Christopher Labos, MD CM, MSc
Does it matter when you take your blood pressure medications? This question has proved surprisingly hard to answer. While one hopes the value of treating hypertension is beyond doubt, we’ve been debating, discounting and re-debating whether the timing of drug administration — morning vs night — matters.
The recently published OMAN trial reignited a debate that has been marred by controversy, flip-flopping evidence, accusations that randomized trials weren’t actually randomized, and results so spectacular that some people think they can’t possibly be true.
From HOPE to the Hygia Controversy
If you haven’t been keeping track, here’s the story so far. In key trials such as HOPE, patients received ramipril (or placebo) in the evening. But convenience and simplicity mean that most people wake up and take all their medications in one go. It may not be strictly speaking evidence-based practice, but it does help with compliance. After all, medications only work if you remember to take them.
“Some people have a system that they take pills at night, and some people have a system they take pills in the morning,” says Swapnil Hiremath, MD, MPH, nephrologist and professor at the University of Ottawa. “I think that’s what’s important.”
Swapnil Hiremath, MD, MPH
The debate heated up with the Hygia Chronotherapy Trial, which claimed to show that bedtime dosing compared with morning dosing cut the risk for cardiovascular death, stroke, myocardial infarction, heart failure, hemorrhagic stroke, and all-cause mortality by half. The dramatic benefit was met with skepticism by some. Questions arose about whether Hygia was a randomized controlled trial at all or just a prospective cohort study. The European Heart Journal, which published the trial, issued a statement of concern, but their investigation did not find evidence of any fraud or wrongdoing. Given the controversy, many people looked forward to the BedMed and TIME studies to settle the issue.
Fast-forward 4 years and one pandemic later. Both BedMed and TIME showed no difference in outcomes for night vs morning dosing of antihypertensives. In brief, BedMed was a randomized trial of almost 3500 Canadian primary care patients followed up for 4.6 years. Taking medications at night vs morning had no effect on death, cardiovascular outcomes, cognitive outcomes, or risk for falls. The TIME study randomly assigned more than 20,000 UK adults to morning or evening drug administration with 5.2 years of follow-up. There was no difference in the primary endpoint of vascular death or hospitalization, nor was there any difference in all-cause mortality between dosing strategies.
OMAN Reignites The Debate
By most standards, two large, randomized studies from different groups in quick succession would have settled the issue. But the publication of the OMAN trial has re-ignited the debate. One might wonder why the OMAN researchers proceeded given the findings of TIME and BedMed, but OMAN started enrolling patients in China before either of those studies was published.
Ultimately, 720 patients were randomly assigned to morning or bedtime dosing of antihypertensives. Nighttime dosing reduced nocturnal systolic blood pressure (SBP) by 3 mm Hg and morning SBP by 3.1mm Hg more than daytime dosing. Evening dosing lowered not just overnight blood pressure, as would be expected, but also morning blood pressure and 24-hour blood pressure control more than daytime dosing. There was also no signal for increased adverse events with nighttime dosing; it did not reduce the efficacy of 24-hour blood pressure control or cause nocturnal hypotension.
The OMAN trial had much to recommend it. They used long-acting medications, such as olmesartan and amlodipine, rather than short acting medications, which could have skewed the results. They assessed blood pressure using both office readings and ambulatory blood pressure monitors (ABPMs), which is the preferred method. The authors concluded that nighttime dosing had potential advantages, and the findings seemed to be in stark opposition to those of the BedMed and TIME trials.
But when I reached out to Scott Garrison, MD, PhD, lead author of BedMed and professor of family medicine at the University of Alberta, he pointed out that OMAN is largely in keeping with BedMed and TIME when you drill down into the results. In TIME, the evening dosing group had an incremental 1.8 mm Hg-lower mean morning blood pressure than the morning dosing group. However, their mean evening blood pressures were not lower. In BedMed, the differences were more pronounced. Overnight mean SBP, assessed with ABPM in a subgroup of patients, was 7.4 mm Hg lower in the bedtime dosing group and mean diastolic BP was 2.7 mm Hg lower. However, mean daytime BP was the same.
Scott R. Garrison, MD, PhD
While the results are not wholly consistent across all three trials, there does appear to a modestly greater blood pressure reduction associated with evening dosing. But importantly, that difference did not translate into reduced cardiovascular events in BedMed or TIME. OMAN was only 12 weeks in duration and did not assess hard clinical endpoints. In short, nighttime dosing may slightly improve blood pressure control but not enough to prevent heart attacks or stroke.
“Maybe absorption is better, maybe adherence is better,” Hiremath speculates about the possible reasons for a nighttime advantage. “But if you step back and see, the outcomes don’t matter.”
Mechanistically, it seems logical that treating nighttime blood pressure would improve outcomes. Nighttime hypertension and loss of the nocturnal dip are associated with negative cardiovascular outcomes. But Hiremath suggests that treating nighttime hypertension without treating the underlying cause, be it sleep apnea, chronic kidney disease, or volume overload, may not meaningfully reduce the negative cardiovascular outcomes.
Night Owls vs Morning Larks
A substudy of TIME that looked at participant chronotype in this chronotherapy study adds more nuance. A subset of participants filled in questionnaires and were categorized as “night owls” or “morning larks.” The researchers found that the hazard ratio for the composite endpoint of hospitalization for nonfatal myocardial infarction and stroke increased if night owls were treated in the morning relative to the evening.
All substudies, even prespecified ones, need to be interpreted with caution. Only one quarter of TIME participants completed the chronotype questionnaire, and assessing circadian rhythm via self-report has its limitations. Also, the questionnaire was completed during the COVID-19 pandemic after the first lockdown in the UK, when sleep patterns possibly diverged from routine.
In a similar post hoc analysis of BedMed participants who self-identified as either morning birds or not were “chronomatched”: morning birds who got their medications in the morning or night owls who got their medications in the evening. Compared to non-chronomatched participants, the investigators found a decrease in hospitalizations as in TIME, but this was driven by fewer strokes rather than nonfatal myocardial infarctions.
With all these caveats in mind, the findings suggest that timing may be important for some individuals based on their specific chronotype or circadian rhythm patterns. “No one time is better for the majority of people,” says Garrison. “But do some people respond better to a specific dosing schedule? That’s a big question mark.”
Perhaps future studies will determine that chronotype and circadian rhythm dictate an optimal dosing strategy. Meanwhile, patients can organize their lives and take their medications in the morning or evening based on their daily routine. And obviously, patients taking multiple blood pressure medications may choose to space them out during the day to limit hypotensive episodes and minimize side effects.
For now, maximizing compliance may be the more pressing concern for most patients. Ultimately, blood pressure medications only work if you remember to take them. And if that means night owls prefer to take their medications at night, then so be it.
Christopher Labos is a cardiologist with a degree in epidemiology. He spends most of his time doing things that he doesn’t get paid for, like research, teaching, and podcasting. He is a columnist with the Montreal Gazette, CJAD radio, CTV Montreal, and CBC Morning Live. He is host of the award-winning podcast The Body of Evidence and the author of Does Coffee Cause Cancer?, a book about food epidemiology set in the framework of a romantic comedy. He occasionally practices as a cardiologist so he can buy groceries.