The Effect of Antihypertensive Medication Timing on Morbidity and Mortality

  • End date
    Dec 31, 2022
  • participants needed
  • sponsor
    University of Alberta
Updated on 22 May 2021
myocardial infarction
antihypertensive drugs
cardiovascular morbidity


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 300 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 the end of 2022, at which point 250 primary outcome events are anticipated.


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). Covariates for the primary analysis will include province (4 variables), age (continuous), sex, physical frailty (binary - score of 3 or higher on Tilburg Frailty Indicator Physical Components sub-score), cognitive impairment (binary - score of 3 or higher on Short Blessed Test), current smoking status, hospitalization in the 6 months prior to enrolment, 3 baseline BP meds (resistant hypertension), presence/absence of specific diagnoses (diabetes, CHF, stroke/TIA, coronary artery disease, sleep apnea), 4 additional non-BP lowering medications (polypharmacy), kidney disease (a claims data renal insufficiency diagnosis or eGFR less than 40), or end-stage kidney disease on dialysis. Subgroup analysis based on the presence or absence of each of these covariates will be carried out (using a threshold of 70 yrs for age). 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 into the fall of 2021 and complete data collection at the end of 2023, at which time 250 primary outcome events are anticipated (based on blinded observation of total events amongst all participants in April 2021). The trial relies heavily on a collaboration between the volunteer family physicians of the Pragmatic Trials Collaborative ( 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 (

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) will review all data in March 2022, at which time approximately 200 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 break early.

Condition Vascular Diseases, Hypertension, Diabetes and Hypertension, High Blood Pressure (Hypertension), High Blood Pressure (Hypertension - Pediatric), Elevated Blood Pressure, high blood pressure, arterial hypertension
Treatment Use of blood pressure lowering medication at bedtime, Use of blood pressure lowering medication in the morning
Clinical Study IdentifierNCT02990663
SponsorUniversity of Alberta
Last Modified on22 May 2021


Yes No Not Sure

Inclusion Criteria

Hypertension diagnosis as assigned by a participating Primary Care Provider
1 Blood pressure medication (taken at any time of day)
Community dwelling (includes assisted living)

Exclusion Criteria

Anticipated life expectancy < 2 years
Unable to provide informed consent
Personal history of glaucoma or use of glaucoma medications
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