Benefits and side effects of blood pressure lowering treatment: what was wrong with doxazosin in the ALLHAT?

The lowering of high blood pressure is supposed to protect target organs from hypertensive damage. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial was designed to compare the cardioprotective properties of three antihypertensives from different classes (lisinopril, amlodipine and doxazosin) with chlorthalidone. Despite effective blood pressure lowering and a favorable metabolic profile, the doxazosin arm of the trial had a significantly higher relative risk of cardiovascular disease and heart failure compared with the chlorthalidone arm. This article speculates on possible causes for this unexpected result and suggests that the culprit may be accentuation of the vascular effects of vasopressin, which are maximized under α-adrenergic blockade. These findings may have implications for the large number of older men who receive monotherapy with α-blockers for treatment of prostatic symptoms.