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Antihypertensive deprescribing in frail long-term care residents (OptimizeBP): protocol for a prospective, randomised, open-label pragmatic trial
http://orcid.org/0000-0003-3354-4955
Kraut Roni Y 12rkraut@ualberta.ca

Youngson Erik 34erik.youngson@ualberta.ca

https://twitter.com/cheryl_sadowski
http://orcid.org/0000-0002-4526-7054
Sadowski Cheryl A 5cherylas@ualberta.ca

https://twitter.com/bakal_jeff
http://orcid.org/0000-0002-3658-2554
Bakal Jeffrey A 34jbakal@ualberta.ca

Faulder Douglas 1Douglas.Faulder@albertahealthservices.ca

http://orcid.org/0000-0003-4953-9392
Korownyk Christina S 12cpoag@ualberta.ca

http://orcid.org/0000-0002-8762-9383
Vucenovic Ana 12avucenov@ualberta.ca

http://orcid.org/0000-0003-2197-0463
Eurich Dean T 6deurich@ualberta.ca

Manca Donna P 1dpmanca@ualberta.ca

https://twitter.com/CarinaLundby
Lundby Carina 78carina.lundby.olesen@rsyd.dk

Kivi Paul 1pkivi@ualberta.ca

Manville Margaret 910Margaret.Manville@islandhealth.ca

http://orcid.org/0000-0002-7024-2158
Garrison Scott R 12scott.garrison@ualberta.ca

1 Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada
2 Pragmatic Trials Collaborative, University of Alberta, Edmonton, Alberta, Canada
3 Provincial Research Data Services, Alberta Health Services, Edmonton, Alberta, Canada
4 The Alberta Strategy for Patient Oriented Research Support Unit, Edmonton, Alberta, Canada
5 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
6 School of Public Health, University of Alberta, Edmonton, Alberta, Canada
7 Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
8 Hospital Pharmacy Funen, Odense University Hospital, Odense, Denmark
9 Department of Family Practice, University of British Columbia, Vancouver, British Columbia, Canada
10 Island Health, Victoria, British Columbia, Canada
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

CAS has received speaker fees from GSK and grant funding from Pfizer Canada. All other authors declare no competing interests related to the submitted work.

Dr; rkraut@ualberta.ca
2024
29 8 2024
14 8 e08461923 1 2024
09 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Abstract

Introduction

Although antihypertensive medication use is common among frail older adults, observational studies in this population suggest blood pressure (BP) lowering may convey limited benefit and perhaps even harm. This protocol describes an antihypertensive deprescribing trial in frail older adults powered for mortality and morbidity outcomes.

Methods and analysis

Design: Prospective, parallel, randomised, open-label pragmatic trial.

Participants: Long-term care (LTC) residents ≥70 years of age, diagnosed with hypertension, with mean systolic BP <135 mm Hg, ≥1 daily antihypertensive medication and no history of congestive heart failure.

Setting: 18 LTC facilities in Alberta, Canada, with eligible residents identified using electronic health services data.

Intervention: All non-opted-out eligible residents are randomised centrally by a provincial health data steward to either usual care, or continually reducing antihypertensives provided an upper systolic threshold of 145 mm Hg is not exceeded. Deprescribing is carried out by pharmacists/nurse practitioners, using an investigator-developed algorithm.

Follow-up: Provincial healthcare databases tracking hospital, continuing care and community medical services.

Primaryoutcome: All-cause mortality.

Secondaryoutcome: Composite of all-cause mortality or all-cause unplanned hospitalisation/emergency department visit.

Tertiaryoutcomes: All-cause unplanned hospitalisation/emergency department visit, non-vertebral fracture, renal insufficiency and cost of care. Also, as assessed roughly 135-days postrandomisation, fall in the last 30 days, worsening cognition, worsening activities of daily living and skin ulceration.

Processoutcomes: Number of daily antihypertensive medications (broken down by antihypertensive class) and average systolic and diastolic BP over study duration.

Primaryoutcomeanalysis: Cox proportional hazards survival analysis.

Samplesize: The trial will continue until observation of 247 primary outcome events has occurred.

Currentstatus: Enrolment is ongoing with ~400 randomisations to date (70% female, mean age 86 years).

Ethics and dissemination

Ethics approval was obtained from the University of Alberta Health Ethics Review Board (Pro00097312) and results will be published in a peer-reviewed journal.

Trial registration number

NCT05047731.

Hypertension
Frailty
Polypharmacy
Aged, 80 and over
Blood Pressure
Randomized Controlled Trial
Northern Alberta Academic Family Medicine Fund R14P13, R17P02, R18P23 Alberta Innovates through Enhancing Alberta Primary Care Research Networks (EnACt) N/A These funders have no involvement in trial design, management, analysis or reporting of findings.
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pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

This trial examines mortality and morbidity in an understudied population (frail older adults).

Given a low opt-out rate (~3%), results should generalise well to long-term care residents.

Our intervention is implemented by usual care providers and our outcomes are drawn from electronic health data routinely collected on all Albertans.

Our results will not apply to those with congestive heart failure, who are excluded from the study.

Introduction

The risk for adverse drug–drug and drug–disease interactions increases exponentially with each additional medication and comorbidity.1 This is especially problematic for the frail older adult population, who are seldom included in the randomised controlled trials (RCTs) which guide their care,2 and for whom the risk/benefit ratio of therapeutics may differ meaningfully, sometimes even leading to net harm.3 Recognising this, researchers have moved to explore the hypothesised benefit of ‘deprescribing’,4 which is often defined as the systematic reduction or discontinuation of medications, supervised by the responsible healthcare professional, when (1) those medications are no longer needed, (2) the potential harms outweigh the potential benefits or (3) use of that medication does not align with the patient’s healthcare goals and treatment preferences.

Deprescribing trials typically focus on a subset of medications deemed potentially inappropriate for use in older adults (eg, antipsychotics).5 However, such medications account for only a small minority of adverse drug reactions leading seniors to present to the emergency department (ED).6 Rather, the majority of such presentations involve common medications that are not deemed potentially inappropriate. This includes antihypertensive medications, which are prescribed to roughly 25% of frail older adults,7 and which observational studies in this population associate with falls, cognitive impairment, orthostatic hypotension and pressure ulcers.8 9 Importantly, in a population-based Dutch study, for hypertensive individuals ≥85 years of age, more aggressive blood pressure (BP) lowering was associated with higher all-cause mortality and faster decline in cognitive function.10

A 2020 Cochrane systematic review of antihypertensive deprescribing trials identified six eligible RCTs11 but was unable to reach a conclusion regarding the effect of antihypertensive deprescribing on mortality and morbidity given the small number of events (eg, only 18 deaths in total across all trials). The results of this review are also poorly generalisable to antihypertensive deprescribing in frail older adults given (1) at least 2 of these trials enrolled participants who were not particularly elderly (mean ages 58 years and 60 years, respectively), (2) none of the trials assessed or required frailty as an inclusion criterion and (3) in four of the six trials only diuretics were deprescribed. Our trial, known as ‘OptimizeBP’, examines antihypertensive deprescribing in a long-term care (LTC) population who are no longer capable of independent living, targets all antihypertensives for potential deprescribing and powers for mortality as a primary outcome (anticipating 247 deaths at trial conclusion). In addition to examining for clinical outcomes, we believe our intervention might improve, we will also be looking for potential harms, in particular an increase in hospitalisation for stroke, myocardial infarction/acute coronary syndrome, congestive heart failure (CHF) or atrial fibrillation. This manuscript describes the protocol for OptimizeBP and does so in accordance with Standard Protocol Items: Recommendations for Interventional Trials guidelines (online supplemental file 1).12

Objective

To determine, in a population of frail older adults, whether less aggressive systolic BP lowering, compared with usual care, reduces mortality or morbidity.

Methods

Trial design

OptimizeBP is a phase IV pragmatic clinical superiority trial with an event-driven, parallel enrolment, open-label design. Recruitment began on 27 September 2021 and is expected to complete in early 2024 with over 400 participants. Observation will continue until 247 primary outcomes have been observed, which is anticipated to occur sometime in 2025, given an observed ~30% annual event rate.

Setting

This trial is being conducted in the Canadian province of Alberta (population 4.6M) which has a publicly funded, free at point-of-care, healthcare system run by a single health authority, Alberta Health Services. This includes oversight of residents in LTC facilities (often referred to as a ‘nursing homes’) which provide 24-hour scheduled and unscheduled care to individuals with complex or unpredictable medical needs—typically older adults who can no longer manage independently at home.13 In Alberta, pharmacists and nurse practitioners (NPs), have prescribing authority which allows them to prescribe medication independently. The name, location and number of beds of currently participating LTC facilities are shown in figure 1.

Figure 1 Long-term care facilities participating in OptimizeBP. Each bullet indicates a separate physical location. Bracketed numbers are the total number of facility beds as of 30 September 2023.

Data sources

Alberta Health Services Databases

Alberta Health Services is a steward of the linked databases which track encounters with the healthcare system for all Albertans. This includes community physician services and diagnoses, prescriptions dispensed (PIN), reasons for hospitalisation and emergency visits (Discharge Abstract Database (DAD), National Ambulatory Care Reporting System (NACRS), laboratory results (Lab), vital statistics (eg, mortality) and the Alberta Continuing Care Information System which contains LTC admission and discharge dates, mortality, and clinical data from Resident Assessment Instrument–Minimum Dataset 2.0 (RAI-MDS).

