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 (target N = 8750) 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 event driven (ending upon the occurrence of 406 primary outcome events) and expected to run over a period of roughly 3 years.
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 age, sex, physical frailty (continuous, as determined by the Tilburg Frailty Indicator Physical Components sub-score), cognitive impairment (continuous, as determined by the Short Blessed Test score), 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), BMI > 30, ≥ 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 an age threshold of ≥ 70 yrs, a Tilburg physical frailty threshold of ≥ 3, and a Short Blessed cognitive impairment threshold of ≥ 7). BedMed is government funded/facilitated, event driven (with the trial breaking upon 406 primary outcome events), will have over 300 volunteer primary care providers recruiting, is expected to enrol 8,750 consenting community patients with hypertension, and 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 (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 (excluding diuretic / non-diuretic combination pills) 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 upon reaching 200 events (estimated to occur ~20 months in). 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.
- Use of blood pressure lowering medication at bedtime Other
Intervention Desc: 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. ARM 1: Kind: Experimental Label: Bedtime BP Meds Description: Use of blood pressure lowering medication at bedtime
- Use of blood pressure lowering medication in the morning Other
Intervention Desc: 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. ARM 1: Kind: Experimental Label: Morning BP Meds Description: Use of blood pressure lowering medication in the morning
|Type||Measure||Time Frame||Safety Issue|
|Primary||Major Adverse Cardiovascular Events||This study is event driven with quarterly evaluation of total (both groups combined) primary outcome events. The primary analysis takes place upon the occurrence of 406 primary outcome events (anticipated to occur, on average, at 2.5 years follow-up).|
|Secondary||All-cause mortality||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Acute coronary syndrome||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||CHF Hospitalization||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Stoke||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||All-cause hospitalization||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Nursing home admission||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Worsening of vision||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Hip fracture||Upon observation of 406 primary outcome events - anticipated to occur at 2.5 years on average.|
|Secondary||Cognitive decline||18 months|
|Secondary||Nocturia burden||6 weeks|