Since their introduction in the mid-1980s, angiotensin converting enzyme (ACE) inhibitors have become well established for the treatment of hypertension and heart failure. In addition, they slow progression of renal impairment in diabetic nephropathy. There have now been several major studies investigating the role of ACE inhibitors in heart failure including the SAVE, SOLVD and AIRE studies.
ACE inhibitors improve survival in heart failure when added to conventional treatment. The greatest benefit is seen in those patients with the most severe heart failure. A smaller benefit is seen in patients with mild-to-moderate heart failure. However, despite the improved survival, the prognosis of moderate-to -severe heart failure remains poor. Nevertheless, largely because of the potential survival benefit, most cardiologists now believe that an ACE inhibitor should be added to diuretic therapy in all patients with overt heart failure, even if the heart failure is only mild. Some physicians prescribe ACE inhibitors before diuretics, although there is no trial-based evidence for this approach.
The benefits of treatment are not restricted to survival. The addition of an ACE inhibitor to diuretic therapy improves the control of heart failure, an important symptomatic benefit. This reduces the need for hospitalisation and probably improves the patient's quality of life. There may also be economic benefits for the health care system.
Another group of patients who also derive a benefit from ACE inhibitors are those with asymptomatic left ventricular dysfunction. This is defined as the presence of a left ventricular ejection fraction of <40-45%, in the absence of symptoms or signs of heart failure. Most of these patients are identified following acute myocardial infarction. These patients can be considered to have asymptomatic or 'pre-clinical' heart failure. Most patients have reduced effort tolerance on formal stress testing, and many will progress to overt heart failure with time. ACE inhibitors started within 1-2 weeks of the infarction improve survival, reduce the chance of developing overt heart failure and reduce the need for hospitalisation.
How do ACE inhibitors work? At least part of their beneficial effect is mediated through vasodilatation. Intravenous infusion of vasodilators such as nitroprusside or glyceryl trinitrate improves haemodynamics in heart failure. This effect can be sustained with hydralazine and isosorbide dinitrate given orally. This drug combination also improves survival in heart failure, suggesting that improvement in haemodynamics is at least in part responsible. However, the improvement in survival with ACE inhibitors is somewhat greater than with other vasodilators, suggesting that other mechanisms may play a part.
One possible mechanism is a beneficial effect on electrolyte and water balance. While vasodilators tend to increase salt and water retention, ACE inhibitors facilitate salt and water excretion by complex effects on the kidney. These effects include the attenuation of secondary hyperaldosteronism with a reduction in mineral ocorticoid-stimulated sodium reabsorption. ACE inhibitors also inhibit angiotensin-mediated thirst by an action on the hypothalamus. The attenuation of aldosterone effects reduces any tendency to hypokalaemia, and this may contribute to the antiarrhythmic effect of ACE inhibitors.
Another possible mechanism involves the favourable effects of ACE inhibitors on the adverse neurohumoral profile which accompanies heart failure. In addition to activation of the renin-angiotensin-aldosterone system, heart failure activates several other neurohumoral systems. The increased sympathetic nerve activity and increased secretion of adrenal catecholamines probably contribute to the high incidence of malignant ventricular arrhythmias and sudden death in heart failure. ACE inhibitors produce major reductions in sympathetic nerve activity and plasma levels of catecholamines.
Heart failure is a progressive process, during which the heart undergoes major changes. For example, the patient with asymptomatic left ventricular dysfunction early post-infarction will probably have only relatively minor chamber enlargement. By the time this patient develops clinical heart failure, the heart will have enlarged substantially. This process is called 'remodelling'. One of the major hypotheses of the SAVE study was that ACE inhibitors would prevent this process of remodelling, thereby reducing the development of heart failure and the incidence of death. The echocardiographic data from this study suggest that this hypothesis is correct, highlighting yet another mechanism of action for the beneficial effects of ACE inhibitors.
The actions of the ACE inhibitors are often assumed to be largely a consequence of reduced angiotensin formation. However, some angiotensin continues to be formed, particularly at lower doses. In addition, ACE is quite 'promiscuous', cleaving dipeptides from a variety of other substrates e.g. the vasodilator peptide bradykinin. ACE inhibitors increase bradykinin levels, and this almost certainly contributes to their vasodilator action and possibly to other effects such as cough and inhibition of cardiac hypertrophy.
A surprising finding from the SAVE study, confirmed subsequently by the SOLVD investigators, was the reduced incidence of recurrent myocardial infarction in patients treated with ACE inhibitors. If confirmed in larger studies designed specifically to test the hypothesis, this may well provide another mechanism for the long-term benefit of ACE inhibitors. An interaction between angiotensin and fibrinolysis may explain the reduced incidence of recurrent infarction.
What dose of ACE inhibitor should be used? The published studies have all used relatively high target doses e.g. captopril 150 mg/day, enalapril 20 mg/day, ramipril 10 mg/day. The majority of patients have been able to tolerate these doses, although often only after gradual titration, and with careful monitoring of renal function. These should therefore be the target doses for the treatment and prevention of heart failure.
ACE inhibitors should be used as second or even first line therapy in the drug treatment of clinical heart failure. They should also be prescribed for patients with asymptomatic left ventricular dysfunction. Benefits include improved survival, better control of heart failure, reduced need for hospitalisation and improved quality of life.
The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35.
The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.
The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327:669 -77.
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.