The Effect of Antihypertensive Medication Timing on Morbidity and Mortality
Primary Purpose
Hypertension
Status
Active
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Use of blood pressure lowering medication at bedtime
Use of blood pressure lowering medication in the morning
Sponsored by

About this trial
This is an interventional treatment trial for Hypertension focused on measuring Pragmatic, Primary Care, Chronotherapy, Administrative Data, Stroke, Myocardial Infarction, Congestive Heart Failure, Glaucoma, Dementia, Hip Fracture
Eligibility Criteria
Inclusion Criteria:
- 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)
Exclusion Criteria:
- 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)
Sites / Locations
- University of Alberta
- University of Manitoba
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Bedtime BP Meds
Morning BP Meds
Arm Description
Use of blood pressure lowering medication at bedtime
Use of blood pressure lowering medication in the morning
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
All-cause mortality
Death from any cause.
Acute coronary syndrome
Hospitalization or ER visit for acute coronary syndrome or MI.
CHF Hospitalization
Hospitalization or ER visit for congestive heart failure.
Stoke
Hospitalization or ER visit for stroke (excludes TIA).
All-cause hospitalization
Hospitalization or ER visit for any cause
Long term care admission
Newly admitted to a nursing home or assisted living facility as primary residence
New glaucoma diagnosis
First-ever glaucoma diagnosis
Non-vertebral fracture
Fracture of any bone other than the vertebra of the back or neck
Cognitive decline
Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test
Full Information
NCT ID
NCT02990663
First Posted
December 5, 2016
Last Updated
June 15, 2023
Sponsor
University of Alberta
Collaborators
Alberta Innovates Health Solutions, Alberta Health services, Canadian Institutes of Health Research (CIHR)
1. Study Identification
Unique Protocol Identification Number
NCT02990663
Brief Title
The Effect of Antihypertensive Medication Timing on Morbidity and Mortality
Official Title
The Effect of Antihypertensive Medication Timing on Morbidity and Mortality: The "BedMed" RCT
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 2016 (undefined)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Alberta
Collaborators
Alberta Innovates Health Solutions, Alberta Health services, Canadian Institutes of Health Research (CIHR)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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 254 primary outcome events are anticipated.
Detailed Description
THE OPPORTUNITY BEDTIME PRESCRIBING MIGHT PROVIDE: Blood pressure normally exhibits a circadian rhythm with relatively lower pressures during sleep.(Ref 1) Lack of this sleep time "dip" correlates strongly with adverse cardiovascular events and BP correlates most strongly with such events when measured at night (i.e. during sleep).(Ref 2-5) Motivated by such observations, Spanish researchers studied the effect of taking BP medication at BEDTIME (when the effect on nighttime BP would be greatest) versus conventional morning use, when most BP medications are taken. The results of this study (the MAPEC trial) were striking.(Ref 6) Over a median 5.6 years follow-up, adverse cardiovascular events occurred in 187 of 1084 subjects taking BP medication in the morning but only 68 of 1072 subjects who took their BP medication at bedtime (relative risk 0.39, 95%CI [0.29-0.51], p < 0.001). This 61% reduction in adverse events was similar for all individual components of the primary outcome (including death from all causes, stroke, MI, new angina pectoris, CHF and retinal artery occlusions). If true, a switch to bedtime prescribing would have more impact on the health of hypertensive patients than whether high BP is treated at all. However extraordinary claims require extraordinary evidence - independent replication of such surprising findings is needed for widespread practice change to occur.
