Common Conundrums in Venous Thromboembolism Brandon McMahon, MD

Venous Thromboembolism (VTE) ~950,000 cases of VTE annually (incident + recurrent) Rates expected to double by 2050 Mortality 100,000 US deaths annually 10-30% die within a month of diagnosis 25% of PE can present with sudden death Morbidity Post-thrombotic syndrome Chronic thromboembolic pulmonary hypertension Bleeding (therapy) Recurrence Circulation 2012; 125: e2-e220. www.cdc.gov/DVT/data/html.

Overview Malignancy-associated VTE Duration Use of DOACs Management around specific issues Thrombocytopenia Recurrent VTE Duration Extended use of anticoagulation Alternatives to standard anticoagulation Bleeding risk

Malignancy-Associated VTE

67 yo woman with inflammatory breast cancer develops a L femoral DVT and pulmonary embolism after her first course of chemotherapy. You discuss anticoagulation; she has seen an advertisement for Rivaroxaban, and asks if this is an option.

Malignancy-Associated Thrombosis Cancer: 7-10x risk for VTE ~20% of all patients with VTE Type (pancreatic, hematologic, brain, etc), stage, grade, surgery & chemotherapy all associated with ↑ risk Common cause of morbidity & mortality Higher bleeding risk with anticoagulation VTE: 4x ↑ risk of death Second leading cause of death in cancer patients Blood 2013; 122: 1712.

Treatment of Malignancy-Associated VTE CLOT: Dalteparin vs VKA x6 months LITE: Tinzaparin vs Warfarin x3 months CANTHANOX: Enoxaparin vs warfarin x3 months Blood 2013; 122: 2310-2317.

Recommendations: Malignancy-Associated VTE Blood 2013; 122: 2310-2317.

DOAC in Cancer-Associated Thrombosis Currently no prospective clinical studies evaluating use specifically in malignancy-associated VTE Published phase III studies: small number of cancer patients (~5%, range 3-10%) No information on cancer type, stage, treatments Warfarin or placebo controls (not LMWH) Concerns: No widely available monitoring, limited options for reversal (Xa) Potential drug-drug interactions that have not been fully studied 9 ongoing/enrolling studies of DOAC in malignancy-associated VTE (5 w/apixaban, 1 edoxaban, 3 rivaroxaban) Some prevention, some treatment.

Unknown clinical significance, if any NOAC = New Oral Anticoagulants Blood 2013; 122: 2310-2317.

DOAC in Cancer VTE: Recurrence Chest 2015; 147: 475-483.

DOAC in Cancer-Associated Thrombosis: Pooled Data Recurrent VTE Bleeding Pooled analysis of all phase III studies of NOAC in VTE had 1581 patients with malignancy. Lower thrombotic recurrence with NOAC (3.4%) versus VKA (5.9%), reaching statistical significance RR 0.57 Bleeding rates higher in cancer versus no cancer, but comparable bleeding rates in those with cancer whether treated with VKA or DOAC No data on type of malignancy, stage, treatment, etc. Blood 2014; 124(12): 1968-1975.

DOAC in Cancer VTE: Major Bleeding Chest 2015; 147: 475-483.

55 yo man with AML, began standard induction with 7+3. He developed a symptomatic pulmonary embolism involving the R main pulmonary artery on D#3 of chemotherapy. Labs at time of diagnosis include a platelet count of 73K, with expected continued drop. How should his anticoagulation be managed when his platelets decrease to <50? <20?

IMPROVE study: Multinational, observational study (N=15,156) medical patients Evaluated in-hospital bleeding incidence. Multiple regression model analysis performed to identify risk factors at admission associated with bleeding. Bleeding risk increased with length of hospital stay Cumulative incidence of major and non-major in-hospital bleeding w/in 14 days: 3.2% (1.2% major bleeding, 2.1% nonmajor but clinically relevant bleeding) Of 83 major bleeds, 12 contributed to deaths Chest 2011; 139: 69-79.

VTE, Thrombocytopenia, and Bleeding: Conundrum 1514 patients post-HSCT: 75 VTE events (4.6%) BUT… Clinically significant bleeding: 230 (15.2%) 55 (3.6%) fatal bleeding Bleeding risk higher with: Anticoagulation (OR 3.1) GVHD (OR 2.4) VOD (OR 2.2) Retrospective cohort 1514 patients undergoing HSCT (various indications) No protocolized VTE prophylaxis Followed until D#180, but most VTE occurred by D#80 (and most were catheter-associated) 55 (3.6%) vs 11 (0.7%) DVT vs 9 (0.6%) PE Anticoagulation biggest risk factor for bleeding VTE 3x less common than bleeding in this cohort <50: 34% <20: 13% Blood 2008; 112: 504.

