Benzodiazepines and sedative hypnotics such as zolpidem (“z-drugs”) are commonly prescribed for anxiety and sleep disorders. Epidemiologic evidence links their use to increased risk of venous thromboembolism. We investigated venous thromboembolism risk among concomitant users of individual benzodiazepines/z-drugs (examined separately) with other prescription medications to generate data-driven hypotheses about drug interactions resulting in clinically meaningful harm to inform future etiologic studies of specific drug combinations. We conducted a series of self-controlled case series studies within a 50

BackgroundUsage of medication brand names in electronic health records may introduce conflicts of interest, perpetuate false perceptions of brand superiority, alter prescribing practices, and cause confusion leading to errors. ObjectiveWe sought to identify the frequency of brand name medication usage in clinical documentation, as well as factors associated with increased usage. Designs, Settings, and ParticipantsWe conducted a retrospective analysis of all clinical documentation written at our healthcare system (a multifacility academic urban healthcare system) between 2015 and 2020. Main Outcomes and MeasuresWe used string-matching and regular expressions to identify medication mentions. We conducted bivariate analyses to identify associations between brand name usage and author-, note-, and medication-level factors, and a multivariate Poisson regression to clarify independent associations between individual factors and brand usage. ResultsA total of 104,456,653 notes from 37,285 unique authors were included in our analysis. A total of 162,906,009 medication mentions were identified, of which 36.0% were brand name mentions with a steady year-over-year decrease. Factors associated with the usage of a brand name include: author role, years since release, length and syllabic complexity of the generic name, service type, and encounter context. Over-the-counter availability did not affect usage. There was sizable individual variation between note writers.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999–2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13–0.77) for metaxalone to 3.44 (95% confidence interval: 1.53–7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

Background Studies report hypercoagulability in coronavirus disease 2019 (COVID-19), leading many institutions to escalate anticoagulation intensity for thrombosis prophylaxis. Objective To determine the bleeding risk with various intensities of anticoagulation in critically ill patients with COVID-19 compared with other respiratory viral illnesses (ORVI). Patients/Methods This retrospective cohort study compared the incidence of major bleeding in patients admitted to an intensive care unit (ICU) within a single health system with COVID-19 versus ORVI. In the COVID-19 cohort, we assessed the effect of anticoagulation intensity received on ICU admission on bleeding risk. We performed a secondary analysis with anticoagulation intensity as a time-varying covariate to reflect dose changes after ICU admission. Results Four hundred and forty-three and 387 patients were included in the COVID-19 and ORVI cohorts, respectively. The hazard ratio of major bleeding for the COVID-19 cohort relative to the ORVI cohort was 1.26 (95% confidence interval [CI]: 0.86-1.86). In COVID-19 patients, an inverse-probability treatment weighted model found therapeutic-intensity anticoagulation on ICU admission had an adjusted hazard ratio of bleeding of 1.55 (95% CI: 0.88-2.73) compared with standard prophylactic-intensity anticoagulation. However, when anticoagulation was assessed as a time-varying covariate and adjusted for other risk factors for bleeding, the adjusted hazard ratio for bleeding on therapeutic-intensity anticoagulation compared with standard thromboprophylaxis was 2.59 (95% CI: 1.20-5.57). Conclusions Critically ill patients with COVID-19 had a similar bleeding risk as ORVI patients. When accounting for changes in anticoagulation that occurred in COVID-19 patients, therapeutic-intensity anticoagulation was associated with a greater risk of major bleeding compared with standard thromboprophylaxis.

As the Coronavirus disease 2019 (COVID-19) pandemic spread to the US, so too did descriptions of an associated coagulopathy and thrombotic complications. Hospitals created institutional protocols for inpatient management of COVID-19 coagulopathy and thrombosis in response to this developing data. We collected and analyzed protocols from 21 US academic medical centers developed between January and May 2020. We found greatest consensus on recommendations for heparin-based pharmacologic venous thromboembolism (VTE) prophylaxis in COVID-19 patients without contraindications. Protocols differed regarding incorporation of D-dimer tests, dosing of VTE prophylaxis, indications for post-discharge pharmacologic VTE prophylaxis, how to evaluate for VTE, and the use of empiric therapeutic anticoagulation. These findings support ongoing efforts to establish international, evidence-based guidelines.

