Relationship of Antihypertensive Treatment Regimens and Change in Blood Pressure to Risk for Heart Failure in Hypertensive Patients Randomly Assigned to Doxazosin or Chlorthalidone: Further Analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial

3 September 2002 | Volume 137 Issue 5 Part 1 | Pages 313-320

Background: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial reported that treatment initiated with doxazosin compared with chlorthalidone doubled the risk for heart failure in high-risk hypertensive patients (relative risk, 2.04 [95% CI, 1.79 to 2.32]). Patients assigned to doxazosin therapy had a mean in-trial systolic/diastolic blood pressure 3/0 mm Hg higher than that in patients assigned to chlorthalidone. Sixty-eight percent (6167 of 9061) of the former patients and 59% (9081 of 15 256) of the latter patients were given additional medications to achieve a target blood pressure of less than 140/90 mm Hg.

Objective: To ascertain the influence of open-label antihypertensive drugs and subsequent blood pressure on relative risk for heart failure.

Design: Randomized, double-blind, active-controlled clinical trial.

Setting: 623 sites in the United States and Canada.

Patients: Hypertensive patients 55 years of age or older with at least one additional risk factor for cardiovascular disease.

Intervention: Chlorthalidone (12.5 to 25 mg/d) or doxazosin (2 to 8 mg/d) for a planned follow-up of 4 to 8 years.

Measurements: Data on blood pressure, medication, and incident heart failure (treated outside hospital, hospitalized, or fatal) from February 1994 through December 1999.

Results: After the treatment groups were categorized as having no exposure to open-label medications (monotherapy) or exposure to open-label therapy, the relative risk for heart failure with doxazosin versus chlorthalidone was 3.10 (CI, 2.51 to 3.82) and 1.42 (CI, 1.20 to 1.69), respectively. After adjustment for follow-up systolic/diastolic blood pressure, the overall relative risk was 2.00 (CI, 1.72 to 2.32).

Conclusion: In high-risk patients with hypertension, the higher risk for heart failure while taking doxazosin compared with chlorthalidone is attenuated but not eliminated by adding other antihypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk.

*For a complete list of members of the ALLHAT Collaborative Research Group, see JAMA. 2000; 283:1973-5.

Editors' Notes Context Previously published results of this randomized, double-blind trial showed that hypertensive patients treated with doxazosin rather than chlorthalidone more often developed heart failure. Did differences in blood pressure control or treatment with other drugs explain these findings? Contribution This analysis shows that the slightly worse blood pressure control achieved with doxazosin did not explain higher risks for heart failure. Risks with doxazosin versus chlorthalidone were highest among patients who received monotherapy (relative risk, 3.10) and lowest among patients who received stepped care with additional drugs (relative risk, 1.42). Implications Increased risks for heart failure with doxazosin versus chlorthalidone are attenuated but not eliminated when additional antihypertensive drugs are used. –The Editors

 

Author and Article Information

From the University of Texas School of Public Health, Houston, Texas; the National Heart, Lung, and Blood Institute, Bethesda, Maryland; Wake Forest University School of Medicine, Winston-Salem, North Carolina; Case Western Reserve University School of Medicine, Cleveland, Ohio; Pitman Internal Medicine Associates, Pitman, New Jersey; and Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona.

Grant Support: By contract NO-HC-35130 from the National Heart, Lung, and Blood Institute. Study medications were supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin); Pfizer, Inc., provided financial support to the National Heart, Lung, and Blood Institute.

Potential Financial Conflicts of Interest:Consultancies: B.R. Davis, J.T. Wright Jr., J.V. Felicetta; Honoraria: C.D. Furberg, J.T. Wright Jr., J.V. Felicetta; Stock Ownership: M.A. Farber; Grants Received: C.D. Furberg, J.T. Wright Jr., J.V. Felicetta.

Requests for Single Reprints: Barry R. Davis, MD, PhD, the University of Texas School of Public Health, 1200 Herman Pressler Street, Houston, TX 77030; e-mail, bdavis{at}sph.uth.tmc.edu.

Current Author Addresses: Dr. Davis: The University of Texas School of Public Health, 1200 Herman Pressler Street, Houston, TX 77030.

Dr. Cutler: The National, Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Bethesda, MD 20892.

Dr. Furberg: Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.

Dr. Wright: Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106.

Dr. Farber: Pitman Internal Medicine Associates, 410 North Broadway, Pitman, NJ.

Dr. Felicetta: Carl T. Hayden Veterans Affairs Medical Center, 650 East Indian School Road, Phoenix, AZ 85012.

Dr. Stokes: 2323 Curlew Road, Palm Harbor, FL 34683.

Author Contributions: Conception and design: B.R. Davis, J.A. Cutler, C.D. Furberg, J.T. Wright.

Analysis and interpretation of the data: B.R. Davis, J.A. Cutler, C.D. Furberg, J.T. Wright.

Drafting of the article: B.R. Davis, J.A. Cutler, J.T. Wright, M.A. Farber.

Critical revision of the article for important intellectual content: B.R. Davis, J.A. Cutler, C.D. Furberg, J.T. Wright, M.A. Farber, J.V. Felicetta, J.D. Stokes.

Final approval of the article: B.R. Davis, J.A. Cutler, C.D. Furberg, J.T. Wright, J.V. Felicetta.

Provision of study materials or patients: B.R. Davis, M.A. Farber, J.D. Stokes.

Statistical expertise: B.R. Davis.

Obtaining of funding: B.R. Davis, J.A. Cutler.

Administrative, technical, or logistic support: B.R. Davis, J.A. Cutler, C.D. Furberg.

Collection and assembly of data: B.R. Davis, J.V. Felicetta, J.D. Stokes.