The Effect of Antihypertensive Medication Timing on Morbidity and Mortality

NCT02990663 | Completed Phase 4 DMC

• 1 other identifier: BedMed Nov 30 2016
• Study Type: interventional
• Target: 3,357
• Locations: 1 country
• Sites: 5

Brief Summary

High blood pressure is common and its presence increases the risk of cardiovascular mortality and morbidity (most notably stroke, myocardial infarction, and congestive heart failure). Given blood pressure is normally higher during the day than it is overnight, blood pressure lowering medications are traditionally taken in the morning. However a randomized trial of 2156 Spanish hypertension patients published in 2010 ("MAPEC"), suggests a large (61%) reduction in mortality and cardiovascular morbidity if such medications are instead taken at bedtime. This degree of benefit far exceeds other established methods of cardiovascular risk reduction - and such a surprisingly large effect requires independent confirmation for practice to change. BedMed is a pragmatic randomized controlled trial facilitated by over 400 Canadian family physician members of the Pragmatic Trials Collaborative. During the conduct of this trial consenting hypertensive primary care patients, already established on one or more antihypertensive medications, will be randomized to either morning or bedtime antihypertensive use. Patient oriented trial outcomes evaluating both potential benefits and harms will be drawn largely from administrative health data that is routinely collected on all residents of Canada's publicly funded health care system. This trial is being conducted in 5 Canadian provinces and will continue to collect data until late 2023, at which point more than 255 primary outcome events are anticipated.

Conditions

Hypertension

Keywords

Pragmatic; Primary Care; Chronotherapy; Administrative Data; Stroke; Myocardial Infarction; Congestive Heart Failure; Glaucoma; Dementia; Hip Fracture

Outcome Measures

Primary Outcomes (1)

• Major Adverse Cardiovascular Events

  First occurrence of either death (all-cause), or hospitalization or emergency department visit for acute coronary syndrome / MI, congestive heart failure, or stroke.

  Through study completion, an average of 4 years

Secondary Outcomes (9)

• All-cause mortality

  Through study completion, an average of 4 years

• Acute coronary syndrome

  Through study completion, an average of 4 years

• CHF Hospitalization

  Through study completion, an average of 4 years

• Stoke

  Through study completion, an average of 4 years

• All-cause hospitalization

  Through study completion, an average of 4 years

Other Outcomes (13)

• Acute care costs

  Through study completion, an average of 4 years

• Total cost of care

  Through study completion, an average of 4 years

• Self-reported Overall Health Score

  1 year

Study Arms (2)

Bedtime BP Meds

EXPERIMENTAL

Use of blood pressure lowering medication at bedtime

Other: Use of blood pressure lowering medication at bedtime

Morning BP Meds

ACTIVE COMPARATOR

Use of blood pressure lowering medication in the morning

Other: Use of blood pressure lowering medication in the morning

Interventions

Use of blood pressure lowering medication at bedtime OTHER

Blood pressure lowering medications will be switched (one at a time as tolerated) to bedtime, or maintained at bedtime if already taken at that time. All decisions related to which, and how many, medications to switch are at the discretion of the care provider.

Bedtime BP Meds

Use of blood pressure lowering medication in the morning OTHER

Blood pressure lowering medications will be switched (one at a time as tolerated) to morning, or maintained in the morning if already taken at that time. All decisions related to which, and how many, medications to switch are at the discretion of the care provider.

Morning BP Meds

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hypertension diagnosis as assigned by a physician or nurse practitioner
• ≥ 1 blood pressure medication taken once daily, or primary care provider willing to convert ≥ 1 blood pressure medication to once daily
• Community dwelling (i.e. not residing in a nursing home; assisted living permitted)

You may not qualify if:

• Palliative (as per primary care provider's judgement)
• Unable to provide informed consent (as per primary care provider's judgement)
• Personal history of glaucoma or use of glaucoma medications
• Sleep disrupting shift work (more than 3 shifts/month during participant's regular sleeping hours)

Sponsors & Collaborators

• University of Alberta: lead
• Alberta Innovates Health Solutions: collaborator
• Alberta Health services: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (5)

University of Alberta

Edmonton, Alberta, T6G 2T4, Canada

Location

University of British Columbia

Vancouver, British Columbia, V6T 1Z4, Canada

Location

University of Manitoba

Winnipeg, Manitoba, R3T 2N2, Canada

Location

University of Toronto

Toronto, Ontario, M5S 1A1, Canada

Location

University of Saskatchewan

Saskatoon, Saskatchewan, S7N 5A2, Canada

Location

Related Publications (11)

• Veerman DP, Imholz BP, Wieling W, Wesseling KH, van Montfrans GA. Circadian profile of systemic hemodynamics. Hypertension. 1995 Jul;26(1):55-9. doi: 10.1161/01.hyp.26.1.55.

