Aims
- To design and model in a collaborative way among the stakeholders involved (healthcare professionals, patients, managers and researchers) a set of de-implementation strategies to favour the reduction and/or abandonment of low-value prescribing of statins in primary prevention of CVD. This strategy will be designed using a systematic, comprehensive framework based on theory and evidence for the design of implementation strategies (the CFIR, TDF and BCW) focused on addressing the main determinants (barriers and facilitators) of clinical practice for primary prevention of CVD and adapted to the specific context of primary care (PC) in the Basque Health Service (Osakidetza).
- To evaluate the feasibility and potential effectiveness of the de-implementation strategies applied for reducing the low-value prescribing of statins in primary prevention of CVD and for increasing the delivery of healthy lifestyle promotion, in accordance with recommended clinical practice, compared to the usual procedures of dissemination of clinical practice guidelines, focused on the provision of educational materials, support tools and training.
Design
Implementation trial in Phase I (formative mixed methods research) and Phase II (feasibility and potential effectiveness evaluation using mixed methods). The DE-imFAR study was reviewed and approved by the Clinical Research Ethics Committee of the Basque Country (Ref: PI2019102, approved on 10 April 2019) and has been registered in the US NLM´s clinical trials database (clinicaltrials.gov NCT04022850, 17 July 2019).
Osakidetza provides universal coverage that is free at the point of use, aside from co-payment for drugs, funded through regional general taxation. Primary, specialized and social health-related service provision is organized around 13 Integrated Healthcare Organizations (IHOs) that cover the three provinces of the Autonomous Community of the Basque Country: Araba, Bizkaia and Gipuzkoa. Each resident is on the list of one family physician (FP) or pediatrician who offers comprehensive primary care and refers patients for hospital and specialty services. Primary care professionals work in full-time teams, including FPs, pediatricians, nurses, and administrative staff based at local centers providing access to healthcare for users in a defined geographical area.
1) Phase I Formative mixed methods research.
With the aim of designing and packaging context-specific de-implementation strategies to favour a reduction in low-value pharmacological prescribing in CVD primary prevention, the following actions will be carried out:
1.1) Cross-sectional observational study of inappropriate prescribing of statins in primary prevention of CVD
With the objective of quantifying and describing the magnitude and distribution of the problem regarding low-value pharmacological prescribing in CVD primary prevention, an observational descriptive study regarding inappropriate prescribing of statins in the last 5 years by Osakidetza PC physicians will be carried out. To this end, a clinical scenario in which the prescribing of statins is clearly inappropriate will be established. Specifically, the study population will consist of all patients attending PC consultations in the 2014-2018 period, aged between 40 and 74 years in men and between 45 and 74 years in women with hypercholesterolemia (LDL cholesterol >70-189 mg/dL and/or total cholesterol >200-289 mg/dL), but no known cardiovascular disease and an estimated cardiovascular risk <5% according to the REGICOR scale [13]. The proportion of patients with and without an inappropriate prescription of statins as well as the annual incidence rate of new inappropriate prescriptions will be estimated both overall and by physician and IHO. Additionally, PC physicians will be classified into groups of low, moderate and high rates of inappropriate prescribing. The data will be extracted from the electronic medical record system of Osakidetza (OSABIDE), at all times satisfying the legal and ethical requirements of anonymity and confidentiality.
1.2) Literature review: determinants of and effective intervention strategies to modify low-value pharmacological prescribing in CVD primary prevention.
In order to describe the current state of knowledge in relation to factors that determine low-value pharmacological prescribing in the primary prevention of CVD, two areas will be reviewed: a) determinants of pharmacological prescribing behavior in the context of CVD primary prevention, paying special attention to factors (personal, interpersonal, organizational, etc.) that favor/hinder low-value pharmacological prescribing; and b) effective individual/organizational intervention strategies for the reduction, abandonment or de-implementation of low-value pharmacological prescribing. To achieve this, a systematic search will be carried out in the MEDLINE, EMBASE and Cochrane Library databases, for research published in the last 10 years. Terms will be used referring to the behavior of interest (pharmacological prescribing of statins or drugs for the reduction of cholesterol levels), to factors associated with prescribing at the level of professional, patient or organization, to interventions to encourage abandonment or adaptation of the pharmacological prescribing according to practice recommendations (e.g., inappropriate prescribing), and to the type of study (e.g., descriptive or qualitative studies on determinants or associated factors; interventional studies or clinical trials to identify effective interventions). The following will be excluded: studies concerning the dissemination of clinical practice guidelines or recommendations without a systematic search process, reviews of such studies and associated analysis of evidence; studies not performed in a routine clinical context with characteristics similar to that of Osakidetza; and studies conducted in the context of secondary or tertiary prevention.
