The main question for this trial was if amlodipine with or without an ACE inhibitor is more beneficial to the older combination of a beta blocker + thiazide diuretic. Remember, at this time, calcium channel blockers and ACE inhibitors were newer and more expensive than chlorthalidone. Pfizer had patent protection on amlodipine until 2007. Patent protection for Lisinopril lasted until June of 2002. This trial enrolled patients who were 4279 years old who either had untreated hypertension with BP >160/100mmHg, or treated hypertension with a BP >140/90mmHg. in addition, the participants had to have additional cardiovascular risk factors. The patients were randomized to start either amlodipine or atenolol to target a blood pressure <140/90mmHg (for patients without diabetes) or <130/80 (for patients with diabetes). If the blood pressure was not controlled with one agent, the arm randomized to amlodipine would have the addition of perindopril. The other arm, randomized to atenolol would have the addition bendroflumethiazide (a thiazide diuretic). Atenolol and a thiazide were chosen as comparitor drugs since these comprised the most common combination antihypertensive therapy used at the time. The primary outcome was the combined endpoint of non-fatal MI and fatal coronary heart disease (CHD). Secondary endpoints were all-cause mortality, total stroke, primary endpoint minus silent MI, all coronary events, total cardiovascular events and procedures, CV mortality, and non-fatal and fatal heart failure.
Median follow up was 5.5 years, but the trial was stopped early due to a Data Safety and Monitoring board recommendation to stop due to a reduction in all-cause mortality in the amlodipine + perindopril group. This reduction in all-cause mortality was unexpected and may have been due to confounding factors, such as smoking cessation efforts (which did not differ between the two groups). This trial did show that the amlodpine + perindopril arm lowered cardiovascular events and all-cause mortality. The primary outcome was not significantly different, possibly due to lower than expected event rate. The study was powered for the assumption of 1150 individuals to have non-fatal MI or fatal CHD. The study only observed 903 individuals with these events. Additionally, the achieved BP in the amlodipine arm was slightly lower than the atenolol arm and this may have influenced the supposed reduction in the secondary outcomes of fatal and non-fatal stroke and total cardiovascular events and procedures. Overall, this study suggested the benefit of amlodipine + perindopril and was one of the first to do so, Interestingly, this study was not directly cited in the ACCOMPLISH Trial, published a few years later, which ended up showing that the amlodipine + ACE inhibitor combination is beneficial. Even more interesting is that the primary author of the ASCOT-BPLA Trial was one of the main authors of the ACCOMPLISH Trial. Limitations of the trial design may have caused this omission as well as the ability of the trial to fully inform future BP trials. A nice review of the findings of the paper (Fuchs 2006) cast major doubt on the trial outcomes. Beta blockers have little role in BP lowering in older adults without coronary heart disease. Per the authors of this review (Fuchs 2006), the atenolol given can essentially be considered a placebo. This dovetails nicely with the fact that systolic BP was lower in the amlodipine arm. In summary, this trial could be viewed as a trial of amlodipine + perindopril vs bendroflumethiazide alone. Better trials would be needed in the future for a more fair comparison of BP medications.
The ASCOT-BPLA Trial: Dahlöf, B., Sever, P. S., Poulter, N. R., Wedel, H., Beevers, D. G., Caulfield, M., ... & Mehlsen, J. (2005). Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. The Lancet, 366(9489), 895-906.
The ASCOT-BPLA Trial PMID: 16154016
Other References: Fuchs, F. D., Gus, M., & Ribeiro, J. P. (2006). ASCOT-BPLA. The Lancet, 367(9506), 205.
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