June 19, 2021
Hermida, R. et al.
Hypertension affected about 847 million people in the world in 2015. It resulted to 143 million disability-adjusted life years and accounted for 14% of total deaths in the same year.1 Annually, hypertension is said to claim 9.4 million lives worldwide.2
Cardiovascular disease remained to be the leading cause of mortality globally with 17.9 million people dying from it in 2016. Heart attack and stroke represent the most common forms of CVD.3 Hypertension is part and parcel of cardiovascular disease (CVD). It increases the risk of coronary heart disease and ischemic and hemorrhagic stroke twofold.2
Numerous strategies can be used to achieve a normal blood pressure (BP). Healthy diet, lifestyle, and exercise are some examples. Antihypertensive medications, when used adequately and appropriately, can target the blood pressure to normal. Aside from these, the form of BP measurement and monitoring also matter in terms of achieving BP control.
Ambulatory blood pressure (ABP) can be used as a predictor of CVD risk. It is a dynamic predictor of blood pressure since it helps identify whitecoat, masked, and nocturnal hypertension.4 Related to this is the timing of antihypertensive administration. The most vital question now is the best time to give antihypertensive.
Hermida R. et al studied the effects of bedtime antihypertensive medication on cardiovascular risk reduction and compared the timing of administration with the usual upon waking up intake. They published the results of the trial they named Hygia chronotherapy in 2019.5 This technical review article discusses the main points of the said trial.
The study by Hermida, R. et al primarily aimed to identify better cardiovascular risk reduction with bedtime antihypertensive medication administration rather than the usual upon waking up administration.
The trial also aimed to achieve better ABP control with bedtime administration of antihypertensive medication. Specifically, it assessed CVD risk, included ABP monitoring in the routine management of hypertension, evaluated treatment response to bedtime antihypertensive medication, and reassessed CVD risk reduction after the chronotherapy trial.
Control of blood pressure cannot be overemphasized since hypertension doubles the risk of CVDs. Bedtime antihypertensive administration may result to better blood pressure control, specifically ambulatory blood pressure. This, in turn, decreases the risk of CVD.
The Hygia Chronotherapy trial is a multicenter, prospective, controlled trial conducted by 292 trained investigators in 40 primary care centers in Northern Spain from 2008 to 2018. Study subjects were hypertensive Spanish men and women aged 18 and above.
Pregnant patients, those who have secondary hypertension, history of CVD and end organ damage, life-threatening arrhythmia, and those with a history of alcoholism or narcotic addiction, acquired immunodeficiency syndrome, intolerance to ABPM, and those with nighttime or rotating shift-work employment were excluded from the study.
A total of 19084 hypertensive subjects underwent the trial. Their mean age was 60.5±13.7 (mean ± SD) years. Median follow-up was set at 5 years with a minimum follow-up of more than a year for each study subject.
Subjects were randomized to either ingestion of entire daily dose of a single or combination antihypertensive at bedtime (n=9552) or upon awakening (n=9532). The following medications were used by the study subjects: Angiotensin receptor blocker (ARB), ACE-inhibitors (ACE-I), Calcium channel blockers (CCB), Beta blockers (BB), and diuretics.
Three consecutive Office-based blood pressure (OBP) readings were recorded at inclusion and at every clinic visit and follow-up. ABP monitoring was done thereafter, measuring SBP, DBP, and heart rate from 7 AM to 11 PM every 20 minutes and was continued at night every 30 minutes up to of 48 hours. ABPM was measured for 48 hours to accurately assess CVD risk, determine mean BP values, and identify dippers or subjects whose BP went down at night.
There was no significant difference in terms of demographic and clinical profile of both treatment-time groups at baseline. There was also no significant difference between the daytime OBPM, average ABP values, and prevalence of non-dipping in both groups.
At the end of the trial, there was a significant reduction in the number of prescribed antihypertensives among the bedtime group. The levels of creatinine and LDL cholesterol were also significantly lower in the bedtime group than the group who took the antihypertensive upon awakening. Moreover, HDL cholesterol and eGFR was significantly higher in the bedtime group.
Significantly lower asleep SBP and DBP was observed among the subjects in the bedtime group. In addition, there was a significantly lower number of subjects with the higher CVD risk nondipper BP pattern in the bedtime treatment group compared to the upon-waking group.
There were 1752 subjects who had experienced a primary CVD outcome (myocardial infarction; coronary revascularization, heart failure, stroke, and death) during the median followup of 6.3 years. There was a significantly better risk reduction for CVD death, hemorrhagic stroke, heart failure, and peripheral artery disease for the bedtime treatment group.
A significantly lower Hazard Ratio for primary CVD outcome was observed among subjects in the bedtime treatment group regardless of the subject’s age, sex, hypertension treatment at baseline, smoking habit, awake or asleep SBP mean, dipper or nondipper classification, and presence or absence of diabetes, CKD, or previous CVD event.
Only 0.3% of participants experienced sleep-time hypotension (39 from the upon-waking treatment group and 26 from the bedtime group) during the entire 6.3 year median follow-up. This very low rate was due to strict and periodic ABP monitoring.
Bedtime antihypertensive administration resulted to significant improvement in asleep ABP control and significantly reduced CVD morbidity and mortality. It was also found that bedtime antihypertensive administration was as safe as upon-waking up intake.