Genotype-guided drug prescribing vs. usual care reduced clinically relevant adverse drug reactions at 12 wk.

SOURCE CITATION: Swen JJ, van der Wouden CH, Manson LE, et al; Ubiquitous Pharmacogenetics Consortium. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet. 2023;401:347-356. 36739136.

Comparability of Objective Structured Clinical Examinations (OSCEs) and Written Tests for Assessing Medical School Students' Competencies: A Scoping Review.

Objective Structured Clinical Examinations (OSCEs) and written tests are commonly used to assess health professional students, but it remains unclear whether the additional human resources and expenses required for OSCEs, both in-person and online, are worthwhile for assessing competencies. This scoping review summarized literature identified by searching MEDLINE and EMBASE comparing 1) OSCEs and written tests and 2) in-person and online OSCEs, for assessing health professional trainees' competencies. For Q1, 21 studies satisfied inclusion criteria. The most examined health profession was medical trainees (19, 90.5%), the comparison was most frequently OSCEs versus multiple-choice questions (MCQs) (18, 85.7%), and 18 (87.5%) examined the same competency domain. Most (77.5%) total score correlation coefficients between testing methods were weak (r < 0.40). For Q2, 13 articles were included. In-person and online OSCEs were most used for medical trainees (9, 69.2%), checklists were the most prevalent evaluation scheme (7, 63.6%), and 14/17 overall score comparisons were not statistically significantly different. Generally low correlations exist between MCQ and OSCE scores, providing insufficient evidence as to whether OSCEs provide sufficient value to be worth their additional cost. Online OSCEs may be a viable alternative to in-person OSCEs for certain competencies where technical challenges can be met.

Coordination of Oral Anticoagulant Care at Hospital Discharge (COACHeD): protocol for a pilot randomised controlled trial.

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.

In healthy older adults, daily aspirin increased cancer mortality.

SOURCE CITATION: McNeil JJ, Gibbs P, Orchard SG, et al. Effect of aspirin on cancer incidence and mortality in older adults. J Natl Cancer Inst. 2021;113:258-65. 32778876.

Cost-related medication nonadherence in Canada: a systematic review of prevalence, predictors, and clinical impact.

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.

USPSTF recommends asking adults screening questions about unhealthy drug use.

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.

Evaluation of online clinical pharmacology curriculum resources for medical students.

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.

Healthcare resource utilization and costs among patients with direct oral anticoagulant or warfarin-related major bleeding.

INTRODUCTION: Direct oral anticoagulants (DOACs) have expanded the options for antithrombotic therapy. DOAC-related major bleeds are associated with favorable outcomes compared to warfarin in clinical trials and routine practice. However, it is unclear whether management of DOAC-associated major bleeding incurs higher resource utilization and costs. MATERIALS AND METHODS: We screened medical records of patients ≥ 66 years with atrial fibrillation admitted to one of five tertiary care hospitals in Ontario, Canada with a hemorrhage. We abstracted bleeds involving DOACs or warfarin and linked them to administrative databases to capture length of hospital stay, blood product use, procedural interventions, intensive care unit (ICU) utilization and related direct medical costs. To control for confounders, multivariate logistic and linear regressions were used for binary and linear outcomes respectively. RESULTS: Among 19,061 records screened, 1978 (10.4%) cases involving 1632 patients met criteria of oral anticoagulant-associated bleeding. Baseline characteristics between DOAC and warfarin groups were similar. Blood product costs were higher for DOACs (all comparisons DOACs vs. warfarin, $1456 vs. $1109, mean difference $347, 95% CI $185 to $509), but length of stay and ICU use were similar. Mean direct medical costs did not differ ($9217 vs. $10,790, adjusted relative ratio 0.94, 95% CI 0.84-1.05). CONCLUSIONS: Prior to introduction of DOAC-specific reversal agents, resource utilization and medical costs were comparable between DOAC- and warfarin-associated major bleeds, despite marginally higher blood product costs incurred by the former. Resource intensity associated with anticoagulant-related bleeding remains high, and our data provide measures for cost-effectiveness evaluation of emerging DOAC antidotes.

Deprescribing benzodiazepine receptor agonists taken for insomnia: a review and key messages from practice guidelines.

Long­term benzodiazepine receptor agonist (BZRA) use for insomnia is common and highly prevalent in adults in all care settings. Evidence syntheses suggest that the therapeutic benefits of benzodiazepines for insomnia are marginal and very short term. On the harm side, BZRAs are associated with daytime sedation and confusion. Long­term use increases the risk of falls, fractures, cognitive impairment, and motor vehicle accidents. An evidence­based clinical practice guideline has been developed to assist with deprescribing BZRAs. This review highlights the rationale for deprescribing BZRAs used for insomnia and summarizes key messages for clinicians from the new BZRA deprescribing guideline and their supporting evidence.

Patterns of borrowing to finance out-of-pocket prescription drug costs in Canada: a descriptive analysis.

BACKGROUND: Out-of-pocket drug costs lead many Canadians to engage in cost-related nonadherence to prescription medications, but our understanding of other consequences such as borrowing money remains incomplete. In this descriptive study, we sought to quantify the frequency of borrowing to pay for prescription drugs in Canada and characteristics of Canadians who borrowed money for this purpose. METHODS: In partnership with Statistics Canada, we designed and administered a cross-sectional rapid-response module in the Canadian Community Health Survey administered by telephone to Canadians aged 12 years or more between January and June 2016. We restricted our analyses to participants who responded to the question regarding borrowing money to pay for prescription drugs and used logistic regression to identify characteristics associated with borrowing. RESULTS: A total of 28 091 Canadians responded to the survey (overall response rate 61.8%). The weighted proportion of respondents who reported having borrowed money to pay for prescription drugs in the previous year was 2.5% (95% confidence interval 2.2%-2.8%), an estimated 731 000 Canadians. The odds of borrowing were higher among younger adults, people in poor health and people lacking prescription drug insurance. Other factors associated with increased adjusted odds of borrowing were having 2 or more chronic conditions, low household income and higher out-of-pocket prescription drug costs. INTERPRETATION: Many Canadians reported borrowing money to pay for out-of-pocket prescription drug costs, and borrowing was more prevalent among already vulnerable groups that also report other compensatory behaviours to address challenges in paying for prescription drugs. Future research should investigate policy responses intended to increase equity in access to prescription drugs.

The consequences of patient charges for prescription drugs in Canada: a cross-sectional survey.

BACKGROUND: Many Canadians face substantial out-of-pocket charges for prescription drugs. Prior work suggests that this causes some patients to not take their medications as prescribed; however, we have little understanding of whether charges for prescription medicines lead patients to forego basic needs or to use more health care services. Our study aimed to quantify the consequences of patient charges for medicines in Canada. METHODS: As part of the 2016 Canadian Community Health Survey, we designed and fielded cross-sectional questions to 28 091 Canadians regarding prescription drug affordability, consequent use of health care services and trade-offs with other expenditures. We calculated weighted population estimates and proportions, and used logistic regression to determine which patient characteristics were associated with these behaviours. RESULTS: Overall, 5.5% (95% confidence interval 5.1%-6.0%) of Canadians reported being unable to afford 1 or more drugs in the prior year, representing 8.2% of those with at least 1 prescription. Drugs for mental health conditions were the most commonly reported drug class for cost-related nonadherence. About 303 000 Canadians had additional doctor visits, about 93 000 sought care in the emergency department, and about 26 000 were admitted to hospital at the population level. Many Canadians forewent basic needs such as food (about 730 000 people), heat (about 238 000) and other health care expenses (about 239 000) because of drug costs. These outcomes were more common among females, younger adults, Aboriginal peoples, those with poorer health status, those lacking drug insurance and those with lower income. INTERPRETATION: Out-of-pocket charges for medicines for Canadians are associated with foregoing prescription drugs and other necessities as well as use of additional health care services. Changes to protect vulnerable populations from drug costs might reduce these negative outcomes.

Managing High-Cost Healthcare Users: The International Search for Effective Evidence-Supported Strategies.

High-cost healthcare users (HCUs) are a small proportion of the population who use a disproportionate amount of healthcare resources. Although the phenomenon occurs across the entire age spectrum, older adults represent the majority of HCUs. HCUs have drawn increasing attention internationally from clinicians, health policy-makers, and government administrators. Many experts have suggested that the short- and long-term sustainability of the healthcare system is threatened unless current approaches to the care and healthcare costs of this population are modified. Complex case management and care coordination models are being implemented internationally to address HCUs despite a lack of strong evidence to support their effectiveness in improving clinical outcomes or savings in costs of care. We review what is known about HCUs and the available evidence for the effectiveness of interventions designed to manage their high and costly healthcare use.

Understanding the patient experience of cost-related non-adherence to prescription medications through typology development and application.

Many patients report skipping doses, splitting pills, or not filling prescriptions due to out-of-pocket costs-a phenomenon known as cost-related non-adherence (CRNA). This study investigated CRNA from the patient's perspective, and, to our knowledge, is the first study to undertake a qualitative investigation of CRNA specifically. We report the results from 35 semi-structured interviews conducted in 2014-15 with adults in four Canadian cities across two provinces. We used framework analysis to develop a CRNA typology to characterize major factors in patients' CRNA decisions. Our typology identifies four major components: (1) the insurance reason driving the drug cost, (2) the individual's overall financial flexibility, (3) the burden of drug cost on the individual's budget, and (4) the importance of the drug from the individual's perspective. The first two components set the context for CRNA and the final two components are the drivers for the CRNA decision. We also found four major patterns in CRNA experiences: (1) CRNA in individuals with low financial flexibility occurred for all levels of drug importance and all but the lowest level of cost burden; (2) CRNA for high importance drugs only occurred when the drug cost had a high burden on an individual's budget; (3) CRNA in individuals with more financial flexibility primarily occurred in drugs with medium importance but high or very high cost burdens; and (4) CRNA for low importance drugs occurred at almost all levels of drug cost burden. Our study furthers the understanding of how numerous factors such as income, insurance, and individual preferences combine and interact to influence CRNA and suggests that policy interventions must be multi-faceted or encourage significant insurance redesign to reduce CRNA.

Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study.

BACKGROUND: Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC-related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in < 40% of cases, raising concerns about the generalizability of this finding. METHODS: Consecutive patients ≥ 66 years presented to five tertiary care hospitals across three cities in Ontario, Canada from October 2010 to March 2015 with diagnoses that included hemorrhage. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases. RESULTS: Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19-2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49-0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61-1.03). CONCLUSIONS: In this unselected cohort of patients with oral anticoagulant-related hemorrhage with high rates of warfarin reversal, in-hospital mortality was lower among DOAC-associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents.

Successful reintroduction of statin therapy after statin-associated rhabdomyolysis.

The case report demonstrates the successful use of an alternative statin after a statin-related episode of rhabdomyolysis. Statin-associated rhabdomyolysis is a serious adverse event with a very low incidence and is considered the most severe of the muscle-related side effects of the statins. Rechallenge with statins is not a recommended practice after rhabdomyolysis. The patient experienced a myocardial infarct 1 y after the episode of rhabdomyolysis. He used alternative lipid-lowering therapy for 2 y. His low-density lipoprotein cholesterol was not meeting typical secondary prevention targets. An alternative statin was introduced and the patient has been followed for 4 years without recurrence of the rhabdomyolysis. This case suggests it may be time to reconsider the accepted practice of permanently avoiding statin therapy after rhabdomyolysis.

Integrating Clinical Decision Support into EMR and PHR: a Case Study Using Anticoagulation.

Clinical decision support (CDS) for atrial fibrillation is expected to ease the implementation of often-complex guidelines for atrial fibrillation and anticoagulation. Most clinical decision support systems (CDSS) for anticoagulation are stand-alone systems that do not integrate with electronic medical records (EMR). We have developed an architecture that consists of a computerized CDS that can integrate with multiple EMRs and multiple patient health records (PHRs). The design process revealed some significant issues that were resolved through systematic business/clinical analysis and creative clinical design in the diagnostic and treatment domains. Key issues identified and resolved include: 1) how to correctly allocate existing patients into various CDSS states (e.g., MAINTENANCE, HOLD, DISCONTINUE, etc), 2) identify when a patient becomes eligible for CDSS guidance over time, 3) how the CDSS maintains information about the patient's anticoagulation state and 4) how to transform vague human-readable concepts to explicit computable concepts. The management of anticoagulation for atrial fibrillation is no easy task and we believe our architecture will improve patient care at all levels and ultimately better balance the reduction of stroke risk while minimizing harms from major bleeding. In addition, the architecture presented is scalable to other treatment guidelines and is scalable to multiple EMRs and PHRs, making it suitable for use in a platform approach.

Anticoagulation control with daily low-dose vitamin k to reduce clinically adverse outcomes and international normalized ratio variability: a systematic review and meta-analysis.

