(March 8, 2005, Orlando, Florida) Treating hypertension with a calcium channel blocker plus an ACE inhibitor reduced cardiovascular outcomes in hypertensive patients compared to treatment with a beta blocker and a diuretic. The preliminary data for the main results of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Study Blood Pressure Lowering Arm) study were eagerly awaited, because the trial was terminated early in November 2004, based on the recommendation of the trial’s Data and Safety Monitoring Board (DSMB). The co-principal investigators presented the data at the American College of Cardiology Annual Scientific Sessions.

Dr. Peter Sever, ImperialCollege, London, stated there was at least one piece of evidence that the differences in outcomes found in ASCOT-BPLA cannot be explained by blood pressure. A time-dependent analysis for all CV events and procedures was performed, because of the concerns about the impact of early blood pressure changes on CV outcomes. The analysis showed “complete consistency across the study period,” said Sever, despite the fact that the blood pressures were different between groups during the first 6 months of the trial, but were nearly identical thereafter.

The significant 14% reduction in all-cause mortality in the amlodipine/perindopril group was the basis for the DSMB recommendation for early termination of the study. The treatment strategy of amlodipine/perindopril, compared to atenolol/bendroflumethiazide-K, resulted in a:

• 10% reduction in the primary endpoint of nonfatal MI and fatal CHD.
• 14% reduction in total coronary endpoints (nonfatal MI, CHD, new onset angina, fatal/nonfatal heart failure).
• 23% reduction in fatal/nonfatal stroke.
• 16% reduction in all CV events and revascularization procedures.
• 24% reduction in CV mortality.
• 32% reduction in new-onset diabetes.

Although the primary endpoint did not achieve statistical significance, the presenters noted that only 850 events had occurred at the time of study termination, and that perhaps if the trial had continued to the planned 1150 events, statistical significance may have been achieved. The study was not statistically powered for assess all-cause mortality.

InASCOT-BLPA, 19,257 patients with hypertension were randomized using the PROBE design to either atenolol (50-100 mg) plus bendroflumethiazide-K (1.25 mg to 2.5 mg) or to amlodipine (5 mg to 10 mg) [perindopril (4mg to 8 mg) was added if needed to reach target blood pressure levels. Then, if needed, doxazosin GITS (4 mg to 8 mg) could be added in either arm. The treatment goals were <140/90 mm Hg or <130/80 mm Hg in diabetic patients. In the atenolol arm were 9,619 patients and in the amlodipine arm 9,634 patients.

Importantly, Sever noted, ASCOT-BPLA was designed to look at a strategy of anti-hypertensive therapy, not a comparison of individual drugs. Because multiple drugs are required to reach blood pressure targets, studies need to determine the best combination drug strategies.

The study patients, aged 40-79 years, had a screening and baseline blood pressure ≥160/100 mm Hg untreated or a baseline BP ≥140/90 mm Hg after treatment with 1 or more drugs, no prior MI or current clinical CHD, and 3 or more risk factors for a future CV event. On average, patients were 63 years old, 23% women, 95% Caucasian, 33% current smoker, SBP 164 mm Hg, DBP 94.8 mm Hg, BMI of 28.7 Kg/m2 and had 3.7 risk factors. Only 19% were previously untreated for hypertension, 44% were taking 1 antihypertensive agent, and 36.5% were taking more than 2 antihypertensive agents. Also, 10.5% were taking lipid-lowering therapy and 18.8% aspirin. The median follow-up at termination was 5.4 years.

Blood pressure difference. The mean between group blood pressure difference was 2.9/1.8 mm Hg. The blood pressure in the atenolol/thiazide group was reduced from 163.9/94.5 mm Hg to 136.3/78.4 mm Hg, and in the amlodipine/perindopril group reduced from 164.1/94.8 mm Hg to 135.5/77.1 mm Hg.

The majority of patients were taking the two study drugs +/- another antihypertensive agent (52.6% of amlodipine/perindopril group and 54.2% of atenolol/thiazide group. Only 14.3% of the amlodipine/perindopril group and 8.6% of the atenolol/thiazide group were taking only amlodipine or atenolol.

A similar reduction in total cholesterol and LDL-C was seen in both groups, but a greater improvement in triglycerides and HDL-cholesterol in the amlodipine/perindopril group

At baseline, only 10% of patients were taking a statin and this was increased to 40% of patients after randomization into the trial, and further increased to 60% of patients after the ASCOT-Lipid Lowering Arm trial was terminated early.

Possible explanations for the observed differences in outcomes, presented by Sever and Dr. Bjorn Dahlof, University Hospital/Ostra, Gothenburg University, Sweden, include:

• Better blood pressure lowering with amlodipine/perindopril
• Adverse interaction between atenolol/thiazide and statin
• Beneficial interaction between amlodipine/perindopril and statins
• Non-blood pressure-lowering benefits of amlodipine/perindopril
• Non-blood pressure-related disadvantages of atenolol/thiazide

Sever conjectured that in the UK, the hypertension guidelines committee will re-evaluate the use of beta blockers as first-line treatment in hypertension. Except for particular patients in whom a beta blocker is indicated, e.g., post-MI, the results of ASCOT-BPLA raise serious questions about the position of beta blockers in treating hypertension.

The results presented included only the adjudicated events as of November 30, 2004. Presentation of the final results is anticipated to be in September 2005 at the European Society of Cardiology meeting.