Pragmatic Trials Collaborative

Measuring What Matters

Trials In Progress


BedMed is our first large pragmatic trial and has a target enrolment of 8,750 community dwelling patients with hypertension. Like INRange, BedMed is about medication timing. In particular this project is designed to determine if switching the time of day blood pressure medications is taken to bedtime (compared to conventional morning use) reduces death, stroke, heart attack or hospital admission for congestive heart failure.

Why would we want to look at this?

Blood pressure (BP) normally exhibits a circadian rhythm, with relatively lower pressures during sleep1. 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)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 virtually all BP meds are taken). The results of this study (the MAPEC trial) were striking6. 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, myocardial infarction, new angina pectoris, heart failure and occlusion of the retinal artery). If true, a switch to bedtime prescribing would have more impact on the health of hypertensive Canadians than whether high BP is treated at all.

And yet this trial failed to change practice. This is because 1) most health care providers are unaware of the MAPEC trial and 2) replication of such surprising results is required for these findings to be believed – primarily because the benefit seems “too good to be true”, far exceeding all other methods of cardiovascular risk reduction (e.g. high dose statins convey a 35% relative risk reduction, morning BP meds 30%, exercise 25%, aspirin 15%). Neither relatively recent (Oct 2013) literature review, nor a 2011 Cochrane systematic review found ANY RCTs (besides MAPEC) evaluating the effect of BP medication timing on “hard” endpoints7,8. The only other published trials looking at the timing of BP medication examine its effect on blood pressure and other surrogates – not on cardiovascular events.

Additionally, a sub-study of early-enrolled patients will allow us to evaluate whether diuretics can be successfully switched to bedtime. In the early phase of the study using an adaptive trial design, we will adjust recruitment to either allow, or exclude, patients whose only antihypertensive is a diuretic depending on how well it is tolerated.


We will begin enrolment across Alberta in Nov 2016 and anticipate results to be available in 2020.


The BedMed Initiative is supported in Alberta by a 3 year, $1,191,998 Partnership for Research & Innovation in the Health System (PRIHS) award from Alberta Innovates - Health Solutions (AIHS).

  1. Veerman DP, Imholz BP, Wieling W, Wesseling KH, van Montfrans GA. Circadian profile of systemic hemodynamics. Hypertension. Jul 1995;26(1):55-59.
  2. Clement DL, De Buyzere ML, De Bacquer DA, et al. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. Jun 12 2003;348(24):2407-2415.
  3. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension. Dec 1994;24(6):793-801.
  4. 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. Jun 2007;49(6):1235-1241.
  5. Fagard RH, Celis H, Thijs L, et al. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension. Jan 2008;51(1):55-61.
  6. 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. Sep 2010;27(8):1629-1651.
  7. Carter BL, Chrischilles EA, Rosenthal G, Gryzlak BM, Eisenstein EL, Vander Weg MW. Efficacy and safety of nighttime dosing of antihypertensives: review of the literature and design of a pragmatic clinical trial. J Clin Hypertens (Greenwich). Feb 2014;16(2):115-121.
  8. Zhao P, Xu P, Wan C, Wang Z. Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database Syst Rev. 2011(10):CD004184.