Reference: Lancet. 2022 Oct 22;400(10361):1417-1425
Practice Point: The timing of antihypertensive drug dosing does not seem to substantially affect cardiovascular morbidity and mortality.
EBM Pearl: Significant differences in baseline characteristics between groups usually suggests a problem with randomization. Turns out sometimes it can also be a sign of no randomization at all!
This was supposed to be a ‘regular’ EBM Focus about the TIME trial which evaluated the timing of antihypertensive dosing and, spoiler alert, found no benefit of evening dosing compared to morning dosing for cardiovascular outcomes. But a little background research for this summary uncovered quite the controversy surrounding the TIME trial’s predecessor, the highly publicized 2020 Hygia Chronotherapy trial, and not just because of the contradictory results! While it may not quite be Gray’s Anatomy-level drama, this is about as juicy as it gets for medical literature.
The basis for both of these studies is the hypothesis that bedtime antihypertensive dosing would better control the physiologic morning blood pressure surge and therefore reduce cardiovascular morbidity and mortality (which is more likely to occur around this time of day). As pointed out in a prior EBM Focus, the Hygia trial found that bedtime dosing was associated with a “striking” 45% decrease in all-cause and cardiovascular death. Other experts wrote that “the results reported almost seem too good to be true…” True or not, the results got a ton of attention in the lay press and social media based on the study’s Altmetric Attention Score of 2124 (where a score of 20 is considered good for a journal article).
The problems brought forth about the Hygia trial resulted in a formal “Expression of Concern” by the European Heart Journal and an investigation which ultimately found “no grounds for an ethical or factual concern.” However, many continue to seriously question the validity of the results of the Hygia trial. Here are the [alleged] problems in a nutshell:
- There are questions about whether the Hygia trial was truly randomized based on lack of the word “randomized” anywhere in the study, observed statistically significant differences in important baseline characteristics between groups, the combining of treated and untreated patients, and separate allocation of patients based on different medication classes.
- The “implausibly large” treatment effect observed (45% reduction in death) outpaced the ~20% expected benefit, and was followed by a trial expansion rather than a more ethically-sound early termination (despite author reports of being underfunded).
- There is no description of adjudication of endpoints, no description of how the study was monitored, and no source verification.
- There were unusually low drop-out rates (only 607 losses out of more than 19,000 participants over 6 years), raising questions about falsification of data.
- There were multiple protocol problems, including 15 primary endpoints.
SO, the strong background of skepticism about the validity of the Hygia results lead to perhaps less excitement about the contradictory results of the TIME trial published in October 2022, which may be why it took us so long to get around to writing about it here.
The CliffsNotes version of the TIME trial goes like this: it was an (actually) randomized, controlled, open-label trial of more than 21,000 adults being treated for hypertension that enrolled a low-risk, mostly White European population who all had internet and a PCP. Most people were taking their (mean 1.5) blood pressure medications in the morning, and were likely medication compliant or had mild hypertension because the average pre-trial BP was 135/79. Participants were randomized to either take all of their BP meds in the morning or the evening and evaluated for the composite primary endpoint of vascular death or hospitalization for non-fatal MI or non-fatal stroke after a mean of 5.2 years. The study was well-powered to detect a difference if one were there, but an intention-to-treat analysis (ITT) showed no significant difference in the primary outcome between groups. There were more side effects in the morning-meds group and more noncompliance in the evening-meds group (presumably because the participants were used to taking their meds in the morning). But get this- there was an uptick in noncompliance in the direction of switching from morning to evening dosing around the time the Hygia trial was published that seemingly leveled out by the end of the trial!
While there was variable adherence in both groups in the TIME trial, there was more crossover in the evening meds group which could have muddied the waters a bit. If a per-protocol analysis had also been done and had shown a benefit of evening dosing, this might have helped explain the dramatic discrepancy in results between the two trials (outside of fraudulent data). To be clear, an ITT is preferred in superiority trials because it preserves prognostic equivalence and is thought to be closer to the “truth”. Ultimately, however, the generalizability of the TIME trial seems to be its biggest downfall considering the population was low-risk and highish-resourced.
Now, if you experienced the roller coaster of emotions about this trial controversy that “we” did, you may, like us, be on the nerd-empath spectrum. This whole thing is a good reminder that the peer-review process is not a guarantee that what you see is what you get. As depressing as it is, we have to remain skeptical of new studies and do our due diligence to look for rips in the seams, especially when the results seem “too good to be true”. Replication of important findings is critical.
As far as the timing of antihypertensive medication goes, our advice to patients is to take their blood pressure medications when they are most likely to remember to take them. One thing we can be sure of is that blood pressure medications dosed at morning, noon, or night definitely won’t help if patients forget to take them.
For more information, see the topic Hypertension in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Associate Editor at DynaMed.