The CHARM-Preserved trial: Candesartan in heart failure with preserved ejection fraction [Classics Series]

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1. In patients with heart failure and preserved ejection fraction, candesartan does not significantly reduce the rate of cardiovascular death, but does significantly reduce the rate of hospitalization for heart failure as compared with placebo

Original Date of Publication: September 6, 2003

Study Rundown: A large body of evidence exists supporting various interventions to improve outcomes in heart failure with reduced left-ventricular ejection fraction (LVEF). The SOLVD and ATLAS trials demonstrated that treatment with angiotensin-converting-enzyme inhibitor (ACE-I) significantly reduced mortality in heart failure patients with reduced LVEF. The Val-HEFT and CHARM-Alternative trials demonstrated the benefits of angiotensin-receptor blocker (ARB) therapy, while the MERIT-HF and COPERNICUS trials supported the use of beta-blockers. The RALES, EMPHASIS-HF, and EPHESUS trials provide evidence for aldosterone blockade in these patients and the MADIT-II trial found that prophylactic implantable defibrillators also reduced mortality.

The literature exploring the treatment of heart failure with preserved LVEF is much more scarce. At the time of the CHARM-Preserved trial, many guidelines for heart failure management did not specifically address treating patients with preserved ejections fractions. Given that there was some evidence to support the use of ACE-Is in treating heart failure with preserved ejection fraction, the aim of the CHARM-Preserved trial was to explore whether angiotensin blockade using an ARB would have similar benefits.

In summary, there were no significant differences between the two groups in terms of the rate of cardiovascular death and hospitalization for heart failure (adjusted HR 0.86; 95%CI 0.74-1.00, p=0.051). There was a small but significant reduction in hospitalizations for heart failure (adjusted HR 0.84; 95%CI 0.70-1.00, p=0.047), while there were a significantly higher rate of adverse events in the candesartan group (17.8% vs. 13.5%, p=0.001).

Click to read the study in The Lancet

In-Depth [randomized, controlled study]: This randomized, controlled trial involved 3,025 patients from 618 centres in 26 countries. Patients were eligible for the study if they were 18 years of age or older, had New York Heart Association (NYHA) functional class II-IV symptoms for at least 4 weeks, had a history of hospital admission for a cardiac reason, and had LVEF>40%.  Eligible patients were randomized to receive either candesartan or placebo. The primary outcome was cardiovascular death or unplanned admission to hospital for the management of worsening heart failure. Secondary outcomes included several combinations of cardiovascular death, admission to hospital for heart failure, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, all-cause mortality, and new development of diabetes.

There was no significant difference between the candesartan and placebo groups in terms of the rate of the primary outcome (adjusted HR 0.86; 95%CI 0.74-1.00, p=0.051). Specifically, there was no significant difference between the two groups in terms of the rate of cardiovascular death (adjusted HR 0.95; 95%CI 0.76-1.18, p=0.635). The rate of hospital admission for heart failure was significantly reduced in the candesartan group as compared with the placebo group (adjusted HR 0.84; 95%CI 0.70-1.00, p=0.047). The rates of study-drug discontinuation due to adverse events or laboratory abnormalities were significantly higher in the candesartan group (17.8% vs. 13.5%, p=0.001), with the commonest causes being rising creatinine (4.8% vs. 2.4%, p=0.0005), hypotension (2.4% vs. 1.1%, p=0.009), and hyperkalemia (1.5% vs. 0.6%, p=0.029), all of which were higher in the candesartan group.

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