Diuretic suggested as initial hypertension treatment

Increased use of diuretics could save billions

The largest hypertension trial ever conducted is recommending thiazide diuretics as initial therapy over newer, more costly angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers. The researchers do say, however, that most patients will need to be prescribed more than one drug to control their blood pressure.

Results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were published in the Dec. 18, 2002, issue of The Journal of the American Medical Association. The researchers recommended that physicians should consider switching patients who already are being treated with a medication other than a diuretic to a thiazide-type diuretic or adding diuretics to the existing regimen.

The cost implications of the recommendations are huge. The researchers say diuretic use to treat hypertension fell from 56% in 1982 to 27% in 1992. The switch from diuretics to the more expensive antihypertensive medications cost about $3.1 billion.

ALLHAT was a randomized, double-blind trial conducted from February 1994 through March 2002. It involved 33,357 participants ages 55 and older, and was conducted at 623 clinics and centers in the United States, Canada, Puerto Rico, and the U.S. Virgin Islands. About 7,000 participants were treated at Veterans Affairs clinics. The National Heart, Lung, and Blood Institute, part of the National Institutes of Health, supported the trial.

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.

Almost 50% of the participants were women, 47% were non-Hispanic whites, and 32% were black. Thirty-six percent had diabetes. All participants were followed at three, six, nine, and 12 months after beginning the study and every four months afterward. Participants were followed on average for 4.9 years.

Participants were randomly assigned to receive one of four drugs:

  • a diuretic (chlorthalidone, 12.5-25.0 mg/day);
  • a calcium channel blocker (amlodipine, 2.5-10.0 mg/day);
  • an ACE inhibitor (lisinopril, 10-40 mg/day);
  • an alpha-adrenergic blocker (doxazosin). The alpha-adrenergic blocker arm of the study was stopped in March 2000 because those on the drug had increased cardiovascular events and hospitalizations for congestive heart failure as compared to users of the diuretic.

Participants received additional antihypertensive drugs if their doctor thought it necessary to control their blood pressure.

The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction. The primary outcome occurred in 2,956 participants, with no difference between treatments.

Secondary outcomes were all-cause mortality, stroke, combined CHD, and combined cardiovascular disease. All-cause mortality did not differ between groups. Compared to participants who were taking the diuretic, however, those on the calcium channel blocker had systolic blood pressure that was about 1 mm Hg higher on average, as well as a 38% higher risk of developing heart failure and a 35% higher risk of being hospitalized for the condition.

Compared to participants who were taking the diuretic, those on the ACE inhibitor had:

  • systolic blood pressure that was about 2 mm Hg higher on average, and 4 mm Hg higher in African-Americans;
  • 15% higher risk of stroke (40% higher risk of stroke for African-Americans);
  • 19% higher risk of developing heart failure;
  • 11% greater risk of being hospitalized or treated for angina;
  • 10% greater risk of having to undergo a coronary revascularization (such as coronary artery bypass surgery).

Some physicians disputed ALLHAT’s findings, saying beta-blockers should not have been the add-on therapy for the lisinopril group because the drugs are not complementary in their actions. In addition, chlorthalidone frequently is used in clinical trials but not in clinical practice. The possibility exists that other thiazide diuretics may not be comparable.

ALLHAT doesn’t dramatically change any of the ideas about treating hypertension that have resulted from previous research, such as the reports from the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure, says Daniel Albrant, PharmD, president of Pharmacy Dynamics, a pharmaceutical consulting company in Arlington, VA. "There are some nuances of difference. There is some support for using diuretics early, which has been known for close to a decade."

It appears now that diuretics and beta-blockers are certainly the way to go to treat hypertension in most people, he says. "In certain subsets, calcium channel blockers may be more appropriate; ACE inhibitors may be more appropriate plus or minus a diuretic." Most important, however, is getting patients on some type of therapy and convincing them to persist with their medications. "Getting them on appropriate therapy, titrating it to the goals, and getting them to persist in their compliance to take the medication — those are the things that make the big outcomes."

ALLHAT’s cholesterol study results

In addition to the hypertension trial, ALLHAT included a cholesterol-lowering study that compared the effects of a statin drug (pravastatin) 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.

ALLHAT’s cholesterol study involved 10,355 of ALLHAT participants. At the start of the trial, the participants had moderately elevated blood cholesterol but were judged by their doctors not to need cholesterol-lowering medication.

During the trial, participants 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% of those who had heart disease at the start of the study and 29% of those without heart disease at the outset used a cholesterol-lowering drug.

After four years, both the statin and usual care groups had reductions in total and low-density lipoprotein cholesterol. Total cholesterol dropped by 17.2% in the pravastatin group and 7.6% in the usual care group.

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.