<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02990663</url>
  </required_header>
  <id_info>
    <org_study_id>BedMed Nov 30 2016</org_study_id>
    <nct_id>NCT02990663</nct_id>
  </id_info>
  <brief_title>The Effect of Antihypertensive Medication Timing on Morbidity and Mortality</brief_title>
  <official_title>The Effect of Antihypertensive Medication Timing on Morbidity and Mortality: The &quot;BedMed&quot; RCT</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alberta Innovates Health Solutions</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alberta Health services</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alberta</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      High blood pressure is common and its presence increases the risk of cardiovascular mortality&#xD;
      and morbidity (most notably stroke, myocardial infarction, and congestive heart failure).&#xD;
      Given blood pressure is normally higher during the day than it is overnight, blood pressure&#xD;
      lowering medications are traditionally taken in the morning. However a randomized trial of&#xD;
      2156 Spanish hypertension patients published in 2010 (&quot;MAPEC&quot;), suggests a large (61%)&#xD;
      reduction in mortality and cardiovascular morbidity if such medications are instead taken at&#xD;
      bedtime. This degree of benefit far exceeds other established methods of cardiovascular risk&#xD;
      reduction - and such a surprisingly large effect requires independent confirmation for&#xD;
      practice to change. BedMed is a pragmatic randomized controlled trial facilitated by over 400&#xD;
      Canadian family physician members of the Pragmatic Trials Collaborative. During the conduct&#xD;
      of this trial consenting hypertensive primary care patients, already established on one or&#xD;
      more antihypertensive medications, will be randomized to either morning or bedtime&#xD;
      antihypertensive use. Patient oriented trial outcomes evaluating both potential benefits and&#xD;
      harms will be drawn largely from administrative health data that is routinely collected on&#xD;
      all residents of Canada's publicly funded health care system. This trial is being conducted&#xD;
      in 5 Canadian provinces and will continue to collect data until late 2023, at which point 254&#xD;
      primary outcome events are anticipated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      THE OPPORTUNITY BEDTIME PRESCRIBING MIGHT PROVIDE: Blood pressure normally exhibits a&#xD;
      circadian rhythm with relatively lower pressures during sleep.(Ref 1) Lack of this sleep time&#xD;
      &quot;dip&quot; correlates strongly with adverse cardiovascular events and BP correlates most strongly&#xD;
      with such events when measured at night (i.e. during sleep).(Ref 2-5) Motivated by such&#xD;
      observations, Spanish researchers studied the effect of taking BP medication at BEDTIME (when&#xD;
      the effect on nighttime BP would be greatest) versus conventional morning use, when most BP&#xD;
      medications are taken. The results of this study (the MAPEC trial) were striking.(Ref 6) Over&#xD;
      a median 5.6 years follow-up, adverse cardiovascular events occurred in 187 of 1084 subjects&#xD;
      taking BP medication in the morning but only 68 of 1072 subjects who took their BP medication&#xD;
      at bedtime (relative risk 0.39, 95%CI [0.29-0.51], p &lt; 0.001). This 61% reduction in adverse&#xD;
      events was similar for all individual components of the primary outcome (including death from&#xD;
      all causes, stroke, MI, new angina pectoris, CHF and retinal artery occlusions). If true, a&#xD;
      switch to bedtime prescribing would have more impact on the health of hypertensive patients&#xD;
      than whether high BP is treated at all. However extraordinary claims require extraordinary&#xD;
      evidence - independent replication of such surprising findings is needed for widespread&#xD;
      practice change to occur.&#xD;
&#xD;
      BEDMED: The BedMed trial is a pragmatic primary care trial intended to verify whether bedtime&#xD;
      antihypertensive use, as compared to conventional morning use, reduces major adverse&#xD;
      cardiovascular events. It is designed as an adaptive randomized registry trial within&#xD;
      community primary care and draws both trial outcomes and baseline covariates from provincial&#xD;
      administrative claims data (vital statistics, hospital separations, physician services,&#xD;
      prescription dispenses, laboratory data). BedMed is government funded/facilitated, and has&#xD;
      over 400 volunteer primary care providers recruiting participants in 5 Canadian provinces&#xD;
      (Alberta, British Columbia, Saskatchewan, Manitoba, and Ontario). It was originally intended&#xD;
      that the trial would continue until 406 primary outcome events were observed, however funding&#xD;
      will expire before this occurs. As a result, BedMed will continue to recruit participants&#xD;
      until early 2022 and complete data collection in late 2023, at which time 254 primary outcome&#xD;
      events are anticipated (based on blinded observation of total events gathered at the end of&#xD;
      2021). The trial relies heavily on a collaboration between the volunteer family physicians of&#xD;
      the Pragmatic Trials Collaborative (www.PragmaticTrials.ca) who will recruit for the trial&#xD;
      and the Alberta SPOR Support Unit's Data Platform - which will facilitate accessing and&#xD;
