Rebecca Clark, PharmD 10/27/18

Transcription

1 Rebecca Clark, PharmD 10/27/18

2 Managing Anticoagulation in Malignancy: The Choice Will Not Be in Vein Rebecca Clark, PharmD PGY-2 Oncology Pharmacy Resident Huntsman Cancer Institute University of Utah Health 2

3 Disclosure Relevant Financial Conflicts of Interest CE Presenter Rebecca Clark, PharmD None CE Mentor Shelly Hummert, PharmD None Off-Label Use of Medications Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Dabigatran (Pradaxa ) Enoxaparin (Lovenox ) Fondaparinux (Arixtra ) Heparin 3

4 Pharmacist Learning Objectives 1. Recognize risk factors for developing venous thromboembolisms (VTE) in patients with active malignancies 2. Choose an appropriate anticoagulation regimen for treatment of VTE in a patient with an active malignancy 3. Analyze guideline recommendations for VTE prophylaxis in patients with multiple myeloma 4. Review agents used for reversal of anticoagulants 4

5 Technician Learning Objectives 1. Identify anticoagulants used for prevention and treatment of cancer-associated VTE 2. Differentiate proper storage, handling, and dispensing of anticoagulants and reversal agents 3. Describe cost differences between anticoagulants 5

6 VTE Overview Imbalance of the body s pro- and anti-thrombotic forces Formation of a blood clot within a vein Consists of fibrin, red blood cells, and platelets Common Types of VTE Deep vein thrombosis (DVT) Pulmonary embolism (PE) Superficial vein thrombosis (SVT) VTE venous thromboembolism Monie DD, et al. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S291 S298 National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI: /wjm/ ISSN [CC BY 3.0 ( from Wikimedia Commons 6

7 Epidemiology 4-7 fold greater risk of VTE in active malignancy 2-9 fold increased risk for recurrent VTE compared to general population 8-12% of acute DVTs are diagnosed with occult malignancy Up to 20% recurrence rate 2-6 fold increased likelihood of death DVT deep vein thrombosis VTE venous thromboembolism Monie DD, et al. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S291 S298 Wun T, et al. Best Pract Res Clin Haematol. 2009;22(1):9 23 Chee CE, et al. Blood. 2014;123(25): Sorensen HT, et al. N Engl J Med. 2000;343: White RH, et al. Arch Intern Med. 2005;165; Piran et al. Thrombosis Research. 2018;164:S172 S177 7

8 Pathophysiology of CA-VTE Stasis Thrombosis Vessel Wall Injury Hypercoagulability CA VTE Cancer Associated Venous Thromboembolism Virchow s Triad in Malignancy Kyrle PA, et al. Blood. 2009;114(6): Khalil J, et al. World J Surg Oncol. 2015;13:204 8

9 Pathophysiology of CA-VTE Bed rest Tumor compression Stasis Thrombosis Vessel Wall Injury Hypercoagulability CA VTE Cancer Associated Venous Thromboembolism Virchow s Triad in Malignancy Kyrle PA, et al. Blood. 2009;114(6): Khalil J, et al. World J Surg Oncol. 2015;13:204 9

10 Pathophysiology of CA-VTE Bed rest Tumor compression Stasis Vessel Wall Injury Thrombosis Hypercoagulability Release of procoagulant factors from malignant cells CA VTE Cancer Associated Venous Thromboembolism Virchow s Triad in Malignancy Kyrle PA, et al. Blood. 2009;114(6): Khalil J, et al. World J Surg Oncol. 2015;13:204 10

11 Pathophysiology of CA-VTE Bed rest Tumor compression Stasis Intravasation of cancer cells, drugs, devices Vessel Wall Injury Thrombosis Hypercoagulability Release of procoagulant factors from malignant cells CA VTE Cancer Associated Venous Thromboembolism Kyrle PA, et al. Blood. 2009;114(6): Khalil J, et al. World J Surg Oncol. 2015;13:204 Virchow s Triad in Malignancy 11

12 General Risk Factors of CA-VTE Cancer-Related Treatment-Related Patient-Related Biomarkers Primary site, bulky disease Major surgery (> 60 mins) Advanced stage IV catheterization / Indwelling venous access devices Cancer history (adenocarcinoma > squamous cell) Time after initial diagnosis (first 3-6 months) Therapy: Antiangiogenic, hormonal, platinumanalogues Non-antineoplastic therapy: ESA, transfusions, radiation therapy, Hypercoagulability Platelet count > 350,000 Medical comorbidities Leukocyte count > 11,000 Performance status, older age, prior VTE Modifiable risk factors: tobacco, obesity, activity level Hemoglobin < 10 CA VTE Cancer Associated Venous Thromboembolism ESA erythropoiesis stimulating agents National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). Lyman GH, et al. J Clin Oncol. 2013;31:

13 Epidemiology 120 Rate of DVT/PE per 10,000 Patients Levitan N, et al. Medicine. 1999;78(5)

14 General VTE Risk Assessment Khorana Score Estimates risk of VTE in ambulatory cancer patients receiving chemotherapy Includes 5 predictive variables: cancer site, platelet count, hemoglobin level (+ ESA use), leukocyte count, and BMI Formed basis for risk assessment models Set stage for evaluating risk-targeted VTE prophylaxis in clinical trials Not commonly used in clinical practice BMI body mass index ESA erythropoiesis stimulating agent VTE venous thromboembolism National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). Khalil J, et al. World J Surg Oncol. 2015;13:204 14

15 Assessment Question PharmD Which of the following is a risk factor for cancer-associated VTE? A. Younger age B. Bulky Disease C. Use of immunotherapy D. > 6 months after cancer diagnosis E. Non-tobacco use 15

16 Assessment Question PharmD Which of the following is a risk factor for cancer-associated VTE? A. Younger age B. Bulky Disease C. Use of immunotherapy D. > 6 months after cancer diagnosis E. Non-tobacco use 16

17 Treatment By Fuzis [CC BY SA 4.0 ( sa/4.0)], from Wikimedia Commons 17

18 Guideline Recommendations ASCO GUIDELINES 2014 NCCN GUIDELINES 2018 ACCP GUIDELINES 2016 ACCP American College of Chest Physicians ASCO American Society of Clinical Oncology NCCN National Comprehensive Cancer Network Treatment goal: prevent recurrence Should not be used to extend survival 18

19 Guideline Recommendations Recommendation ASCO (2014) ACCP (2016) NCCN (2018) Initial therapy LMWH recommended LMWH recommended LMWH recommended Chronic therapy LMWH recommended LMWH recommended LMWH LMWH + edoxaban Alternatives UFH Fondaparinux Warfarin DOACs not currently recommended Warfarin DOACs not currently recommended LMWH + Warfarin Apixaban Rivaroxaban LMWH + dabigatran DOAC direct oral anticoagulant LMWH low molecular weight heparin Lyman GH, et al. J Clin Oncol. 2013;31: Kearon C, et al. CHEST. 2016;149(2): National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 19

20 NCCN Guidelines (Updated March 22, 2018) Initial 6 months of therapy (monotherapy) LMWH low molecular weight heparin UFH unfractionated heparin LMWH Dalteparin (Category 1): o 200 IU/kg subq daily x 30 days, then 150 IU/kg subq daily x 2-6 months Enoxaparin: o 1 mg/kg subq BID Alternatives: Fondaparinux o 5 mg (< 50 kg); 7.5 mg ( kg); 10 mg (> 100 kg) subq daily Apixaban o 10 mg PO BID x 7 days, then 5 mg BID Rivaroxaban o 15 mg PO BID x 21 days, then 20 mg daily UFH IV/subQ (Category 2B) o 80 IU/kg x 1, then 18 IU/kg/hr (aptt x control), then 250 IU/kg subq BID o 333 IU/kg x 1, then 250 IU/kg subq BID National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 20

21 NCCN Guidelines (Updated March 22, 2018) Initial 6 months of therapy (combinations) LMWH/UFH with Edoxaban (Category 1) > 5 days of parenteral anticoagulation, then edoxaban 60 mg PO daily 30 mg PO daily if: o CrCl ml/min o Weight < 60 kg o P-gp inhibitors LMWH/UFH with Warfarin > 5 days of parenteral anticoagulation until INR > 2 x 24 hours (INR 2-3) LMWH/UFH with Dabigatran > 5 days of parenteral anticoagulation, then dabigatran 150 mg PO BID (CrCl > 30 ml/min only) CrCl creatinine clearance LMWH low molecular weight heparin UFH unfractionated heparin National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 21

22 Assessment Question CPhT Based on the NCCN 2018 guidelines, which of the following anticoagulants can be used for treatment of cancer-associated VTE? A. Enoxaparin B. Rivaroxaban C. Apixaban D. Edoxaban E. All of the above 22

23 Assessment Question CPhT Based on the NCCN 2018 guidelines, which of the following anticoagulants can be used for treatment of cancer-associated VTE? A. Enoxaparin B. Rivaroxaban C. Apixaban D. Edoxaban E. All of the above 23

24 CLOT Trial Population Intervention Endpoints Active cancer Newly diagnosed symptomatic proximal DVT, PE, or both N = 672 Dalteparin 200 IU/kg subq daily n = 336 Warfarin LMWH subq bridge x > 5 days, then warfarin monotherapy daily (INR 2-3) n = 336 Primary First episode of symptomatic, recurrent DVT, PE, or both Secondary Bleeding Mortality DVT deep vein thrombosis, PE pulmonary embolism, LMWH low molecular weight heparin Lee AY, et al. N Engl J Med. 2003;349:

25 CLOT Trial Primary Endpoint Outcome Dalteparin n = 336 Warfarin n = 336 p-value Recurrent DVT, Nonfatal PE, Fatal PE, n (%) 27 (8) 53 (16) Secondary Endpoints Major Bleeding, n (%) 19 (6) 12 (4) 0.27 Death, n (%) 130 (39) 136 (41) 0.53 DVT deep vein thrombosis PE pulmonary embolism Lee AY, et al. N Engl J Med. 2003;349:

