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The ACCOMPLISH study

Introduction
Hypertension affects approximately 72 million Americans and is one of the most significant risk factors for cardiovascular (CV) disease.¹ The prevalence of hypertension increases with age and is common in patients greater than 55 years of age.^1,2 The risk of myocardial infarction (MI), heart failure (HF), stroke, and kidney disease is greater when blood pressure (BP) is not controlled. The overall goal of therapy is to reduce the risk of morbidity and mortality associated with CV disease and renal dysfunction. A surrogate goal of therapy is to treat patients to achieve a target BP; however, achieving such a number is not a guarantee that organ damage will not occur.^1,3 Current guidelines recommend that achieving a target BP of <140/90 mm Hg is associated with a reduction of CV events.² This goal is lower (<130/80 mm Hg) for hypertensive patients with diabetes or renal disease. The results of the ALLHAT trial showed that thiazide-type diuretics were superior in preventing at least 1 or more CV event(s) when compared to amlodipine, a calcium channel blocker (CCB), or lisinopril, an angiotensin converting enzyme inhibitor (ACE-I).⁴ As a result of this study, practice guidelines recommend that thiazide-type diuretics should be first-line therapy, either alone or in combination with an ACE-I, CCB, or a beta-blocker (BB), for most patients.² This excludes high-risk patients with compelling indications that require certain antihypertensive agents (i.e. BB for post-MI). The majority of patients with hypertension require 2 or more agents to meet their BP goals. Optimal combination therapy has not been established, which is the premise for the following study.

ACCOMPLISH
The Avoiding Cardiovascular Events through COMbination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was a randomized, double-blind multicenter study designed to determine whether high-dose fixed combination of benazepril-amlodipine would be more effective than benazepril-hydrochlorothiazide in reducing CV morbidity and mortality.^3,5 Over 11,500 patients were randomized to receive either benazepril-amlodipine (n=5744) or benazepril-hydrochlorothiazide (n=5762).⁵ The study population consisted of high risk hypertensive men and women ≥55 years of age with a systolic BP ≥160 mm Hg or currently receiving antihypertensive therapy. Patients had to have signs of CV disease or target organ damage such as: prior MI; hospitalization for unstable angina; coronary revascularization; history of stroke; peripheral arterial occlusive disease; diabetes; left ventricular hypertrophy; or evidence of renal dysfunction (increased serum creatinine levels and/or microalbuminuria).³ The primary outcome measure was the time to first event of composite CV morbidity and mortality. Secondary and additional outcome and measures were the composite CV morbidity, new onset diabetes, evidence of renal dysfunction, progression of renal dysfunction, and hospitalization for HF.

Patients started once daily treatment with either 20 mg benazepril-5 mg amlodipine or 20 mg benazepril-12.5 mg hydrochlorothiazide.⁵ One month after initiation, benazepril was increased to 40 mg and if necessary, the doses of amlodipine and hydrochlorothiazide could be increased to 10 mg and 25 mg, respectively. Other antihypertensive agents excluding CCB, ACE-I, angiotensin-II receptor blockers, and thiazide diuretics, were permitted to achieve a target BP of <140/90 mm Hg or <130/80 for patients with diabetes or kidney disease.

Efficacy results were based on an intention-to-treat analysis.⁵ After a mean of 30 months, the trial was terminated after the first interim analysis due to the benefits of benazepril-amlodipine. The primary outcome event occurred in 552 patients (9.6%) in the benazepril-amlodipine group compared with 679 patients (11.8%) in the benazepril-hydrochlorothiazide group (relative risk reduction [RRR]=19.6%, hazard ratio [HR]=0.80; p<0.001). For the secondary endpoints of death from CV causes, nonfatal MI, and nonfatal stroke, 288 events (5%) occurred in the benazepril-amlodipine group compared with 364 events (6.3%) in the benazepril-hydrochlorothiazide group (RRR=21.2%, HR=0.79; p=0.002). The composite of CV events was 494 events (8.6%) in the benazepril-amlodipine group compared with 592 events (10.3%) in the benazepril-hydrochlorothiazide group (RRR=17.4%, HR=0.83; p=0.002).

Mean BP was 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group.⁵ The mean difference in BP between the 2 groups was 0.9 mm Hg systolic and 1.1 mm Hg diastolic (p<0.001 for both comparisons). The treatment regimens were well tolerated with similar discontinuation rates. Dizziness was the main side effect for both treatments; patients in the benazepril-amlodipine group experienced more peripheral edema.

The authors concluded that combination treatment with benazepril-amlodipine is superior to treatment with benazepril-hydrochlorothiazide in achieving BP control, as well as reducing the risk of CV morbidity and mortality in high-risk patients with hypertension.

Editorial comments
In an editorial published in the New England Journal of Medicine, Dr. Chobanian from the Boston University School of Medicine cites that most comparisons of antihypertensive agents have failed to show significant differences in the primary outcome provided equivalent BP targets are achieved.⁶ ACCOMPLISH is the first trial to compare combination treatment with an ACE-I plus CCB versus an ACE-I plus thiazide diuretic.⁵ Although ALLHAT compared chlorthalidone, amlodipine, and lisinopril, these were not used in combination.⁴ It is difficult to compare the effect of the thiazide-type diuretics between these 2 studies since equivalent doses were not used.⁶ Chlorthalidone is twice as potent as hydrochlorothiazide and has a longer duration of action. Therefore, it is possible that 24-hour BP control was better maintained with the combination of benazepril-amlodipine compared to benazepril-hydrochlorothiazide.

Dr. Chobanian also mentions that ACE-Is and CCBs can have vasoprotective effects.⁶ Studies in animals with hypercholesterolemia have shown that these agents inhibit atherosclerosis and improve endothelium-dependent vasodilatation in isolated arteries in patients with vascular disease. The clinical relevance of these findings is unclear; however, diuretics do not share these properties.

The seventh report of the Joint Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends thiazides as first-line therapy in patients without compelling indications for other antihypertensive agents.² The author suggests that the results of the ACCOMPLISH trial may now offer practitioners additional options when choosing initial therapy; however, these results should not diminish the efficacy of an ACE-I and thiazide diuretic.⁶

Conclusion
The ACCOMPLISH trial is the first study to compare combination treatment with an ACE-I and CCB to an ACE-I and thiazide diuretic. Previous studies have not demonstrated superiority of one class of antihypertensives over another in the population included in this study. The JNC 7 guidelines remain the standard for the treatment of high BP. The impact of the ACCOMPLISH study for the treatment of hypertension in high-risk individuals remains to be seen. Until then, patients should be treated with the best combination regimen to achieve target BP goals, and an ACE-I plus a CCB is a viable option for combination therapy.

References