The Effect of Antihypertensive Medication Timing on Morbidity and Mortality

Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02990663
• Other study ID #: BedMed Nov 30 2016
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: December 2016
• Est. completion date: June 30, 2024

Study information

• Verified date: June 2024
• Source: University of Alberta
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 254 primary outcome events are anticipated.

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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 3357
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Hypertension

Intervention

Other:
• Use of blood pressure lowering medication at bedtime
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.
• Use of blood pressure lowering medication in the morning
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.

Locations

Country	Name	City	State
Canada	University of Alberta	Edmonton	Alberta
Canada	University of Manitoba	Winnipeg	Manitoba

Sponsors (4)

Lead Sponsor	Collaborator
University of Alberta	Alberta Health services, Alberta Innovates Health Solutions, Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

References & Publications (8)

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. — View 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. — View Citation

Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, Gheeraert PJ, Missault LH, Braun JJ, Six RO, Van Der Niepen P, O'Brien E; Office versus Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. 2003 Jun 12;348(24):2407-15. doi: 10.1056/NEJMoa022273. — View 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. — View 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. — View 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. — View Citation

Veerman DP, Imholz BP, Wieling W, Wesseling KH, van Montfrans GA. Circadian profile of systemic hemodynamics. Hypertension. 1995 Jul;26(1):55-9. doi: 10.1161/01.hyp.26.1.55. — View 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. Erratum In: Hypertension 1995 Mar;25(3):462. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Acute care costs	Acute care costs (derived from each admission's resource intensity weight and length of stay)	Through study completion, an average of 4 years
Other	Total cost of care	Acute care costs + medication costs + physician billings	Through study completion, an average of 4 years
Other	Self-reported Overall Health Score	As measured by the EQ-5D-5L	1 year
Other	Light-headedness	Self-reported light-headedness or feeling "faint" without loss or consciousness in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)	Through study completion, an average of 4 years
Other	Syncope	Self-reported fainting (loss of consciousness) in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)	Through study completion, an average of 4 years
Other	Falling	Self-reported falling in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)	Through study completion, an average of 4 years
Other	Nocturnal and daytime blood pressure	302 subjects will undergo 24-hour BP monitoring after 6 months to determine differences in blood pressure between groups.	6 months
Other	Self-reported worsening of vision	Vision self-reported as "much worse" compared to the last follow-up at any point, or "slightly worse" than the last follow-up, on 2 or more occasions (Note: vision is reported at 6-weeks, 6-months, and every 6-months, as either "unchanged", "slightly worse", or "much worse" than the last follow-up)	Through study completion, an average of 4 years
Other	New impairment consistent with dementia	Short Blessed Test score newly 10 or greater at 18-month assessment, or new physician administrative claims diagnosis of dementia at any point during follow-up	Through study completion, an average of 4 years
Other	Hip fracture	Any break of the hip joint or femoral neck	Through study completion, an average of 4 years
Other	Nocturia frequency	Self-reported change from baseline in the number of overnight urinations per week (at 6-weeks and 6-months)	6-months
Other	Nocturia burden	Self-reported nocturia burden in the prior month, recorded as no nocturia, or nocturia that is "no problem", "minor problem", or "major problem" (at 6-weeks and 6-months)	6-months
Other	Adherence to medication timing allocation	Proportion of BP medication doses taken at the allocated time at 6-months (twice daily medications being considered as ½ dose in the AM and ½ dose in the PM for this calculation)	6-months
Primary	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	All-cause mortality	Death from any cause.	Through study completion, an average of 4 years
Secondary	Acute coronary syndrome	Hospitalization or ER visit for acute coronary syndrome or MI.	Through study completion, an average of 4 years
Secondary	CHF Hospitalization	Hospitalization or ER visit for congestive heart failure.	Through study completion, an average of 4 years
Secondary	Stoke	Hospitalization or ER visit for stroke (excludes TIA).	Through study completion, an average of 4 years
Secondary	All-cause hospitalization	Hospitalization or ER visit for any cause	Through study completion, an average of 4 years
Secondary	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
Secondary	New glaucoma diagnosis	First-ever glaucoma diagnosis	Through study completion, an average of 4 years
Secondary	Non-vertebral fracture	Fracture of any bone other than the vertebra of the back or neck	Through study completion, an average of 4 years
Secondary	Cognitive decline	Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test	18 months

External Links

•   The Pragmatic Trials Collaborative