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Immune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders.To develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia.We designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict-ITP Tool. The case definition for ITP was a platelet count less than 100 × 10The final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism-corrected c-statistic was 0.83, the calibration slope was 0.88, and calibration-in-the-large for all performance measures was0.001 with standard error0.001, indicating good discrimination and excellent calibration.The Predict-ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP.

Background: The use of direct oral anticoagulants (DOACs) in obese patients is uncertain. It is unclear if body mass index (BMI) affects the safety and efficacy of DOACs for the primary prevention of venous thromboembolism (VTE) in high-risk ambulatory patients with cancer. We sought to determine the outcomes associated with the use of apixaban for the primary prevention of cancer-associated VTE according to BMI. Methods: The randomized, double-blinded, placebo-controlled AVERT trial evaluated apixaban thromboprophylaxis in intermediate-to-high risk ambulatory cancer patients receiving chemotherapy. For this post-hoc analysis, the primary efficacy and safety outcomes were objectively confirmed VTE and clinically relevant bleeding (major and clinically relevant non-major bleeding), respectively. Obesity was defined as BMI ≥30 kg/m2. Results: Among 574 patients randomized, 217 (37.8 %) patients had BMI ≥30 kg/m2. Obese patients were overall younger, more likely to be female, had higher creatinine clearance and hemoglobin, lower platelet count, and better ECOG performance status. Compared to placebo, apixaban thromboprophylaxis was associated with reduced VTE in both obese (hazard ratio [HR] 0.26; 95 % confidence interval [CI], 0.14–0.46; p < 0.0001) and non-obese (HR 0.54; 95%CI, 0.29–1.00; p = 0.049) patients. The HR for clinically relevant bleeding (apixaban vs. placebo) was numerically higher in obese (2.09; 95%CI, 0.96–4.51; p = 0.062) than non-obese subjects (1.23; 95%CI, 0.71–2.13; p = 0.46), but overall in line with the risks observed in the general trial population. Conclusions: In the AVERT trial enrolling ambulatory cancer patients receiving chemotherapy, we found no substantial differences in the efficacy or safety of apixaban thromboprophylaxis across obese and non-obese subjects.

Objective The SOX-PTS, Amin, and Méan models are three different clinical prediction scores stratifying the risk for postthrombotic syndrome (PTS) development in patients with acute deep vein thrombosis (DVT) of the lower limbs. Herein, we aimed to assess and compare these scores in the same cohort of patients. Methods We retrospectively applied the three scores in a cohort of 181 patients (196 limbs) who participated in the SAVER pilot trial for an acute DVT. Patients were stratified into PTS risk groups using positivity thresholds for high-risk patients as proposed in the derivation studies. All patients were assessed for PTS 6 months after index DVT using the Villalta scale. We calculated the predictive accuracy for PTS and area under receiver operating characteristic (AUROC) curve for each model. Results The Méan model was the most sensitive (sensitivity 87.7%; 95% confidence interval [CI]: 77.2–94.5) with the highest negative predictive value (87.5%; 95% CI: 76.8–94.4) for PTS. The SOX-PTS was the most specific score (specificity 97.5%; 95% CI: 92.7–99.5) with the highest positive predictive value (72.7%; 95% CI: 39.0–94.0). The SOX-PTS and Méan models performed well for PTS prediction (AUROC: 0.72; 95% CI: 0.65–0.80 and 0.74; 95% CI: 0.67–0.82), whereas the Amin model did not (AUROC: 0.58; 95% CI: 0.49–0.67). Conclusion Our data support that the SOX-PTS and Méan models have good accuracy to stratify the risk for PTS.

Patients with cancer-associated thrombosis (CAT) are treated with full-dose anticoagulation for at least 3 months, but optimal dosing thereafter is unknown.We explored the feasibility of extended prophylactic-dose low molecular weight heparin (LMWH) treatment following a minimum of 3 months of full-dose LMWH.We conducted a multicenter prospective pilot study of patients with CAT who completed at least 3 months of therapeutic-dose LMWH. Patients received 6 months of prophylactic-dose subcutaneous enoxaparin (40 mg once daily). The primary outcome was recurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE), and secondary outcomes included major, clinically relevant non-major (CRNM), and minor bleeding.From August 2016 to May 2019, 52 patients with a mean age of 64.1 years were included. The study was stopped early because of poor recruitment. Breast (23.1%) and colorectal (19.2%) were the most common cancers, and 61.0% had stage IV malignancy. Index CAT consisted of DVT alone in 57.7% of patients and pulmonary embolism (PE) with or without DVT in 42.3%. Patients received a mean of 7.6 months of weight-adjusted LMWH before enrollment. During a mean follow-up of 5.6 months, one patient was diagnosed with recurrent incidental PE (0.0035 events/subject-month). There were no major bleeding events, one CRNM, and one minor bleeding event. Eight (15.4%) patients died; six from cancer and two from respiratory disease unrelated to PE.These results, in part, provide support for trials of extended reduced-dose anticoagulation for the secondary prevention of CAT. (ClinicalTrials.gov: NCT02752607).

Central venous catheters (CVC) are associated with an increased risk of venous thromboembolism (VTE) in patients with cancer. Primary thromboprophylaxis using a direct oral anticoagulant decreases the risk of VTE in intermediate-to-high risk ambulatory cancer patients. We assessed the efficacy and safety of thromboprophylaxis with apixaban in the subpopulation of patients with cancer and a CVC in the AVERT trial.The AVERT study was a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban for primary thromboprophylaxis in patients with cancer initiating chemotherapy who were at intermediate to high risk of VTE. The primary efficacy outcome was objectively confirmed VTE within 180 days of randomization and the primary safety outcome was major bleeding. The hazard ratios (HRs) were calculated using a Cox regression model controlling for age, gender, and center.A total of 217 patients had a CVC and were included in the subgroup analyses with 126 and 91 patients receiving apixaban or placebo, respectively. 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 0.0001). Major bleeding occurred in 2 (1.6%) patients in the apixaban group and 2 (2.2%) patients in the placebo group (HR 0.69; 95% CI, 0.20-2.35; p = 0.556).Primary thromboprophylaxis with apixaban in patients with cancer and a CVC was associated with a reduced risk of VTE in the AVERT study population, without an increased risk of bleeding. (Funded by the CIHR and Bristol-Myers Squibb-Pfizer Alliance; NCT02048865).

Clinical decisions for NSCLC patients are often based on TNM stage, which does not account for different histological subtype. Whether histological subtype affects survival still remains unclear. The main objective of this study was to determine the extent to which the survival outcomes of patients with early-stage NSCLC differ by histological subtype.Retrospective cohort study of SEER data base. Patients with stage IA and IB NSCLC that underwent surgery with lymph node dissection were included. The primary outcome was the time to death. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS). The secondary outcome was the time to death from lung cancer. A Cox model and a Fine-Gray subdistribution hazards model in which death from causes other than lung cancer was considered a competing risk event were used to identify risk factors for death from lung cancer.Analysis of the SEER database identified 28,584 NSCLC patients, of whom 19,750 (69 %) had adenocarcinoma and 8834 (31 %) had squamous cell carcinoma. In the multivariate for OS, older age (p 0.001), male gender (p 0.001), pneumonectomy (p 0.001), larger tumor size (p 0.001), squamous cell carcinoma (p 0.001) not being Hispanic or Asian were associated with increased risk of death. In the competing risk model, older age (p 0.001), male gender (p 0.001), pneumonectomy (p 0.001), larger tumor size (p 0.001), and squamous cell carcinoma (p 0.001) were was associated with an increased risk of death from lung cancer.This study suggests that among patients with stage I NSCLC, those with squamous histology have a higher risk of mortality than those with adenocarcinoma histology taking into account competing risks.

Background The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. Methods We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. Results In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, −4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, −0.3%; 95%-CI, −10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, −10.1–12.4), 3.1% and 11.7% for breast cancer (RD, −8.6; 95%-CI, −19.3–2.2), 8.9% and 10.9% for hematological malignancies (RD, −2.0; 95%-CI, −13.1–9.1), and 10.4% and 17.4% for gynecological cancer (RD, −7.0; 95%-CI, −19.8–5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. Conclusion Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

BACKGROUND The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING Eighteen sites between February 2011 and February 2021. PATIENTS Patients with isolated subsegmental pulmonary embolism. INTERVENTION At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Post-thrombotic syndrome (PTS) is one of the most frequent complications of venous thromboembolism (VTE) leading to considerable morbidity and cost. Apart from appropriate anticoagulation, there is no drug or medical intervention that helps to prevent PTS. We conducted a multicenter randomized controlled trial to determine whether rosuvastatin can prevent PTS.312 patients receiving standard anticoagulation for a newly diagnosed VTE were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days (n = 155) or no rosuvastatin (n = 157). At the last study visit (Day 180 ± 21), an independent observer who was blinded to study treatment performed a PTS assessment using the Villalta scale. The primary clinical outcome of the trial was mean Villalta score at Day 180. We also explored the presence of PTS as defined by Villalta score 4 at Day 180. Patients mean age was 46.7 ± 10.8 years, 55.8% were female.At Day 180, the Villalta score was 3.5 ± 0.3 in the rosuvastatin arm vs. 3.3 ± 0.3 in the control arm (p = 0.59), and presence of PTS (Villalta4) was 29.7% in the rosuvastatin arm vs. 25.5% in the control arm (p = 0.41). Secondary analyses showed no difference between trial arms for presence of severe PTS at Day 180 (2.0% vs. 2.7%, p = 1) and for changes in Villalta score between baseline and Day 180 (-3.7 ± 4.4 vs. -4.0 ± 5.0, p = 0.59).This randomized controlled pilot trial did not demonstrate efficacy of rosuvastatin to reduce Villalta score. Further studies with longer duration of exposure to rosuvastatin are needed.ClinicalTrials.gov, number NCT02679664.

IntroductionAfter deep vein thrombosis, up to 50% of patients develop post-thrombotic syndrome (PTS). PTS is a chronic condition that reduces quality of life (QOL). Cornerstones of PTS treatment include the use of elastic compression stockings but this treatment is usually incompletely effective and is burdensome. Venoactive drugs have been reported to be effective to treat chronic venous insufficiency (CVI). However, the level of evidence supporting their use in CVI in general and in PTS in particular is low.Methods and analysisThe MUFFIN-PTS trial is an academic, publically funded, multicentre randomised placebo-controlled trial assessing the efficacy of micronised purified flavonoid fraction (MPFF, Venixxa), a venoactive drug, to treat PTS. Eighty-six patients with PTS (Villalta score (VS) ≥5) and experiencing at least two of the following PTS manifestations among daily leg heaviness, cramps, pain or oedema will be randomised to receive 1000 mg of oral MPFF or a similar appearing placebo for 6 months, in addition to their usual PTS treatment. Total study follow-up will be 9 months, with visits at inclusion/baseline, 3, 6 and 9 months. Primary outcome is the proportion of patients with improvement in VS in each group, where improvement is defined as a decrease of at least 30% in VS or a VS Ethics and disseminationPrimary ethics approval was received from Centre intégré universitaire de santé et de services sociaux (CIUSSS) West-Central Montreal Research Ethics Board. Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03833024); Pre-results.

Eck RJ, Elling T, Sutton AJ, et al.

An amendment to this paper has been published and can be accessed via the original article.

Background There is uncertainty regarding the safety and effectiveness of direct oral anticoagulant agents in patients with antiphospholipid syndrome (APS). We performed a multicenter feasibility study to examine our ability to identify and obtain consent from eligible APS patients and to obtain 95% adherence with daily rivaroxaban administration, in order to inform and power a larger study. Clinical outcomes of bleeding and thrombosis were also collected. Methods APS patients with prior venous thromboembolism (VTE) were recruited over 2 years (Oct 2014–Sept 2016) and followed for ≥ 1 year. Patients were assessed clinically every 3 months and had pill counts performed every 6 months. Numbers of patients fulfilling study criteria, as well as those consenting to participate, were tracked, and percentage adherence based on pill counts was recorded. These data were compared against the feasibility endpoints. Rates of thrombosis and bleeding were calculated. Criterion for feasibility was obtaining consent from 135 of 150 identified APS patients over 2 years. Results Ninety-six eligible patients were identified, and 14 declined participation. Eighty-two patients were followed for a mean of 19 months, representing 129.8 patient-years. Average rivaroxaban adherence was 95.0%. During follow-up, there were 4 thromboembolic events (2 cerebrovascular and 2 VTE). There were no episodes of major bleeding. Conclusions Adequately powered comparative trials using patient-important outcomes in APS are unlikely to be successful due to inability to recruit sufficient numbers of study subjects. This study does not reveal a higher than expected risk of recurrent thromboembolic disease compared to historical cohorts; however, this is an uncontrolled study in relatively low-risk APS patients. Trial registration The study was registered with clinicaltrials.gov, identifier NCT02116036, April 16, 2014.

