Cardiovascular Outcomes With Evening vs. Morning Dosing of Antihypertensives
- Evening dosing of usual antihypertensive medication did not improve the primary composite endpoint of vascular death or hospitalization for nonfatal MI or nonfatal stroke compared with morning dosing.
- Patients may be advised that they need not change their antihypertensive medication dosing time but might choose to take their medication at a time that suits them best.
- Clinicians should focus on selecting appropriate medications and emphasize adherence to assented treatment plans rather than timing of doses.
Does evening dosing of usual antihypertensive medication improve major cardiovascular outcomes compared with morning dosing in patients with hypertension?
The TIME study investigators conducted a prospective, pragmatic, decentralized, parallel-group study in the United Kingdom, which recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimization, to take all of their usual antihypertensive medications in either the morning (0600–1000 hours) or in the evening (2000–0000 hours). Participants were followed up for the composite primary endpoint of vascular death or hospitalization for nonfatal myocardial infarction (MI) or nonfatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (i.e., all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The primary endpoint was assessed using an unadjusted Cox proportional hazards model.
Between December 17, 2011, and June 5, 2018, 24,610 individuals were screened and 21,104 were randomly assigned to evening (n = 10,503) or morning (n = 10,601) dosing groups. Mean age at study entry was 65.1 years (standard deviation, 9.3); 12,136 (57.5%) participants were men; 8,968 (42.5%) were women; 19,101 (90.5%) were White; 98 (0.5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1,637 [7.8%] participants); and 2,725 (13.0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5.2 years (interquartile range, 4.9–5.7), and 529 (5.0%) of 10,503 participants assigned to evening treatment and 318 (3.0%) of 10,601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3.4%) participants assigned to evening treatment (0.69 events [95% CI, 0.62–0.76] per 100 patient-years) and 390 (3.7%) assigned to morning treatment (0.72 events [95% CI, 0.65–0.79] per 100 patient-years; unadjusted hazard ratio, 0.95 [95% CI, 0.83–1.10]; p = 0.53). No safety concerns were identified.
The authors concluded that evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes.
This pragmatic study reflecting usual care reports that evening dosing of usual antihypertensive medication did not improve the primary composite endpoint of vascular death or hospitalization for nonfatal MI or nonfatal stroke compared with morning dosing. Of note, taking medication in the evening was not harmful but provided no incremental benefit versus morning dosing. Based on this, patients may be advised that they need not change their antihypertensive medication dosing time but might choose to take their medication at a time that suits them best. Clinicians should focus on selecting appropriate medications and emphasize adherence to assented treatment plans rather than timing of dose.
Keywords: Acute Coronary Syndrome, Antihypertensive Agents, Blood Pressure, Blood Pressure Monitoring, Ambulatory, Hypertension, Myocardial Infarction, Outcome Assessment, Health Care, Primary Prevention, Stroke, Vascular Diseases
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