Exploring new treatment strategies in heart failure.

Heart failure remains a major and increasing cause of mortality and morbidity, even when the best available treatments are used. One of its key causes is neuroendocrine activation via the sympathetic nervous system and the renin-angiotensin system (RAS). Neuroendocrine blockers of the sympathetic nervous system (beta-blockers) and of the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II type 1 [AT1] receptor blockers) therefore have an important potential therapeutic role in heart failure. The promising results from clinical trials with beta-blockers suggest that these drugs will become an established part of the future management of patients with mild to moderate symptomatic heart failure. Blockade of the RAS with ACE inhibitors has also been shown to be effective in reducing the risk of morbidity and mortality in patients with heart failure. Blockade of the AT1-receptor, with agents such as candesartan, produces more specific and, theoretically, more complete blockade of the major negative cardiovascular effects of angiotensin II than is possible using ACE inhibitors, whilst maintaining placebo-like tolerability. Furthermore, AT1-receptor blockade leads to increased stimulation of the angiotensin II type 2 (AT2) receptor, which, according to experimental data, may have favourable cardiovascular effects. Following encouraging results from two pilot studies, a major new international study programme - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been initiated to define the clinical benefits of candesartan cilexetil in a wide variety of patients with symptomatic heart failure. CHARM is the first study to accept all relevant heart failure patients who may benefit from RAS blockade, irrespective of their left ventricular function or tolerance of ACE inhibitors. The 6500 patients to be recruited will be divided among three integrated outcome studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who are tolerant or intolerant of ACE inhibitors. The third study arm will examine the benefits of candesartan cilexetil in a previously seldom studied group: those with symptomatic heart failure, but with preserved left-ventricular systolic function. Recruitment of patients into the study has started.