The Hygia Chronotherapy Trial compared clinical results for patients taking their antihypertensive medication upon awakening with those taking their medication at bedtime.1 Ambulatory blood pressure (BP) readings, sleep time BP, and cardiovascular outcomes were all improved in those taking medication at bedtime. A 45% relative reduction in cardiovascular disease (CVD) events was achieved by those consuming their blood pressure medications at bedtime compared to those taking medications upon awakening. The absolute reduction in risk was 5.4%.2
This multi-center prospective trial assigned 19,084 hypertensive patients to take their entire daily antihypertensive regimen either at bedtime or upon awakening.1 Baseline characteristics of the two groups did not differ with respect to age, gender, BP, body mass index, waist circumference, or the presence of risk factors for or history of CVD. The proportion of patients taking statins was similar in both groups.
Baseline ambulatory blood pressure monitoring (ABPM) was performed for 48 hours, and again at least annually for a 6.3-year follow-up period.1 Adjusting for age, gender, type 2 diabetes, chronic kidney disease, smoking, high-density lipoprotein cholesterol, previous CVD events, and other potentially confounding factors, those taking bedtime medication had a significantly lower hazard ratio (HR) for a subsequent CVD event (0.55, 95% confidence interval [CI] [0.50 – 0.61]). Significantly lower hazard ratios (all p values <0.001) were also found for each specific event including CVD death (HR 0.44, 95% CI [0.34 – 0.56]), myocardial infarction (HR 0.66, 95% CI [0.52 – 0.75]), coronary revascularization (HR 0.60, 95% CI [0.47 – 0.75]), heart failure [HR 0.58, 95% CI [0.49 – 0.70]), and stroke (HR 0.51, 95% CI [0.41 – 0.63]).
In addition, ABPM, absolute BP readings during sleep, and relative declines in BP between waking and sleeping were all improved for those taking their antihypertensives at bedtime.1 Improvements that occurred during sleep did not interfere with daytime BP control. Systolic blood pressure normally dips between 10% to 20% during sleep, and for reasons that are not completely understood, the absence of this dipping increases the risk of CVD. In the Hygia study, the greater sleep-time relative BP decline resulted in a significantly lower prevalence of non-dipping in those taking medication at bedtime.
A Cochrane Systematic review published in 2011 evaluated dosing-time-of-day effects of antihypertensives on blood pressure and cardiovascular events.3 Although there did seem to be a trend of improved blood pressure control in the evening dosing groups, there was no randomized clinical trial that reported on cardiovascular disease outcomes. Previous studies have demonstrated that the time of administration alters the BP-lowering effects of certain antihypertensive medication and may impact some mechanisms of BP regulation that are governed by circadian rhythms.3–6 The renin-angiotensin-aldosterone system, for example, that contributes to BP regulation reaches its peak activity during sleep. Angiotensin-II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors that are taken at bedtime result in enhanced reduction in BP during sleep with no detrimental effect on BP during waking hours.4,7 In addition, mean BP reading during sleep determined by ABPM has been shown to be a more sensitive marker of CVD risk than daytime office BP, 24-hour ABPM mean, or ABPM awake mean.1,8 The Hygia Chronotherapy Trial was unique in comparing bedtime dosing with morning dosing of a large cohort of hypertensives in a primary care setting that measured both BP control and major CVD outcomes.1
The bedtime cohort in the Hygia study had improved renal function as measured by significantly lower serum creatinine, albumin/creatinine ratio, and higher estimated glomerular filtration rate.1 Low-density lipoprotein cholesterol was significantly lower and high-density lipoprotein cholesterol was significantly higher in the bedtime cohort compared to the morning cohort, although the absolute differences were small.
Patients in the Hygia study continued on the medications they were taking at the time of enlistment into the study.1 There was a slightly higher percentage of diuretics and lower percentage of calcium channel blockers (CCBs) in the morning treatment group. Approximately 69% of participants were taking ARBs or ACE inhibitors as monotherapy and 13% were taking CCBs. The most frequently prescribed dual therapy was an ARB or ACE inhibitor with a diuretic (43%) or with a CCB (26%). The authors of the Hygia study point out that there may be medications which do not result in better CVD outcomes when given at bedtime. The bedtime administration of Controlled Onset Extended-Release (COER) verapamil, as studied in the Controlled Onset Extended-Release (COER) Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, for example, showed no difference in CVD outcomes when compared with morning treatment with atenolol or hydrochlorothiazide.9,10 The COER verapamil is a CCB specially formulated to achieve peak drug concentrations upon morning arising, and as a result increased the incidence of nighttime non-dipping, which raises CVD risk. In the case of COER verapamil, morning dosing may be preferable to nighttime dosing.
- Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. October 2019. doi:10.1093/eurheartj/ehz754
- NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals. https://www.jwatch.org/na50538/2019/12/26/antihypertension-medications-might-best-be-taken-night. Accessed January 24, 2020.
- Zhao P, Xu P, Wan C, Wang Z. Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database Syst Rev. 2011;(10):CD004184. doi:10.1002/14651858.CD004184.pub2
- Hermida RC, Ayala DE, Smolensky MH, Fernández JR, Mojón A, Portaluppi F. Chronotherapy with conventional blood pressure medications improves management of hypertension and reduces cardiovascular and stroke risks. Hypertens Res. 2016;39(5):277-292. doi:10.1038/hr.2015.142
- Portaluppi F, Tiseo R, Smolensky MH, Hermida RC, Ayala DE, Fabbian F. Circadian rhythms and cardiovascular health. Sleep Med Rev. 2012;16(2):151-166. doi:10.1016/j.smrv.2011.04.003
- Wang C, Ye Y, Liu C, et al. Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis. Intern Med J. 2017;47(8):900-906. doi:10.1111/imj.13490
- Bowles NP, Thosar SS, Herzig MX, Shea SA. Chronotherapy for hypertension. Curr Hypertens Rep. 2018;20(11):97. doi:10.1007/s11906-018-0897-4
- Hermida RC, Ayala DE, Mojón A, Fernández JR. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol. 2011;58(11):1165-1173. doi:10.1016/j.jacc.2011.04.043
- Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289(16):2073-2082. doi:10.1001/jama.289.16.2073
- White WB, Black HR, Weber MA, Elliott WJ, Bryzinski B, Fakouhi TD. Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product. Am J Cardiol. 1998;81(4):424-431. doi:10.1016/s0002-9149(97)00935-1