Anticoagulation with Thrombocytopenia: ISTH Guidelines Acute VTE (DVT/PE ≤ 1 month) Subacute or chronic VTE (DVT/PE >1 month ago) Platelets ≥ 50 Full dose anticoagulation Platelets <50 Platelet transfusion to keep >50, continue full dose anticoagulation Platelets <50, transfusion not possible/effective Consider retrievable IVC filter Platelets ≥50 Full dose anticoagulation Platelets <50 but >25 Reduce LMWH dose by 50% OR Prophylactic dose LMWH Platelets <25* Discontinue anticoagulation * Could consider prophylactic anticoagulation in select individuals J Thromb Haemost 2013; 11: 1760.

Anticoagulation with Thrombocytopenia in Cancer: Alternative Algorithms Acute Thrombosis: Based on small observational studies suggesting lower doses of anticoagulation could be used for patients with lower platelet counts Differences with ISTH: Not restricted to LMWH. Based soley on safety evidence. Used UFH due to reversibility, short half-life . Lower platelet threshold for transfusion Blood Coagul Fibrinolysis 2016; 27: 615.

76 yo woman with advanced pancreatic cancer developed a R femoral DVT and pulmonary embolism 3 months into her course. She completed dalteparin 200 units/kg daily x4 weeks, and thereafter was placed on dalteparin 150 units/kg. Four months later, she develops a symptomatic DVT in the L popliteal & posterior tibial veins despite not missing any doses of dalteparin. What is the best approach to managing her anticoagulation?

Malignancy-associated VTE: Recurrence 3x ↑ risk recurrent VTE compared to non-cancer population despite anticoagulation 9-17% at 6 months More likely to have interrupted therapy Lower overall survival Optimal management unclear Change agent Increase dose Add antiplatelet agent NEJM 2003; 349:146.

Risk for Recurrent VTE in Cancer Hematology Am Soc Hematol Educ Program 2016; 1: 196.

International registry of 212 patients with “breakthrough” VTE despite anticoagulation. Followed for ONLY 3 months thereafter 73% patients had known metastatic disease At time of breakthrough: 70% on LMWH, 27% on VKA 70% on therapeutic or “supra” therapeutic dose at time of breakthrough After breakthrough: Unchanged therapeutic dose (33%), dose increased (31%), switched agent (24%), other (11%) During 3 month follow up: another 11% had ANOTHER VTE, 8% major bleeding, and 27% died Only 6 patients changed to VKA after initial recurrence (not clear how many total on VKA at time of 2nd recurrence since some stayed on VKA I think) J Thromb Haemost 2015; 13: 1010.

Malignancy-associated VTE: Recurrence At time of breakthrough VTE: Intervention Recurrent VTE at 3 months 15 patients on therapeutic LMWH ↑ LMWH dose by 20-25% 3 patients 24 patients on intermediate-dose LMWH (70-80% therapeutic) 8 patients on low-dose LMWH (<70% therapeutic) 23 on VKA Δ to therapeutic LMWH (at least 1 month) 3 patients Of the 6 recurrent recurrences: 5 with metastatic disease, 4 with lung cancer Only 3 patients with bleeding complications at 3 months, all on therapeutic dose LMWH (2 minor, 1 ICH with malignant brain tumor) J Thromb Haemost 2009; 7: 760.

Recurrent VTE: ISTH Guidelines Regimen @ Recurrence Intervention Follow up 5-7 days VKA Δ to therapeutic LMWH Symptomatic improvement Continue same Δ to therapeutic LMWH < therapeutic LMWH Do not recommend increasing VKA INR goal to 2.5-3.5 due to bleeding concerns Do not recommend routine anti-Xa levels due to lack of data Do not recommend placement of IVC filter due to lack of benefit Do not specify if QD or BID regimen is preferred (I prefer BID) Check peak anti-Xa: once daily 1.6-2.0 U/mL BID: 0.8-1.0 U/mL Therapeutic LMWH ↑ dose ~25% No symptomatic improvement J Thromb Haemost 2013; 11: 1760.