      analyzing the relevant administrative databases from multiple provinces&#xD;
      (http://www.aihealthsolutions.ca/initiatives-partnerships/spor/).&#xD;
&#xD;
      DIURETIC SUB-STUDY: The &quot;adaptive&quot; element of the BedMed trial design refers to an interim&#xD;
      examination of bedtime diuretic tolerance. Although it is commonly believed that diuretics&#xD;
      can't be taken at bedtime without inducing unwanted nocturia, the sparse evidence in the&#xD;
      literature suggests this may not be the case.(Ref 7,8) Rather than excluding patients whose&#xD;
      only medication is a diuretic the investigators will instead initially include such patients&#xD;
      and evaluate bedtime diuretic tolerance early on in the trial to determine whether or not&#xD;
      such patients should continue to be enrolled. Specifically, upon allocating to bedtime dosing&#xD;
      203 patients whose only BP medication is an AM diuretic, the investigators will analyze&#xD;
      6-week compliance to bedtime allocation for all participants with a single morning BP&#xD;
      medication (of all types). If diuretic compliance is worse, the &quot;adaptive&quot; trial design will&#xD;
      exclude enrolment of additional patients whose only BP medication is a diuretic. The BedMed&#xD;
      investigators will report on bedtime diuretic tolerance separate from (and in advance of) the&#xD;
      main BedMed analysis.&#xD;
&#xD;
      INTERIM SAFETY ANALYSIS: An independent data safety monitoring board (DSMB) organized and&#xD;
      chaired by Jim Wright (Cochrane Hypertension Review Group Coordinating Editor) is expected to&#xD;
      review all data in March 2022, at which time approximately 150-160 primary outcome events are&#xD;
      expected. If p is ≤ 0.001 for benefit (the Haybittle-Peto boundary - recommended to reduce&#xD;
      the chance of stopping too early and magnifying benefit), or if p is ≤ 0.05 for harm, the&#xD;
      DSMB will apply clinical judgement and make recommendations to the steering committee on&#xD;
      whether the trial should stop early.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Major Adverse Cardiovascular Events</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>First occurrence of either death (all-cause), or hospitalization or emergency department visit for acute coronary syndrome / MI, congestive heart failure, or stroke.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute coronary syndrome</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Hospitalization or ER visit for acute coronary syndrome or MI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CHF Hospitalization</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Hospitalization or ER visit for congestive heart failure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stoke</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Hospitalization or ER visit for stroke (excludes TIA).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause hospitalization</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Hospitalization or ER visit for any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long term care admission</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Newly admitted to a nursing home or assisted living facility as primary residence</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New glaucoma diagnosis</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>First-ever glaucoma diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-vertebral fracture</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Fracture of any bone other than the vertebra of the back or neck</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive decline</measure>
    <time_frame>18 months</time_frame>
    <description>Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Acute care costs</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Acute care costs (derived from each admission's resource intensity weight and length of stay)</description>
  </other_outcome>
  <other_outcome>
    <measure>Total cost of care</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Acute care costs + medication costs + physician billings</description>
  </other_outcome>
  <other_outcome>
    <measure>Self-reported Overall Health Score</measure>
    <time_frame>1 year</time_frame>
    <description>As measured by the EQ-5D-5L</description>
  </other_outcome>
  <other_outcome>
    <measure>Light-headedness</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Self-reported light-headedness or feeling &quot;faint&quot; without loss or consciousness in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)</description>
  </other_outcome>
  <other_outcome>
    <measure>Syncope</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Self-reported fainting (loss of consciousness) in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)</description>
  </other_outcome>
  <other_outcome>
    <measure>Falling</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Self-reported falling in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)</description>
  </other_outcome>
  <other_outcome>
    <measure>Nocturnal and daytime blood pressure</measure>
    <time_frame>6 months</time_frame>
    <description>302 subjects will undergo 24-hour BP monitoring after 6 months to determine differences in blood pressure between groups.</description>
  </other_outcome>
  <other_outcome>
