Candesartan in Heart Failure—Added Trial - CHARM Added Trial

Description:

The goal of the CHARM Added Trial was to evaluate the effects of the addition of the long-acting angiotensin II type 1 receptor blocker candesartan compared with placebo in patients with symptomatic heart failure (HF) treated with angiotensin-converting enzyme (ACE) inhibitors.

Hypothesis:

Treatment with the angiotensin II receptor antagonist candesartan will be associated with a reduction in the primary endpoint of cardiovascular (CV) death or HF hospitalizations in patients with symptomatic heart failure receiving ACE inhibitor therapy.

Study Design

Study Design:

Patients Enrolled: 2,548
NYHA Class: NYHA class III 73%
Mean Follow Up: Minimum 2 years; mean 41 months
Mean Patient Age: Mean age 64 years
Female: 21

Patient Populations:

Age >18 years with symptomatic CHF corresponding to New York Heart Association (NYHA) class II-IV for ≥4 weeks prior to randomization, LVEF ≤40%; ACE and inhibitor use

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 chronic heart failure (CHF) hospitalization

Secondary Endpoints:

1) Combined endpoint of CV mortality, nonfatal myocardial infarction (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 symptomatic HF. In the CHARM Added component trial, patients who had left ventricular ejection fraction (LVEF) ≤40% and were treated with an ACE inhibitor (n=2,548) were randomized to candesartan (4 or 8 mg/day, titrated to target dose of 32 mg; n=1,276), or placebo (n=1,272) and followed for a minimum of two years.

Concomitant Medications:

ACE inhibitors 100%, beta-blockers 56%, and diuretics 90%

Principal Findings:

ACE inhibitors were used in 100% of patients (enalapril 27%; lisinopril 19%; captopril 17%), with beta-blocker use in 56% and diuretics in 90%. The primary endpoint of CV death or HF hospitalizations occurred in 37.9% of patients in the candesartan arm and 42.3% in the placebo arm (hazard ratio [HR] 0.85, p=0.011). After adjustment for baseline covariates, the adjusted HR was 0.85 (95% confidence interval 0.75-0.96, p<0.01). Among the components of the primary endpoint, both CV death (HR 0.84, p=0.029) and HF hospitalizations occurred less frequently in the candesartan arm (HR 0.83, p=0.014).

The percent of patients with investigator reported HF hospitalizations and the total number of hospitalizations were both lower in the candesartan arm (p=0.008 and p=0.002, respectively). Patients discontinued the study drug more often in the candesartan arm (24.2% vs. 18.3%, p=0.0003), with the reason for discontinuation more often hypotension and increased creatinine (7.8% vs. 4.1%, p=0.0001) than in the placebo arm.

Interpretation:

Among patients with symptomatic HF and an EF ≤40% treated with an ACE inhibitor, additional treatment with the angiotensin II receptor antagonist candesartan was associated with a reduction in the primary endpoint of CV death or HF hospitalizations.

Other recent trials have studied angiotensin-receptor blocker (ARB) therapy in HF patients, including the ValHeft trial, which showed that ARB therapy was superior to placebo, and the ELITE 2 trial, which found that ARB therapy was not superior to ACE inhibitors. However, the present trial is the largest to examine ARB therapy when added to an ACE inhibitor.

A limitation of the added therapy is an increase in the number of medications the patients must take in a population often already receiving multiple drugs (100% on ACE inhibitors, 90% on diuretics, 56% on beta-blockers). Patients treated with candesartan should be carefully monitored, given the increase in study drug discontinuation due to hypotension and increased creatinine.

References:

Presented by J.J.V. McMurray at the European Society of Cardiology Congress, Vienna, Austria, September 2003.

McMurray JJV, Ostergren J, Swedberg K, et al. 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.

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

Keywords: Angiotensin Receptor Antagonists, Enalapril, Receptor, Angiotensin, Type 1, Diuretics, Hypotension, Creatinine, Tetrazoles, Captopril, Peptidyl-Dipeptidase A, Lisinopril, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Heart Failure, Stroke Volume, Hospitalization


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