A simple no-cost intervention lowers the risk for cardiovascular (CV) disease in patients with hypertension. Spanish researchers, reporting at the XLVIII European Renal Association-European Dialysis and Transplant Association Congress, showed that taking antihypertensive medications at bedtime significantly reduced risk, compared with taking the drugs in the morning, upon awakening, for patients with resistant hypertension.

Previous prospective studies have shown that sleep-time blood pressure (BP) is a better predictor of CV disease (CVD) risk than either a single daytime or a 24-hour BP measurement. However, all those studies relied on a single baseline ambulatory BP monitoring (ABPM) profile for each participant, so the researchers could not follow changes in the pattern or level of BP over the years of follow-up.

Ramón Hermida, PhD, director of the laboratory of bioengineering and chronobiology at the University of Vigo in Spain, told Medscape Medical News that this study was 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 in which patients take all their BP medications in the morning. He added that having patients take their medications at bedtime is a cost-effective and simple strategy to achieve adequate BP reductions during sleep and to preserve or reestablish a normal 24-hour pattern in which BP drops at night (dipping pattern).

This is a substudy of a larger prospective randomized open-label study of people with hypertension. In this phase, 776 participants with resistant hypertension (mean age, 61.6 years), equally balanced between men and women, were randomly assigned to take all their prescribed antihypertensive medications upon awakening or to take at least 1 of them at bedtime.

The bedtime group originally took all BP medications at night, but if they were prescribed additional medication during the study (at the discretion of their physicians), they were allowed to take the additional medication at any time. The control group took all medications in the morning, and any additional BP medications had to be taken in the morning.

At baseline, BP was measured in 20-minute intervals during waking hours and in 30-minute intervals at night. Periods of daytime activity and nocturnal sleep were determined using a wrist actigraph. The researchers carried out these measurements annually, or quarterly if treatment adjustments were required. Median follow-up was 5.4 years (range, 0.5 to 8.5 years).

Bedtime Dosing Reduces Risk of CV Events

Those in the bedtime group had significantly better BP control during sleep; they had a greater reduction in mean BP and had prolonged BP declines, with a more normal dipping pattern, than those in the control group.

The decrease in BP during sleep was the only independent predictor significantly associated with survival when other characteristics of the ABPM, such as mean daytime BP and morning surge in BP, were included in a Cox regression model. Those in the bedtime group had a lower relative risk of total CV events than those in the control group (relative risk, 0.38; P < .001). The difference in relative risk of major CVD events (CVD-related death, myocardial infarction, ischemic or hemorrhagic stroke) between the bedtime and control groups was 0.35 (P = .002).

Survival Advantage With Bedtime Dosing

Kaplan–Meier analysis showed that at 8 years of follow-up, the bedtime group had more event-free survival than the control group (approximately 81% vs 64%; P < .001). In calculating CVD event-free survival, the researchers found a relative risk of 0.89 for each 5 mm Hg decrease in mean BP during sleep.

Dr. Hermida explained that the renin-angiotensin-aldosterone system activates at night, so angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers are more effective if given at night.

"They also provide additional effects, [such as] better metabolic control, potential reduction in glucose, and . . . highly significant reduction in albuminuria." he said. Those effects, "taking into account the significant impact on nighttime blood pressure and cardiovascular risk, clinically explain our findings."

Speaking about the BP study as a whole, not just the results in resistant hypertension, Dr. Hermida said that reductions in CV risk were apparent in the bedtime group, compared with the control group, even when the individual end points of CV mortality, myocardial infarction, development of heart failure, and stroke were analyzed separately. "These results applied to the whole population, as well as in particular to patients with diabetes analyzed separately and to patients with chronic kidney disease, also analyzed separately," he said. "These two groups are relevant because they are characterized by a significantly higher cardiovascular risk, compared to the general population."

He added that it is recommended that antihypertensive drugs normally be taken once a day; physicians don't specify a time of day. 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, 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," Dr. Hermida said. "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," including all classes of antihypertensive drugs.

"Controlling nighttime blood pressure needs to be considered as a therapeutic target for cardiovascular risk reduction; the best way of actually achieving this therapeutic goal is by prescribing antihypertensive medications in the evening," he said.

Dr. Hermida recommends incorporating ABPM as a required clinical test for CV risk assessment and stratification, and to follow the BP control status of patients receiving treatment.

Jonathan Odum, MD, medical director at the Royal Wolverhampton Hospitals NHS Trust, and consultant nephrologist at New Cross Hospital in the United Kingdom, who was not involved in the study, toldMedscape Medical News that he sees the findings as "very interesting. If substantiated in larger studies, the effect of taking medication at bedtime and lowering nocturnal blood pressure significantly — with its impact on mortality and risk factors — will have substantial implications for what time patients take their medication." He said he sees no reason not to have patients take their antihypertensive medications at bedtime even now, and would be interested in seeing the effect of nighttime dosing on symptomatic daytime hypotension.

The Spanish group's main study results were published last year in Chronobiology International (2010;27:1629-1651). A substudy of patients with type 2 diabetes was recently published in Diabetes Care (2011;34:1270-1276).

The study received no commercial funding. Dr. Hermida and Dr. Odum have disclosed no relevant financial relationships.

XLVIII European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress: Abstracts Sa029 and Sa030. Presented June 25, 2011.

Daniel M. Keller, PhD • Medscape Medical News © 2011 WebMD, LLC