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Clinician Article

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.



  • Mackenzie IS
  • Rogers A
  • Poulter NR
  • Williams B
  • Brown MJ
  • Webb DJ, et al.
Lancet. 2022 Oct 22;400(10361):1417-1425. doi: 10.1016/S0140-6736(22)01786-X. Epub 2022 Oct 11. (Original)
PMID: 36240838
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Disciplines
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Nephrology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Cardiology
    Relevance - 5/7
    Newsworthiness - 6/7
  • Endocrine
    Relevance - 5/7
    Newsworthiness - 5/7

Abstract

BACKGROUND: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension.

METHODS: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that 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 minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal 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 (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete.

FINDINGS: Between Dec 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 (SD 9·3); 12 136 (57·5%) participants were men; 8968 (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 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 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.

INTERPRETATION: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects.

FUNDING: British Heart Foundation.


Clinical Comments

Cardiology

Simple clinical issue that is nicely resolved!

Endocrine

This outcome is interesting and helpful to general physicians endocrinologists. It will help simplify patient medication management. Glad to see that this is a proper prospective RCT with a solid number of patients that helps validate and solidify the outcome.

Family Medicine (FM)/General Practice (GP)

Kind of news to me. Good to hear!

General Internal Medicine-Primary Care(US)

The follow-up time scale of 5.2 years for the effect of blood pressure medications on a composite of vascular death or non-fatal MI or stroke is adequate, although ideally would be longer. The outcome between morning and evening doses was convincingly the same at 5.2 years. We can advise patients to take their medications at whatever time of day they are most likely to remember to take them.

Internal Medicine

I haven't followed this topic closely, but my (imperfect) memory of at least one prior publication, which had a positive effect on BP control, was that they looked at splitting up the dosing so that some meds were given in the morning and some in the evening. Obviously, this looked at a different question in terms of both intervention and outcome.

Internal Medicine

As a hospitalist, advising patients as to when they take their anti-hypertensives is likely not as important as it would be to an outpatient provider. Nevertheless, the results demonstrate that evening vs morning dosing doesn't appear to make a difference as to adverse outcomes, and convenience of dosing time can safely be used as a guiding factor for medication receipt.

Internal Medicine

After much discussion, it is wonderful to have a pragmatic trial that shows we need not make a major point about timing of medications.

Internal Medicine

This chronotherapy question has been up in the air for a long time. It is very good to see a very large trial targeting clinical outcomes.

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