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Long‐term safety of different antihypertensive regimens: The risk of unfair comparisons

To the Editor: The longterm safety trial by Neutel and colleagues1 comparing two different fixeddose combination regimens of a reninangiotensin system blocker (azilsartan vs olmesartan) with a diuretic (chlorthalidone vs hydrochlorothiazide) suggested that the combination of azilsartan/chlorthalidone was equally safe to that of olmesartan/hydrochlorothiazide over a period of 1 year. The study is of importance because “the Benjamin” of reninangiotensin system blockers, azilsartan, was compared with an established and potent agent of the same class, olmesartan, and also because the wellknown diuretic, chlorthalidone, was used in a fixed azilsartanbased combination instead of hydrochlorothiazide used to date in most reninangiotensin system–based fixed combinations. I would like to comment on some issues for an alternative interpretation of the present safety study results. The most important (because objective) aspect when dealing with safety issues is treatmentrelated permanent discontinuations corresponding to drugrelated adverse events that lead to withdrawal.2 In the present paper, this measure reported in the supplementary file shows that the rate of drugrelated permanent discontinuations in the azilsartan arm was twofold higher compared with the olmesartan arm (17.9% vs 8.8%). This issue is important because permanent discontinuations following blood pressure (BP) lowering are associated with increased incidence of cardiovascular events, as previously demonstrated in a subanalysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial.3 The azilsartan arm was associated with greater attained systolic (by 5–6 mmHg) and diastolic (3–4 mmHg) BP reduction as compared with the olmesartan arm. It has been previously demonstrated that the extent of BP lowering is associated with higher incidence of treatment discontinuations.2 The more pronounced BPlowering effect in the azilsartan/chlorthalidone arm was indeed accompanied by an increased rate of those who discontinued for adverse events. However, the authors examined the longterm safety according to incipient adverse events regardless of their intensity and, surprisingly, regardless of their relationship with the study drug. With this perspective, it is at least questionable whether there is an encouraging benefitrisk profile for the combination of azilsartan with chlorthalidone as claimed by the authors.1 In other words, the greater BP lowering offered by the azilsartan/chlorthalidone combination should be balanced against treatmentrelated permanent discontinuations. It should also be acknowledged that chlorthalidone is a more potent BPlowering agent compared with hydrochlorothiazide (1.5to 2fold) for the same dose.4 This means that treatment discontinuations with chlorthalidone are expected to be more increased than with hydrochlorothiazide. This expectation was confirmed by Neutel and colleagues because they initially used the same dose for both diuretics, ie, 12.5 mg.1 “The clinical rule,” that 12.5 mg of chlorthalidone has the same effect on BP lowering as 25 mg of hydrochlorothiazide (for the same baseline BP levels), should have been considered in the design of the present study independently of the titratetotarget BPlowering strategy. Overall, I would expect that the conclusions by Neutel and colleagues1 might have been more balanced, because treatment discontinuations were largely different among arms and because comparison for all outcomes in headtohead trials including safety should be for 0/0 mm Hg attained systolic/diastolic BP difference among arms.