Unprovoked VTE: Anticoagulant Duration

38 yo woman, otherwise healthy, diagnosed with an unprovoked pulmonary embolism. She has no other medical problems, has no family history of VTE, is a non-smoker, and an extensive ROS is otherwise negative besides chest pain and dyspnea. She is started on anticoagulation. On follow up 4 weeks later, she is feeling well, no active symptoms. She inquires as to how long she needs to remain on anticoagulation.

68 yo man, otherwise healthy, diagnosed with an unprovoked pulmonary embolism. He has no other medical problems, has no family history of VTE, is a non-smoker, and an extensive ROS is otherwise negative besides chest pain and dyspnea. He is up to date with age-appropriate cancer screening. He is started on anticoagulation. On follow up 4 weeks later, he is feeling well, no active symptoms. He inquires as to how long he needs to remain on anticoagulation.

ACCP VTE Guidelines 2016 Current guidelines: Minimum 3 months anticoagulation after 1st VTE event No clear consensus or data defining optimal length of anticoagulation Chest 2016; 149 (2): 315.

Duration of Anticoagulation: Idiopathic Protective effect of anticoagulation lost on discontinuation: Placebo: 8.3% Anticoagulation: 0.7% Placebo + Anticoagulation: ~16% Patients with 1st idiopathic VTE episode who completed 3 months of anticoagulation randomized to continue or discontinue anticoagulation. Primary endpoint: recurrent, symptomatic VTE during at least 2 years of follow up At 1 year, placebo group with 8.3% recurrence, and continued AC only 0.7%; p=0.003. Bleeding in continued AC group = 3% At follow up of 37.8 months, rates similar with RR 0.99 Conclusion: Clinical benefit of extending duration of anticoagulation to one year is not maintained after the therapy is discontinued NEJM 2001; 345: 165.

VTE Recurrence: Sex 3 years: Men: 20% Women: 6% NEJM 2004; 350: 2558. 826 pts followed for avg 36 months All with 1st idiopathic VTE Excluded hypercoaguability, malignancy Evaluated recurrence based on sex NEJM 2004; 350: 2558.

Incident rate 40.9/1000 pt years 474 patients with 1st VTE prospectively followed Men with with an unprovoked 1st event had the highest recurrence risk Age at dx had little effect on recurrence rate, no had time elapsed from 1st event Incident rate 40.9/1000 pt years ~1/3 with idiopathic event had a 2nd idiopathic event at 8 years Incident rate 15.8 per 1000 pt years 3x lower risk for recurrent idiopathic VTE compared w/ men ~1/2 recurrences: provoked (pregnancy, estrogen) J Thromb Haemost 2010; 8: 2159.

Idiopathic VTE Recurrence Bleeding Risk 1st episode 10% first year 5%/year thereafter 30-50% risk at 5-10 years 2nd episode 15% first year 7.5%/year thereafter Bleeding Risk Major bleeding: 2.7 per 100 patient years “Low risk” 1.6% first 3 months 0.8%/year thereafter “Intermediate risk” 3.2% first 3 months 1.6%/year thereafter “High risk” 12.8% first 3 months 6.5%/year thereafter Chest 2012; 141: e419S. Ann Int Med 2003; 139: 893.

Case Fatality: VTE Ann Intern Med 2010; 152: 578. Systematic review of 69 articles; 13 prospective cohort, 56 RCT that reported on rate if fatal recurrent VTE and fatal major bleeding Received AC for at least 3 months; majority were UFH or LMWH as bridge to VKA x3 months During first 3 mos of AC, rate of fatal recurrent VTE was 0.4%, and case-fatality rate of recurrent VTE was 11.3% Ann Intern Med 2010; 152: 578.

Case Fatality: VTE Ann Intern Med 2010; 152: 578. After completion of anticoagulation, rate of fatal recurrent VTE was 0.3 per 100 patient years, and case fatality rate was 3.6% Studies following patients after discontinuation of anticoagulation did not distinguish outcomes by presentation (DVT only, PE only, DVT/PE or both)or did not report recurrent VTE or fatal recurrent VTE in the pulmonary embolism subgroup. Therefore could not determine the rate of fatal recurrent VTE and case-fatality rate after AC in pts who initially presented w/ PE or PE with or without DVT Ann Intern Med 2010; 152: 578.

