The ALLHAT Trial: What's been learned to date?
Volume X, Issue 4
Anna Constantinou, Pharm.D., BCPS Pharmacy Consultant, PCHI and Harold J. DeMonaco, M.S., Director of Drug Therapy Management

The National Heart, Lung, and Blood Institute (NHLBI) has stopped one arm of its landmark clinical trial commonly known as ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). ALLHAT was originally designed to examine the effects of four classes of antihypertensive medications on the incidence of cardiovascular disease. The NHLBI acted after an independent safety review committee identified an unacceptable incidence of cardiovascular events in subjects treated with doxazosin (Cardura) as compared to chlorthalidone.

An interim report from the ALLHAT study group was published on line in JAMA: http://jama.ama-assn.org/issues/v283n15/full/joc00401.html. The NHLBI press release is available at http://www.nhlbi.nih.gov/new/press/mar08-00.htm.

Background

ALLHAT was originally designed to compare chlorthalidone, amlodipine, lisinopril and doxazosin therapy in a real-world setting. The study was begun in 1994 and is scheduled to be completed in 2002. To be eligible, patients were:

Patients were assigned to one of the four treatment arms. If BP goals were not met, a second open-label drug (atenolol, reserpine or clonidine) could be added. If BP goal was not met, a third step included open-label hydralazine.

Doxazosin vs. chlorthalidone

To date a total of 15,268 patients were entered into the chlorthalidone arm. Another 9,067 received doxazosin. Patient demographics were similar in both groups. Median period of follow-up was 3.3 years.

Some interesting findings at 4 years into the study include:

  1. 86% of patients assigned to chlorthalidone or another diuretic were still taking it at follow-up
  2. 75% of patients on doxazosin or another alpha blocker were taking it at follow-up
  3. 40% of the patients on chlorthalidone and 47% of those taking doxazosin advanced to one or more Step 2 or Step 3 drugs
  4. At the time of follow-up, 64% of patients on chlorthalidone and 58% of those taking doxazosin met BP treatment goals.

The primary outcome (composite endpoint consisting of fatal coronary heart disease and non-fatal MI) was not different for chlorthalidone and doxazosin; however, the relative risk of combined cardiovascular disease was 25% higher in the doxazosin group (RR 1.25; 95% CI 1.17-1.33). This was primarily due to a doubling in the risk of congestive heart failure (RR 2.04; 95% CI 1.79-2.32) and an increase in the risk of angina (RR 1.16; 95% CI 1.05-1.27). The relative risk for stroke was also higher for the doxazosin group than those treated with chlorthalidone (RR 1.19; 95%CI 1.01-1.40).

The Kaplan Meier estimates for outcomes include:

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Important considerations:

  1. The choice of drug may be of greater importance than has been previously assumed, especially in patients with additional risk factors.
  2. The beneficial effects of doxazosin on serum cholesterol do not appear to provide any benefit in clinical outcomes when doxazosin is used as a first-line agent alone for blood-pressure lowering.
  3. The JNC-VI recommendations including the use of doxazosin and other alpha blockers as first-line drugs for patients with coexisting prostatic hypertrophy or dyslipidemias may need modification.
  4. The optimal use of doxazosin and alpha-blockers in the management of hypertension remains to be defined.