Search

Background: Whether clinicians should decrease the warfarin dose in response to a mild, asymptomatic elevation in the international normalized ratio (INR) is unknown.Objectives: The study objectives were as follows: (1) to evaluate the safety of an anticoagulation service (ACS) policy advocating that the warfarin dose not be changed for isolated, asymptomatic INRs of < or = 3.4; (2) to compare the dosing strategies of an ACS and primary care providers (PCPs); and (3) to quantify the relationship between reduction of the warfarin dose and the subsequent fall in the INR.Design and Setting: Randomized controlled study of health maintenance organization outpatients who were receiving warfarin.Patients: We identified 231 patients with a target INR of 2.5 and an isolated, asymptomatic INR between 3.2 and 3.4. Our ACS monitored 103 of the patients; PCPs monitored the remaining 128 patients.Measurements: From all 231 patients, we obtained INRs and warfarin dosing history. From the 103 ACS enrollees, we also recorded adverse events.Results: One ACS patient had epistaxis in the 30 days after the elevated INR. Twenty-three percent of ACS enrollees and 47% of PCP patients reduced their warfarin dose (p < 0.001). The median follow-up INRs were similar in both cohorts: 2.7 in the ACS enrollees and 2.6 in the PCP patients. However, in a subgroup analysis of 190 patients who presented with an INR of 3.2 or 3.3, ACS enrollees were more likely to have a follow-up INR in the range of 2 to 3 (p = 0.03). The median follow-up INR was 2.7 in 148 patients who maintained their warfarin dose, 2.5 in 77 patients who decreased their dose by 1 to 20%, and 1.7 in 6 patients who decreased their dose by 21 to 43% (p < 0.001).Conclusions: These findings support maintaining the same warfarin dose in asymptomatic patients with an INR of < or = 3.3, and reducing the dose for patients who have a greater INR or an increased risk of hemorrhage. Warfarin dose reductions > 20% should be avoided for mildly elevated INRs. [ABSTRACT FROM AUTHOR]

Context: Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions.Objective: To assess the predictive value of classification schemes that estimate stroke risk in patients with AF.Design, Setting, and Patients: Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS( 2) index, and all 3 classification schemes were validated. The CHADS( 2) was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge.Main Outcome Measure: Hospitalization for ischemic stroke, determined by Medicare claims data.Results: During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], 0.65-0.71) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, 0.71-0.76) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, 0.80-0.84), the CHADS( 2) index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, 1.3-1.7) for each 1-point increase in the CHADS( 2) score: 1.9 (95% CI, 1.2-3.0) for a score of 0; 2.8 (95% CI, 2.0-3.8) for 1; 4.0 (95% CI, 3.1-5.1) for 2; 5.9 (95% CI, 4.6-7.3) for 3; 8.5 (95% CI, 6.3-11.1) for 4; 12.5 (95% CI, 8.2-17.5) for 5; and 18.2 (95% CI, 10.5-27.4) for 6.Conclusion: The 2 existing classification schemes and especially a new stroke risk index, CHADS( 2), can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy. [ABSTRACT FROM AUTHOR]

Objective: To examine the cost-effectiveness of prescribing warfarin sodium in patients who have nonvalvular atrial fibrillation (NVAF) with or without additional stroke risk factors (a prior stroke or transient ischemic attack, diabetes, hypertension, or heart disease).Design: Decision and cost-effectiveness analyses. The probabilities for stroke, hemorrhage, and death were obtained from published randomized controlled trials. The quality-of-life estimates were obtained by interviewing 74 patients with atrial fibrillation. Costs were estimated from literature review, phone survey, and Medicare reimbursement.Patients: In the base case, the patients were 65 years of age and good candidates for warfarin therapy.Interventions: Treatment with warfarin, aspirin, or no therapy in the decision analytic model.Main Outcome Measures: Quality-adjusted survival and marginal cost-effectiveness of warfarin as compared with aspirin or no therapy.Results: For patients with NVAF and additional risk factors for stroke, warfarin therapy led to a greater quality-adjusted survival and to cost savings. For patients with NVAF and one additional risk factor, warfarin therapy cost $8000 per quality-adjusted life-year saved. For 65-year-old patients with NVAF alone, warfarin cost about $370,000 per quality-adjusted life-year saved, as compared with aspirin therapy. However, for 75-year-old patients with NVAF alone, prescribing warfarin cost $110,000 per quality-adjusted life-year saved. For patients who were not prescribed warfarin, aspirin was preferred to no therapy on the basis of both quality-adjusted survival and cost in all patients, regardless of the number of risk factors present.Conclusions: Treatment with warfarin is cost-effective in patients with NVAF and one or more additional risk factors for stroke. In 65-year-old patients with NVAF but no other risk factors for stroke, prescribing warfarin instead of aspirin would affect quality-adjusted survival minimally but increase costs significantly. [ABSTRACT FROM AUTHOR]

