Is Evening Dosing of Antihypertensive Therapy Ready for Prime Time?

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. In this issue of the Journal, Roush and colleagues 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 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 brokendown into at least two categories: epidemiological and experimental. Experimental data include both individual trials specifically designed to determine the impact of evening vs morning dosing on pressure-related clinical outcomes as well as retrospective pooling of prospective clinical trials that determined clinical outcomes using rigorous adjudication protocols. It is an informative exercise to critically examine the strengths of these aforementioned data while simultaneously acknowledging the less understood issues related to the timing of administration of antihypertensive medications. Ambulatory BP monitoring has been the indispensable tool of BP measurement in both epidemiological and experimental studies. Ambulatory BP data differ from clinic BP measurements in important ways. First, ambulatory BP measurement provides many more BP measurements over the recording period that can be averaged for the entire period of observation as well as for distinct time periods (eg, daytime, nighttime). The availability of a large number of BP readings provides much greater precision in determining the habitual BP level of patients than is possible with office BP readings. Accordingly, compared with office BP, ambulatory BP better predicts all-cause mortality as well as CV morbidity and mortality. Importantly, within the 24-hour recording period, nocturnal BP levels predict CV risk more so than either daytime or 24-hour BP level. The lack of the normal nocturnal decline in BP (10%–20%) has also been linked to higher CVD risk. Also, the white-coat effect, which is potentially observed in office BP readings, is essentially eliminated with extended ambulatory BP recordings. In addition, ambulatory BP and office BP readings are not directly interchangeable. That is, 24-hour ambulatory BP readings that are much lower than office BP readings portend similar CVD risk. The experimental data comparing evening vs morning dosing of antihypertensive drugs have, however, been mixed, depending on the endpoint(s) actually measured. Hermida and colleagues reported an intriguing study in hypertensive patients that favored nocturnal (bedtime) dosing of ≥1 antihypertensive medication compared with administration of all antihypertensive medications being Address for correspondence: John M. Flack, MD, MPH, Professor of Medicine and Physiology, Wayne State University, Detroit, MI 48201, USA. E-mail: jflack@med.wayne. edu