Avoiding Cardiovascular Events Through COMbination Therapy in Patients LIving With Systolic Hypertension - ACCOMPLISH

Dec 03, 2008
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Trial Sponsor:
Novartis
Date Presented:
01/01/2008
Date Published:
01/01/2008
Date Updated:
12/03/2008
Original Posted Date:
12/03/2008
References

Description:

The goal of this trial was to evaluate the safety and efficacy of the combination of amlodipine/benazepril, compared with hydrochlorothiazide (HCTZ)/benazepril in reducing cardiovascular morbidity and mortality in high-risk patients with systolic hypertension.

Hypothesis:

The fixed dose combination of amlodipine/benazepril would be superior to HCTZ/benazepril in reducing cardiovascular mortality and morbidity in high-risk patients with hypertension.

Study Design

Study Design:

Patients Screened: 13,782
Patients Enrolled: 11,506
Mean Follow Up: 36 months
Mean Patient Age: 68.4 years
Female: 40

Patient Populations:

  • Systolic blood pressure ≥160 mm Hg or currently on antihypertensive therapy
  • Age: ≥60 years (one or more risk factor), ≥55 years (two or more risk factors)
  • Cardiovascular (prior MI, revascularization, unstable angina) or renal disease (serum creatinine >1.5 mg/dl for women, >1.7 mg/dl for men, or macroalbuminuria), diabetes, peripheral arterial disease, stroke, left ventricular hypertrophy, or target organ damage

Exclusions:

  • Angina within 3 months
  • History of symptomatic CHF or EF <40%
  • MI, other acute coronary syndromes, or coronary revascularization within 1 month
  • Stroke or other ischemic cerebrovascular accident within 3 months
  • Severe hypertension, known to be refractory or secondary in nature

Primary Endpoints:

Cardiovascular mortality or cardiovascular event (stroke, nonfatal MI, coronary revascularization, unstable angina, and resuscitation from death)

Secondary Endpoints:

  • Cardiovascular event
  • All-cause mortality
  • Hospitalization for heart failure
  • Death from cardiovascular causes, nonfatal stroke, and nonfatal MI

Drug/Procedures Used:

After a screening phase, patients with hypertension were randomized to either fixed dose combination of amlodipine 5 mg/benazepril 20 mg or HCTZ 12.5 mg/benazepril 20 mg. After 1 month, benazepril was titrated to 40 mg in both arms. Thereafter, HCTZ was titrated to 25 mg daily, and amlodipine was titrated to 10 mg daily, as tolerated.

After 3 months, other antihypertensive agents could be added on as needed to achieve a blood pressure target of <140/90 mm Hg, or <130/80 mm Hg in patients with diabetes or renal insufficiency.

Concomitant Medications:

Lipid-lowering therapy (68%), beta-blockers (47%), and antiplatelet therapy (64%)

Principal Findings:

A total of 11,506 patients were randomized, 5,744 to the amlodipine/benazepril arm, and 5,762 to the HCTZ/benazepril arm. About 50% were obese, 60% had diabetes, 23% had a history of myocardial infarction (MI), 6% had renal disease, and about 36% had undergone prior revascularization. About 97% were previously being treated for hypertension. Only 37.3% had adequately controlled hypertension (blood pressure <140/90 mm Hg). The prespecified efficacy boundary was crossed with 60% of the expected trial information; therefore, the trial was terminated early.

Systolic and diastolic blood pressure were significantly reduced by amlodipine/benazepril, compared with HCTZ/benazepril by 0.9/1.1 mm Hg over 5 years of follow-up (p < 0.001). Target blood pressure was achieved in 72.4% of patients in the HCTZ/benazepril arm, and 75.4% of patients in the amlodipine/benazepril arm. A total of 16.2% of patients in the HCTZ/benazepril arm compared with 15.0% in the amlodipine/benazepril arm were on two or more add-on medications, although about 50% of patients were on one pill only.

There was a 20% reduction in the primary endpoint of cardiovascular mortality, stroke, MI, coronary revascularization, unstable angina, and resuscitation from death in the amlodipine/benazepril arm (9.6%) compared with the HCTZ/benazepril arm (11.8%) (p < 0.001). Cardiovascular death, stroke, and MI were also reduced by 21% (p = 0.002). Fatal and nonfatal MI were significantly reduced in the amlodipine/benazepril arm (2.2%) compared with the HCTZ/benazepril arm (2.8%) (p = 0.04). Other endpoints, including cardiovascular mortality, stroke, and resuscitated sudden death were similar between the two groups. On further analysis, the combination of amlodipine and benazepril was superior to the combination of HCTZ and benazepril for older patients, men and women, and presence or absence of diabetes.

The incidence of adverse effects, including dizziness, cough, angioedema, and hypotension, was similar between the two groups; peripheral edema was noted more commonly in the amlodipine/benazepril group (31.2% vs. 13.4%).

Interpretation:

The results of this large, randomized trial indicate that a single combination therapy of amlodipine/benazepril is superior to HCTZ/benazepril in the reduction in blood pressure as well as cardiovascular endpoints in patients with high-risk hypertension. These findings are very important, and are contrary to those of the ALLHAT trial, which found no difference in outcomes between amlodipine and chlorthalidone (also a diuretic).

The current study may require a revision of current guidelines, including Joint National Committee-7, which recommend an initial diuretic-based approach to the treatment of hypertension. Cost considerations will also be important.

References:

Jamerson K, Weber MA, Bakris GL, et al., on behalf of the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-28.

Avoiding Cardiovascular Events Through COMbination Therapy in Patients LIving with Systolic Hypertension, the Early Termination of the ACCOMPLISH Trial for Efficacy. Presented by Dr. Kenneth Jamerson at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Keywords: Hypertrophy, Left Ventricular, Hypotension, Death, Sudden, Blood Pressure, Peripheral Arterial Disease, Edema, Creatinine, Benzazepines, Calcium Channel Blockers, Dizziness, Hydrochlorothiazide, Cough, Hypertension, Myocardial Infarction, Stroke, Resuscitation, Chlorthalidone, Diuretics, Systole, Renal Insufficiency, Amlodipine, Diabetes Mellitus


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