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Abstract

Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality in patients with heart failure due to systolic left ventricular dysfunction and are indicated in all patients unless contraindicated or not tolerated. Despite their ef~cacy, a relatively large percentage of patients in whom these agents are indicated do not receive them, and the patients who do are often given doses less than those shown to be effective in the major morbidity-mortality trials. The failure to use ACE inhibitors appears to be in large part due to their perceived side effects, many of which are related to bradykinin accumulation. The introduction of angiotensin II antagonists such as losartan provides an opportunity to block the effect of angiotensin II without many of the bradykinin-mediated side effects. Emerging data suggest that losartan may have an advantage compared to ACE inhibitors in reducing mortality, which appears to be due primarily to a reduction in sudden cardiac death. The potential mechanisms whereby an angiotensin II antagonist might reduce mortality in comparison to an ACE inhibitor include 1) a possible direct antiarrhythmic effect of the antagonist, 2) the fact that bradykinin, which may promote ventricular brillation by causing the prejunctional release of norepinephrine from sympathetic neurons, does not accumulate with use of angiotensin II antagonists as opposed to ACE inhibitors, 3) blockade of effects of angiotensin II produced in the vascular wall and myocardium by non-ACE-dependent mechanisms, and 4) the fact that angiotensin II antagonists increase angiotensin II levels, which may stimulate angiotensin II type 2 and/or other angiotensin receptors with bene~cial effects. Large-scale clinical trials are currently under way comparing the effectiveness of angiotensin II antagonists alone and in combination with ACE inhibitors to ACE inhibitors alone in reducing total mortality. These trials will clearly establish whether angiotensin II antagonists are superior to ACE inhibitors in reducing mortality in patients with heart failure due to systolic left ventricular dysfunction, as has been observed with losartan versus captopril in the ELITE study.