Ramipril is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. Ramipril also is used to reduce the risk of mortality (mainly cardiovascular mortality) following myocardial infarction (MI) in hemodynamically stable patients who have demonstrated clinical signs of heart failure within a few days following acute MI; ramipril therapy also may reduce rate of heart failure-associated hospitalization and progression to severe and/or resistant heart failure. In addition, ramipril has been shown to reduce the rate of death, MI, and stroke in patients at high risk for cardiovascular events.
Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease) or in patients receiving immunosuppressive therapy, the possibility that similar adverse effects may occur with ramipril should be considered since current evidence is insufficient to rule out such risk.
Ramipril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. ACE inhibitors are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease, or cerebrovascular disease or following MI. (See Uses: Hypertension in and in )
In general, black hypertensive patients tend to respond better to monotherapy with diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors. Although ACE inhibitors have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension; however, this population difference in response does not appear to occur during combined therapy with an ACE inhibitor and a thiazide diuretic or calcium-channel blocker. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied. (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in and in )
For additional information on the role of ACE inhibitors in the management of hypertension, and in . For information on overall principles and expert recommendations for treatment of hypertension, .
Heart Failure After Acute Myocardial Infarction
Ramipril is used to reduce the risk of mortality (mainly cardiovascular mortality) following MI in hemodynamically stable patients who have demonstrated clinical signs of heart failure within a few days following acute MI; ramipril therapy also may reduce the rate of heart failure-associated hospitalization and progression to severe and/or resistant heart failure. In these patients, when compared with those receiving placebo, ramipril therapy initiated on average 5 (range: 2-9) days after acute MI reduced risk of mortality from any cause by approximately 27% (90% of mortality was cardiovascular, mainly sudden death); risk of progression to severe heart failure and heart failure-associated hospitalization were reduced by 23 and 26%, respectively. In addition, ramipril reduced risk of mortality combined with other events (e.g., reinfarction, stroke, development of severe heart failure) by 19%. This evidence of efficacy was obtained from a large, controlled, long-term (average: 15 months; range: 6-46 months) study (the Acute Infarction Ramipril Efficacy; AIRE). Benefits of ramipril were observed by day 30 of drug therapy and were not affected by gender, exact timing of initiation of drug therapy, or by concomitant drugs (e.g., aspirin, nitrates, β-adrenergic blocking agents [β-blockers], thrombolytic agents, calcium-channel blocking agents, cardiac glycosides); however, such benefits appeared to be increased in patients 65 years and older and in those receiving diuretics. Ramipril did not appear to reduce the rates of reinfarction, although there was a trend to fewer such events when compared with placebo.
Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI. The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia). In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular ''remodeling'') following acute MI. Evidence regarding the efficacy of such therapy has been somewhat conflicting, particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline left ventricular dysfunction. However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.
Current expert guidelines recommend the use of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction). While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction. ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, chronic kidney disease). The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.
Prevention of Major Cardiovascular Events
Ramipril may reduce the rate of death, MI, and stroke in patients 55 years of age and older who are at high risk for cardiovascular events (e.g., those with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus, in addition to at least one other cardiovascular risk factor, including hypertension, elevated serum total cholesterol and/or decreased high-density lipoprotein [HDL]-cholesterol concentrations, smoking, or documented microalbuminuria) and who are not known to have low left ventricular ejection fraction (LVEF) or heart failure. Ramipril may be used concomitantly with antihypertensive, antiplatelet, or antilipemic drugs. Results of a randomized, multicenter, double-blind, placebo-controlled study (Heart Outcomes Prevention Evaluation [HOPE]) of approximately 5 years' duration in more than 9000 patients 55 years of age or older with a history of coronary artery disease, stroke, peripheral vascular disease, and at least one other cardiovascular risk factor (see above) indicate that ramipril (10 mg daily after an initial dosage of 2.5 mg daily for 1 week followed by 5 mg daily for 3 weeks) reduced the risk of cardiovascular death, stroke, and MI by about 25, 32, and 20%, respectively, compared with placebo. When compared with placebo, the drug also reduced the risk of cardiac arrest and heart failure by approximately 34 and 21%, respectively, and the need for coronary revascularization procedures by 15%. The exact mechanism of the beneficial effects of ramipril in high-risk patients for cardiovascular events has not been fully elucidated, but it appears that ACE inhibitors may antagonize the direct effects of angiotensin II thereby preventing the proliferation of vascular smooth muscle cells and rupture of fibrous plaques. ACE inhibitors also may improve vascular endothelial function, reduce left ventricular hypertrophy, and enhance fibrinolysis.
In addition to these beneficial cardiovascular effects, a reduction in the incidence of diabetic complications was reported in 6.2% of patients receiving ramipril compared with 7.4% of those receiving placebo. New diagnosis of diabetes was reported in fewer patients receiving ramipril compared with those receiving placebo. Although the exact mechanism of the endocrine effects of ramipril is not known, it has been suggested that ACE inhibitors may prevent diabetic complications and new diagnosis of diabetes by improving insulin sensitivity and blood flow to the pancreas and by decreasing hepatic clearance of insulin. In addition, results of other studies indicate that in patients with type 2 diabetes mellitus, intensive control of blood pressure (e.g., an approximate target systolic pressure of less than 150 mm Hg and diastolic pressure of less than 85 mm Hg) using an ACE inhibitor (e.g., captopril) or a β-blocker (e.g., atenolol) resulted in a reduction of development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease).
In the HOPE study, reduction of cardiovascular risk factors was observed within 1 year of initiation of ramipril therapy and continued throughout the study (approximately 5 years). Because interim analysis of this study after about 5 years revealed a clear evidence of a beneficial effect of ramipril, the study was discontinued.
ACE inhibitors have been used in the management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced LVEF (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of ACE inhibitors in the management of heart failure, and .
Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see