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In 2018, Ontario implemented a pharmacare program (Ontario Health Insurance Plan Plus [OHIP+]) to provide children and youth younger than 25 years with full coverage for prescription medications in the provincial formulary. We aimed to assess the use of public drug plans and costs of publicly covered prescriptions before and after the program's implementation and modification.We conducted a population-based, interrupted time-series analysis using data on prescription drug claims, from the Canadian Institute for Health Information's National Prescription Drug Utilization Information System, for people younger than 25 years from January 2016 to October 2019 in Ontario, using British Columbia as the control. We assessed changes in the level and trend of publicly covered prescriptions and expenditures after the introduction of OHIP+ in January 2018 and after program modifications in April 2019. We also assessed plan use and expenditures for publicly covered prescriptions for diabetes and asthma.Publicly covered prescriptions in Ontario increased by 290%, from 756 per 1000 people before OHIP+ to 2952 per 1000 (ip/ilt; 0.001) after its implementation. After program modification, prescriptions decreased by 52% to 1421 per 1000 (ip/ilt; 0.001). Similarly, total public drug expenditures increased by 254%, from $379 million in 2017 to $839 million in 2018, then reduced by 49% to $204 million in 2019. Monthly public plan expenditures increased by $115.94 (95% confidence interval [CI] $100.93 to $130.94) post-OHIP+ implementation and decreased by $99.97 (95% CI -$119.79 to -$80.15) per person per month after April 2019.Adopting OHIP+ increased use of public drug plans and expenditures for publicly funded prescription medicines, and the program modification was associated with decreases in both outcomes. This study's findings can inform the national pharmacare debate; future research should investigate associations with health outcomes.

RationaleTransitions in, through, and out of hospital define the highest risk periods for patient safety. Hospitalized senior high-cost health care users taking high risk medications, are a large group of patients, usually highly complex with polypharmacy, and at high risk of serious adverse medication events. We will assess whether an expert Clinical Pharmacology Toxicology (CPT) medication management intervention during hospitalization with follow-up post-discharge and communication with circle of care, is feasible and can decrease drug therapy problems amongst this group.DesignPragmatic pilot randomized trial at SJHH with 1:1 patient-level concealed randomization with blinded outcome assessment and data analysis.ParticipantsAdults 65 years of age and older, admitted to Internal Medicine services for more than 2 days, who are high-cost users defined as at least one other hospitalization in the prior year, taking 5 or more chronic medications including at least one high risk medication.InterventionCPT consult service identifies medication target(s), completes consult, including priorities for improving prescribing negotiated with the patient, starts the care plan, ensures a detailed discharge medication reconciliation and circle-of-care communication, and sees the patient at least twice after hospital discharge via integrated virtual visits to consolidate the care plan in the community. Control group receives usual care as provided by admitting services.OutcomesInclude a) Feasibility Outcomes and b) Clinical Outcomes including the number of drug therapy problems improved, medication appropriateness and safety, the quality and coordination of transitions in care, quality of life, and health care utilization and costs by 3-month follow-up.ImpactIf results support feasibility of ramp-up and promising clinical outcomes, a follow-up definitive trial will be organized using a developing national platform and medication appropriateness network.RESEARCH QUESTIONOur detailed research question is ‘In a randomized pilot trial, can an expert Clinical Pharmacology team coordinate and improve medication management during the very high-risk transition period from hospitalization through post-hospital discharge follow-up for senior high-cost users of healthcare taking high risk medications, meeting key feasibility outcomes while improving patient-important outcomes and health care costs sufficiently to warrant a large subsequent trial?’

Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias.A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting.In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well.Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Introduction Oral anticoagulant (OAC)-related adverse events are high post-hospitalization. We planned to develop and validate a prediction model for OAC-related harm within 30 days of hospitalization. Methods We undertook a population-based study of adults aged ≥66 years who were discharged from hospital on an OAC from September 2010 to March 2015 in Ontario, Canada. The primary outcome was a composite of time to first hospitalization or emergency department visit for a hemorrhagic or thromboembolic event, or mortality within 30 days of hospital discharge. Cox proportional hazards regression was used to build the model. Results We included 120,721 patients of which 5423 experienced the outcome. Most patients were aged ≥75 years (59.5%) and were female (55.6%). Sixty percent of the cohort had a follow-up visit with a healthcare provider within 7 days of discharge. Patients discharged on a direct acting OAC versus warfarin (apixaban: Hazard Ratio [HR] 0.82, 95% confidence interval [CI] 0.71-0.94; dabigatran: HR 0.73, 95% CI 0.63-0.84; rivaroxaban: HR 0.79, 95% CI 0.71-0.88), were prevalent users of the dispensed OAC versus incident users (HR 0.82, 95% CI 0.69-0.96), had a joint replacement in the past 35 days (HR 0.40, 95% CI 0.33-0.50) or major surgery during index hospital stay (HR 0.69, 95% CI 0.60-0.80) had a lower risk for the outcome. The Cox model was stable with acceptable discrimination but poor goodness-of-fit. Conclusions A model for OAC-related harm in the early post-discharge period was developed. External validation studies are required to understand the model's poor calibration.

Background Oral anticoagulants (OACs) are commonly prescribed, have well-documented benefits for important clinical outcomes but have serious harms as well. Rates of OAC-related adverse events including thromboembolic and hemorrhagic events are especially high shortly after hospital discharge. Expert OAC management involving virtual care is a research priority given its potential to reach remote communities in a more feasible, timely, and less costly way than in-person care. Our objective is to test whether a focused, expert medication management intervention using a mix of in-person consultation and virtual care follow-up, is feasible and effective in preventing anticoagulation-related adverse events, for patients transitioning from hospital to home. Methods and analysis A randomized, parallel, multicenter design enrolling consenting adult patients or the caregivers of cognitively impaired patients about to be discharged from medical wards with a discharge prescription for an OAC. The interdisciplinary multimodal intervention is led by a clinical pharmacologist and includes a detailed discharge medication reconciliation and management plan focused on oral anticoagulants at hospital discharge; a circle of care handover and coordination with patient, hospital team and community providers; and early post-discharge follow-up virtual medication check-up visits at 24 h, 1 week, and 1 month. The control group will receive usual care plus encouragement to use the Thrombosis Canada website. The primary feasibility outcomes include recruitment rate, participant retention rates, trial resources management, and the secondary clinical outcomes include adverse anticoagulant safety events composite (AASE), coordination and continuity of care, medication-related problems, quality of life, and healthcare resource utilization. Follow-up is 3 months. Discussion This pilot RCT tests whether there is sufficient feasibility and merit in coordinating oral anticoagulant care early post-hospital discharge to warrant a full sized RCT. Trial registration NCT02777047.

Introduction Oral anticoagulant (OAC) intervention trials have typically included clinical event outcomes. However, there is no standard list of outcomes to be used in OAC research. This study aimed to describe and classify the outcomes used in recent prospective clinical studies involving OACs. Materials and methods We searched MEDLINE, EMBASE, and CINAHL databases from January 2009 to July 2019 for prospective studies with an intervention or control group that included one or more oral anticoagulants. We abstracted details about each included study and the outcomes used from the study report and its accompanying protocol. Using the Core Outcome Measures in Effectiveness Trials (COMET) Initiative recommendations, we categorised each outcome into one of five domains (mortality/survival, physiological/clinical, life impact, resource use, and adverse events). Our primary outcome was the prevalence of use of an outcome domain across studies. Results We included 70 prospective studies, including 52 randomized controlled trials and 18 prospective cohort studies. A total of 121 different outcomes were reported. The COMET domains were represented in the 70 studies as follows: mortality (63/70, 90.0%); physiological/clinical domain (70/70, 100%), life impact domain (43/70, 61.4%), resource use domain (26/70, 37.1%), and adverse events domain (55/70, 78.6%). Conclusion Outcome reporting in prospective studies of OACs more frequently concentrates on mortality, physiological/clinical domains, and adverse events compared to life impact and resource utilization domains, the latter uncommonly used. A priority for future research includes developing a core outcome set (COS) for OAC research that represents all domains.

