Angiotensin inhibition in heart failure

Abstract

Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS) is not completely blocked by angiotensin-converting enzyme (ACE) inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is) prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme compared the angiotensin receptor blocker (ARB) candesartan (target dose 32 mg once daily) to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF) who were ACE-I-intolerant (CHARM-Alternative); patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added); and patients with preserved left ventricular systolic function (CHARM-Preserved). There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure) in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was reduced by 12% in the two CHARM trials in patients with low LVEF. CHARM succeeded in answering a number of questions about the safety and efficacy of ARB use in heart failure. It showed evidence for a clinical benefit of candesartan both additive to and independent of ACE-I use. The benefits in terms of clinical outcomes were seen irrespective of beta-blocker usage. Benefits in patients with preserved LVEF were shown in the proportion of patients hospitalised with worsening heart failure and in overall number of admissions for heart failure. Candesartan had expected effects on blood pressure and renal function, emphasising the need for careful patient monitoring.