Background: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin.Methods: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples.Results: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination.Conclusions: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to determine whether genotype testing for patients initiating warfarin treatment will reduce the incidence of hospitalizations, including those due to bleeding or thromboembolism.Background: Genotypic variations in CYP2C9 and VKORC1 have been shown to predict warfarin dosing, but no large-scale studies have prospectively evaluated the clinical effectiveness of genotyping in naturalistic settings across the U.S.Methods: This national, prospective, comparative effectiveness study compared the 6-month incidence of hospitalization in patients receiving warfarin genotyping (n = 896) versus a matched historical control group (n = 2,688). To evaluate for temporal changes in the outcomes of warfarin treatment, a secondary analysis compared outcomes for 2 external control groups drawn from the same 2 time periods.Results: Compared with the historical control group, the genotyped cohort had 31% fewer hospitalizations overall (adjusted hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.58 to 0.82, p < 0.001) and 28% fewer hospitalizations for bleeding or thromboembolism (HR: 0.72, 95% CI: 0.53 to 0.97, p = 0.029) during the 6-month follow-up period. Findings from a per-protocol analysis were even stronger: 33% lower risk of all-cause hospitalization (HR: 0.67, 95% CI: 0.55 to 0.81, p < 0.001) and 43% lower risk of hospitalization for bleeding or thromboembolism (HR: 0.57, 95% CI: 0.39 to 0.83, p = 0.003) in patients who were genotyped. During the same period, there was no difference in outcomes between the 2 external control groups.Conclusions: Warfarin genotyping reduced the risk of hospitalization in outpatients initiating warfarin. (The Clinical and Economic Impact of Pharmacogenomic Testing of Warfarin Therapy in Typical Community Practice Settings [MHSMayoWarf1]; NCT00830570). [ABSTRACT FROM AUTHOR]

Background: Mycophenolic Acid (MPA) is the most used anti-proliferative in lung transplantation, but its pharmacokinetic (PK) variability has precluded therapeutic drug monitoring. Both genetic and clinical factors have been implicated in MPA variability. This study aimed to integrate genetic and clinical factors with PK measurements to quantify MPA exposure., Methods: We performed 12-hour pharmacokinetic analysis on 60 adult lung transplant recipients maintained on MPA for immunosuppression. We genotyped a SLCO1B3 polymorphisms previously associated MPA metabolism and collected relevant clinical data. We calculated area under the curve (AUC 0-12 ) and performed univariate linear regression analysis to evaluate its association with genetic, clinical, and pharmacokinetic variables. We performed lasso regression analysis to create final AUC estimation tools., Results: PK-only measurements obtained 2, 3, and 8 hours after MPA administration (C 2 , C 3, and C 8 ) were strongly associated with MPA AUC 0-12 (R 2 67%, 67% and 68% respectively). Clinical and genetic factors associated with MPA AUC 0-12 included the MPA dose (p = 0.001), transplant diagnosis (p = 0.015), SLCO1B3 genotype (p = 0.049), and body surface area (p = 0.050). The best integrated single-sampling strategy included C 2 and achieved an R 2 value of 80%. The best integrated limited-sampling strategy included C 0 , C 0.25 , and C 2 and achieved an R 2 value of 90%., Conclusions: An integrated limited sampling strategy (LSS) for MPA allows increased accuracy in prediction of MPA AUC 0-12 compared to PK-only modeling. Validation of this model will allow for clinically feasible MPA therapeutic drug monitoring and help advance precision management of MPA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-variceal hemorrhage in patients with chronic liver disease (CLD) increases morbidity, mortality, and healthcare costs. There are limited data on risk factors for non-variceal hemorrhage in the CLD population. The aim of this study was to assess the predictive value of various clinical and laboratory parameters for non-variceal hemorrhage in CLD patients., Methods: We conducted a retrospective cohort study of US veterans diagnosed with CLD between 2002 and 2018 within the Veterans Health Administration database. We derived candidate variables from existing risk prediction models for hemorrhage, risk calculators for severity of liver disease, Charlson index of prognostic comorbidities, and prior literature. We used a competing risk analysis to study the relationship between putative risk factors and incidence of non-variceal hemorrhage in patients with CLD., Results: Of 15,183 CLD patients with no history of cancer or anticoagulation use, 674 experienced non-variceal hemorrhage within 1 year of CLD diagnosis. In multivariable analysis, 11 of the 26 candidate variables independently predicted non-variceal hemorrhage: race, international normalized ratio (INR) > 1.5, bilirubin ≥ 2 mg/dL, albumin ≤ 3.5 g/dL, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, proton pump inhibitor prescription, and recent infection., Conclusions: In this study of almost 15,000 veterans, risk factors for non-variceal bleeding within the first year after diagnosis of CLD included non-Caucasian race, laboratory parameters indicating severe liver disease and recent infection in addition to the risk factors for bleeding observed in a general non-CLD population., Competing Interests: None to declare., (Copyright 2024, Afzal et al.)

