Antihypertensive efficacy of aliskiren: is hydrochlorothiazide an appropriate benchmark?

The thorough prospective, randomized, double-blind trial of Schmieder et al1 in the current issue of Circulation convincingly documents that aliskiren treatment provided significantly greater blood pressure (BP) reduction than hydrochlorothiazide. The study is well done; the number of patients (n 1124) is impressive; and the efficacy variables were analyzed, as is appropriate for an intention-to-treat population, with the last observation carried forward method. The authors concluded that aliskiren provided “more effective BP lowering than a thiazide-type diuretic, the drug class recommended by JNC 7 [Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure] guidelines2 as first-line therapy for the treatment of hypertension.” Indeed, not only JNC 7 but also JNC VI, V, IV, III, and I have recommended a thiazide-type diuretic, most commonly hydrochlorothiazide in the United States, as first-line therapy. Thus, over the years and decades, the JNC has elevated hydrochlorothiazide to the gold standard of antihypertensive therapy. Not surprisingly, therefore, hydrochlorothiazide remains the most prescribed drug in the United States. In 2007, 130 million prescriptions for hydrochlorothiazide, either alone or in combination, were written in this country. The doses of hydrochlorothiazide almost exclusively prescribed are 12.5 and 25 mg/d. This begs the question as to how solid the evidence is that hydrochlorothiazide in the dose of 12.5 to 25 mg reduces cardiovascular events (ie, stroke and heart attacks). A thorough scrutiny of the literature reveals little, if any, outcome evidence for low-dose hydrochlorothiazide. All outcome studies were done with higher doses, with hydrochlorothiazide in fixed combinations with a potassium-sparing diuretic, or with chlorthalidone, which obviously is an entirely different antihypertensive drug.3 Hydrochlorothiazide was compared with and found to be inferior to enalapril in the Australian National Blood Pressure 2 study, but the dose is not specified.4 Thus, we have to conclude that for the most prescribed drug in the United States, outcome evidence is paltry. Article p 417