Clinical trial NCT02990663: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Keywords: Pragmatic
Primary Care
Chronotherapy
Administrative Data
Stroke
Myocardial Infarction
Congestive Heart Failure
Glaucoma
Dementia
Hip Fracture
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Alberta Innovates Health Solutions
name: Alberta Health services
name: Canadian Institutes of Health Research (CIHR)
First posted: 2016-12-13
Enrollment: 3357
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 more than 255 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.

Eligibility criteria: Inclusion Criteria:

1. Hypertension diagnosis as assigned by a physician or nurse practitioner
2. ≥ 1 blood pressure medication taken once daily, or primary care provider willing to convert ≥ 1 blood pressure medication to once daily
3. Community dwelling (i.e. not residing in a nursing home; assisted living permitted)

Exclusion Criteria:

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

Primary outcomes:
measure: Major Adverse Cardiovascular Events
timeFrame: Through study completion, an average of 4 years
Secondary outcomes:
measure: All-cause mortality
timeFrame: Through study completion, an average of 4 years
measure: Acute coronary syndrome
timeFrame: Through study completion, an average of 4 years
measure: CHF Hospitalization
timeFrame: Through study completion, an average of 4 years
measure: Stoke
timeFrame: Through study completion, an average of 4 years
measure: All-cause hospitalization
timeFrame: Through study completion, an average of 4 years
measure: Long term care admission
timeFrame: Through study completion, an average of 4 years
measure: New glaucoma diagnosis
timeFrame: Through study completion, an average of 4 years
measure: Non-vertebral fracture
timeFrame: Through study completion, an average of 4 years
measure: Cognitive decline
timeFrame: 18 months
Other outcomes:
measure: Acute care costs
timeFrame: Through study completion, an average of 4 years
measure: Total cost of care
timeFrame: Through study completion, an average of 4 years
measure: Self-reported Overall Health Score
timeFrame: 1 year
measure: Light-headedness
timeFrame: Through study completion, an average of 4 years
measure: Syncope
timeFrame: Through study completion, an average of 4 years
measure: Falling
timeFrame: Through study completion, an average of 4 years
measure: Nocturnal and daytime blood pressure
timeFrame: 6 months
measure: Self-reported worsening of vision
timeFrame: Through study completion, an average of 4 years
measure: New impairment consistent with dementia
timeFrame: Through study completion, an average of 4 years
measure: Hip fracture
timeFrame: Through study completion, an average of 4 years
measure: Nocturia frequency
timeFrame: 6-months
measure: Nocturia burden
timeFrame: 6-months
measure: Adherence to medication timing allocation
timeFrame: 6-months
Locations:
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Saskatoon
country: Canada
facility: University of Saskatchewan
state: Saskatchewan
Study officials:
affiliation: University of Alberta
name: Scott R Garrison, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
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.
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.
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.