Background: Clinical risk assessment scores, such as IMPEDE VTE, can identify patients with multiple myeloma (MM) at high-risk of venous thromboembolism (VTE). Refinement of these scores, by including 1 or more biomarkers, could improve risk assessment., Objectives: We sought to determine the association between soluble P-selectin (sP-selectin) and D-dimer with VTE in MM., Methods: We identified 545 patients with newly diagnosed MM. Using a nested case-control design, we identified 38 cases of VTE within 6-months of MM treatment and 137 randomly selected controls. Using logistic regression, we examined the association between D-dimer and sP-selectin with VTE. We also analyzed the association after adjusting for IMPEDE VTE., Results: Each 1-point increase in IMPEDE VTE score was associated with a 27% increase in odds of VTE (odds ratio 1.27; 95% CI 1.08-1.51; c -statistic 0.61; 95% CI 0.51-0.71). There was no association between sP-selectin and VTE. Each one increase in natural log of D-dimer was associated with a 44% increase in odds of VTE, so we assigned points (ranging from -2 to +2) to D-dimer values and incorporated them into IMPEDE VTE, forming IMPEDED VTE . There was a 30% increase in odds of VTE per each 1-point increase in IMPEDED VTE (OR 1.30; 95% CI 1.12-1.52; c -statistic 0.65; 95% CI 0.55-0.75)., Conclusion: Among patients with newly diagnosed MM starting chemotherapy, D-dimer was associated with increased odds of developing VTE within the subsequent 6-months. The addition of D-dimer to IMPEDE VTE- IMPEDED VTE -could improve prediction of VTE among patients with MM.

Left ventricular assist devices (LVAD) reduce mortality in patients with end-stage heart failure, but LVAD management is frequently complicated by bleeding. Bleeding prediction post-LVAD implantation is challenging as prediction rules for hemorrhage have not been rigorously studied in this population. We aimed to validate clinical prediction rules for bleeding, derived in the atrial fibrillation and venous thromboembolism populations, in an LVAD cohort. This was a retrospective cohort study of LVAD recipients at an academic center. The primary end-point was time to gastrointestinal bleed or intracranial hemorrhage after implant; the secondary end-point was time to any major hemorrhage after hospital discharge. Four hundred and eighteen patients received an LVAD (135 HeartMate II, 125 HeartMate 3, 158 HVAD) between November 2009 and January 2019. The primary end-point occurred in 169 (40.4%) patients with C -statistics ranging 0.55-0.58 (standard deviation [SD] 0.02 for all models). The secondary end-point occurred in 167 (40.0%) patients with C -statistics ranging 0.53-0.58 (SD 0.02 for all models). Modifying the age and liver function thresholds increased the C -statistic range to 0.56-0.60 for the primary and secondary end-points. In a sensitivity analysis of HeartMate 3 patients, prediction rules performed similarly. Existing prediction rules for major bleeding had mediocre discrimination in an LVAD cohort., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

