JNC-7 versus renin-based strategies for optimal antihypertensive drug treatment

To the Editor: Blumenfeld has addressed the contentious issue about the first drug option in the management of hypertension in a sound and creative way.1 He has shown that we may be facing two different alternatives in the management of high blood pressure (BP) not controlled by the first BP-lowering medication, the replace versus the add-on strategies. The rationale for choosing a drug according to the volume or renin pathophysiologic mechanism of hypertension has been repeatedly demonstrated by Laragh.2 Blumenfeld proposes the adoption of an “attempt and error” strategy to test the effect of the first option. If the patient does not respond to a drug of the renin group—angiotensin antagonists (“A”) or β-blockers (“B”), it should be replaced by a drug of the volume group, namely calcium antagonist (“C”) or diuretic (“D”) or vice versa. The rotation between BP-lowering drugs was proposed before,3 but this study failed to control for the long-lasting effect of diuretics,4 a property that was recently fully documented.5 Besides, Blumenfeld suggested that in a re-analysis of the findings of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), restricted to participants who remained in monotherapy,6 lisinopril gave better results than in the whole trial. I argue that despite the limitation of this “ad hoc” analysis, it did not demonstrate a superiority of lisinopril over diuretic. The relative risks for combined cardiovascular events were, compared with chorthalidone, 1.11 (P = .006) for amlodipine, 1.15 for doxazocin (P = .01), and 1.04 for lisinopril (P = .30), differences that were largely driven by heart failure results. It seems that lisinopril was not inferior but also not superior to chorthalidone in this analysis, which is surely at risk for a selection bias (allocation to one or another drug by the response to the first option and not by random allocation). The demonstration of superiority of the replace or add-on strategies should require a clinical trial with hard end point or at least with intermediate outcome (BP), with parallel design and long periods of washout and follow-up. For a while, the option for diuretic as the first option has the higher odds of being right,7 and the addition of a drug of the angiotensin antagonist or β-blocker (“AB”) group in patients with uncontrolled BP may be the most appropriate second step.