Ramipril

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Abstract
Ramipril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which is rapidly hydrolysed after absorption to the active metabolite ramiprilat. Earlier trials have shown that ACE inhibitors, when given to patients with low ejection fractions, have reduced the relative risk of myocardial infarction (MI) and other ischaemic events by 14 to 23%. Subsequently, the double-blind, randomised, placebo-controlled, multicentre Heart Outcomes Prevention Evaluation (HOPE) study has shown that, in patients who are not known to have low ejection fraction or heart failure but are at increased risk for developing cardiovascular events, ramipril reduced the incidence of stroke, MI and death due to cardiovascular disease. Results from the HOPE study, in which 9297 patients were randomised to receive either ramipril 10 mg/day or placebo for a mean of 4.5 years, indicate that ramipril reduced the relative risk of the composite outcome of MI, stroke and cardiovascular death by 22%. The incidence of the composite outcome was significantly lower in the ramipril group than in the placebo group (14.0 vs 17.8%). Patients who received ramipril, compared with placebo recipients, had a significantly decreased incidence of stroke, MI or death due to cardiovascular disease (3.4 vs 4.9%, 9.9 vs 12.3% and 6.1 vs 8.1%, respectively). The relative risk of death from any cause was reduced among patients who received ramipril. In addition, treatment with ramipril reduced as the incidence of revascularisation procedures, and, among patients with diabetes mellitus, ramipril reduced the incidence of complications related to diabetes mellitus, including the development of overt nephropathy. Moreover, in patients without a previous diagnosis of diabetes mellitus, ramipril, compared with placebo, significantly reduced the development of diabetes mellitus. Furthermore, compared with patients receiving placebo, patients receiving ramipril had a reduced rate of progression of carotid artery wall thickness. Conclusion: Ramipril 10 mg/day can significantly reduce the incidence of MI, stroke or death from cardiovascular causes in patients aged ≥55 years who are at increased risk for the development of ischaemic cardiovascular events due to a history of stroke, coronary artery disease (with controlled blood pressure), diabetes mellitus plus at least one other risk factor or peripheral vascular disease but no heart failure or low ejection fraction. Therefore, in addition to dietary and lifestyle modifications, ramipril should be an integral part of secondary prevention therapy in patients at increased risk for the development of cardiovascular events. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor. This prodrug itself is a poor inhibitor of ACE but is rapidly hydrolysed after absorption to the active metabolite ramiprilat, which has a higher affinity for ACE than enalaprilat or captopril. Ramipril administration to rats attenuated toxic effects on the aorta from oxidised low-density lipoprotein and resulted in a decrease in carotid artery intimai thickening after balloon injury. The drug limited dysfunction in adjacent non-infarcted areas during left ventricular (LV) remodelling after surgically induced myocardial infarcts in sheep; it also reduced cardiac fibrosis and left ventricular hypertrophy (LVH), and improved postinfarction survival and LV function in spontaneously hypertensive rats (SHR). Moreover, administration of ramipril increased the survival of old SHR and doubled the lifespan of young SHR. Carotid artery compliance and distensibility increased significantly in a double-blind, randomised study of patients with hypertension who were treated with ramipril 2.5 mg/day for 12 weeks; similar results were observed with nitrendipine 10 mg/day. In a randomised 3-year study involving patients with hypertension, LVH was prevented in the ramipril 5 mg/day group but not in the felodipine 5 mg/day group. Heart rate response and cardiac workload were reduced during stress tests in a double-blind, placebo-controlled, crossover study of patients with hypertension who received ramipril 5 mg/day. Plasma fibrinolytic activity was positively affected by ramipril (0.625 or 10 mg/day) administration for 14 days in a double-blind, placebo-controlled study of patients with acute myocardial infarction (MI). LV systolic function was significantly improved by ramipril (5mg twice daily, or 1.25 or 5 mg/day) treatment in two 6-month, randomised, double-blind, placebo-controlled trials involving patients with either systolic dysfunction and heart failure after acute MI, or stable ischaemic heart disease and preserved LV function. Ramipril 1.25 or 5 mg/day significantly reduced urinary albumin excretion in patients with type 1 diabetes mellitus without hypertension in a randomised, double-blind, placebo-controlled, multicentre trial and in patients with type 2 diabetes mellitus and hypertension in a randomised trial. Ramipril also induced a significant regression in LVH in a randomised, double-blind, placebo-controlled trial of patients with type 2 diabetes mellitus but no hypertension or albuminuria. Patients with chronic nephropathy and persistent proteinuria with or without hypertension who received ramipril were significantly less likely than placebo recipients to progress to end-stage renal disease or overt proteinuria in a 2.5-year, randomised, double-blind, placebo-controlled, multicentre trial. Moreover, in patients with severe renal dysfunction ramipril significantly slowed the decline in glomerular filtration rate compared with placebo. Approximately 56% of an oral administered dose of ramipril is absorbed and converted to the active metabolite ramiprilat. After a single 5mg dose of ramipril, bioavailability values of ramipril and ramiprilat were 28 and 44%, respectively. The peak plasma concentration (Cmax) of ramiprilat is linearly related