Impact of bedtime dosing of antihypertensives compared to morning therapy: A meta-analysis of randomised controlled trials

Blood pressure (BP) fluctuates over 24 h, and the sympathomimetic autonomic nervous system drives these circadian variations due to increased activity of renin-angiotensin-aldosterone.1 Patients with a lower reduction (<10%) in the nocturnal BP (called non-dippers) have a worse prognosis.2 Patients who exhibit non-dipping pattern are more likely to have resistant hypertension, diabetes, and chronic kidney disease.3 There has been some evidence that normalization of this persistently elevated bedtime BP may lead to slowing the progression of cardiorenal outcomes.4 Therefore, bedtime antihypertensive therapy has been touted to alter the non-dipper profile of these patients to dipper without significant adverse effects. Also, a morning surge in BP is a known independent risk factor for the development of cardiovascular disease and stroke.5 Accordingly, we sought to systematically evaluate the impact of bedtime-dosing of antihypertensives compared to morning therapy in a meta-analysis of randomized controlled trials (RCTs). PubMed and Embase were searched from the inception through November 2019. The keywords of ‘bedtime dosing’ or ‘antihypertensives’ were used to identify relevant RCTs with the limits for human and RCTs activated. Full manuscripts of potentially relevant studies were then reviewed by two independent authors (RG and AHM). Supplementary Material Figure 1 describes the detailed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guided search flowchart. Our outcomes of interest were major adverse cardiac events (MACEs) and stroke. A MACE was defined as at least one of the following, fatal or non-fatal myocardial infarction, cardiovascular death, or revascularization. Study quality was assessed via the Cochrane risk of bias tool for RCTs. We used the respective odds ratio (OR), relative risk or hazard ratio and converted them into treatment effect and standard error. We have used a similar technique in the past.6 The generic inverse variance method was then used to perform a random-effects meta-analysis to account for the expected clinical and methodological heterogeneity among trials. Results are presented as ORs with 95% confidence intervals (CIs). The consistency and heterogeneity were assessed by calculating I2. Due to a low number of studies (<10), publication bias was not tested. Outcomes of major adverse cardiac events (MACEs) and stroke. CI: confidence interval. The initial search yielded 630 articles. After electronic and manual deduplication on title review, 467 studies remained. A further abstract review led to exclusion of the least relevant articles, and 34 articles were selected for final full-text review. After full-text review, there were seven RCTs with 54,608 patients for which quantitative analysis was possible.7–13Table 1 shows the baseline characteristics of patients in the included trials, respectively. The mean age of our study population was 64 ± 3 years with 51 ± 4% males. The mean duration of follow-up was around 4 years. Baseline characteristics of the included trials. BP: blood pressure; CAD: coronary artery disease; CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular End Points; DM: diabetes mellitus; FACET: Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial; HOPE: Heart Outcomes Prevention Evaluation; MAPEC: Monitorización Ambulatoria de la Presión arterial y Eventos Cardiovasculares; NA: not available; Syst-China: Systolic Hypertension in China; SBP: systolic blood pressure; Syst-Eur: Systolic Hypertension in Europe. Study quality was assessed using Cochrane study quality assessment that gives one ‘+’ to each of selection bias, allocation concealment, performance bias, detection bias, attrition bias, reporting bias and other bias. The maximum number of ‘+' are out of 6. Baseline characteristics of the included trials. BP: blood pressure; CAD: coronary artery disease; CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular End Points; DM: diabetes mellitus; FACET: Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial; HOPE: Heart Outcomes Prevention Evaluation; MAPEC: Monitorización Ambulatoria de la Presión arterial y Eventos Cardiovasculares; NA: not available; Syst-China: Systolic Hypertension in China; SBP: systolic blood pressure; Syst-Eur: Systolic Hypertension in Europe. Study quality was assessed using Cochrane study quality assessment that gives one ‘+’ to each of selection bias, allocation concealment, performance bias, detection bias, attrition bias, reporting bias and other bias. The maximum number of ‘+' are out of 6. All seven trials reported outcomes of MACEs and stroke (Figure 1). Compared with patients taking