    <measure>Self-reported worsening of vision</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Vision self-reported as &quot;much worse&quot; compared to the last follow-up at any point, or &quot;slightly worse&quot; 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 &quot;unchanged&quot;, &quot;slightly worse&quot;, or &quot;much worse&quot; than the last follow-up)</description>
  </other_outcome>
  <other_outcome>
    <measure>New impairment consistent with dementia</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>Hip fracture</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Any break of the hip joint or femoral neck</description>
  </other_outcome>
  <other_outcome>
    <measure>Nocturia frequency</measure>
    <time_frame>6-months</time_frame>
    <description>Self-reported change from baseline in the number of overnight urinations per week (at 6-weeks and 6-months)</description>
  </other_outcome>
  <other_outcome>
    <measure>Nocturia burden</measure>
    <time_frame>6-months</time_frame>
    <description>Self-reported nocturia burden in the prior month, recorded as no nocturia, or nocturia that is &quot;no problem&quot;, &quot;minor problem&quot;, or &quot;major problem&quot; (at 6-weeks and 6-months)</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence to medication timing allocation</measure>
    <time_frame>6-months</time_frame>
    <description>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)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3357</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Bedtime BP Meds</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Use of blood pressure lowering medication at bedtime</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Morning BP Meds</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Use of blood pressure lowering medication in the morning</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Use of blood pressure lowering medication at bedtime</intervention_name>
    <description>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.</description>
    <arm_group_label>Bedtime BP Meds</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Use of blood pressure lowering medication in the morning</intervention_name>
    <description>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.</description>
    <arm_group_label>Morning BP Meds</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Hypertension diagnosis as assigned by a physician or nurse practitioner&#xD;
&#xD;
          2. ≥ 1 blood pressure medication taken once daily, or primary care provider willing to&#xD;
             convert ≥ 1 blood pressure medication to once daily&#xD;
&#xD;
          3. Community dwelling (i.e. not residing in a nursing home; assisted living permitted)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Palliative (as per primary care provider's judgement)&#xD;
&#xD;
          2. Unable to provide informed consent (as per primary care provider's judgement)&#xD;
&#xD;
          3. Personal history of glaucoma or use of glaucoma medications&#xD;
&#xD;
          4. Sleep disrupting shift work (more than 3 shifts/month during participant's regular&#xD;
             sleeping hours)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Scott R Garrison, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alberta</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alberta</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2T4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Manitoba</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3T 2N2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>http://pragmatictrials.ca/</url>
    <description>The Pragmatic Trials Collaborative</description>
  </link>
  <reference>
    <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.</citation>
    <PMID>7607733</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>12802026</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>7995639</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>17389258</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>18039980</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>20854139</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>14616455</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16083452</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 13, 2016</study_first_posted>
  <last_update_submitted>June 15, 2023</last_update_submitted>
  <last_update_submitted_qc>June 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pragmatic</keyword>
  <keyword>Primary Care</keyword>
  <keyword>Chronotherapy</keyword>
  <keyword>Administrative Data</keyword>
  <keyword>Stroke</keyword>
  <keyword>Myocardial Infarction</keyword>
  <keyword>Congestive Heart Failure</keyword>
  <keyword>Glaucoma</keyword>
  <keyword>Dementia</keyword>
  <keyword>Hip Fracture</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Upon completion of all planned studies related to this project, anonymized patient level data for all outcomes and baseline characteristics will be made available in the form of a downloadable spreadsheet accessed through the Pragmatic Trials Collaborative's website (www.PragmaticTrials.ca)</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02990663
org study id: BedMed Nov 30 2016
nct id: NCT02990663
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Major Adverse Cardiovascular Events
time frame: Through study completion, an average of 4 years
description: First occurrence of either death (all-cause), or hospitalization or emergency department visit for acute coronary syndrome / MI, congestive heart failure, or stroke.
