NHLBI Study Finds Traditional Diuretics Better Than Newer Medicines for Treating Hypertension
Less costly, traditional diuretics work better than newer medicines to treat high blood pressure and prevent some forms of heart disease, according to results from the largest hypertension clinical trial ever conducted. The long-term, multi-center trial, which was supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, compared the drugs for use in starting treatment for high blood pressure.
The trial also included a cholesterol-lowering study that compared the effects of a statin drug with "usual care." Both groups had a substantial decrease in cholesterol levels. The difference in cholesterol levels between the groups was too small to show a difference in death rates and produced only a small, non-significant decrease in the rates of heart attacks and strokes in the statin group.
Findings of the "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial," or ALLHAT, appear in two articles in the December 18, 2002, issue of The Journal of the American Medical Association.
"ALLHAT shows that diuretics are the best choice to treat hypertension and reduce the risk of its complications, both medically and economically," said NHLBI Director Dr. Claude Lenfant.
"Many of the newer drugs were approved because they reduce blood pressure and the risk of heart disease compared with a placebo," he continued. "But they were not tested against each other. Yet, these more costly medications were often promoted as having advantages over older drugs, which contributed to the rapid escalation of their use. Now, at last, we can make those needed comparisons and know which blood pressure drug to choose to begin therapy."
According to the ALLHAT high blood pressure article, diuretic use fell from 56 percent of antihypertensive prescriptions in 1982 to 27 percent in 1992. The article notes that, had the pattern not changed, antihypertensive prescriptions for that period would have cost about $3.1 billion less.
About 24 million Americans take drugs to lower high blood pressure, at an estimated annual cost of about $15.5 billion, the article states.
"ALLHAT was conducted in a variety of practice settings and included many primary care clinics," said Dr. Barry Davis, Director of the ALLHAT Clinical Trials Center and Professor of Biometry at the University of Texas-Houston Health Science Center. "It also included high proportions of women, seniors, minorities, and those with type 2 diabetes. Thus, the high blood pressure results add crucial information about how well such patients do on the different drugs."
High blood pressure affects about 50 million Americans, or one in four adults, and its prevalence increases with age — more than half of those over age 60 have hypertension. High blood pressure is a risk factor for heart attack and the chief risk factor for heart failure and stroke.
About 65 million American adults have high blood cholesterol levels that require medical attention. High blood cholesterol is a major cause of coronary heart disease, the main form of heart disease.
Treatment of patients with hypertension and/or high cholesterol involves lifestyle changes, including becoming physically active, losing weight, if overweight, following a low-saturated fat, low-cholesterol eating plan, limiting dietary salt, and not smoking. If these changes alone can not lower elevated blood pressure or cholesterol enough, then drug therapy is added to the treatment.
ALLHAT, which began in 1994, consisted of two trials: One compared a diuretic with newer antihypertensive drugs to start blood pressure-lowering treatment; the other compared a statin drug to usual care.
All participants underwent medical checkups at 3, 6, 9, and 12 months after entry into the study and every 4 months after that.
The ALLHAT blood pressure study was a randomized, double-blind trial. It involved 42,418 participants aged 55 and older, and was conducted at 623 clinics and centers across the United States and in Canada, Puerto Rico, and the U.S. Virgin Islands. About 7,000 US veterans participated in the study through 69 Department of Veterans Affairs clinics.
Participants had hypertension (140/90 mm Hg or higher) and at least one other of the risk factors for heart disease, which include cigarette smoking and type 2 diabetes.
About 47 percent of the participants were women, 47 percent non-Hispanic white, 32 percent were black, 16 percent were Hispanic, and 36 percent had type 2 diabetes. Participants were followed on average for 4.9 years.
Participants were randomly assigned to receive one of four drugs–a diuretic (chlorthalidone); a calcium channel blocker (amlodipine); an angiotensin converting enzyme (ACE) inhibitor (lisinopril); and an alpha-adrenergic blocker (doxazosin). They received additional antihypertensive drugs if their doctor thought it necessary to control their blood pressure.
The alpha-adrenergic blocker arm of the study was stopped in March 2000 because those on the drug had 25 percent more cardiovascular events and were twice as likely to be hospitalized for heart failure as users of the diuretic.
All three classes of drugs reported on in the December 18 issue of JAMA — diuretics, calcium channel blockers, and ACE inhibitors — have been previously shown to lower blood pressure and reduce cardiovascular complications. In head-to-head comparisons, the diuretics were shown to be superior in treating high blood pressure and preventing cardiovascular events.