Buparlisib is an orally available pan-Class I PI3K inhibitor, that is more potent than idelalisib in vitro. Its distinct toxicities include hyperglycemia, hypertension, and mood disturbance. IND216...

The authors regret that panel E of Fig. 1 was missing, showing the cumulative incidence of the primary outcome in hematologic cancer. The authors would like to apologise for any inconvenience caused.

ObjectiveTo evaluate the safety and efficiency of a diagnostic algorithm for deep vein thrombosis (DVT) that uses clinical pretest probability based D-dimer thresholds to exclude DVT.DesignProspective diagnostic management study.SettingUniversity based emergency departments or outpatient clinics in Canada.ParticipantsPatients with symptoms or signs of DVT.InterventionDVT was considered excluded without further testing by Wells low clinical pretest probability and D-dimer 3000 ng/mL or high clinical pretest probability and D-dimer >1500 ng/mL. If DVT was not diagnosed, patients did not receive anticoagulant treatment.Main outcome measureSymptomatic venous thromboembolism at three months.Results1508 patients were enrolled and analysed, of whom 173 (11.5%) had DVT on scheduled diagnostic testing. Of the 1275 patients with no proximal DVT on scheduled testing who did not receive anticoagulant treatment, eight (0.6%, 95% confidence interval 0.3% to 1.2%) were found to have venous thromboembolism during follow-up. Compared with a traditional DVT testing strategy, this diagnostic approach reduced the need for ultrasonography from a mean of 1.36 scans/patient to 0.72 scans/patient (difference −0.64, 95% confidence interval −0.68 to −0.60), corresponding to a relative reduction of 47%.ConclusionsThe diagnostic strategy using a combination of clinical pretest probability and D-dimer identified a group of patients at low risk for DVT during follow-up while substantially reducing the need for ultrasound imaging.RegistrationClinicalTrials.govNCT02038530.

Importance Unprovoked venous thromboembolism (VTE) can be the first manifestation of cancer. It is unclear if extensive screening for occult cancer including a comprehensive computed tomography (CT) scan of the abdomen/pelvis is cost-effective in this patient population. Objective To assess the health care related costs, number of missed cancer cases and health related utility values of a limited screening strategy with and without the addition of a comprehensive CT scan of the abdomen/pelvis and to identify to what extent testing should be done in these circumstances to allow early detection of occult cancers. Participants and setting Cost effectiveness analysis using data that was collected alongside the SOME randomized controlled trial which compared an extensive occult cancer screening including a CT of the abdomen/pelvis to a more limited screening strategy in patients with a first unprovoked VTE, was used for the current analyses. Main outcomes and measures Analyses were conducted with a one-year time horizon from a Canadian health care perspective. Primary analysis was based on complete cases, with sensitivity analysis using appropriate multiple imputation methods to account for missing data. Results Data from a total of 854 patients with a first unprovoked VTE were included in these analyses. The addition of a comprehensive CT scan was associated with higher costs ($551 CDN) with no improvement in utility values or number of missed cancers. Results were consistent when adopting multiple imputation methods. Conclusions and relevance The addition of a comprehensive CT scan of the abdomen/pelvis for the screening of occult cancer in patients with unprovoked VTE is not cost effective, as it is both more costly and not more effective in detecting occult cancer.

A State of the Art lecture titled “What’s New in VTE Risk and Prevention in Orthopedic Surgery” was presented at the ISTH congress in 2019. Patients undergoing orthopedic surgery have long been recognized to be at increased risk of venous thromboembolism (VTE) and were among the first patient groups to be studied in VTE prophylaxis trials. From the late 1950s to 2010s, prophylaxis trials in major orthopedic surgery tended to focus on venographic deep vein thrombosis and assessed thromboprophylaxis in all patients based on a population approach. In general, anticoagulants were favored over mechanical prophylaxis or aspirin, and longer‐duration prophylaxis was favored over shorter durations. As discussed in this paper, more recently, orthopedic prophylaxis has started to become more nuanced and individualized. Modern trials are focusing on symptomatic VTE as outcomes; there has been a resurgence in interest in aspirin for prophylaxis, and there has been a slow move to studying ways to evaluate VTE risk in patients undergoing orthopedic surgery and recommending thromboprophylaxis to patients based on individual attributes, in whom risk stratification and weighing of benefit versus risk of thromboprophylaxis is becoming key. We also touch on VTE risk and guideline recommendations to prevent VTE in 2 other commonly encountered orthopedic populations: patients undergoing knee arthroscopy and those with distal leg fractures. Finally, we summarize relevant new data on this topic presented during the 2019 ISTH annual congress in Melbourne.

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.).

Importance: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective: To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (

Background In 2010, wait-times for new patients referred to see a haematologist at our outpatient tertiary care centre clinic exceeded 6 months. The provision of written recommendations for a subset of referred patients was undertaken to reduce patient wait-times. These recommendation letters outlined possible causes of the abnormality for which the patient was being referred and suggested a course of action for follow-up, and patients were then managed by their referring practitioner. We sought to characterize the cohort of patients for whom written recommendations were written and assess whether written recommendations were a satisfactory alternative for the referring practitioner. Methods All haematology patient referrals managed with written recommendations in 2010 were included in the study and were assessed one year later. Referring practitioners who received written recommendations were sent a short survey to evaluate their satisfaction with this process. Results A total of 444 of 2400 referrals were managed with a letter. At 1-year follow-up, 58 (13%, 95% CI) of the abnormalities which prompted the referral had resolved and 201 (45%, 95%CI) had remained stable. There was a single haematology-related death during the 1-year follow-up and the haematological abnormality worsened in 4 (1%) patients. Of 203 (71%) referring practitioners who responded to the satisfaction survey, 90% (95% CI) indicated that they would be satisfied with written recommendations in the future. Interpretation The provision of written recommendations appears to be a safe and satisfactory alternative to an inperson outpatient assessment in certain well-defined subsets of stable outpatients with haematologic abnormalities.

