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Prof. Philippe Gabriel Steg ,
The role of angiotensin-converting enzyme inhibitors in patients with coronary artery disease is intriguing. This class of agent has proved very effective therapy for hypertension and heart failure. The HOPE trial (1) established its benefits in patients at high risk of cardiovascular events, including diabetics. This was strongly suggestive of benefits beyond treatment of hypertension or heart failure. The European trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease (EUROPA) study was established to test the ability of perindopril to reduce cardiovascular death, myocardial infarction and cardiac arrest in patients with stable coronary artery disease and without heart failure or hypertension (2). 13655 patients were registered with either previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%) prior coronary revascularisation (55%) or a positive stress test only (5%) After a run-in period of 4 weeks, patients were randomly assigned to perindopril (8mg once daily) or matching placebo. At baseline, more than 90% of the patients were on platelet inhibitors, 57% on lipid-lowering therapy, and 61% on beta-blockers.
After a mean follow-up of 4.2 years, patients randomly assigned to perindopril had a lower rate of cardiovascular death, myocardial infarction or cardiac arrest than patients randomised to placebo (8.0 vs. 9.9%, p=0.0003). This benefit started to appear after one year and gradually increased throughout the trial. This was associated with a consistent benefit on secondary endpoints, notably the combined endpoint of total mortality, MI, unstable angina and cardiac arrest (14.8 vs. 17.1%, p=0.0009), which had been the original primary endpoint of the study (changed prior to unblinding, during the course of the trial). Most of the benefit appeared to be driven by a reduction in fatal and non-fatal myocardial infarction. The clinical benefit was also consistent across predefined subsets of age, gender, previous history, risk factors and therapy. Treatment with perindopril was well tolerated with 10% of the patients who did not continue therapy after the open-label run-in phase, but afterwards, with a withdrawal rate similar to that of placebo. The average difference in blood pressure between groups was 5/2 mmg Hg. With respect to the primary endpoint of the trial, approximately 50 patients must be treated for 4 years to prevent one major cardiovascular event.
This trial is a landmark trial because it shows clear clinical benefit of perindopril on top of other preventive medications, on “hard” endpoints in a large, well-treated, patient population. It confirms and extends the results seen in the HOPE trial with another ACE-inhibitor, ramipril, although at this stage, it is probably premature to conclude to a class effect. In EUROPA, perindopril was beneficial in a population who had extensive background therapy with secondary prevention agents. It is also unlikely that the modest drop in blood pressure seen is entirely responsible for the cardiovascular benefits of perindopril, suggesting that ACE inhibition probably has direct and clinically relevant effects on the arterial wall. Interestingly, EUROPA is the first large scale long term prevention trial using the new consensus ESC/ACC/AHA definition of myocardial infarction. After EUROPA, strong consideration should be given to adding 8 mg perindopril once daily to the standard therapy of patients with stable coronary artery disease.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10639539&dopt=Abstract
2. EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13678872&dopt=Abstract
Prof. G. Steg Paris, France ESC Spokesperson on Acute Coronary Syndromes
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