Differences Among ACE Inhibitors

A ngiotensin-converting enzyme inhibitors (ACEIs) are used widely in the treatment of cardiovascular diseases. They differ in chemical class, the ligand to ACE, potency, and pharmacokinetics including absorption, elimination, and duration of action.1 Differences in the degree of lipophilicity influence the pharmacokinetic properties mentioned above as well as the affinity and association and dissociation constants to ACE. Increased local activity of angiotensin II, probably due to enhanced ACE activity and downregulation of the angiotensin II receptors within the myocardium, has been observed in heart failure (HF).2 Reduced sympathetic activity, improved endothelial function, kinin effects with increased availability of nitric oxide, increased fibrinolysis, and improved arterial compliance may underlie the effects in HF and coronary artery disease that are more pronounced than those expected from blood pressure (BP) lowering alone. Ruzicka and associates3 tested the hypothesis that lipophilic ACEI with high affinity for ACE (perindopril and quinapril) would cause more marked blockade of cardiac angiotensin II and aldosterone generation in patients with HF. Angiotensin II and aldosterone gradients between the coronary sinus and the aortic root were not significantly different between the lipophilic agents and lisinopril, a hydrophilic agent with low affinity to ACE. The study was interrupted after 19 patients were completed because in an interim analysis, the likelihood that the hypothesis would be confirmed was <1%. In many, large, randomized double-blind placebo controlled clinical trials, ACEIs were associated with significant reductions in mortality, hospitalizations, and the occurrence of myocardial infarction (MI) in patients with HF due to systolic left ventricular dysfunction (LVD) regardless of severity, in asymptomatic patients with LVD, and in survivors of MI without LVD and are class I indication for these conditions.4 ACEIs are also effective antihypertensive agents controlling BP in about 60% of the patients as monotherapy. The BP-lowering effect of ACEI is primarily due to decreased formation of angiotensin II, although decreased degradation of kinins probably plays a role. Head-to-head clinical trials of different ACEI in HF or hypertension are not available. However, overview of published trials does not indicate superiority of perindopril or quinapril to other ACEIs. With respect to coronary artery disease, HOPE and EUROPA using ramipril and perindopril, respectively, showed significant benefits, whereas PEACE and QUIET using perindopril and quinapril, respectively, did not show statistically significant benefits. In HF, benefits have been observed with enalapril and lisinopril, both hydrophilic, and ramipril. Differences among these trials may be due to differences in trial design, the population studied, in BP lowering, background therapy, and rate of revascularization. Rather than scrutinizing differences among medications in their biochemical, physiological, animal and intermediate end points, among ACEI, practice should be guided by the results of randomized controlled clinical trials indicating a benefit and the specific doses where the particular benefit accrued. In hypertension, controlling BP is the major target.5 Because many patients need more than one medication to control their BP, differences among individual compounds are much less important.