  PMID: 7607733 BACKGROUND

• Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, Gheeraert PJ, Missault LH, Braun JJ, Six RO, Van Der Niepen P, O'Brien E; Office versus Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. 2003 Jun 12;348(24):2407-15. doi: 10.1056/NEJMoa022273.

  PMID: 12802026 BACKGROUND

• Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G, et al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension. 1994 Dec;24(6):793-801. doi: 10.1161/01.hyp.24.6.793.

  PMID: 7995639 BACKGROUND

• Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M. Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension. 2007 Jun;49(6):1235-41. doi: 10.1161/HYPERTENSIONAHA.107.087262. Epub 2007 Mar 26.

  PMID: 17389258 BACKGROUND

• Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension. 2008 Jan;51(1):55-61. doi: 10.1161/HYPERTENSIONAHA.107.100727. Epub 2007 Nov 26.

  PMID: 18039980 BACKGROUND

• Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010 Sep;27(8):1629-51. doi: 10.3109/07420528.2010.510230.

  PMID: 20854139 BACKGROUND

• Rembratt A, Norgaard JP, Andersson KE. Nocturia and associated morbidity in a community-dwelling elderly population. BJU Int. 2003 Nov;92(7):726-30. doi: 10.1046/j.1464-410x.2003.04467.x.

  PMID: 14616455 BACKGROUND

• Asplund R. Nocturia in relation to sleep, health, and medical treatment in the elderly. BJU Int. 2005 Sep;96 Suppl 1:15-21. doi: 10.1111/j.1464-410X.2005.05653.x.

  PMID: 16083452 BACKGROUND

• Garrison SR, Bakal JA, Kolber MR, Korownyk CS, Green LA, Kirkwood JEM, McAlister FA, Padwal RS, Lewanczuk R, Hill MD, Singer AG, Katz A, Kelmer MD, Gayayan A, Campbell FN, Vucenovic A, Archibald NR, Yeung JMS, Youngson ERE, McGrail K, O'Neill BG, Greiver M, Manca DP, Kraut RY, Wang T, Manns BJ, Mangin DA, MacLean C, McCormack J, Wong ST, Norris C, Allan GM. Antihypertensive Medication Timing and Cardiovascular Events and Death: The BedMed Randomized Clinical Trial. JAMA. 2025 Jun 17;333(23):2061-2072. doi: 10.1001/jama.2025.4390.

  PMID: 40354045 DERIVED

• Garrison SR, Kelmer M, Korownyk T, Kolber MR, Allan GM, Bakal J, Singer A, Katz A, Mcalister F, Padwal RS, Lewanczuk R, Hill MD, McGrail K, O'Neill B, Greiver M, Manca DP, Mangin D, Wong ST, Kirkwood JEM, McCormack JP, Yeung JMS, Green L. Tolerability of bedtime diuretics: a prospective cohort analysis. BMJ Open. 2023 Jun 6;13(6):e068188. doi: 10.1136/bmjopen-2022-068188.

  PMID: 37280022 DERIVED

• Garrison SR, Kolber MR, Allan GM, Bakal J, Green L, Singer A, Trueman DR, McAlister FA, Padwal RS, Hill MD, Manns B, McGrail K, O'Neill B, Greiver M, Froentjes LS, Manca DP, Mangin D, Wong ST, MacLean C, Kirkwood JE, McCracken R, McCormack JP, Norris C, Korownyk T. Bedtime versus morning use of antihypertensives for cardiovascular risk reduction (BedMed): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial. BMJ Open. 2022 Feb 24;12(2):e059711. doi: 10.1136/bmjopen-2021-059711.

  PMID: 35210352 DERIVED

Related Links

• The Pragmatic Trials Collaborative

MeSH Terms

Conditions

Hypertension; Stroke; Myocardial Infarction; Heart Failure; Glaucoma; Dementia; Hip Fractures

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Myocardial Ischemia; Heart Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Ocular Hypertension; Eye Diseases; Neurocognitive Disorders; Mental Disorders; Femoral Fractures; Fractures, Bone; Wounds and Injuries; Hip Injuries; Leg Injuries

Study Officials

• Scott R Garrison, MD, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2016
• First Posted: December 13, 2016
• Study Start: March 31, 2017
• Primary Completion: December 22, 2023
• Study Completion: December 22, 2023
• Last Updated: August 27, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share

Locations

CA (5)