Amlodipine-perindopril regimen in hypertension superior to beta blocker-diuretic

Cardiology Review® Online, October 2005, Volume 22, Issue 10

Hypertension

Stockholm—Final results of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Blood Pressure Lowering Arm (BPLA) indicate significant reductions in all-cause mortality and other adverse cardiovascular end points with an antihypertensive regimen starting with amlodi-pine/atorvastatin (Caduet), with perindopril (Aceon) added as required, compared with a regimen of atenolol (Tenormin) with addition of a diuretic. The results were

presented at the 2005 Congress of the European Society of Cardiology.

With this finding, beta blocking agents should no longer be considered first-line treatment for patients with uncomplicated hypertension, especially those older than 55 years, said study coinvestigator Peter Sever, MD.

The ASCOT-BPLA included 19,257 patients with hypertension who had at

least three other cardiovascular risk factors. Patients were randomly assigned to either:

• amlodipine/atorvastatin, 5 to 10 mg, with perindopril, 4 to 8 mg, as required, or

• atenolol, 50 to 100 mg, with the addition of bendroflumethiazide (Naturetin), 1.25 to 2.5 mg, and potassium as required.

The primary end point was the incidence of nonfatal myocardial infarction and fatal coronary heart disease. By the end of the trial, 78% of patients were taking two or more antihypertensive agents and only 15% and 9% were receiving amlodipine and atenolol monotherapy, respectively.

The study was stopped prematurely after a median of 5.5 years when mortality and several other secondary outcomes were determined to be worse in the patients assigned to atenolol-bendroflumethiazide compared with amlodipine-perindopril. At this time, the primary end point was lowered by a nonsignificant 10% in patients assigned to the amlodi-pine-perindopril regimen.

There were, however, significant reductions in almost all of the secondary end points with the amlodipine-perindopril regimen, including total coronary events (13% reduction; P = .007), total cardiovascular events and procedures (16% reduction; P < .001), all-cause mortality (11% reduction; P = .0247), cardiovascular mortality (24% reduction; P = .001), and fatal and nonfatal stroke (23% reduction; P = .003). In addition, the incidence of new-onset diabetes was reduced by 30% (P < .001) in the amlodipine-perindopril arm relative to the atenolol-bendroflumethiazide arm. The incidence of new-onset renal dysfunction was also reduced by 15% (P = .02) in the amlodipine-perindopril arm. The clinical advantage with the amlodipine-perindopril strategy was observed in all prespecified subgroups.

There was a mean blood pressure difference of 2.7/1.9 mm Hg throughout the trial in favor of the amlodipine-perindopril regimen. “Blood pressure accounted for about 15% of the coronary differences and 30% of the stroke differences,” said Neil R. Poulter, MD, coinvestigator of ASCOT. “Blood pressure differences are unlikely to be a single explanation.”

Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in strokes between the treatment strategies, he said. Statistical analysis actually showed more coronary events in the amlodipine-based regimen during the first year of the study, even though blood pressure differences between the two regimens were greatest during this time, making it highly unlikely that blood pressure was responsible for the entire difference in outcomes between the two strategies, said Dr. Poulter, professor of preventive cardiology medicine, Imperial College, London.

In addition, when using a technique called serial mean matching, which includes in an analysis only those patients with similar systolic blood pressures during the trial, the incidences of coronary events and strokes were still less with the amlodipine-perindopril strategy, he said. “Given the large population burden of hypertension, even modest incremental benefits of specific agents over others can translate into an important public-health impact,” commented Salim Yusuf, MBBS, PhD, professor of medicine and director of the Population Health Research Institute, McMaster University, Ontario, Canada.