Background: Elderly patients undergoing hip or knee arthroplasty are at a risk for myocardial injury after noncardiac surgery (MINS). We evaluated the ability of five common cardiac risk scores, alone or combined with baseline high-sensitivity cardiac troponin I (hs-cTnI), in predicting MINS and postoperative day 2 (POD2) hs-cTnI levels in patients undergoing elective total hip or knee arthroplasty., Methods: This study is ancillary to the Genetics-InFormatics Trial (GIFT) of Warfarin Therapy to Prevent Deep Venous Thrombosis, which enrolled patients 65 years and older undergoing elective total hip or knee arthroplasty. The five cardiac risk scores evaluated were the atherosclerotic cardiovascular disease calculator (ASCVD), the Framingham risk score (FRS), the American College of Surgeon's National Surgical Quality Improvement Program (ACS-NSQIP) calculator, the revised cardiac risk index (RCRI), and the reconstructed RCRI (R-RCRI)., Results: None of the scores predicted MINS in women. Among men, the ASCVD ( C -statistic of 0.66; p =0.04), ACS-NSQIP ( C -statistic of 0.69; p =0.01), and RCRI ( C -statistic of 0.64; p =0.04) predicted MINS. Among all patients, spearman correlations ( r s ) of the risk scores with the POD2 hs-cTnI levels were 0.24, 0.20, 0.11, 0.11, and 0.08 for the ASCVD, Framingham, ACS-NSQIP, RCRI, and R-RCRI scores, respectively, with p values of <0.001, <0.001, <0.001, 0.006, and 0.025. Baseline hs-cTnI predicted MINS ( C -statistics: 0.63 in women and 0.72 in men) and postoperative hs-cTnI ( r s  = 0.51, p =0.001)., Conclusion: In elderly patients undergoing elective hip or knee arthroplasty, several of the scores modestly predicted MINS in men and correlated with POD2 hs-cTnI., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Merih T. Tesfazghi et al.)

Since the development of the Khorana score to predict risk of cancer-associated venous thromboembolism (VTE), many modified and de novo risk prediction models (RPMs) have been proposed. Comparison of the prognostic performance across models requires comprehensive reporting and standardized methods for model development, validation and evaluation. To improve the standardization of RPM reporting, the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) tool was published in 2015. To better understand the quality of reporting and development of RPMs for cancer-associated VTE, we performed a literature search of published RPMs and assessed each model using the TRIPOD checklist. Our results yielded 29 RPMs for which 30 items were evaluated. There was a non-significant (p = 0.15) improvement in reporting of the 30 items in the post-TRIPOD era (81%) versus the pre-TRIPOD era (75%). Of seven items (title, sample size, missing data handling, baseline demographics, methods and results for model performance, and supplemental resources) with the lowest reporting in the pre-TRIPOD era (<70%), there was an average improvement of 22% in the post-TRIPOD era. Only two of the 22 studies published in the post-TRIPOD era acknowledged compliance with TRIPOD. Informed by the results of this assessment, the Scientific and Standardization Committee (SSC) Subcommittee on Hemostasis & Malignancy of the International Society on Thrombosis and Hemostasis (ISTH) advocates for standardization of four key elements of RPMs for cancer-associated VTE: (1) inclusion of the TRIPOD checklist, (2) clear definition of the derivation population, with justification of sample size, (3) clear definition of predictors, and (4) external validation prior to implementation., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Patients with chronic liver disease (CLD) often present with an elevated international normalized ratio (INR). Although elevated INR reflects a higher risk of hemorrhage among warfarin users, its clinical significance in CLD patients is less clear., Objectives: We used Veterans Health Administration data to quantify the association between INR and (non-variceal) hemorrhage in patients with CLD compared to warfarin users., Methods: We performed a multivariate competing risk analysis to study the association between INR and hemorrhage in the two cohorts. We used an interaction term between INR and cohort (CLD/warfarin users) to test if INR had different effects on hemorrhage in the two cohorts., Results: Data from 80 134 patients (14, 412 with CLD and 65, 722 taking warfarin) were analyzed. The effect of INR on the risk of hemorrhage differed between CLD patients and warfarin users (interaction P < .001). As INR increased above 1.5, the adjusted hazard ratio (aHR) for hemorrhage in CLD patients increased to 2.25 but remained fairly constant with further elevation of INR values. In contrast, the risk of hemorrhage in patients taking warfarin remained low with INR in the subtherapeutic (INR <2.0) and therapeutic ranges (INR 2.0-3.0), and increased exponentially with INR in the supratherapeutic range (aHR 1.64 with INR >3.0-3.5, and 4.70 with INR >3.5)., Conclusions: The relationship between INR and risk of hemorrhage in CLD patients is different from that in warfarin users. Caution should be exercised extrapolating data from warfarin users to make clinical decisions in CLD patients., (© 2022 International Society on Thrombosis and Haemostasis.)

Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19-40%), P < 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P < 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org)., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Background: Guidelines recommend thromboprophylaxis for patients with multiple myeloma (MM) at high risk for venous thromboembolism (VTE). However, the optimal risk prediction model for VTE in MM remains unclear. Khorana et al developed a VTE risk score (Khorana score) in ambulatory cancer patients receiving chemotherapy. We aimed to evaluate the predictive ability of the Khorana score in patients with MM., Methods: We identified patients with MM within the Veterans Affairs health care system between 2006 and 2013. The Khorana score was calculated before treatment initiation. Using logistic regression, the relationship between risk group and VTE was assessed at 3 and 6 months. We tested model discrimination using the concordance statistic., Results: In the cohort of 2870 patients with MM, there were 1328 at low risk (0 points), 1521 at intermediate risk (1-2 points), and 21 at high risk (≥3 points) for VTE by the Khorana score. The 6-month cumulative incidence of VTE was 5.1% (95% confidence interval [CI], 4.0%-6.4%) in low risk, 3.9% (95% CI, 3.0%-5.0%) in intermediate risk, 4.8% (95% CI, 0.3%-20.2%) in high risk. The Khorana score did not strongly discriminate between patients who did and did not develop VTEs at 3 or 6 months (concordance statistic, 0.58; 95% CI, 0.54-0.63; and 0.53, 95% CI, 0.50-0.57, respectively., Conclusions: In conclusion, in this cohort of 2870 patients with MM, the Khorana score did not predict VTE. Our study supports the need to use myeloma-specific risk models to predict VTE risk in patients with MM., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Automated phone appointment reminders have improved adherence with follow-up appointments in a variety of hospital settings, but have mixed results in patients discharged from the emergency department (ED). Increasing adherence to follow-up care has been a priority in the ED to improve patient outcomes and reduce unnecessary future visits., Methods: We conducted a prospective randomized open, blinded end-point (PROBE) trial of 278 adult patients discharged from the ED and referred to a provider for follow-up care. Participants in the intervention arm received a self-scheduling text or phone message that automatically connected them to their referral provider to schedule a follow-up appointment and sent them appointment reminders. Those in the control arm received standard-of-care written instructions to contact listed referral providers. The primary outcome was time to appointment. The secondary outcome was time to return visit to the ED., Results: The automated reminders increased the cumulative incidence of keeping the referral appointment after ED discharge (p < 0.001, Gray's test). Of participants randomized to the automated phone intervention, 49.3% (n = 74) kept their follow-up appointment versus 23.4% (n = 30) in the control arm, with a hazard ratio (HR) and 95% confidence interval (CI) over the duration of the study period of 2.4 (1.6 to 3.7; p < 0.001). In a sensitivity analysis using 30 days of follow-up data, 42.0% (n = 63) of participants randomized to the phone intervention kept their follow-up versus 21.1% (n = 27) in the control arm, with a HR (95% CI) of 2.2 (1.4 to 3.5; p < 0.001). There was no difference in ED revisits between the intervention and control group within 120 days postdischarge., Conclusions: An automated self-scheduling phone system significantly improved follow-up adherence after ED discharge, but did not decrease ED revisits., (© 2020 by the Society for Academic Emergency Medicine.)

