Implementation of Pharmacist Case-Finding and Care Pathway Intervention for Vascular Prevention (PR_xOACT): Protocol for a Randomized Controlled Trial

Abstract

Cardiovascular (CV) disease (CVD) is the leading cause of death worldwide. The risk factors contributing to CVD development have been well known for decades, but treatment gaps persist. Pharmacists are frontline primary healthcare providers whose interventions to lower CV risk are supported by rigorous evidence. However, efforts to support the widespread implementation of pharmacist interventions to reduce CV risk are needed. To support such implementation, we developed an electronic tool (the “Care Pathway”) for guideline-directed assessment, prescription, and follow-up for CVD risk reduction that incorporates shared decision-making. The aim of this trial is to determine the impact of the pharmacist-led Care Pathway intervention on participants’ estimated risk for major CV events. This investigator-initiated, multicentre, open-label, randomized controlled trial will include 982 patients (aged ≥ 18 years) with ≥ 1 risk factor for CVD. Patients will be randomized in a 1:1 ratio to receive either a pharmacist-led Care Pathway intervention or usual care. Participants’ estimated CV risk will be calculated at baseline and at a 6-month follow-up evaluation. The primary outcome is the difference in change in estimated CV risk from baseline to the 6-month follow-up evaluation between the groups. Pharmacist-led assessment and management of patients’ CV risk factors may serve as an effective intervention to reduce patients’ estimated risk for major CV events. Formal evaluation of widespread implementation of a Care Pathway intervention will be conducted for the first time in a pharmacy practice CV risk–reduction trial.

Clinical Trial Registration

The University of Alberta Human Research Ethics Board (Pro00139142). NCT06405880.

Background and Rationale

Cardiovascular (CV) disease (CVD) is the leading cause of death worldwide,¹ accounting for an estimated 17.9 million deaths each year.² Despite advances in treatment, and the fact that the majority of CVD cases and deaths are caused by well known modifiable risk factors (tobacco use, physical inactivity, high-fat diet, obesity, diabetes, hypertension, and dyslipidemia)^3,4 CVD prevalence is still substantial in many countries, including Canada.^1,5 Treatment gaps for risk factors have been reported in Canada,⁶ with only 13% of Canadians with diabetes achieving their composite triple target (glycemic, blood pressure, and lipid control).⁷

Guidelines recommend using CV risk assessment to guide the treatment and prevention of vascular disease and its risk factors.8, 9, 10, 11 Despite these recommendations and the availability of several CV risk–assessment equations, CV risk assessment, in many cases, has not been integrated into clinicians’ daily routine.^12,13 The majority of patients seen by a family physician report never having had their CV risk assessed.^12,13 This lack of assessment could be due to lack of time, competing demands of other healthcare needs (eg, other chronic diseases, cancer, diabetes), and shortages of family physicians.¹⁴ Therefore, a need remains for new and innovative ways to tackle one of the world’s main public health issues.

Pharmacists are frontline primary healthcare providers who practice in the heart of the communities where people live, work, and play (and develop CVD).¹⁵ They see patients with chronic conditions more frequently than do any other types of healthcare providers.^16,17 Their interventions in cases of such conditions have been associated with improved patient outcomes.18, 19, 20, 21, 22, 23, 24 Indeed, the largest CV risk–reduction randomized controlled trial in a community pharmacy setting demonstrated that pharmacists’ case finding and intervention was associated with a 21% relative risk reduction in estimated CV risk, vs usual care.²³ Furthermore, such care also was associated with a high level of patient satisfaction,²² as well as significant cost savings (an estimated $CAD 4.4 billion over 30 years).²⁰

Although strong evidence shows the impact of pharmacist care in CVD treatment,²³ implementation of changes related to this evidence is lacking. Emerging initiatives, such as pharmacist primary care clinics, may improve patients’ access to care in many contexts, including for chronic disease management,²⁵ and may serve as a facilitator for implementation. Existing literature suggests that shared decision-making —a process by which patients’ goals and preferences are sought—is an important component of patient-centred care,²⁶ and that it also may facilitate the uptake and acceptability of clinical interventions.²⁷ Implementation of pharmacist care may be facilitated further by electronic tools based on current national guidelines for the assessment and treatment of CVD.²⁶ No formal evaluation has been conducted of the impact of broader implementation of pharmacist care incorporating pharmacist primary care clinics and structured guidance on CVD management.

Objectives

The primary objective is to determine the impact of a pharmacist-led “Care Pathway” implementation tool on participants’ estimated risk for major CV events, vs usual care, among adults with at least one uncontrolled risk factor for CVD.

Secondary objectives include determination of the following:

Implementation:

• •the number of participants recruited by each enrollment approach (see enrollment approach description below);
• •the impact of pharmacy type (clinic vs nonclinic) on implementation outcomes;
• •implementation outcomes, including feasibility (assessed by eligibility rate and recruitment rate) and fidelity (degree to which intervention is delivered as intended); and
• •quality indicators for CV risk–reduction care as recommended by the Canadian Cardiovascular Society and in the literature (full list available in Supplemental Table S1).28, 29, 30

Clinical:

• •the impact of the pharmacist Care Pathway on individual risk factors (blood pressure, glycated hemoglobin level [A1C; in those with diabetes], low-density lipoprotein cholesterol [LDL-C] level, and tobacco and/or vape use cessation) and quality of life.

Process:

• •patient satisfaction with the intervention, as measured by the Consultation Satisfaction Questionnaire³¹;
• •the extent to which shared decision-making is achieved, as measured by the Shared Decision Making 9-item Questionnaire (SDM-Q-9) tool³²; and
• •the type of interventions (ie, topic of education, prescribing) provided by the pharmacists.

Trial Design

This study is a multicentre, investigator-initiated, open-label, randomized controlled trial. Following screening in community pharmacies, eligible patients are randomized 1:1 to receive either a pharmacist-led CV risk–reduction intervention or usual care. This protocol is written in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement 2013 guideline,³³ and the study intervention is reported in accordance with the Template forxIntervention Description and Replication (TIDieR) guide (Supplemental Table S2).³⁴

Methods: Participants, Interventions and Outcomes

Study setting

The study will be conducted at community pharmacies in Alberta, Canada. Approximately 100 pharmacies will be included in the trial. Pharmacists involved in the trial are required to have prescribing authorization granted by Alberta College of Pharmacy.

Eligibility criteria

Inclusion criteria are as follows:

• •being an adult aged ≥ 18 years;
• •
  reporting having at least one uncontrolled risk factor for CVD, including the following:

  • o
    diabetes with A1C level > 7%;
  • o
    hypertension with systolic and diastolic blood pressure > 140 and 90 mm Hg, respectively, for people without diabetes, or > 130 and 80 mm Hg, respectively, for people with diabetes;
  • o
    dyslipidemia with LDL-C concentration > 2 mmol/L;
  • o
    a chronic inflammatory condition (including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gout, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis);
  • o
    chronic kidney disease, defined as the presence of > 1 of the following factors for ≥ 3 months—glomerular filtration rate < 60 mL/min per 1.73 m² or markers of kidney damage (such as albuminuria [albumin-to-creatinine ratio ≥ 30 mg/g or ≥ 3 mg/mmol], abnormalities in urine sediment, persistent hematuria, kidney structural or tubular disorders or abnormalities) ³⁵; and
  • o
    current tobacco or vape use.

Exclusion criteria are as follows:

• •being unwilling or unable to give informed consent for study participation;
• •being unwilling or unable to participate in regular follow-up visits; and
• •being pregnant.

Informed consent

Potentially eligible participants will be identified by the pharmacist and/or the pharmacy team in participating community pharmacy sites. Eligible participants will be invited to provide consent for study involvement after receiving verbal and written information from the study pharmacist co-investigator. The patient will be given the opportunity to ask questions prior to giving informed consent. The patient will be enrolled in the study after written informed consent is given. The study flow diagram is shown in Figure 1.

Figure 1.

Study flow diagram. t_0, initiation timepoint; t_1, timepoint 1. t₀ is the baseline measurement time. t₁ is the final measurement time

Additional consent provisions for collection and use of participant data and biological specimens

As a part of participation in the trial, patients consent to the collection of their data for research purposes. Data collected will be stored for 5 years following the completion of the study, and then destroyed.

Recruitment

The recruitment period is planned to be 1 year from the enrollment of the first patient. Recruitment will occur in community pharmacies, and will be conducted through both active and passive methods.

Active recruitment methods include case finding, which involves the use of a patient’s demographics, risk factors, and/or symptoms to determine whether to proceed with further investigation and recruitment into the trial.³⁶ Opportunities for case finding include producing a dispensing record report and either contacting patients to make an appointment to assess eligibility and CV risk or adding a flag in dispensing software to discuss CV risk during the patient’s next visit to the pharmacy.

Passive methods include the following: (i) display of posters around the pharmacy and the addition of small cards describing the trial, with bags of dispensed medications. Potentially eligible patients are asked to speak with their pharmacist. (ii) Patients can be identified by a pharmacist when the latter is prescribing and/or dispensing a medication, providing clinical education, conducting a medication review, ordering and/or interpreting a laboratory test, or administering a vaccination. (iii) Patients may access a CV risk calculator to calculate their own CV risk online (which uses the same validated CV risk equations—Framingham,³⁷ the United Kingdom Prospective Diabetes Study (UKPDS),³⁸ and the Second Manifestations of Arterial Disease (SMART³⁹) equations, on either the patient-friendly version of the trial’s webpage)⁴⁰ or their local pharmacy’s webpage, and can self-refer to their local participating pharmacy and speak to a pharmacist about the trial.

To ensure a representative sample is enrolled, we will strive to recruit at least 50% female participants, via the following means:

• •engagement and promotion of women’s heart health campaigns during the recruitment period (eg, the Wear Red Canada campaign⁴¹);
• •recruitment materials tailored to women; and
• •promotion of the trial via women’s heart health advocacy bodies.

Assignment of interventions: allocation

Sequence generation

The allocation sequence is generated using a computer-based random number generator. Block sizes were randomly picked from the integers 2, 3, and 4, to preserve integrity of the allocation process and prevent inadvertent bias.

Concealment mechanism

Participants will be randomized using a centralized, secure “Care Pathway” Web site at the Epidemiology Coordinating and Research (EPICORE) data management centre at the University of Alberta. After generation, the allocation sequence is securely stored and concealed within a custom-built electronic case report form (eCRF) system on the secure Care Pathway Web site prior to assignment.

Implementation

Upon enrolling a patient, the pharmacist will access the e-case report form (eCRF) on the secure Care Pathway Web site, which will assign each patient to either the intervention or the control group in a 1:1 manner.

Assignment of interventions: blinding

Who will be blinded

Due to the nature of the intervention, clinicians and participants cannot be blinded to treatment allocation. However, data analysts will be blinded.

Procedure for unblinding if needed

Unblinding is not applicable, as the treatment allocation is not blinded.

Interventions

Explanation for the choice of comparators

CVD remains among the leading causes of death in Canada and the world, due to inadequate management of factors that contribute to CV risk. Pharmacists are accessible and well trained primary healthcare providers who can practice to their full scope in Alberta. Previous evidence from the largest CV risk–reduction randomized trial in a community pharmacy setting demonstrated that pharmacist interventions were associated with a 21% relative risk reduction in estimated CV risk, vs usual care.²³

Intervention description

Intervention group

The intervention will be delivered by registered community pharmacists who have “additional prescribing authority” in Alberta, Canada. Pharmacists will be offered an educational package that summarizes Canadian guidelines and literature describing the management of CV risk factors such as hypertension^11,42 diabetes,^8,9,43 dyslipidemia,¹⁰ and tobacco or vape use.⁴⁴

Pharmacists will deliver intervention to participants in community pharmacies in a 1:1 manner— in most circumstances face-to-face, but they may deliver the intervention using teleconferencing or telephone modes if required (such as for remote patients). Participants will receive an initial assessment and follow-up appointments with their pharmacist as needed. Each appointment may be up to 60 minutes in duration. Participants in the intervention arm will receive care using a shared decision-making pharmacist-led intervention guided by a literature- and guideline-based electronic algorithm implementation tool, which we call a Care Pathway. The Care Pathway implementation tool was designed based on the following principles: (i) building upon previous pharmacist interventions; (ii) co-design with patient partners; (iii) guideline- and evidence-based recommendations and CV risk calculation; and (iv) shared decision-making.

The Pharmacist Case-Finding and Care Pathway Intervention for Vascular Prevention (PR_xOACT) Care Pathway is modelled after the intervention delivered in the largest CV risk–reduction randomized controlled trial conducted in a community pharmacy setting (R_xEACH).²³

Two patient partners with lived experience of CVD were engaged in the co-design of the trial intervention. Co-design was conducted through biweekly meetings (in person and via video); at the meetings, the patient partners contribute to the study design and conduct and review all the study materials and Care Pathway elements, collection of feedback, and design iteration. The study intervention was also co-designed through review and feedback from other key stakeholders, including 2 practicing pharmacists in Alberta (S.G. and D.B.) and a cardiovascular specialist (M.M.G.).

The PR_xOACT Care Pathway is an Internet Web-based program; it includes step-by-step, algorithm-guided patient assessment, including conditions requiring escalation or referral (ie, “red-flag” conditions), treatment, documentation of care, and follow-up. A summary of the Care Pathway algorithm is presented in Figure 2, and the full algorithm is portrayed in Supplemental Figure S1. The electronic algorithm is informed by the latest CV risk–reduction guidelines, such as the Hypertension Canada guidelines, the Canadian Cardiovascular Society guidelines for the management of dyslipidemia, the Diabetes Canada clinical practice guidelines, and the Canadian Cardiovascular Harmonized National Guideline Endeavour.8, 9, 10, 11^,44, 45, 46 CV risk is calculated using an appropriate, validated risk equation, including the Framingham equation,³⁷ the UKPDS equation³⁸ and the SMART³⁹ equation. The algorithm selects the most appropriate risk equation based on the participant’s comorbidities and, if more than one equation is suitable, selects the most conservative equation (ie, the equation producing the highest CV risk).

Figure 2.

Simplified Care Pathway (electronic tool for guideline-directed assessment, prescribing, and follow-up for cardiovascular disease risk reduction, incorporating shared decision-making) algorithm.

Shared decision-making is a core component of the PR_xOACT Care Pathway. The Care Pathway presents the participant’s risk factors contributing to their CV risk and encourages the pharmacist and participant to engage in shared decision-making to determine which CV risk factor(s) the participant wishes to work on during each visit. For each CV risk factor selected, the Care Pathway suggests individualized guideline-informed targets (eg, blood pressure, serum lipid concentration, or A1C levels) and treatments (including lifestyle modification and pharmacologic therapy). The pharmacist and participant are prompted to engage in shared decision-making, to reach an agreed-on CV risk management plan (eg, treatment goals and treatment actions can be tailored to individuals).

Participants’ treatment regimen will be optimized by initiating new prescription medications or adjusting the dosage or frequency of prescription medications, and monitored by ordering laboratory tests. All the aforementioned activities are within the scope of practice for pharmacists in Alberta,⁴⁷ so pharmacists can perform them as part of the routine care they are providing to their patients. Changes to participants’ treatment regimen made by the pharmacist will be communicated to the participant’s family physician.

Following the initial assessment, an individualized CV risk–reduction plan is provided to the participant (hard and/or soft copy). Regular follow-up appointments will continue (eg, every 2-4 weeks) for a total follow-up period of 6 months. The 6-month follow-up period is guided by existing guidelines and literature to inform an adequate duration of treatment to reveal the full effects of lifestyle and/or medication changes.8, 9, 10, 11^,19,24,42, 43, 44^,48 Each appointment may be up to 90 minutes in duration, as required.

The pharmacist will provide the following to all the participants randomized to the intervention group:

• •
  patient assessment with the following measures:

  • o
    weight;
  • o
    height;
  • o
    social history (self-reported);
  • o
    lifestyle (self-reported); and
  • o
    blood pressure (measured according to Hypertension Canada guidelines¹¹).
• •
  lab assessment with the following measures:

  • o
    as part of routine care, the pharmacist will check the most recent laboratory test results for A1C, lipid profile, and kidney function and status through the provincial electronic health record; those who have not had these tests done in 6 months will be given a laboratory requisition;
• •individualized CV risk calculation and education about this risk;
• •
  treatment initiation/adjustment incorporating shared decision-making, with the following measures:

  • o
    prescription adaptation;
  • o
    prescribing as appropriate to meet the treatment targets according to the most recent Canadian guidelines or evidence-based literature;
  • o
    lifestyle and medication education;
• •adherence assessment; and
• •
  regular follow-up

  • o
    follow-up every 2-4 weeks for 6 months.

As a part of standard professional practice, the pharmacist will inform the participant’s family physician and all members of the participant’s healthcare team (such as their cardiologist, nephrologist, physiotherapist etc.) of the participant’s involvement in the study. The pharmacist may inform the participant’s healthcare team of all updates to their medicines and healthcare plan.

Control group

Participants in the control group will be provided with usual care, defined here as facilitated relay of information to the participants’ family physician. Pharmacists will collect information informing them about the participant’s CV risk. Participants are then given a letter that reviews their CV risk factors (including their blood pressure, A1C level, and lipid panel) and are advised to present the letter to their family physician. No specific suggestions for CV risk reduction are detailed in the letter. In cases in which patients do not have a family physician, they will be referred to a physician walk-in clinic. A follow-up appointment in 6-months is booked for all participants in the control group.

During the 6-month follow-up appointment, participants will have their CV risk reassessed using an appropriate CV risk calculator (as conducted in the intervention arm) and will be offered a crossover to the intervention arm.

Criteria for discontinuing or modifying allocated interventions

In compliance with ethical and legislative guidelines, participants retain the right to withdraw from the trial at any time and for any reason, without any consequence for their healthcare. If participants decide to withdraw their consent to participate, the study intervention will be discontinued immediately. Data collected up to the date of withdrawal will be retained.

Strategies to improve adherence to interventions

Study pharmacists are provided with training and detailed standard operating procedures. To ensure access to support, study pharmacists are able to contact a trial coordinator on any day of the week, at any time, by e-mail and receive a response within 24 hours. Ongoing monitoring of the Care Pathway will be conducted throughout the duration of the trial, to ensure adherence to interventions.

Relevant concomitant care permitted or prohibited during the trial

Participant screening and recruitment occur concurrently with the delivery of intervention or control treatments. Pharmacists will provide care regardless of the treatment group assigned, in accordance with their duty of providing care. All interventions are documented for subsequent analysis and reporting.

Provisions for post-trial care

After the final follow-up visit, any patient-reported or observed clinical indicators of new or deterioration of diseases will be assessed and managed and/or referred as clinically appropriate. After the final follow-up visit, participants in the control group will be offered the opportunity to cross over to receive the Care Pathway intervention. The Care Pathway intervention will continue to be offered to participants in the intervention group after the final follow-up visit. After the final follow-up visit, no formal evaluations for either group are planned.

Outcomes

The primary endpoint is the difference in change in estimated CV risk (using an appropriate CV risk equation) from baseline to the 6-month follow-up between the groups (pharmacist-led intervention vs control).

Secondary endpoints include the following:

• •the difference in change in individual CV risk factors (including blood pressure, A1C level, lipid profile, tobacco and/or vape use cessation) from baseline to the end of the study (6 months) between groups (pharmacist-led intervention vs control);
• •the number of participants recruited using different enrollment approaches;
• •the impact of pharmacy type (clinic vs nonclinic) on the primary outcome (a pharmacy care clinic is characterized by a separate physical area [eg, examination rooms, waiting and reception areas], as well as dedicated staffing for the clinic, both of which are separate from the dispensary of the pharmacy⁴⁹;
• •types of interventions provided by the pharmacists, such as education on lifestyle factors (tobacco cessation, diet, exercise), prescribing or changing the dose of medications, education on new or changed medications, education on adherence to medications, and/or lifestyle recommendations;
• •patient satisfaction as measured by the Consultation Satisfaction Questionnaire³¹;
• •the extent to which shared decision-making was achieved in the intervention, as measured by the Shared Decision Making 9-item Questionnaire (SDM-Q-9)³²;
• •quality of life, as measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Scale⁵⁰;
• •between-group differences in quality indicators for CV risk–reduction care as recommended by the Canadian Cardiovascular Society and in the literature (full list available in Supplemental Table S1)28, 29, 30 and
• •implementation outcomes, including feasibility (assessed by eligibility rate and recruitment rate) and fidelity (degree to which the intervention is delivered as intended).

Data collection and management

Plans for assessment and collection of outcomes

Trained pharmacists are responsible for the entry of clinical data during appointments held in community pharmacies. Data from the baseline visit, follow-up visits (as necessary in the intervention group), and the 6-month follow-up appointment for all patients are collected by pharmacists as a part of the Care Pathway algorithm. That is, the same data collection procedures used to inform treatment recommendations within the Care Pathway algorithm are used for assessment of trial outcomes so that data entry procedures are not repeated. Quality indicators for CV risk–reduction care as recommended by the Canadian Cardiovascular Society and in the literature28, 29, 30 also are included in the data collected (full list available in Supplemental Table S1) in the Care Pathway for all participants, to facilitate quantifiable measurement of the care delivered and its benchmarking against Canadian guidelines. Study investigators routinely audit entered data to ensure data quality. A summary of data collected and time points for data collection are available in Table 1.

Table 1.

Participant timeline and data-collection timepoints

	Study period
	Enrollment	Post-allocation	Follow-up
Timepoint	t0	tn	6 mo
Enrollment
Eligibility screen	X
Informed consent	X
Randomization	X
Interventions
Pharmacist-led intervention/control		X
Assessments
Demographics	X
CV risk factors & estimated CV risk	X		X
Whether CV risk has been calculated before	X
Type of community pharmacy (clinic or nonclinic)	X
Method of enrollment	X
Details of interventions delivered by pharmacist		X
Consultation Satisfaction Questionnaire			X
Shared Decision Making 9-item Questionnaire			X
Quality of Life (EQ-5D-5L)	X		X
Quality indicators		X	X

t₀ indicates baseline measurements.

CV, cardiovascular; EQ-5D-5L, EuroQol, 5-dimension, 5-level quality of life scale.

Study participants are sent questionnaires to assess patient-reported outcomes, including the perceived extent of shared decision-making, using the SDM-Q-9, consultation satisfaction using the Consultation Satisfaction Questionnaire, and quality of life using the EQ-5L-5D. All data are stored within the eCRF.

Plans to promote participant retention and complete follow-up

All interventions are initiated during the patient’s index visit to the community pharmacy. Patients are given written materials, including the contact information of a study investigator who can be contacted at any time during the follow-up period. The follow-up visit is scheduled during each visit, and the patient is offered e-mail and/or text message reminders of follow-up appointments.

Data management

All trial data are recorded in the eCRF within a secure custom-built Web site by the EPICORE data management centre at the University of Alberta. This configuration adheres to scientific and regulatory criteria for data entry, coding, security, and storage. Data accuracy and integrity are maintained by rigorous quality-control procedures and regular auditing for data quality.

Confidentiality

All data are collected and stored securely on password- and firewall-protected University of Alberta servers to maintain the confidentiality and privacy of participant information.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial and/or for future use

Not applicable—no biological specimens will be collected.

Statistical methods

Statistical methods for primary and secondary outcomes

Statistical analysis will be conducted blindly with respect to participants’ allocation. Analysis will be performed based on as-observed and intention-to-treat (ITT) principles and by using R 3.4.0 (R Foundation, Vienna, Austria) and SAS 9.4 software (SAS Institute, Cary, NC).

Participants’ demographic information and clinical characteristics (including quality indicators) will be examined with descriptive statistics, using frequency (percentage) for categorical variables, and mean (standard derivation), or median (interquartile range), for continuous variables, as appropriate. The primary outcome, the difference in change in CV risk between the intervention and control group, will be analyzed using an independent ttest. A regression analysis using a linear regression model will be performed to quantify the impact of patients’ demographic and clinical factors on the primary outcome, presenting coefficient (standard error), 95% confidence interval, and P-values. Variables that show statistical or clinical significance then will be used in multivariable regression models to evaluate their joint impact.

Secondary analysis will be performed using descriptive statistics and several hypothesis tests, including but not limited to the χ² or Fisher’s test (when small frequencies are present) for the categorical variables, and the t test or the Wilcoxon rank sum test (when data are heavily skewed) for continuous variables. Patient satisfaction, the number of participants recruited by each enrollment approach, and the types of interventions provided by the pharmacists will be analyzed using descriptive statistics, and the change in blood pressure, A1C level, and LDL-C level will be analyzed using independent t tests. Change in tobacco use will be analyzed using the χ² test.

Interim analyses

No interim analyses are planned.

Methods for additional analyses (eg, subgroup analyses)

We plan to conduct a subgroup analysis to compare primary and implementation outcomes among pharmacies with vs without pharmacy care clinics. We will also conduct subgroup analyses of primary and secondary outcomes among female and male participants.

Methods in analysis to handle protocol nonadherence and any statistical methods to handle missing data

ITT and as-treated analyses will be performed to examine protocol nonadherence. Missing data caused by missing visits, losses to follow-up, etc. will be imputed in the ITT analysis using the “last observation carried forward,” method replacing the missing value with that subject's previously observed one. The combination of the observed and imputed data then will be analyzed. Missing data will also be assessed for the presence of patterns, and the multiple Imputation method will be used as needed.

Plans to give access to the full protocol, participant level-data, and statistical code

The full protocol and statistical code are available upon reasonable request. Participant-level data are not available due to restrictions related to ethics approval.

Sample size

This trial is powered toward the primary endpoint. Using the information from Tsuyuki et al.²³ and the assumptions of 90% power and a 2-sided alpha of 0.05, a sample size of 834 will be required to detect a relative change of 17% in estimated CV risk between the groups. To account for a 15% loss-to-follow-up, a total of 982 patients will be enrolled in the trial. The sample size was calculated using G∗Power (Heinrich Heine University, Düsseldorf, Germany).

Oversight and monitoring

Composition of the coordinating centre and trial steering committee

Coordination of the trial is overseen by the study primary investigators on a daily basis. The trial coordinators have experience in conducting clinical trials involving similar patient populations. When required, meetings involving study co-investigators, stakeholders, and/or patient partners are held to address trial implementation or operations and evaluate the trial’s progress.

Composition of the data monitoring committee, its role, and its reporting structure

In this trial, data are monitored by the primary study investigators. No separate data-monitoring committee has been established. Daily audits to monitor the assigned intervention and quality of data generated for primary endpoint analyses are performed. Random audits also may be conducted by the University of Alberta.

Adverse event reporting and harms

If participants experience any adverse reactions, the pharmacist will exercise clinical judgement to manage the reactions if it is within their scope to do so, and if required, they will refer the patient to consult their family physician or go to the nearest emergency room, as clinically appropriate. This approach does not deviate from standard practice, as pharmacists in Alberta possess the scope to diagnose, prescribe, and manage medication regimens, including the management of potential adverse reactions to medications.

Frequency and plans for auditing trial conduct

Daily audits by the study investigators will be conducted to monitor the interventions delivered and the quality of the data generated.

Plans for communicating important protocol amendments to relevant parties (eg, trial participants, ethical committees)

In the event that a protocol amendment is required, ethics approval will be sought. After ethics approval for a protocol modification is granted, study investigators will be informed, and the registered trial protocol will be updated.

Dissemination plans

Trial findings will be prepared for publication in peer-reviewed journals. Data from the trial also will be presented to healthcare professionals involved in the trial and at national and international conferences.

Discussion

PR_xOACT is an investigator-initiated, multicentre, open-label randomized controlled trial that includes adults with at least one risk factor for CVD. Although the risk factors that contribute to CVD development have been well known for decades,^3,4 CVD remains the leading cause of death worldwide.^1,2 Appropriate assessment and management of CV risk are important for improving patients’ clinical outcomes, and may lead to improvements that include a reduced risk of CV events, such as myocardial infarction and stroke, reduced comorbidities such as diabetes or chronic kidney disease, an improved quality of life, and lower healthcare resource utilization.

The PR_xOACT trial is designed to identify adults with at least one risk factor for CVD, through community pharmacies, and evaluate the effect on participants’ estimated risk for a major CV event of a pharmacist-led, shared–decision-making intervention guided by the evidence- and guideline-based Care Pathway electronic algorithm implementation tool. To maintain a patient-centred approach, this intervention was co-designed by engaging 2 patient partners with lived experience of CVD. The PR_xOACT Care Pathway provides pharmacists and patients with guidance on the assessment and calculation of estimated CV risk, situations requiring further escalation, therapeutic targets, and treatment recommendations, including lifestyle changes and pharmacologic therapy. In addition, shared decision-making allows pharmacists to empower patients to better understand how to manage their own health, and build better rapport with patients; it also has been shown to lead to better outcomes and treatment adherence.²⁷ This initiative builds on well-studied interventions^{12,19,21,23,24} and is designed to not only improve patients’ access to CV care, but also enhance their understanding of their CV risk and risk factors and empower them to take an active role in their own care.

Our hypothesis is that delivery of the PR_xOACT Care Pathway implementation tool for adults with at least one risk factor for CVD will facilitate large-scale implementation of pharmacist-led CV risk–reduction interventions, leading to a reduction in individuals’ estimated risk for a major CV event, such as myocardial infarction or stroke within 10 years. This trial has been designed to detect clinical differences in estimated CV risk, calculated using validated equations, such as the Framingham,³⁷ the UKPDS equation,³⁸ and the SMART equation.³⁹ Findings that support the feasibility and fidelity of the intervention, as well as a lower estimated CV risk among participants receiving the pharmacist-led Care Pathway intervention vs those in the control group would support this hypothesis. The Care Pathway implementation tool may also improve the control of individual modifiable CV risk factors, such as blood pressure, A1C level, blood lipid concentrations, and tobacco and/or vape use. Quality indicators for CV risk–reduction care as recommended by the Canadian Cardiovascular Society and in the literature28, 29, 30 are incorporated within the PR_xOACT Care Pathway implementation tool to facilitate quantifiable measurement and external validation of the care delivered. If this trial demonstrates a beneficial effect, the study findings would provide rigorous evidence supporting the positive clinical impact of widespread implementation of a pharmacist-led CV risk–management model of care. Further research is warranted to evaluate the cost effectiveness of this model of care and explore the application of the Care Pathway implementation tool within other therapeutic areas.

To our knowledge, the PR_xOACT trial is the first to evaluate the impact of the Care Pathway tool on large-scale implementation of pharmacist-led interventions to reduce patients’ estimated risk for a major CV event. Findings from this trial have the potential to impact and optimize CV risk assessment and management, which may lead to a reduction in the burden of CVD among an at-risk population.

Trial Status

Protocol version 1.0; August 9, 2024: Recruitment commenced on November 1, 2024 and is proceeding as planned. As of December 10, a total of 44 (of 98) sites have been trained and started, and 71 patients have been enrolled. The last patient is estimated to be included by August 2025.

Perspectives from Our Patient Partners

• •Being a part of the PRxOACT Team felt inclusive and fostered shared decision-making.
• •We were grateful to understand how to assist in changes for an improved healthcare system.
• •We contributed as full participants in discussions and decision points especially on what and how the project will communicate with patients and retain their interest.
• •As a patient advisor (PA), I appreciate that my contributions are always well received. There is a large degree of mutual respect between all members of the study team, including PAs. This established an environment for candid and meaningful discussions including PAs. It really brings out the best in the PAs.