Background Oral anticoagulants are commonly used high-risk medications, but little is known about their safety in transition from hospital to home. Our objective was to measure the rates of hemorrhage and thromboembolic events among older adults receiving oral anticoagulant treatment early after hospital discharge compared to later. Methods We conducted a retrospective population-based cohort study among Ontario residents aged 66 years or more who started, continued or resumed oral anticoagulant therapy at hospital discharge between September 2010 and March 2015. We calculated the rates of hemorrhage and thromboembolic events requiring hospital admission or an emergency department visit over a 1-year follow-up period, stratified by the first 30 days after discharge and the remainder of the year. We used multivariable regression models, adjusting for covariates, to estimate the effect of sex, prevalent versus incident use, and switching anticoagulants on events. Results A total of 123 139 patients (68 408 women [55.6%]; mean age 78.2 yr) were included. About one-quarter (32 563 [26.4%]) had a Charlson Comorbidity Index score of 2 or higher. The rates of hemorrhage and thromboembolic events per 100 person-years were highest during the first 30 days after hospital discharge (25.8, 95% CI 24.8-26.8 and 19.3, 95% CI 18.4-20.2, respectively), falling to 15.7 (95% CI 15.3-16.1) and 6.9 (95% CI 6.6-7.1), respectively, during the subsequent 11 months. Multivariable analysis showed that patients whose anticoagulant was switched in hospital and men had more hemorrhages and thromboembolic events in follow-up. Interpretation The first few weeks following hospital discharge represent a very high-risk period for adverse events related to oral anticoagulant treatment among older adults. The results support an intervention trial addressing anticoagulation management in the early postdischarge period.

Background Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not. Methods We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan-Meier method. Results We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6-550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50-0.72) and mortality (adjusted HR 0.54, 95% CI 0.48-0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64-2.17). Interpretation We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Background Health interventions and policies for high-cost health care users (HCUs) who are older adults need to be informed by a better understanding of their multimorbidity and medication use. This study aims to determine the financial contribution of medications to HCU expenditures and explore whether potentially inappropriate prescribing is associated with incident HCU development. Methods This is a protocol for a retrospective population-based matched cohort analysis of incident older adult HCUs (those with the highest 5% of costs and 66 years of age or older) in Ontario during fiscal year 2013. We will obtain person-level data for the index year and year before HCU status from health administrative databases and match each HCU to 3 non-HCUs based on age, sex and geographic location. Average annual medication costs (per patient) and the ratio of medication to total health care costs (at population level) will be examined over the HCU transition period and compared with non-HCUs. We will explore potential quality improvement areas for prescribing by analyzing chronic conditions and the use of medications with a strong evidence base for either clinical benefit or risk of harms outweighing benefits in older adults with these diagnoses. The relation between these medication classes and incident HCU status will be explored using logistic regression. Interpretation Using a matched cohort design and focusing on incident rather than prevalent HCUs, this protocol will explore our hypotheses that medications and the quality of their prescribing may be important triggers of HCU status and facilitate the identification of potential preventive clinical interventions or policies. Dissemination of results will occur via publications in peer-reviewed journals, presentations at conferences and academic settings, and knowledge translation activities with relevant health system and patient stakeholder groups. Study registration Clinicaltrials.gov, no. NCT02815930.

Background Cost-related nonadherence to medications (CRNA) is common in many countries and thought to be associated with adverse outcomes. The characteristics of CRNA in Canada, with its patchwork coverage of increasingly expensive medications, are unclear. Objectives Our objective in this systematic review was to summarize the literature evaluating CRNA in Canada in three domains: prevalence, predictors, and effect on clinical outcomes. Methods We searched MEDLINE, Embase, Google Scholar, and the Cochrane Library from 1992 to December 2019 using search terms covering medication adherence, costs, and Canada. Eligible studies, without restriction on design, had to have original data on at least one of the three domains specifically for Canadian participants. Articles were identified and reviewed in duplicate. Risk of bias was assessed using design-specific tools. Results Twenty-six studies of varying quality (n = 483,065 Canadians) were eligible for inclusion. Sixteen studies reported on the overall prevalence of CRNA, with population-based estimates ranging from 5.1 to 10.2%. Factors predicting CRNA included high out-of-pocket spending, low income or financial flexibility, lack of drug insurance, younger age, and poorer health. A single randomized trial of free essential medications with free delivery in Ontario improved adherence but did not find any change in clinical outcomes at 1 year. Conclusion CRNA affects many Canadians. The estimated percentage depends on the sampling frame, the main predictors tend to be financial, and its association with clinical outcomes in Canada remains unproven.

