The Effect of Antihypertensive Medication Timing on Morbidity and Mortality

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effect of Antihypertensive Medication Timing on Morbidity and Mortality: The BedMed RCT

Conditions
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Hypertension

Intervention / Treatment
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* Other: Use of blood pressure lowering medication at bedtime
* Other: Use of blood pressure lowering medication in the morning


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bedtime BP Meds<br>Use of blood pressure lowering medication at bedtime | Other: Use of blood pressure lowering medication at bedtime<br>* 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.<br>|
| Active Comparator: Morning BP Meds<br>Use of blood pressure lowering medication in the morning | Other: Use of blood pressure lowering medication in the morning<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Death from any cause. | Through study completion, an average of 4 years | 
| Acute coronary syndrome | Hospitalization or ER visit for acute coronary syndrome or MI. | Through study completion, an average of 4 years | 
| CHF Hospitalization | Hospitalization or ER visit for congestive heart failure. | Through study completion, an average of 4 years | 
| Stoke | Hospitalization or ER visit for stroke (excludes TIA). | Through study completion, an average of 4 years | 
| All-cause hospitalization | Hospitalization or ER visit for any cause | Through study completion, an average of 4 years | 
| Long term care admission | Newly admitted to a nursing home or assisted living facility as primary residence | Through study completion, an average of 4 years | 
| New glaucoma diagnosis | First-ever glaucoma diagnosis | Through study completion, an average of 4 years | 
| Non-vertebral fracture | Fracture of any bone other than the vertebra of the back or neck | Through study completion, an average of 4 years | 
| Cognitive decline | Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Care, Pragmatic, Chronotherapy, Administrative Data, Stroke, Myocardial Infarction, Congestive Heart Failure, Glaucoma, Dementia, Hip Fracture