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BARCELONA -- Patients did not get more out of their antihypertensives by taking them only at night, according to the randomized TIME trial.

Those told to take their usual blood pressure (BP) therapies in the morning (6 a.m. to 10 a.m.) or evening (8 p.m. to midnight) had comparable rates of myocardial infarction (MI), stroke, or vascular death over the next 5 years (HR 0.95, 95% CI 0.83-1.10), reported Thomas MacDonald, MD, of the University of Dundee in Scotland, during the .

Moreover, the morning and evening groups showed no difference between them -- "nothing, not a smidge" -- in terms of the individual outcomes of stroke, MI, cardiovascular death, all-cause mortality, or heart failure hospitalization or death, he added.

Notably, the 13% of participants who had diabetes also had similar results with morning or evening dosing.

"Patients can take their BP medication in either the morning or evening, as the timing makes no difference to cardiovascular outcomes," MacDonald concluded. "This is the result and I think it's definitive."

The evidence for nighttime antihypertensives has been controversial. In 2010, the found that bedtime antihypertensive dosing improved BP control and reduced cardiovascular morbidity and mortality. A subsequent study, the Hygia Chronotherapy trial, favored this approach as well, but has had its conduct questioned by skeptics.

"Why is TIME neutral? I think that's the big mystery," MacDonald said.

Circadian variability of BP usually results in a dipping of BP at night. In theory, evening dosing would help people, given that ambulatory monitoring suggests higher nighttime pressure is a good predictor of bad outcomes.

On the other hand, nighttime antihypertensives are associated with morning hypotension, which can predispose people to increased risk, noted ESC session discussant Rhian Touyz, MBBCh, PhD, of McGill University in Montreal.

For her, the question of the chronobiology of BP drugs may not be totally settled for every person. She said the present study did not fully consider special groups, such as those with nocturnal hypertension.

MacDonald added that it's possible that certain groups, like people with resistant hypertension and obstructive sleep apnea, could still be shown to benefit from evening BP medication dosing in a large enough study.

He highlighted the observation that patients experienced daily fluctuations in systolic blood pressure on home monitoring, suggesting that their once-daily medications were not providing adequate coverage throughout the day.

"The push should be we should have tablets that really work 24 hours," he said.

The TIME trial employed a decentralized design that enrolled and randomized patients through an online portal. Eligible participants were patients of the U.K. NHS with high BP.

MacDonald noted that TIME's original sample size had been doubled due to concerns about low cardiovascular event rates.

Ultimately, there were 21,104 participants split between morning and evening medication groups. Mean age was 65 years, and 57.5% of the group were men. Baseline BP was 135/79 mm Hg -- quite well controlled from the start, Touyz noted.

Patient characteristics were well balanced between groups at study entry.

As for safety, MacDonald reported no excesses in falls and fractures associated with taking antihypertensives in either the morning or evening.

The lack of a standardized treatment protocol was a limitation of TIME, Touyz cautioned. She added that adherence may also be an issue in the study, as patients reporting nonadherence to their dosing schedule at any time during the study reached 22.5% vs 39.0% (P<0.0001).

Adherence in TIME wasn't so bad considering the long duration of the study, MacDonald argued.

"I am absolutely confident that we did our study ... as best as we could," he said, citing his team's adjudication of events and the intention-to-treat analysis.

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