By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: Taking all antihypertensive agents before bed vs. upon awakening in hypertensive patients showed there was less hypertension during sleep and few cardiovascular events over a six-year follow-up.

SOURCE: Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: The Hygia Chronotherapy Trial. Eur Heart J 2020;41:4565-4576.

Although known to reduce sleeping blood pressure (BP), there are few data on the effect of bedtime administration of the entire daily dose of antihypertensive medications vs. administration upon awakening in the morning on BP control and cardiovascular (CV) outcomes. The Hygia Chronotherapy Trial was a randomized, multicenter, controlled, open-label, blinded, endpoint study of whether bedtime administration is superior. Hermida et al conducted this work in 40 primary care practices in Northern Spain, using 24-hour ambulatory BP (ABP) measurements to diagnose and manage hypertension. They recruited more than 22,000 patients with hypertension. Each participant underwent confirmatory 48-hour ABP measurements. After excluding those with an invalid study or normotension in untreated subjects, the authors randomized 19,168 subjects to all antihypertensive pharmacologic treatment at awakening or at bedtime. Pregnant patients, rotating shift workers, those with secondary hypertension, those with known CV disease, and those with renal failure all were excluded. A minimum follow-up of one year was required, with a target of five years. Eighty-four subjects were excluded for failing to follow up at one year. In the final study population (19,084), the mean age was 61 years, and 56% were men. Each of the 292 physicians involved chose the antihypertensive drugs. At each outpatient visit (at least annually), 48-hour ABP was performed, with the subject noting in a diary when he or she retired and awakened. The primary outcome was a combination of myocardial infarction, coronary revascularization, heart failure, ischemic stroke, or CV death.

The bedtime group achieved lower sleeping BP readings than the morning group, but there was no difference in awake BP measurements. Sleep hypotension was rare (0.3% of participants), and there was no difference between groups. Poor drug compliance was about 3% for both groups. CV events occurred in 1,752 subjects over the median six-year follow-up. The adjusted hazard ratio (HR) for the combined primary endpoint in the bedtime group vs. the morning group was 0.55 (95% CI, 0.50-0.61; P < 0.001). The HR for CV death was 0.44 (95% CI, 0.34-0.56; P < 0.001). The HR for hemorrhagic stroke was 0.39 (95% CI, 0.23-0.65; P < 0.001). The HR for heart failure was 0.58 (95% CI, 0.49-0.70; P < 0.001). Total adverse events were not significantly different between groups (6.7% morning, 6% bedtime). No subgroup demonstrated better outcomes with morning drug administration.

The authors concluded bedtime administration of all antihypertensive medications resulted in lower sleeping BP control and markedly reduced CV events compared to taking all BP medications upon awakening.

COMMENTARY

Prior studies have shown ABP is superior for predicting outcomes in hypertensive patients, especially if blunted nocturnal BP reduction is detected (non-dipper pattern). Also, studies have demonstrated that bedtime administration of at least one antihypertensive medication abrogates the non-dipper pattern of sleep BP and lowers CV disease risk, but these studies did not include a control arm. In a randomized, controlled study, the authors observed 2,000 patients who experienced fewer CV events with bedtime drug administration compared to awakening.1

The strengths of the Hygia trial include its large size (almost 20,000 patients) and the use of primary care centers. Asking patients to keep diaries to establish the circadian pattern of sleep and awake periods was helpful. The 48-hour ABP tactic improved reproducibility. In addition, there was a long follow-up period, with a robust number of CV events. The Hygia study showed there was better sleeping BP control with bedtime drug administration without loss of awake BP control. There was less non-dipping observed in the bedtime group and markedly fewer CV events. Finally, bedtime administration was safe, and patient adherence was excellent.

But there were some weaknesses. First, the subjects were all Spanish Caucasians. Transferability to other ethnic groups is unknown. Second, the medication regimens used were not prescribed by the study protocol; rather, each participating physician devised his or her own treatment program. They were given the Spanish government’s documents on selecting drugs for BP control, but how much they applied these recommendations is unknown. Third, the authors could not separate the effects of bedtime administration in dippers and non-dippers. Interestingly, there were other positive results of bedtime administration. Serum creatine and LDL cholesterol levels were lower, and HDL cholesterol levels were higher in the bedtime group.

How do clinicians translate these finding into practice? Not all medications may be well-tolerated when taken at bedtime (e.g., diuretics). In the Hygia study, there was less diuretic use in the bedtime group. However, there are studies that showed changing one medication to bedtime produced similar results as Hygia, and the medications shifted usually were calcium blockers or ACEI/ARBs. Culling one medication would thwart the triple-drug combination pills that are so popular with patients, but would solve the diuretic-before-bed issue.

The authors of other studies have suggested ACEI/ARBs would work best if taken at bedtime since the renin-angiotensin-aldosterone system is more active during sleep. The asleep mean SBP was 115 mmHg in the Hygia study, and hypotension during sleep was rare (0.3%). Still, the medications used here were calibrated by ABP, which usually would not be the case in U.S. clinical practice.

Finally, splitting the antihypertensive agents might reduce compliance if no other medication were taken twice a day. Thus, there are advantages to taking all the BP medications at once. I have moved at least one medication to the evening when patients note early morning hypertension, but may have to rethink my usual all-in-the-morning routine advice. Further trials that include more diverse populations would help me change my practice.

REFERENCE

  1. Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: Results of the MAPEC study. Chronobiol Int 2010;27:1629-1651.