{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T05:31:08Z","timestamp":1792992668025,"version":"4.5.0"},"reference-count":39,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n The effect of antihypertensive administration time on major adverse cardiovascular events is unclear, and has never been studied in frail older adults, for whom risks and benefits may differ from the general population.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine, in frail seniors, the effect of bedtime vs morning administration of antihypertensive medications on major cardiovascular events and death, as well as on potentially ischemic or hypotensive adverse events.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This multicenter, open-label, pragmatic randomized clinical trial recruited from 13 continuing care facilities in Canada (17 wards; 14 long-term care and 3 supportive-living wards) from May 25, 2020, to September 18, 2023, with follow-up until February 29, 2024. Residents with hypertension and at least 1 once-daily antihypertensive medication were included. Data analysis was from March to August 2024.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Patients were randomized 1:1 to taking all once-daily antihypertensive medications either at bedtime (intervention) or per usual care control (largely morning use).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The composite primary outcome was first occurrence of all-cause death or either hospitalization or emergency department (ED) visit for stroke, acute coronary syndrome, or heart failure. All-cause unplanned hospitalization or ED visits, falls and fractures, decubitus ulcers, and worsening cognition or behavioral problems were also assessed.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 776 older adults (median [IQR] age, 88 [81-92] years; 562 female [72.4%]; 664 [85.6%] with some degree of dementia; 367 [47.3%] with diabetes; 307 [39.6%] with coronary artery disease) were randomized to bedtime (394 participants) vs usual care (382 participants) administration and were followed-up for a median (IQR) of 415 (251-735) days. Of 320 primary outcome events, 293 (91.6%) were deaths; there was no difference in primary outcomes for bedtime vs usual care in a modified intention-to-treat analysis (29.4 vs 31.5 events per 100 patient-years; adjusted hazard ratio [aHR], 0.88; 95% CI, 0.71-1.11;\n P<\/jats:italic>\n \u2009=\u2009.28). Other outcomes were similarly no different between groups, excepting all-cause unplanned hospitalization and ED visits, which favored bedtime (22.6 vs 30.0 events per 100 patient-years; aHR, 0.74; 95% CI, 0.57-0.96;\n P<\/jats:italic>\n \u2009=\u2009.02).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this randomized clinical trial of antihypertensive medication timing, switching antihypertensives to bedtime failed to reduce a composite of death or major cardiovascular events that were primarily all-cause death, and had no effect on potentially ischemic and hypotensive adverse events, suggesting that in a population of frail older adults, administration time had little or no influence on the benefits and risks of antihypertensive medication.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04054648<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.13812","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T11:00:59Z","timestamp":1747047659000},"page":"e2513812","source":"Crossref","is-referenced-by-count":28,"title":["Bedtime vs Morning Antihypertensive Medications in Frail Older Adults"],"prefix":"10.1001","volume":"8","author":[{"given":"Scott R.","family":"Garrison","sequence":"first","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik R. E.","family":"Youngson","sequence":"additional","affiliation":[{"name":"Provincial Research Data Services, Alberta Health Services, Edmonton, Alberta, Canada"},{"name":"Alberta Strategy for Patient Oriented Research Support Unit (AbSPORU), Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A.","family":"Perry","sequence":"additional","affiliation":[{"name":"College of Family Physicians of Canada, Mississauga, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah N.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina S.","family":"Korownyk","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee A.","family":"Green","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Kolber","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica E. M.","family":"Kirkwood","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Michael","family":"Allan","sequence":"additional","affiliation":[{"name":"College of Family Physicians of Canada, Mississauga, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni Y.","family":"Kraut","sequence":"additional","affiliation":[{"name":"Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada"},{"name":"Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finlay A.","family":"McAlister","sequence":"additional","affiliation":[{"name":"Alberta Strategy for Patient Oriented Research Support Unit (AbSPORU), Edmonton, Alberta, Canada"},{"name":"Division of General Internal Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Bakal","sequence":"additional","affiliation":[{"name":"Provincial Research Data Services, Alberta Health Services, Edmonton, Alberta, Canada"},{"name":"Alberta Strategy for Patient Oriented Research Support Unit (AbSPORU), Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"issue":"1","key":"zoi250458r1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1161\/01.HYP.26.1.55","article-title":"Circadian profile of systemic hemodynamics.","volume":"26","author":"Veerman","year":"1995","journal-title":"Hypertension"},{"issue":"1","key":"zoi250458r2","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1161\/01.RES.53.1.96","article-title":"Blood