to the dose; the time to Cmax was approximately 3 hours after a 10mg dose. Protein binding of ramiprilat is about 56% and appears to be concentration independent. The mean apparent volume of distribution for ramipril is approximately 90L. Ramipril is rapidly and almost completely de-esterified during first-pass metabolism in the liver to ramiprilat; however, metabolism was decreased by 50% in patients with decreased liver function due to cirrhosis, although these individuals still metabolised sufficient ramipril to produce a therapeutic effect. Ramipril and ramiprilat are both conjugated to their respective inactive glucuronides and to diketopiperazine derivatives, all of which are renally eliminated. Afterreaching Cmax, plasma concentrations decline in a triphasic manner, with the initial rapid decline phase having a half-life (t½) of 1.1 to 4.5 hours, the apparent elimination phase having a t½ of 9 to 18 hours and the phase involving the dissociation of ramiprilat from ACE and its subsequent elimination having a t½ of >50 hours. Ramipril and its metabolites are 60% renally eliminated with the remaining 40% being eliminated in the faeces as either unabsorbed drug or metabolites of biliary excretion. Renal dysfunction can reduce the clearance and elimination rate of ramiprilat. Concomitant use of ramipril and lithium may lead to elevated serum lithium concentrations and possibly lithium toxicity. Caution should be exercised and appropriate monitoring should be undertaken in this situation. Ramipril, compared with placebo, was found to significantly reduce (14.0 vs 17.8%; p < 0.001) the incidence of the primary outcome (i.e. the composite of MI, stroke and death due to cardiovascular disease) in patients aged ≥55 years at high risk for the development of such events. Moreover, ramipril reduced the relative risk of the primary outcome in the HOPE study by 22%. Patients included in the large, randomised, double-blind, placebo-controlled, multicentre Heart Outcomes Prevention Evaluation (HOPE) study, were at increased risk for developing ischaemic cardiovascular events due to a history of coronary artery disease, stroke or diabetes mellitus with at least one other risk factor or peripheral vascular disease, but without low ejection fraction or history of heart failure. The HOPE study included 9297 patients randomised to receive in a factorial design, ramipril 10 mg/day (patients were started on 2.5 mg/day and gradually titrated to 10 mg/day over a 4-week period) or placebo, and, in addition, tocopherol (vitamin E) 400 IU/day or placebo for a mean of 4.5 years. Tocopherol therapy did not reduce the incidence of cardiovascular events throughout the duration of this study. Compared with placebo, ramipril was also shown to significantly reduce the incidence of stroke (3.4 vs 4.9%; p < 0.001), MI (9.9 vs 12.3%; p < 0.001) and death due to cardiovascular causes (6.1 vs 8.1%; p< 0.001) as separate outcomes. Furthermore, ramipril therapy in the HOPE study significantly reduced the number of deaths from any cause and revascularisation procedures compared with placebo therapy (relative risk reductions of 16 and 15%, respectively) and significantly decreased the incidence of diabetes mellitus-related complications (composite of retinal laser therapy, overt nephropathy or dialysis). Additionally, amongst the group of patients with diabetes mellitus [the MIcroalbuminuria, Cardiovascular and Renal Outcomes in the HOPE (MICRO-HOPE) study], ramipril treatment (10 mg/day) significantly decreased the incidence of the development of overt nephropathy compared with placebo. Indeed, ramipril therapy in the population of patients without a previous history of diabetes mellitus significantly decreased the development of diabetes mellitus. In the Study to Evaluate Carotid Ultrasound Changes in patients treated with Ramipril and vitamin E (SECURE), ramipril (10 mg/day) has also been found to reduce the progression of carotid artery wall thickening to a significant degree, when compared with placebo. Tocopherol administration, however, did not significantly affect this parameter. The tolerability profile of ramipril (1.25 to 20 mg/day) is similar to that of placebo, with the most frequent adverse events reported as increased cough (12%), headache (5.4%), dizziness (2.2%) and asthenia (fatigue) [2.0%], with only cough and asthenia being reported more frequently in ramipril than in placebo recipients. Cough required treatment discontinuation in about 4% of ramipril recipients. In the HOPE study, the incidence of treatment discontinuation due to cough was 7.3% for the ramipril group versus 1.8% for the placebo group. Treatment discontinuation in the HOPE study due to the potentially serious adverse effect of angioedema was reported in 0.4% of ramipril recipients and in 0.2% of placebo recipients. The US and UK recommended prescribing regimen in the prevention of cardiovascular events is a starting dosage of ramipril 2.5 mg/day for 1 week, which is increased to 5 mg/day for 3 weeks and then increased to a final dosage of 10 mg/day as tolerated. If patients have a history of hypertension or recent MI, the dosage may be divided. The dosage of ramipril should be adjusted in patients with impaired renal function [creatinine clearance 2 (2)], and caution is advised with the administration of ramipril to patients with severe hepatic impairment. Caution and frequent potassium monitoring is advised with the coadministration of ramipril and potassium-sparing diuretics, potassium supplements or potassium salt substitutes because of the potential for hyperkalaemia. Administration of the initial dose of ramipril to patients taking diuretics may lead to hypotension. Ramipril should not be administered to pregnant women, as ACE inhibitor therapy has been reported to cause fetal and neonatal morbidity and mortality, or to women who are breastfeeding.

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