Resident Assessment Instrument–Minimum Dataset

RAI-MDS is a comprehensive, standardised assessment tool used in LTC throughout Canada. In Alberta, RAI-MDS assessments are administered by LTC staff on admission to LTC and every 3 months thereafter, with an additional assessment potentially performed if there is a significant change in health status. Data from the assessment tool are used to inform and guide clinical practice and policy decisions. Alberta Health Services has an RAI-MDS provincial team and a zone team for each of its five geographically defined zones to support LTC operators and provide quality assurance of the assessment data.

Although it is not directly part of RAI-MDS, we will be using elements of RAI-MDS data to calculate a frailty index for each participant. The frailty index is an internationally validated frailty measure that accommodates a variety of datasets, with diverse data elements, by simply determining the proportion of detectable deficits/limitations that are present.14 The scores can be categorised as follows: fit (0 to 0.12), mild frailty (>0.12 to 0.24), moderate frailty (>0.24 to 0.36) and severe frailty (>0.36 to 1.0).15 Hubbard and Peel’s validated frailty index coding16 17 will be used for the trial.

BP data

PointClickCare is healthcare management software used by many Alberta LTC facilities that tracks, among other things, BP measurements. The vast majority of facilities participating in OptimizeBP record BP collected as part of routine care, including BP collected to support deprescribing for this trial, directly into PointClickCare. PointClickCare transfers these BP measurements to Alberta Health Services for the purpose of determining eligibility and process outcomes for this study. If participating LTC facilities instead record BP onto paper charts, facility staff are supporting the trial by entering BP measurements into either a REDCap database,18 or an electronic spreadsheet that is transferred securely to Alberta Health Services.

To optimise generalisability of our findings, during the trial, each facility continues to collect BP measurements as per their prior routine (table 1), except for frequency of assessment—which increases to biweekly for the intervention group until deprescribing is completed (ie, until 2 weeks after the last dose reduction/discontinuation).

Table 1 Usual care method of measuring BP in participating facilities

	Response	
Staff member performing	Nurse (13 facilities), nurse or healthcare aide (3 facilities), healthcare aide (2 facilities)	
Frequency	Monthly (18 facilities)	
Type of device	Automated (18 facilities)	
Frequency calibrated	Yearly (18 facilities)	
Time of day	No specific time (18 facilities)	
Position	No specific position (15 facilities), seated (3 facilities)	
Relax prior to BP taken	Yes (3 facilities), no (15 facilities)	
Quiet setting	Yes (14 facilities), no (4 facilities)	
Number of readings	One (18 facilities)	
Bare arm	Yes (13 facilities), over a sleeve (2 facilities), variable (3 facilities)	
BPblood pressure

Consent

The University of Alberta Health Ethics Review Board approved opt-out consent for this trial, waiving the requirement to obtain individual written consent from patients or their power of attorney. In large part, this model of consenting was allowable because the intervention is already recommended care for frail older adults.19 To operationalise this, families and/or residents (if they have capacity) are provided handouts describing the trial 30 days prior to randomisation. This information (online supplemental file 2) includes a phone number for opting out that reaches a member of the research team, who in turn enters the name and health card number of the opted out resident into an exclusion database within the University of Alberta’s implementation of REDCap. The Alberta Health Services analyst checks this exclusion database immediately prior to randomisation to ensure that no opted out individuals are included in the trial.

Additionally, it is standard practice for Alberta LTC facilities to notify each resident’s primary decision-maker (usually a family member or the resident themselves) before medication changes are made. Therefore, nursing staff, facility pharmacists or NPs (based on the preference of the LTC facility) confirm the acceptability of each deprescribing order with family/residents before it is implemented.

Physicians managing patients in each participating facility are provided with a different handout describing the trial (online supplemental file 3) and instructed to contact the principal investigator if they would like to opt out all, or a portion of, residents under their care. As the trial nears completion of recruitment, only one physician has opted their residents out of the trial. To date, accounting for all sources of opt-outs, only ~3% of residents have opted out of the trial.

Trial population

Inclusion criteria

Resident of a participating Alberta LTC facility for at least 30 days prior to randomisation.

≥70 years old.

≥2 health system encounters with a diagnosis of hypertension (ICD-9 and ICD-10 codes) since 2002.

Taking ≥1 daily antihypertensive medication (requires a dispensation in the preceding 15 days).

Average recorded systolic BP<135 mm Hg. The average BP is calculated from the three most recent BP readings taken on separate days. If a resident only has one or two BP measurements, the average of these is taken. If a resident has >1 BP measurement in a single day, then the average BP for this day is calculated and used as a single data point to calculate the overall average (ie, each day can contribute only one value to the overall average BP calculation). As these were usual care BP assessments, no set time period for collection was required (with periods for collection potentially as long as 4 months).

Exclusion criteria

History of CHF

Either ≥2 community physician encounters or ≥1 hospitalisation/ED encounter with a diagnosis of CHF (ICD-9 and ICD-10 codes) since 2002.

History of CHF recorded in RAI-MDS .

Dispensation of furosemide in the preceding 15 days (a loop diuretic commonly prescribed for CHF in Canada and uncommonly used for hypertension management).

Only one antihypertensive and it is likely not being used to manage hypertension.

The only antihypertensive is a betablocker (common treatment for angina, atrial fibrillation, tremor and migraine).

The only antihypertensive is a calcium channel blocker and the resident has ≥1 health system encounter with a diagnosis of angina, tachyarrhythmia, or atrial fibrillation (ICD-9 and ICD-10 codes) since 2002.

The only antihypertensive is an alpha-blocker (common treatment for prostatism/nocturia).

Admitted to hospital at the time of randomisation.

Opted out of the trial by the resident, their family, their physician or the facility.

Randomisation and allocation

An Alberta Health Services data analyst with no clinical interactions randomises all non-opted-out eligible residents centrally in blocks of 4, stratified by LTC facility, using a random number generator. This ensures concealed and irreversible allocation. Randomisations are periodically ‘batched’ so that all eligible residents in each participating facility are randomised on the same day. The date of each batched randomisation is several months apart and intended to capture new residents. Facilities have the option to participate in as many batched randomisations as they feel the capacity to support (with six such randomisations carried out between fall 2021 and fall 2023). Residents who were not eligible at the time of one batched randomisation might subsequently become eligible, and randomised, at a later date.

Intervention

Treatment

Continually reducing antihypertensives provided an upper systolic threshold of 145 mm Hg is not exceeded (achieved using a trial-specific antihypertensive deprescribing algorithm).

Control

Usual care.

Antihypertensive deprescribing algorithm

The deprescribing algorithm was developed through an iterative and informal process. First, two family physicians (RYK and SRG), two Care of the Elderly physicians (MM and PK), one pharmacist (CAS) and the co-ordinating editor of the Cochrane Hypertension Review Group provided input. The algorithm was then further revised with pharmacy/nursing feedback from the first few sites enrolling participants. We selected an upper systolic BP threshold of 145 mm Hg for our trial based on the most applicable guidelines for BP targets in frail older adults.8 The algorithm appears in figure 2. Essentially, BP medications are continually targeted for reduction or discontinuation every 2 weeks so long as the systolic BP is less than 145 mm Hg. If the systolic BP rises and stays above 145 mm Hg, sufficient BP medication is reintroduced to place the systolic BP at or below 145 mm Hg. Pharmacists/NPs are given flexibility in determining the order of medications to deprescribe when more than one antihypertensive is in use, and the amount of each dose decreases (ie, 25%–50%, until the smallest dose has been reached, at which point it can be discontinued).

Figure 2 OptimizeBP antihypertensive deprescribing algorithm. BP, blood pressure.

Pilot

CapitalCare Lynnwood was our pilot site, which we used to test and refine our methods. As the only major alteration to our methods was the expansion of our exclusion criteria to better pick out those with CHF, or those using antihypertensives for reasons other than hypertension, our pilot participants were rolled into the overall trial. While fully blinded to allocation, and prior to our interim analysis being conducted, we additionally added some secondary and tertiary outcomes we believed would more comprehensively capture process, cost and hypoperfusion-related outcomes—in particular the addition of ulcers and renal insufficiency. All protocol changes are fully disclosed on ClinicalTrials.gov.

Implementation

Facility pharmacists (n=19) and NPs (n=3) perform the deprescribing. They are asked to first attend an orientation session led by RYK and CAS. This session provides background in support of less aggressive BP targets in frail older adults, resources and evidence for deprescribing, as well as the trial timeline and protocols. Pharmacists and NPs are provided with trial materials including the deprescribing algorithm, trial selection criteria and a tracking sheet used to help them keep track of their deprescribing. Facilities complete a survey prior to their initial randomisation to determine the method for measuring BP at the facility (table 1).

During the agreed on start week, the Alberta Health Services data analyst sends an encrypted email to the pharmacist/NP with the names and personal health numbers of residents randomised to the intervention group. Within a week, the research team emails the pharmacist/NP to ensure they have received this list and will start deprescribing. Subsequently, the research team emails the pharmacist/NP monthly to troubleshoot any issues with implementation. Most pharmacists or NPs use the tracking sheet and forward it (after they have removed all identifiers) to the study team. This further aids in identifying process hurdles.

BP measurements of residents in the intervention group are taken biweekly, using the facility’s usual method, during the period that deprescribing is actively being carried out. BP measurements of residents in the control group continue to be taken at their usual frequency (table 1).

Pharmacists/NPs deprescribe per the trial algorithm, typically every 2 weeks, basing their decision on at least 4 BP readings during that 2-week interval. Depending on the procedures at the facility, pharmacists/NPs either sign the deprescribing order themselves or require approval of the primary care physician. The resident’s care team (often a family physician, pharmacist, NP and/or care manager) remain responsible for the resident’s care and are free to alter/reintroduce antihypertensives if clinically indicated.

Follow-up and data management

All outcome data are derived from routinely collected health system data within Alberta Health Services (the outcomes are already coded), supplemented by BP measurements obtained either directly from PointClickCare or directly from facilities after facility staff extract BP readings from usual care paper charts. At no point does, any participant-level electronic health data leave the secure environment of the Alberta Health Services data steward. Residents will be followed until observation of 247 primary outcomes.

Outcomes

Trial outcomes are listed in table 2. All outcomes are recorded over the duration of the trial unless indicated otherwise.

Table 2 OptimizeBP outcomes

Outcome	Source	
Primary	
 All-cause mortality	ACCIS, vital statistics	
Secondary	
 Composite of all-cause mortality or all-cause unplanned hospitalisation/ED visit	ACCIS, vital statistics, DAD, NACRS	
Tertiary efficacy		
 All-cause unplanned hospitalisation/ED visit	DAD, NACRS	
 Non-vertebral fracture	DAD, NACRS	
 Fall in the last 30 days*	RAI-MDS	
 Partial or full-thickness skin ulceration (stage 2–4)*	RAI-MDS	
 Renal Insufficiency (any eGFR <30 mL/min/1.73 m2)†	Lab	
Tertiary safety	
 Composite of unplanned hospitalisation/ED visit with a diagnosis of stroke, myocardial infarction/acute coronary syndrome, CHF or atrial fibrillation using validated health services data coding2326	DAD, NACRS	
Cognitive/behavioural	
 ‘Deteriorated cognition as compared with status 90 days prior’*	RAI-MDS	
 ‘Deteriorated mood as compared with status 90 days prior’*	RAI-MDS	
 ‘Deteriorated activities of daily living as compared with status 90 days prior’*	RAI-MDS	
 ‘Behavioural symptoms that are present a minimum of 4 days per week and not easily altered in the last 7 days’*	RAI-MDS	
Costs	
 Acute care costs (estimated from each hospital/ED admission’s resource intensity weight)	DAD, NACRS	
 Total cost of care and total daily cost of care (acute care costs+medication costs+physician billings+nursing/facility costs)	DAD, NACRS, PIN, billings, RAI-MDS	
Process	
 Number (%) of baseline antihypertensive medications with ≥25%, ≥50% and 100% reduction from baseline in dosage dispensed (3 and 6 months postrandomisation; in total and by antihypertensive class)	PIN	
 Number (%) of participants with ≥1 baseline antihypertensive medication with ≥25%, ≥50% and 100% reduction in dosage dispensed (3- and 6 months post-randomisation)	PIN	
 Number (%) of participants with the addition of ≥1 new antihypertensive medication or increase in dose from baseline (3 and 6 months postrandomisation)	PIN	
 Number of discrete antihypertensive medications used in the last 15 days (baseline, 3 and 6 months postrandomisation)‡	PIN	
 Number of discrete medications used in the last 15 days (baseline, 3 and 6 months postrandomisation)‡	PIN	
 Average systolic BP and average diastolic BP over duration of follow-up (Multiple readings on the same day will be averaged together to contribute a single reading, and only one reading per day will be averaged to prevent overweighting of BP collected during an acute health crisis.)	PointClickCare or facility	
* Binary outcomes as recorded by usual care nurses in the Quarterly RAI-MDS report in the 3–6 months window postrandomisation (on average these assessments should take place roughly 135 days postrandomisation; the assessment closest to 135 days is chosen when more than one is available).

† Includes eGFR results ≥6 weeks postrandomisation to ensure deprescribing has taken place.

‡ Discrete medications are defined by (Anatomical Therapeutic Chemical) codes.

ACCISAlberta Continuing Care Information SystemCHFcongestive heart failureDADDischarge Abstract DatabaseEDemergency departmenteGFRestimated glomerular filtration rateNACRSNational Ambulatory Care Reporting SystemPINprescriptions dispensedRAI-MDSResident Assessment Instrument–Minimum Dataset

Blinding

The research team is fully blinded to all outcomes except process outcomes, which are unblinded to permit revision of the protocol should the intervention appear poorly applied. Facility staff and primary care providers (who contribute to RAI-MDS, BP measurement, PIN and cost outcomes) are potentially aware of those in the intervention group but are not informed which residents are controls. Acute care physicians, who provide the diagnoses for all hospitalisation and ED visits, are generally meeting the patient for the first time and are unlikely to be aware their patient is in a clinical trial. The Alberta Health Services data analyst is not blinded. Aggregated outcome totals are provided to the research team monthly to permit the planning of event-driven interim and final analyses.

