, Volume 66, Issue 2, pp 235-255
Date: 17 Sep 2012

Perindopril

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Summary

Abstract

Perindopril (Coversyl®) is a prodrug ester of perindoprilat, an ACE inhibitor. This agent has shown pharmacodynamic effects beyond those responsible for lowering blood pressure (BP), including the improvement of endothelial function and the normalisation of vascular and cardiac structure and function.

Perindopril has a well established role in the treatment of patients with hypertension or heart failure. In the EUROPA trial, once-daily perindopril 8mg prevented cardiovascular events in patients with stable coronary artery disease (CAD) without any apparent heart failure receiving standard recommended therapy. In the ASCOT-BPLA trial, a calcium channel antagonist ± perindopril regimen demonstrated significant cardiovascular benefits compared with a conventional β-blocker ± diuretic regimen in patients with hypertension who were at risk of developing cardiovascular events. These trials demonstrate that while perindopril, in addition to standard recommended therapy, has a potential role in preventing cardiovascular events in hypertensive patients, its role in the management of patients with stable CAD is clearly established.

Pharmacological Properties

Perindopril is a prodrug ester of perindoprilat, an ACE inhibitor. This agent demonstrates pharmacodynamic effects beyond those responsible for lowering BP involving the improvement of endothelial dysfunction and reduction in markers of inflammation and thrombosis. In the PERTINENT trial, perindopril significantly increased plasma levels of bradykinin, and improved endothelial cell nitric oxide synthetase activity. Perindopril reduced levels of angiotensin II, D-dimer and von Willebrand factor and reduced the rate of endothelial apoptosis.

Perindopril demonstrated anti-remodelling effects in small resistance arteries, large arteries and in the heart. Perindopril reduced the media thickness-to-lumen diameter ratio of small arteries and reduced peripheral vascular resistance in patients with hypertension. In small coronary arterioles, the reduction in periarteriolar collagen area and total interstitial collagen volume density in perindopril recipients was associated with a significant increase in coronary blood flow and in coronary reserve. Long-term treatment with perindopril reduced carotid and radial artery wall hypertrophy. In patients with end-stage renal disease, perindopril, independent of BP changes, reduced aortic pulse wave velocity. In the heart, perindopril significantly reduced left ventricular mass in patients with hypertension.

Following oral administration, perindopril is rapidly absorbed, with peak plasma concentrations being reached within 1 hour. Approximately 20–50% of the perindopril absorbed is converted to the active metabolite perindoprilat. Peak plasma concentrations of perindoprilat occur after 3–7 hours; protein binding of perindoprilat is 10–20%. The apparent mean half-life for the majority of perindoprilat elimination is about 3–10 hours, but perindoprilat has a prolonged terminal elimination half-life of 30–120 hours, reflecting slow dissociation from ACE binding sites. Perindoprilat is eliminated in the urine. Food intake may reduce biotransformation of perindopril to perindoprilat.

Therapeutic Efficacy

In the randomised, double-blind EUROPA trial, 12 218 patients with stable CAD and without heart failure were randomised to once-daily perindopril 8mg or placebo. After a mean follow-up of 4.2 years, a significant (p = 0.0003) relative risk reduction (RRR) of 20% for the primary endpoint (cardiovascular death, nonfatal myocardial infarction [MI] and resuscitated cardiac arrest) occurred with perindopril versus placebo. This benefit was consistent in predefined subgroups and was irrespective of treatment with other standard recommended therapy, including platelet inhibitors, lipid-lowering agents and β-blockers.

In the 12-month, randomised, double-blind PREAMI trial in 1252 elderly patients with recent MI and preserved left ventricular ejection fraction, once-daily perindopril 8mg, compared with placebo, was associated with a significant RRR of 38% (p < 0.001) for the primary endpoint (death, hospitalisation for heart failure and cardiac remodelling). Significantly less left ventricular remodelling occurred in perindopril recipients than in placebo recipients (27.7% vs 51.2%, RRR 46%; p < 0.001).

In the randomised, double-blind PROGRESS study in 6105 patients with a previous history of stroke or transient ischaemic attack, the risk of stroke was 10% in recipients of perindopril ± indapamide and 14% in placebo recipients (RRR 28%; p < 0.0001) over a mean follow-up of 3.9 years. BP was reduced by 9/ 4mm Hg in recipients of perindopril ± indapamide compared with placebo. Perindopril ± indapamide reduced the risk of nonfatal myocardial infarction by 38% (95% CI 14, 55) and congestive heart failure by 26% (p = 0.02).

The randomised, open-label ASCOT-BPLA trial in 19 257 hypertensive patients at moderate risk of developing cardiovascular events was terminated prematurely (median follow-up of 5.5 years) because the risk reduction of all-cause mortality was 11 % lower in those treated with amlodipine ± perindopril than in those treated with atenolol ± thiazide. The RRR of 10% for the primary endpoint (nonfatal MI and fatal CHD) in recipients of amlodipine ± perindopril was not significant; however, because of the early termination of the trial, the study was not sufficiently powered for this endpoint.

Tolerability

Perindopril is generally well tolerated in patients with hypertension, heart failure or CAD. Generally, adverse events were mild and transient, with cough, gastrointestinal disturbances and asthenia/fatigue (all <10%) being most commonly reported in a large (n = 47 351) postmarketing surveillance study in patients with hypertension. In the EUROPA trial in patients with CAD, withdrawals in perindopril and placebo recipients were for cough (2.7% vs 0.5%), hypotension (1.0% vs 0.3%) or drug intolerance (2.4% vs 1.3%).