Data Monitoring in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Early Termination of the Doxazosin Treatment Arm

Abstract

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial’s (ALLHAT) hypertension component was designed to determine whether the incidence of fatal coronary heart disease or non-fatal myocardial infarction differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs—a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons aged 55 years and older. A Data and Safety Monitoring Board met twice yearly to review data on participant recruitment, retention, endpoints, and other patient safety issues. The doxazosin arm of the trial was terminated earlier than planned due to the low likelihood of finding a significant difference in the primary outcome by the study’s scheduled end and a significant 25% increase in cardiovascular events for doxazosin compared with chlorthalidone. This decision was made based on recommendations from an ad hoc review committee following a split vote of the Data and Safety Monitoring Board. This paper describes the monitoring guidelines established for ALLHAT and how they were used, the role of secondary endpoints in DSMB deliberations, advance preparations for possible closeout of a study arm, the role of a Special Review Committee, processes for closeout of the doxazosin arm, and lessons learned.