Antihypertensives at night cut CV risk in resistant hypertension

Daniel M Keller

June 29, 2011

Prague, Czech Republic - Taking antihypertensive medications at bedtime significantly reduced risk of cardiovascular events compared with taking the drugs upon awakening for patients with resistant hypertension, Spanish researchers reported here at the European Renal Association/European Dialysis and Transplant Association (ERA/EDTA) 2011 Congress[1].

Previous prospective studies have shown that sleep-time blood pressure (BP) is a better predictor of CVD risk than either a single daytime or a 24-hour BP measurement.

Dr Ramón Hermida (University of Vigo, Spain) said in an interview that his study was designed to test the hypothesis that taking at least one blood-pressure 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 asleep-BP reductions and to preserve or reestablish a normal 24-hour pattern, in which BP drops at night. Hermida and colleagues have previously reported full results of the MAPEC trial, showing that taking antihypertensive drugs at night-time can improve BP control in a heterogeneous group of people with hypertension [2].

Hermida et al's new analysis looked only at the 776 MAPEC men and women with resistant hypertension who 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 the additional medication at any time. None of the nighttime medications was allowed in the morning, meaning that any one drug could not be taken at both times. For controls, who took all medications in the morning, any additional BP medications had to be taken in the morning.

BP was measured at baseline at 20-minute intervals throughout waking hours and at 30-minute intervals at night. Periods of daytime activity and nocturnal sleep were determined using a wrist actigraph. Median follow-up was 5.4 years.

Nighttime dosing reduces risk of CV events

The group of subjects assigned to take at least one medication at bedtime had significantly better BP control during sleep. They had a greater reduction in mean BP during sleep and had prolonged asleep-BP declines, with a more normal dipping pattern, compared with subjects taking all their antihypertensive drugs in the morning.

The decrease in asleep BP was the only independent predictor significantly associated with survival when other characteristics of ambulatory blood-pressure monitoring (ABPM), such as daytime BP mean or morning surge in BP, were included in a Cox regression model. Subjects with nighttime dosing had a lower relative risk of total CV events and major CV events, compared with those taking all BP medications in the morning.

Primary end point (events/1000 patient-years)

Outcome Dosing on awakening (n =391) Dosing at bedtime (n=385) p
Total events 50.48 21.58 <0.001
Total deaths 7.42 3.16 0.028
Cardiovascular deaths 3.46 1.05 0.042
Other cause of death 3.96 2.11 0.166
Cardiov ascular events 17.32 8.95 0.004
Cerebrovascular events 7.42 2.11 0.006
Heart failure 10.89 3.68 0.002
Other events 7.42 3.68 0.043
Survival advantage with nighttime dosing

Kaplan-Meier analysis showed that at 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 (p<0.001). In calculating CVD event-free survival, the researchers found a 0.89 relative risk for each 5-mm-Hg decrease in the asleep-BP mean.

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 morning.

"They also provide additional effects, [such as] better metabolic control, potential reduction in glucose, and . . . highly significant reduction in albuminuria." he said. "So for those reasons all together, and taking into account the significant impact on nighttime blood pressure and cardiovascular risk, those clinically explain the results that we found in this study."

Speaking about the BP study as a whole and not just the results in resistant hypertension, Hermida said that reductions in CV risk were apparent for the bedtime-dosing group compared with the morning group even when the individual end points of CV mortality, MI, development of heart failure, or stroke were analyzed separately. "These results applied for the whole population as well as in particular for patients with diabetes analyzed separately or for 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 as compared with the general population."

He added that antihypertensive drugs are normally recommended once a day without the physician specifying 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," 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, and in addition, the best way of actually achieving this therapeutic goal is by prescribing antihypertensive medications in the evening rather than in the morning," he said.

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

Commenting on the findings, Dr J onathan Odum (New Cross Hospital, Wolverhampton, UK) called the findings as "very interesting." If corroborated by further research, the work could have "substantial implications for at what time patients take their medication." Even now, he said, he sees no reason not to have patients take their antihypertensive medications at bedtime and would be interested in seeing the effect of nighttime dosing on symptomatic daytime hypotension.

The study received no commercial funding. Hermida and Odum reported no disclosures.




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