TIME Study: No Added Benefit from Nighttime Dosing of Blood Pressure Medications

Thomas MacDonald, MBCHB, MD

For people with high blood pressure taking blood pressure medications in the evening as opposed to the morning provided no additional benefit, according to results of the TIME study.

Although the Hygia study produced evidence suggesting nocturnal dosing could improve outcomes, results of the randomized trial, which included 21,104 patients followed for more than 5 years, demonstrate evening dosing did not result in a significant difference in cardiovascular outcomes among patients with hypertension included in the trial compared to standard morning dosing.

“TIME was one of the largest cardiovascular studies ever conducted and provides a definitive answer on the question of whether blood pressure lowering medications should be taken in the morning or evening. The trial clearly found that heart attack, stroke and vascular death occurred to a similar degree regardless of the time of administration,” said lead investigator Thomas MacDonald, a professor at the University of Dundee, in a statement. “People with high blood pressure should take their regular antihypertensive medications at a time of day that is convenient for them and minimizes any undesirable effects.”

As a result of the hypothesis-generating Hygia Chronotherapy trial that provided evidence suggesting evening dosing of hypertension medications could improve the cardiovascular risk reduction achieved from these therapies, the TIME study found itself among the most anticipated studies to be presented at the European Society of Cardiology (ESC) Congress 2022. Conducted in the UK, the study was designed with the intent of comparing the effects of morning versus nocturnal dosing in a large, prospective trial.

Potential participants were defined as those taking at least one antihypertensive medication and with a valid email address were recruited by advertising in the community, from primary and secondary care, and from databases of consented patients in the UK. These individuals were directed to sign up using a website and, once eligibility was confirmed, were randomized in a 1:1 ratio to taking their antihypertensive medication in the morning or the evening. A total of 21,104 patients underwent randomization in the study, with 10,503 randomized to evening dosing and 10,601 randomized to morning dosing. This cohort had a mean age of 65 years, 58% were men, and 98% were White. The cohort had a median follow-up time of 5.2 years, with the longest follow-up lasting more than 9 years.

The primary outcome of interest was a composite of hospitalization for nonfatal myocardial infarction or nonfatal stroke and vascular death. Investigators pointed out information related to these outcomes was obtained through record linkage to national databases and independently adjudicated by a blinded committee.

Upon analysis, results of the study indicated a primary endpoint event occured among 3.4% of participants in the evening dosing group (0.69 events per 100 person-years) and 3.7% of the morning growing group (0.72 events per 100 person-years), which investigators pointed out resulted in an unadjusted hazard ratio (HR) of 0.95 (95% CI, 0.83-1.10; P=.53). Other outcomes of interest for the trial and their respective HRs are listed below:

• Non-fatal Stroke (HR, 0.93 [95% CI,0.73-1.18]; P=.54)
• Non-fatal MI (HR, 0.92 [95% CI, 0.73-1.16]; P=.48)
• CV Death (HR, 1.1 [95% CI, 0.84-1.43]; P=49)
• All-Cause Mortality (HR, 1.04 [95% CI, 0.91-1.18]; P=.59)
• HF Hospitalization/Death (HR, 0.79 [95% CI, 0.59-1.07]; P=.12)

“We did not find evening dosing was at all harmful in terms of falls or anything like that. Our conclusion is that patients can take their tablets whenever it is convenient,” Thomas added, during his presentation.

This study, “The Treatment in Morning versus Evening (TIME) Study,” was presented at ESC Congress 2022.