Hospitalized patients with acute medical illnesses are at risk for venous thromboembolism (VTE) during and after a hospital stay. Risk factors include physical immobilization and underlying pathophysiologic processes that activate the coagulation pathway and are still present after discharge. Strategies for optimal pharmacologic VTE thromboprophylaxis are evolving, and recommendations for VTE prophylaxis can be further refined to protect high-risk patients after hospital discharge. An early study of extended VTE prophylaxis with a parenteral agent in medically ill patients yielded inconclusive results with regard to efficacy and bleeding. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, extended use of betrixaban halved symptomatic VTE, decreased hospital readmission, and reduced stroke and major adverse cardiovascular events compared with standard enoxaparin prophylaxis. Based on findings from APEX, the Food and Drug Administration approved betrixaban in 2017 for extended VTE prophylaxis in acute medically ill patients. In the Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER) study, extended use of rivaroxaban halved symptomatic VTE in high-risk medical patients compared with placebo. In 2019, rivaroxaban was approved for extended thromboprophylaxis in high-risk medical patients, thus making available a new strategy for in-hospital and post-discharge VTE prevention. To address the critical unmet need for VTE prophylaxis in medically ill patients at the time of hospital discharge, the North American Thrombosis Forum (NATF) is launching the Anticoagulation Action Initiative, a comprehensive consensus document that provides practical guidance and straightforward, patient-centered recommendations for VTE prevention during hospitalization and after discharge.

Drug‐drug interactions (DDIs) with oral anticoagulants may lead to under‐anticoagulation and increased risk of thromboembolism. Although warfarin is susceptible to numerous DDIs, few studies have examined DDIs resulting in thromboembolism or those involving direct‐acting oral anticoagulants (DOACs). We aimed to identify medications that increase the rate of hospitalization for thromboembolic events when taken concomitantly with oral anticoagulants. We conducted a high‐throughput pharmacoepidemiologic screening study using Optum Clinformatics Data Mart, 2000–2016. We performed self‐controlled case series studies among adult users of oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban) with at least one hospitalization for a thromboembolic event. Among eligible patients, we identified all oral medications frequently co‐prescribed with oral anticoagulants as potential interacting precipitants. Conditional Poisson regression was used to estimate rate ratios comparing precipitant exposed vs. unexposed time for each anticoagulant‐precipitant pair. To minimize within‐person confounding by indication for the precipitant, we used pravastatin as a negative control object drug. Multiple estimation was adjusted using semi‐Bayes shrinkage. We screened 1,622 oral anticoagulant‐precipitant drug pairs and identified 226 (14%) drug pairs associated with statistically significantly elevated risk of thromboembolism. Using pravastatin as the negative control object drug, this list was reduced to 69 potential DDI signals for thromboembolism, 33 (48%) of which were not documented in the DDI knowledge databases Lexicomp and/or Micromedex. There were more DDI signals associated with warfarin than DOACs. This study reproduced several previously documented oral anticoagulant DDIs and identified potential DDI signals that deserve to be examined in future etiologic studies.

INTRODUCTION:Risk prediction scores have been devised to identify patients at increased risk for Venous Thromboembolism (VTE) in different patient populations and settings. Guideline recommendations for VTE risk assessment vary greatly. We performed a systematic review to synthesize evidence on clinical risk prediction scores for VTE in hospitalized medical and surgical patients.METHODS:We systematically searched Medline, EMBASE, Cochrane, National Institute of Health and Care Excellence (NICE), National Guidelines Clearinghouse (NGC), and Guidelines International Network (GIN) databases up to March 2016. We included studies validating risk prediction scores for adult hospitalized patients. We excluded studies for any of the following reasons: non-English publication, conducted in non-OECD (Organisation for Economic Co-operation and Development) countries, validation cohorts focused solely on critical care patients, or scores developed for specific surgical or medical sub-specialty populations. We plotted receiver operating characteristic (ROC) curves of included studies and performed summary ROC meta-analyses for scores in which >1 external validation studies were combinable. Risk of bias was assessed qualitatively. We assessed the strength of the evidence base using Grading of Recommendations Assessment, Development and Evaluation (GRADE).RESULTS:We screened 110 primary studies and included 18 of those for analysis. There were seven studies of the Caprini score, three studies of the Padua score, two studies of the IMPROVE score; and one study each of the Arcelus, Geneva, Khorana, RAP, and Kucher scores . Strength of evidence was downgraded for study risk of bias because most studies disproportionately included patients at high risk of VTE. Our summary estimates of the performance of the three combinable scores at clinically-relevant thresholds are: Caprini score at a threshold of three in surgical patients – 96 percent sensitivity, 44 percent specificity; IMPROVE at a threshold of one in medical patients – 96 percent sensitivity, 20 percent specificity; and Padua at a threshold of 4–87 percent sensitivity and 58 percent specificity.CONCLUSIONS:There is moderate strength evidence for use of the Caprini score to predict VTE in surgical patients and for the Padua and IMPROVE scores in medical patients. Lower thresholds may be warranted to achieve sufficient sensitivity to identify low risk populations who may not require routine VTE prophylaxis. Studies making direct comparisons of risk prediction scores in similar patient populations are lacking and are necessary to ascertain which score is most effective.