BEDMED: The BedMed trial is a pragmatic primary care trial intended to verify whether bedtime antihypertensive use, as compared to conventional morning use, reduces major adverse cardiovascular events. It is designed as an adaptive randomized registry trial within community primary care and draws both trial outcomes and baseline covariates from provincial administrative claims data (vital statistics, hospital separations, physician services, prescription dispenses, laboratory data). BedMed is government funded/facilitated, and has over 400 volunteer primary care providers recruiting participants in 5 Canadian provinces (Alberta, British Columbia, Saskatchewan, Manitoba, and Ontario). It was originally intended that the trial would continue until 406 primary outcome events were observed, however funding will expire before this occurs. As a result, BedMed will continue to recruit participants until early 2022 and complete data collection in late 2023, at which time 254 primary outcome events are anticipated (based on blinded observation of total events gathered at the end of 2021). The trial relies heavily on a collaboration between the volunteer family physicians of the Pragmatic Trials Collaborative (www.PragmaticTrials.ca) who will recruit for the trial and the Alberta SPOR Support Unit's Data Platform - which will facilitate accessing and analyzing the relevant administrative databases from multiple provinces (http://www.aihealthsolutions.ca/initiatives-partnerships/spor/).
DIURETIC SUB-STUDY: The "adaptive" element of the BedMed trial design refers to an interim examination of bedtime diuretic tolerance. Although it is commonly believed that diuretics can't be taken at bedtime without inducing unwanted nocturia, the sparse evidence in the literature suggests this may not be the case.(Ref 7,8) Rather than excluding patients whose only medication is a diuretic the investigators will instead initially include such patients and evaluate bedtime diuretic tolerance early on in the trial to determine whether or not such patients should continue to be enrolled. Specifically, upon allocating to bedtime dosing 203 patients whose only BP medication is an AM diuretic, the investigators will analyze 6-week compliance to bedtime allocation for all participants with a single morning BP medication (of all types). If diuretic compliance is worse, the "adaptive" trial design will exclude enrolment of additional patients whose only BP medication is a diuretic. The BedMed investigators will report on bedtime diuretic tolerance separate from (and in advance of) the main BedMed analysis.
INTERIM SAFETY ANALYSIS: An independent data safety monitoring board (DSMB) organized and chaired by Jim Wright (Cochrane Hypertension Review Group Coordinating Editor) is expected to review all data in March 2022, at which time approximately 150-160 primary outcome events are expected. If p is ≤ 0.001 for benefit (the Haybittle-Peto boundary - recommended to reduce the chance of stopping too early and magnifying benefit), or if p is ≤ 0.05 for harm, the DSMB will apply clinical judgement and make recommendations to the steering committee on whether the trial should stop early.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension
Keywords
Pragmatic, Primary Care, Chronotherapy, Administrative Data, Stroke, Myocardial Infarction, Congestive Heart Failure, Glaucoma, Dementia, Hip Fracture
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
3357 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bedtime BP Meds
Arm Type
Experimental
Arm Description
Use of blood pressure lowering medication at bedtime
Arm Title
Morning BP Meds
Arm Type
Active Comparator
Arm Description
Use of blood pressure lowering medication in the morning
Intervention Type
Other
Intervention Name(s)
Use of blood pressure lowering medication at bedtime
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Use of blood pressure lowering medication in the morning
Intervention Description
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.
Primary Outcome Measure Information:
Title
Major Adverse Cardiovascular Events
Description
First occurrence of either death (all-cause), or hospitalization or emergency department visit for acute coronary syndrome / MI, congestive heart failure, or stroke.
Time Frame
Through study completion, an average of 4 years
Secondary Outcome Measure Information:
Title
All-cause mortality
Description
Death from any cause.
Time Frame
Through study completion, an average of 4 years
Title
Acute coronary syndrome
Description
Hospitalization or ER visit for acute coronary syndrome or MI.
Time Frame
Through study completion, an average of 4 years
Title
CHF Hospitalization
Description
Hospitalization or ER visit for congestive heart failure.
Time Frame
Through study completion, an average of 4 years
Title
Stoke
Description
Hospitalization or ER visit for stroke (excludes TIA).
