Commentary

The CHARM study extends our knowledge of the role of ARBs in patients with CHF.

Least surprising but still important was the finding in the CHARM-Alternative study that candesartan resulted in a significant reduction in cardiovascular mortality and hospital admission for heart failure. The Valsartan Heart Failure Trial (ValHeFT) reached a similar conclusion,¹ and valsartan is indicated in patients with heart failure caused by systolic left ventricular dysfunction who are not taking an ACE inhibitor. However, the result of ValHeFT was determined in a retrospective analysis and included a relatively small number of patients and events. The CHARM-Alternative study, on the other hand, was prospective and adequately powered with a significant number of events.

It is likely that ARBs used at the appropriate dose, such as valsartan 160 mg twice daily or candesartan 32 mg daily, are equivalent to target doses of an ACE inhibitor, such as enalapril 10 mg twice daily. However, the therapy of choice in patients with CHF caused by systolic left ventricular dysfunction will probably remain an ACE inhibitor because of the relatively large number of patients in whom these agents have been studied and their reasonable cost.

The CHARM-Added trial is also important because it suggests that an ARB should be added to an ACE inhibitor and a β blocker in patients with mild to moderate CHF caused by systolic left ventricular dysfunction. Whereas the reduction in cardiovascular mortality in the CHARM-Added trial was moderate, the reduction in the combined endpoint of cardiovascular mortality and hospital admission for heart failure is both clinically and statistically significant. ValHeFT suggested that in a patient with CHF already treated with both an ACE inhibitor and a β blocker, adding an ARB was associated with an increased risk of death. The CHARM-Added results, however, suggest that the ValHeFT results in this particular subset were due to chance.

Somewhat less clear is the explanation for the discrepancy between ValHeFT and CHARM on cardiovascular mortality. In ValHeFT, valsartan had no effect on cardiovascular mortality and its significant benefit on the combined endpoint of cardiovascular mortality and hospital admission for heart failure was entirely the result of a reduction in hospital admissions for heart failure. In the CHARM-Added study, there was a reduction in both cardiovascular mortality and hospital admissions for heart failure. Whether this disparity reflects a difference in the effectiveness of valsartan and candesartan, their relative dosing strategy, or other factors remains to be determined. A further study of an ARB in this situation would therefore be ethical and useful.

In patients with severe heart failure, an aldosterone blocker might be the preferred agent to add to an ACE inhibitor and a β blocker rather than an ARB based on the results of the Randomized Aldactone Evaluation Study (RALES).² However, in RALES only a relatively small proportion of patients were receiving both an ACE inhibitor and a β blocker. Direct comparative studies of an ARB and an aldosterone blocker when added to an ACE inhibitor and a β blocker in patients with CHF caused by systolic left ventricular dysfunction are needed.

In patients with CHF and preserved systolic function (CHARM-Preserved), candesartan was shown to be of only marginal benefit. Further studies are clearly required to determine the optimal strategy to reduce cardiovascular events in this important subset of patients whose incidence is increasing because of aging and increasing incidence of hypertension and diabetes mellitus.