The search will not be limited to any language or country. In addition to searching these databases, the references of all studies selected will be consulted to identify additional potentially eligible studies. The starting point of the search has been set as 2009 in order to focus on relatively recent studies that may better represent current working conditions, trends, and procedures in pharmacological prescribing. Two team members will independently review the abstracts and make an initial selection of studies identified by each search strategy. The final selection will be made by consensus after discussion of potential inconsistencies. The key information (methodological features, main results, quality of the research and the evidence) for each of the studies selected in each of the aforementioned literature searches will be extracted using data forms and assessed.
1.3) Collaborative design and mapping of the de-implementation strategies
A working group will be created, composed of experts in the design of implementation strategies, methodologists, pharmacists, qualitative researchers, clinicians and health service managers. The group will carry out a structured and theory-informed process to map implementation strategies seeking to address the determinants of low-value pharmacological prescribing in CVD primary prevention. More specifically, they will follow the process outlined by the BCW [35,36] to identify, select, adapt and define possible behavioral change interventions operationalized as de-implementation strategies to address the prioritized determinants of low-value pharmacological prescribing in CVD primary prevention. This process involves eight steps grouped into three stages:
1st stage - Understand the behavior: 1) define the problem in behavioral terms; 2) select the target behaviors; 3) specify the target behaviors; and 4) identify what has to change. To this end, two main actions will be carried out:
First, a semi-structured interview with a sample of FPs will be conducted to identify and break down the chain of behaviors and concomitant non-behavioral (e.g., contextual) factors that define the overall behavioral scenario. Three members of the working group, with different backgrounds, will independently review the recordings of the FP interviews and identify and propose a set of possible target behaviors and the complete behavioral scenario composed of the chain of micro-behaviors and concomitant factors. After that, they will agree on a single definition of the problem in behavioral terms. Subsequently, based on the information compiled from the interviews and using matrices and exercises proposed by the BCW, the working group will specify and select the final target behaviors most likely to lead to the desired behavior change, to be the focus of the next steps. Discrepancies will be resolved through discussion until agreement is reached. The result of this analysis will be shown to the interviewees in order to validate the response and increase the level of consensus.
Second, a qualitative study using focus groups will be conducted to identify the determinants (barriers/enablers) of each of the target behaviors previously identified and selected. An intentional sample of FPs will be recruited, stratified by pharmacological prescribing rate (low, moderate and high) based on the descriptive study. To ensure that all perspectives are represented, sampling will continue until saturation, understood as two consecutive focus groups in which no additional material is gathered. The main goal of this qualitative inquiry process will be to identify the main barriers and facilitators for each of the selected target behaviors related to the provision of recommended clinical practice for primary prevention of CVD (e.g., intervention to promote healthy lifestyles for primary prevention of CVD) and those related to low-value pharmacological prescribing practice.
The groups will be led by two researchers with experience in qualitative research methods, as well as knowledge of the clinical field and the study objectives. The focus groups will be audio recorded, with prior consent, and verbatim transcribed. The script of the focus groups will explore in detail potential determinants with questions formulated to cover each of the TDF and CFIR domains [37-39]. Both the TDF and CFIR are comprehensive multi-level implementation frameworks based on theory and evidence. The rationale for using both frameworks is their ability to identify a broad range of determinants, especially at the individual level with the TDF, and organizational level with the CFIR. This script will be developed by researchers with experience in behavioral change and implementation research, and clinicians with experience in the primary prevention of CVD in primary care settings. The script and operative procedures for the discussion groups will be piloted and refined, prior to the field work. The data will be analyzed using an iterative process in which two researchers will perform an independent review and coding of the transcripts. Transcripts will be imported into the Atlas Ti program to manage the data and facilitate analysis. Any coding discrepancies will be discussed until consensus is reached.
Additionally, seeking to explore the determinants of low-value pharmacological prescribing practice in CVD primary prevention related to other stakeholders, these being patients in the target population, primary care nurses and cardiologists, qualitative inquiry processes will be performed based on discussion groups or key-informant interviews. As with physician groups, these qualitative procedures will be recorded and verbatim transcribed and analyzed. Informed consent of all participants will be obtained prior to these qualitative research procedures.
2nd stage - Identify intervention options: 5) select intervention functions; 6) select the specific behavior change techniques.
In order to identify the behavior change techniques most likely to produce changes for each of the identified determinants of selected target behaviors, the working group will proceed to map the barriers and facilitators identified and grouped in the TDF and/or CFIR domains, with behavior change strategies, intervention functions and policy categories using the process established by the BCW [35,36]. For all the range of possible interventions identified through this structured mapping process, the following will be set out: clear definitions of the techniques to be applied, the actual content of the interventions, their possible formats and modes of execution, etc. A similar process for identifying potential implementation strategies will be also conducted using the CFIR-ERIC Implementation Strategy Matching Tool [40]. Convergences or divergences regarding strategies that emerge from the aforementioned processes will be resolved by consensus.
3rd stage - Identify implementation procedures: 7) select strategies and intervention techniques; 8) select the mode of execution of the intervention.
Final selection of previously identified de-implementation strategies will be performed through a participatory consensus process involving the working group as representatives of the main stakeholders. In short, the working group will carry out a structured group process based on the nominal group technique to rank each of the tentative de-implementation strategies based on the APEASE criteria: affordability, practicability, effectiveness and cost-effectiveness, acceptability, side effects/safety and equity. Strategies considered both highly feasible and relevant for enacting behaviour change will be included the final set of specific strategies to be contained in at least one broad de-implementation strategy seeking to reduce low-value pharmacological prescribing in the primary prevention of CVD.
2) Phase II feasibility and potential effectiveness evaluation
A comparative hybrid type-II feasibility/potential effectiveness implementation trial will be designed and conducted for evaluating at least one active de-implementation strategy defined through the phase I formative mixed research compared with the usual procedures of dissemination of clinical practice guidelines (e.g., “what-not-to-do” guidelines), focused on the provision of materials, support tools and training (reference group). A mixed methods evaluation will be undertaken: quantitative for assessing the results of implementation at the professional level (process and implementation outcomes regarding reductions in low-value pharmacological prescribing and the adoption, reach and implementation of the recommended clinical practice in CVD primary prevention) and qualitative for assessing the feasibility and perceived impact of the de-implementation strategy from the clinicians’ perspective and ascertaining the experience and satisfaction of patients concerning the clinical care received. The unit of intervention will be the PC physician, while observation and analysis will be performed at professional and patient levels. Thus, the trial will tentatively be randomized at the level of PC physician with at least two intervention arms (dissemination vs. de-implementation strategy). The diffusion of the final design of the planned evaluation is warranted.
Participants
- i) Professionals: Osakidetza PC physicians willing to be involved in a process focused on the optimization of CVD primary prevention; and ii) Patients: All women aged 45-74 years and men aged 40-74 years with hypercholesterolemia but without diagnosed ischemic heart or cardiovascular disease and with a low estimated CVD Risk (<5%) according to REGICOR who attend at least one appointment at the collaborating PC practices during the study period. Informed consent of PC physicians as representatives of the clusters will be obtained prior to trial commencement.
Comparison de-implementation strategies
The active comparator will be passive dissemination, defined as a set of usual procedures for the dissemination of clinical practice guidelines (“what-not-to-do” guidelines) focused on the diffusion of knowledge and abilities mainly through the provision of materials, support tools and training. This control intervention will be compared with at least one active experimental de-implementation strategy, emerging from the formative research, defined by a set of de-implementation strategies targeting the facilitators of the non-desired behaviour (seeking to supress it), while tackling the barriers to and encouraging the preferred/desired behaviour. This experimental de-implementation intervention could tentatively be broken down into several distinct de-implementation strategies to be compared to the control intervention.
