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1/27/2003

ALLHAT Finds Diuretics Best for Initial Hypertension Therapy

Kate Traynor

The results of a major study indicate that diuretics, not calcium-channel blockers or angiotensin-converting-enzyme (ACE) inhibitors, should be the first-line treatment for hypertension among patients with a high risk for cardiovascular events.1

The study, known as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, or ALLHAT, examined the likelihood that a patient would die of heart disease or have a myocardial infarction during long-term treatment with the ACE inhibitor lisinopril (10–40 mg/day) or the calcium-channel blocker amlodipine (2.5–10 mg/day). These two treatments were compared with the thiazide-like diuretic chlorthalidone (12.5–25 mg/day), which was used as an active control in the double-blind study.

Data for the current report were obtained from approximately 33,400 people who participated in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored study.

Clinician Says Diuretics Save Lives, Money

Lawrence J. Appel,1 of Baltimore's Johns Hopkins University, argued in an editorial accompanying a report on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) that paying attention to the study's findings makes good clinical and financial sense.2

According to Appel, a clinical investigator of various hypertension treatments, ALLHAT demonstrated unequivacally that chlorthalidone, amlodipine, and lisinopril are equally effective at preventing fatal coronary heart disease and nonfatal myocardial infarction among patients with hypertension and at least one additional risk factor for heart disease. Chlorthalidone also proved more effective than the other two drugs for preventing heart failure. Both Appel and the ALLHAT report's authors concluded that thiazide-type diuretics like chlorthalidone should be used as first-line therapy for hypertension.

In addition to performing at least as well as the other study drugs, chlorthalidone costs much less than lisinopril and amlodipine—a further incentive to favor the diuretic over other potential initial therapies, according to Appel.

Appel urged clinicians to resist the temptation to supplement diuretic therapy with an "on-patent" angiotensin-converting-enzyme (ACE) inhibitor or calcium-channel blocker. Instead, he stated that supplementation, when appropriate, should make use of drugs like the calcium-channel blocker verapamil and the ACE inhibitors captopril, enalapril maleate, and lisinopril—all of which are available in generic formulations.

The report on ALLHAT noted that diuretics accounted for 56% of antihypertensive drug prescriptions in 1982 but just 27% 10 years later. According to the report, the switch from diuretics may have cost about $3.1 billion during this period.

  1. Appel LJ. The verdict from ALLHAT-thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-42. Editorial.   
  2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97.

ALLHAT's major finding was that all three drugs had the same effect on the frequency of myocardial infarction or death from heart disease. In addition, initial treatment with chlorthalidone, which costs considerably less than the other two drugs, was associated with several benefits, including the following:

  • Patients in the amlodipine group were 38% more likely than patients assigned to the chlorthalidone group to suffer heart failure and 35% more likely to be hospitalized or die of the disease during six years of treatment.    
  • The six-year risk of heart failure was 19% higher in the lisinopril group than in the chlorthalidone group. Patients who used lisinopril were 11% more likely than chlorthalidone users to be hospitalized for heart failure and 10% more likely to die of the disease.    
  • Patients who used lisinopril were 15% more likely than those in the chlorthalidone group to have a stroke during six years of treatment. The combined risk for cardiovascular diseases, including stroke, angina, and death from heart disease, was 10% higher in the lisinopril group than among patients assigned to the chlorthalidone group.    
  • Black men and women in the lisinopril group were 40% more likely to suffer a stroke than were black patients who used chlorthalidone.    
  • Angioedema, a rare complication of ACE inhibitor use, occurred four times as frequently in the lisinopril group as in patients assigned to receive chlorthal-idone. One patient, a lisinopril user, died of angioedema during the study.    
  • After five years of treatment, the systolic blood pressure of patients who used chlorthalidone was, on average, 2 mm Hg lower than in patients assigned to the lisinopril group and 0.8 mm Hg lower than in patients who used amlodipine. The report's authors estimated that a reduction of 2–4 mm Hg in systolic blood pressure could lead to a 6–12% decrease in the occurrence of stroke.

ALLHAT got under way in 1994 and enrolled approximately 42,500 adults age 55 or older. Each study participant had hypertension, defined as blood pressure of >140/90 mm Hg, and at least one other risk factor for coronary heart disease events. Study enrollees were recruited from 623 office-based practices and general medical and specialty clinics in the United States, Puerto Rico, the Virgin Islands, and Canada.

The study's original design included a group of patients treated with the alpha-adrenergic blocker doxazosin. This drug was dropped from the study in 2000 after an interim analysis of data revealed that doxazosin-treated patients were much more likely than diuretic users to have cardiovascular problems and to be hospitalized for heart failure.

Although ALLHAT data were analyzed on an intention-to-treat basis, physicians were allowed to supplement their patients' assigned antihypertensive regimen with other drugs when necessary. By year 5 of treatment, about 40% of the patients in each group were also receiving atenolol, clonidine, reserpine, or hydralazine or more than one of these medications—all of which were supplied through ALLHAT. Physicians were also allowed to prescribe other drugs.

Five years into treatment, 68% of patients in the chlorthalidone group were still taking that drug or another diuretic but no ACE inhibitor or calcium-channel blocker. At the five-year mark, 64% of patients in the amlodipine group and 57% in the lisinopril group were taking their assigned drug or another one in the same class without using a diuretic.

In a press release announcing the ALLHAT results, NHLBI Director Claude Lenfant said the study "shows that diuretics are the best choice to treat hypertension and reduce the risks of its complications, both medically and economically." Despite this endorsement of diuretic therapy, NHLBI cautioned patients not to change their regimen without first consulting a physician.

Current hypertension treatment guidelines from NHLBI recommend the use of a diuretic or a beta-blocker for first-line treatment of hypertension.2 According to Jeffrey Cutler, an NHLBI senior adviser, the ALLHAT findings "refine the current clinical guidelines."

Additional information about the ALLHAT results is available from NHLBI at www.nhlbi.nih.gov/health/allhat/index.htm.

  1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97.    
  2. National Heart, Lung, and Blood Institute. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. www.nhlbi.nih.gov/guidelines/hypertension/jnc6.pdf (accessed 2003 Jan 3).