Antihypertensive dosing TIME does not affect CV outcomes

Timing of antihypertensive medication intake, be it in the morning or evening, does not appear to affect the risk of cardiovascular death or hospitalization for non-fatal myocardial infarction (MI) or non-fatal stroke, according to results of the TIME trial presented at ESC 2022.

“The trial clearly found that heart attack, stroke, and vascular death occurred to a similar degree regardless of the time of administration [of antihypertensive medication],” said principal investigator Professor Thomas MacDonald from the University of Dundee, Scotland, UK.

The findings were based on analysis of 21,104 patients (mean age 65.1 years, 57.5 percent male, 98 percent White, mean BMI 28.4 kg/m²) with hypertension who were being treated by the UK National Health Service (NHS). They were randomized 1:1 to take their regular prescribed antihypertension medication either in the morning (6–10 am) or the evening (8 pm–midnight).

Four percent of the population were current smokers. Thirteen percent had a history of cardiovascular disease, 13.8 percent had diabetes, and 3.4 percent had impaired renal function. Mean blood pressure (BP) level at baseline was 135/79 mm Hg. Baseline characteristics were comparable between patients assigned to the morning and evening dosing groups.

The patients were followed up for a median 5.2 years, with the longest follow-up documented at 9.3 years. The outcomes were obtained from the patients, clinicians, and UK NHS hospital databases and death records. Consent withdrawal occurred more frequently in the evening vs morning dose group (5.0 percent vs 3.0 percent), as did non-adherence at any time (39.0 percent vs 22.5 percent; p<0.0001), with last known non-adherence documented in 21.8 percent vs 7.5 percent.

The primary endpoint, defined as time to first occurrence of hospitalization for non-fatal MI, hospitalization for non-fatal stroke, or cardiovascular death, did not significantly differ between patients assigned to morning or evening intake of antihypertensive medication (3.7 percent vs 3.4 percent; unadjusted hazard ratio [HR], 0.95, 95 percent confidence interval, 0.83–1.10; p=0.53). This corresponded to 0.72 vs 0.69 events per 100 patient-years in the morning vs evening dosing group. [ESC 2022, Hot Line Session 1]

Subgroup analysis showed that the results were consistent regardless of baseline factors such as age, sex, BMI, smoking history, and comorbidities.

The results were also consistent in the separate entities of the composite endpoint (non-fatal MI: HR, 0.92; p=0.48; non-fatal stroke: HR, 0.93; p=0.54; cardiovascular death: HR, 1.1; p=0.49), and there was no significant between-group difference in terms of all-cause mortality (HR, 1.04; p=0.59).  

There was a trend toward a lower number of falls among patients assigned to the evening vs morning dosing strategy (21.1 percent vs 22.2 percent; p=0.05). However, the incidence of fractures was comparable between the two groups, be it fractures that did (0.8 percent in each group) or did not lead to hospitalization (6.0 percent in each group).

The trial was conducted to assess if evening intake of antihypertensive medications would be better than morning intake. “Nocturnal BP … is a better predictor of CV outcomes than daytime pressure,” said MacDonald.

“TIME was one of the largest cardiovascular studies ever conducted and provides a definitive answer on the question of whether BP-lowering medications should be taken in the morning or evening,” he continued.

“Taking medication in the evening was not harmful. Patients can take their BP medication in either the morning or evening as the timing makes no difference to cardiovascular outcomes,” MacDonald concluded.