Venous thromboembolism (VTE) occurs frequently in patients with cancer. It can be difficult to manage, sometimes delay cancer therapy and predicts for a worse prognosis. Hence, effective methods to prevent and treat VTE can reduce morbidity and mortality. Prophylaxis with anticoagulants is recommended for patients hospitalized for surgery or medical conditions, but is not routinely administered in the ambulatory setting. Traditional anticoagulation with a heparin followed by vitamin K antagonist therapy for cancer patients with acute VTE is associated with a high frequency of treatment failure and bleeding complications. Low molecular weight heparins (LMWHs) have simplified and improved the management of VTE, and recent studies suggest these agents may improve survival in patients with limited or early stage disease. This brief review will provide an update on the primary prevention and treatment of VTE and discuss the evidence for the survival advantage associated with LMWH use in patients with malignancy.

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<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol). 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 <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5). 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 (<2%) and ATE (<1%). Further, a high proportion of patients (>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 Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. Despite therapeutic anticoagulation, the risks of recurrent VTE and major bleeding are approximately 10% and 5%, respectively, during the first 6 months of treatment. Overall mortality ranges from 25% to 40%, depending on the study population. Knowing the case fatality rates of these outcomes is also important for weighing the relative risks and benefits of anticoagulation in patients with cancer-associated VTE but these rates have not been reported previously. Objective To determine the incidence of recurrent VTE and major bleeding events and to calculate the case fatality rates of these outcomes in patients undergoing anticoagulation for cancer-associated VTE. Methods An electronic search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials from January 1980 to May 2018 was performed. English language publications (observational studies and randomized controlled trials [RCTs]) that reported on patients with active cancer and VTE who received anticoagulation with low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or a direct oral anticoagulant (DOAC) for at least 3 months were retrieved for review. In addition, a hand search of references of review articles was done to complement the electronic literature search. Studies that provided information on recurrent VTE, major bleeding events, mortality, and causes of death were included in analyses. Retrospective studies and prospective cohorts with fewer than 50 patients were excluded. Two reviewers independently screened for study eligibility and extracted data onto standardized forms. Study outcomes were recurrent VTE, major bleeding and death. Pooled proportions with 95% confidence intervals (CI) were calculated according to anticoagulant treatment and study design. Results The search identified 7327 studies of which 29 studies (15 prospective cohort studies and 14 randomized controlled trials) were included. Data from 8000 cancer patients followed for a total of 4786 patient-years (range 3 to 36 months) were summarized. The rate of recurrent VTE and fatal recurrent VTE were 15.7% (95% CI, 14.4% to 17.1%) and 2.5% (95% CI, 2.0% to 3.0%) per patient-year of follow-up, respectively, with a case fatality rate of 15.8% (95% CI, 12.7% to 18.8%). A sub-analysis revealed case fatality rates for recurrent VTE to be 16.3% (95% CI, 12.2% to 20.4%) for LMWH, 20.4% (95% CI, 14.0% to 26.8%) for VKA, and 10.8% (95% CI, 3.2% to 18.3%) for DOAC therapies. The rate of major bleeding and fatal major bleeding events were 6.4% (95% CI, 5.5% to 7.3%) and 1.2% (95% CI, 0.8% to 1.6%) per patient-year of follow-up, respectively, with a case fatality rate of 12.3% (95% CI, 8.7% to 15.9%). A sub-analysis revealed case fatality rates for major bleeding events to be 14.9% (95% CI, 9.6% to 20.2%), 27.9% (95% CI, 14.5% to 41.3%), and 1.9% (95% CI, 0% to 5.5%) for LMWH, VKA, and DOAC therapies, respectively. Among RCTs, case fatality for recurrent VTE was 17.3% (95% CI, 13.5% to 21.2%) and for major bleeding was 10.8% (95% CI, 3.2% to 18.3%). Among prospective cohort studies, respective case fatality rates were 12.8% (95% CI, 8.0% to 17.5%) and 15.3% (95% CI, 8.6% to 22.0%). Studies were heterogeneous in the duration of follow up and their reporting of the causes of death and definition of fatal PE. Conclusion The incidences of recurrent VTE and major bleed events are high in patients with cancer-associated VTE on anticoagulant therapy. Case fatality from recurrent thrombosis is higher than the case fatality from major bleeding. Differences among various anticoagulants likely reflect patient selection bias and heterogeneity of studies. Disclosures Lee: BMS: Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Honoraria.

