Cardiovascular Disease; Study evaluates effect of blood pressure drugs on arterial function

Copyright 2005, Drug Week via NewsRx.com

Drug Week Atlanta:Dec 9, 2005. p. 176

A new substudy of the Anglo- Scandinavian Cardiac Outcomes Trial (ASCOT), presented during a late- breaking clinical trial session of the American Heart Association (AHA) meeting, gave an explanation for the amlodipine / Coversyl (perindopril) benefits in terms of total mortality, cardiovascular mortality, stroke, and cardiovascular events in comparison with the beta-blocker plus diuretic combination.

The Conduit Artery Function Evaluation (CAF=C9) study is the largest ever prospective evaluation of the effects of cardiovascular drugs on derived central aortic pressures and hemodynamics. It found that blood pressure (BP)-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics, despite a similar impact on brachial (upper arm) BP. This demonstrates that central pulse pressure appears to be an important determinant of clinical outcomes. It provides a new plausible explanation for the improved clinical outcomes seen in patients treated with the amlodipine / perindopril combination.

Bryan Williams, MD, professor of medicine in the Department of Cardiovascular Sciences at the University of Leicester in the U.K. is the principal investigator for the differential impact-principal results of the Conduit Artery Function Evaluation (CAFE) study in ASCOT.

Brachial BP measurements are routinely used to monitor the efficacy of BP-lowering treatments. Different BP-lowering drugs could have differing effects on central aortic pressure leading to different cardiovascular outcomes, despite similar effects on brachial BP.

Previously, the REASON study demonstrated that a perindopril (Coversyl)-based regimen reduces central systolic and pulse pressure to a greater degree than the beta-blocker atenolol.

This was found to reflect a significant improvement of large artery function. Thus, in addition to its other beneficial effects, such as improved endothelial function, decreased vascular inflammation, and reduced cardiac remodeling (a major cause of heart failure in elderly patients), as demonstrated in the EUROPA and PREAMI studies, these beneficial vascular effects of perindopril at the level of large arteries may have contributed to the decrease in cardiovascular events seen in ASCOT.

The CAF=C9 study found that in a group of 2073 ASCOT patients, central aortic pulse pressure was significantly lower by 4.3 mm Hg (P<0.0001) in the amlodipine / perindopril group throughout the study, even though the brachial pulse pressure was similar in the two groups. Central pulse pressure was a significant determinant of cardiovascular events and renal impairment (P<0.05).

ASCOT was a major, landmark cardiovascular outcomes study showing that amlodipine / perindopril treatment is significantly more effective in reducing cardiovascular events than an older treatment regimen.

Coversyl, which was discovered and developed by Servier, is licensed worldwide for hypertension and heart failure at the dosages of 4 to 8 mg. In the EU, the EMEA has given the go-ahead for a new indication for Coversyl in stable coronary artery disease to reduce the risk of cardiac events in patients with a history of MI and/or revascularization. In the U.S., the Food and Drug Administration (FDA) has just approved a label extension for perindopril for a similar indication.

The ASCOT trial involved over 19 000 patients from the UK, Ireland, and Scandinavia, and is endorsed by the British Hypertension Society. All the patients had hypertension and at least three prespecified cardiovascular risk factors, such as being over 55 years old, being a smoker, and having a family history of coronary events. The aim of the ASCOT trial was to test the hypothesis that a newer antihypertensive regimen is more effective than an older regimen in the primary prevention of coronary heart disease. The average length of treatment was about 5 1/2 years.

The newer treatment strategy (the calcium channel blocker, amlodipine, and the angiotensin-converting enzyme (ACE) inhibitor, perindopril) offered such significant advantages over the older treatment strategy (the b-blocker, atenolol, and the thiazide diuretic, bendroflumethiazide) that the trial was stopped early by the data safety monitoring board in December 2004.

The ESC presentation revealed that the perindopril plus amlodipine treatment combination significantly reduced the risk of death by any cause (by 11%), cardiovascular death (by 24%), stroke (by 23%), total coronary events (by 13%), and new-onset diabetes (by 30%), compared with the atenolol plus bendroflumethiazide combination.

This article was prepared by Drug Week editors from staff and other reports. Copyright 2005, Drug Week via NewsRx.com.