Prescribing skills are a crucial competency in medical practice considering the increasing numbers of medications available and the increasingly complex patients with multiple diseases faced in clinical practice. Medical students need to become proficient in these skills during training, as required by medical licensing colleges. Not only is teaching the fundamentals of safe and cost-effective prescribing to medical students challenging but evaluating their prescribing skills by faculty members is difficult and time consuming. The COVID-19 pandemic has accelerated the interest in clinically relevant online exams, including automated assessment of short answer style questions. The goal of this project was to design a software to automate the assessment of learners' prescriptions written during low stakes formative assessments. After establishing the components of a legal prescription with multiple medications, and identifying the sources of errors in prescribing and prescribing assessment, we designed and validated an architecture and developed a prototype for automated parsing of learner prescriptions.

Background. Observational economic evaluations (i.e., economic evaluations in which treatment allocation is not randomized) are prone to confounding bias. Prior reviews published in 2013 have shown that adjusting for confounding is poorly done, if done at all. Although these reviews raised awareness on the issues, it is unclear if their results improved the methodological quality of future work. We therefore aimed to investigate whether and how confounding was accounted for in recently published observational economic evaluations in the field of cardiology. Methods. We performed a systematic review of PubMed, Embase, Cochrane Library, Web of Science, and PsycInfo databases using a set of Medical Subject Headings and keywords covering topics in “observational economic evaluations in health within humans” and “cardiovascular diseases.” Any study published in either English or French between January 1, 2013, and December 31, 2017, addressing our search criteria was eligible for inclusion in our review. Our protocol was registered with PROSPERO (CRD42018112391). Results. Forty-two (0.6%) out of 7523 unique citations met our inclusion criteria. Fewer than half of the selected studies adjusted for confounding ( n = 19 [45.2%]). Of those that adjusted for confounding, propensity score matching ( n = 8 [42.1%]) and other matching-based approaches were favored ( n = 8 [42.1%]). Our results also highlighted that most authors who adjusted for confounding rarely justified their methodological choices. Conclusion. Our results indicate that adjustment for confounding is often ignored when conducting an observational economic evaluation. Continued knowledge translation efforts aimed at improving researchers’ knowledge regarding confounding bias and methods aimed at addressing this issue are required and should be supported by journal editors.

Oral anticoagulants (OACs) are high-priority medications, frequently used with clinically important benefit and serious harm. Our objective was to compare the safety and effectiveness of direct-acting oral anticoagulants (DOACs) versus warfarin in a population where anticoagulation management and DOACs were readily available. A retrospective cohort study of all adults living in British Columbia with a diagnosis of atrial fibrillation and a first prescription for an OAC was conducted. Co-primary outcomes were ischemic stroke and systemic embolism, and major bleeding. Secondary outcomes included a net clinical outcome composite and analysis of discontinuation, switching, and key subgroups. We estimated the effects of treatment using time-to-event models with high-dimensional propensity score adjustment to control confounding. After adjustment for prescribing bias, a cohort (n = 20,113, 43.8% female, mean age 72.4 years) with a mean follow-up of 18.1 months showed that patients taking warfarin tended to be poorer, sicker, and less likely to have a cardiologist prescriber. Outcome event rates were not significantly different for DOACs compared to warfarin [adjusted rate ratio of 1.15 (0.91, 1.46) for systemic embolism, 0.94 (0.82, 1.08) for major bleeding, and 0.98 (0.90, 1.06) for net clinical outcome]. Only the effect of age on net clinical outcome met our strict criteria for predicting which group might be superior. Switch of drug class was associated with increased risk of events (p < 0.003). In this population, we found no difference in important clinical outcomes between warfarin and DOACs. Switching compared to not switching was associated with harm.

Background Because not all medicines are equally safe, effective, and affordable, health systems often use formularies to define explicitly which medicines will be included and excluded from coverage. Objective We sought to synthesize methods and findings from published studies of formulary variation across health systems in high-income countries. Methods We conducted a systematic review of peer-reviewed research papers published from 2000 to 2017, inclusively. Because of the heterogeneous nature of the literature, we used an inductive approach to summarize methods and findings. Results Nine studies met our study inclusion criteria. Included studies used a variety of methods for selecting medicines for analysis, for measuring coverage levels, and for measuring concordance between formularies. Studies assessing variations in coverage of all licensed medicines and found lower rates of cross-national coverage variation than studies of coverage for selected specialty drugs and indications. The one study that focused on coverage of high-volume medicines found the most complete and consistent levels of formulary listings across countries. Conclusion Although published studies contain interesting findings that likely have prompted discussions about their policy implications, the literature can be improved with greater transparency concerning the overarching objective of work in this area and more rigor concerning the selection, analysis, and reporting of data.

