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Background This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously. Methods We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. Results The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update. Conclusion New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations.

Background This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously. Methods We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. Results The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update. Conclusion New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations.

Background Life dissatisfaction varies with different factors––particularly in the presence of chronic conditions, such as cancer. The combination of cancer and mental health disorders may increase life dissatisfaction due to lowered resilience against stress. We sought to determine if life dissatisfaction is higher in Canadians aged 40 and above with cancer compared to the cancer‐free population and if there is a synergistic effect between cancer and mental health disorder on life dissatisfaction. Methods We conducted a cross‐sectional study using the 2015–2016 Canadian Community Health Survey. We included 67,294 subjects aged 40+, and evaluated the association between cancer, mental health disorders, and life dissatisfaction using logistic regression and odds ratios (ORs) while adjusting for age, sex, marital status, education level, and chronic conditions. Relative excess risk due to interaction (RERI), attributional proportion due to interaction (AP), and Synergy index (S‐index), were calculated to determine the significance of additive interaction. Results Compared to the cancer‐free population, life dissatisfaction was higher in patients with cancer (OR 2.44, 95% CI: 1.88–3.16) and mental health disorders (OR 5.17, 95% CI: 4.56–5.85). The adjusted ORs for life dissatisfaction were 2.45 (95% CI: 1.74–3.43) and 5.17 (95% CI: 4.55–5.87) for cancer and mental health disorders, respectively, but when both conditions were present, the OR increased to 12.50 (95% CI: 8.40–18.62). The results suggested a synergistic interaction (RERI: 5.89 [95% CI: 0.91–10.87]; AP: 0.47 [95% CI: 0.25–0.69]; and S‐index: 2.05 [95% CI: 1.30–3.23]). Conclusion This study showed higher life dissatisfaction in cancer and mental health disorder patients. A synergistic effect was detected between cancer and mental health disorder on life dissatisfaction. These results suggest cancer patients with mental health disorders require additional support and psychological resources to improve their quality of life.

Background Patients on dialysis are at higher risk of major bleeding and recurrent thrombosis creating acute venous thromboembolism (VTE) treatment challenges. DOACs represent an interesting option but there are concerns of bioaccumulation and increased bleeding risk. Anti-Xa trough levels may be used to monitor for bioaccumulation but there is little data. Case presentation We describe a case, a 51 yo female, 36 kg on hemodialysis with a provoked acute upper extremity deep vein thrombosis in whom body habitus and calciphylaxis contraindicated the use of standard therapy. She received apixaban 2.5 mg twice daily for 6 weeks. The apixaban anti-Xa trough levels were measured weekly 12 h after the morning dose and ranged from 58 to 84 ng/mL, similar to expected levels with normal renal function. There were no adverse events in the 3 months follow-up. Conclusions We saw no evidence of bioaccumulation indicating a potential role for low dose apixaban for acute VTE in dialysis patients.

Background Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE. This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Methods A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. Results The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. Conclusions The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.

Background The challenging clinical dilemma of detecting pulmonary embolism (PE) in suspected patients is encountered in a variety of healthcare settings. We hypothesized that the optimal diagnostic approach to detect these patients in terms of safety and efficiency depends on underlying PE prevalence, case mix, and physician experience, overall reflected by the type of setting where patients are initially assessed. The objective of this study was to assess the capability of ruling out PE by available diagnostic strategies across all possible settings. Methods and findings We performed a literature search (MEDLINE) followed by an individual patient data (IPD) meta-analysis (MA; 23 studies), including patients from self-referral emergency care (n = 12,612), primary healthcare clinics (n = 3,174), referred secondary care (n = 17,052), and hospitalized or nursing home patients (n = 2,410). Multilevel logistic regression was performed to evaluate diagnostic performance of the Wells and revised Geneva rules, both using fixed and adapted D-dimer thresholds to age or pretest probability (PTP), for the YEARS algorithm and for the Pulmonary Embolism Rule-out Criteria (PERC). All strategies were tested separately in each healthcare setting. Following studies done in this field, the primary diagnostic metrices estimated from the models were the “failure rate” of each strategy—i.e., the proportion of missed PE among patients categorized as “PE excluded” and “efficiency”—defined as the proportion of patients categorized as “PE excluded” among all patients. In self-referral emergency care, the PERC algorithm excludes PE in 21% of suspected patients at a failure rate of 1.12% (95% confidence interval [CI] 0.74 to 1.70), whereas this increases to 6.01% (4.09 to 8.75) in referred patients to secondary care at an efficiency of 10%. In patients from primary healthcare and those referred to secondary care, strategies adjusting D-dimer to PTP are the most efficient (range: 43% to 62%) at a failure rate ranging between 0.25% and 3.06%, with higher failure rates observed in patients referred to secondary care. For this latter setting, strategies adjusting D-dimer to age are associated with a lower failure rate ranging between 0.65% and 0.81%, yet are also less efficient (range: 33% and 35%). For all strategies, failure rates are highest in hospitalized or nursing home patients, ranging between 1.68% and 5.13%, at an efficiency ranging between 15% and 30%. The main limitation of the primary analyses was that the diagnostic performance of each strategy was compared in different sets of studies since the availability of items used in each diagnostic strategy differed across included studies; however, sensitivity analyses suggested that the findings were robust. Conclusions The capability of safely and efficiently ruling out PE of available diagnostic strategies differs for different healthcare settings. The findings of this IPD MA help in determining the optimum diagnostic strategies for ruling out PE per healthcare setting, balancing the trade-off between failure rate and efficiency of each strategy.

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non–high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice.

Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5years in patients with a first unprovoked VTE. Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. Results: Twenty-six studies and 15603 patients were included in the analysis. During 11631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03–1.84) and 0.09 (0.04–0.16), with 5-year cumulative incidences of 7.1% (3.0%–13.2%) and 1.2% (0.4%–4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77–1.44) with direct oral anticoagulants and 1.55 (1.01–2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%–8.7%). Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE. © 2021 International Society on Thrombosis and Haemostasis.

Background: Apixaban (2.5 mg) taken twice daily has been shown to substantially reduce the risk of venous thromboembolism (VTE) compared with placebo for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE. We aimed to compare the health system costs and health benefits associated with primary thromboprophylaxis using apixaban with those associated with the current standard of care (where no primary thromboprophylaxis is given), from the perspective of Canada’s publicly funded health care system in this subpopulation of patients with cancer over a lifetime horizon. Methods: We performed a cost–utility analysis to estimate the incremental cost per quality-adjusted life-year (QALY) gained with primary thromboprophylaxis using apixaban. We obtained baseline event rates and the efficacy of apixaban from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial on apixaban prophylaxis. We estimated relative risk for bleeding, risk of complications associated with VTE treatment, mortality rates, costs and utilities from other published sources. Results: Over a lifetime horizon, apixaban resulted in lower costs to the health system (Can$7902.98 v. Can$14 875.82) and an improvement in QALYs (9.089 v. 9.006). The key driver of cost–effectiveness results was the relative risk of VTE as a result of apixaban. Results from the probabilistic analysis showed that at a willingness to pay of Can$50 000 per QALY, the strategy with the highest probability of being most cost-effective was apixaban, with a probability of 99.87%. Interpretation: We found that apixaban is a cost-saving option for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE.

Objective To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. Design Prospective, double blind, randomised controlled trial. Setting 10 thrombosis research sites in Canada and India between February 2007 and March 2016. Participants 1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure. Intervention Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure. Main outcome measures Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure. Results The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference −0.3%, 95% confidence interval −1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference −0.7, 95% confidence interval −2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups. Conclusions In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism. Trial registration Clinicaltrials.gov NCT00432796 .

Background: Major bleeding is the most serious complication of oral anticoagulation. Consensus criteria to define major bleeding have been established by the International Society for Thrombosis and Haemostasis (ISTH), Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI). Significant variability exists across these definitions, and their agreement for identifying oral anticoagulant (OAC) related major bleeding is unknown. Furthermore, the association between each definition and mortality in cases of OAC bleeding has not been evaluated. We therefore, sought to evaluate the agreement of cases identified as major bleeding by the ISTH, BARC and TIMI definitions, and to assess associated in-hospital (emergency department or inpatient) and 30-day mortality of cases identified by these criteria. Methods: We used an existing dataset of individuals ≥66 years in Ontario, Canada, who presented to one of five tertiary care institutions with OAC related bleeding across three cities from 2010-2015. Detailed clinical data on consecutive episodes of OAC-associated bleeding were linked to population-based databases held at the Institute for Clinical Evaluative Sciences. We calculated Cohen's κ for agreement between the three major bleeding definitions, and used Pearson's χ2 to determine any differences in in-hospital and 30-day mortality for cases defined as major bleeding by ISTH, BARC and TIMI criteria. Results: We included 2,002 cases of OAC related bleeding in the analysis (460 on direct oral anticoagulants, 1,542 on warfarin). ISTH, BARC and TIMI major bleeding definitions were met in 75%, 77% and 29% of cases, respectively. 18% of cases did not meet criteria for major bleeding by any definition. Age, sex, CHA2DS2-VASc and HAS-BLED score, as well as proportion of chronic kidney disease were similar across ISTH-, BARC- and TIMI-defined cases. Over 9 in 10 cases of TIMI-defined major bleeding events involved an intracranial hemorrhage (94.4%), compared to 37% and 36% of cases identified by ISTH or BARC definitions respectively (p Conclusions: Among patients with OAC-associated bleeding, major bleeding events identified by ISTH and BARC criteria showed good agreement and similar prognostic utility. Meanwhile, TIMI criteria identified patients with higher clinical risk and subsequent mortality. Patients presenting with OAC-associated bleeding who did not fulfill ISTH or BARC major bleeding criteria had considerable risk of 30-day mortality and was even higher among those not meeting the TIMI criteria. Our findings suggest the need to refine current major bleeding definitions to identify additional patients at risk of death. Disclosures Wells: Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria. Sholzberg:Amgen: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Shire: Research Funding.

Introduction The risk of recurrent venous thromboembolism (VTE) after combined oral contraceptive (COC) use is variably reported. We assessed the long-term risk of recurrent VTE in women on COC at the time of a first VTE, in comparison to women without COC use. Our secondary aim assessed the impact of COC use on the recurrent VTE risk in high-risk and low-risk hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 μg/L; obesity with body mass index ≥30; or older age, ≥65 years (HERDOO2) subgroups. Methods The REVERSE cohort study derived the HERDOO2 clinical decision rule to predict recurrent VTE in patients who discontinued anticoagulation after 5-7 months for a first unprovoked VTE. Incidence rates of recurrent VTE among women with and without COC exposure were calculated as the number of recurrent VTE over the number of person-years of follow-up, and Cox proportional hazards model was used to compare risks between groups. Results The risk of recurrent VTE among COC users was 1.1% (95% confidence interval [CI] 0.3-2.9) per patient-year as compared with 3.2% per patient-year (95% CI 2.4-4.3) among nonusers (hazard ratio 0.37; 95% CI 0.1-1.0). Women who were COC users and high risk by HERDOO2 score had a recurrence rate of 3.5% (95% CI 0.4-12.5) compared with 6.1% (95% CI 4.3-8.5) among women who were non-COC users and at high risk by HERDOO2 score (HR 0.6, 95% CI 0.1-2.5). Conclusions Women who were COC users at the time of an otherwise unprovoked VTE event had a lower VTE recurrence rate during long-term follow-up, compared with nonusers. The use of HERDOO2 rule may help identify higher risk women with COC use.

BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Background Previous studies regarding survival in patients with splanchnic vein thrombosis (SVT) are limited. This study measured overall survival in a large cohort of SVTs through linkage to population‐based data. Methods and Results Using a previously derived text‐search algorithm, we screened the reports of all abdominal ultrasound and contrast‐enhanced computed tomography studies at The Ottawa Hospital over 14 years. Screen‐positive reports were manually reviewed by at least 2 authors to identify definite SVT cases by consensus. Images of uncertain studies were independently reviewed by 2 radiologists. One thousand five hundred sixty‐one adults with SVT (annual incidence ranging from 2.8 to 5.9 cases/10 000 patients) were linked with population‐based data sets to measure the presence of concomitant cancer and survival status. Thrombosis involved multiple veins in 314 patients (20.1%), most commonly the portal vein (n=1410, 90.3%). Compared with an age‐sex‐year matched population, patients with SVT had significantly reduced survival in particular with local cancer (adjusted relative excess risk for recent cases 12.0 [95% CI, 9.8–14.6] and for remote cases 9.7 [7.7–12.2]), distant cancer (relative excess risk for recent cases 5.7 [4.5–7.3] and for remote cases 5.4 [4.4–6.6]), cirrhosis (relative excess risk 8.2 [5.3–12.7]), and previous venous thromboembolism (relative excess risk 3.8 [2.4–6.0]). One hundred fifty (23.9%) of patients >65 years of age were anticoagulated within 1 month of diagnosis. Conclusions SVT is more common than expected. Most patients have cancer and the portal vein is by far the most common vein involved. Compared with the general population, patients with SVT had significantly reduced survival, particularly in patients with concomitant cancer, cirrhosis, and previous venous thromboembolic disease. Most elderly patients did not receive anticoagulant therapy.

Objective The Stress Management and Resilience Training (SMART) program is an evidence-based intervention designed to build resilience in physicians in clinical practice. The objective of the current study was to assess the impact of the SMART program on academic physicians’ levels of resilience, subjective happiness, stress, and anxiety, and specifically during the implementation of a new hospital-wide Health Information System (HIS). Methods A total of 40 physicians in a tertiary care academic hospital were randomized (allocation ratio 1:1) to either the SMART intervention or the control condition. The SMART intervention consisted of one mandatory two-hour in-person workshop and an optional 24-week online program, designed to support the materials delivered in the workshop. Outcome measures were assessed using validated scales administered online at baseline and at 3-months and 6-months follow-up. Results After adjusting for baseline levels of each outcome, no statistically significant intervention effect was observed for resilience, subjective happiness, stress or anxiety at 3-months or 6-months follow-up. However, physicians in the intervention group demonstrated improvements in resilience, stress and anxiety at follow-up that were within the range of clinically relevant differences. Conclusions The findings of this exploratory study provide modest support that the SMART intervention may be beneficial for proactively addressing physician wellness during the implementation of a new HIS and that larger randomized trials are warranted. Trial registration NCT04384861.

Background Thromboprophylaxis for ambulatory patients with cancer is effective, although uncertainties remain on who should be targeted. Using D-dimer values from individuals enrolled to the AVERT trial, we sought to identify and validate a more efficient venous thromboembolism (VTE) risk threshold for thromboprophylaxis. Materials and Methods The AVERT trial compared thromboprophylaxis with apixaban with placebo among patients with cancer with a Khorana Risk Score ≥2. The D-dimer measured at randomization was used to calculate an individualized 6-month VTE risk using the validated CATScore. A modified intention-to-treat analysis was used to assess efficacy (VTE) and safety (major and overall bleeding) in the (a) complete cohort and (b) ≥8% and Results Five hundred seventy-four patients were randomized in the AVERT trial; 466 (81%) with baseline D-dimer were included in the study. Two hundred thirty-seven subjects received apixaban; 229 received placebo. In the complete cohort, there were 13 (5.5%) VTE events in the apixaban arm compared with 26 (11.4%) events in the placebo arm (adjusted hazard ratio [aHR] 0.49 [0.25–0.95], p < .05). Number needed to treat (NNT) to prevent one VTE = 17. Eighty-two (35%) and 72 (31%) patients in the apixaban and placebo arms, respectively, had a 6-month VTE risk ≥8%. In this subgroup, 7 (8.4%) VTE events occurred with apixaban and 19 (26.3%) events with placebo (aHR 0.33 [0.14-0.81], p < .05), NNT = 6. Individuals with a VTE risk Conclusion A 6-month VTE risk threshold of ≥8% increases the efficiency of risk-targeted thromboprophylaxis in ambulatory patients with cancer. Implications for Practice Ambulatory patients with cancer receiving chemotherapy have an increased risk of venous thromboembolism (VTE). A Khorana Risk Score (KRS) ≥2 is currently the suggested threshold for thromboprophylaxis. Using baseline D-dimer values from individuals enrolled to the AVERT trial, this retrospective validation study identifies a 6-month VTE risk of ≥8% as a more efficient threshold for thromboprophylaxis. At this threshold, the number needed to treat to prevent one VTE is 6, compared with 17 when using a KRS ≥2. Conversely, individuals with a predicted risk of

In patients with cancer-associated venous thromboembolism, knowledge of the estimated rate of recurrent events is important for clinical decision-making regarding anticoagulant therapy. The Ottawa score is a clinical prediction rule designed for this purpose, stratifying patients according to their risk of recurrent venous thromboembolism during the first six months of anticoagulation. We conducted a systematic review and meta-analysis of studies validating either the Ottawa score in its original or modified versions. Two investigators independently reviewed the relevant articles published from 1st June 2012 to 15th December 2018 and indexed in MEDLINE and EMBASE. Nine eligible studies were identified; these included a total of 14,963 patients. The original score classified 49.3% of the patients as high-risk, with a sensitivity of 0.7 [95% confidence interval (CI): 0.6-0.8], a 6-month pooled rate of recurrent venous thromboembolism of 18.6% (95%CI: 13.9-23.9). In the low-risk group, the recurrence rate was 7.4% (95%CI: 3.4-12.5). The modified score classified 19.8% of the patients as low-risk, with a sensitivity of 0.9 (95%CI: 0.4-1.0) and a 6-month pooled rate of recurrent venous thromboembolism of 2.2% (95%CI: 1.6-2.9). In the high-risk group, recurrence rate was 10.2% (95%CI: 6.4-14.6). Limitations of our analysis included type and dosing of anticoagulant therapy. We conclude that new therapeutic strategies are needed in patients at high risk for recurrent cancer-associated venous thromboembolism. Low-risk patients, as per the modified score, could be good candidates for oral anticoagulation. (This systematic review was registered with the International Prospective Registry of Systematic Reviews as: PROSPERO CRD42018099506).

Essentials Exercise Limitation 1 year after an acute pulmonary embolism is common.Serial imaging after acute pulmonary embolism is not well described and how it affects exercise limitation remains unknown.1 year after an acute pulmonary embolism chronic changes are common, more so on perfusion lung scanning than CT pulmonary angiography, but imaging findings did not predict exercise limitation. Introduction Risk factors for exercise limitation after acute pulmonary embolism (PE) are unknown. As a planned sub‐study of the prospective, multicenter ELOPE (Evaluation of Long‐term Outcomes after PE) Study, we aimed to describe the results of serial imaging by computed tomography pulmonary angiography (CTPA) and perfusion scan during 1 year after a first episode of acute pulmonary embolism, and to assess the association between imaging parameters and exercise limitation at 1 year. Methods In a prospective cohort study, 100 patients were recruited between June 2010 and February 2013 at five Canadian university–affiliated hospitals. CT pulmonary angiography was performed at baseline and 12 months, perfusion scan at 6 and 12 months, and cardio‐pulmonary exercise testing at 1 and 12 months. Imaging parameters included: on CT pulmonary angiography, CT obstruction index (CTO) (% clot burden in the pulmonary vasculature), and on perfusion scan, pulmonary vascular obstruction (PVO) (% perfusion defect). Abnormal cardio‐pulmonary exercise test (primary outcome) was defined as percent of predicted peak oxygen uptake (VO2) 80% on 1‐year cardio‐pulmonary exercise testing (1.4% [0%; 5.7%] vs 1.0% [0%; 2.4%]; P = .70). Mean (SD) pulmonary vascular obstruction at 6 and at 12 months was similar in patients with percent‐predicted VO2 peak 80% (6 months: 5.9% [0%; 10.4%] vs 6.2% [4.5%; 9.0%]; P = .91; 12 months: 5.1% [0%; 10.2%] vs 6.0% [0%; 9.7%]; P = .71). Conclusions Imaging findings after pulmonary embolism did not predict exercise limitation. Residual thrombus does not appear to explain long‐term functional limitation after pulmonary embolism.

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.

Pulmonary embolism (PE) studies used direct oral anticoagulants (DOACs) with or without initial heparin. We aimed to (1) evaluate if PE patients benefit from initial heparin; (2) describe patient characteristics in the DOAC studies; and (3) investigate whether the anatomical extent of PE correlates with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, cause of PE, and recurrence rate. Our methods were (1) an indirect meta-analysis comparing the recurrence risk in DOAC-treated patients with or without initial heparin to those patients given heparin/vitamin K antagonist (VKA). (2) To compare the PE studies, information was extracted on baseline characteristics including anatomical extent. (3) The Hokusai-VTE study was used to correlate anatomical extent of PE with NT-proBNP levels, causes of PE, and recurrent venous thromboembolism (VTE). The meta-analysis included 11,539 PE patients. The relative risk of recurrent VTE with DOACs versus heparin/VKAs was 0.8 (95% confidence interval [CI]: 0.6–1.1) with heparin lead-in and 1.1 (95% CI: 0.8–1.5) without heparin. In the DOAC studies, the proportion of patients with extensive PE varied from 24 to 47%. In Hokusai-VTE, NT-proBNP was elevated in 4% of patients with limited and in over 60% of patients with extensive disease. Cause of PE and anatomical extent were not related. Recurrence rates increased from 1.6% with limited to 3.2% with extensive disease in heparin/edoxaban-treated patients, and from 2.4 to 3.9% in heparin/warfarin recipients. In conclusion, indirect evidence suggests a heparin lead-in before DOACs may be advantageous in PE. Anatomical extent was related to elevated NT-proBNP and outcome, but not to PE cause.

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin.

Background Patients with cancer have an increased risk of venous thromboembolism (VTE) and associated morbidity and mortality. Renal dysfunction is more common in patients with cancer, leading to heightened risks of bleeding and thrombotic complications. In the AVERT trial, thromboprophylaxis with apixaban resulted in a significantly lower rate of VTE and higher rate of major bleeding compared to placebo among intermediate-to-high-risk ambulatory cancer patients starting chemotherapy. As apixaban depends on some degree of renal clearance, there may be concerns regarding the safety and efficacy of apixaban thromboprophylaxis in patients with renal insufficiency. In this post-hoc analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis according to renal function at randomization. Methods Eligible patients were randomized to apixaban (2.5mg twice daily) or placebo. First dose of study drug was given within 24 hours of the first chemotherapy administration with the intended treatment period of 180 days. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated accordingly to renal function (calculated creatinine clearance [CrCl] by Cockcroft-Gault Equation) at randomization. Patients with CrCl < 30 mL/min were excluded from the trial. The primary efficacy outcome was objectively confirmed major VTE (proximal deep vein thrombosis or pulmonary embolism) within 180 days (±3 days) following randomization. The primary efficacy outcome was evaluated by modified intention-to-treat analysis, which included all patients who had undergone randomization and received at least one dose of study medication on or before day 180 (±3 days). The primary safety outcome was major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. The primary safety outcome was evaluated by on-treatment analysis, when events were counted only if they occurred on study drugs or up to two days after discontinuation of the study drugs. Secondary outcomes included clinically relevant non-major bleeding and overall mortality. Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis (288 apixaban and 275 placebo). Upon randomization, 66 (11.5%) patients had CrCl < 60 mL/min and 508 (88.5%) patients had CrCl ≥ 60 mL/min. Patients with CrCl < 60 mL/min were significantly older, more female, had lower weight and fewer with body mass index (BMI) > 35 kg/m 2 and poorer ECOG performance status (Table 1). In patients with CrCl < 60 mL/min, VTE occurred in no patient on apixaban compared to 1 on placebo, and major bleeding episode occurred in 1 on apixaban and 0 on placebo. In patients with CrCl ≥ 60 mL/min, VTE occurred in 13 out of 257 (5.1%) in the apixaban group and 28 out of 242 (11.6%) in the placebo group [HR 0.41 (95% CI 0.26-0.64), p=0.0001] (Table 2). There were no significant differences between apixaban and placebo groups in major bleeding and clinically relevant non-major bleeding events. Overall mortality was significantly lower in the apixaban group (HR 0.25 [95% CI 0.13-0.45], p Conclusions In the AVERT trial, patients with CrCl < 60 mL/min were significantly older, more likely to be female, with lower weight or BMI and poorer ECOG performance status. There were very few VTE or major bleeding events in patients with CrCl < 60 mL/min. In patients with CrCl ≥ 60 mL/min, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE and overall mortality compared to placebo, with no significant differences in the rates of major bleeding or clinically relevant non-major bleeding events. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria. Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. OffLabel Disclosure: apixaban for primary thromboporphylaxis in ambulatory cancer patients receiving chemotherapy

Background Venous thromboembolism (VTE) is a common complication in ambulatory patients with cancer initiating systemic chemotherapy. Central venous catheters (CVCs) used for chemotherapy administration are associated with a heightened risk of VTE in this patient population. Primary thromboprophylaxis using a direct oral anticoagulant decreases the risk of VTE without significantly increasing the risk of major bleeding complications in ambulatory cancer patients at intermediate-to-high risk of VTE with a Khorana risk score of ≥ 2. We sought to determine the efficacy and safety of apixaban in intermediate-to-high risk patients with cancer and a CVC. Methods This post-hoc analysis was done using the AVERT trial data, which was a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban for primary thromboprophylaxis in intermediate-to-high risk patients with cancer initiating chemotherapy. The primary efficacy outcome was major VTE within 180 days of randomization and the primary safety outcome was major bleeding. The hazard ratios (HRs) for the primary efficacy and safety outcomes in patients with and without CVC were calculated using a Cox regression model controlling for age, gender, and study center. Results A total of 217 patients were included in the subgroup analyses with 126 and 91 patients receiving apixaban or placebo, respectively. The baseline characteristics are depicted in Table 1. Major VTE occurred in 6 (4.8%) patients in the apixaban group and 17 (18.7%) patients in the placebo group (HR 0.26; 95% CI, 0.14-0.47; p Conclusions Primary thromboprophylaxis with apixaban in patients with cancer and a CVC seems to reduce the risk of VTE without increasing the risk of major bleeding. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Servier: Honoraria. Carrier: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; Servier: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer and is associated with significant morbidity and healthcare expenditure. The risk of VTE is also increased following the insertion of a central venous catheter (CVC) for chemotherapy deliverance and supportive care. The risks and benefits of primary thromboprophylaxis in patients with cancer and newly inserted CVC are unclear. Objective We sought to assess the rates of VTE and major bleeding complications to determine the safety and efficacy of primary thromboprophylaxis in adult patients with cancer and a CVC. Methods A systematic search of MEDLINE, EMBASE, and all EBM was conducted. Randomized controlled trials (RCTs) of adult patients with cancer and a CVC receiving primary thromboprophylaxis or observation/placebo were included. The primary efficacy and safety outcomes were total VTE and major bleeding episodes, respectively. Results A total of 9 RCTs (3155 patients) were included in the analysis. The total rates of VTE were significantly lower in patients receiving primary thromboprophylaxis compared to those not receiving primary prevention (7.6% vs. 13%; Odds Ratio (OR) 0.51, 95% CI 0.32 to 0.82, p < 0.01, I² = 52%) (Figure 1). The rate of major bleeding complication was not increased in patients receiving thromboprophylaxis (0.9% vs. 0.7%; OR 1.12, 95% CI 0.29 to 4.40, p = 0.87, I² = 32%) (Figure 2). Conclusions Primary thromboprophylaxis significantly reduced the risk of VTE without increasing the risk of major bleeding complications in patients with cancer and CVC. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Ikesaka: LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wells: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; BMS/Pfizer: Research Funding; Servier: Honoraria. Carrier: Servier: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

Background We hypothesized that the clinical course of venous thromboembolism in patients with active cancer may differ according to the specificities of primary tumor site. Aim and Methods We used data from RIETE (international registry of patients with venous thromboembolism) to compare the clinical venous thromboembolism-related outcomes during the course of anticoagulation in patients with one of the 4 more frequent cancers (breast, prostate, colorectal, or lung cancer). Results As of September 2014, 3947 cancer patients were recruited, of whom 938 had breast, 629 prostate, 1189 colorectal, and 1191 lung cancer. Overall, 55% had metastatic disease (42%, 36%, 53%, and 72%, respectively). During the course of anticoagulant therapy (mean duration, 139 days), the rate of thromboembolic recurrences was similar to the rate of major bleeding in patients with breast (5.6 [95% confidence interval (CI), 3.8-8.1] vs 4.1 [95% CI, 2.7-5.9] events per 100 patient-years) or colorectal cancer (10 [95% CI, 7.6-13] vs 12 [95% CI, 9.4-15] per 100 patient-years). In contrast, in patients with prostate cancer, the rate of venous thromboembolic recurrences was half the rate of major bleeding (6.9 [95% CI, 4.4-10] vs 13 [95% CI, 9.2-17] events per 100 patient-years), whereas in those with lung cancer, the rate of thromboembolic recurrences was twofold higher than the rate of major bleeding (27 [95% CI, 22-23] vs 11 [95% CI, 8.6-15] per 100 patient-years). Conclusions Significant differences in the clinical profile of venous thromboembolic-related outcomes were observed according to the site of cancer. These findings suggest the development of cancer-specific anticoagulant strategies as an area for further research.

Background: The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6 months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).Methods: To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6 months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2).Results: Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2.Conclusions: This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons. (C) 2016 Elsevier Ltd. All rights reserved.

Background It is unclear if direct oral anticoagulant (DOAC) is efficacious and safe for prophylaxis of venous thromboembolism (VTE) in ambulatory patients with cancer. Methods We performed a systematic review using EMBASE, MEDLINE, and CENTRAL. Inclusion criteria included adult ambulatory patients with cancer, prophylactic use of DOAC, and randomized controlled trials. Exclusion criteria included pediatric patients, inpatient or postoperative setting, therapeutic indication of DOAC, or non-phase III randomized controlled trial. Two authors screened/reviewed articles and abstracted the data. Meta-analysis was performed using random-effects model. Efficacy outcome included overall and symptomatic VTE incidence during the first 6 months. Safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB) incidence during the on-treatment period. Subgroup analysis was performed for intermediate- and high-risk Khorana score. Results A total of 202 records were identified and 28 full-text articles were assessed. Two studies with 1415 participants were included for meta-analysis. For DOAC vs placebo, the relative risks for overall and symptomatic VTE incidence by 6 months were 0.56 (0.35-0.89) and 0.58 (0.29-1.13), respectively. The relative risks for major bleeding and CRNMB while on-treatment were 1.96 (0.80-4.82) and 1.28 (0.74-2.20), respectively. Patients with high-risk Khorana score (3+) derived the largest absolute risk reduction of VTE. Conclusions Low-dose DOAC reduces the rate of overall VTE in higher risk cancer patients starting systemic chemotherapy. It may reduce the rate of symptomatic VTE but increase the likelihood of bleeding.

Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis.We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode.Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24).Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Immediate initiation of anticoagulant therapy is imperative when acute venous thromboembolism (VTE) is diagnosed; 3 months is the minimum duration of treatment. Subsequently, the choice between anticoagulant agents and the continuation of treatment should be guided by the etiology of the VTE event.

BACKGROUND: Using data from the Reduced-Dose Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism (EINSTEIN-CHOICE) trial, this study assessed cost impact of continued anticoagulation therapy with rivaroxaban vs aspirin.METHODS: Total health-care costs (2016 USD) associated with rivaroxaban and aspirin were calculated as the sum of clinical event costs and drug costs from a US managed care perspective. Clinical event costs were calculated by multiplying event rate by cost of care. One-year Kaplan-Meier clinical event rates for recurrent pulmonary embolism, recurrent DVT, all-cause mortality, and bleeding were obtained from EINSTEIN-CHOICE. Cost of care was determined by literature review. Drug costs were the product of drug price (wholesale acquisition cost) and treatment duration. A one-way sensitivity analysis was conducted.RESULTS: Rivaroxaban users had lower per patient per month (PPPM) clinical event costs compared with aspirin users ($123, $243, and $381 for rivaroxaban 10 mg, rivaroxaban 20 mg, and aspirin, respectively). However, vs aspirin, PPPM total health-care costs were $24 higher for patients treated with rivaroxaban 10 mg ($143 higher for rivaroxaban 20 mg) due to higher cost of rivaroxaban. With a 15% discount for rivaroxaban 10 mg, the lower cost of clinical events for the rivaroxaban-treated patients more than fully offset the higher drug costs, and yielded a $19 lower total health-care cost.CONCLUSIONS: Continued therapy with rivaroxaban 10 and 20 mg vs aspirin was associated with lower clinical event costs but higher total health-care costs; with a 15% drug discount rivaroxaban 10 mg had lower total health-care costs than aspirin.

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown if the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged

In past decades, stark differences in practice pattern, cost, and outcomes of care across regions with similar health demographics have prompted calls for reform. As health systems answer the growing call for accountability in the form of quality indices, while responding to increased scrutiny on practice variation in the form of pay for performance (P4P), a rift is widening between the system and individual patients. Currently, three areas are inadequately considered by P4P structures based largely on physician adherence to guidelines: diversity of patient values and preferences; time and financial burden of therapy in the context of multimorbidity; and narrow focus on quantitative measures that distract clinicians from providing optimal care. As health care reform efforts place greater emphasis on value-for-money of care delivered, they provide an opportunity to consider the other “value”—the values of each patient and care delivery that aligns with them. The inherent balance of risks and benefits in every treatment, especially those involving chronic conditions, calls for engagement of patients in decision-making processes, recognizing the diversity of preferences at the individual level. Shared decision making (SDM) is an attractive option and should be an essential component of quality health care rather than its adjunct. Four interwoven steps toward the meaningful implementation of SDM in clinical practice—embedding SDM as a health care quality measure, “real-world” evaluation of SDM effectiveness, pursuit of an SDM-favorable health system, and patient-centered medical education—are proposed to bring focus back to the beneficiary of health care accountability, the patient.