Is Evening Dosing of Antihypertensive Therapy Ready for Prime Time?

Abstract

Evening dosing of antihypertensive therapy has emerged as an easily implemented strategy that stands in contradistinction to the long-standing paradigm of morning administration of once-daily antihypertensive therapy. However, the morning dosing strategy was never based on clinical evidence, per se. Rather, it seems to have been chosen by default, perhaps influenced by the perceived convenience of morning dosing of once-daily drugs. The emergence of hard endpoint data suggesting clinical benefit of evening compared with morning dosing clearly brings into question which dosing strategy should be preferred. 1,2 In this issue of the Journal, Roush and colleagues 3 present a meta-analysis of hypertension endpoint trials examining the question of the relative impact of evening vs morning dosing on cardiovascular (CV) risk reduction. They started with a universe of 175 hypertension trials including both blood pressure (BP) difference and drug comparison trials. Five trials were determined to be evening dosing trials (EDTs). A total of 35,075 participants were in EDT trials compared with 312,057 in the usual dosing trials (UDTs). In the trials included in their meta-analysis, stroke and/or coronary heart disease (CHD) events were reported. In the EDT trials, there were 2320 CV disease (CVD) events while in the UDT trials there were 18,129 events-the majority of which were CHD events. The timing of the dosing of antihypertensive drug was determined by reviewing the methods section of original publications. Any trial with greater than once-daily drug dosing was included in the UDT trial category. EDTs were those where a single daily dose of antihypertensive drug was explicitly dosed in the evening. Hazards ratios (HRs) were reported separately for stroke and CHD events; these events were also combined to create a composite HR.The study results generally favored evening dosing. Although neither individual HR attained statistical significance, the composite HR demonstrated a statistically significant 37% lower risk in favor of evening dosing. The risk reduction favoring evening dosing appeared to be even greater with angiotensin-converting enzyme inhibitors than calcium antagonists. The authors astutely conducted sensitivity analyses to determine the impact of individual trials included in the EDT group on the reported outcomes. The Heart Outcomes Prevention Evaluation (HOPE) trial 4 had an outsized impact on the reported results as it was the only EDT trial that when excluded from the analysis resulted in a loss of statistical significance favoring evening dosing. The HOPE trial was notable in that its participants were selected for high CVD risk and it was the only EDT where the antihypertensive dose was administered prior to sleep; however, there was no direct contrast of evening to morning dosing of ramipril.What other evidence exists to support the premise that evening dosing is superior to morning dosing of antihypertensive medications? The lines of evidence can be broken down into at least two categories: epidemiolo...

Ethical complexities in standard of care randomized trials: A case study of morning versus nighttime dosing of blood pressure drugs

“…Does the MAPEC study, an RCT involving over 2000 people with a large effect size, along with prior smaller studies as well as systematic reviews 20, 26 form a sufficient basis for physicians to tell their patients with hypertension to take their antihypertensive medication at night? Commentators who advocate additional study point out that the MAPEC trial was conducted at one site 24, 27, 28 that it was a ‘small’ study, 12,13 and its results may not generalize to an ethnically heterogeneous population in the United States.…”

“…26 One can make an argument that a definitive answer may require a larger, multi-site study. 28 Such a trial is already underway in Spain.…”

“…In short, the current evidence—many small studies with BP as outcome, a systematic review and meta-analysis comparing evening versus morning dose using data from large clinical trials, and a large single-site RCT with hard outcomes—supports the superiority of evening dosing over morning dosing on balance. 26 One can make an argument that a definitive answer may require a larger, multi-site study. 28 Such a trial is already underway in Spain.…”