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Amlodipine/Perindopril Consistently Reduces Blood Pressure Better Than Atenolol/Thiazide in High-Risk Patients: Presented at ESC

By Chris Berrie

STOCKHOLM, SWEDEN -- September 8, 2005 -- An antihypertensive drug regimen that starts with the calcium-channel blocker (CCB) amlidopine and adds the angiotensin converting enzyme (ACE) inhibitor perindopril as required is better than one that starts with the beta-blocker atenolol and adds the diuretic bendroflumethiazide as required for patients with hypertension who are at moderate risk of developing cardiovascular events.

The improvements with the amlidopine/perindopril regimen are significant with respect to the reduction in the incidence of all types of cardiovascular events and all-cause mortality, and to the risk of subsequent new-onset diabetes, according to results of an international, multicentre, randomised, controlled study.

Results of the randomised controlled trial were presented here September 4^th at the European Society of Cardiology (ESC) Congress 2005 in a combined presentation by the three co-principal investigators on behalf of the Anglo-Scandinavian Cardiac Outcomes Trial: Blood-Pressure-Lowering Arm (ASCOT-BPLA) investigators.

Peter S. Sever, PhD, Professor of Clinical Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom, introduced the study saying that the aim was to use a factorial design to evaluate the efficacy of the regimens for prevention of coronary heart disease (CHD) and other vascular events by lowering blood pressure and cholesterol.

The primary objective of the study was to compare the effects on non-fatal myocardial infarction (MI) and fatal CHD of a standard antihypertensive regimen (beta-blocker with or without diuretic) against a more contemporary regimen (CCB with or without ACE inhibitor). There were also numerous secondary and tertiary endpoints specified.

ASCOT-BPLA enrolled and randomised 19,257 hypertensive patients to up-titration regimens of atenolol (50-100 mg) followed by bendroflumethiazide (1.25-2.5 mg), or amlidopine (5-10 mg) followed by perindopril (4-8 mg). The treatment algorithms were designed to obtain blood pressure targets of <140/90 mmHg, or <130/80 mmHg for patients with diabetes, and to achieve this, doxazosin GITS (4-8 mg) and additional drugs could be combined with either arm.

The patient inclusion criteria were a minimum baseline untreated blood pressure of 160/100 mm Hg or a treated baseline level of at least 140/90 mm Hg with one or more drugs, age 40 to 79 years, no previous MI or current clinical CHD, and at least 3 cardiovascular risk factors.

When considering these cardiovascular risks, Dr. Sever stressed that the absolute cardiovascular risks of ASCOT were much lower than those seen in most other recent trials, with about half the cardiovascular risks of those involved in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), and an annual risk of coronary heart disease of less than 1%.

Following randomisation, there were 9639 patients in the amlodipine/perindopril arm and 9618 in the atenolol/thiazine arm. All demographic and clinical characteristics, and drug therapies, were very well matched between groups.

Despite about 80% of patients already being on some form of antihypertensive, blood pressure levels were poorly controlled, with a mean systolic pressures of 164.1 mm Hg and 163.9 mm Hg, respectively, and diastolic pressures of 94.8 mm Hg and 94.5 mm Hg, respectively.

Dr. Sever also noted that the study was brought to a premature close as suggested by the Data Safety Monitoring Board because of the differences in cardiovascular events and total mortality between the two arms.

Throughout the study, blood pressure levels in the amlodipine/perindopril arm were consistently lower than in the atenolol/thiazide arm, with the largest difference seen at 3 months (systolic/diastolic difference, 5.9/2.4 mm Hg), and with the mean difference throughout the study of 2.7/1.9 mm Hg.

Björn Dahlöf, MD, Associate Professor, Department of Medicine, Sahlgrenska University Hospital, Östra, Göteborg, Sweden, then presented the final results of this ASCOT-BPLA trial.

Starting with the primary endpoint of non-fatal MI and fatal CHD, there was no significant difference between the two arms, but the trend reached a 10% decrease in favour of the amlodipine/perindopril arm (P =.1052). However, as Dr Dahlöf indicated, exclusion of silent MI from the primary endpoint increased this trend to 13% and just reached significance (P =.0458).

Dr. Dahlöf said that for all the endpoints analysed, all the benefits were in favour of the amlodipine/perindopril arm, as follows: 23% decrease in fatal and non-fatal stroke (P =.0003); 16% decrease in total cardiovascular events and procedures (P <.0001); 11% decrease in all-cause mortality (P =.0247); 24% decrease in cardiovascular mortality (P =.0010); 16% decrease in fatal and non-fatal heart failure (P =.1257); 32% decrease in unstable angina (P =.0115); no difference in chronic stable angina (P =.8323); 35% decrease in peripheral arterial disease (P =.0001); 15% decrease in new-onset renal impairment (P =.0187); and 30% decrease in new-onset diabetes mellitus (P <.0001).

Post-hoc analysis showed that the combination of coronary revasculation with the primary endpoint produced a significant 14% benefit, and that of cardiovascular death, MI and stroke produced a significant 16% benefit, both for the amlodipine/ perindopril arm, Dr. Dahlöf noted.

Finally, there was no significant heterogeneity among any of the prespecified subgroups for total cardiovascular events and procedures.

For the adverse events, although there was a significant difference in favour of amlodipine/perindopril arm for the proportion of patients who stopped therapy due to serious adverse events (2% vs. 3%; P <.0001), there were no trends seen for the full range of adverse events considered.

The full details of both ASCOT-BPLA and the researchers' interpretation can be found in their two papers published online in the Lancet on September 4^th, 2005.

Pfizer provided financial support for this study.


[Study title: ASCOT-BPLA: The Anglo-Scandinavian Cardiac Outcomes Trial: Blood-Pressure-Lowering Arm. Abstract 753]

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