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Which Heart-Failure Patients Benefit from Candesartan?

Results from the CHARM trial require careful scrutiny to identify which findings should directly influence practice.

In patients with chronic heart failure, angiotensin-receptor blockers (ARBs) have shown promise for enhancing the benefit of ACE inhibitors and as an alternative to ACE inhibitors when patients cannot tolerate them. In the manufacturer-sponsored, double-blind CHARM trial, symptomatic heart-failure patients were randomized to the ARB candesartan (target dose, 32 mg once daily) or placebo.

The randomization protocol was used in 3 separate trial arms, each featuring a different category of patients: 2548 with LV ejection fractions of 40% who already were taking ACE inhibitors; 2028 with LVEFs of 40% who could not tolerate ACE inhibitors; and 3023 with LVEFs >40% (19% were taking ACE inhibitors). The primary endpoint of the entire trial was all-cause mortality; however, each arm had a primary composite endpoint of cardiovascular death or unplanned hospitalization for worsening heart failure.

For the trial as a whole, all-cause mortality incidence by the end of follow-up (median, 38 months) was 23% in the candesartan group and 25% in the placebo group (P=0.055); after adjustment for other factors that might affect prognosis, the difference became significant (P=0.032). Notably, the incidence of cardiovascular death or unplanned hospitalization for worsening heart failure in the overall trial was significantly lower with candesartan than with placebo (30% vs. 35%, P<0.0001). Baseline use of beta-blockers, spironolactone, diuretics, and digitalis glycoside did not diminish candesartan's advantage over placebo.

In the 2 trial arms that included patients with LVEFs 40%, incidence of the primary composite endpoint (and of its components) was significantly lower with candesartan than with placebo. However, in the arm that included patients with LVEFs >40%, candesartan did not show a significant benefit over placebo for the composite endpoint or for cardiovascular death alone, but it did for hospitalization for worsening heart failure.

Overall, permanent study-drug discontinuations for adverse events or abnormal laboratory values were significantly more common with candesartan than with placebo -- e.g., hypotension (3.5% vs. 1.7%), increase in serum creatinine (6.2% vs. 3.0%), and hyperkalemia (2.2% vs. 0.6%).

Comment: In CHARM, the overall mortality benefit of the ARB candesartan was better than in previous trials of ARBs (e.g., Journal Watch Cardiology Jan 25 2002), but it still was not definitive. Within the trial arms that constituted CHARM, all-cause mortality was not a primary endpoint, leaving the composite of cardiovascular death and readmission for worsening heart failure to be considered. In patients who were intolerant of ACE inhibitors and in patients with LVEFs 40% who were taking ACE inhibitors, candesartan did provide benefit over placebo for this composite endpoint, but a close look at the data shows that the readmission reduction was substantially greater in the number of readmissions than in the number of patients who required readmission. This limited benefit might warrant using candesartan in patients who cannot tolerate ACE inhibitors. However, in patients who tolerate ACE inhibitors and have LVEFs 40%, candesartan might need to clear a higher bar before it is added. For patients with LVEFs >40%, candesartan's lack of benefit over placebo in the composite endpoint clearly suggests this subgroup must be studied further before changing practice. Given that only 20% of CHARM subjects were taking ACE inhibitors, beta-blockers, and spironolactone simultaneously, it is important to have a trial that compares adding an ARB, adding an aldosterone antagonist, and adding both in symptomatic heart-failure patients who already are using these 3 other types of heart-failure drugs.

— Beat J. Meyer, MD

Published in Journal Watch Cardiology October 10, 2003

Citation(s):

Pfeffer MA et al. for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet 2003 Sep 6; 362:759-66.

• Medline abstract (Free)

McMurray JJV et al. for the CHARM Investigators and Committees. 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 Sep 6; 362:767-71.

• Medline abstract (Free)

Granger CB 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-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003 Sep 6; 362:772-6.

• Medline abstract (Free)

Yusuf S et al. for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved trial. Lancet 2003 Sep 6; 362:777-81.

• Medline abstract (Free)

White HD. Candesartan and heart failure: The allure of CHARM. Lancet 2003 Sep 6; 362:754-5.

• Medline abstract (Free)