By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: An online study of evening vs. morning administration of patients’ usual antihypertensive medications, with a median five-year follow-up, revealed there is no difference in major cardiovascular outcomes between the two periods.
SOURCE: Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): A prospective, randomized, open-label, blinded-endpoint clinical trial. Lancet 2022;400:1417-1425.
Controversy exists over the purported benefits of night time dosing of antihypertensive drugs vs. morning dosing on cardiovascular outcomes. Investigators from the United Kingdom conceived and conducted the Treatment in Morning versus Evening (TIME) study.
TIME was a prospective, randomized, open-label, blinded-endpoint, controlled, parallel-group, superiority trial that included patients with treated hypertension taking at least one antihypertension drug daily. The authors excluded patients working overnight shifts or who were taking antihypertension medications more than once a day. Participants recruited between 2011 and 2018 were randomized to taking their usual antihypertensive therapy either in the morning (6 a.m. to 10 a.m.) or the evening (8 p.m. to 12 a.m.). All study activities were conducted through an online portal or by email. The only allowed deviation from the study protocol was patients assigned to evening medications who were taking a diuretic and experienced intolerable nocturia. Patients were allowed to take the diuretic earlier in the evening (6 p.m.) or in the morning.
After exclusions, 21,104 patients were enrolled (mean age = 65 years, 43% were women, 91% were white). After excluding the non-adherent and dropouts, 19,386 completed the study. A subgroup (59%) who possessed a blood pressure (BP) monitor provided measurements every three months. The primary outcome was a composite of vascular death or hospitalization for myocardial infarction (MI) or stroke. Median follow-up was five years, and the maximum was nine years. Prior to the study, 85% of participants took their medications in the morning. The primary endpoint occurred in 3.4% of the evening dosing group and 3.7% of the morning dosing group (HR, 0.95; 95% CI, 0.83-1.10; P = 0.53). Only 3% had to change their diuretic administration time. No safety concerns occurred during the trial, and there were no subgroups based on patient characteristics or antihypertensive drugs that changed the primary outcome. The authors concluded there was no difference in major cardiovascular outcomes between morning and evening dosing of antihypertensive medications in patients with treated hypertension.
COMMENTARY
There have been a few trials of evening dosing, which have produced conflicting data. Only two were randomized trials and were performed by the same group of investigators in Spain (MAPEC and the Hygia Chronotherapy trials).1,2 Both were judged to be highly biased and showed reductions in major cardiovascular events that were perceived to be not plausible (HR, 0.33 and 0.55, respectively). There is one trial in progress (Canadian BedMed study).3
The TIME trial was funded by several UK societies that played no role in the design or conduct of the study. Also, it was a large-scale, pragmatic trial conducted online. The authors only evaluated BP in a subgroup with home monitors. However, the primary clinical outcomes were assessed in all participants and verified by the UK National Health Service (NHS) clinical records. The subgroup who provided home BP data did show significant differences in morning and evening BP; the evening dosing group recorded lower morning BP, and the morning dosing group recorded lower evening BP. Thus, conventional antihypertensive drugs do not lower BP evenly over 24 hours, but the differences were small (1 mmHg to 2 mmHg). Also, there were no safety differences between the two groups, so evening medication administration is not harmful. The finding that there was no difference in major cardiovascular events over a median follow-up of five years supports the concept that patients can take antihypertensive medications when it is most convenient for them.
Consider some other limitations to this work. Pragmatic, online studies are subject to biases, especially when they are not blinded. Also, such studies probably recruit more educated patients who are better informed and interested in their health. This is reflected in the characteristics of the study population at baseline: 4% were current smokers, mean BMI was 28 kg/m2, only 13% reported prior cardiovascular disease, and the mean number of antihypertensive drugs taken was 1.5.
Since there were few adverse outcomes, there was insufficient power to evaluate subgroups, although no subgroup trends based on clinical characteristics and medication types were identified. The home BP subgroup probably is not representative of the whole population. Since the authors did not include 24-hour BP monitoring data, this was not a study of nocturnal hypertension. Finally, the authors did not assess adherence to medication consumption, which is a well-recognized issue with pharmacologic therapy of hypertension. The major strengths of the TIME study were that it included a large cohort, and an independent board adjudicated outcomes using the UK NHS database. At this point, it is reassuring that clinicians can tailor pharmacologic antihypertensive therapy to prevent adverse effects and conform to the patient’s lifestyle without concern that adverse outcomes are not abrogated.
REFERENCES
1. Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: Results of the MAPEC study. Chronobiol Int 2010;27:1629-1651.
2. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: The Hygia
Chronotherapy trial. Eur Heart J 2020;41:4565-4576.
3. Pragmatic Trials Collaborative. BedMed. The High Blood Pressure Study.
An online study of evening vs. morning administration of patients’ usual antihypertensive medications, with a median five-year follow-up, revealed there is no difference in major cardiovascular outcomes between the two periods.
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