Providing 0.1 Full-Time Equivalent (FTE) Support to Fellowship Core Faculty Improves Faculty Involvement in Fellowship Education and Recruitment.

In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them "feel rewarded," gave them "a sense of commitment" to the fellowship, and helped "offset clinical requirements." HO fellows reported "a positive impact" of the new program with faculty being "more present at lectures." The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment.

Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab ± other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in 2 major randomized clinical trials. The addition of caplacizumab to SOC also led to increased bleeding from transient reductions in von Willebrand factor and increased relapse rates. Using data from the 2 clinical trials of caplacizumab, we performed the first-ever cost-effectiveness analysis in TTP. Over a 5-year period, the projected incremental cost-effectiveness ratio (ICER) in our Markov model was $1 482 260, significantly above the accepted 2019 US willingness-to-pay threshold of $195 300. One-way sensitivity analyses showed the utility of the well state and the cost of caplacizumab to have the largest effects on ICER, with a reduction in caplacizumab cost demonstrating the single greatest impact on lowering the ICER. In a probabilistic sensitivity analysis, SOC was favored over caplacizumab in 100% of 10 000 iterations. Our data indicate that the addition of caplacizumab to SOC in treatment of acquired TTP is not cost effective because of the high cost of the medication and its failure to improve relapse rates. The potential impact of caplacizumab on health system cost using longer term follow-up data merits further study.

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.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Clinical characteristics and outcomes of splenic infarction in cancer patients: a retrospective, single center report of 206 cases.

Cancer patients have a high risk of thromboembolic events including splenic infarct (SI). However, risk factors for SI in cancer patients are poorly understood, and the utility of systemic anticoagulation in such patients is uncertain. We performed a retrospective cohort study of all cancer patients with SI treated at Yale New Haven Hospital from 2008 to 2017. Central review of radiology imaging was performed to confirm the diagnosis of SI. Baseline differences in variables among patients with and without recurrent SI were compared using Fisher's exact test, Pearson's χ2 test, and t-test. Multivariable regression models were conducted to identify factors associated with recurrent SI. Of 206 patients with cancer and SI, 42 had a prior venous thromboembolic event, while 29 had atrial fibrillation/flutter. At a median follow-up of 11.4 months (range: 0-142.3 months), 152 patients underwent follow-up imaging, with only 6 having recurrent SI. The use of anticoagulation after initial SI was associated with a nonsignificant increase in recurrent SI (p = 0.054) and was not associated with development of venous thromboembolism after SI (p = 0.414). In bivariate analyses, the risk of recurrent SI showed a significant association with lower platelet counts (p < 0.001) and with atrial fibrillation/flutter (p = 0.036). In a multivariable logistic regression model, no variables were identified that were associated with a higher risk of recurrent SI. SI in cancer patients is typically an isolated event with low recurrence risk. Anticoagulation use should be guided by other thromboembolic risk factors.

A novel approach to the program evaluation committee.

BACKGROUND: The Accreditation Council for Graduate Medical Education requires each residency program to have a Program Evaluation Committee (PEC) but does not specify how the PEC should be designed. We sought to develop a PEC that promotes resident leadership and provides actionable feedback. METHODS: Participants were residents and faculty in the Traditional Internal Medicine residency program at Yale School of Medicine (YSM). One resident and one faculty member facilitated a 1-h structured group discussion to obtain resident feedback on each rotation. PEC co-facilitators summarized the feedback in written form, then met with faculty Firm Chiefs overseeing each rotation and with residency program leadership to discuss feedback and generate action plans. This PEC process was implemented in all inpatient and outpatient rotations over a 4-year period. Upon conclusion of the second and fourth years of the PEC initiative, surveys were sent to faculty Firm Chiefs to assess their perceptions regarding the utility of the PEC format in comparison to other, more traditional forms of programmatic feedback. PEC residents and faculty were also surveyed about their experiences as PEC participants. RESULTS: The PEC process identified many common themes across inpatient and ambulatory rotations. Positives included a high caliber of teaching by faculty, highly diverse and educational patient care experiences, and a strong emphasis on interdisciplinary care. Areas for improvement included educational curricula on various rotations, interactions between medical and non-medical services, technological issues, and workflow problems. In survey assessments, PEC members viewed the PEC process as a rewarding mentorship experience that provided residents with an opportunity to engage in quality improvement and improve facilitation skills. Firm chiefs were more likely to review and make rotation changes in response to PEC feedback than to traditional written resident evaluations but preferred to receive both forms of feedback rather than either alone CONCLUSIONS: The PEC process at YSM has transformed our program's approach to feedback delivery by engaging residents in the feedback process and providing them with mentored quality improvement and leadership experiences while generating actionable feedback for program-wide change. This has led to PEC groups evaluating additional aspects of residency education.

Burnout in US hematologists and oncologists: impact of compensation models and advanced practice provider support.

Burnout is prevalent throughout medicine. Few large-scale studies have examined the impact of physician compensation or clinical support staff on burnout among hematologists and oncologists. In 2019, the American Society of Hematology conducted a practice survey of hematologists and oncologists in the AMA (American Medical Association) Masterfile; burnout was measured using a validated, single-item burnout instrument from the Physician Work-Life Study, while satisfaction was assessed in several domains using a 5-point Likert scale. The overall survey response rate was 25.2% (n = 631). Of 411 respondents with complete responses in the final analysis, 36.7% (n = 151) were from academic practices and 63.3% (n = 260) from community practices; 29.0% (n = 119) were female. Over one-third (36.5%; n = 150) reported burnout, while 12.0% (n = 50) had a high level of burnout. In weighted multivariate logistic regression models incorporating numerous variables, compensation plans based entirely on relative value unit (RVU) generation were significantly associated with high burnout among academic and community physicians, while the combination of RVU + salary compensation showed no significant association. Female gender was associated with high burnout among academic physicians. High advanced practice provider utilization was inversely associated with high burnout among community physicians. Distinct patterns of career dissatisfaction were observed between academic and community physicians. We propose that the implementation of compensation models not based entirely on clinical productivity increased support for women in academic medicine, and expansion of advanced practice provider support in community practices may address burnout among hematologists and oncologists.

Thrombosis questions from the inpatient wards.

The multifaceted pathophysiologic processes that comprise thrombosis and thromboembolic diseases take on a particular urgency in the hospitalized setting. In this review, we explore 3 cases of thrombosis from the inpatient wards: purpura fulminans, cancer-associated thrombosis with thrombocytopenia, and coronavirus disease 2019 (COVID-19) and the use of dose-escalated anticoagulation therapy and antiplatelet agents. We discuss the evaluation and management of purpura fulminans and the roles of plasma transfusion, protein C and antithrombin replacement, and anticoagulation in treating this disease. We present a framework for evaluating the etiologies of thrombocytopenia in cancer and review 2 strategies for anticoagulation management in patients with cancer-associated thrombosis and thrombocytopenia, including recent prospective data supporting the use of dose-modified anticoagulation based on platelet count. Last, we dissect the major clinical trials of therapeutic- and intermediate-dose anticoagulation and antiplatelet therapy in hospitalized patients with COVID-19, reviewing key recommendations from consensus guidelines while highlighting ways in which institutional and patient-tailored practices regarding antithrombotic therapies in COVID-19 may differ. Together, the cases highlight the diverse and dramatic presentations of macro- and microvascular thrombosis as encountered on the inpatient wards.

COVID-19 and antiphospholipid antibodies.

Antiphospholipid syndrome and the coagulopathy of COVID-19 share many pathophysiologic features, including endotheliopathy, hypercoagulability, and activation of platelets, complement pathways, and neutrophil extracellular traps, all acting in concert via a model of immunothrombosis. Antiphospholipid antibody production in COVID-19 is common, with 50% of COVID-19 patients being positive for lupus anticoagulant in some studies, and with non-Sapporo criteria antiphospholipid antibodies being prevalent as well. The biological significance of antiphospholipid antibodies in COVID-19 is uncertain, as such antibodies are usually transient, and studies examining clinical outcomes in COVID-19 patients with and without antiphospholipid antibodies have yielded conflicting results. In this review, we explore the biology of antiphospholipid antibodies in COVID-19 and other infections and discuss mechanisms of thrombogenesis in antiphospholipid syndrome and parallels with COVID-19 coagulopathy. In addition, we review the existing literature on safety of COVID-19 vaccination in patients with antiphospholipid antibodies and antiphospholipid syndrome.

Impact of COVID-19 on Hematology-Oncology Trainees: A Quantitative and Qualitative Assessment.

PURPOSE: Graduate medical and research training has drastically changed during the COVID-19 pandemic, with widespread implementation of virtual learning, redeployment from core rotations to the care of patients with COVID-19, and significant emotional and physical stressors. The specific experience of hematology-oncology (HO) fellows during the COVID-19 pandemic is not known. METHODS: We conducted a mixed-methods study using a survey of Likert-style and open-ended questions to assess the training experience and well-being of HO fellows, including both clinical and postdoctoral trainee members of the American Society of Hematology and ASCO. RESULTS: A total of 2,306 surveys were distributed by e-mail; 548 (23.8%) fellows completed the survey. Nearly 40% of fellows felt that they had not received adequate mental health support during the pandemic, and 22% reported new symptoms of burnout. Pre-existing burnout before the pandemic, COVID-19-related clinical work, and working in a primary research or nonclinical setting were associated with increased burnout on multivariable logistic regression. Qualitative thematic analysis of open-ended responses revealed significant concerns about employment after training completion, perceived variable quality of virtual education and board preparation, loss of clinical opportunities to prepare for independent clinical practice, inadequate grant funding opportunities in part because of shifting research priorities, variable productivity, and mental health or stress during the pandemic. CONCLUSION: HO fellows have been profoundly affected by the pandemic, and our data illustrate multiple avenues for fellowship programs and national organizations to support both clinical and postdoctoral trainees.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines. RESULTS: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19-related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. CONCLUSION: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19-related acute illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis for patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 and May 2021 as part of the living phase of these guidelines. RESULTS: The panel made 1 additional recommendation: a conditional recommendation for the use of prophylactic-intensity over therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of thrombotic and bleeding risk. CONCLUSIONS: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation for patients with COVID-19-related critical illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation. CONCLUSIONS: This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis.

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. Research Question: How does in-hospital mortality compare with intermediate- versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19? Study Design and Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. CONCLUSIONS: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19-related critical illness and acute illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness or acute illness who do not have confirmed or suspected VTE. CONCLUSIONS: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available.

Which patients with unprovoked venous thromboembolism should receive extended anticoagulation with direct oral anticoagulants? A systematic review, network meta-analysis, and decision analysis.

INTRODUCTION: Direct oral anticoagulants (DOACs) effectively prevent recurrent venous thromboembolism (VTE). However, it is unknown which agents should be used to prevent recurrent VTE and which patients with unprovoked VTE should receive extended anticoagulation. We therefore sought to compare the efficacy and safety among DOACs for secondary prevention of VTE. We also determined a risk-adapted threshold for initiating extended anticoagulation based on the likelihood of VTE recurrence (without treatment) and bleeding (with treatment) in patients with unprovoked VTE. METHODS: Our systematic review of randomized controlled trials compares extended anticoagulation with DOACs to another DOAC, aspirin, or placebo for the prevention of recurrent VTE. We searched PubMed, EMBASE, and Cochrane Registry of Controlled Trials (CENTRAL) in October 2018. Our outcomes of interest were VTE recurrence, major bleeding, and all clinically relevant bleeding. We used network meta-analysis to make indirect comparisons among DOACs. We populated the threshold decision-analytic model with data from our meta-analysis to determine the risk of VTE recurrence above which the benefits of extended anticoagulation outweigh the harms compared with no treatment. RESULTS: We included four, high-quality, randomized trials comprising 8386 participants. Low-dose apixaban, full-dose apixaban, low-dose rivaroxaban, full-dose rivaroxaban, and dabigatran reduce VTE recurrence compared with placebo (RR = 0.19, 95% CI, 0.12-0.31; RR = 0.20, 95% CI, 0.12-0.32; RR = 0.08, 95% CI, 0.03-0.27; RR = 0.14, 95% CI, 0.06-0.35; RR = 0.19, 95% CI, 0.09-0.40, respectively). No DOACs increased major bleeding risk compared with placebo. A VTE recurrence risk above 0.3% to 0.4% at approximately 1 year is the threshold to treat a patient with unprovoked VTE with extended anticoagulation (with any DOAC). CONCLUSIONS: All DOACs exhibit comparable efficacy for the prevention of recurrent VTE. Given that the risk of VTE recurrence is much higher than the calculated threshold for treatment, extended thromboprophylaxis should be considered in all patients with unprovoked VTE who do not have increased bleeding risk.