As reported in JAMA, after about 5 years of followup, compared to participants who were taking the diuretic, those on the calcium channel blocker had —
Compared to participants who were taking the diuretic, those on the ACE inhibitor had —
"The take-home message is that doctors should begin drug treatment for high blood pressure with a diuretic," said Dr. Paul Whelton, Senior Vice-President for Health Sciences at Tulane University in New Orleans, LA, and an ALLHAT Regional Coordinator. "A great majority of patients can tolerate a diuretic but, for those who can't, then a calcium-channel blocker, an ACE-inhibitor, or a beta blocker may be used to start treatment.
"ALLHAT's findings also indicate that most patients will need more than one drug to adequately control their blood pressure, and one of the drugs used should be a diuretic," he continued.
"Those who are now on a calcium channel blocker or an ACE inhibitor or another hypertension drug besides a diuretic should not stop taking their medication," he added. "But they should certainly talk with their doctor about adding or switching to a diuretic for their treatment."
"ALLHAT's findings refine the current clinical guidelines that recommend starting therapy for hypertension with a diuretic or a beta blocker," said Dr. Jeffrey Cutler, NHLBI Senior Advisor. "The new findings will allow doctors to achieve better blood pressure control and, more importantly, better cardiovascular health for their patients. And, it will do this at a more affordable price for their patients.
"I want to stress," he continued, "that people should not stop or change their blood pressure-lowering medication on their own. They should talk with their doctor about the treatment that's best for them."
Current blood pressure control recommendations are given in The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, issued by the NHLBI's National High Blood Pressure Education Program in 1997. The report is available online at http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm.
ALLHAT's cholesterol study, the first one done exclusively in patients with high blood pressure, involved 10,355 of the hypertension trial's participants. At the start of the trial, they had moderately elevated blood cholesterol but were judged by their doctors not to need cholesterol-lowering medication. All had at least one heart disease risk factor in addition to high blood pressure and elevated cholesterol. About 49 percent of them were women, 38 percent were black, and 23 percent were Hispanic. About 35 percent had type 2 diabetes, and about 14 percent had heart disease at the start of the study. They were followed for an average of 4.8 years.
Participants were assigned to receive either pravastatin, an HMG CoA reductase inhibitor (statin), or usual care, which at the start of the study involved no cholesterol-lowering drug. Both groups followed a cholesterol-lowering diet. The study was not blinded, and participants and their health care providers knew what treatment was received.
Pravastatin was chosen for the trial because it had been shown in prior studies to safely yield long-term total cholesterol reductions of 20 percent or more, an improvement necessary to gauge the therapy's effects on heart disease and overall deaths in ALLHAT's relatively short span (average of 5 years).
During the trial, those in the usual care group were prescribed a cholesterol-lowering drug (not provided by the study) when their doctor felt it was warranted by changes in their condition, such as a heart attack or marked cholesterol increase. Of those in the usual care group, 32 percent who had heart disease at the start of the study and 29 percent of those without heart disease at the outset used a cholesterol-lowering drug.
After 4 years, both the statin and usual care groups had reductions in total and low density lipoprotein (LDL) cholesterol. Total cholesterol dropped by 17.2 percent in the pravastatin group and 7.6 percent in the usual care group–a modest 9.6 percent difference.
There were no significant differences between the pravastatin and usual care groups in overall mortality or in mortality from any single cause. There were 631 deaths in the pravastatin group and 641 in the usual care group.
There also were only modest, non-significant differences in the rates of fatal and nonfatal heart attacks or strokes between the pravastatin and usual care groups. There were 380 coronary heart disease events and 209 strokes in the pravastatin group, compared with 421 heart disease events and 231 strokes in the usual care group.
Rates of heart failure and cancer also were similar in the two groups.
Results for death rates did not differ by age, gender, race, or the presence of type 2 diabetes.
"Both the pravastatin and usual care groups had substantial cholesterol reductions," said Whelton. "This is probably because many of those in the usual care group received a cholesterol-lowering drug. The magnitude of the trend toward increasing use of cholesterol-lowering drugs in usual care during the 8 years of the trial reflects the impact on clinical practice of the many positive statin trials that have taken place in those years. This trend was not fully anticipated when ALLHAT began in 1994. Thus, no difference was found between the groups in deaths and only a modest difference in the rates of heart attack and stroke."
"The ALLHAT findings," said Cutler, "when considered along with the results of other statin trials in which larger reductions in total and LDL cholesterol were associated with proportionally greater reductions in heart attacks and mortality, are consistent with the current national guidelines about the need to aggressively lower high cholesterol."
Sources: National Heart, Lung, and Blood Institute (NHLBI)
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