Case Vignette A 68-year-old woman with obesity was admitted to the Medical Service with COPD and pneumonia and was treated with oral corticosteroids, bronchodilators, and antibiotics. She responded well and was discharged after 3 days. While she had been receiving prophylactic enoxaparin 40 mg once daily in hospital, this was discontinued at the time of discharge. Case Vignette At home, she followed her treatment regimen to the letter and convalesced while binge-watching Game of Thrones. 72 hours after hospital discharge, she developed severe recurrent dyspnea that did not respond to home nebulizer treatments. In the ED, she was noted to be profoundly hypoxemic, requiring a non-rebreather mask. A contrast-enhanced chest CT was performed. Medical Patients: A Population at Risk
High-Risk Medical Conditions Triggers for Outpatient VTE Risk Factor RR vs. Control Acute infection 2.9 Transfusion 2.57 Erythropoiesis stimulating drugs 9.33 Piazza G, et al. Thromb Haemost 2009;102:505 Rogers MA, et al. Circulation 2012;125:2092 Inflammation and VTE Risk Folsom Folsom AR, et al. Thromb Haemost 2009;102:615 VTE Risk after Discharge Although much of the emphasis placed on prevention has focused on inhospital prophylaxis, threequarters of patients develop venous thromboembolism (VTE) as outpatients. Of these patients, a substantial proportion have undergone hospitalization (37%) or surgery (23%) in the 3 months preceding the diagnosis of VTE. Spencer FA, et al. Arch Intern Med 2007;167:1471
Observational study of > 11,000 hospitalized medical patients Risk of VTE Extends Post-Hospital Discharge Post-Discharge VTE: Medical Patients The rate of symptomatic VTE more than doubles over 21 days post-discharge. The risk of fatal PE increases fivefold. Amin AN, et al. J Hosp Med. 2012;7:231 Cohen AT, et al. N Engl J Med. 2013;368:513 Goldhaber SZ, et al. N Engl J Med. 2011;365:2167 More Than Half of VTE Occurs after 10 Days of Prophylaxis VTE Risk Factors Do Not Miraculously Go Away When Patients are Discharged Obesity Comorbid medical disease COPD/HF Inflammatory disorders (IBD, RA, lupus) Atherosclerotic cardiovascular disease Thrombophilia Acquired (antiphospholipid antibodies) Inherited (anticoagulant protein deficiencies) Smoking Cohen AT, et al. N Engl J Med. 2013;368:513 Goldhaber SZ, et al. N Engl J Med. 2011;365:2167 Family history
VTE Risk Assessment Risk Stratification Maynard GA, Stein J. J Thromb Thrombolysis 2010;29:159 VTE Prophylaxis after Risk Stratification Implementation Maynard GA, et al. Journal of Hospital Medicine 2010;5:10 VTE Risk Score at Hospital Discharge Major (High) Risk Factors (3 POINTS each): Cancer (active) Prior VTE Hypercoagulability Intermediate Risk Factor (2 POINTS each): Major Surgery ( 60 minutes, during this admission) Minor (Low) Risk Factors (1 POINT each): Advanced Age ( 70 years of age) Obesity (BMI 29, or the presence of the word obesity in admission exam notes) Bed rest / Immobility (not related to surgery) Female hormone replacement therapy or oral contraceptives 4 points = high-risk for VTE Kucher N, et al. N Engl J Med 2005;352:969 Piazza G, et al. Am J Med 2013;126:435
APEX: Enrollment Criteria VTE Prophylaxis after Hospital Discharge Cohen AT, et al. Am Heart J 2014;167:335 Discharge VTE Prophylaxis: Options in Medical Patients Mechanical Graduated compression stockings Intermittent pneumatic compression Inferior vena cava (IVC) filter Pharmacological Injectables (heparin, LMWHs, fondaparinux) Oral (betrixaban) Limitations of Current Therapies for Medically Ill Patients (LMWH and Heparin) Limited VTE protection Patient Adherence Injection Site Hematomas Other agents not approved for extended duration prophylaxis due to excessive major bleeding and lack of efficacy High VTE event rates persist despite in-hospital use Pain/discomfort from injections Patient refusal (10-13%) 9% rate of injection site hematoma Risk of rectus sheath hematoma Combination Pharmacological plus mechanical Unpredictable Anticoagulation HIT Enoxaparin targets multiple factors, each of which has a different half-life Risk of heparin-induced thrombocytopenia
Optimal Duration of Prophylaxis: Orthopedic Patients Optimal Duration of VTE Prophylaxis: ENOXACAN II Eikelboom JW, et al. Lancet 2001; 358: 9 Bergqvist D, et al. N Engl J Med 2002;346:975 Extended-Duration Thromboprophylaxis in Acutely Ill Medical Patients: EXCLAIM Rivaroxaban for Thromboprophylaxis in Medical Patients: MAGELLAN Hull RD, et al. Ann Intern Med 2010;153:8 Cohen AT, et al. N Engl J Med 2013;368:513
Rivaroxaban for Thromboprophylaxis in Medical Patients: MAGELLAN ADOPT: Apixaban vs. Enoxaparin for Extended Prophylaxis in Medical Patients Cohen AT, et al. N Engl J Med 2013;368:513 Goldhaber SZ, et al. N Engl J Med 2011;365:2167 VTE Prophylaxis for Medical Patients at Hospital Discharge: CONTINUUM Decision Support for VTE Prevention after Hospital Discharge: DISCHARGE ALERT TRIAL PLANNED DISCHARGE WITHIN 48 HOURS RISK SCORE 4 ALERT NO ALERT INTERVENTION CONTROL ALERT Physician Check for Prophylaxis Order (within 48 hours of ALERT) 90-DAY FOLLOW UP (performed days 90-120) Fanikos J, et al. Am J Med 2011;124:1143 Piazza G, et al. Am J Med 2013;126:435
Decision Support for VTE Prevention after Hospital Discharge: DISCHARGE ALERT TRIAL Prophylactic Measures* Alert Control p-value Any prophylaxis, n (%) 278 (22) 122 (9.7) < 0.0001 Mechanical prophylaxis, n (%) Pneumatic compression device Graduated compression stockings Inferior vena cava filter Pharmacological prophylaxis, n (%) Unfractionated heparin Enoxaparin Warfarin Fondaparinux 46 (3.7) 6 (13) 29 (63) 13 (28) 234 (19) 15 (6.4) 130 (56) 123 (53) 8 (3.4) 31 (2.5) 2 (6.5) 7 (23) 22 (71) 97 (7.7) 12 (12) 52 (54) 29 (30) 3 (3.1) 0.08 0.46 < 0.001 < 0.001 < 0.0001 0.07 0.75 < 0.001 0.99 Discharge Alert Trial: Symptomatic VTE at 90 days Cumulative rate 0.046 0.044 0.042 0.040 0.038 0.036 0.034 0.032 0.030 0.028 0.026 0.024 0.022 0.020 0.018 0.016 0.014 0.012 0.010 0.008 0.006 0.004 0.002 0.000 log-rank p = 0.5871 0 10 20 30 40 50 60 70 80 90 *Patients could receive more than one type of prophylaxis. Piazza G, et al. Am J Med 2013;126:435 Days from discharge to VTE, starting clock at randomization Alert No Yes Piazza G, et al. Am J Med 2013;126:435 Extended Duration Prophylaxis in Medical Patients: Net Clinical Benefit? Study Study type Study conclusion Net clinical benefit EXCLAIM (Hull, et al.) MAGELLAN (Cohen, et al.) ADOPT (Goldhaber, et al.) DISCHARGE ALERT (Piazza, et al.) CONTINUUM (Fanikos, et al.) RCT RCT RCT RCT Case-Control VTE Major bleeding VTE Major bleeding VTE Major bleeding VTE Major bleeding VTE Major bleeding No No No No No Piazza G, et al. Am J Med 2013;126:435 Subjects enrolled (N=7,513) R 1:1 Loading dose 160 mg APEX: Study Design Standard Prophylaxis 10 ± 4 days Enoxaparin 40 mg Double blind, double dummy Betrixaban 80 mg Extended Prophylaxis 35 42 days Placebo Betrixaban 80 mg Evaluation Ultrasound & Visit 3 Day 35 (+7 days) Follow-up safety visit 30 Days After Visit 3 (+5 days) Primary Efficacy Endpoint: Composite of asymptomatic proximal DVT (detected on ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, and VTE-related death through Visit 3 Primary Safety Endpoint: ISTH Major bleeding through 7 days after drug discontinuation Net Clinical Benefit: Composite of primary efficacy and primary safety endpoints Cohen AT, et al. N Engl J Med. 2016;375:534
Betrixaban Oral direct factor Xa inhibitor Renal clearance: 5% of administered dose and 17% of absorbed dose Half-life of 19-25 hrs No major CYP450 interactions Rapid onset Cmax achieved at 3-4 hours Probability of Symptomatic Event (%) APEX: Symptomatic VTE Parenteral Therapy Composite of Symptomatic Proximal or Distal DVT, Non- Fatal PE, or VTE-related Death Through Visit 3 HR = 0.65 (0.42, 0.99) ARR = 0.51% NNT = 196 Enoxaparin Betrixaban 1.44% p=0.043 0.93% Visit 3 Through End of Trial* HR = 0.56 (0.38, 0.84) ARR = 0.80% NNT = 125 1.84% p=0.004 1.04% Time (Days) *End of Trial defined as final follow-up visit (30 + 5 days after Visit 3) Cohen AT, et al. N Engl J Med. 2016;375:534 APEX: Safety APEX: VTE-Related Rehospitalization Enoxaparin Betrixaban Cohen AT, et al. N Engl J Med. 2016;375:534 Gibson CM, et al. Circulation 2017; in press
DOAC Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients MARINER: Rivaroxaban after Discharge for Medical Patients at High Risk of VTE Goldhaber SZ, et al. N Engl J Med. 2011;365:2167 Cohen AT, et al. N Engl J Med. 2013;368:513;Cohen AT, et al. N Engl J Med. 2016;375:534 Raskob GE, et al. Thromb Haemost. 2016;115:1240 MAGELLAN versus MARINER: What s the Difference? MARINER will enroll higher risk patients than MAGELLAN and will use only symptomatic endpoints, to show more robust risk reductions (not asymptomatic U/S endpoints). MARINER will exclude high bleeding risk patients: active cancer, dual antiplatelet therapy, long-term NSAIDS. Take Home Points VTE is a common and preventable complication of medical illness after hospital discharge. VTE risk factors persist long after hospital discharge. High-risk medically-ill patients with a low-risk of bleeding likely benefit from extended duration thromboprophylaxis. Oral thromboprophylaxis options have the potential to increase access to extended VTE prevention.