Background: Construction workers have high rates of work-related musculoskeletal disorders, which lead to frequent opioid use and opioid use disorder (OUD). This paper quantified the incidence of opioid use and OUD among construction workers with and without musculoskeletal disorders., Methods: We conducted a retrospective study using union health claims from January 2015 to June 2018 from 19,909 construction workers. Claims for diagnoses of chronic musculoskeletal disorders, acute musculoskeletal injuries, musculoskeletal surgery, and other conditions were linked to new opioid prescriptions. We examined the effects of high doses (≥50 morphine mg equivalents per day), large supply (more than 7 days per fill), long-term opioid use (60 or more days supplied within a calendar quarter), and musculoskeletal disorders, on the odds of a future OUD., Results: There were high rates (42.8% per year) of chronic musculoskeletal disorders among workers, of whom 24.1% received new opioid prescriptions and 6.3% received long-term opioid prescriptions per year. Workers receiving opioids for chronic musculoskeletal disorders had the highest odds of future OUD: 4.71 (95% confidence interval 3.09-7.37); workers prescribed long-term opioids in any calendar quarter had a nearly 10-fold odds of developing an OUD., Conclusions: Among construction workers, opioids initiated for musculoskeletal pain were strongly associated with incident long-term opioid use and OUD. Musculoskeletal pain from physically demanding work is likely one driver of the opioid epidemic in occupations like construction. Prevention of work injuries and alternative pain management are needed for workers at risk for musculoskeletal injuries., (© 2020 Wiley Periodicals LLC.)

Background: We studied the effect of statins on mortality in a nationally representative sample of patients with multiple myeloma, and explored the benefit of statins in a subgroup of patients treated with novel agents., Methods: Patients diagnosed with multiple myeloma between 2007 and 2013 were identified in the SEER-Medicare database using International Classification of Diseases (ICD)-03 codes. ICD-9 and Healthcare Common Procedure Coding System codes were used to identify comorbidities and treatments. We assessed the association of statins with mortality in patients with multiple myeloma using multivariate Cox proportional hazards regression analysis. For subanalysis, we used the same statistical technique to investigate the effect of statins on mortality in myeloma patients treated with novel agents., Results: A total of 5922 patients were diagnosed with multiple myeloma within the study period. Use of statins was associated with 21% reduction in risk of death (adjusted hazard ratio [aHR] 0.79; 95% confidence interval [CI] 0.74-0.84) among all patients with multiple myeloma. Among the patents treated with novel agents (n = 3603), statins reduced mortality by 10% (aHR = 0.90, 95% CI 0.83-0.98)., Conclusions: Use of statins is likely associated with lower mortality in patients with multiple myeloma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In multiple myeloma, venous thromboembolism (VTE) is common, and treatments for myeloma, such as lenalidomide, increase the risk of thrombosis while improving survival. The association between VTE and survival is not well known., Objectives: To determine the association between VTE and survival in multiple myeloma (MM) while adjusting for known confounders that affect risk of thrombosis and survival, including patient characteristics and treatment in a retrospective cohort of US veterans., Patients/methods: A cohort of patients with newly diagnosed MM treated within Veterans Health Administration between September 1, 1999, and June 30, 2014, was created to assess the association between VTE and mortality using Cox proportional hazards regression modeling while accounting for known prognostic factors and treatments., Results: The cohort comprised 4446 patients with myeloma, including 2837 patients diagnosed after lenalidomide approval in July 2006. VTE occurred in 327 (7.4%) patients within 1 year and occurred at a median of 77 days (interquartile range, 37-153) after starting therapy for MM. In all patients, VTE was associated with increased mortality at 6 months (adjusted hazard ratio [aHR], 1.67; 95% confidence interval [CI], 1.18-2.37). Patients in the post-lenalidomide cohort with VTE had an increased mortality at both 6 months (aHR, 2.31; 95% CI, 1.52-3.51) and 12 months (aHR, 1.66; 95% CI, 1.19-2.33) after treatment initiation., Discussion: This study shows that VTE during the first 6-12 months of therapy is associated with increased mortality in patients with MM. Studies evaluating thromboprophylaxis in patients at high risk of thrombosis are needed., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

When randomized controlled trials are not feasible, retrospective studies using big data provide an efficient and cost-effective alternative, though they are at risk for treatment selection bias. Treatment selection bias occurs in a non-randomized study when treatment selection is based on pre-treatment characteristics that are also associated with the outcome. These pre-treatment characteristics, or confounders, can influence evaluation of a treatment's effect on the outcome. Propensity scores minimize this bias by balancing the known confounders between treatment groups. There are a few approaches to performing propensity score analyses, including stratifying by the propensity score, propensity matching, and inverse probability of treatment weighting (IPTW). Described here is the use of IPTW to balance baseline comorbidities in a cohort of patients within the US Military Health System Data Repository (MDR). The MDR is a relatively optimal data source, as it provides a contained cohort in which nearly complete information on inpatient and outpatient services is available for eligible beneficiaries. Outlined below is the use of the MDR supplemented with information from the national death index to provide robust mortality data. Also provided are suggestions for using administrative data. Finally, the protocol shares an SAS code for using IPTW to balance known confounders and plot the cumulative incidence function for the outcome of interest.

