Chicago, IL - Interim data from a large-scale hypertension trial has provided a glimpse of what doctors believe might one day become routine clinical care [1]. Although outcome data are still years away, study investigators showed that a single-tablet dual-mechanism therapy initiated in high-risk hypertensive patients is highly effective in reducing blood pressure and significantly better in getting more patients to treatment goals.

Dr Kenneth Jamerson

"When practitioners prescribe medications, we have this old mantra, 'Start low, go slow,' " said lead investigator Dr Kenneth Jamerson (University of Michigan, Ann Arbor, MI). "We've decided that what might make more sense is aggressive therapy, initiated early on and quickly, and there might be better outcomes. The real paradigm shift is to use combination therapy right at the initiation of treatment to try to get better outcomes."

The 18-month blood-pressure results of the study, known as the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), were presented here today at the American Society of Hypertension 2007 Scientific Sessions. Although the full data from this major morbidity and mortality trial won't be known for a few more years, Jamerson said he believes a shift in how early and aggressively physicians treat hypertension is coming.

"Millions of Americans take antihypertensive medication and they don't achieve blood-pressure control," Jamerson told the media during a briefing. "We've found substantial evidence to broaden the use of combination therapy as an initial strategy for the treatment of hypertension."

ACE inhibitor plus calcium-channel blocker vs ACE inhibitor and diuretic

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, or 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 is the first trial to compare the effects of two forms of antihypertensive combination therapies on major fatal and nonfatal cardiovascular events. In total, 11 400 male and female subjects aged 55 years or older and with systolic blood pressure >160 mm Hg or currently on antihypertensive therapy and with 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 >2 hypertensive agents.

Despite being treated previously, 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 (JNC). As part of the study protocol, all patients stopped their medication and, without a washout period, were randomized to combination treatment with the ACE inhibitor benazepril plus hydrochlorothiazide (HCTZ) or the calcium-channel blocker amlodipine plus benazepril.

Presenting just the blood-pressure data, ACCOMPLISH investigators showed significant reductions in systolic blood pressure, a reduction seen across all patient populations, including African Americans. Patients with diabetes mellitus reduced their systolic blood pressure, as did those with chronic kidney disease, getting close to the JNC-7 recommended target of 130/80 mm Hg but just missing. At 18 months, 76% of patients had their blood pressure under control with the ACCOMPLISH combination regimens.

ACCOMPLISH: Reduction in systolic blood pressure in different populations

Patient population	Baseline systolic blood pressure (mm Hg)	Systolic blood pressure at 18 mo (mm Hg)	p
All (n=11 400)	145.4	131.8	<0.05
Nordic (n=3333)	152.6	136.8	<0.05
American (n=8067)	142.4	129.4	<0.05
African American (n=1361)	145.1	133.6	<0.05
Diabetes mellitus* (n=6921)	145.2	131.5	<0.05
Chronic kidney disease* (n=680)	148.7	136.2	<0.05

"If the only goal is get the blood pressure down, and that's a really good goal, then these data would suggest that you would be twice as likely to get the blood pressure to target if you utilized this strategy," said Jamerson. "There are millions of patients taking pills and they're not quite at goal. This would help with physician inertia, and if you think about it, for patients who take two or three different pills, if you reduce that to one tablet they just feel better."

What about the risk of hypotension?

Dr Franz Messerli (St Luke's Hospital, New York, NY), who was not affiliated with the ACCOMPLISH study, told heartwire that the blood-pressure control achieved in the trial is impressive and that clinicians have learned, since the publication of the VALUE trial, that the speed in which blood pressure is controlled is of importance.

Messerli expressed some caution, however, saying he was concerned about moving too fast with some patients, especially the elderly and those with frail cardiovascular systems. The combination therapy, he added, could expose some patients needlessly to drugs they might not need. "Start low and go slow," he said. "I have no problem doing that in the elderly patient."

At 18 months in ACCOMPLISH, the rate of hypotension observed was 1.8%, a figure investigators believe is small in light of the cardiovascular benefits of reducing blood pressure aggressively. "I think that for the potential benefit, if you're talking about a 2-mm-Hg reduction giving you a 10% reduction in the risk of stroke," Jamerson told heartwire, "this is probably a very acceptable price to pay."

Messerli, on the other hand, is not entirely convinced, pointing out that at the population level, hypotension translates into thousands of falls and fractures, especially dangerous hip fractures in the elderly. Jamerson said the investigators intend to sort through the data to determine the exact number of medication-related hypotensive events, although he still believes this risk is small.

Dr Suzanne Oparil (University of Alabama, Birmingham) told heartwire that while the morbidity and mortality data still need to come, she believes combination therapy is the wave of the future. The caveat, however, is that many of these early trials eliminate sick and fragile patients, the type many doctors see in practice.

"We don't have all the evidence yet, but all the pressures are going to lower levels. People are talking about 130 mm Hg for sure, and some are talking about 120 mm Hg," said Oparil. "If going to lower levels proves to be true regarding end point data, there are very few monotherapies that are going to be able to get you to that level. Also, people are older, fatter, and on so many drugs, there is a convenience factor."