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Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes : the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study
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Pigazzani, F., Dyar , K. A., Morant , S. V., Vetter , C., Rogers , A., Flynn , R. W. V., Rorie , D. A., Mackenzie , I. S., Cappuccio, Francesco, Manfredini, R. and MacDonald, T. M. (2024) Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes : the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study. eClinicalMedicine, 72 . 102633. doi:10.1016/eclinm.2024.102633 ISSN 2589-5370.
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Official URL: https://doi.org/10.1016/eclinm.2024.102633
Abstract
Background
Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes.
Methods
This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype.
Findings
Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14–1.86] and 0.96 [95% CI 0.70–1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18–2.22] and 0.66 [95% CI 0.44–1.00] per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events.
Interpretation
Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a ‘misaligned’ dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI.
Item Type: | Journal Article | |||||||||
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Subjects: | R Medicine > RM Therapeutics. Pharmacology | |||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Mental Health and Wellbeing Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | eClinicalMedicine | |||||||||
Publisher: | Elsevier | |||||||||
ISSN: | 2589-5370 | |||||||||
Official Date: | June 2024 | |||||||||
Dates: |
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Volume: | 72 | |||||||||
Article Number: | 102633 | |||||||||
DOI: | 10.1016/eclinm.2024.102633 | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||
Date of first compliant deposit: | 14 May 2024 | |||||||||
Date of first compliant Open Access: | 14 May 2024 | |||||||||
RIOXX Funder/Project Grant: |
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