A Nighttime Experiment

https://www.medscape.com/viewarticle/rise-and-fall-and-rise-again-bp-chronotherapy-2025a1000t3a

Dr. Christopher Labos, a cardiologist and epidemiologist at McGill University, wrote a nice article for Medscape entitled “The Rise and Fall and Rise Again of BP Chronotherapy,” in which he outlines the debate about whether it matters when during the day you taking your blood pressure medication.

Following the controversial “Hygia Chronotherapy Trial,” which was stamped with a statement of concern by the journal that published it, three subsequent trials, BedMed (https://jamanetwork.com/journals/jama/fullarticle/2833860), TIME (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01786-X/fulltext), and OMAN (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2836172) were undertaken to settle the question.

Besides their straightforward intended purpose, these studies are interesting because they offer a unique opportunity to examine the effects of medical management (as opposed to yoga) of blood pressure without the confounding effects of changing overall medication exposure.

In the BedMed trial, there was no statistically significant difference in daytime blood pressure between the morning and evening groups, but overnight blood pressures were lower in the evening group. Over a median of 4.6 years, there was no difference in death or major adverse cardiovascular events. In the TIME trial, the relative blood pressures between the two groups in the morning and evening were both significantly different and were the inverse of one another. Again, over a median follow-up of 5.2 years, there was no difference in major adverse cardiovascular events. The more recent OMAN trial (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2836172) showed overall lower blood pressures in the nocturnal dosing group than in the morning group, but was not long enough in duration to assess risk of adverse cardiovascular events.

Dr. Labos summarizes the findings as follows:

“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.:

His assessment:

“In short, nighttime dosing may slightly improve blood pressure control but not enough to prevent heart attacks or stroke.“

This is a fair interpretation, and if we believe it, that’s fine. End of story.

But if we take these blood pressure reductions — some measured over the course of years — as real and meaningful, we have to consider the possibility that when the drug exposure is the same, we do not benefit from lower blood pressure. In other words, assuming we think 5mg of lisinopril gives the same ACE-blocking exposure whether it is given at 8am or 8pm, the blood pressure that is achieved is not the key driver of clinical benefit. Otherwise, we would expect that treating to a lower blood pressure, even if only by changing the time of administration, should yield the benefits commonly attributed to this increased blood pressure lowering.

Since we do not observe this, maybe it is that when we treat blood pressure more intensively, we accrue benefit by increasing drug exposure (as you would by increasing the dose of a statin), and lower blood pressure is just a side effect.