ACCOMPLISH, a major morbidity and mortality trial, compared the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events. It was stopped early because treatment with antihypertensive combination therapy—the ACE inhibitor benazepril plus the calcium-channel blocker amlodipine—was more effective than treatment with the ACE inhibitor plus diuretic.

Lead investigator Dr Kenneth Jamerson (University of Michigan, Ann Arbor), who presented the results of the study during the late-breaking clinical-trials session, said he was "absolutely thrilled" to present the findings of a study designed to challenge current guidelines in defining the optimal strategy for blood-pressure control and preventing cardiovascular events in high-risk patients.

"If you use the combination of a calcium-channel blocker with an ACE inhibitor, you get exquisite blood-pressure control," said Jamerson, who added that similar control was observed with the ACE inhibitor and diuretic. Despite the similar blood pressure, the combination with the calcium-channel blocker and ACE inhibitor reduced cardiovascular morbidity and mortality 20%.

During a press conference announcing the results, Jamerson told the media that the findings are "paradigm-shifting" and the data are a clear win with a clear message. He said the ACCOMPLISH findings challenge the guidelines, especially in terms of starting with a one-drug strategy and the use of diuretics in combination with ACE inhibitors.

Current recommendations for the treatment of stage 1 hypertension include the use of thiazide-type diuretics for most patients, with additional consideration given to ACE inhibitors, angiotensin-receptor blockers (ARBs), beta blockers, and calcium-channel blockers. In patients with stage 2 hypertension—those with blood pressure >160/>100 mm Hg—two-drug combination therapy, usually with a diuretic and ACE inhibitor, is recommended.

ACCOMPLISH compared the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events. In total, 11 400 men and women aged 55 years or older who had systolic blood pressure >160 mm Hg or were currently on antihypertensive therapy and who had evidence of cardiovascular or renal disease or target-organ damage were included in the trial. Patients enrolled in the trial were obese, with 60% having diabetes mellitus, and nearly all had been treated previously for hypertension.

More than 70% had been treated with two or more hypertensive agents, but, as was previously reported by heartwire at the American Society of Hypertension 2007 Scientific Sessions, just 37.5% of patients had their blood pressure controlled to <140/90 mm Hg at baseline, the currently recommended target of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. As part of the study protocol, all patients stopped their medication and, without a washout period, were randomized to combination treatment with benazepril plus hydrochlorothiazide or amlodipine plus benazepril.

At 36 months, blood-pressure levels were significantly improved, with more than 75% of patients in both treatment arms having blood-pressure levels <140/90 mm Hg. Investigators report that combination treatment with benazepril plus amlodipine reduced cardiovascular morbidity and mortality, defined as cardiovascular death, fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for unstable angina, and coronary revascularization, by 20%, compared with those treated with benazepril plus a diuretic.

Speaking with the media, Jamerson noted that the average patient in the study was 68 years old, and the oldest patient was 98 years old. Although hypotension might be a concern and can result in falls and fractures in elderly patients or in the frail, this was not borne out in the ACCOMPLISH study.

Dr Michael Weber (SUNY Downstate Medical Center, Brooklyn, NY), who was on the executive committee of the ACCOMPLISH trial, agreed with Jamerson, telling heartwire that the findings will change the guidelines.

"Right now, there is a recommendation that when you're putting together combination treatment for hypertension you need to normally include a diuretic as one of the two agents," said Weber. "I'm sure that recommendation will change. It might not change to the point of stating that a calcium-channel blocker like amlodipine be the preferred partner, but it will take away the recommendation for diuretics, and adding the calcium-channel blocker will invariably be a part of that."

Commenting on the results of ACCOMPLISH for heartwire, Dr William Cushman (University of Tennessee Health Science Center, Memphis), who was a member of the study's executive committee, said he does not believe the results negate the diuretic benefits observed in ALLHAT. While the trial was well conducted, the dose of diuretic used in ACCOMPLISH makes it less definitive. No placebo-controlled or usual-care outcome study has used a dose this low, he said, noting that other trials used between 25 mg and 50 mg. While ALLHAT used the 12.5- to 25-mg doses, the same dose used in ACCOMPLISH, chlorthalidone is at least twice as potent at lowering blood pressure and reducing events, said Cushman.

"That being said, ACCOMPLISH has a definitive result and clearly tells us that the very low doses of [hydrochlorothiazide] HCTZ commonly used in practice and in many newer combination products are not as effective in lowering CVD events compared with amlodipine 5 to 10 mg when each is combined with benazepril," said Cushman. "I have been consistent for many years, including long before ACCOMPLISH was started, in saying these doses of HCTZ may not give the benefits on outcomes that we have seen in trials, since they were never tested. We assume other drugs are less effective when used at one-quarter or one-half the doses that were used in trials—why not diuretics?"

Dr Salim Yusuf (McMaster University, Hamilton, ON) said the study "looks good" but held back full praise until the complete findings are published. He agreed, though, that, based on the presented data, the ACCOMPLISH study will challenge current guidelines.