Time Frame
Through study completion, an average of 4 years
Title
All-cause hospitalization
Description
Hospitalization or ER visit for any cause
Time Frame
Through study completion, an average of 4 years
Title
Long term care admission
Description
Newly admitted to a nursing home or assisted living facility as primary residence
Time Frame
Through study completion, an average of 4 years
Title
New glaucoma diagnosis
Description
First-ever glaucoma diagnosis
Time Frame
Through study completion, an average of 4 years
Title
Non-vertebral fracture
Description
Fracture of any bone other than the vertebra of the back or neck
Time Frame
Through study completion, an average of 4 years
Title
Cognitive decline
Description
Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test
Time Frame
18 months
Other Pre-specified Outcome Measures:
Title
Acute care costs
Description
Acute care costs (derived from each admission's resource intensity weight and length of stay)
Time Frame
Through study completion, an average of 4 years
Title
Total cost of care
Description
Acute care costs + medication costs + physician billings
Time Frame
Through study completion, an average of 4 years
Title
Self-reported Overall Health Score
Description
As measured by the EQ-5D-5L
Time Frame
1 year
Title
Light-headedness
Description
Self-reported light-headedness or feeling "faint" without loss or consciousness in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)
Time Frame
Through study completion, an average of 4 years
Title
Syncope
Description
Self-reported fainting (loss of consciousness) in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)
Time Frame
Through study completion, an average of 4 years
Title
Falling
Description
Self-reported falling in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)
Time Frame
Through study completion, an average of 4 years
Title
Nocturnal and daytime blood pressure
Description
302 subjects will undergo 24-hour BP monitoring after 6 months to determine differences in blood pressure between groups.
Time Frame
6 months
Title
Self-reported worsening of vision
Description
Vision self-reported as "much worse" compared to the last follow-up at any point, or "slightly worse" than the last follow-up, on 2 or more occasions (Note: vision is reported at 6-weeks, 6-months, and every 6-months, as either "unchanged", "slightly worse", or "much worse" than the last follow-up)
Time Frame
Through study completion, an average of 4 years
Title
New impairment consistent with dementia
Description
Short Blessed Test score newly 10 or greater at 18-month assessment, or new physician administrative claims diagnosis of dementia at any point during follow-up
Time Frame
Through study completion, an average of 4 years
Title
Hip fracture
Description
Any break of the hip joint or femoral neck
Time Frame
Through study completion, an average of 4 years
Title
Nocturia frequency
Description
Self-reported change from baseline in the number of overnight urinations per week (at 6-weeks and 6-months)
Time Frame
6-months
Title
Nocturia burden
Description
Self-reported nocturia burden in the prior month, recorded as no nocturia, or nocturia that is "no problem", "minor problem", or "major problem" (at 6-weeks and 6-months)
Time Frame
6-months
Title
Adherence to medication timing allocation
Description
Proportion of BP medication doses taken at the allocated time at 6-months (twice daily medications being considered as ½ dose in the AM and ½ dose in the PM for this calculation)
Time Frame
6-months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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)
Exclusion Criteria:
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott R Garrison, MD, PhD
Organizational Affiliation
University of Alberta
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2T4
Country
Canada
Facility Name
University of Manitoba
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3T 2N2
Country
Canada
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Upon completion of all planned studies related to this project, anonymized patient level data for all outcomes and baseline characteristics will be made available in the form of a downloadable spreadsheet accessed through the Pragmatic Trials Collaborative's website (www.PragmaticTrials.ca)
Citations:
PubMed Identifier
7607733
Citation
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Results Reference
background
PubMed Identifier
12802026
Citation
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.
Results Reference
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7995639
Citation
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Results Reference
background
PubMed Identifier
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Citation
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Results Reference
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PubMed Identifier
18039980
Citation
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Results Reference
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PubMed Identifier
20854139
Citation
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Results Reference
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PubMed Identifier
14616455
Citation
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.
Results Reference
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PubMed Identifier
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Citation
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.
Results Reference
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PubMed Identifier
35210352
Citation
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.
Results Reference
derived
Links:
URL
http://pragmatictrials.ca/
Description
The Pragmatic Trials Collaborative
Learn more about this trial
The Effect of Antihypertensive Medication Timing on Morbidity and Mortality
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