Increasing Stay-on-therapy in Hypertensive Patients Treated With First-line Diuretics: An Active Pharmacosurveillance and Pharmacogenetic Study.

Background and rationale

Many comments have been issued about similarities and differences between 2003 American and European guidelines for the management of arterial hypertension (1,2), especially after the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study (3-5). Both guidelines agree that the majority of hypertensive patients require more than one medication to achieve optimal blood pressure control and, consistent with the most recent findings, the need of expensive, large clinical trials to demonstrate the superiority of one medication on another is probably over (3,6). What is clear now is that blood pressure must be optimally controlled to reduce risk of cardiovascular mortality and morbidity in population, no matter which combination of medications is used. Comparison between single medications is substantially academic and conceals the reality: in all trials, in most circumstances comparison is between combinations, more than single medications. In the Losartan Intervention for Endpoint Reduction Study (LIFE study) (6), for instance, there has been a comparison between the combination of losartan with low dose hydrochlorothiazide versus the combination of atenolol with the same diuretic.

The difference between the seventh Joint National Committee (USA) on Prevention, Diagnosis and Management of Hypertension (JNC VII) and European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2003 guidelines, often presented as substantial, is in the priority that Americans still give to the diuretic therapy, consistent with the most waited results of the ALLHAT (3).

The ALLHAT was a randomized, double-blind, multicenter clinical institutional trial, entirely sponsored by the National Heart, Lung, and Blood Institute (NHLBI) (3), and designed to determine whether occurrence of fatal or nonfatal coronary heart disease is lower for high risk hypertensive patients treated with amlodipine, lisinopril, doxazosin, or chlorthalidone. The protocol was also approved by an independent Review Committee external to the NHLBI (7). The ALLHAT recruited 9,000-15,000 participants/intervention arm (total: 33,357), and the follow-up was quite long (4-8 years). The doxazosin arm was closed prematurely because of higher mortality (8). Despite a number of important limitations of this study (4,9), the overall impact of its findings remains very high.

The baseline characteristics of the ALLHAT participants were substantially similar in the 3 arms completing the study. Chlortalidone was significantly more effective than both amlodipine and lisinopril in achieving optimal control of blood pressure at year 1 and year 2 and more effective than lisinopril in blood pressure control at year 3, 4 and 5 (all p<0.001). Consistent with the better control of blood pressure, chlortalidone tended to provide a 10% more protection for combined fatal and non fatal coronary heart disease than lisinopril whereas protection was similar for amlodipine, though this protection was less evident than the superiority in controlling blood pressure. In fact, the difference in risk profile versus the lisinopril arm achieved statistical significance only for elderly and African-American participants.