Oral anticoagulants (OACs) are high alert medications and require high-quality management to optimize health outcomes. The objective of this scoping review was to identify barriers and facilitators (B&Fs) associated with the quality of OAC management. We searched MEDLINE, EMBASE, and CINAHL databases until July 12, 2018, and cross-referenced the bibliographies of the retrieved studies. We included quantitative and qualitative studies that assessed B&Fs to OAC management. The study selection and data extraction processes were performed in duplicate. Analyses included measuring the prevalence of reported B&Fs from studies reporting quantitative data, identifying B&Fs in narrative analyses, and identifying their impact on important outcomes of OAC management. B&Fs were coded and aggregated to higher-level themes using a consensus approach. Factors were described as "key" if they were statistically associated with important outcomes in a randomized trial or observational study. We included 62 studies-three randomized clinical trials (RCTs), 46 observational studies (cross-sectional studies, cohort studies, and case-control studies), 11 qualitative studies, and two mixed-methods studies. Factors identified could be grouped into four themes-therapy-related, patient-related, healthcare provider-related, and health system-related. Key barriers to optimal OAC management were mostly patient-related, whereas interventions focused on education or implementing protocols were shown through RCTs to be effective at improving knowledge scores of OAC patients. While multiple barriers and some facilitators were identified in this review, none was proven to be associated with clinical outcomes. With this in mind, individual physicians may wish to address the key barriers in their practice as a quality improvement initiative but system-wide or policy changes should await high-quality evidence. Future trials should address these factors.Systematic review registration: PROSPERO CRD42017069043.

BackgroundPolypharmacy in older adults can be associated with negative outcomes including falls, impaired cognition, reduced quality of life, and general and functional decline. It is not clear to what extent these are reversible if the number of medications is reduced. Primary care does not have a systematic approach for reducing inappropriate polypharmacy, and there are few, if any, approaches that account for the patient’s priorities and preferences. The primary objective of this study is to test the effect of TAPER (Team Approach to Polypharmacy Evaluation and Reduction), a structured operationalized clinical pathway focused on reducing inappropriate polypharmacy. TAPER integrates evidence tools for identifying potentially inappropriate medications, tapering, and monitoring guidance and explicit elicitation of patient priorities and preferences. We aim to determine the effect of TAPER on the number of medications (primary outcome) and health-related outcomes associated with polypharmacy in older adults.MethodsWe designed a multi-center randomized controlled trial, with the lead implementation site in Hamilton, Ontario. Older adults aged 70 years or older who are on five or more medications will be eligible to participate. A total of 360 participants will be recruited. Participants will be assigned to either the control or intervention arm. The intervention involves a comprehensive multidisciplinary medication review by pharmacists and physicians in partnership with patients. This review will be focused on reducing medication burden, with the assumption that this will reduce the risks and harms of polypharmacy. The control group is a wait list, and control patients will be given appointments for the TAPER intervention at a date after the final outcome assessment. All patients will be followed up and outcomes measured in both groups at baseline and 6 months.DiscussionOur trial is unique in its design in that it aims to introduce an operationalized structured clinical pathway aimed to reduce polypharmacy in a primary care setting while at the same time recording patient’s goals and priorities for treatment.Trial registrationClinicalTrials.govNCT02942927. First registered on October 24, 2016.

Aims To identify and evaluate clinical pharmacology (CP) online curricular (e-Learning) resources that are internationally available for medical students. Methods Literature searches of Medline, EMBASE and ERIC databases and an online survey of faculty members of international English language medical schools, were used to identify CP e-Learning resources. Resources that were accessible online in English and aimed to improve the quality of prescribing specific medications were then evaluated using a summary percentage score for comprehensiveness, usability and quality, and for content suitability. Results Our literature searches and survey of 252 faculty (40.7% response rate) in 219 medical schools identified 22 and 59 resources respectively. After screening and removing duplicates, 8 eligible resources remained for evaluation. Mean total score was 53% (standard deviation = 13). The Australian National Prescribing Curriculum, ranked highest with a score of 77%, based primarily on very good ratings for usability, quality and suitable content. Conclusion Using a novel method and evaluation metric to identify, classify, and rate English language CP e-Learning resources, the National Prescribing Curriculum was the highest ranked open access resource. Future work is required to implement and evaluate its effectiveness on prescribing competence.