pressure and heart rate variabilities in normotensive and hypertensive human beings.","volume":"53","author":"Mancia","year":"1983","journal-title":"Circ Res"},{"issue":"10393","key":"zoi250458r3","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1016\/S0140-6736(23)00733-X","article-title":"Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59?124 patients.","volume":"401","author":"Staplin","year":"2023","journal-title":"Lancet"},{"issue":"24","key":"zoi250458r4","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1056\/NEJMoa022273","article-title":"Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension.","volume":"348","author":"Clement","year":"2003","journal-title":"N Engl J Med"},{"issue":"1","key":"zoi250458r5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1161\/HYPERTENSIONAHA.107.100727","article-title":"Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension.","volume":"51","author":"Fagard","year":"2008","journal-title":"Hypertension"},{"issue":"1-2","key":"zoi250458r6","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3109\/07420528.2012.709448","article-title":"Administration-time differences in effects of hypertension medications on ambulatory blood pressure regulation.","volume":"30","author":"Hermida","year":"2013","journal-title":"Chronobiol Int"},{"issue":"8","key":"zoi250458r7","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.3109\/07420528.2010.510230","article-title":"Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study.","volume":"27","author":"Hermida","year":"2010","journal-title":"Chronobiol Int"},{"issue":"48","key":"zoi250458r8","doi-asserted-by":"publisher","first-page":"4565","DOI":"10.1093\/eurheartj\/ehz754","article-title":"Bedtime hypertension treatment improves cardiovascular risk reduction: the hygia chronotherapy trial.","volume":"41","author":"Hermida","year":"2020","journal-title":"Eur Heart J"},{"issue":"10361","key":"zoi250458r9","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/S0140-6736(22)01786-X","article-title":"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.","volume":"400","author":"Mackenzie","year":"2022","journal-title":"Lancet"},{"issue":"2","key":"zoi250458r10","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1097\/HJH.0000000000003581","article-title":"Impact of timing of antihypertensive treatment on mortality: an observational study from the Spanish Ambulatory Blood Pressure Monitoring Registry.","volume":"42","author":"de la Sierra","year":"2024","journal-title":"J Hypertens"},{"issue":"11","key":"zoi250458r11","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1001\/jama.297.11.1233","article-title":"Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.","volume":"297","author":"Van Spall","year":"2007","journal-title":"JAMA"},{"issue":"8","key":"zoi250458r12","doi-asserted-by":"publisher","first-page":"2662","DOI":"10.1161\/STROKEAHA.109.551812","article-title":"Patients enrolled in large randomized clinical trials of antiplatelet treatment for prevention after transient ischemic attack or ischemic stroke are not representative of patients in clinical practice: the Netherlands stroke survey.","volume":"40","author":"Maasland","year":"2009","journal-title":"Stroke"},{"issue":"6","key":"zoi250458r13","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-005402","article-title":"Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland.","volume":"4","author":"Ruokoniemi","year":"2014","journal-title":"BMJ Open"},{"issue":"6","key":"zoi250458r14","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1016\/j.rmed.2006.10.011","article-title":"External validity of randomized controlled trials in COPD.","volume":"101","author":"Travers","year":"2007","journal-title":"Respir Med"},{"issue":"4","key":"zoi250458r15","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1111\/bcp.12596","article-title":"Adverse drug reactions in special populations\u2014the elderly.","volume":"80","author":"Davies","year":"2015","journal-title":"Br J Clin Pharmacol"},{"issue":"8","key":"zoi250458r16","doi-asserted-by":"publisher","first-page":"627.e1","DOI":"10.1016\/j.jamda.2013.05.003","article-title":"Hypotension is a risk factor for new pressure ulcer occurrence in older patients after admission to an acute hospital.","volume":"14","author":"Man","year":"2013","journal-title":"J Am Med Dir Assoc"},{"issue":"1","key":"zoi250458r17","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1186\/s12877-018-0997-7","article-title":"An overview of co-morbidities and the development of pressure ulcers among older adults.","volume":"18","author":"Jaul","year":"2018","journal-title":"BMC Geriatr"},{"issue":"8","key":"zoi250458r18","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1111\/jgs.15421","article-title":"Hypotensive drugs and syncope due to orthostatic hypotension in older adults with dementia (syncope and dementia study).","volume":"66","author":"Testa","year":"2018","journal-title":"J Am Geriatr Soc"},{"issue":"8","key":"zoi250458r19","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1111\/jgs.14225","article-title":"Etiology of syncope and unexplained falls in elderly adults with dementia: syncope and dementia (SYD) study.","volume":"64","author":"Ungar","year":"2016","journal-title":"J Am Geriatr Soc"},{"issue":"3","key":"zoi250458r20","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1097\/WNN.0000000000000003","article-title":"Orthostatic hypotension in patients with dementia: clinical features and response to treatment.","volume":"26","author":"Freidenberg","year":"2013","journal-title":"Cogn Behav