Candesartan in Heart Failure—assessment of reduction in mortality and morbidity - CHARM Overall Programme Results

Description:

The goal of the CHARM Overall Programme Results study was to assess the effect of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in a broad spectrum of patients with symptomatic heart failure (HF).

Hypothesis:

In patients with symptomatic HF who have systolic or diastolic dysfunction and may or may not be on angiotensin-converting enzyme (ACE) inhibitors, the addition of an angiotensin II receptor antagonist will lead to decreased mortality and hospitalizations.

Study Design

Study Design:

Patients Enrolled: 7,601
Mean Follow Up: Minimum 2 years; mean 38 months
Mean Patient Age: Mean age 66 years
Female: 32
Mean Ejection Fraction: Mean LVEF 39% 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 inhibitor 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

Study on patients with LVEF ≤40% on ACE inhibitor therapy:
Baseline therapy with ACE inhibitors for at least 30 days before randomization. Patients with NYHA class II symptoms must have been hospitalized for a cardiac reason within the prior six months.

Study on patients with LVEF >40% not on ACE inhibitor:
History of hospitalization for a cardiac reason and no current treatment with an ACE inhibitor

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:

In pooled analyses of the three studies, the effect on all-cause mortality; in individual studies, 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 for CHF individually; 4) Resource utilization, safety, and tolerability; and 5) New diabetes

Drug/Procedures Used:

CHARM consists of three independent, parallel, placebo-controlled studies in patients with: 1) CHARM Added—left ventricular ejection fraction (LVEF) ≤40% treated with an ACE inhibitor (n=2,548); 2) CHARM Alternative—LVEF ≤40%, ACE inhibitor intolerant (n=2,028); and 3) CHARM Preserved—LVEF >40%, not treated with ACE inhibitors (n=3,025).

The three studies will be combined to evaluate the effect of candesartan on all-cause mortality in the broad spectrum of symptomatic HF. Patients were randomized to candesartan (4 or 8 mg/day, titrated to target dose of 32 mg; n=3,803) or placebo (n=3,796) and followed for a minimum of two years.

Concomitant Medications:

ACE inhibitors 41%, beta-blockers 55%, and diuretics 83%

Principal Findings:

All-cause mortality trended lower in the candesartan arm compared with placebo (23.3% vs. 24.9%, hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83-1.00; p=0.055), but was not statistically significant. After adjustment for baseline characteristics, all-cause mortality HR was 0.90 (p=0.032). Cardiovascular (CV) death was significantly reduced in the candesartan arm (HR 0.88, 95% CI 0.79-0.97, p=0.012), but there was no difference in non-CV death (p=0.45). The composite of CV mortality or chronic heart failure (CHF) hospitalization was lower in the candesartan arm (30.2% vs. 34.5%, HR 0.84, p<0.0001), as was the individual component of CHF hospitalization (HR 0.79, p<0.0001).

There was no difference in the individual endpoints of myocardial infarction (MI), stroke, or revascularization. Diabetes occurred less frequently in candesartan patients (6.0% vs. 7.4%, HR 0.78, p=0.020). In the subset of patients with LVEF ≤40%, all-cause mortality was lower in the candesartan arm (28.0% vs. 31.0%, HR 0.88, p=0.018).

Study drug discontinuation occurred more frequently in the candesartan arm (21.0% vs. 16.7%, p<0.0001), with hypotension and increased creatinine reported as the reason for discontinuation more frequently with candesartan. Fatal cancer occurred more frequently in candesartan patients (n=83 vs. n=56, p=0.032), but no difference was observed in nonfatal cancers.

Interpretation:

Among a broad spectrum of patients with symptomatic HF, treatment with the angiotensin II type 1 receptor blocker candesartan was associated with a nonsignificant decrease in all-cause mortality compared with placebo, driven primarily by a reduction in CV mortality.

The results of the overall pooled CHARM analysis were unlike the ValHeft trial, which showed that angiotensin-receptor blocker (ARB) was not associated with a reduction in mortality compared with conventional HF therapy (ACE inhibitors, diuretics, and beta-blockers). Of the three individual studies that made up the CHARM trial, candesartan was associated with a reduction in CV death and HF in the Alternative trial of patients with LVEF ≤40% who were ACE inhibitor intolerant, and in the Added trial of patients with LVEF ≤40% who were also treated with an ACE inhibitor, but not in the Preserved trial in patients with LVEF >40% with or without ACE inhibitor therapy.

References:

Presented by M. Pfeffer at the European Society of Cardiology Congress, Vienna, Austria, September 2003.

Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on morbidity and mortality in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759-66.

Swedberg K, Pfeffer M, Granger C. Candesartan in heart failure—assessment of reduction in mortality and morbidity (CHARM): rationale and design. CHARM-Programme Investigators. J Card Fail 1999;5:276-82.

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

Keywords: Myocardial Infarction, Stroke, Neoplasms, Receptor, Angiotensin, Type 1, Diuretics, Hypotension, Creatinine, Tetrazoles, Biphenyl Compounds, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Heart Failure, Stroke Volume, Cough, Hospitalization, Diabetes Mellitus


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