Introduction: Current guidelines recommend low-molecular-weight heparins (LMWH) over Vitamin K Antagonists (VKA) or Non-Vitamin K Antagonist Oral Anticoagulants (NOAC) for the treatment of cancer-associated venous thromboembolism (CAT), but also highlight that ultimately the choice of anticoagulant depends on patient-specific factors such as patient preferences, which is important for the acceptance of the treatment and, thus, for adherence and persistence. So far, little is known about the specific preferences of patients with CAT with respect to anticoagulation therapy. More specifically, the impact of dosing regimen, convenience and costs on patient preferences in CAT is poorly understood. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. Methods: Adult patients with active cancer who experienced a CAT event and for whom the decision was made to start a treatment with rivaroxaban after being treated with the standard of care anticoagulation (LMWH/VKA) for at least four weeks were included in a multinational, observational, single-arm study (COSIMO). As part of this study, a DCE was presented to the participants, who were asked to decide between complete hypothetical treatment options based on a combination of different attributes, regardless of efficacy or safety. The following attributes were preselected in a face-to-face discussion with three focus patients and in-depth interviews with four additional patients: route of administration (injection / tablet),frequency of intake (once / twice daily),need of regular controls of the International Normalized Ratio (INR) at least every 3-4 weeks (yes/no),interactions with food/alcohol (yes/no). Additionally, distance to treating physician (1 km vs. 20 km) was included as neutral comparator to express patients' overall utility in terms of a comprehensible unit. The relative importance of treatment attributes in terms of distances were calculated based on ratios between the utility estimates for each attribute. A fractional factorial design was generated resulting in nine hypothetical choice sets, supplemented by a test choice set to assess the consistency of a patient's responses. DCE data was collected by semi-structured telephone interviews, performed between week 4 and week 12 after enrollment of patients in the study and start of rivaroxaban. For each patient participating in the DCE interview, a written informed consent was obtained. Patient preferences were analyzed based on a conditional logit regression model. Results: Overall, 163 patients were included (Europe: 119; Canada: 41; Australia: 3), mean age 63.7 years, 49.1% were females and diagnosed with cancer for on average 22.4 months. Most patients in the COSIMO study changed to rivaroxaban from LMWH (> 95.0 %). The median time from diagnosis of index CAT event to conduct of DCE was 150 days (IQR 88-229). Patients strongly preferred oral administration compared to self-injections and drugs that can be taken irrespective of type of food or alcohol consumption (Figure 1). Furthermore, patients indicated slight preference for a shorter distance to the treating physician and a once daily dosing regimen compared to a twice-daily intake. The attribute "INR controls" showed no significant impact on the treatment decision. In order of patients' preference for their choice of treatment, the route of administration was by far the most important attribute for a patient's choice (73.8% of the overall decision), followed by food interactions (11.8%), the distance to treating physician (7.2%) and the intake frequency (6.5%). Accordingly, the expected utility of patients receiving an oral anticoagulation can be expressed as willingness to travel an additional distance of 192 km to the treating physician in order to avoid an injection. Conclusions Treatment related decision-making of patients with CAT, assuming equal effectiveness and safety of treatments, is predominantly driven by "route of administration", indicating a strong preference for oral intake. Disclosures Picker: Ingress-Health: Employment. Cohen:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; GLG: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; Boston Scientific: Consultancy; AbbVie: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Aspen: Consultancy, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Maraveyas:Bayer AG: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mantovani:Fondazione Charta: Consultancy; Bayer AG: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Wilke:Astra Zeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pharmerit: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria.