myocardial infarction (MI) occurred less frequently in the candesartan arm (HR 0.78, p=0.0007). There was no difference in overall study drug discontinuation (21.5% vs. 19.3%, p=0.23).

Interpretation:

Among patients with symptomatic HF, LVEF ≤40%, and ACE inhibitor intolerance, treatment with the angiotensin II type 1 receptor blocker candesartan was associated with a reduction in the primary endpoint of CV mortality or CHF hospitalization compared with placebo.

References:

Presented by Chris Granger at the European Society of Cardiology Congress, Vienna, Austria, September 2003.

Granger CB, McMurray JJV, Yusuf S, et al. 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.

Clinical Topics: Heart Failure and Cardiomyopathies, Novel Agents, Acute Heart Failure

Keywords: Angiotensin Receptor Antagonists, Myocardial Infarction, Pyridinolcarbamate, Receptor, Angiotensin, Type 1, Tetrazoles, Biphenyl Compounds, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Heart Failure, Stroke Volume, Cough, Hospitalization


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