Ann Arbor, MI - The Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a large morbidity and mortality study comparing the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events, is now published in the December 4, 2008 issue of the New England Journal of Medicine [1].

The trial 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 and diuretic. First presented at the American College of Cardiology 2008 Scientific Sessions in Chicago, IL and reported by heartwire at that time, the results showed that the single-tablet benazepril/amlodipine combination reduced the risk of morbidity and mortality by 20% compared with conventional therapy.

"We have guidelines stating a preference for diuretics as monotherapy or to use diuretics and an ACE inhibitor in combination therapy," lead investigator Dr Kenneth Jamerson (University of Michigan, Ann Arbor) told heartwire. "We now have data that suggest that combination therapy is probably a good initial strategy for high-risk patients, rather than starting with one drug and going slow. Putting patients on either combination doubled their control rate, so combination therapy is something clinicians need to think about, even if they want to keep the diuretic. But the drug that gives superior cardiovascular outcomes is the calcium-channel blocker and ACE inhibitor."

Commenting on the results, Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York), who was not part of the study, said ACCOMPLISH should change the way clinicians treat patients with hypertension.

"This landmark study unequivocally relegates hydrochlorothiazide from first-line to third-line therapy at least in a patient population with similar demographic and clinical features as in ACCOMPLISH," said Messerli. "The issue is not to be taken lightly, since hydrochlorothiazide remains one of the most commonly prescribed antihypertensive drugs. Every year more than 100 million prescriptions of hydrochlorothiazide are written in the US. Almost half of those prescriptions are written for hydrochlorothiazide alone, and the remainder for fixed combinations, mostly with either ACE inhibitors or angiotensin receptor blockers."

ACCOMPLISH compared the effects of the two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events in 11 506 men and women aged 55 years or older who had systolic blood pressure >160 mm Hg. All patients were currently on antihypertensive therapy and had evidence of cardiovascular or renal disease or target-organ damage. Patients enrolled in the trial were obese, with 60% having diabetes mellitus, and nearly all had been treated previously for hypertension.

Despite being treated previously—more than 70% of patients in the trial were currently taking two or more hypertensive agents—just 37.3% 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 (JNC-7). 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.

The study was terminated after a mean follow-up of 36 months. Jamerson noted that patients in both treatment arms received excellent blood-pressure control, with blood pressures of 132/73 mm Hg in the benazepril/amlodipine arm and 133/74 mm Hg in the benazepril/ hydrochlorothiazide arm.

Regarding the primary end point, a composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization, 9.6% of patients in the benazepril/amlodipine arm had an event compared with 11.8% in the benazepril/ hydrochlorothiazide arm. This absolute 2.2% benefit translated into a 20% relative reduction in risk.

In an editorial accompanying the published study [2], Dr Aram Chobanian (Boston University School of Medicine, MA), who served as chair for the JNC-7 hypertension guidelines, agrees that a recommendation of thiazide-type diuretics as initial therapy for most patients with hypertension needs to be reexamined.

"The results from the many recent studies, including the ACCOMPLISH trial, when considered together, suggest that greater flexibility is now indicated in the choice of the initial drug," writes Chobanian. The drug of choice depends on criteria such as compelling indications or contraindications, as well as coexisting conditions, adverse effects, race, and the clinician's experience, he said.

This increased flexibility, however, "should not negate the importance of diuretics," a cornerstone of antihypertensive therapy for 50 years, stressed Chobanian. In addition, the findings "should not diminish the value of treatment with the combination an ACE inhibitor and a diuretic," an effective combination for lowering blood pressure, as observed in ACCOMPLISH, "that was recently shown to produce major reductions in mortality and morbidity in the very old," noted Chobanian.

In his editorial, Chobanian, like others before him, pointed out that the diuretic used in ACCOMPLISH differed from the diuretic used in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Chlorthalidone, the ALLHAT diuretic, is estimated to be twice as potent as hydrochlorothiazide and to have a longer duration of effect in the 12.5- to 25-mg dose range.

Countering these criticisms, Jamerson said that 90% of clinicians in the US use hydrochlorothiazide, and most of these are using it at doses ranging from 12.5 mg to 25 mg, the dose used in ACCOMPLISH.

"Our message is really simple," said Jamerson. "For the thiazide that most people are using, even if they were able to get the blood pressure down to 130 mm Hg, which most clinicians in the US are not doing, the ACE inhibitor/calcium-channel-blocker combination would still give you better cardiovascular outcomes. For a lot of people, if you're using a combination, this ought to be a strategy to consider."

With doctors using hydrochlorothiazide for hypertension for half a century, Messerli told heartwire that ACCOMPLISH indicates that it is time to turn the page.