Randomization
The FPs will be randomly assigned to one of at least two study arms, using a random number sequence generated by computer prior to the start of the trial: one of the groups will be exposed to the de-implementation strategy that emerges from the systematic process of identifying determinants and mapping tailored interventions established by the BCW; and the other the usual procedures for disseminating clinical practice guidelines ("what-not-to-do" recommendations) focused on the provision of materials, support tools and training. The allocation sequence will be generated using a specific restricted scheme by one member of the research team using PROC PLAN/alternatives. The sequence will be concealed at the coordination centre. Physician will be allocated only after they have given written informed consent. The random assignment in a tentative three-arm design will be similar. Given that the strategy is an optimization of services or clinical care already offered in Osakidetza, participants are expected to be blind to allocation group. The data analyst and the personnel in charge of measurements will be blind to physician allocation to study arms.
Outcome measures
To assess the feasibility/potential effectiveness of compared de-implementation strategies in terms of public health significance, we will use the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework [41].
Reach
- Percentage of eligible patients (low-risk patients with hypercholesterolemia but without ischemic heart or cardiovascular disease) ascribed to collaborating FP who received the recommended CVD primary prevention practice as dictated by the CVD Prevention Clinical Practice Guideline [13], this being the health promotion intervention action (e.g., assessment of advice regarding healthy lifestyles), 12 months after exposure of the FP to the compared de-implementation strategies
Effectiveness
- Changes observed in attitudes towards health promotion and perceived ability of physicians to provide a health promotion intervention considered the recommended practice for the primary prevention of CVD in low-risk patients, measured through the Preventative Activity Questionnaire [42]
- Changes observed in two clinical and behavioural indicators in a random sample of eligible patients by comparison group exposed to CVD primary prevention actions that emerges from the compared de-implementation strategies, stratified by age and sex. Specifically, a sample of 180 exposed patients will be selected, 15 patients per stratum (2 sex strata, 3 age strata, 2 de-implementation strategies). The use of the aforementioned sampling scheme reflects the intention to maximise the comparability of the populations of exposed users.
- As an objective clinical measurement, the change in the REGICOR estimate 12 months after the exposure to the CVD prevention intervention.
- As a subjective measurement, the self-reported changes in lifestyle (physical activity, diet and smoking) 12 months after the intervention, measured through the “prescribe healthy life" (PVS) questionnaire [43], operationalized as: i) Proportion of people who have achieved the recommended levels of physical activity (150 min/week of moderate physical activity or 75 min/week of intense physical activity), healthy diet (5 portions/day of fruits and vegetables), and smoking cessation, among those who did not meet these recommended levels on entry into the study; and ii) Weekly minutes dedicated to physical activity of at least moderate intensity, daily number of fruit and vegetable servings.
Adoption
- Percentage of FPs out of the total addressed to participate that collaborate in a process to optimize CVD primary prevention practice; characteristics of those participating/not-participating.
- Percentage of FPs who change their CVD prevention practice by reducing low-value statin prescribing and increasing health promotion actions in the target population at risk of receiving CVD prevention, 12 months after exposure of physicians to the compared de-implementation strategies.
Implementation (Main outcome)
The main outcome measures will compare the incidence of both the pharmacological prescribing of statins and the health promotion actions in patients of the target population at risk of receiving CVD primary prevention care, over the 12 months after exposure of collaborating physicians to the compared de-implementation strategies. Specifically the two following indicators will be compared:
- Incidence of low-value prescriptions of statins in patients with no history of statin prescriptions aged between 40 and 74 years in men and between 45 and 74 years in women, with hypercholesterolemia but without ischemic heart disease/CVD, and with an estimated CVD Risk <5%, attending during the 12 months after exposure of physicians to the compared implementation strategies
- Incidence of advice regarding healthy lifestyles in patients with no history of statin prescriptions aged between 40 and 74 years in men and between 45 and 74 years in women, with hypercholesterolemia but without ischemic heart disease/CVD, and with an estimated CVD Risk <5%, attending PC consultations during the 12 months after exposure of physicians to the compared implementation strategies.
Maintenance
- Incidence of low-value pharmacological prescriptions of statins and of an advice regarding healthy lifestyles in eligible patients, 36 months after exposure of physicians to the compared implementation strategies
Spreading
With the aim of assessing a possible spill-over effect of the compared de-implementation strategies in the optimization on the CVD prevention practice, de-prescribing rates in patients with a low-value prescription of statins prescribed before the exposure of physicians to the de- implementation strategies
Fidelity and Feasibility Measures
A complete recording and subsequent description of the execution process of the compared de-implementation strategies by group will be carried out to assess the level of fidelity with which they have been carried out with respect to what was been planned: Number and percentage of professionals included among those addressed to participate; Description of actions carried out (training, work sessions, etc.) and Final duration compared to what was planned; Participation of professional collaborators in each action (Exposure); Assessment of the content and usefulness of the implementation actions received by the clinicians; Resources dedicated to the execution of de-implementation strategies: support materials, external resources (e.g., external facilitator), organizational support resources (release of professionals, coverage of services, etc.). All changes made to the de-implementation strategy will be thoroughly described: what has been modified, how, why, by whom and at what level of delivery (e.g., comparison group level).
Management, quality and safety in data processing
All data related to patient sociodemographic characteristics (age, sex, socioeconomic status, etc.) and the clinical practice of their healthcare professionals (e.g., pharmacological prescribing, heath promotion actions, etc.) will be extracted from the electronic health record system of Osakidetza (OSABIDE). The Primary Care Research Unit of Bizkaia is formally authorized to extract and use data from electronic health records for research purposes by the Healthcare Directorate of Osakidetza. The confidentiality of the people included in the study will be safeguarded at all times, in accordance with the provisions of the Spanish Organic Law on Protection of Personal Data (3/2018 December 5th, LOPD).
Analysis
Frequencies and proportions along with their corresponding 95% confidence intervals (CIs) will be used to describe the prevalence and the incidence of low-value pharmacological prescribing of statins in primary prevention of CVD of PC professionals (2018 prescriptions being used as the reference level). Factors associated with inappropriate prescribing of statins will be analyzed through stratified statistical analysis and fitting linear logistic models. Given the three levels involved (patients, clinicians and health organizations), the average variability and possible associated factors will be estimated using hierarchical models and models based on Bayesian estimators.
The primary outcome will be the incidence of new inappropriate prescriptions of statins in patients of the target population (hypercholesterolemic patients without past or current CVD and with an estimated 10-year cardiovascular risk < 5%) 12 months after exposure of physicians to the compared de-implementation strategies. Therefore, to evaluate the impact of the alternative de-implementation strategies, the relative risk of receiving an inappropriate prescription of statins in patients in the target population of the experimental intervention over that of patients from the reference/control group will be estimated by intention-to-treat. Change in new inappropriate prescription incidence rates from baseline to those observed 12 months after physicians’ exposure to the de-implementation strategies and the relative risk reduction ratio will be estimated with the corresponding 95% confidence intervals. In order to adjust for potential confounding factors, stratified statistical analyses and logistic models will be used. These models will be extended to generalized mixed effects models to take into account the hierarchical structure of data (patients nested in physicians and physicians in PC teams or specialized care services), with fixed effects (comparison group, effect of time on outcome indicators and time-group interaction) and random effects on the intercept and the time slope (for each patient, physician, center, etc.). These models will be adjusted for potential confounding variables, following a “forward” strategy guided by the stratified analyses. A similar analytic strategy will be followed for secondary outcomes. The analyses will be carried out with SAS, Stata and R.
Based on: i) a baseline incidence of 2.7% of new inappropriate statin prescriptions estimated among the patients of the target population seen in 2018 by physicians with an inadequate prescription incidence > 0% with a minimum cluster size n ≥20 patients, ii) an intra-class correlation coefficient of 0.01, iii) an average cluster size of 56 patients with a coefficient of variation of 0.43, iv) α = 0.05 and statistical power of 80%, and v) a hypothetical reduction in annual inappropriate prescription rates in the intervention group of 1.7% in absolute terms or 63% in relative terms (from 2.7% to 1%), the interventional phase will require two study groups with at least 22 physicians each, i.e., at least 44 PC physicians.