This transcript has been edited for clarity.
Tricia Ward: I’m joined today by Dr. Scott R. Garrison, MD, PhD. He is a professor in the Department of Family Medicine at the University of Alberta in Edmonton, Alberta, Canada, and director of the Pragmatic Trials Collaborative.
You presented two studies at ESC. One is the BedMed study, comparing day vs nighttime dosing of blood pressure therapy. Can you tell us the top-line findings?
BedMed and BedMed-Frail
Dr. Garrison: We were looking to validate an earlier study that suggested a large benefit of taking blood pressure medication at bedtime, as far as reducing major adverse cardiovascular events (MACEs). That was the MAPEC study. They suggested a 60% reduction. The BedMed trial was in hypertensive primary care patients in five Canadian provinces. We randomized well over 3000 patients to bedtime or morning medications. We looked at MACEs — so all-cause death or hospitalizations for acute coronary syndrome, stroke, or heart failure, and a bunch of safety outcomes.
Essentially, . It was safe to take it at bedtime. But it did not convey any extra cardiovascular benefit.
Ms. Ward: And then you did a second study, called BedMed-Frail. Do you want to tell us the reason you did that?
Dr. Garrison: BedMed-Frail took place in a nursing home population. We believed that it was possible that frail, older adults might have very different risks and benefits, and that they would probably be underrepresented, as they normally are in the main trial.
We thought that because bedtime blood pressure medications would be theoretically preferentially lowering night pressure, which is already the lowest pressure of the day, that if you were at risk for hypotensive or ischemic adverse events, that might make it worse. We looked at falls and fractures; worsening cognition in case they had vascular dementia; and whether they developed decubitus ulcers (pressure sores) because you need a certain amount of pressure to get past any obstruction — in this case, it’s the weight of your body if you’re lying in bed all the time.
We also looked at problem behaviors. People who have dementia have what’s called “sundowning,” where agitation and confusion are worse as the evening is going on. We looked at that on the off chance that it had anything to do with blood pressures being lower. And the BedMed-Frail results mirror those of BedMed exactly. So there was no cardiovascular benefit, and in this population, that was largely driven by mortality; one third of these people died every year.
Ms. Ward: The median age was about 88?
Dr. Garrison: Yes, the median age was 88. There was no cardiovascular mortality advantage to bedtime dosing, but neither was there any signal of safety concerns.
Other Complementary and Conflicting Studies
Ms. Ward: These two studies mirror the TIME study from the United Kingdom.
Dr. Garrison: Yes. We found exactly what TIME found. Our point estimate was pretty much the same. The hazard ratio in the main trial was 0.96. Theirs, I believe, was 0.95. Our findings agree completely with those of TIME and differ substantially from the previous trials that suggested a large benefit.
Ms. Ward: Those previous trials were MAPEC and the Hygia Chronotherapy Trial.
Dr. Garrison: MAPEC was the first one. While we were doing our trial, and while the TIME investigators were doing their trial, both of us trying to validate MAPEC, the same group published another study called Hygia, which also reported a large reduction: a 45% reduction in MACE with bedtime dosing.
Ms. Ward: You didn’t present it, but there was also a meta-analysis presented here by somebody independent.
Dr. Garrison: Yes, Ricky Turgeon. I know Ricky. We gave him patient-level data for his meta-analysis, but I was not otherwise involved.
Ms. Ward: And the conclusion is the same.
Dr. Garrison: It’s the same. He only found the same five trials: MAPEC, Hygia, TIME, BedMed, and BedMed-Frail. Combining them all together, the CIs still span 1.0, so it didn’t end up being significant. But he also analyzed TIME and the BedMed trials separately — again suggesting that those trials showed no benefit.
Ms. Ward: There was a TIME substudy of night owls vs early risers or morning people, and there was a hint (or whatever you should say for a subanalysis of a neutral trial) that timing might make a difference there.
Dr. Garrison: They recently published, I guess it is a substudy, where they looked at people’s chronotype according to whether you consider yourself an early bird or a night owl. Their assessment was more detailed. They reported that if people were tending toward being early birds and they took their blood pressure medicine in the morning, or if they were night owls and they took it in the evening, that they tended to have statistically significantly better outcomes than the opposite timing. In that analysis, they were only looking at nonfatal myocardial infarction and nonfatal stroke.
We did ask something that was related. We asked people: “Do we consider yourself more of an early bird or a night owl?” So we do have those data. For what I presented at ESC, we just looked at the primary outcome; we did subgroups according to early bird, night owl, and neither, and that was not statistically significant. It didn’t rule it out. There were some trends in the direction that the TIME group were suggesting. We do intend to do a closer look at that.
But, you know, they call these “late-breaking trials,” and it really was in our case. We didn’t get the last of our data from the last province until the end of June, so we still are finishing up the analysis of the chronotype portion — so more to come in another month or so.