Case Fatality: Bleeding Rates of major bleeding above are during the first 3 mos of anticoagulation Rates of major bleeding, and fatal major bleeding, about half of recurrent VTE, and fatal VTE recurrence rates DURING anticoagulation Rates of recurrent VTE after stopping anticoagulation (previous slide) were much higher than the major bleeding rates above (7.6 per 100 pt years), but fatal major bleeding and fatal recurrent VTE similar (0.3 versus 0.2 %) So: during the initial 6 months of VTE treatment, 11.3 per 100 patients who have a recurrent VTE will die, and 11.3 per 100 pts who have a major bleeding event will die. However after completing 3-6 mos of AC, 3.6 per 100 pts who have a recurrent VTE will die Ann Intern Med 2010; 152: 578.

Therapeutic Options Discontinue anticoagulation Warfarin INR 2.0-3.0 5-15% recurrent VTE risk within first year 30-50% risk at 5-10 years Warfarin INR 2.0-3.0 Recurrent VTE: 0.7 per 100 patient-years Major bleed: 2.7 per 100 patient-years, 9.1% case fatality Warfarin INR 1.5-2.0 Ann Int Med 2003; 139: 893.

Lower Intensity VKA in Idiopathic VTE PREVENT trial Long term low dose warfarin (INR 1.5-2) vs placebo after 3 months warfarin INR 2-3 Stopped after 508 pts followed for mean 2 yrs VTE recurrence: 2.6 (warfarin) vs 7.2% (placebo) Minor bleeding: 12.8 vs 6.7% NEJM 2003; 348: 1425.

Lower Intensity VKA in Idiopathic VTE ELATE trial (n=738) 2 warfarin intensities following 3 months: INR 1.5-2.0 versus 2.0-3.0 2.4 year average follow up VTE recurrence: 1.9 (low intensity) vs. 0.7 per 100 pt years (HR 2.8) No difference in major bleeding: 1.1 vs. 0.9 per 100 pt years NEJM 2003; 349: 631.

Therapeutic Options Discontinue anticoagulation Warfarin INR 2.0-3.0 Aspirin

Recurrent VTE or arterial event Aspirin: WARFASA VTE: Active Treatment Event ASA (N=205) Placebo (N=197) HR P value Recurrent VTE 28 43 0.58 0.02 Bleeding 4 0.98 0.97 Death 6 5 1.04 0.95 Arterial event 8 1.43 0.53 Recurrent VTE or arterial event 36 48 0.67 0.06 11%/year 5.9%/year Double blinded RCT in 402 patients with first idiopathic VTE episode, completed 6-18 months of anticoagulation Randomized to ASA 100 mg/day versus placebo for 2 years VTE: 6.6% versus 11.2%, HR 0.58, CI 0.36-0.93 over median 24 months One patient in each group had major bleeding event Patient demographics no diff between groups (99% white, 62% men, BMI 27, ~60% DVT/40% PE, ~1/2 treated with AC x12 mos) NEJM 2012; 366: 1959.

Aspirin: ASPIRE Annual rate: Annual rate: Placebo 6.5% Placebo 8.0% 822 patients randomized to ASA 100 mg/day versus placebo after 1st episode idiopathic VTE for up to 4 years After 37 mos f/u: recurrent VTE 57/411 ASA (4.8%/year) versus 73/411 placebo (6.5%/year), HR 0.74, p=0.09 BUT ASA reduced the rate of the two prespecified secondary composite endpoints: Rate of VTE, MI, stroke, or CV death reduced by 34% (8.0% per year placebo vs 5.2%/year with ASA, HR 0.66, p=.0.01). AND rate of recurrent VTE, MI, stroke, major bleeding, or death from any cause reduced by 33% (HR 0.67, p=0.01). No difference between bleeding rates 0.6% versus 1.1% 75% of both groups treated with AC for at least 6 months, Annual rate: Placebo 6.5% ASA 4.8% Annual rate: Placebo 8.0% ASA 5.2% NEJM 2012; 367: 1979

Aspirin: Pooled Data NEJM 2012; 367: 2039. 1977: ASA at 600 mg BID reduced risk of VTE after THA. Guidelines still list as an option. The two studies (WARFASA and ASPIRE) together show a VTE reduction of 1/3 with ASA, as well as rate of major vascular events, a composite outcome of venous thromboembolism, stroke, MI, or CV death. WARFASA: 402 pts showed 42% reduction in VTE recurrence rate c/w placebo (6.6% vs 11.2%), with HR 0.58, CI 0.36-0.93, p=0.02. BUT 8 pts on ASA and 5 on placebo had arterial event, so secondary endpoint of major vascular event (VTE, MI, stroke CV death) was nonsignificantly reduced with ASA ASPIRE: reverse happened. 822 pts. Nonsignificant decrease in the rate of recurrent VTE with ASA c/w placebo (4.8% vs 6.5%, HR 0.74, CI 0.52-1.05, p=0.09). But arterial events only half as common in ASA (10 vs 19 events), so there was a reduction in secondary endpoint of major vascular event HR 0.66; CI 0.48-0.92, p=0.01. When data pooledthere was a 32% reduction in rate of recurrence of VTE (HR 0.68 CI 0.51-0.90, p=0.007) and 34% reduction in rate of major vascular event (HR 0.66 CI 0.51-0.86). NEJM 2012; 367: 2039.

