In the 1930s a British professor of medicine wrote, "The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it."
Today the importance of treating high blood pressure to prevent cardiovascular events is, hopefully, accepted by everyone. However, there is still debate as to the how. Two competing editorials in Hypertension address the issue of whether taking antihypertensives at bedtime rather than in the morning makes any difference. One group of researchers argues that switching from morning to bedtime can drastically cut not just cardiovascular but all-cause mortality, while the opposing group has deep reservations about the trial data used to advocate for this paradigm shift.
Dippers and Non-Dippers
Blood pressure follows a normal circadian rhythm with a peak shortly after waking and a dip during sleep. The nighttime dipping seems to be particularly important physiologically, and so-called "non-dippers" may be at increased risk for cardiovascular events. This observation has led some to champion chronotherapy, or the idea that when you take your blood pressure medication could influence its effectiveness.
On one side of the debate stands Ramón Hermida, professor of medicine at the University of Vigo in Spain and senior author of the Hygia Chronotherapy Trial. He argues that nighttime administration of antihypertensive medications is beneficial and reduces clinical events to a much greater level than daytime pill-taking.
Hermida points out that in the entirety of the medical literature, there is little evidence to support the idea of morning administration of blood pressure medication. In several key clinical trials that showed the cardiovascular benefits of blood pressure lowering, such as HOPE, antihypertensive medications were taken at night.
"Where is the actual clinical evidence that antihypertensive medication should be preferentially taken in the morning?" asks Hermida. He cited his own systematic review of the literature which failed to show any convincing benefit to preferential morning administration of blood pressure medication. "The most significant and the most relevant finding," says Hermida, "is that no single one of those 155 trials show any significant advantage to morning hypertension treatment [over bedtime treatment]."
Office-Based vs 24-Hour BP Readings
Other systematic reviews seem to support the idea of administering blood pressure medication at night. But these reviews include trials like HOPE, Syst-China, and Syst-Eur, which compared evening dosing to placebo, not evening vs morning dosing.
By contrast, a 2011 Cochrane review that limited its analysis to randomized controlled trials comparing evening with morning administration of blood pressure monotherapy offers up a more muted evaluation of the literature. The authors found that none of the published randomized trials at that time reported clinically relevant outcomes, and that evening administration of medication had no impact on morning blood pressure readings. There was a small reduction in 24-hour blood pressure measurements with nighttime dosing (1.71/1.38 mm Hg) but this was unlikely to be clinically significant.
Hermida points out that many of these trials used office-based blood pressure measurements rather than 24-hour blood pressure measurements (CHOSA and HARMONY did assess ambulatory blood pressure). He also notes that many trials used inappropriately broad dosing windows rather than individualizing the dose window to each patient's sleep-wake cycle to more accurately reflect their circadian rhythm. He says that these methodologic issues explain why some trials failed to show a clear benefit for nighttime dosing.
Hygia Trial vs Project?
Of course, the main data supporting the idea of bedtime administration of blood pressure medication come from Hermida's study, the Hygia Chronotherapy Trial. This prospective trial of over 19,000 patients diagnosed with hypertension used 48-hour ambulatory blood pressure monitoring. Patients were assigned to take their prescribed blood pressure medication at bedtime or upon awakening and were followed for a median of 6.3 years.
The published results are striking. Bedtime dosing was associated with a near halving in the risk for cardiovascular death, stroke, myocardial infarction, heart failure, hemorrhagic stroke, and all-cause mortality compared with morning dosing.
These dramatic findings have been met with skepticism. Controversy over the trial has not abated even after a European Heart Journal investigation concluded that "No grounds for an ethical or factual concern were found," while the editors conceded that verifying the source data was beyond their scope.
One of the main sources of contention is whether the Hygia Chronotherapy Trial is actually a randomized trial.
Critics have pointed out that the word "assigned," not "randomized," is used in the study flow diagram. Importantly, there is no description of the randomization process in the methods section of the paper. A recent perspective in Hypertension, from some big-name hypertension experts, points out inconsistencies in how the trial has been described over the years. The experts suggest that the data may have been drawn from a concurrent observational study.
