Ramipril: A review of its use in preventing cardiovascular outcomes in high-risk patients

Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged ≥55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients. Pharmacological Properties Orally administered ramipril is rapidly hydrolyzed to ramiprilat, which inhibits ACE, decreasing vasopressor activity, aldosterone secretion, and the rate of bradykinin degradation. This results in a reduction in BP, improvements in other hemodynamic factors, and reductions in thrombotic and inflammatory factors in patients at high CV risk. After oral administration of ramipril, ≈50-60% of the dose is absorbed, and although food does not appear to affect the extent of absorption, it may reduce the absorption rate. Ramiprilat has a linear dose-proportional pharmacokinetic profile, with a peak plasma concentration achieved in 2.5 hours. The bioavailabilies of ramipril and ramiprilat are 28% and 44%. Elimination of ramipril occurs via renal (60%) and fecal (40%) routes, with <2% excretion as unchanged drug. Ramiprilat has a long elimination half-life, consisting of an apparent elimination phase that clears unbound ramiprilat (9-18 hours), and a terminal elimination phase (>50 hours), during which the active drug slowly dissociates from ACE and is eliminated. Therapeutic Efficacy In the large, randomized, placebo-controlled, multicenter Heart Outcomes Prevention Evaluation (HOPE) trial, ramipril 10mg once daily significantly reduced the incidence of the combined outcomes of stroke, MI, and CV death (primary outcome) versus placebo, as well as each individual outcome, in patients aged ≥55 years with CV disease or diabetes plus at least one risk factor. In addition, there was a significant reduction in the risk of all-cause mortality, revascularization, a new diagnosis of, or complications related to, diabetes, heart failure (HF), cardiac arrest, and worsening angina. In subgroup analyses, the primary composite outcome was beneficially altered regardless of PAD status, renal function, or gender. Other subgroup analyses indicated that the progression of atherosclerosis in patients with high CV risk was slowed in ramipril recipients versus that in placebo recipients. Ramipril therapy also reduced the risk of nonfatal cardiac arrests and sudden death, and reduced the incidence of HF events. In a small sample of HOPE participants, left ventricular (LV) mass and volume were significantly reduced, and LV ejection fraction was increased with long-term ramipril treatment. At the end of a 2.6-year observational extension of the HOPE study (HOPE-TOO), the incidence of the primary composite outcome and its individual components (over a total of 7.2 years) was significantly lower in patients who had received ramipril during the HOPE trial than in those who had received placebo. Tolerability Ramipril 10mg once daily was generally well tolerated. Adverse events were usually mild to moderate in severity and of short duration. The most commonly reported adverse events were cough, dizziness, and headache. Cough occurred more often in ramipril than placebo recipients; in the HOPE study, the most common adverse events that led to discontinuation of treatment were cough (7% vs 2%), uncontrolled hypertension (2% vs 4%), and hypotension or dizziness (2% vs 2%). Clinically important changes in BP and laboratory parameters, such as serum creatinine levels, were usually mild to moderate. © 2006 Adis Data Information BV. All rights reserved.