Therapeutic Options Discontinue anticoagulation Warfarin INR 2.0-3.0 Aspirin “Novel/new” oral anticoagulants

DOACs: Extended Use Schulman, S. Thromb Haemostasis 2014; 111: 575-582.

“Real World” Continuation of Rivaroxaban Retrospective study using Truven Health Analytics MarketScan Databases over 4 year period (2/2011-4/2015) Adult patients, completed at least 3 months of Rivaroxaban. Followed those who continued versus discontinued anticoagulation thereafter 5,933 patients continued (63.4% unprovoked) 1,536 discontinued (68.4% unprovoked) MEDIAN OBSERVATION PERIOD: 149.3 days in continued cohort BUT 211 in discontinued Primary outcome: Recurrent VTE identified as a primary diagnosis documented during a hospitalization Blood 2016; 128: 144.

Recurrent VTE Bleeding Stop all therapy ~8% per patient year Warfarin (INR 2.0-3.0) 0.7 per 100 pt years 2.7 per 100 pt years Warfarin (INR 1.5-2.0) 1.9-2.6 per 100 pt years 1 per 100 pt years Aspirin 4.8% per year .05-1% per year Apixiban 1.7% per year 0.2-2.1% per year* Rivaroxaban 82% risk reduction ~2% per year* Dabigatran 0.8-2.6% per year

ISTH Guidelines 1st unprovoked VTE: 3-6 months anticoagulation, continued as long as bleeding risk < thrombotic risk Favors Discontinuation AC: Female Mild/absent post-thrombotic syndrome Low D-dimer off AC Poor AC control Favors Longer term AC: Male Post-thrombotic syndrome Persistent dyspnea Elevated d-dimer off AC Good AC control J Thromb Haemost 2012; 10:698.

Bleeding with Anticoagulation Warfarin: Major bleeding: 2.7 per 100 patient years “Low risk” 1.6% first 3 months 0.8%/year thereafter “Intermediate risk” 3.2% first 3 months 1.6%/year thereafter “High risk” 12.8% first 3 months 6.5%/year thereafter Chest 2012; 141: e419S. Ann Int Med 2003; 139: 893.

Case Fatality: Bleeding Rates of major bleeding above are during the first 3 mos of anticoagulation Rates of major bleeding, and fatal major bleeding, about half of recurrent VTE, and fatal VTE recurrence rates DURING anticoagulation Rates of recurrent VTE after stopping anticoagulation (previous slide) were much higher than the major bleeding rates above (7.6 per 100 pt years), but fatal major bleeding and fatal recurrent VTE similar (0.3 versus 0.2 %) So: during the initial 6 months of VTE treatment, 11.3 per 100 patients who have a recurrent VTE will die, and 11.3 per 100 pts who have a major bleeding event will die. However after completing 3-6 mos of AC, 3.6 per 100 pts who have a recurrent VTE will die Ann Intern Med 2010; 152: 578.

Bleeding with Targeted Oral Anticoagulants (TOAC) Phase III RCT demonstrated comparable to slightly lower bleeding risk vs. VKA (annual): Major bleeding: 0.6-3.1% Major or clinical relevant non-major bleeding: 4-16% Rates vary depending on bleeding classification, dose, and follow up The 0.6% annual major bleeding risk above: Apixaban in VTE treatment study (AMPLIFY), and the 3.1 in Dabigatran in Afib (RELY) Clinically relevant or major bleeding rates: 4% in AMPLIFY, and 16.1% in RECOVER (Dabigatran in VTE- listed as “any” bleeding, though) Rivaroxaban major bleeding in VTE (EINSTEIN) 1.1%, but clinically relevant or major bleeding = 14.5%

Bleeding with Targeted Oral Anticoagulants (TOAC) Meta-analysis of 12 RCT in over 100,000 evaluable patients on TOAC for VTE: statistically significant reduction in major bleeding Blood 2014; 124(12): 1968-1975.

Bleeding with Targeted Oral Anticoagulants (TOAC) The 0.6% annual major bleeding risk above: Apixaban in VTE treatment study (AMPLIFY), and the 3.1 in Dabigatran in Afib (RELY) Clinically relevant or major bleeding rates: 4% in AMPLIFY, and 16.1% in RECOVER (Dabigatran in VTE- listed as “any” bleeding, though) Rivaroxaban major bleeding in VTE (EINSTEIN) 1.1%, but clinically relevant or major bleeding = 14.5% Blood 2014; 124(12): 1968-1975.

“Real World” Experience Prospective national surveillance registry, evaluated rates & bleeding types in everyday practice over a 2 year time frame 762 patients (42.9%) reported 1082 bleeding events 6% of the bleeding events were considered “major”- of major, surgical intervention required in 37.8% Bleeding rates per 100 patient years: Atrial fibrillation- 3.1 VTE- 4.1 Blood 2014; 124: 955-962.

“Real World” Experience Retrospective study using Truven Health Analytics MarketScan Databases over 4 year period (2/2011-4/2015) Adult patients, completed at least 3 months of Rivaroxaban. Followed those who continued versus discontinued anticoagulation thereafter 5,933 patients continued (63.4% unprovoked) 1,536 discontinued (68.4% unprovoked) MEDIAN OBSERVATION PERIOD: 149.3 days in continued cohort BUT 211 in discontinued Primary outcome: Recurrent VTE identified as a primary diagnosis documented during a hospitalization POINT OUT ON THIS SLIDE: BLEEDING RATE FOR CONTINUING AC IS CONSISTENT WITH PRIOR STUDIES (MAJOR BLEEDING 1-3%) BUT rate seems awfully high for having discontinued AC! Blood 2016; 128: 144.

Bleeding Risk Assessment Odds Ratio (95% CI) Points Recent major bleed 2.7 (1.6-4.6) 2 Creatinine >1.2 mg/dL 2.1 (1.7-2.8) 1.5 Anemia 2.1 (1.7-2.7) Cancer 1.7 (1.4-2.2) 1 Clinically overt PE Age >75 1.7 RIETE study: ongoing registry of consecutive patients with VTE Bleeding score to predict major bleeding during the fist THREE MONTHS of therapy 13,057 (67%) assigned to derivation sample, 6,572 to validation sample Derivation: 2.4% (n=314) with major bleeding, and 105 of these were fatal Multivariate analysis: Age >75, recent bleeding, cancer, anemia, creatinine >1.2, and PE on presentation independently associated with bleeding “recent” major bleed defined as <15 days prior to starting AC Other factors evaluated: gender, wt <70kg, inpatient, surgery, chronic heart or lung dz, antiplatelet therapy, plt <100K, anemia Score of 2 for recent bleed, 1.5 for abnl Cr or anemia, 1 point remaining variables Major bleeding in validation sample based on score (low, int, high risk): 0.1%, 2.8%, and 6.2% Limitations: lack of information on INR control. Risk for bleeding modified by characterstics that change during therapy (meds, other illnesses). p<0.001 for all Thromb Haemost 2008; 100 (1): 26-31.

Bleeding Risk Score Derivation sample (N=13,057 Validation sample (N=6,572) Points Patients N (%) Major bleeding N (%) Low risk (0) 2654 (20%) 9 (0.3%) 1340 (21%) 1 (0.1%) Intermediate risk (1-4) 9645 (74%) 250 (2.6%) 4891 (74%) 137 (2.8%) High Risk (>4) 758 (5.8%) 55 (7.3%) 341 (5.2%) 21 (6.2%) Thromb Haemost 2008; 100 (1): 26-31.

Summary LMWH still preferred agent in malignancy-associated VTE, but ongoing prospective studies evaluating DOACs Management of malignancy-associated VTE complicated around times of thrombocytopenia. Approach needs to consider thrombotic & bleeding risk Recurrent VTE common in malignancy despite adequate anticoagulation. No great evidence-based approach to management, although most recommend increasing dose of LMWH by 25% Maximum duration of anticoagulation in unprovoked VTE still not known Male sex consistently a significant risk factor for recurrence Options after treatment period include continuing full-dose anticoagulation, lower- dose DOAC, ASA, or discontinuation with close monitoring Longer-term risk for bleeding with anticoagulation include age >75, renal insufficiency, prior bleed, and malignancy