Sample size determination

OptimizeBP is an event-driven trial, with residents under observation until the occurrence of 247 primary outcome events (deaths). This number of events should provide (1) 80% power, at an alpha of 0.05, to detect a difference in the median survival time between the two groups of ≥30% and (2) the ability to declare observed differences as small as ~16% to be statistically significant (the latter is conservatively estimated by determining event numbers in each group, and iteratively applying a z-test for proportions to find the significance threshold). However, the true mortality benefit from our intervention could easily be smaller than ~16%, and hence undetectable by our trial. If this proves to be the case, we will use the direction of benefit, and the width of our CI to infer the maximum benefit that is likely to be achieved from maintaining a BP lower than 135 mm Hg, vs deprescribing antihypertensives, in a frail older adult population. To maximise the relatability of such an analysis, we will present it along with the difference in median survival, measured in months. Given our current event rates and enrolment plans, and our assumption of negligible censoring, we anticipate reaching our event target in 2025, with over 400 randomised participants.

Statistical analysis

All analyses will be intention to treat unless otherwise specified. The proportional hazards assumption will be tested using appropriate methods, and we will present both adjusted and unadjusted results.

Intention-to-treat assumptions

Loss to follow-up: We will follow all randomised residents given complete data capture within the province, and we will continue to follow residents even if they change facilities. We will not censor residents that move outside the province given (1) few LTC residents are expected to migrate and (2) there is a delay in accurately detecting this (those who leave Alberta are not quick to cancel their provincial health insurance and the registry database is infrequently updated).

Withdrawal: In some instances, family/residents/physicians do not initially opt out of the trial but ultimately decline or are unable to participate when notified about an intended reduction in antihypertensive medication. As this happens only in the intervention group, we will continue to follow and analyse outcomes in all such individuals to prevent attrition from being imbalanced, even though antihypertensive deprescribing did not take place.

Lag in electronic health data: Alberta Health Services databases and PointClickCare BP data access can be up to several weeks behind for informing our inclusion/exclusion criteria. If, when these data are updated, it is clear that residents were not actually eligible on the date of randomisation (eg, were no longer taking an antihypertensive medication, had died or were in the hospital), those individuals will be retroactively excluded from the trial. This applies equally to both groups of the trial.

Missing RAI-MDS data: If RAI-MDS baseline or postrandomisation reports are not available for a resident, we will exclude the resident from the relevant analysis.

Inability to deprescribe: All individuals will be included in each analysis as allocated irrespective of whether deprescribing was possible (eg, antihypertensives are in use for reasons other than BP lowering).

Selecting regression covariates

For continuous outcomes, we will use a maximum of 1 covariate per 20 randomised subjects. For dichotomous outcomes, we will use a maximum of 1 covariate per 10 outcomes. Table 3 predefines the covariate list and all are measured at baseline (date of randomisation). We will always use the maximum number of covariates an analysis can support and employ them in the order listed. If a given covariate has too many levels to be accommodated by the remaining number of outcomes or subjects (eg, facility), we will skip it and go to the next covariate in the list.

