Efficacy and tolerability of adding an angiotensin receptor blocker in patients with heart failure already receiving an angiotensin‐converting inhibitor plus aldosterone antagonist, with or without a beta blocker. Findings from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)‐Added trial

BACKGROUND: The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin-angiotensin-aldosterone system (RAAS) together. METHODS AND RESULTS: 2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49). The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline. CONCLUSIONS: An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely.