HARMONY: Same BP Effect for Morning vs Night Antihypertensive Med Dosing

Deborah Brauser

June 17, 2016

PARIS, FRANCE — Taking antihypertensive medications during evening or morning hours makes no difference when it comes to 24-hour ambulatory blood-pressure monitoring (ABPM) levels in patients with hypertension, suggests new research[1].

The Hellenic-Anglo Research Into Morning or Night Antihypertensive Drug Delivery (HARMONY) study is a randomized, crossover trial of 95 hypertension patients in the UK and Greece. It showed almost identical results whether meds were taken in the morning between 6:00 and 11:00 or in the evening between 6:00 and 11:00, with regard to the primary end point of mean 24-hour systolic BP (129.65 and 129.75 mm Hg, respectively).

There was also no significant difference between delivery times for mean 24-hour diastolic BP, mean daytime SBP, mean daytime and nighttime DBP, and mean clinic SBP and DBP. In addition, quality-of-life scores did not differ.

The largest difference found was for nighttime SBP at 122.76 mm Hg for morning dosing vs 121.08 for evening dosing, "which at a 1.68 difference is nowhere near statistical significance," said lead author Dr Neil R Poulter (Imperial College London, UK). "If this was at a population level, that one might be important in regard to cardiovascular events. But certainly, within this trial, there was no sign of a significant benefit in terms of ABPMs or any other blood pressure associated with taking your tablets in the morning or the evening."

The study findings were presented here at the European Society of Hypertension (ESH) 2016 Annual Meeting.

Session moderator Dr Eivind Berge (Oslo University Hospital, Norway) told heartwire from Medscape that "although it's difficult to draw conclusions about clinical end points" from a trial of this size, the findings are useful.

"It lays the groundwork for doing other trials of different timings of treatment, which is a clinically useful question. A small study like this can't actually provide any guidance on when to give treatments, but the results were very interesting," said Berge.

HARMONY Until TIME Is Completed

Poulter reported that previous studies, "especially Spanish trials," have suggested that including at least some nighttime dosing of medications that lower BP may convey better protection against major adverse cardiovascular events (MACE) than daytime dosing.

"The TIME trial, which is currently in progress, will hopefully provide definitive evidence one way or the other of any preferential impact of nocturnal dosing on MACE," said Poulter. That trial is expected to randomize more than 10,000 participants, with 4 years of follow-up.

In the meantime, the HARMONY study was designed to compare dosing times on ABPM levels, said Poulter.

The included patients, between the ages of 18 and 80 years (mean age 62 years; 56% men), were enrolled at a center in London or at one in Thessaloniki, Greece between July 2013 and January 2015. All were on at least one BP-lowering agent at baseline and had had their BP "stable and controlled" (<150/<90 mm Hg) for at least 3 months prior. The mean body-mass index at baseline for the entire group was 29.1.

A total of 51 participants were randomized to take their usual BP medication between 6 and 11 am for 12 weeks and 52 were randomized to dosing between 6 and 11 pm. Then the groups switched dosing times for an additional 12 weeks. There was no washout period.

In addition to measuring heart rate, clinic BP "using standardized methods," and 24-hour ABPM at randomization, start of crossover, and at the end of both treatment periods, the investigators also distributed a standardized quality-of-life questionnaire at each time point.

Poulter noted that 90 patients were needed "to provide 80% power to detect a 3-mm-Hg difference in mean 24-hour SBP." After dropouts, 95 patients remained through all three ABPM points.

Treatment Delivery Differences

At the end of analysis, the observed difference in 24-hour SBP between morning and evening treatment delivery was 0.10 mm Hg (adjusted difference 0.11; 95% CI -3.20 to 3.42). The 24-hour DBP was 77.24 vs 77.99 mm Hg, respectively (adjusted difference 0.77; 95% CI -1.38 to 2.91).

Other between-group measurements included:

  • Daytime SBP: 132.24 vs 132.77 mm Hg, respectively.

  • Daytime DBP: 79.27 vs 80.55 mm Hg.

  • Nighttime DBP: 70.92 vs 70.57 mm Hg

  • Clinic SBP: 129.37 vs 129.81 mm Hg.

  • Clinic DBP: 77.26 vs 77.41 mm Hg.

Quality-of-life scores were 84.14 vs 84.04 for morning vs night dosing, respectively.

"Further analyses of subgroups, including by country, age, and sex, gave consistent findings," reported Poulter. He added that the most common class type of antihypertensive used at both centers was renin-angiotensin-system blockers (about 80% use), followed by calcium-channel blockers. And the mean number of drugs taken was two.

After his presentation, he was asked by an audience member whether he's willing to extrapolate the findings to hard end points. "I think we've got to be cautious about that, because there may be other issues about nocturnal and daytime dosing other than the ABPMs," answered Poulter. "We'll need to wait to see what the TIME trial shows us."

Berge later told heartwire that he would like to see data on the differences between the different types of drugs used by the participants. "Calcium-channel blockers can behave differently from ACE inhibitors, for example." But he said the overall findings "are absolutely" worthwhile to build upon.

"This was a very pragmatic approach that clinicians will find useful, I'm sure."

The study was funded by the Foundation for Circulatory Heath. Poulter and Berge reported no relevant financial relationships.

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