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

Background: The Anti hypertensive 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 anti hypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk.