Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Combining Super Learner with high-dimensional propensity score to improve confounding adjustment: A real-world application in chronic lymphocytic leukemia.

PURPOSE: High-dimensional propensity score (hdPS) is a semiautomated method that leverages a vast number of covariates available in healthcare databases to improve confounding adjustment. A novel combined Super Learner (SL)-hdPS approach was proposed to assist with selecting the number of covariates for propensity score inclusion, and was found in plasmode simulation studies to improve bias reduction and precision compared to hdPS alone. However, the approach has not been examined in the applied setting. METHODS: We compared SL-hdPS's performance with that of several hdPS models, each with prespecified covariates and a different number of empirically-identified covariates, using a cohort study comparing real-world bleeding rates between ibrutinib- and bendamustine-rituximab (BR)-treated individuals with chronic lymphocytic leukemia in Optum's de-identified Clinformatics® Data Mart commercial claims database (2013-2020). We used inverse probability of treatment weighting for confounding adjustment and Cox proportional hazards regression to estimate hazard ratios (HRs) for bleeding outcomes. Parameters of interest included prespecified and empirically-identified covariate balance (absolute standardized difference [ASD] thresholds of <0.10 and <0.05) and outcome HR precision (95% confidence intervals). RESULTS: We identified 2423 ibrutinib- and 1102 BR-treated individuals. Including >200 empirically-identified covariates in the hdPS model compromised covariate balance at both ASD thresholds. SL-hdPS balanced more covariates than all individual hdPS models at both ASD thresholds. The bleeding HR 95% confidence intervals were generally narrower with SL-hdPS than with individual hdPS models. CONCLUSION: In a real-world application, hdPS was sensitive to the number of covariates included, while use of SL for covariate selection resulted in improved covariate balance and possibly improved precision.

Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors.

BACKGROUND: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors. METHODS: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated. RESULTS: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg. CONCLUSION: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination. TRIAL REGISTRATION NUMBER: NCT03666988.

Redefining outcomes in immune TTP: an international working group consensus report.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.

Early initiation of second-line therapy in primary immune thrombocytopenia: insights from real-world evidence.

To compare patients with primary immune thrombocytopenia (ITP) prescribed early (within 3 months of initial ITP treatment) second-line treatment (eltrombopag, romiplostim, rituximab, immunosuppressive agents, splenectomy) with or without concomitant first-line therapy to those who received only first-line therapy. This real-world retrospective cohort study of 8268 patients with primary ITP from a large US-based database (Optum® de-identified Electronic Health Record [EHR] dataset) combined electronic claims and EHR data. Outcomes included platelet count, bleeding events, and corticosteroid exposure 3 to 6 months after initial treatment. Baseline platelet counts were lower in patients receiving early second-line therapy (10‒28 × 109/L) versus those who did not (67 × 109/L). Counts improved and bleeding events decreased from baseline in all treatment groups 3 to 6 months after the start of therapy. Among the very few patients for whom follow-up treatment data were available (n = 94), corticosteroid use was reduced during the 3- to 6-month follow-up period in patients who received early second-line therapy versus those who did not (39% vs 87%, p < 0.001). Early second-line treatment was prescribed for more severe cases of ITP and appeared to be associated with improved platelet counts and bleeding outcomes 3 to 6 months after initial therapy. Early second-line therapy also appeared to reduce corticosteroid use after 3 months, although the small number of patients with follow-up data on treatment precludes any substantive conclusions. Further research is needed to determine whether early second-line therapy has an effect on the long-term course of ITP.

Real-world safety and effectiveness of recombinant porcine sequence factor VIII in acquired haemophilia A: A non-interventional, post-authorization safety study.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII, susoctocog alfa) is indicated for the treatment of bleeding episodes in adults with acquired haemophilia A (AHA). AIM: To provide long-term real-world safety and effectiveness data for rpFVIII in the management of AHA bleeding episodes. METHODS: US PASS (NCT02610127) was a multicentre, uncontrolled, open-label, post-marketing safety surveillance study conducted in adults with AHA. Data were collected retrospectively or prospectively for 180 days after rpFVIII treatment. The primary outcome was the incidence of treatment-related serious adverse events (SAEs). Secondary outcomes included haemostatic effectiveness of rpFVIII and rpFVIII utilization. RESULTS: Fifty-three patients were enrolled from December 2015 to June 2019 (prospective, n = 30; retrospective, n = 23). Six patients experienced seven treatment-related SAEs (incidence 12.0%). The most common treatment-related SAE was FVIII inhibition (inhibiting antibodies to rpFVIII; incidence 8.0%, 95% CI: 2.2-19.2). Five patients reported seven thromboembolic events; one was an SAE and possibly related to rpFVIII. Of bleeding events treated with rpFVIII, 80.3% (57/71) of bleeds resolved with rpFVIII. The median (range) dose of rpFVIII per infusion was 50 (10-300) units/kg, with a median (range) of 6.0 (1-140) infusions and a median (range) time from bleed onset to bleed resolution of 14.0 (2.0-132.7) days. CONCLUSION: In this real-world study of rpFVIII for AHA, no new safety signals were identified compared with previous clinical trial findings. Eighty percent of bleeds resolved with rpFVIII treatment.

Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.

Major options for second-line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost-effectiveness of these therapies. Using prospective, observational, and meta-analytic data, we performed the first cost-effectiveness analysis of second-line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20-year time-horizon, our six-strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost-effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality-adjusted life-year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10 000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost-effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost-effective treatment in adults with chronic ITP.

Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease : A Population-Based Study.

BACKGROUND: Although apixaban and rivaroxaban are commonly used in patients with atrial fibrillation (AF) and valvular heart disease (VHD), there is limited evidence comparing the 2 drugs in these patients. OBJECTIVE: To emulate a target trial of effectiveness and safety of apixaban and rivaroxaban in patients with AF and VHD. DESIGN: New-user, active comparator, cohort study design. SETTING: Commercial health insurance database from 1 January 2013 to 31 December 2020. PATIENTS: New users of apixaban or rivaroxaban who had a diagnosis of AF and VHD before initiation of anticoagulant therapy. MEASUREMENTS: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of gastrointestinal or intracranial bleeding. Cox proportional hazards regression with a robust variance estimator was used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: When compared with rivaroxaban in a propensity score-matched cohort of 19 894 patients (9947 receiving each drug), apixaban was associated with a lower rate of ischemic stroke or systemic embolism (HR, 0.57 [95% CI, 0.40 to 0.80]) and bleeding (HR, 0.51 [CI, 0.41 to 0.62]). The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation. LIMITATION: Short follow-up time and inability to ascertain some types of VHD. CONCLUSION: In this study of patients with AF and VHD, patients receiving apixaban had a lower risk for ischemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban. PRIMARY FUNDING SOURCE: National Institutes of Health.

Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

BACKGROUND: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited. OBJECTIVE: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE. DESIGN: Retrospective new-user cohort study. SETTING: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020. PARTICIPANTS: Adults with VTE who were newly prescribed apixaban or rivaroxaban. MEASUREMENTS: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding. RESULTS: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation. LIMITATION: Short follow-up. CONCLUSION: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban. PRIMARY FUNDING SOURCE: None.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study.

Patients with immune thrombocytopenia (ITP) may respond to one thrombopoietin receptor agonist (TPO-RA) but not another. Limited data are available describing outcomes in patients who switched from romiplostim or eltrombopag to avatrombopag, a newer oral TPO-RA. We performed a retrospective observational study of adults with ITP who switched from eltrombopag or romiplostim to avatrombopag at four US tertiary ITP referral centres. Forty-four patients were included, with a mean ITP duration of 8.3 years and a median (range) of four prior ITP treatments. On avatrombopag, 41/44 patients (93%) achieved a platelet response (≥50 × 109 /l) and 38/44 patients (86%) achieved a complete response (≥100 × 109 /l). In all patients, the median platelet count on eltrombopag or romiplostim was 45 × 109 /l vs 114 × 109 /l on avatrombopag (p < 0.0001); in patients switched for ineffectiveness of romiplostim/eltrombopag, it was 28 × 109 /l on romiplostim/eltrombopag vs 88 × 109 /l on avatrombopag (p = 0.025). Fifty-seven percent of patients receiving concomitant ITP medications before switching discontinued them after switching, including 63% of patients receiving chronic corticosteroids. In a heavily pretreated chronic ITP population, avatrombopag was effective following therapy with romiplostim or eltrombopag, with high response rates even in patients with inadequate response to a prior TPO-RA.

Thrombopoietin receptor agonist discontinuation rates and reasons among patients with immune thrombocytopenia: a study of administrative claims linked with medical chart review.

Administrative claims provide a rich data source for retrospective studies of real-world clinical practice, yet some important data may be inconsistent or unavailable. This study explored factors influencing discontinuation of thrombopoietin receptor agonists (TPO-RAs) among patients with immune thrombocytopenia (ITP), by adding medical chart abstraction for additional details. Adult (≥ 18 years) patients with continuous commercial or Medicare Advantage with Part D health insurance coverage were included. Inclusion criteria were ≥ 1 claim for eltrombopag or romiplostim and ≥ 2 diagnoses of ITP between December 31, 2017, and January 1, 2020. Providers were asked to provide access to medical charts for abstraction. The analyses included only patients who discontinued TPO-RA and described patient characteristics, treatment patterns, platelet values, and reasons for discontinuation. Among 207 ITP patients treated with a TPO-RA, 137 (66%) discontinued treatment during the observation period. The mean TPO-RA treatment duration was 185 days. Mean platelet count at the time of discontinuation was 197 × 109/L. The most common reason for discontinuation was improvement of the patient's condition (42%). Other reasons included worsening of ITP/lack of response (12%), adverse events (12%), and cost-related or social reasons (23%). No reason was reported for 10%. Notably 26% of patients who discontinued remained off all ITP therapy for the remainder of the study, with a mean treatment-free period of 262 days. These results emphasize that some patients with ITP are able to discontinue TPO-RA therapy and achieve durable treatment-free periods.

Eltrombopag treatment of patients with secondary immune thrombocytopenia: retrospective EHR analysis.

Immune thrombocytopenia (ITP) may occur in isolation (primary) or in association with a predisposing condition (secondary ITP [sITP]). Eltrombopag is a well-studied treatment for primary ITP, but evidence is scarce for sITP. We evaluated real-world use of eltrombopag for sITP using electronic health records. Eligible patients had diagnoses of ITP and a qualifying predisposing condition, and eltrombopag treatment. We described patient characteristics, treatment patterns, platelet counts, and thrombotic and bleeding events. We identified 242 eligible patients; the most common predisposing conditions were hepatitis C and systemic lupus erythematosus. Average duration of eltrombopag treatment was 6.1 months. Most (81.4%) patients achieved a platelet count ≥ 30,000/µL at a mean of 0.70 months, 70.2% reached ≥ 50,000/µL at a mean of 0.95 months, and 47.1% achieved a complete response of > 100,000/µL at a mean of 1.43 months after eltrombopag initiation. At eltrombopag discontinuation, 105 patients (43%) experienced a treatment-free period for a mean 3.3 months. Bleeding events occurred with similar frequency before and during eltrombopag treatment whereas thrombotic events were less frequent during eltrombopag treatment. Our results suggest similar rates of platelet response with eltrombopag in patients with sITP as compared with primary ITP. In addition, a treatment-free period is possible for a substantial minority of patients.

Optimal Medical Therapy Following Deep Venous Interventions: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

The optimal medical management of patients following endovascular deep venous interventions remains ill-defined. As such, the Society of Interventional Radiology Foundation (SIRF) convened a multidisciplinary group of experts in a virtual Research Consensus Panel (RCP) to develop a prioritized research agenda regarding antithrombotic therapy following deep venous interventions. The panelists presented the gaps in knowledge followed by discussion and ranking of research priorities based on clinical relevance, overall impact, and technical feasibility. The following research topics were identified as high priority: 1) characterization of biological processes leading to in-stent stenosis/rethrombosis; 2) identification and validation of methods to assess venous flow dynamics and their effect on stent failure; 3) elucidation of the role of inflammation and anti-inflammatory therapies; and 4) clinical studies to compare antithrombotic strategies and improve venous outcome assessment. Collaborative, multicenter research is necessary to answer these questions and thereby enhance the care of patients with venous disease.

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited. OBJECTIVE: To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF. DESIGN: New-user retrospective propensity score-matched cohort study. SETTING: U.S.-based commercial health care database from 1 January 2010 to 30 June 2019. PARTICIPANTS: Adults with valvular AF who were newly prescribed DOACs or warfarin. MEASUREMENTS: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding. RESULTS: Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]). LIMITATION: Relatively short follow-up; inability to ascertain disease severity. CONCLUSION: In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF. PRIMARY FUNDING SOURCE: None.

Trends in post-discharge prophylactic anticoagulant use among stroke patients in the United States between 2006 and 2019.

BACKGROUND: Stroke is an independent risk factor for venous thromboembolism (VTE). Although the risk of VTE persists after hospital discharge, information on the utilization of anticoagulants among stroke patients after discharge remains limited. OBJECTIVE: To evaluate changes in post-discharge thromboprophylaxis among stroke patients between 2006 and 2019. METHODS: We conducted a retrospective repeated cross-sectional analysis using a commercial healthcare insurance database in the United States. We included patients aged ≥ 18 years with incident stroke diagnosis and assessed prophylactic use of anticoagulants in the 30 days following hospital discharge including low-molecular-weight heparin (enoxaparin ≤40 mg/day, dalteparin ≤5000 IU/day), unfractionated heparin ≤5000 IU/ twice daily or 3 times a day, apixaban 2.5 mg twice daily, and rivaroxaban 10 mg/day. Patients with atrial fibrillation, VTE, mechanical heart valves, cancer, antiphospholipid antibody syndrome, and users of therapeutic doses of anticoagulants were excluded. We used the Cochrane-Armitage test to assess changes in the use of anticoagulants across the study period. RESULTS: There was a small increase in the overall use of post-discharge prophylactic anticoagulants among stroke patients between 2006 and 2019 from 0.5% to 1.9%. The use of heparin decreased from 0.5% in 2006 to 0.3% in 2019 (P-value for trend = 0.001). In contrast, the use of apixaban or rivaroxaban increased from 0.1% in 2013 to 1.6% in 2019 (P-value for trend < 0.001). Apixaban was more commonly used than rivaroxaban. CONCLUSIONS: In this population-based study of stroke patients, we found that post-discharge anticoagulant use remains low through 2019. Prophylactic use of heparin or rivaroxaban was relatively low but the use of apixaban increased over the study period. Further research is needed to determine if these agents are safe and effective for VTE prevention in stroke patients.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.