their medications in the morning, antihypertensive therapy at bedtime was associated with a 28% significant reduction in MACEs (OR 0.72; 95% CI 0.57–0.91, p <0.01; I2 = 73%). Similarly, for the outcome of stroke, the odds are 32% lower in patients with nocturnal chronotherapy (OR 0.68; 95% CI 0.50–0.93, p <0.01; I2 = 82%) compared with patients taking their medications in the morning. There was a significant heterogeneity noted in the results. The main finding of the current meta-analysis is that nocturnal chronotherapy with antihypertensive seems to be associated with much reduced cardiovascular outcomes, including MACEs or stroke. The current meta-analysis provides further evidence for the added beneficial effect of taking anti-hypertensives at bedtime. The reduced odds of cardio- and cerebrovascular events with bedtime dosing of antihypertensives are likely to be a result of improved nocturnal BP control and not the morning surge. These trials did not differentiate the patient population that was non-dipping, and therefore we are unable to attribute this benefit to the conversion of non-dipping to dipping BP profile. However, previous data have confirmed that night dosing of antihypertensives is effective in reducing nocturnal BP by utilizing home BP monitoring systems.14 The American Heart Association/American College of Cardiology guidelines defer the decision of night-time dosing of antihypertensive therapy to the specialists’ prerogative.14 The guidelines also provide a consensus recommendation to use single-dose therapy compared with multiple dosing to improve adherence. Considering this fact, optimal timing of antihypertensive therapy becomes much more important. A previous Cochrane review failed to show any additional adverse effects associated with night-time dosing.15 The same analysis, comprised of trials with significant heterogeneity, found that BP-lowering efficacy was significantly better (1.71 mm Hg reduction in 24-hour systolic BP and 1.38 mm Hg reduction in 24-hour diastolic BP) with bedtime dosing compared with morning administration of antihypertensives. The authors concluded that these findings are of unknown clinical significance due to a lack of clinically meaningful outcomes. Our analysis adds to prior data by reporting on clinically relevant cardiovascular outcome measures. As previously mentioned, BP varies throughout the day. With the renin angiotensin aldosterone system being most active at night, nocturnal BP and its dipping are dependent on sodium excretion. Sierra et al. reported that half of the treated hypertensive patients and two-fifths of the untreated patients show a non-dipping pattern.16 This pattern has been found to accelerate endothelial dysfunction in patients with hypertension.17,18 It also leads to end-organ hydrostatic insult especially to microcirculation of heart, brain, and kidneys, which further leads to an increase in BP of medium and large-sized arteries causing a vicious cycle.19 Consequently, non-dipping has been shown to be associated with a 25% increase in cardiovascular morbidity and mortality after adjusting for 24-hour BP control and other cardiovascular risk factors.20 Restoration of normal dipping pattern is also expected to prevent long-term end-organ damage.21 Our meta-analysis has some limitations. First, there is significant heterogeneity amongst trials included, likely due to the design and population differences of the included studies. Second, we are unable to assess the impact of dose-response relationship and certain important subgroups due to lack of individual patient data. Furthermore, although the MACE composition was not consistent in all of the studies, reported events from each study trended to have better outcomes with bedtime therapy. Finally, we were not able to assess individual antihypertensive efficacies due to a lack of data. Some antihypertensives such as diuretics at bedtime may be associated with poor compliance. In conclusion, bedtime ingestion of antihypertensives seems to be associated with a reduction of cardiovascular and cerebrovascular events compared with morning consumption. In light of previous evidence of improved BP control and reduced adverse events, future recommendations should consider bedtime dosing of antihypertensives. However, more evidence is needed in the contemporary era and to see the differential impact of bedtime dosing of different antihypertensives, as some medications such as diuretic antihypertensives may not be preferable at night-time due to poor compliance counterbalancing any potential benefits. Supplementary material is available at European Journal of Preventive Cardiology online. RG and AHM contributed equally as first authors. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.