Pharmacy Times

ACCOMPLISH: Mortality/Morbidity Trial of Initial Fixed-dose Combination Antihypertensive Therapy

Author: Kenneth A. Jamerson, MD

"Where?s the data to support it?" asked Kenneth A. Jamerson, MD, about the recommendation from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) that diuretics be the mainstay of any initial combination drug regimen (Chobanian AV, et al. JAMA. 2003;289:2560-2571).

If any theme has emerged from the past 4 decades of antihypertensive therapy trials, it is that actually lowering blood pressure (BP) is more important than the choice of agent by which it is accomplished, Dr. Jamerson observed.Virtually all relevant trials have shown no significant outcome differences when comparing diuretics with other drug classes, given comparable BP reductions. Such trials were the underpinning of the JNC 7 guidelines, Dr. Jamerson said, yet they did not show diuretics to be indispensable in initial therapy.

The recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) attempted to compare diuretics with other drug classes (ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997), Dr. Jamerson noted.However,"the study design did not allow us to distinguish whether 1 drug class is better than another."

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial just getting under way will compare morbidity and mortality outcomes between high-risk patients with hypertension randomized to 1 of 2 initial combination regimens: a calcium-channel blocker (CCB) plus an angiotensin-converting enzyme (ACE) inhibitor versus an ACE inhibitor plus a diuretic (Jamerson KA, et al. Am J Hypertens. 2003;16[part II]:193A).

With ACCOMPLISH, Dr. Jamerson said, "we hope to provide some firm data on which to base drug selection when initiating combination therapy."

ACE inhibitors and CCBs are known to have actions that highly recommend them as a drug combination for lowering BP and protecting the heart and kidneys. ACE inhibition attenuates various effects of increased angiotensin II activity, including endothelial dysfunction, vasoconstriction, abnormal smooth muscle cell (SMC) migration, and increased platelet aggregation. Calcium-channel blockade enhances lipid resistance to oxidative stress, inhibits SMC migration, and promotes endothelial nitric oxide production.

A recent study, Dr. Jamerson said, compared the effects of amlodipine, ramiprilat, and their combination on indices of nitric oxide activity in canine coronary microvessels (Zhang X, et al. J Cardiovasc Pharmacol. 2000;35:195-202).

Table

Both agents increased nitric oxide production individually, but the combination of the 2 had a far greater effect than did either one alone. Thus, improvements in nitric oxide activity may represent a common mechanism of benefit for the 2 drug classes in hypertension, and help explain their apparently synergistic effects,according to Dr. Jamerson."Combining a CCB and an ACE inhibitor is probably a reasonable way to get BP down and provide some target-organ protection."

The ACCOMPLISH trial will randomize a planned 12 600 patients at approximately 650 multinational centers.The blood pressure target will be < 140/90 mm Hg and a more aggressive target of < 130/80 mm Hg for patients with  diabetes or renal disease (Table). "Hypertension trials started off trying to demonstrate whether controlling BP is important. In the next era, they tried to determine whether 1 drug class can be better than another," Dr. Jamerson said. "ACCOMPLISH is the first hypertension trial driven by clinical events that will start patients on a combination regimen and try to determine whether an ACE-CCB inhibitor strategy is better than an ACE-diuretic inhibitor strategy."