Table 3 Analysis plan

Outcome	Statistical method	Baseline covariates	
Primary	
 All-cause mortality	Cox proportional hazards	Facility-specific mortality rate (prior 3 years), Frailty index, systolic BP, sex, new admission*, old admission†, number of all-cause unplanned hospitalisations/ED visits in prior 6 months, eGFR<30‡, age, total number of non-BP medications, total number of BP medications	
Secondary			
 Composite of all-cause mortality/all-cause unplanned hospitalisation/ED visit	Cox proportional hazards	Facility-specific hospitalisation rate (prior 3 years), facility-specific mortality rate (prior 3 years), Frailty index, systolic BP, sex, new admission*, old admission†, number of all-cause unplanned hospitalisations/ED visits in prior 6 months, eGFR<30‡, age, total number of non-BP medications, total number of BP medications	
Tertiary efficacy	
 All-cause unplanned hospitalisation/ED visit	Cox proportional hazards	Facility-specific hospitalisation rate (prior 3 years), Frailty index, systolic BP, new admission*, old admission†, number of all-cause unplanned hospitalisations/ED visits in prior 6 months, eGFR<30‡, age, total number of non-BP medications, total number of BP medications	
 Non-vertebral fracture	Cox proportional hazards	Facility-specific non-vertebral fracture rate (prior 3 years), prior non-vertebral fracture, sex, Frailty index, systolic BP, Facility-specific prior % fallers, (prior 3 years), new admission*, old admission†, total number of non-BP medications, total number of BP medications	
 Fall in the last 30 days	Poisson regression	Facility-specific prior % fallers (prior 3 years)§, Record of falling previously, Frailty index, systolic BP, facility-specific non-vertebral fracture rate (prior 3 years), new admission*, old admission†, total number of non-BP medications, total number of BP medications	
 Partial or full-thickness skin ulceration (stages 2–4)	Poisson regression	Facility-specific prior % ulcerated (prior 3 years)§, prior skin ulceration (any stage), Frailty index, systolic BP, New admission*, old admission†, stroke, total number of non-BP medications, total number of BP medications	
 eGFR<30 mL/min/1.73 m2	Poisson regression	eGFR<30‡, systolic BP, age, sex, Frailty index, total number of non-BP medications, total number of BP medications	
Tertiary safety	
 Composite of unplanned hospitalisation/ED visit with a diagnosis of stroke, myocardial infarction/acute coronary syndrome, CHF or atrial fibrillation	Cox proportional hazards	Facility-specific hospitalisation rate (prior 3 years), systolic BP, new admission*, old admission†, Frailty index, number of all-cause unplanned hospitalisations/ED visits in prior 6 months, stroke, sex, eGFR<30‡, age, total number of non-BP medications, total number of BP medications	
Cognitive/behavioural	
 ‘Deteriorated cognition as compared with status 90 days prior’*	Poisson regression	Facility-specific prior % deteriorated cognitition (prior 3 years)§, New admission*, old admission†, Frailty index, sex, total number of non-BP medications, total number of BP medications, age	
 ‘Deteriorated mood as compared with status 90 days prior’*	Poisson regression	Facility-specific prior % deteriorated mood (prior 3 years)§, new admission*, old admission†, Frailty index, sex, total number of BP medications, total number of non-BP medications	
 ‘Deteriorated ADL as compared with status 90 days prior’*	Poisson regression	Facility-specific prior % deteriorated ADL (prior 3 years)§, new admission*, old admission†, systolic BP, Frailty index, sex, total number of BP medications, total number of non-BP medications, age	
 ‘Behavioural symptoms that are present a minimum of 4 days per week and not easily altered in the last 7 days’	Poisson regression	Facility-specific prior % behaviour problems (prior 3 years)§, new admission*, old admission†, number of all-cause unplanned hospitalisations/ED visits in prior 6 months, sex, Frailty index, total number of non-BP medications, total number of BP medications	
Costs	
   Acute care costs   Total cost of care   Total daily cost of care	Multiple linear regression	Frailty Index, new admission*, old admission†, sex, number of unplanned hospital/emergency room admissions in prior 6 months, total number of non-BP medications, total number of BP medications, eGFR<30‡, age	
* Resident in current facility less than 60 days at time of randomisation.

† Resident in current facility more than 3 years at time of randomisation.

‡ Any eGFR in the last 2 years <30 mL/min/1.73 m2. If a resident does not have an eGFR result, it will be assumed to be ≥30 mL/min/1.73 m2.

§ % of all RAI-MDS reports from this facility over the last 3 years indicating this outcome.

ADLactivities of daily livingBPblood pressureeGFRestimated glomerular filtration rateRAI-MDSResident Assessment Instrument–Minimum Dataset

Subgroup analyses

We plan to do subgroup analysis on the primary outcome based on baseline characteristics including frailty index (median split), the number of antihypertensives (1, ≥2), sex, age (<85, ≥85 years), systolic BP (≤120 mm Hg, >120 mm Hg) and antihypertensive medication class (separately examining diuretics, ACE inhibitors, angiotensin receptor blockers and calcium channel blockers).

Sensitivity analyses

Per-protocol analysis: Excluding any facilities where <66% of residents in the intervention group were successfully deprescribed at 3 months (ie, had at least one medication with a 50% reduction from baseline).

Process outcomes

For systolic and diastolic BP, we will graph a time series of average BP in both groups over the duration of follow-up (monthly increments). We will also report the proportion of residents with an average BP≤145 mm Hg at 6 months. For reduction in the number of antihypertensives, we will graph a time series (monthly increments) of the percentage of resident’s baseline antihypertensives with a ≥50% reduction in mg dispensed over the duration of follow-up (comparing the most recent dispensation in the last 15 days to the 15 days prior to randomisation). We will also provide a table describing the percentage of deprescribing broken down by class of antihypertensive.

Patient and public involvement

The trial was designed by a former LTC medical director (SRG) and an attending LTC physician (RYK) with input from knowledge users (CAS, DF, CL, PK and MM). LTC pharmacists assisted with the design of the algorithm to guide deprescribing, the trial process and the pharmacist survey. There was no direct involvement in the trial design by residents, their families or the general public.

Substudies

To help delineate barriers and facilitators of antihypertensive deprescribing, we will survey participating pharmacists preimplementation and postimplementation. The surveys (online supplemental file 4) are designed based on the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) research translation framework.20 RE-AIM evaluates five dimensions (reach, effectiveness, adoption, implementation and maintenance) to determine whether an initiative is workable in the real world. Survey questions cover the adoption, implementation and maintenance dimensions, as these are the most relevant from the pharmacist perspective, and survey construction incorporated feedback from four pharmacists with front-line experience in LTC settings. Data permitting, we will examine for variations in responses based on years worked as a pharmacist, the number of days working in LTC each month, the number of residents provided care and additional prescribing authorisation certification.