Introduction: Pancreatic cancer is a thrombogenic malignancy with nearly half of venous thrombotic events occurring in the splanchnic circulation. The effect of splanchnic vein thrombosis on mortality in pancreatic cancer is unknown. We studied the effect of splanchnic vein thrombosis on mortality in veterans with advanced pancreatic adenocarcinoma, and explored the association of anticoagulant therapy on mortality and hemorrhage., Methods: Using International Classification of Diseases (ICD) codes, we identified eligible patients and outcomes in the Veterans Health Administration database. Using Cox proportional hazards regression, we analyzed the association between splanchnic vein thrombosis and mortality among patients with advanced pancreatic cancer. We used propensity score inverse probability-of-treatment weighting to balance the groups who did and did not receive anticoagulation. To understand the role of anticoagulant therapy, we used Cox proportional hazards regression to analyze mortality and competing risk analysis to assess the risk of hemorrhage., Results: Of the patients with advanced pancreatic cancer (N = 6164), 122 developed splanchnic vein thrombosis. Splanchnic vein thrombosis was associated with a two-fold increase in mortality, aHR 2.02, 95% CI 1.65-2.47. The finding held true after restricting the analysis to patients undergoing treatment for pancreatic cancer, and after adjusting for immortal time bias by a 30-day landmark analysis. Anticoagulant therapy did not affect mortality (aHR 0.99, 95% CI 0.65-1.51), and increased the risk of hemorrhage (aHR 2.7, 95% CI 1.02-7.07)., Conclusion: Splanchnic vein thrombosis predicts worse survival in patients with advanced pancreatic adenocarcinoma. Anticoagulant therapy may not mitigate this increased mortality, and increases the risk of hemorrhage., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Cardiopulmonary bypass-related platelet dysfunction can increase the risk of intra- and post-operative bleeding in children undergoing cardiac surgery. More accurate laboratory tests that identify acquired platelet abnormalities could allow for rapid identification of patients at risk of bleeding and provide therapies that could reduce bleeding and platelet transfusions. We hypothesized that thromboelastography with platelet mapping (TEG-PM) and multiple electrode impedance aggregometry (MEIA) as functional measures of platelet function would predict who will require platelet transfusion. Our secondary hypothesis was that platelet aggregation at both arachidonic acid (AA) and adenosine diphosphate (ADP) receptors would correlate between TEG-PM and MEIA results. Methods: In this prospective study from August 2013 to December 2015, children from newborn to 5 years of age with congenital heart disease undergoing cardiopulmonary bypass had blood samples collected and analyzed at four time points: pre-bypass, post-bypass, post-operatively on arrival to the Cardiac Intensive Care Unit, and 24 h after arrival. Results: Of the 44 patients analyzed, the 10 patients who received peri-operative platelet transfusion were significantly younger ( p = 0.05), had higher STAT (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery) Mortality Categories ( p < 0.002) and longer cardiopulmonary bypass times ( p = 0.02). In univariate analysis, four variables were associated with peri-operative platelet transfusion: pre-operative age [OR 0.95 (0.93, 0.98), p = 0.03], cardiopulmonary bypass time [1.5 (1.31, 1.68), p = 0.008], STAT Mortality Category [3.64 (3.40, 3.87), p < 0.001], and TEG-PM ADP [0.79 (0.65, 0.93), p = 0.04]. ROC analysis demonstrated moderate predictive value of TEG-PM ADP with AUC of 0.745 (0.59, 0.91). A TEG-PM ADP value of less than or equal to 21 had 85% sensitivity and 70% specificity for platelet transfusion. In the multivariate analysis, only STAT Mortality Category predicted platelet transfusion. TEG-PM and MEIA results correlated for the AA receptor at all 4 time points, but the same tests at the ADP receptors did not correlate. Conclusions: TEG-PM ADP may provide more clinically relevant information regarding platelet function compared to the MEIA at the ADP receptor in children requiring cardiopulmonary bypass. There was limited correlation between TEG-PM and MEIA results which raises a concern about the accuracy of these tests at the ADP receptor. Lower pre-operative TEG-PM ADP MA may predict intra-operative platelet transfusions; however, larger studies are needed to determine the utility of TEG-PM and MEIA in guiding platelet transfusions in this population., (Copyright © 2019 Barker, Saini, Gazit, Shea, Baltagi, Gage and Spinella.)

Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m 2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM., (© 2019 Wiley Periodicals, Inc.)

Importance: The optimal international normalized ratio (INR) to prevent venous thromboembolism (VTE) in warfarin-treated patients with recent arthroplasty is unknown., Objective: To determine the safety and efficacy of a target INR of 1.8 vs 2.5 for VTE prophylaxis after orthopedic surgery., Design, Setting, and Participants: The randomized Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis enrolled 1650 patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016., Interventions: In a 2 × 2 factorial design, participants were randomized to a target INR of 1.8 (n = 823) or 2.5 (n = 827) and to either genotype-guided or clinically guided warfarin dosing. For the first 11 days of therapy, open-label warfarin dosing was guided by a web application., Main Outcomes and Measures: The primary outcome was the composite of VTE (within 60 days) or death (within 30 days). Participants underwent screening duplex ultrasound postoperatively. The hypothesis was that an INR target of 1.8 would be noninferior to an INR target of 2.5, using a noninferiority margin of 3% for the absolute risk of VTE. Secondary end points were bleeding and INR values of 4 or more., Results: Among 1650 patients who were randomized (mean age, 72.1 years; 1049 women [63.6%]; 1502 white [91.0%]), 1597 (96.8%) received at least 1 dose of warfarin and were included in the primary analysis. The rate of the primary composite outcome of VTE or death was 5.1% (41 of 804) in the low-intensity-warfarin group (INR target, 1.8) vs 3.8% (30 of 793) in the standard-treatment-warfarin group (INR target, 2.5), for a difference of 1.3% (1-sided 95% CI, -∞ to 3.05%, P = .06 for noninferiority). Major bleeding occurred in 0.4% of patients in the low-intensity group and 0.9% of patients in the standard-intensity group, for a difference of -0.5% (95% CI, -1.6% to 0.4%). The INR values of 4 or more occurred in 4.5% of patients in the low-intensity group and 12.2% of the standard-intensity group, for a difference of -7.8% (95% CI, -10.5% to -5.1%)., Conclusions and Relevance: Among older patients undergoing hip or knee arthroplasty and receiving warfarin prophylaxis, an international normalized ratio goal of 1.8 compared with 2.5 did not meet the criterion for noninferiority for risk of the composite outcome of VTE or death. However, the trial may have been underpowered to meet this criterion and further research may be warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT01006733.

Background: Fever is common in mechanically ventilated patients and may be uniquely detrimental in those with lung injury because of its injurious effects on pulmonary vascular permeability and alveolar epithelium. We evaluated the association of fever and antipyretic medication with mortality in mechanically ventilated emergency department (ED) patients., Methods: This is a retrospective cohort study of 1,264 patients requiring mechanical ventilation initiated in the ED with subsequent admission to an intensive care unit. Maximum body temperature was recorded for the first 24 h after ED admission and categorized into four categories: <37°C, 37°C to 38.2°C, 38.3°C to 39.4°C, and ≥39.5°C. The primary outcome was 28-day mortality. We conducted a planned subgroup analysis of patients with sepsis at the time of intubation. Multivariable Cox proportional hazard ratios (HRs) were used to assess the relationship between temperature, antipyretics, and mortality., Results: Multivariable Cox proportional HRs demonstrated that a maximum temperature ≥39.5°C was associated with increased mortality (adjusted hazard ratio [aHR] 1.59 [95% confidence interval, CI, 1.05-2.39]). In the subgroup of patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was associated with survival (aHR 0.61 [95% CI, 0.39-0.99]). There was no difference in 28-day mortality between patients who did and did not receive antipyretic medication in either the overall cohort or the septic subgroup., Conclusion: High fever (≥39.5°C) was associated with increased risk for mortality in mechanically ventilated patients. However, in patients with sepsis, moderate fever (38.3°C-39.4°C) was protective. Antipyretic medication was not associated with changes in outcome. This suggests that fever may have different implications in septic versus nonseptic mechanically ventilated patients.