The efficacy of chronotherapy in reducing nocturnal BP has been presented mainly by the aforementioned Spain research group. In the MAPEC study by Hermida et al., 2156 hypertensive subjects were randomized to either morning dosing or ≥ 1 medications taken at bedtime [
5]. That study showed that bedtime dosing resulted in a significantly greater reduction in asleep SBP compared to morning dosing (-11.8 ± 13.2 vs. -6.6 ± 12.5 mmHg,
P < 0.001) [
5]. In the Hygia Chronotherapy trial also performed by the Hermida group, bedtime dosing of ≥ 1 medications was associated with significantly higher percentage of nighttime BP lowering (12.2 ± 7.7 vs. 8.5 ± 8.4%,
P < 0.001) than morning dosing [
7]. However, results from previous studies regarding chronotherapy were inconsistent. In a meta-analysis of 21 randomized controlled trials in 1,993 patients with primary hypertension, there was no significant difference between bedtime dosing and morning dosing for reduction of morning BP [
20]. In a multicenter, randomized, double blind trial that randomized valsartan 320 mg to AM or PM dosing, there was no significant benefit of PM dosing in terms of nocturnal BP or early morning BP reduction [
21]. A randomized crossover trial of 103 patients with relatively well controlled hypertension on ≥ 1 antihypertensive medications also showed that morning and bedtime dosing had no significant difference in daytime or night time BP lowering [
22]. The above mentioned findings might be explained by the fact that while medications with short half-lives might not sufficiently lower nocturnal or early morning BP [
23], the timing of administration would not matter for the majority of antihypertensive drugs with sufficient half-lives once they are in a steady state [
24]. However, as bedtime dosing could allow for peak effect in the early morning, theoretically it should have better efficacy in lowering nocturnal BP in those with non-dipping patterns and nocturnal hypertension. Some hypertensive patients are known to have high percentage of nocturnal hypertension and non-dipping status, such as those with diabetes mellitus (DM), chronic kidney disease (CKD), and obstructive sleep apnea (OSA) [
25‐
28], in whom the benefit of chronotherapy has been demonstrated in some clinical trials. In a randomized, open labeled, cross over study of 41 patients with DM, bedtime administration of antihypertensive medications significantly reduced both nighttime BP (7.5 mmHg, P < 0.001) and 24 h BP (3.1 mmHg, P = 0.014) without significant difference in morning BP surge [
28]. In a prospective non placebo clinical trial of 32 patients with CKD and non-dipping pattern, one antihypertensive drug was shifted from morning to evening. Results showed a decrease in the night/day mean ABP ratio in 93.7% of patients and normal circadian rhythm restored in 87.5% of patients [
29]. In a meta-analysis of five randomized controlled trials of 3732 patients with CKD, bedtime dosing was associated with a 40% reduction (95% CI: 43-84%) in non-dipping patterns and significant decreases in nocturnal systolic BP (SBP: -3.17 mmHg, 95% CI: -5.41 to -0.94 mmHg) and nocturnal diastolic BP (DBP: -1.37 mmHg, 95% CI: -2.05 to – 0.69 mmHg) with a small but significant increase in awake SBP (1.15 mmHg, 95% CI: 0.10–2.19 mmHg) [
30]. Similar to CKD, some data suggest that bedtime dosing might be beneficial in OSA. In a prospective, cross over trial of 41 patients with newly diagnosed hypertension and asymptomatic OSA (apnea-hypopnea index (AHI) ≥ 15/hour), patients received treatment with valsartan or valsartan/amlodipine for eight weeks in a single morning dose followed by an 8-week regimen in a single bedtime dose. Results showed further reduction of nighttime SBP/DBP by 4.4 ± 8.6/2.9 ± 5.6 mmHg (P = 0.007 and P = 0.006, respectively) and increase in dippers from 34 to 61% in the bedtime dosing group [
31]. However, currently there are no data to show that reducing nocturnal hypertension by bedtime dosing could reduce cardiovascular outcomes in patients with CKD or OSA. One other important point to consider with regard to bedtime dosing is that it might be associated with a lower compliance, which might affect BP control in the long term [
12,
32]. In summary, there are no consistent evidence to suggest that routine administration of antihypertensive medications at bedtime could improve nocturnal BP or early morning BP control. However, for cases with uncontrolled nocturnal hypertension and morning hypertension despite sufficient administration of long-acting antihypertensive medications in the morning, bedtime dosing might be considered.