PRAGUE—Taking antihypertensive medications at bedtime significantly reduces cardiovascular disease (CVD) risk compared with ingesting the drugs upon awakening, according to researchers.

Ramón Hermida, PhD, Director of the Laboratory of Bioengineering and Chronobiology at the University of Vigo in Vigo, Spain, reported that in resistant hypertension the reduction in blood pressure (BP) while asleep was the strongest predictor of survival. Having patients take their medications at bedtime is a cost-effective and simple strategy to achieve adequate asleep BP reductions and to preserve or re-establish a normal 24-hour pattern of BP in which BP drops at night (“dipping”).

Dr. Hermida, who reported study findings at the European Renal Association-European Dialysis and Transplant Association 48th congress, told Renal & Urology News that previous studies found that sleep-time BP is a better predictor of CVD risk than is the awake BP or 24-hour BP means. All previous studies, however, were limited by reliance on a single baseline ambulatory BP monitoring (ABPM) profile on each participant at the beginning of the study, so they could not follow possible changes in the pattern or level of BP over the years of follow-up. The current studies were designed to test the hypothesis that taking at least one BP medication at bedtime would be more effective in reducing CVD risk than would conventional dosing of taking all medications in the morning.

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The 776 participants had a mean age of 61.6 years, were equally balanced between men and women, and were randomly assigned to take all their prescribed antihypertensive medications upon awakening or at least one of them at bedtime. The bedtime group originally took all BP medications at night, but if they required additional medication during the study at the discretion of their physicians, they could take them in the morning or at bedtime. None of the night time medications was allowed in the morning, meaning that any one drug could not be taken at both times.

Investigators measured BP at baseline and at 20-minute intervals throughout waking hours and at 30-minute intervals at night. A wrist actigraph measured physical activity to determine periods of daytime activity and nocturnal sleep. Identical measurements occurred annually, or quarterly if treatment adjustments were required. Median follow-up was 5.4 years (range 0.5-8.5 years).

The group of subjects assigned to take at least one medication at bedtime had significantly better BP control during sleep, with a greater reduction in the asleep BP mean and prolonged asleep BP declines toward a more dipping pattern as compared to subjects taking all their BP medications in the morning.
The decrease in BP while asleep was the only independent predictor significantly associated with survival when other characteristics of the ABPM (e.g., daytime BP mean or morning surge in BP) were included in a Cox regression model. Subjects taking medication at bedtime had a significant 62% decreased relative risk of total events compared with those taking all BP medications in the morning. Additionally, they had a significant 65% decreased relative risk of major CVD events (cardiovascular-related deaths, myocardial infarction, ischemic or hemorrhagic stroke).

After eight years of follow-up, participants taking at least one BP medication at bedtime had an event-free survival of about 81% compared with approximately 64% for people taking all their BP medications in the morning. Each 5 mm Hg decrease in asleep BP was associated with an 11% increased likelihood of CVD event-free survival.

Dr. Hermida explained that the renin-angiotensin-aldosterone system activates at night, so ACE inhibitors and angiotensin receptor blockers all have greater efficacy if given in the evening compared with the morning.

He added that these drugs are normally recommended once a day without the physician specifying a time of day, and surveys have shown that more than 80% of all patients with hypertension in Spain take all their antihypertensive drugs in a single morning dose, mostly with breakfast.

“We found… no clinical meaning behind this kind of a schedule,” Dr. Hemrida said, “and the results from this first prospective study investigating the potential benefits of chronotherapy actually indicate that looking into the circadian blood pressure pattern with ambulatory blood pressure [monitoring] is the most sensible way of choosing proper timing for hypertension therapy. From the point of view of cardiovascular risk reduction and renal protection what we found is that most if not all of the hypertensive medications perform much better when ingested in the evening.”

Dr. Hermida recommends incorporating ambulatory BP measurements as a required clinical test for cardiovascular risk assessment, stratification, and following the BP control status of patients receiving treatment.