Morning and bedtime dosing of antihypertensives have similar rates of major cardiovascular events (TIME)

Reference

Mackenzie IS, Rogers A, Poulter NR, et al, for the TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022;400(10361):1417-1425.

Synopsis

The Hygia Chronotherapy Trial included more than 19,000 adults with hypertension and found that bedtime administration of antihypertensive medications decreased cardiovascular death and morbidity over more than 6 years of follow-up. However, it created a firestorm among hypertension researchers who thought the results were “too good to be true.” An independent review of the data confirmed the original study findings. In the Treatment in Morning versus Evening (TIME) study, researchers randomly assigned adults with treated hypertension to take all their antihypertension medications either in the morning (6 AM - 10 AM; n = 10,601) or in the evening (8 PM - midnight; n = 10,503). The researchers instructed the evening-dose patients who were also taking a diuretic to take the diuretic earlier (6 PM) if they were troubled by nocturia, or in the morning if the nocturia continued. The researchers used intention-to-treat analysis to compare the rate of the primary outcome — a composite of vascular death or hospitalization for nonfatal myocardial infarction or nonfatal stroke. The researchers used patient-submitted data supplemented by data from national registries. Adjudicators masked to allocation made the final outcome determinations. A total of 90.5% of participants were white, 42.5% were women, and 12.9% had preexisting cardiovascular disease. The mean baseline characteristics of each group were balanced. After a median follow-up of 5.2 years, 3.7% of the morning-dose patients and 3.4% of the evening-dose patients experienced the endpoint, and their time to first occurrence was similar. Additionally, there was no difference in the rate of any of the individual outcome components or in all-cause mortality (4.1% vs 4.2%, respectively). The rate of adverse effects, including excessive visits to the toilet (day or night: 36.4% vs 40.0%, respectively), were similar for both groups.