A long-awaited study designed to help American doctors decide how to treat high blood pressure has found that the cheapest category of drug -- diuretics -- works the best and should be the first choice.
While the differences in treatment results between diuretic drugs and the alternatives were not dramatic, the findings could have major effects on the cost of treating hypertension, which affects about 50 million Americans. Diuretics, which help the body get rid of water and sodium, cost about 10 cents a day. The alternatives cost about 10 times as much, but millions of dollars in pharmaceutical marketing have helped make them dominant.
In the study, people who took diuretics had slightly fewer episodes of congestive heart failure, heart attacks and strokes than those taking either of two other types of blood pressure medicines -- calcium channel blockers and ACE inhibitors. Over five years, there was no difference in mortality among the users of each medicine.
Diuretics were among the first blood pressure medicines widely prescribed in this country, arriving on the market in the 1950s. In the past two decades, their popularity steadily declined as a half-dozen newer classes of drugs were introduced. In 1982, diuretics accounted for 56 percent of antihypertensive prescriptions. In 1993, they had dropped to 27 percent, and have fallen further since.
"As of now, we are spending on ACE inhibitors and calcium channel blockers about $10 billion a year," said Curt D. Furberg, a physician at Wake Forest University in North Carolina who helped lead the study, at a news conference yesterday. "The issue is what we got for that cost. Now we know there is no added value."
The principal investigator of the study, Barry R. Davis of the University of Texas School of Public Health, minced no words in describing the message for physicians.
"What we hope will happen is that diuretics should be the first choice for initial treatment. For those already on an antihypertensive, physicians should seriously consider switching to a diuretic," he said.
The study, published in today's Journal of the American Medical Association, marks a huge government investment in trying to address an increasingly common problem for doctors: deciding which drug to choose from a marketplace crowded with competing advertising claims, patient demands and huge differences in cost.
The Food and Drug Administration decides whether to approve a drug based on studies showing only whether it is safe and does what it is intended to, such as lower blood pressure. The agency generally does not require that a new drug be compared head-to-head with others to determine which ones work best. Pharmaceutical companies generally eschew such studies as well, preferring to market one product as better than another on other grounds.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), started in 1994, was conducted at 623 hospitals and clinics at a cost of about $120 million. With about 42,000 volunteers, it was the largest clinical study of blood pressure treatment ever conducted in the United States. To make its results as widely applicable as possible, it included a higher proportion of women (47 percent), blacks (35 percent) and Hispanics (19 percent) than nearly every previous study.
The diuretic tested was chlorthalidone. The calcium channel blocker was amlodipine, sold by Pfizer under the trade name Norvasc. With $1.6 billion in sales in the United States last year, it was the country's biggest selling blood pressure medicine. (Worldwide sales were $3.5 billion.) The ACE inhibitor was lisinopril, sold by Merck as Prinivil and by AstraZeneca as Zestril.
Beta blockers, another common and frequently prescribed class of hypertensive drugs, were not studied in the trial.
ACE inhibitors were the fourth most frequently prescribed class of drugs last year in the United States, and calcium channel blockers were the sixth, according to IMS Health, a firm that tracks pharmaceutical sales. Diuretics were not in the top 10.
People in the study, whose average age was 67, were randomly assigned to take one of the three drugs. If their blood pressure was not controlled with it, doctors could add a second medicine from categories not included in the study. By the end, about 40 percent in each group was on a second medicine.
Compared with people on the diuretic, those on the calcium channel blocker amlodipine had slightly higher rates of congestive heart failure. Those on the ACE inhibitor had slightly higher rates of stroke, angina and heart procedures.
Michael Berelowitz, vice president for cardiovascular and metabolic drugs at Pfizer, said that the company markets Norvasc as effective in lowering blood pressure and as safe in many types of patients and "that there is little that ALLHAT tells us that doesn't support that."
An allied study, which enrolled about 10,000 ALLHAT participants with mildly elevated cholesterol, found that the cholesterol-lowering drug pravastatin did not do significantly better in reducing mortality or heart attack rates than a program of "usual care." Volunteers were randomly assigned to get either the drug or usual care, which consisted of dietary advice and whatever other treatment their physicians advised, over five years.
The researchers attributed the unexpected result to the fact that cholesterol levels fell significantly in both groups -- about 17 percent in those assigned to pravastatin, and about 8 percent in those getting usual care.
By the end of the study, it turned out, nearly one-quarter of the usual care patients had been prescribed a "statin," a class of cholesterol-lowering drugs that includes pravastatin, making the two groups much more similar to each other than originally anticipated.
The researchers said the results should not dissuade physicians from prescribing statins to people with slightly elevated cholesterol who have other risk factors for heart disease.