Time Antihypertensives Taken Doesn’t Matter: New Trials

LONDON — Two new trials have confirmed that time of day does not matter when it comes to taking antihypertensive medication.
Both the BedMed and BedMed-Frail trials, presented at the European Society of Cardiology (ESC) Congress, showed no difference in death or cardiovascular events between patients taking their antihypertensive medication at night and those taking it in the morning.
The timing of when to take blood pressure–lowering medication became an issue when Spanish researchers reported results from the 2010 MAPEC trial and the 2019 Hygia Chronotherapy Trial, which showed large reductions in cardiovascular events when antihypertensive medications were taken at bedtime as opposed to in the morning.
To see if this finding could be confirmed, other groups conducted similar trials.
Results from the first of these, the 2022 TIME trial, showed no difference in outcomes between morning and nighttime antihypertensive dosing.
And now the two BedMed studies show the same result, which should settle the issue, said Scott Garrison, MD, PhD, from the University of Alberta in Edmonton, Canada, who was lead investigator of both trials.
“We are the second of two teams of independent investigators to refute the Spanish group’s findings. I think we can now say with confidence that the benefits and risks of antihypertensive medications do not vary with the time of day they are used,” he said. 
The issue of when to take antihypertensive medication stemmed from the observation that high overnight blood pressure poses greater risk for heart attack and stroke than does high daytime blood pressure, Garrison explained. This led to the suggestion that taking an antihypertensive at bedtime may do a better job of lowering overnight blood pressure, which could translate into a reduction in cardiovascular events.
The BedMed Trials
In the BedMed trial, 3357 hypertensive patients in Canada were randomly assigned to either bedtime or morning dosing of their antihypertensive medication. Most patients were taking one (54%) or two (33%) once-daily antihypertensive medications.
The BedMed-Frail trial had a similar design but involved 776 patients from 17 residential care homes in Alberta. In both trials, patients with a history of glaucoma were excluded. 
Both trials showed no harm, but also no benefit, of taking antihypertensives at bedtime rather than in the morning.
The primary outcome in both trials was death or hospitalization for acute coronary syndrome, stroke, or heart failure.
In the BedMed trial, during a follow-up period of up to 6 years, more patients who took their medication at bedtime than in the morning experienced a primary outcome event (9.7% vs 10.3%; hazard ratio [HR], 0.96; 95% CI, 0.77-1.19).
In the BedMed-Frail trial, which had a follow-up period of up to 42 months, primary outcome event rates were 40.6% in the bedtime-dosing group and 41.9% in the morning-dosing group (HR, 0.88; 95% CI, 0.71-1.11).
There was no difference between bedtime dosing and morning dosing in terms of safety events, which included postural hypotension, falls, and vision-related and cognition-related adverse effects.
“Collectively, the BedMed trials, together with TIME, resolve uncertainty surrounding whether or not bedtime antihypertensive prescribing should be actively promoted, and show that it shouldn’t,” Garrison said.
People should take their antihypertensives at a time that best suits them, he added.
Some medications do have timing-related side effects. “For example, calcium blockers are more likely to cause ankle swelling when used in the morning, whereas diuretics are more likely to cause patients to wake in the night needing to urinate when taken at bedtime,” he said.
And some people might want to take their blood pressure medications at a particular time so that they can take all of their medications at once. 
“Our findings suggest that blood pressure–medication timing can be adjusted in whatever way people prefer, and that meds should be taken whenever it is most convenient and least likely to be forgotten,” Garrison said.
‘Hugely Controversial Topic’
The timing of antihypertensive medication has been a hugely controversial topic in recent years, said Isla Mackenzie, MD, from the University of Dundee, United Kingdom, who was discussant of the BedMed trials at the ESC Hotline session.
The MAPEC and Hygia trials showed “what many consider to be an implausibly large benefit” on cardiovascular outcomes with nighttime dosing of antihypertensives, she said. However, the methods of those trials have been questioned.
In the TIME trial, there was no difference between bedtime and morning antihypertensive dosing in terms of the composite primary endpoint of cardiovascular death, myocardial infarction, and stroke; the HR of 0.95 was very similar to that reported in the BedMed trials.
Both BedMed trials were well designed and well conducted, and they had very relevant safety endpoints. It was good to see the BedMed-Frail trial conducted in patients from residential homes, which is a very underserved population, Mackenzie said.
With three trials now showing similar results, “I advise my patients to take their antihypertensive medication at a regular time of day when they will best remember to take their tablets,” Mackenzie said.
 
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