STUDY OBJECTIVES: Difficulties managing warfarin therapy have led to speculation that daily supplementation with a low dose of vitamin K might improve anticoagulation control and clinical outcomes. Thus we sought to review the available medical literature systematically examining the effectiveness of low-dose vitamin K supplementation for the reduction of clinically relevant adverse events due to vitamin K antagonist (VKA) use and for stabilization of the international normalized ratio (INR). DESIGN: We searched the Medline and Embase databases, the Cochrane Library, International Pharmaceutical Abstracts, and the U.S. National Institutes of Health clinical trials registry for randomized controlled trials of vitamin K supplementation versus placebo in patients receiving a VKA. We evaluated the outcomes of hemorrhage, thromboembolic events, and percentage of time in therapeutic range (TTR) of INRs by using the Grading of Recommendations Assessment, Development and Evaluation system for rating quality of evidence in the abstracted studies. SETTING: All randomized controlled trials studies published between 1970 and August 2012 which fitted our search strategy. PATIENTS: Patients over the age of 18 years on VKA therapy. RESULTS: Of the 624 studies we identified and screened, three studies (626 patients) were included in the meta-analysis. Most of the patients had a satisfactory TTR at baseline. We found low-quality evidence--downgraded for imprecision and risk of bias (i.e., limitation in study design and/or execution)--of no effect of vitamin K use (100 to 200 µg) on hemorrhagic events (relative risk [RR] 3.2, 95% confidence interval [CI] 0.2-64.2) and thromboembolic events (RR 2.2, 95% CI 0.1-47.5) and a significant but clinically unimportant effect on TTR with an absolute increase of 3.5% (95% CI 1.1-6.0). CONCLUSION: This meta-analysis, despite the few studies and overall low quality, suggests no beneficial role of low-dose (100 to 200 µg) vitamin K supplementation on the reduction of clinically relevant adverse events in patients taking VKAs, despite a small improvement of the TTR. Data were insufficient, however, from patients with unstable INRs.

Hospitalization for hemorrhage among warfarin recipients prescribed amiodarone.

Amiodarone inhibits the hepatic metabolism of warfarin, potentiating its anticoagulant effect. However, the clinical consequences of this are not well established. Our objective in this study was to characterize the risk of hospitalization for a hemorrhage associated with the initiation of amiodarone within a cohort of continuous warfarin users in Ontario. We conducted a population-based retrospective cohort study among Ontario residents aged ≥66 years receiving warfarin. Among patients with at least 6 months of continuous warfarin therapy, we identified those who were newly prescribed amiodarone and an equal number who were not, matching on age, gender, year of cohort entry, and a high-dimensional propensity score. The primary outcome was hospitalization for hemorrhage within 30 days of amiodarone initiation. Between July 1, 1994, and March 31, 2009, we identified 60,497 patients with at least 6 months of continuous warfarin therapy, of whom 11,665 (19%) commenced amiodarone. For 7,124 (61%) of these, we identified a matched control subject who did not receive amiodarone. Overall, 56 (0.8%) amiodarone recipients and 23 (0.3%) control patients were hospitalized for hemorrhage within 30 days of initiating amiodarone (adjusted hazard ratio 2.45; 95% confidence interval, 1.49-4.02). Seven of 56 (12.5%) patients hospitalized for a hemorrhage after starting amiodarone died in hospital. In conclusion, initiation of amiodarone among older patients receiving warfarin is associated with a more than twofold increase in the risk of hospitalization for hemorrhage, with a relatively high fatality rate. Physicians should closely monitor patients who initiate amiodarone while receiving warfarin.

Rates of hemorrhage during warfarin therapy for atrial fibrillation.

BACKGROUND: Although warfarin has been extensively studied in clinical trials, little is known about rates of hemorrhage attributable to its use in routine clinical practice. Our objective was to examine incident hemorrhagic events in a large population-based cohort of patients with atrial fibrillation who were starting treatment with warfarin. METHODS: We conducted a population-based cohort study involving residents of Ontario (age ≥ 66 yr) with atrial fibrillation who started taking warfarin between Apr. 1, 1997, and Mar. 31, 2008. We defined a major hemorrhage as any visit to hospital for hemorrage. We determined crude rates of hemorrhage during warfarin treatment, overall and stratified by CHADS(2) score (congestive heart failure, hypertension, age ≥ 75 yr, diabetes mellitus and prior stroke, transient ischemic attack or thromboembolism). RESULTS: We included 125 195 patients with atrial fibrillation who started treatment with warfarin during the study period. Overall, the rate of hemorrhage was 3.8% (95% confidence interval [CI] 3.8%-3.9%) per person-year. The risk of major hemorrhage was highest during the first 30 days of treatment. During this period, rates of hemorrhage were 11.8% (95% CI 11.1%-12.5%) per person-year in all patients and 16.7% (95% CI 14.3%-19.4%) per person-year among patients with a CHADS(2) scores of 4 or greater. Over the 5-year follow-up, 10 840 patients (8.7%) visited the hospital for hemorrhage; of these patients, 1963 (18.1%) died in hospital or within 7 days of being discharged. INTERPRETATION: In this large cohort of older patients with atrial fibrillation, we found that rates of hemorrhage are highest within the first 30 days of warfarin therapy. These rates are considerably higher than the rates of 1%-3% reported in randomized controlled trials of warfarin therapy. Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policy-makers as new options for treatment become available.