Introduction Diagnostic testing for deep vein thrombosis (DVT) is a multi-step and time-consuming process. Testing starts with clinical pretest probability (C-PTP) assessment. A negative D-dimer in combination with low C-PTP is widely used to exclude DVT; otherwise ultrasound imaging is required. When proximal vein ultrasound is used, a repeat ultrasound after a week is usually required to exclude DVT in moderate or high C-PTP patients. Ultrasound imaging is costly and can introduce delays. The goal of this study was to evaluate the safety and efficiency of a diagnostic algorithm for DVT that was designed to minimize the need for ultrasound imaging by using C-PTP-based D-dimer thresholds to exclude DVT (the 4D algorithm), rather than a standard fixed D-dimer cut-off value. Methods Consenting patients were enrolled in a Canadian prospective multicentre management study. Outpatients with symptoms or signs of DVT were eligible to be included in this study. Physicians used the 9-item Wells score to categorize the patient's C-PTP as low (Wells score, -2 to 0), moderate (1 or 2), or high (≥3). Patients with low C-PTP and a D-dimer Results From April 2014 through March 2020, a total of 1512 patients were enrolled and analyzed. The mean age was 60 years and 58% were female. Overall, 173 (11%) had DVT on initial or serial diagnostic testing (168 had DVT on ultrasound imaging on the day of presentation and 5 had DVT on repeat ultrasound imaging at one week). Of all 1298 patients (86% of total) who did not have DVT (at either initial presentation or at scheduled repeat ultrasound imaging) and who did not receive anticoagulant therapy, 7 had VTE during follow-up (0.5%, 95% confidence interval (CI): 0.3 to 1.1%). In the 579 patients who had low (378 patients) or moderate (201 patients) C-PTP and negative D-dimer results (i.e. Conclusions The 4D diagnostic algorithm ruled out DVT safely while substantially reducing the requirement for ultrasound imaging. Disclosures Wu: BMS-pfizer: Honoraria, Other: advisory board; leo pharma: Other: advisory board; Pfizer: Honoraria; Servier: Other: advisory board.

Background Intensive chemotherapy is the standard of care for remission induction for fit patients with newly diagnosed acute myeloid leukemia (AML). However, assessing the prognostic impact of comorbidities on outcomes when counselling patients remains a challenge. To this end, we sought to validate the prognostic validity of a newly proposed AML composite model (AML-CM) which incorporates both comorbidities and leukemia-specific features to predict overall mortality following administration of intensive induction chemotherapy. Methods We retrospectively collected data on patients with newly diagnosed AML who received their first induction chemotherapy in Halifax, NS and St. John's, NL, Canada. The AML-CM scores were calculated as per previously published guidelines (Sorror et al in 2017). Logistic regression models were performed to analyze 8-week and 1-year mortality and competing risk regression with Fine and Grey model to model overall survival after adjusting for known variables. Results 194 patients treated January 1, 2009 to December 31, 2017 were identified. Fifty-six percent were males. Median age at induction was 54 years with an age range from 18 to 75 years. Thirty-eight percent of patients were 60 years or older. Molecular/cytogenetic risk per ELN classification was as follows: 23% favourable risk, 37% intermediate risk, 34% high risk, and 6% unknown. The most frequently used regimen was the standard 3+7 regimen (daunorubicin and cytarabine). The AML-CM was predictive of 8-week, odds ratio 2.39 (95%CI 1.09-5.239) AML-CM 7-9 vs AML-CM 1-4, (p-value 0.0284) and 1-year mortality, odds ratio 11.76 (95% CI 2.45-56.51) AML-CM 10+ vs AML-CM 1-4 (p-value 0.0021). Overall survival was inversely proportional to increasing AML-CM scores (p Conclusions The AML-CM is a valid prognosticator for early and late mortality in our patient population. Our findings emphasize the significance of comorbidities assessment prior to induction therapy for AML and the potential use in tailoring targeted interventions to mitigate their risks alongside leukemia treatments. Additionally, the AML-CM could be utilized to adjust for the impact of comorbidities in clinical trials investigating newer intensive AML therapies.

Management of anticoagulant therapy for the treatment of venous thromboembolism (VTE) in cancer patients is complex because of an increased risk of recurrent VTE and major bleeding complications in those patients relative to the general population. Subgroups of patients with cancer also show variation in their risk for recurrent VTE and adverse bleeding events. Accordingly, a committee of 10 Canadian clinical experts developed the consensus risk- stratification treatment algorithm presented here to provide guidance on tailoring anticoagulant treatment choices for the acute and extended treatment of symptomatic and incidental VTE, to prevent recurrent VTE, and to minimize the bleeding risk in patients with cancer. During a 1-day live meeting, a systematic review of the literature was performed, and a draft treatment algorithm was developed. The treatment algorithm was refined through the use of a Web-based platform and a series of online teleconferences. Clinicians using this treatment algorithm should consider the bleeding risk, the type of cancer, and the potential for drug–drug interactions in addition to informed patient preference in determining the most appropriate treatment for patients with cancer-associated thrombosis. Anticoagulant therapy should be regularly reassessed as the patient’s cancer status and management change over time.