IntroductionProton pump inhibitors (PPIs) are widely used for primary and secondary prevention of upper gastrointestinal bleeding. However, there remains controversy about the overall net clinical benefit of PPIs (omeprazole, rabeprazole, pantoprazole, lansoprazole) when coprescribed with direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, edoxaban). Our objective is to explore the risk of clinically relevant events, including bleeding, thromboembolic events and death, in patients prescribed DOACs while taking PPIs versus no PPI.Methods and analysisThe protocol describes a retrospective cohort study of all Ontario residents aged 66 years or older with atrial fibrillation and at least one pharmacy dispensation for a DOAC identified using linked administrative healthcare databases covering 2009–2020. Ontario drug benefit dispensation records will be used to ascertain PPI exposure during DOAC therapy. The primary outcome is a composite of clinically relevant bleeding, thrombotic events or all-cause death. A minimum of 520 patients in total with at least one of the components of the composite outcome are needed. Poisson regression with a generalised estimating equation model will be used to calculate the adjusted incidence rate difference, incidence rate ratios 95% CI, adjusting for propensity for PPI use using inverse probability of treatment weights.Ethics and disseminationThis research is exempt from REB review under section 45 of Ontario’s Personal Health Information Protection Act. We will report our findings in a peer-reviewed biomedical journal and present them at conferences. The study will provide useful evidence to optimise the coprescription of DOACs and PPIs in practice.

RATIONALE, AIMS AND OBJECTIVES The successful conduct of randomized clinical trials (RCTs) is often impeded by recruitment difficulties. Community hospitals see large volumes of patients but rarely participate in trials. The objective of this study was to explore how research stakeholders identify and understand the contextual, organizational, research, and individual-level factors that influence the engagement of community hospitals in Ontario to participate in RCTs as partner sites. METHODS In this descriptive, qualitative study, semi-structured interviews were conducted with a purposeful sample of 18 individuals who are familiar with the processes associated with engaging community hospitals for research or recruiting participants from these sites into trials. Demographic data were summarized using descriptive statistics. The principles of conventional content analysis were used to code, categorize and synthesize the interview data. RESULTS Informed by participants' descriptions, the results were organized within three unique stages that describe the process of recruitment within community hospitals: (a) community hospital engagement; (b) initiation of the project in the community hospitals; and (c) recruiting patients. The key barriers were the invisibility of the community hospitals to research investigators and the lack of research infrastructure in most of the community hospitals. Increased communication and sharing of resources between academic centers and community hospitals facilitated recruitment across all three stages. CONCLUSION Our results illustrated a willingness of community hospitals to participate in RCTs, but a lack of capacity for research. Additional efforts by trial coordinating sites are required to recruit community hospitals, but their inclusion improves the generalizability of trial results.

Aims The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes. Methods MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens. Conclusions This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.

SOURCE CITATION Krist AH, Davidson KW, Mangione CM, et al. Screening for unhealthy drug use: US Preventive Services Task Force recommendation statement. JAMA. 2020;323:2301-09. 32515821.

Essentials The factors influencing anticoagulation management after gastrointestinal bleeding are unclear. Focus groups and a discrete choice experiments survey of health-care providers were conducted. Re-bleeding risk and thrombosis risk were the most important factors influencing decision making. Preference variability exists with a minority most sensitive to the anticoagulation indication. ABSTRACT: Background Oral anticoagulants (OACs) are permanently discontinued in up to 50% of patients after gastrointestinal (GI) bleeding despite evidence of benefit to restarting. Objectives We aimed to identify factors influencing health-care provider decision making regarding resuming OAC after GI bleeding and to identify preference groups. Patients/Methods We conducted focus group discussions (FGDs) with health-care providers. Themes identified and ranked through a dot voting exercise became the attributes for a discrete choice experiment survey of health-care providers developed using Sawtooth (Sawtooth Software, Provo, UT, USA). Hierarchical Bayes analysis was used to estimate preference coefficients (utilities) for each attribute. Preference groups were identified using latent class analysis. Results We conducted four FGDs involving 29 participants. The five most important factors identified in the FGDs were included in the survey. There were 250 survey respondents (mean age 45 years, 53% male). The most important factor was re-bleeding risk followed by thrombosis risk, index bleed severity, indication for OAC, and patient characteristics. Two preference groups were identified, a majority group (87% of respondents) placed the highest utility on re-bleeding risk followed by thrombosis risk, while a minority group (13% of respondents) placed the highest utility on OAC indication. Conclusions Overall, the most important factor influencing provider decision making was re-bleeding risk followed closely by thrombosis risk, although the indication for OAC was most important for a minority of respondents. This highlights variability among providers in an area lacking high-quality data to guide practice. Further research is needed to determine absolute rates of outcomes and patient values and preferences.

Oral anticoagulants (OACs) are high alert medications and require high-quality management to optimize health outcomes. The objective of this scoping review was to identify barriers and facilitators (BFs) associated with the quality of OAC management. We searched MEDLINE, EMBASE, and CINAHL databases until July 12, 2018, and cross-referenced the bibliographies of the retrieved studies. We included quantitative and qualitative studies that assessed BFs to OAC management. The study selection and data extraction processes were performed in duplicate. Analyses included measuring the prevalence of reported BFs from studies reporting quantitative data, identifying BFs in narrative analyses, and identifying their impact on important outcomes of OAC management. BFs were coded and aggregated to higher-level themes using a consensus approach. Factors were described as "key" if they were statistically associated with important outcomes in a randomized trial or observational study. We included 62 studies-three randomized clinical trials (RCTs), 46 observational studies (cross-sectional studies, cohort studies, and case-control studies), 11 qualitative studies, and two mixed-methods studies. Factors identified could be grouped into four themes-therapy-related, patient-related, healthcare provider-related, and health system-related. Key barriers to optimal OAC management were mostly patient-related, whereas interventions focused on education or implementing protocols were shown through RCTs to be effective at improving knowledge scores of OAC patients. While multiple barriers and some facilitators were identified in this review, none was proven to be associated with clinical outcomes. With this in mind, individual physicians may wish to address the key barriers in their practice as a quality improvement initiative but system-wide or policy changes should await high-quality evidence. Future trials should address these factors.Systematic review registration: PROSPERO CRD42017069043.

Background Oral anticoagulants (OAC) are permanently discontinued in up to 50% of patients after gastrointestinal (GI) bleeding despite ongoing thrombotic risk and evidence of benefit to restarting. The reasons for permanent discontinuation of OAC are unclear, but likely include concerns about re-bleeding and a lack of high-quality evidence. There are no studies evaluating healthcare provider values and preferences following OAC-related GI bleeding and their influence on decision-making about whether and when to resume OACs. Aims We aimed to (i) identify key factors (attributes) that influence healthcare provider decision-making regarding resumption of OAC after GI bleeding, (ii) determine the relative importance of these attributes, and (iii) to identify preference groups. Methods We conducted focus group discussions (FGD) with healthcare providers involved in the care of patients with OAC-related GI bleeding. Participants ranked the relative importance of the attributes identified during the FGD through a dot voting exercise. Transcripts were reviewed and themes (attributes) were identified. Results of the FGD informed a discrete choice experiments survey developed and analyzed using the Sawtooth software platform (Sawtooth Software, USA). The survey was pilot tested and modified by iterative feedback. A sample choice task is shown in Image 1. Hierarchical Bayes analysis was used to estimate preference coefficients (utilities) for each attribute. Latent class analysis was used to identify preference groups. Results There were 4 FGD involving 29 participants. The most important attributes identified and included in the survey were thrombosis risk, indication for OAC, index bleed severity, re-bleeding risk, and patient characteristics. There were 130 survey respondents practicing in hematology (n=68), internal medicine (n=30), gastroenterology (n=7), cardiology (n=4), family medicine (n=3), and others (n=18). The mean age was 45 years (±11) and 51% were male. Thrombosis risk and re-bleeding risk equally had the highest utility followed by index bleed severity, patient characteristics, and indication for OAC. Two preference groups were identified. The dominant preference group (78% of respondents) placed the highest utility on thrombosis risk and re-bleeding risk, while a minority (22% of respondents) placed the highest utility on index bleed severity. Conclusions Thrombosis risk and re-bleeding risk are equally the most important factors influencing OAC resumption following OAC-related GI bleeding. The severity of the index bleed is the most important factor in decision-making for a minority segment of healthcare providers. Further research on the dose, type and timing of OAC resumption is needed to determine the optimal balance between thrombosis and re-bleeding. Funding Agencies Heart and Stroke Foundation