Hermida proposes that some of the confusion is because of the similarly named Hygia Project. This is a multicenter research network with several ongoing projects, among them a prospective cohort with a similar patient population to the Hygia Chronotherapy Trial. But commentators continue to question whether the data are derived from the same source. Hermida insists that the Hygia Chronotherapy Trial and the Hygia Project are distinct entities, though he concedes that giving them the same name was, in retrospect, a poor choice.
"If you ask me now, I will not do it again. But it has been done. And I confess it was probably an error in as much as it was conducting some people to make wrong assumptions about the trial," Hermida said in an interview via Skype.
Does Chronotherapy Make Physiologic Sense?
Among those making assumptions about the Hygia Chronotherapy Trial is Swapnil Hiremath, a nephrologist and associate professor at the University of Ottawa. He laid out his concerns in a counter-editorial that ran in the same issue of Hypertension as Hermida's. Hiremath is skeptical about the whole notion of chronotherapy because most modern-day antihypertensives have a very long half-life.
With short-acting medications from the past, such as hydralazine or captopril, dose timing might have had an effect. But medications with long half-lives such as amlodipine or perindopril are generally used today; morning or bedtime dosing is unlikely to make a difference given what we know of their pharmacokinetics, he argues.
"It doesn't make physiologic sense," Hiremath told me about the idea of chronotherapy. "It doesn't make pharmacologic sense." And when he looks at the data empirically, it still does not make sense.
In addition to questioning whether Hygia was a randomized trial, he points out several other issues. Despite early and impressive benefits in the nighttime dosing arm, the trial was not stopped early as would typically happen after an interim analysis.
The editors of the European Heart Journal wrote that this was because the trial did not have formal stopping rules or a Data and Safety Monitoring Board. While the editors claimed that this "may fall short of current standards," there was no indication to suggest fraud.
Another issue for Hiremath is that loss to follow-up was only 0.4% and poor adherence under 3%, which is extremely low compared with other blood pressure trials. For example, in ALLHAT, the rates of loss to follow-up and drug discontinuation were 3% and 13%, respectively. Hermida maintains that specific elements of the trial protocol, such as having patients keep their medications by their bed and tying medication times to their particular sleep-wake cycles, explains the high adherence.
Daytime Dosing Bad?
The most difficult thing for Hiremath to buy is that changing blood pressure drug dosing from waking to bedtime could result in such a large reduction not just in cardiovascular mortality but also in non-cardiovascular mortality. The 45% reduction in all-cause mortality seen in Hygia is almost 2.5 times larger than the reduction seen in HOPE (16%), despite the fact that HOPE compared ramipril with placebo and Hygia had an active control. This discrepancy suggests that morning dosing of antihypertensives is harmful relative to placebo — a conclusion that strikes Hiremath as biologically implausible.
The Canadian nephrologist doesn't dispute that ambulatory blood pressure monitors help identify patients with white-coat or masked hypertension (he uses them regularly in his practice). He also doesn't argue against Hermida's assertion that we may miss patients with hypertension if we rely only on office measurement. His argument is that switching blood pressure medication from morning to nighttime, or vice versa, is unlikely to have a major effect.
"I've tried changing the timing [of blood pressure medication] and doing a repeat ABPM, and in my hands it does nothing," says Hiremath. "They are non-dippers and they remain non-dippers."
For now, many clinicians probably have lingering doubts about the validity and biological plausibility of chronotherapy. Many of us already space out antihypertensive doses for patients taking multiple medications in order to avoid hypotensive episodes. And I would hope that we recognize the advantage of not taking diuretics in the evening. But whether there is an advantage to moving blood pressure medications from morning to evening remains unclear and unproven in the minds of many.
Hiremath is eagerly awaiting the results of two upcoming clinical trials, the Canadian BedMed trial and the UK-based TIME trial. Both test the theory of chronotherapy, and if positive, would provide a crucial independent verification of the Hygia findings. Maybe then we can put the controversy of nighttime BP medication to bed once and for all.
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, podcasting, and writing for the newspaper. Occasionally, he finds time to practice as a cardiologist so he can pay his rent. He realizes that half of his research findings will be disproved in 5 years; he just doesn't know which half. He is a regular contributor to the Montreal Gazette, CJAD radio, and CTV television in Montreal. To date, no one has recognized him on the street or asked for his autograph.
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Cite this: Day vs Night Blood Pressure Drug Dosing Debate Continues - Medscape - Aug 19, 2021.