Background Several barriers exist for training and retention of clinician scientists, including difficulty in navigating research-related tasks in the workplace and insufficient mentorship. Objective Our aim was to identify what core research knowledge and skills are important for the success of clinician scientists in thrombosis research, and trainees' perceived confidence in those skills, in order to develop a targeted educational intervention. Methods A pre-tested online survey was administered to trainees and research faculty of the Canadian thrombosis research network, CanVECTOR, between September 2016 and June 2017. The importance (research faculty) and confidence (trainees) of 45 research knowledge/skills were measured using a 5-point Likert scale. Results The survey response rate was 49% (28/57) for research faculty and 100% (10/10) for trainees. All research faculty rated developing a good research question, grant writing and writing strategies for successful publication as ‘very’ or ‘extremely’ important for trainees to learn to better transition in becoming independent researchers. Other important areas included practical aspects of research. A qualitative thematic analysis of open text responses identified ‘time management’ and ‘leadership and teamwork’ as additional important research skills. Confidence reported for each topic varied across trainees. There were three research knowledge and/or skills that ≥ 75% of research faculty deemed highly important and ≥ 50% of trainees reported lacking confidence in: grant writing, the peer-review grant process, and knowledge translation strategies. Conclusions Developing a good research question, communicating research ideas and results and the practical aspects of research are important areas to focus future efforts in thrombosis research training.

Background The risk of recurrent venous thromboembolism (VTE) in cancer patients despite anticoagulant therapy is high. Clinical factors and pro-coagulant markers may identify high-risk patients and guide decisions about intensifying anticoagulation therapy. Aims To evaluate whether serial measurements of pro-coagulant markers can identify patients at high risk of recurrent VTE. Methods In this multicenter, prospective cohort study, patients with active cancer and acute deep vein thrombosis or pulmonary embolism were enrolled. Patients received standard low-molecular-weight heparin therapy and were followed for 6 months. D-dimer and soluble P-selectin levels were measured at baseline and 1, 4, 5, 12, and 24 weeks post treatment initiation. The association between recurrent VTE and a previously developed risk score, baseline values of the biomarkers, and individual relative changes from baseline were assessed. Results We enrolled 117 cancer patients (22% lung, 21% colorectal, 9% breast) with a mean age of 63 years; 62% had metastatic cancer. Eleven patients (9.4%) developed recurrent VTE, including two cases of fatal pulmonary embolism. VTE recurrence rates were 7.8% (95% CI, 3.1–18) in patients with a risk score of ≤0 points compared to 11% (95% CI, 5.2–20) for those with a score of ≥1 point (hazard ratio 1.3; 95% CI, 0.39–4.5). Baseline P-selectin levels but not D-dimer levels were significantly associated with a high risk of recurrence; the risk was four-fold higher in patients with elevated P-selectin levels than in those with normal levels (hazard ratio 4.0; 95% CI, 1.1–14). Changes in biomarker levels during treatment were not associated with recurrent VTE. Conclusion Baseline P-selectin but not D-dimer levels predict recurrent VTE and may be a valuable addition to clinical prediction rules to select patients for more intensive therapy or closer observation.

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in MEDLINE, EMBASE, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.

Background: To date, there have been few economic evaluations, from a Canadian perspective, of direct oral anticoagulants (DOACs) for the prevention of recurrent venous thromboembolism (VTE) in patients with acute unprovoked VTE. As a result, there is a lack of consensus about which treatment strategy should be adopted in the clinical setting.Objectives: To assess the cost-effectiveness of currently approved anti - coagulant options, in terms of cost per quality-adjusted life-year (QALY) gained, for the prevention of recurrent VTE in patients with unprovoked events managed on an outpatient basis.Methods: Microsoft Excel was used to develop a Markov model. Model parameters were determined using published literature, local hospital data, expert opinion, and chart review. The analysis considered the costs associated with pharmaceuticals, laboratory testing, hematologist fees, and treatment of recurrent VTE and major bleeding events. Effectiveness was measured in terms of QALYs, and incremental cost-effectiveness ratios (ICERs) were calculated.Results: For treatment lasting 3 months, apixaban represented the most cost-effective DOAC relative to low-molecular-weight heparin (LMWH) + vitamin K antagonist, with an ICER of $7379.66. For 6 months of treatment, apixaban again represented the most cost-effective treatment, with an ICER of $84.08 per QALY gained, and this drug dominated all the other strategies at 12 months. For lifetime treatment, DOACs were unlikely to be cost-effective, given a maximum willingness to pay of $50 000 to $100 000 per QALY. In a probabilistic sensitivity analysis at 6 months, 46.4% of iterations resulted in apixaban having lower costs and better outcomes than LMWH + vitamin K antagonist, and 78.6% of iterations resulted in an ICER below $100 000Conclusions: The findings of this study suggest that apixaban is likely cost-effective for treatment durations of 3, 6, and 12 months. However, for indefinite treatment, DOACs were unlikely to be cost-effective.RÉSUMÉContexte : À ce jour, on a réalisé peu d’évaluations économiques, d’un point de vue canadien, sur les anticoagulants oraux directs (AOD) utilisés dans la prévention de la thromboembolie veineuse (TEV) récurrente chez les patients atteints de TEV idiopathique aiguë. Pour cette raison, aucun consensus n’a été établi quant à la stratégie thérapeutique à adopter en milieu clinique.Objectif : Évaluer le rapport coût-efficacité des anticoagulothérapies actuellement approuvées, en ce qui a trait au coût par année de vie pondérée par la qualité (QALY) gagnée, pour la prévention de la TEV récurrente chez les patients ayant subi des événements idiopathiques qui ont été traités en consultation externe.Méthodes : Le logiciel Excel de Microsoft a servi à créer un modèle de Markov. Les paramètres du modèle ont été établis à l’aide de la littérature, de données de l’hôpital local, d’opinions d’experts et d’une analyse de dossiers médicaux. L’analyse prenait en compte les coûts associés aux médicaments, aux examens de laboratoire, aux honoraires d’hématologues et au traitement de la TEV récurrente et d’hémorragies importantes. L’efficacité était mesurée en nombre de QALY et les rapports coûtefficacité différentiels ont été calculés.Résultats : Pour un traitement de trois mois, l’apixaban représentait l’AOD offrant le meilleur rapport coût-efficacité comparativement à l’héparine de bas poids moléculaire (HBPM) + un antagoniste de la vitamine K; il présentait un rapport coût-efficacité différentiel de 7379,66 $. Pour un traitement de six mois, l’apixaban représentait à nouveau le traitement le plus efficace par rapport au coût; il présentait un rapport coût-efficacité différentiel de 84,08 $ par QALY gagnée. Ce médicament surclassait toutes les autres stratégies après douze mois de traitement. En ce qui concerne un traitement à vie, les AOD offraient probablement un moins bon rapport coût-efficacité, compte tenu d’une propension à payer maximale se situant entre 50 000 $ et 100 000 $ par QALY. Dans une analyse de sensibilité probabiliste au sixième mois de traitement, 46,4 % des itérations se traduisaient par des coûts moins élevés et de meilleurs résultats pour l’apixaban relativement à l’HBPM + un antagoniste de la vitamine K. De plus, 78,6 % des itérations se traduisaient par un rapport coût-efficacité différentiel de moins de 100 000 $.Conclusions : Ces résultats laissent croire que l’apixaban présente probablement un rapport coût-efficacité intéressant pour les traitements d’une durée de 3, 6 et 12 mois. Cependant, en ce qui concerne un traitement d’une durée indéterminée, les AOD ne sont sans doute pas avantageux.