Neurol"},{"issue":"6","key":"zoi250458r21","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1093\/ageing\/afw155","article-title":"New horizons: the management of hypertension in people with dementia.","volume":"45","author":"Harrison","year":"2016","journal-title":"Age Ageing"},{"issue":"2","key":"zoi250458r22","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3233\/JAD-230094","article-title":"Sundowning in patients with dementia: identification, prevalence, and clinical correlates.","volume":"94","author":"Toccaceli Blasi","year":"2023","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"zoi250458r23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1532-5415.1987.tb01337.x","article-title":"Sundown syndrome in institutionalized elderly.","volume":"35","author":"Evans","year":"1987","journal-title":"J Am Geriatr Soc"},{"issue":"1","key":"zoi250458r24","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0167-4943(95)00676-1","article-title":"Sundowning syndrome in demented patients without neuroleptic therapy.","volume":"22","author":"Lebert","year":"1996","journal-title":"Arch Gerontol Geriatr"},{"issue":"8","key":"zoi250458r25","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2023-074777","article-title":"Bedtime versus morning use of antihypertensives in frail continuing care residents (BedMed-Frail): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial.","volume":"13","author":"Garrison","year":"2023","journal-title":"BMJ Open"},{"key":"zoi250458r27","doi-asserted-by":"publisher","first-page":"c332","DOI":"10.1136\/bmj.c332","article-title":"CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials.","volume":"340","author":"Schulz","year":"2010","journal-title":"BMJ"},{"issue":"2","key":"zoi250458r28","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1097\/01.icu.0000156134.38495.0b","article-title":"Blood flow in glaucoma.","volume":"16","author":"Grieshaber","year":"2005","journal-title":"Curr Opin Ophthalmol"},{"issue":"6","key":"zoi250458r29","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1097\/00055735-199912000-00017","article-title":"Role of nocturnal arterial hypotension in the development of ocular manifestations of systemic arterial hypertension.","volume":"10","author":"Hayreh","year":"1999","journal-title":"Curr Opin Ophthalmol"},{"issue":"5","key":"zoi250458r30","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/S0002-9394(14)70067-4","article-title":"Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders.","volume":"117","author":"Hayreh","year":"1994","journal-title":"Am J Ophthalmol"},{"issue":"11","key":"zoi250458r31","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1097\/01.mlr.0000182534.19832.83","article-title":"Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.","volume":"43","author":"Quan","year":"2005","journal-title":"Med Care"},{"key":"zoi250458r32","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12911-015-0155-5","article-title":"Methods for identifying 30 chronic conditions: application to administrative data.","volume":"15","author":"Tonelli","year":"2015","journal-title":"BMC Med Inform Decis Mak"},{"issue":"8","key":"zoi250458r33","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1161\/01.STR.0000174293.17959.a1","article-title":"Coding of stroke and stroke risk factors using international classification of diseases, revisions 9 and 10.","volume":"36","author":"Kokotailo","year":"2005","journal-title":"Stroke"},{"issue":"1","key":"zoi250458r35","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1186\/s12872-021-02081-8","article-title":"Chronotherapy for morning blood pressure surge in hypertensive patients: a systematic review and meta-analysis.","volume":"21","author":"Xie","year":"2021","journal-title":"BMC Cardiovasc Disord"},{"issue":"4","key":"zoi250458r36","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1161\/HYPERTENSIONAHA.118.11101","article-title":"Randomized crossover trial of the impact of morning or evening dosing of antihypertensive agents on 24-hour ambulatory blood pressure.","volume":"72","author":"Poulter","year":"2018","journal-title":"Hypertension"},{"issue":"2","key":"zoi250458r37","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)\u2013a metadata-driven methodology and workflow process for providing translational research informatics support.","volume":"42","author":"Harris","year":"2009","journal-title":"J Biomed Inform"},{"issue":"2","key":"zoi250458r38","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-059711","article-title":"Bedtime versus morning use of antihypertensives for cardiovascular risk reduction (BedMed): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial.","volume":"12","author":"Garrison","year":"2022","journal-title":"BMJ Open"},{"issue":"2","key":"zoi250458r39","article-title":"Evening versus morning dosing regimen drug therapy for hypertension.","volume":"2","author":"Wu","year":"2024","journal-title":"Cochrane Database Syst Rev"},{"key":"zoi250458r26","unstructured":"Pragmatic Trials Collaborative. Measuring what matters. Accessed March 23, 2025. https:\/\/www.PragmaticTrials.ca\/"},{"key":"zoi250458r34","unstructured":"Canadian Institute for Health Information. Manuals and forms for continuing and residential care interRAI Assessors. Accessed July 7, 2024. https:\/\/www.cihi.ca\/en\/manuals-and-forms-for-continuing-and-residential-care-interrai-assessors\/?"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2833842\/garrison_2025_oi_250458_1746462703.63397.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T11:01:00Z","timestamp":1747047660000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2833842"}},"subtitle":["The BedMed-Frail Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.13812","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,12]]}}}