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New Ascot-BPLA Substudy Shows Coversyl's Cardioprotective Benefits go Beyond Blood Pressure Reduction

    Dallas, Texas, November 14 (ots/PRNewswire) -

    - CAFÉ Study Shows Central Aortic Pulse Pressure Important Determinant  of Cardiovascular Outcomes

    A new sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)(1), 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 + diuretic combination. The CAFÉ (Conduit Artery Function Evaluation) 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.

    "This study demonstrates for the first time in a large clinical outcomes trial that BP-lowering drugs have profoundly different effects on central aortic pressures and hemodynamics, despite a similar impact on brachial (arm) blood pressure," said Bryan Williams, MD, Professor of Medicine in the Department of Cardiovascular Sciences at the University of Leicester in the UK. "The results of this study are clear-cut, dramatic and potentially very important. It may also explain why certain types of hypertension treatment might be more effective than others."

    Williams 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(2) 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(3,4) and PREAMI studie(5), 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 CAFÉ 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).

    "The CAFÉ study demonstrates that antihypertensive treatment with amlodipine and perindopril has a greater effect on central blood pressure than older antihypertensives such as atenolol and bendroflumethiazide, and this may well explain their superior effects on outcome," commented Prof John Cockroft, Professor of Cardiology at the Wales Heart Research Institute, University Hospital, Cardiff, UK. "CAFE should also stimulate measurement of central blood pressure in further large intervention studies, and perhaps in the future it will be central blood pressure reduction that counts."

    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: "The assumption has been that all types of blood pressure treatment are equally effective at lowering blood pressure (in the arm). We show that this assumption is untrue," says lead investigator Prof Bryan Williams, MD, from the Department of Cardiovascular Sciences, University of Leicester, UK. The CAFÉ results have important implications and provide a mechanism to explain the better clinical outcome for patients treated with amlodipine / perindopril in the ASCOT study and the different effects of BP-lowering agents on cardiovascular structure and clinical outcomes in other recent trials.

    Coversyl (perindopril)

    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 US, the FDA has just approved a label extension for perindopril for a similar indication.

    Perindopril is marketed in 118 countries under the trade names COVERSYL(R), COVEREX(R), ACERTIL(R), PRESTARIUM(R), PREXANIL(R), PREXUM(R),  COVERENE(R), COVERSUM(R), PROCAPTAN(R), ARMIX(R), and marketed by Solvay  Pharmaceutical and CV Therapeutics under the trade name of  ACEON(R) in the USA.

    Notes to Editors:

    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 51/2 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 + 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 + bendroflumethiazide combination.

    References

    1. Dahlof B, Sever PS, Poulter NR et al, for the ASCOT investigators. Lancet 2005; 366: 895-906.

    2. Asmar RG, London GM, O'Rourke ME et al for the REASON Project Coordinators and Investigators. Hypertension 2001;38:922-26.

    3. EUROPA Study Investigators. Lancet 2003; 362: 782-788.

    4. Ferrari R, et al. on behalf of the EUROPA trial investigators. http://www.europa- trial.org/pro/pertinent/pertinent_findings.asp.

    5. Cleland JGF, Coletta AT, Lammiman M et al. Clinical trials update from the European Society of Cardiology meeting 2005: CARE-HF extension study, ESSENTIAL, CIBIS-III, S-ICD, ISSUE-2, STRIDE-2, SOFA, IMAGINE, PREAMI, SIRIUS-II and ACTIVE. Eur J Heart Fail. 2005;7:1070-1075.

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