In the Original Article by Douketis et al. "The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant who Need an Elective Surgery or Procedure: Design and Rationale (Thromb Haemost 2017;117:2415-2424; DOI: 10.1160/TH17-08-0553), the authors have identified two errors that they wish to correct: First, on page 2419, second paragraph, Clinical Outcomes subheading, the authors state that, "The primary clinical outcomes are arterial thromboembolism, comprising stroke (ischemic or haemorrhagic), systemic embolism or transient ischemic attack and major bleeding. The inclusion of "haemorrhagic stroke is incorrect as only ischemic strokes are included in their definition of an arterial thromboembolism outcome. The definitions of study outcomes are correctly indicated in Appendix A (pg. 2424) of the paper, where the authors state: "The second primary outcome is arterial thromboembolism, comprising (1) ischemic stroke, defined as any new focal neurologic deficit that persists for 24 hours or any new focal neurologic deficit of any duration that occurs with evidence of acute infarction on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain; (2) systemic embolism, defined as symptomatic embolism to upper or lower extremity or abdominal organ, confirmed intraoperatively or by objective imaging studies (e.g. CT angiography) and (3) transient ischemic attack, defined as symptomatic focal neurologic deficit (lasting typically 1 hour) that occurs with no evidence of acute infarction on CT/MRI of the brain. Second, the depiction of the pre-procedure interruption interval for dabigatran-treated patientswith a CrCl 50 mL/min is incorrect in Figure 1 (pg. 2418) of the paper, as the arrow should extend so it reflects 2 days off treatment (i.e., day -2 and day -1). The incorrect (currently published) version is shown below, with incorrect area shaded in red: (Figure Presented).

Introduction: Venous thromboembolism (VTE) encompasses a spectrum of disorders involving thrombosis in the venous circulation, namely deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of thrombosis is significantly elevated in patients with malignancy due to a hypercoagulable state. In addition to the elevated risk of thrombus formation in patients with malignancy, certain tumours have a predilection for intravascular extension, termed tumour thrombus. The presence of tumour thrombus considerably worsens prognosis, alters staging, and can influence the treatment options for these patients. While tumour thrombus can have have a significant impact on patients, the clinical course and optimal management of tumour thrombus remains unknown. We aim to describe the natural history of tumour thrombus and compare outcomes in those treated with or without anticoagulation at our centre. Methods: We performed a retrospective, observational review of patients over 16 years of age with tumour thrombus at a single-centre between January 2008 and December 2017. Patients with documented tumour thrombus on computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US) were included in this study. Patients already on anticoagulation were excluded. Data were collected through medical record review including baseline characteristics, treatment history, complications and clinical outcomes. Overall survival and VTE recurrence rates between those treated with or without anticoagulation were demonstrated using Kaplan-Meier survival curves and Log-rank test. Cox-proportional hazards models were used to estimate the hazard ratio for tumor thrombosis with and without adjustment for patient characteristics including comorbidities, treatment, acuity, and location. Results: A total of 153 patients were identified to meet inclusion criteria over the study period. The majority of patients were male (65.4%) with an mean age of 65.7. The most common malignancies associated with tumour thrombus were renal cell carcinoma (34.6%) and hepatocellular carcinoma (28.8%), with 125 patients (82.5%) having stage III or IV malignancies. The most common locations of tumour thrombus were the portal vein (37.5%), renal vein (32.9%) and inferior vena cava (26.3%). Forty-one patients (26.8%) were treated with anticoagulation. Of the entire study population, 18 patients (11.8%) developed VTE within a 6 month study period after being diagnosed with tumour thrombus. Of those that developed VTE following a diagnosis of tumour thrombus, 11 were on anticoagulation (61%) and 7 were not (39%). Five patients receiving anticoagulation experienced major bleeding. Mortality was 42.5% at 6 months with no significant difference in survival between those treated with or without anticoagulation (Figure 1; p = 0.42). Proportion hazards models were not completed at the abstract submission deadline; full study results will be presented at the ASH meeting. Conclusion: In our study, we show that there is no significant difference in survival between patients with tumour thrombus treated with or without anticoagulation. While there is no clear evidence that anticoagulation improves outcomes across all patients with tumour thrombus, further studies are needed to identify subgroups of patients who may benefit from anticoagulation given their increased risk of VTE. Figure 1 Disclosures Keating: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees.

Background: In studies evaluating the prevention of venous thromboembolic events (VTE - composite of deep vein thrombosis (DVT) and pulmonary embolism (PE)) following surgery, VTE is considered as a binary event (present or absent). There is no consensus in the literature in determining the clinical severity of a post-operative VTE. The objectives of our study were to derive a severity scoring model for VTE in the post-operative setting and then apply the model to outcomes from a clinical trial evaluating aspirin vs. rivaroxaban for extended prophylaxis following total hip or knee arthroplasty (EPCATII). Methods: Thirty-one clinical scenarios were written, each describing a VTE event after a total hip or knee arthroplasty procedure. Each scenario varied the severity of the patient's presenting symptoms, the extent of thrombosis observed on radiographic studies, and the presence or absence of long-term symptoms. These scenarios were incorporated into a web-based survey sent to thrombosis clinicians. Respondents were asked to score each scenario on a 9-point scale based on perceived clinical severity. Responses from 29 clinicians were analyzed using mixed-effects regression models to determine the weight of each variable on the respondents' overall severity scores. The sum of scores for each weighted factor present based on parameter estimates from the model was calculated to categorize the scenarios into high, moderate, or low clinical severity categories. The VTE clinical severity scoring model was applied independently by two clinicians to the 36 cases of confirmed VTE from the EPCAT II trial. Two further reviewers gave their clinical opinion of each case's severity. Kappa scores for inter-rater reliability, and for agreement between clinical opinion and the model were determined. The proportion of EPCAT II cases rated as mild, moderate and severe by the model were determined for rivaroxaban and aspirin groups and then compared using the Cochran-Armitage test for trend. Results: The following factors shown as parameter estimates were associated with higher levels of clinical severity: moderate (1.28, p8) clinical severity categories. Independent application of the model to the EPCAT II VTE cases had agreement in 33 of 36 cases (κ=0.89). The agreement between the clinical opinion and the model was 28 of the 36 cases (κ=-0.14). In all cases of disagreement, the clinical gestalt was more severe than the model. Cases randomized to rivaroxaban were scored as 10 mild (55.6%), 4 moderate (22.2%), and 4 severe (22.2%). Cases randomized to aspirin were scored as 12 mild (66.7%), 4 moderate (22.2%) and 2 severe (11.1%). There were no differences in severity of VTE between the aspirin and rivaroxaban groups (p=0.38). Conclusion: A clinical severity scoring model for post-operative VTE was created based upon scenarios rated by experienced thrombosis clinicians and validated by applying it to EPCAT II cases of VTE. This model may be useful for categorizing clinical importance of VTE in the post-operative setting. There was no apparent difference in the severity of post-operative VTE following total hip or knee arthroplasty whether aspirin or rivaroxaban was used for extended prophylaxis. Disclosures No relevant conflicts of interest to declare.

Essentials Heparin-induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat. We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT. One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery. Rivaroxaban may be an effective and safe treatment option for HIT. SummaryBackground Rivaroxaban is a direct oral anti-Xa inhibitor that has the potential to greatly simplify treatment of heparin-induced thrombocytopenia (HIT). Objectives To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single-arm, prospective cohort study of patients with suspected or confirmed HIT. Patients/Methods Twenty-two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30. Results and Conclusions The primary outcome measure, incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT-positive participant (4.5%; 95% confidence interval [CI], 0–23.5%) and one HIT-positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT-positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.

Risk factors predictive of occult cancer detection in patients with a first unprovoked symptomatic venous thromboembolism (VTE) are unknown. Cox proportional hazard models and multivariate analyses were performed to assess the effect of specific risk factors on occult cancer detection within 1 year of a diagnosis of unprovoked VTE in patients randomized in the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial. A total of 33 (3.9%; 95% CI, 2.8%-5.4%) out of the 854 included patients received a new diagnosis of cancer at 1-year follow-up. Age ≥ 60 years (hazard ratio [HR], 3.11; 95% CI, 1.41-6.89; ITALIC! P= .005), previous provoked VTE (HR, 3.20; 95% CI, 1.19-8.62; ITALIC! P= .022), and current smoker status (HR, 2.80; 95% CI, 1.24-6.33; ITALIC! P= .014) were associated with occult cancer detection. Age, prior provoked VTE, and smoking status may be important predictors of occult cancer detection in patients with first unprovoked VTE. This trial was registered atwww.clinicaltrials.govas #NCT00773448.

• A subset of women enrolled in the REVERSE II study underwent a second, blinded assessment for signs of post-thrombotic syndrome (hyperpigmentation, edema, redness).

Introduction Tranexamic acid (TXA) is an anti-fibrinolytic agent that has been increasingly used in various surgeries to reduce bleeding complications. Recently, the use of TXA has extended to orthopedic surgeries, and in some centres it is routinely used during total hip and knee arthroplasties. The majority of data supporting this practice is from meta-analyses, as the trials evaluating TXA in this population consist of small numbers. The EPCATII study was a large, multicenter, double blind randomized trial following total hip and knee arthroplasty, evaluating thromboprophylaxis for venous thromboembolic disease. Data on intraoperative TXA use was collected, noting that the decision to use TXA was made by the attending surgical team. We analyzed the data from the EPCATII study looking at the effect of TXA use on estimated blood loss (EBL) during surgery. Methods The EPCATII study was a randomized controlled trial comparing aspirin to rivaroxaban for extended prophylaxis for venous thromboembolism in patients undergoing hip or knee arthroplasty. EPCATII participants were excluded from this analysis if either use of TXA or EBL were missing. We assessed whether use of TXA was associated with the primary outcome, EBL as reported by the study centre. A matched propensity score analysis was performed to account for confounding as TXA was given based on physician or site preference. Results After excluding 535 participants with missing values for TXA use or EBL during surgery, 2,889 participants were included in the analysis. 1,386 (47.98%) of participants did not receive TXA while 1,503 (52.02%) participants did receive TXA. The mean age in the group that did not receive TXA was 62.13 years, whereas the mean age in the group that did receive TXA was 63.20 years. More participants in the tranexamic group had a history of a major bleed (2.5% vs 0.9%, p=0.001). There were no differences in the remainder of the baseline characteristics. In the unadjusted analysis, participants who did not receive TXA had a mean EBL of 292.87 mL compared to 327.68 mL in the group that did receive TXA (p Conclusions The use of TXA in hip and knee arthroplasty did not have a significant effect on EBL in the EPCATII study population, after propensity score matching. This is contrary to recent evidence showing a benefit of TXA in this population. Variables such as surgery length, surgery type, smoking status and study site appear to be predictors of usage of TXA, and as such, these findings may be partially explained by a physician's identification of higher risk patients in the decision to use TXA. Further studies are needed to determine which patients may benefit most from intraoperative TXA. Disclosures No relevant conflicts of interest to declare.

Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

Background:Occipital condyle syndrome is characterized by severe, unilateral, occipital headache and ipsilateral twelfth-nerve palsy. It is associated with skull-base metastasis.Cases:We identified two patients with sub-acute onset of severe, unilateral, occipital headache and ipsilateral tongue paralysis. The first patient was a 58-year-old woman with a history of limited stage small-cell lung cancer in clinical remission. The second patient was an otherwise healthy 36-year-old man. Neither patient had any other findings on general medical or neurological examination. One patient had only equivocal findings on initial magnetic resonance imaging (MRI), and the other patient's MRI was normal. Although initial work-up for metastatic disease was normal, the first patient developed severe bone pain over the next few months, and follow-up investigations demonstrated metastases to her spine, tibia, skull base and brain. The second patient improved initially, but was admitted to hospital three months later with constitutional symptoms and pancytopenia. Bone marrow and lymph node biopsies were consistent with Stage IVB Hodgkin's lymphoma.Conclusion:Occipital condyle syndrome can be the first presentation of disseminated malignancy. Initial imaging of the brain and skull base may be normal, and recognition of this syndrome warrants thorough investigation and close follow-up.

International audience; Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

Background— The perioperative management of dabigatran in clinical practice is heterogeneous. We performed this study to evaluate the safety of perioperative management of dabigatran using a specified protocol. Methods and Results— Patients treated with dabigatran and planned for an invasive procedure were eligible for inclusion. The timing of the last dose of dabigatran before the procedure was based on the creatinine clearance and procedure-related bleeding risk. Resumption of dabigatran was prespecified according to the complexity of the surgery and consequences of a bleeding complication. Patients were followed up for 30 days for major bleeding (primary outcome), minor bleeding, arterial thromboembolism, and death. We included 541 cases: 324 procedures (60%) with standard risk of bleeding and 217 procedures (40%) with increased risk of bleeding. The last dose of dabigatran was at 24, 48, or 96 hours before surgery according to the protocol in 46%, 37%, and 6%, respectively, of the patients. Resumption was timed according to protocol in 77% with 75 mg as the first dose on the day of procedure in 40% of the patients. Ten patients (1.8%; 95% confidence interval, 0.7–3.0) had major bleeding, and 28 patients (5.2%; 95% confidence interval, 3.3–7.0) had minor bleeding events. The only thromboembolic complication was transient ischemic attack in 1 patient (0.2%; 95% confidence interval, 0–0.5), and there were 4 deaths unrelated to bleeding or thrombosis. Bridging was not used preoperatively but was administered in 9 patients (1.7%) postoperatively. Conclusion— Our protocol for perioperative management of dabigatran appears to be effective and feasible.

At the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, 2,400-2,800 new outpatient referrals for hematology consultation are received annually and approximately 10% of these referrals are specifically for isolated anemia. In recent years, such referrals have been sent from hematology to general internal medicine (GIM) for assessment and management. A retrospective chart review was conducted of a cohort of 99 patients from 2013 to describe the demographics, assessment, management and outcome of these patients, as well as to inform whether this practice should continue. The median age of patients was 60.3 years (min 19.4, max 97.6) and 62% were female. The median hemoglobin level was 109.0 g/L (min 66, max 137) at the time of referral and the median wait time was 53 days (min 8 days, max 171 days). Pearson’s correlation analysis revealed that those with lower hemoglobin levels were seen more quickly. The patients had an additional 2.8 comorbidities on average, and were significantly more likely to receive non-anemia related adjustment to care with increasing number of comorbidities. A small proportion of patients (n = 5, 5.1%) were referred from GIM back to hematology, whereas 21% were referred to gastroenterology. A small number of patients (n = 5, 5.1%) underwent a bone marrow aspirate and biopsy. The most common diagnoses identified in the initial clinic letters were iron deficiency anemia (n = 59, 59.6%) and anemia of chronic disease (n = 8, 8.1%). 26.3% did not have a diagnosis identified. These findings support our practice to have patients with an isolated anemia evaluated by a general internist rather than a hematologist. Most of these patients had iron deficiency anemia or the anemia of chronic disease and received additional care for their comorbid conditions in the GIM clinic. Further work will help to define how such patients can be most effectively assessed and treated.

Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.

Background: To date, there have been few economic evaluations of the direct oral anticoagulants in the treatment of venous thromboembolism (VTE) conducted from a Canadian perspective. As a result, there is a lack of consensus within existing literature regarding which treatment strategy should be adopted into the clinical setting. To our knowledge, this is the first Canadian economic evaluation in patients with VTE who are treated solely on an outpatient basis. Objectives: We conducted a cost-minimization analysis to determine the least costly intervention for the prevention of recurrent venous thrombosis in patients with acute unprovoked VTE including apixaban, rivaroxaban, low molecular weight heparin (LMWH) in combination with dabigatran, and LMWH overlapped with vitamin K antagonists (VKA). We also conducted a cost-effectiveness analysis to assess value for money in terms of cost per quality adjusted life year (QALY) gained. Methods: We used Microsoft Excel to develop a decision model. Decision model parameters were determined using published literature, local hospital data, expert opinion, and chart review. Our cost-minimization analysis aggregated costs related to pharmaceuticals, laboratory testing, and hematologist fees. Our cost-effectiveness analysis also included costs related to health outcomes. Results: Our cost-minimization analysis found apixaban to be the least costly intervention at three months ($609.28). At six months and one year LMWH overlapped with VKA was the least costly intervention ($896.08 and $1,193.88, respectively). With respect to cost-effectiveness, at three months apixaban was the dominant strategy. At six months, apixaban was cost-effective given a willingness-to-pay per QALY as low as $4,986.81. At one year, LMWH overlapped with VKA was cost-effective given a willingness-to-pay per QALY below $135,670.28. Probabilistic sensitivity analysis of our cost-effectiveness analysis found apixaban to be the dominant strategy compared to LMWH overlapped with VKA in 42.6% of iterations and 70.6% of iterations resulted in incremental cost-effectiveness ratio below $100,000 per QALY gained. Conclusions: Our findings suggest apixaban is the least costly and most cost-effective strategy for short-term anticoagulant treatment for VTE but favor LMWH overlapped with VKA for long-term treatment. Disclosures No relevant conflicts of interest to declare.