Antihypertensive drugs in the morning or the evening? A complicated question with no clear answer

The current issue of the Journal hosts a large meta-analysis, conducted by Chinese authors, focused on the most appropriate dosing time of blood pressure (BP) lowering drugs in hypertensive patients with nocturnal hypertension 1. The primary aim of the meta-analysis was to investigate whether an evening dosing of once-daily antihypertensive drugs is superior to a morning dosing in reducing nocturnal BP in patients with evidence of nocturnal hypertension, defined by a nighttime BP at least 120 mmHg systolic or at least 90 mmHg diastolic 1. Which is the current status-of-the-art in this area? Although many randomized trials comparing morning versus evening administration of antihypertensive drugs are accumulating, the results remain disputable 2,3. A large recent meta-analysis included 72 clinical trials in which patients were randomized to either morning or evening administration of their antihypertensive therapy 4. Evening administration of antihypertensive therapy was associated with a significantly greater, albeit quantitatively modest, reduction in nighttime BP by 4.09/2.57 mmHg compared with the morning administration, alongside a greater 0.94/0.87 mmHg reduction in daytime BP 4. However, after exclusion of some controversial 5–7 studies published by Hermida et al., the superiority of evening over morning administration disappeared on 24-h BP, 48-h BP, daytime BP and cardiovascular outcomes, whereas the superiority on nighttime BP was much attenuated, albeit remaining nominally significant 4. Similar findings emerged from a previous smaller meta-analysis by Schillaci et al.8. The present meta-analysis brings essentially three new elements when compared with the one by Maqsood et al.4. First, the authors restricted the search strategy to studies in which nighttime BP at baseline was increased. Focusing on patients with increased nighttime BP looks like a logical tool to test the hypothesis that evening administration is superior to morning administration to lower BP at night. For example, the recently published TIME study, which failed to detect outcome differences between the morning and evening administration of antihypertensive drugs 9, did not target patients with increased nighttime BP because of the absence of 24-h ambulatory BP monitoring among inclusion criteria 10. Second, the authors added several studies published in Chinese language and not included in previous meta-analyses 4. Third, the authors made separate analyses according to the drug class used angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, β-blockers, drug combinations. The meta-analysis was technically well done, in line with current recommendations 11,12. In view of the lack of homogeneity across the studies in terms of ethnicity, comorbidity, and other factors, the authors used a random effect model (restricted maximal likelihood) to pool weighted mean differences. In brief, the meta-analysis confirmed that the evening administration of antihypertensive drugs is modestly superior to the morning administration in reducing nighttime BP with all drug classes except β-blockers. However, all differences between the evening and the morning administration on nighttime BP disappeared not only after exclusion of the studies by Hermida, but also of the studies conducted in China. The studies by Hermida and those from China were thus comparable under this respect. These results confirm those by Maqsood et al. 4 in showing that the superiority of morning over evening administration of antihypertensive drugs is driven by the studies of Hermida and adds that the randomized studies conducted in China exert a similar driving effect. While the perplexities raised by Hermida's studies have been extensively highlighted 5–7, the reasons underlying the driving effect of the studies from China are not obvious. The Authors argue that Chinese people could be potentially more sensitive to evening than morning administration of antihypertensive drugs 1. An increased nighttime BP and an exaggerated early morning BP surge are frequent in Asian people 13–15. In the Japan Ambulatory Blood Pressure Monitoring Prospective study, an increased nighttime BP and a riser pattern (i.e., higher nighttime than daytime BP) were strong independent predictors of major cardiovascular events and heart failure. However, the authors themselves identified other reasons why the results of the Chinese studies might lack credibility. These reasons included a poor quality of evidence from these studies, an unexpected identical number of patients in the two randomized groups in some studies and an extreme benefit in one of the two arms in other studies 1. The authors also mentioned an analysis of individual patient data from randomized controlled trials, which found false data in up to 48% of trials conducted in China 16. Apart from the above considerations, the meta-analysis suffered from a notable variability in terms of patient characteristics across the examined studies. For example, an increased nighttime BP was not a precise inclusion criterion in all studies. One study enrolled patients with average 24-h BP, not nighttime BP, more than 130/80 mmHg 17. Another study included patients with either daytime or nighttime BP increased 18 In another study, although the reported average nighttime BP was more than 120/70 mmHg, inclusion was based on office BP only 19–21. In conclusion, the present meta-analysis, although informative and provocative, does not provide conclusive evidence on the superiority of an evening antihypertensive treatment over a morning one. Some arguments favoring or not favoring a potential superiority of evening dosing over the traditional morning dosing of antihypertensive drugs are reported in the Table 122–33. At the present time, in accordance with a recent European Position Paper 3, we believe that until we have new data from randomized trials, we do not have enough evidence to recommend the preferential administration of antihypertensive drugs in the evening, even in particular clinical settings such as 'nondippers,' 'risers,' or those with increased nighttime BP. It is hoped that ongoing trials such the Canadian BedMed trial 20 will provide important informative data. Theoretically, patients with evidence of marked and reproducible rise in nighttime BP (Fig. 1), such as those with chronic kidney disease 21, might be an ideal population for randomized studies of morning versus evening antihypertensive drug administration. TABLE 1 - Some arguments in favor and not in favor of a potential superiority of evening dosing In favor of a potential superiority of evening dosing Because nighttime BP is more informative than daytime BP about the risk of major cardiovascular outcome events 22–24, particularly in treated patients 25, the evening dosing might be prognostically advantageous through a supposed predominant effect on nighttime BP. Some antihypertensive drugs given once-daily in the morning might not have a duration of action sufficiently long to cover the entire 24-h period 3,26. Because activation of the renin-angiotensin system increases at night 27, some individuals could be more responsible to ACEIs or ARBs administered in the evening 26. In a major outcome trial with ACEIs, ramipril was indeed given in the evening 28. Against the potential superiority of evening dosing Adherence to treatment may be less with evening dosing compared to morning dosing 9,29,30. Several antihypertensive drugs have a long duration of action which covers most of 24-h 31,32, For drugs with a shorter duration of action, increasing the dose up to the full recommended dose may increase the 24-h coverage even after morning administration 33. Administration of diuretics at bedtime may be impractical, forcing many individuals to urinate more often at night. FIGURE 1: Ambulatory blood pressure profile in a patient with chronic kidney disease. Note the markedly higher blood pressure during night (shaded area), with reverse dipping pattern ('riser').ACKNOWLEDGEMENTS Conflicts of interest None of the authors of this study has financial or other reasons that could lead to a conflict of interest.