Objective: Venous thromboembolism (VTE) is a potentially preventable complication following surgery. There is variation with regard to the most effective mode of prophylaxis. We sought to determine if an aggressive approach to VTE prophylaxis would reduce VTE rates on the inpatient vascular surgical service.Methods: Vascular inpatients from a single institution from July 2010 to March 2013 were included in the analysis. A protocol for VTE prophylaxis was implemented on the inpatient vascular surgical service in November 2011. This included subcutaneous (SQ) heparin initiation within 24h of admission unless deemed inappropriate by the attending, as well as intermittent compression devices (ICD) and compression stockings (CS). The rate of VTE was compared prior to and following the intervention. Patients were compared using AHRQ comorbidity categories, APR-DRG severity of illness, insurance status, and principle procedure. T-tests were used to compare continuous variables and chi-square analysis used to compare categorical variables.Results: There were 1483 vascular patients in the pre-intervention group and 1652 patients in the post-intervention group. The rate of pharmacologic prophylaxis was 52.57% pre-intervention compared to 69.33% post-intervention (p<0.001). The rate of pharmacologic or mechanical prophylaxis was 91.76% pre-intervention compared to 93.10% post-intervention (p=0.54). The overall rate of VTE prior to the intervention was 1.49% compared to after intervention which was 0.38% (p=0.033). The DVT rate prior to intervention was 1.09% vs 0.189% after intervention (p=0.0214). The rate of pulmonary embolism trended towards a significant reduction with the intervention (0.681% vs 0.189%, p=0.095). There were no statistically significant differences in patient groups based on gender, comorbidity category, severity of illness, or insurance type.Conclusions: The overall rate of VTE was reduced by 75% after the initiation of a standard protocol for pharmacologic VTE prophylaxis. These findings justify an aggressive approach to VTE prophylaxis in vascular surgery patients.

BACKGROUND:Pharmacological thromboprophylaxis is necessary among many hospitalised patients to prevent venous thromboembolism (VTE). However, a significant number of clinician-ordered doses are not administered with many doses refused by patients. We aimed to assess the impact and sustainability of a multifaceted intervention to improve medication adherence to pharmacological thromboprophylaxis. The intervention included a standardised nursing response to patient refusal, daily assessment of VTE prophylaxis usage and regular feedback on refusal rates. METHODS:We conducted a quasi-experimental study of patients admitted between January 2010 and November 2012 to one of six hospital intervention units (three medical and three oncology units) or five control units. The primary outcome was the proportion of VTE prophylaxis doses missed for any reason. RESULTS:A total of 20,208 admissions occurred at the six hospital units during the study period. In the pre-post analysis, the rate of missed and refused doses decreased significantly after the intervention (24.7% to 14.7% and 18.3% to 9.4%, respectively; p value <0.01 for both comparisons). In multiple regression models with interrupted time series analysis, the intervention was associated with an immediate and sustained decrease in missed (adjusted OR 0.64; 95% CI 0.55 to 0.74 and 0.98; 95%CI 0.97 to 0.99) and refused doses (adjusted OR per month 0.58; 95% CI 0.48 to 0.71 and 0.97; 95%CI 0.96 to 0.98). No immediate or sustained reduction in missed or refused doses was observed in the control units. CONCLUSIONS:Implementation of a multifaceted intervention resulted in an immediate and sustained decrease in the proportion of missed and refused doses of pharmacological thromboprophylaxis. Efforts aimed at increasing patient adherence are a promising approach to improve rates of VTE thromboprophylaxis administration.

PurposeThe aim of this study was to summarize randomized controlled trials (RCTs) of nonpharmacologic interventions for prevention of catheter-related thromboses (CRTs).MethodsMEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials were systematically searched for RCTs examining any nonpharmacologic intervention to prevent symptomatic or asymptomatic CRT. Titles and abstracts were screened by a single reviewer, followed by full-text screening by 2 independent reviewers. Data were extracted and quality assessed by a single analyst and audited by a second analyst. Strength of the evidence for each intervention was assessed using the Grading of Recommendations Assessment, Development and Evaluation.ResultsTen RCTs enrolling 1,378 patients were included. Moderate- to high-quality evidence suggested peripherally inserted central catheters and insertion of central venous catheters (CVCs) at the femoral site increased CRT when compared with other catheter types or insertion sites, respectively. Evidence comparing CRT in CVCs inserted at the jugular vs the subclavian site as well as the placement of the CVC tip was of low quality and inconclusive. Low-quality evidence suggested that valved ports and silver-coated catheters had no effect on CRT. No RCT evidence was identified for other interventions.ConclusionsPeripherally inserted central catheters and femoral insertion of CVCs should be avoided if possible. Randomized controlled trials are needed to ascertain the effects of other nonpharmacologic interventions to prevent CRT.

Background: Venous thromboembolism (VTE) causes morbidity and mortality in hospitalized patients, and regulators and payors are encouraging the use of systems to prevent them. Here, we examine the effect of a computerized clinical decision support (CDS) intervention implemented across a multi-hospital academic health system on VTE prophylaxis and events.Methods: The study included 223,062 inpatients admitted between April 2007 and May 2010, and used administrative and clinical data. The intervention was integrated into a commercial electronic health record (EHR) in an admission orderset used for all admissions. Three time periods were examined: baseline (period 1), and the time after implementation of the first CDS intervention (period 2) and a second iteration (period 3). Providers were prompted to accept or decline prophylaxis based on patient risk. Time series analyses examined the impact of the intervention on VTE prophylaxis during time periods two and three compared to baseline, and a simple pre-post design examined impact on VTE events and bleeds secondary to anticoagulation. VTE prophylaxis and events were also examined in a prespecified surgical subset of our population meeting the public reporting criteria defined by the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator (PSI).Results: Unadjusted analyses suggested that "recommended", "any", and "pharmacologic" prophylaxis increased from baseline to the last study period (27.1% to 51.9%, 56.7% to 78.1%, and 42.0% to 54.4% respectively; p < 0.01 for all comparisons). Results were significant across all hospitals and the health system overall. Interrupted time series analyses suggested that our intervention increased the use of "recommended" and "any" prophylaxis by 7.9% and 9.6% respectively from baseline to time period 2 (p < 0.01 for both comparisons); and 6.6% and 9.6% respectively from baseline to the combined time periods 2 and 3 (p < 0.01 for both comparisons). There were no significant changes in "pharmacologic" prophylaxis in the adjusted model. The overall percent of patients with VTE increased from baseline to the last study period (2.0% to 2.2%; p = 0.03), but an analysis excluding patients with VTE "present on admission" (POA) demonstrated no difference in events (1.3% to 1.3%; p = 0.80). Overall bleeds did not significantly change. An analysis examining VTE prophylaxis and events in a surgical subset of patients defined by the AHRQ PSI demonstrated increased "recommended", "any", and "pharmacologic" prophylaxis from baseline to the last study period (32.3% to 60.0%, 62.8% to 85.7%, and 47.9% to 63.3% respectively; p < 0.01 for all comparisons) as well as reduced VTE events (2.2% to 1.7%; p < 0.01).Conclusions: The CDS intervention was associated with an increase in "recommended" and "any" VTE prophylaxis across the multi-hospital academic health system. The intervention was also associated with increased VTE rates in the overall study population, but a subanalysis using only admissions with appropriate POA documentation suggested no change in VTE rates, and a prespecified analysis of a surgical subset of our sample as defined by the AHRQ PSI for public reporting purposes suggested reduced VTE. This intervention was created in a commonly used commercial EHR and is scalable across institutions with similar systems.

BackgroundPrevious research has suggested that daily lottery incentives could improve medication adherence. Such daily incentives include implicit reminders. However, the comparative effectiveness of reminders alone versus daily incentives has not been tested.MethodsA total of 270 patients on warfarin were enrolled in a four-arm, multi-center, randomized controlled trial comparing a daily lottery-based incentive, a daily reminder, and a combination of the two against a control group (usual care).ResultsParticipants in the reminder group had the lowest percentage of time out of target international normalized ratio (INR) range, the primary outcome, with an adjusted odds of an out-of-range INR 36% lower than among those in the control group, 95%CI [7%, 55%]. No other group had a statistically significant improvement in anticoagulation control relative to the control group or to each other. The only group that had significant improvement in incorrect adherence was the lottery group (incorrect adherence: 12.1% compared with 23.7% in the control group, difference of -7.4% 95%CI [-14%, -0.3%]). However, there was no relationship between changes in adherence and anticoagulation control in the lottery group.ConclusionsAutomated reminders led to the largest improvements in anticoagulation control, although without impacting measured adherence. Lottery-based reminders improved measured adherence but did not lead to improved anticoagulation control. Copyright (c) 2016 John Wiley & Sons, Ltd.