The Lessons of Day vs Night Administration of BP Medications

What a story this is. Perhaps at its core, disproving the Hygia trial exposes science as an utterly human endeavor

The BedMed trial, published in JAMA this month, looks like a regular randomized controlled trial (RCT). One group of patients with high blood pressure took their meds in the morning, the other took the same meds at night. Major adverse cardiac events (MACE) were not different.

The Canadian investigators randomized more than 3500 patients and followed them for nearly 5 years. I don’t know how much money and time were spent on the trial, but it was a lot.

A couple of years ago, researchers from the UK, published results of the TIME trial in the Lancet. This too was an AM vs PM dosing of BP-lowering meds.

TIME enrolled more than 21,000 patients and followed them for 5 years. As you would expect, there was no difference in the incidence of MACE. The British Heart Foundation and other government agencies funded the trial, which was surely costly.

What Gives?

You might wonder why nearly 25,000 patients have been randomized in clinical outcomes trials testing the time of day one takes a once-daily medication.

It dates back to the controversial trial called Hygia, published in the European Heart Journal in 2019. Hygia assigned about 9500 patients with high blood pressure to take their meds in the AM and 9500 to take their meds in the evening.

During the 6-year follow-up, the Spanish authors reported a massive 45% reduction of MACE in the evening meds group. Every component of the composite MACE outcome (Stroke, MI, coronary revascularization, heart failure and CV death). Look at this:

Multiple clinicians soon raised multiple issues with Hygia. The editors of the EHJ posted an “expression of concern,” writing that the trial was under investigation. EHJ editors then wrote a piece called “Scientific integrity: what a journal can and cannot do.”

They discuss the general process of peer review and use Hygia as an example. They write that the source data from Hygia was reviewed by an independent stats team and found that the “statistical evaluation and presentation of the results in the manuscript were consistent to a satisfying degree with the data provided.”

They add the $60k question: “It is obvious that the journal, its independent statistician, and the ESC Journal Ethics Committee cannot verify the source data…”

EHJ received numerous letters to the editors and published all of them. Primary investigator Dr. Ramon Hermida responded in detail to several of the letters, “which clarified some, but not all issues.”

For Sensible Medicine Readers

The first and most important issue that I hope Sensible Medicine readers see is the effect size. It is hard to believe. How did nighttime administration of the same medicine reduce hard outcomes by that much (45%)?

For comparison, consider that in the HOPE trial, the ACE-inhibitor ramipril only reduced MACE vs placebo by 22%.

The journal Hypertension published the most extensive critical appraisal of Hygia. Perhaps the second most compelling criticism of the trial was that nighttime meds reduced noncardiovascular death by 42%. That is a total outlier as no HTN trial has found any reduction in noncardiovascular death.

That observation bolsters the next major concern with Hygia: that it was not randomized. Multiple authors have noted wording in the trial manuscript that patients were assigned a treatment arm rather than randomized to the treatment arm. To wit, an observational study wherein healthier patients were given nighttime meds might explain the large reduction in noncardiovascular death. PI Dr. Hermida admits there was also a Hygia Project, which was an observational study, but says that the two studies were separate.

There were many other concerns—mainly about trial conduct. Things like an exceedingly low reported rate of adverse events, no explanation why early termination did not occur in the presence of major benefit, and poor reporting of loss to follow-up and withdrawal of consent.

Conclusions and Lessons