Drug Tx for Prehypertension Deemed Feasible : Researchers warn more data are needed before drugs oust lifestyle modification as a first-line treatment.


ATLANTA — A first baby step toward drug therapy for prehypertension was taken with the presentation of the Trial of Preventing Hypertension results at the annual meeting of the American College of Cardiology.

TROPHY, a 4-year, 772-patient trial, showed that 2 years of treatment with the angiotensin II receptor blocker candesartan delayed the otherwise nearly inexorable transition from prehypertension to stage 1 hypertension.

But both the TROPHY investigators and other observers were quick to emphasize that key questions remain to be answered by future studies before a policy shift from lifestyle modification to medication as first-line therapy can be seriously considered.

Indeed, Dr. Stevo Julius, chair of the TROPHY executive committee, said the investigators were unwilling to make any major treatment recommendations based on this one study. Their sole strong new recommendation based on TROPHY, he added, is that prehypertensive patients deserve closer follow-up than what is now the norm. That's because nearly two-thirds of those on placebo converted to stage 1 hypertension in 4 years.

“Since there was a very high rate of transition, we are rather confident in recommending that once you have diagnosed prehypertension, these patients should be followed more frequently than they are followed now in order to then detect the development of stage 1 hypertension—and we think that follow-up at 3-month intervals is reasonable,” said Dr. Julius, professor emeritus of medicine and physiology at the University of Michigan, Ann Arbor.

TROPHY participants had to have baseline prehypertension as defined by repeated automated blood pressure readings of either 130–139 mm Hg systolic and 89 mm Hg or lower diastolic, or a systolic pressure of 139 mm Hg or lower plus a diastolic value of 85–89 mm Hg. Their mean age was 48 years. While that's far younger than the patients in other hypertension trials, Dr. Julius expressed regret they weren't even younger, since that might have enabled TROPHY to show whether a brief drug intervention, given early enough, could permanently arrest the hypertensive process.

TROPHY participants were randomized to 2 years of double-blind candesartan (Atacand) at 16 mg once daily or placebo, followed by 2 years in which all participants received placebo.

The primary end point was development of clinical hypertension. At the 2-year mark, it had developed in 14% of the candesartan group and 40% of the patients on placebo, for a 66% relative risk reduction. Blood pressure began to climb soon after drug therapy stopped, and at 4 years, stage 1 hypertension was present in 53% of the candesartan arm and 63% of the placebo arm, for a still significant 16% relative reduction. Drug side effects were mild and similar to those seen with placebo.

It has been estimated that up to 70 million Americans have prehypertension as defined by blood pressures of 120–139 mm Hg systolic or 80–89 mm Hg diastolic. So why consider redefining this group as having a condition warranting drug therapy? Because prehypertension (previously called transient hypertension, borderline hypertension, and high-normal blood pressure) is an established precursor of clinical hypertension and is associated with increased cardiovascular morbidity and mortality.

Furthermore, hypertension is a self-accelerating condition, and animal studies have suggested a relatively brief period of drug therapy during the prehypertensive phase might favorably alter the natural history by reversing the arteriolar hypertrophy and endothelial dysfunction that define prehypertension—thereby not just delaying but preventing clinical hypertension. And last, because guideline-recommended lifestyle modifications have failed badly.

“It is important to acknowledge that although nonpharmacologic therapy has been recommended first as a population strategy, it hasn't worked,” Dr. Julius said. “Body weight is increasing in the population; diabetes is increasing. The time has come to look at this problem in a different way with some large-scale research.”

He said the best-ever performance of lifestyle modification, seen in the Trials of Hypertension Prevention, showed an absolute 8% reduction in new-onset hypertension over 2 years (Arch. Intern. Med. 1997;157:657–67), versus 27% with candesartan in TROPHY.

During the discussion, Dr. William J. Elliott expressed concern that the slope of the curve of new-onset hypertension in the candesartan arm during years 2–4 appeared to be the same as in years 0–2 in the placebo arm. This suggests, disappointingly, that drug therapy didn't halt the hypertensive express train and prehypertensive individuals might need to take drugs for their entire lives to benefit.

He added that lowering the traditional threshold for drug therapy from 140/90 mm Hg to encompass some portion of the 70 million Americans with prehypertension could be a health care budget buster.

“I quake in my boots to think that the economy is strong enough to pay for that and all the other things [President Bush] has proposed,” said Dr. Elliott, professor of preventive medicine, internal medicine, and pharmacology at Rush Medical College, Chicago. TROPHY was funded by AstraZeneca, from which Dr. Julius receives grant support.

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