Trial oversight

Day-to-day management

OptimizeBP is managed collaboratively by RYK, SRG and EY, with input from coinvestigators as needed (CAS, JAB, DF and CSK).

Independent data safety monitoring board

Dr James M. Wright, Co-ordinating Editor of the Cochrane Hypertension Review Group, will chair a 5-member committee set to review all clinical outcomes on 50% of primary outcome events being reached (124). This is expected in the first half of 2024. Stopping rules: If p value is ≤0.001 for primary outcome benefit (the Haybittle-Peto boundary),21 or if p value is ≤0.05 for harm, the board will apply clinical judgement and make recommendations as to whether or not the trial should stop early.

End-point validation committee

A panel of three physicians will examine the spectrum of most responsible diagnostic codes for each hospitalisation and each emergency visit routinely captured in Alberta Health Services databases to ensure they match the outcome definition. Other outcomes will be accepted as they appear in the electronic health claims records, given there are no additional clinical records to review.

Concurrent trials

A French RCT, RETREAT-FRAIL, is also examining antihypertensive deprescribing in an LTC population and tracking clinical outcomes. This trial has completed recruitment (n=1126) and is expected to report results in mid-2024.22 Our trial population differs in that OptimizeBP includes LTC residents on ≥1 antihypertensive and excludes those with CHF while RETREAT-FRAIL requires LTC residents to have ≥2 antihypertensives and includes those with CHF. We are unaware of any other published or ongoing RCTs examining antihypertensive deprescribing and tracking clinical outcomes in frail older adults.

Ethics and dissemination

Ethical approval was obtained from the University of Alberta Health Research Ethics Board (Pro00097312). We will publish our results in a peer-reviewed journal, and knowledge translation will be via deprescribing networks, conferences and the network of LTC operators and pharmacy operators participating in the trial.

supplementary material

10.1136/bmjopen-2024-084619 online supplemental file 1

10.1136/bmjopen-2024-084619 online supplemental file 2

10.1136/bmjopen-2024-084619 online supplemental file 3

10.1136/bmjopen-2024-084619 online supplemental file 4

Acknowledgements

We would like to thank the Alberta SPOR SUPPORT Unit for the in-kind support provided. In addition, we would like to thank Barbara De Angelis from Rexall; Jennifer Lowe, Board Certified Geriatric Pharmacist; and Sandra Woodhead Lyons, former executive director of the Institute of Continuing Care Education and Research for their help with the initial development of the trial. We would also like to thank Dr Darryl Rolfson, Professor, Department of Internal Medicine, University of Alberta for his help selecting the frailty measure for the trial; Dr Nancye Peel, Senior Research Fellow, Faculty of Medicine, University of Queensland and Dr. Ruth Hubbard, Professor, Faculty of Medicine, University of Queensland for sharing their frailty index coding; Dr Jeff Poss, Adjunct Associate Professor, School of Public Health Sciences, University of Waterloo, for his clarifications on RAI-MDS; Dr John Hirdes, University Professor, School of Public Health Sciences, University of Waterloo, for insight into LTC quality of life measures; Vanja Jovic, Professional Practice RAI Lead for LTC in the Edmonton Zone, Alberta Health Services, for explaining the RAI-MDS process in Alberta; Yvonne Appah, Alberta Health Services nurse practitioner for her support and connections within Alberta Health Services Continuing Care and Dr Trevor Hart for providing assistance with the statistical design. We are grateful to Gilles Lamerton, Christine Meffen, and Sandra Brilliant, Alberta Health Services Pharmacy Services–Continuing Care for reviewing the pharmacists presurvey and postsurvey; and Dr Raj Padwal, Professor, Department of Internal Medicine, University of Alberta, for reviewing the facility BP measurement questionnaire. We appreciate the ongoing support of Dr Barbara Farrell, Senior Investigator, Bruyère Research Institute; Dr James M. Wright, the Co-ordinating Editor of the Cochrane Hypertension Review Group; and the Canadian Medication Appropriateness and Deprescribing Network (CADeN). Finally, we are extremely grateful to LTC operators, facilities, medical directors, physicians, pharmacists and NPs for their commitment and support of this trial, without which it would not have been possible.

Review Process File
29 08 2024

Funding: This work is supported by the Northern Alberta Academic Family Medicine Fund (R14P13, R17P02, R18P23) and Alberta Innovates through Enhancing Alberta Primary Care Research Networks (EnACt).

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-084619).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Map disclaimer: The depiction of boundaries on this map does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. This map is provided without any warranty of any kind, either express or implied.
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