Bedtime administration of antihypertensives, while safe, failed to provide additional cardiovascular benefit when put to the test in a randomized trial.

Adults had about the same risk of major cardiovascular events or death over a median 4.6 years whether they had been randomized to take their blood pressure (BP)-lowering medications at bedtime or in the morning (2.3 vs 2.4 per 100 patient-years, adjusted HR 0.96, 95% CI 0.77-1.19).

“Antihypertensive medication administration time did not affect the risks and benefits of blood pressure-lowering medication and instead should be guided by patient preferences,” wrote the BedMed researchers led by Scott Garrison, MD, PhD, of the University of Alberta in Edmonton, Canada.

Published in JAMAopens in a new tab or window, BedMed was a trial of over 3,200 individuals in the primary care setting.

A sister study from Garrison’s group, the BedMed-Frail trial, similarly found that nursing home residents (median age 88 years) fared no better or worse if they starting taking their antihypertensives at bedtime.

BedMed therefore seems to put the controversy of bedtime antihypertensivesopens in a new tab or window to rest since the concept emerged with the MAPEC studyopens in a new tab or window. It also opens the door to more flexible timing.

“Loosening the rules on time of dosing may facilitate better supervision by caregivers, who may be able to provide assistance or oversight later in the day due to other responsibilities. At the end of the day, timing of medications doesn’t matter as much as consistency in taking them,” stressed Sandra Taler, MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorialopens in a new tab or window.

The theory underlying the evening administration of these drugs was that it may lower one’s sleep-time BP and therefore be a better fit for a person’s circadian rhythms. A positive trial that favored this concept, the Hygia randomized trialopens in a new tab or window from Spain, was nonetheless criticized for the implausibility of its findings and the trial’s possibly faulty randomization process.

More recently, the TIME trialopens in a new tab or window found that morning users of BP drugs had about the same 5-year risk of myocardial infarction, stroke, or vascular death as nighttime users. However, the study had the caveats of poor adherence and a low-risk population.

In BedMed, participants had a self-reported adherence to their assigned dose schedule of 83% for the bedtime group versus 95% for the morning group. The cohort was arguably higher risk because it allowed the enrollment of people taking more than one BP-lowering medication.

“The most important finding, that BP medication administration at night did not affect cardiovascular event rates or survival, is clear,” Taler noted.

“The addition of a subgroup of very advanced age with attention to risks of overtreatment adds additional reassurance that time of dosing is not a safety issue. We can all sleep better at night whether medications are dosed before or after bedtime hours,” she wrote.

BedMed was an open-label trial with 436 participating primary care clinicians in Canada and included adults with hypertension who were randomized to bedtime administration (n=1,677) or morning administration (n=1,680) of all once-daily antihypertensives.

Median age was 67 years, and 54% were women. Comorbidities included diabetes (18%), known coronary artery disease (11%), and chronic kidney disease (7%).

Nearly 54% of the group were on monotherapy to lower their blood pressure. The antihypertensives used included angiotensin-converting enzyme inhibitors (36%), angiotensin receptor blockers (30%), calcium channel blockers (29%), diuretics (27%), combination pills (18%), and beta-blockers (17%).

Primary outcome events included all-cause death and hospitalization/emergency department visits for stroke, acute coronary syndrome, or heart failure.

Garrison and colleagues reported that no individual component of this outcome favored either timing strategy.

There was also no difference in falls or fractures, new glaucoma diagnoses, or cognitive decline between groups.

The BedMed investigators conducted a substudy of ambulatory BP monitoring (ABPM) about 10 months into the trial, which found similar mean daytime BP unchanged with nighttime dosing but overnight mean BP significantly reduced by around -7.4/2.7 mm Hg.

Many people had declined to participate in the ABPM substudy, however, and the rest of the cohort only received telephone or email follow-up. The trial had also been stopped early due to difficulties recruiting, with fewer primary outcomes than Hygia and TIME, the authors noted.