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Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: The first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension

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Reducing blood pressure (BP) to target levels is a major priority in preventing clinical events in hypertension. Typically this requires more than one drug, and recent guidelines on hypertension management therefore recommend starting with combination treatment in many patients. Diuretics have often been part of such therapy, usually paired with angiotensin converting enzyme (ACE) inhibitors or similar agents; but calcium channel blockers are also highly efficacious in reducing BP when combined with ACE inhibitors. In addition, these drug classes, separately and in combination, appear to have vasculoprotective properties. Because the primary goal of treating hypertension is to enhance survival and reduce cardiovascular outcomes, the Rationale and Design of Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial is designed as the first blinded and randomized study to prospectively compare the effects on these endpoints of two antihypertensive combinations, benazapril/hydrochlorothiazide (force titrated to 40/12.5 mg) and amlodipine besylate/benazapril (force titrated to 5/40 mg). The doses can be further titrated to 40/25 mg or 10/40 mg, and other classes of drugs can be added as needed for optimal BP control. The primary study endpoint is a composite of cardiovascular mortality and morbidity. The study will be performed in hypertensive patients (systolic BP ≥160 mm Hg or currently on antihypertensive therapy) with risk factors for cardiovascular events (prior events, target organ damage, kidney disease, or diabetes). A total of 6300 subjects will be randomized to each group with the expectation that a total of 1642 primary endpoints will occur during a 5-year period, providing 90% power to detect the 15% relative reduction in events (α = 0.05) hypothesized to favor the amlodipine besylate/benazapril group. The ACCOMPLISH study will be performed in the United States and Europe. The first patient was randomizedduring 2003, and the trial should conclude in 2008.

Section snippets

Considerations regarding BP

There is strong evidence for a relationship between BP and the probability of cardiovascular events.1, 2 Even differences in systolic BP as small as 2 mm Hg have meaningful effects on such outcomes as fatal strokes or coronary events.3 Recently cited data, however, indicate that only about one third of hypertensive individuals in the United States have their BP adequately controlled,4 despite evidence that aggressive BP treatment is associated with more effective prevention of major events.5, 6

Effects of different drug types

Early clinical trials showed that active antihypertensive therapy was superior to placebo in reducing major clinical events. In general, more recent studies have shown similar outcomes when differing drug classes, both older and newer, are compared with each other.7, 12, 13, 14, 15 Meta-analysis of the large trials in general has not demonstrated major overall differences among the antihypertensive drug classes in their outcomes effects,16 although there might be differences when individual

Experience with combinations

Few if any of the major hypertension trials have depended on a single drug. Rather, to achieve adequate BP control in the treatment groups, additional drugs generally have been used, making it difficult to determine whether the original drugs being tested, as opposed to the regimens built around them, were responsible for the clinical effects. The most common combinations tested have used diuretics. Diuretics work well in combination with such agents as angiotensin-converting enzyme (ACE)

First combination comparison

For these reasons, there is considerable interest in comparing the clinical endpoint effects of this ACE inhibitor/calcium channel blocker combination (benazapril/amlodipine) with an ACE inhibitor/diuretic combination. If the newer combination produces greater cardiovascular benefits, it would obviously become a powerful tool for improving clinical outcomes in patients with hypertension. This is the critical question that underlies the rationale and design of the Avoiding Cardiovascular events

Power of the study

Sample size is calculated with 90% power to detect a treatment difference of 15% risk reduction for the primary efficacy endpoint for the benazepril/amlodipine combination group compared with the benazepril/hydrochlorothiazide combination group at a two-sided overall significance level of 5%. An annual event rate of 3.5% for the primary efficacy endpoint is assumed for patients in the benazepril/hydrochlorothiazide combination group. Considerations for the performance of four equally spaced

Discussion

The ACCOMPLISH trial is unique in being the first clinical outcomes trial in hypertension to compare two established forms of fixed-dosed combination therapy. This study is particularly timely, as the most recent clinical guidelines by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),4 International Society on Hypertension in Blacks(ISHIB),10 and the European Society of Hypertension11 all now recommend starting treatment with drug

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