measure: All-cause mortality
time frame: Through study completion, an average of 4 years
description: Death from any cause.
measure: Acute coronary syndrome
time frame: Through study completion, an average of 4 years
description: Hospitalization or ER visit for acute coronary syndrome or MI.
measure: CHF Hospitalization
time frame: Through study completion, an average of 4 years
description: Hospitalization or ER visit for congestive heart failure.
measure: Stoke
time frame: Through study completion, an average of 4 years
description: Hospitalization or ER visit for stroke (excludes TIA).
measure: All-cause hospitalization
time frame: Through study completion, an average of 4 years
description: Hospitalization or ER visit for any cause
measure: Long term care admission
time frame: Through study completion, an average of 4 years
description: Newly admitted to a nursing home or assisted living facility as primary residence
measure: New glaucoma diagnosis
time frame: Through study completion, an average of 4 years
description: First-ever glaucoma diagnosis
measure: Non-vertebral fracture
time frame: Through study completion, an average of 4 years
description: Fracture of any bone other than the vertebra of the back or neck
measure: Cognitive decline
time frame: 18 months
description: Cognitive performance worsening by 2 or more points compared to baseline, as measured by the Short Blessed Test
measure: Acute care costs
time frame: Through study completion, an average of 4 years
description: Acute care costs (derived from each admission's resource intensity weight and length of stay)
measure: Total cost of care
time frame: Through study completion, an average of 4 years
description: Acute care costs + medication costs + physician billings
measure: Self-reported Overall Health Score
time frame: 1 year
description: As measured by the EQ-5D-5L
measure: Light-headedness
time frame: Through study completion, an average of 4 years
description: 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)
measure: Syncope
time frame: Through study completion, an average of 4 years
description: Self-reported fainting (loss of consciousness) in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)
measure: Falling
time frame: Through study completion, an average of 4 years
description: Self-reported falling in the prior month - yes / no. (Asked at 6-weeks, 6 months, and every 6 months)
measure: Nocturnal and daytime blood pressure
time frame: 6 months
description: 302 subjects will undergo 24-hour BP monitoring after 6 months to determine differences in blood pressure between groups.
measure: Self-reported worsening of vision
time frame: Through study completion, an average of 4 years
description: 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)
measure: New impairment consistent with dementia
time frame: Through study completion, an average of 4 years
description: 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
measure: Hip fracture
time frame: Through study completion, an average of 4 years
description: Any break of the hip joint or femoral neck
measure: Nocturia frequency
time frame: 6-months
description: Self-reported change from baseline in the number of overnight urinations per week (at 6-weeks and 6-months)
measure: Nocturia burden
time frame: 6-months
description: 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)
measure: Adherence to medication timing allocation
time frame: 6-months
description: 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)
arm group label: Bedtime BP Meds
arm group type: Experimental
description: Use of blood pressure lowering medication at bedtime
arm group label: Morning BP Meds
arm group type: Active Comparator
description: Use of blood pressure lowering medication in the morning
intervention type: Other
intervention name: Use of blood pressure lowering medication at bedtime
description: 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 group label: Bedtime BP Meds
intervention type: Other
intervention name: Use of blood pressure lowering medication in the morning
description: 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 group label: Morning BP Meds
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Scott R Garrison, MD, PhD
role: Principal Investigator
affiliation: University of Alberta
facility: 
facility: 
country: Canada
url: http://pragmatictrials.ca/
description: The Pragmatic Trials Collaborative
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.
PMID: 7607733
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.
PMID: 12802026
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.
PMID: 7995639
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.
PMID: 17389258
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.
PMID: 18039980
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.
PMID: 20854139
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.
PMID: 14616455
citation: 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.
PMID: 16083452
responsible party type: Sponsor
mesh term: Hypertension
sharing ipd: Yes
ipd description: Upon completion of all planned studies related to this project, anonymized patient level data for all outcomes and baseline characteristics will be made available in the form of a downloadable spreadsheet accessed through the Pragmatic Trials Collaborative's website (www.PragmaticTrials.ca)