26 CLOT Trial Primary Endpoint Outcome Dalteparin n = 336 Warfarin n = 336 p-value Recurrent DVT, Nonfatal PE, Fatal PE, n (%) 27 (8) 53 (16) Secondary Endpoints Major Bleeding, n (%) 19 (6) 12 (4) 0.27 Death, n (%) 130 (39) 136 (41) 0.53 DVT deep vein thrombosis PE pulmonary embolism Lee AY, et al. N Engl J Med. 2003;349:

27 Subgroup Analyses Dabigatran n = 114 RECOVER AMPLIFY EINSTEIN Warfarin n = 107 Apixaban n = 81 Warfarin n = 78 Rivaroxaban n = 354 Warfarin n = 301 Recurrent VTE / VTE-related Death, n (%) Major Bleeding, n (%) 4 (3.5) 5 (4.7) 3 (3.7) 5 (6.4) 16 (5.0) 20 (7.0) 4 (3.8) 3 (3.0) 2 (2.3) 4 (5.0) 8 (2.0) 15 (5.0) VTE venous thromboembolism Agnelli G, et al. J Thromb Haemost. 2015;13: Prins MH, et al. Lancet Haematol. 2014;1:e37 46 Schulman S, et al. Thromb Haemost. 2015;114:

28 Hokusai-VTE Trial Population Intervention Endpoints Active cancer Acute symptomatic or incidental VTE N = 1046 LMWH low molecular weight heparin VTE venous thromboembolism Dalteparin 200 IU/kg subq daily n = 524 Edoxaban LMWH subq x > 5 days, then edoxaban 60 mg PO daily n = 522 Primary Recurrent VTE or major bleeding Secondary Recurrent VTE Bleeding Mortality Raskob GE, et al. N Engl J Med. 2018;378:

29 Hokusai-VTE Trial Outcome Recurrent VTE or Major Bleeding, n (%) Dalteparin n = 524 Primary Endpoint Edoxaban n = (13.5) 67 (12.8) Secondary Endpoints p-value / 95% CI (NI) 0.87 (S) Recurrent DVT, n (%) 35 (6.7) 19 (3.6) 0.56 ( ) Recurrent PE, n (%) 28 (5.3) 27 (5.2) 1.00 ( ) Major Bleeding, n (%) 21 (4.0) 36 (6.9) 0.04 Mortality, n (%) 192 (36.6) 206 (39.5) 1.12 ( ) NI non-inferiority, S superiority VTE venous thromboembolism Raskob GE, et al. N Engl J Med. 2018;378:

30 Hokusai-VTE Trial Outcome Recurrent VTE or Major Bleeding, n (%) Dalteparin n = 524 Primary Endpoint Edoxaban n = (13.5) 67 (12.8) Secondary Endpoints p-value / 95% CI (NI) 0.87 (S) Recurrent DVT, n (%) 35 (6.7) 19 (3.6) 0.56 ( ) Recurrent PE, n (%) 28 (5.3) 27 (5.2) 1.00 ( ) Major Bleeding, n (%) 21 (4.0) 36 (6.9) 0.04 GI Cancer Mortality, n (%) 192 (36.6) 206 (39.5) 1.12 ( ) NI non-inferiority, S superiority VTE venous thromboembolism Raskob GE, et al. N Engl J Med. 2018;378:

31 SELECT-D Trial Population Intervention Endpoints Active cancer Symptomatic PE, incidental PE, symptomatic DVT N = 406 CRNMB clinically relevant nonmajor bleeding DVT deep vein thrombosis PE pulmonary embolism, VTE venous thromboembolism Dalteparin 200 IU/kg subq daily n = 203 Rivaroxaban 15 mg PO BID x 3 weeks, then 20 mg PO daily n = 203 Primary Recurrent VTE (includes other sites) Secondary Major bleeding CRNMB Young AM, et al. J Clin Oncol. 2018;36:

32 SELECT-D Trial Primary Endpoint Outcome Dalteparin n = 203 Rivaroxaban n = 203 HR 95% CI Cumulative VTE, n (%) 22 (11) 8 (4) 0.43 ( ) Secondary Endpoints Major Bleeding, n (%) 8 (4) 12 (6) 1.83 ( ) CRNMB, n (%) 8 (4) 26 (13) 3.76 ( ) CRNMB clinically relevant nonmajor bleeding VTE venous thromboembolism Young AM, et al. J Clin Oncol. 2018;36:

33 SELECT-D Trial Primary Endpoint Outcome Dalteparin n = 203 Rivaroxaban n = 203 HR 95% CI Cumulative VTE, n (%) 22 (11) 8 (4) 0.43 ( ) Secondary Endpoints Major Bleeding, n (%) 8 (4) 12 (6) 1.83 ( ) GI most common event Esophageal / gastroesophageal cancer at high risk CRNMB, n (%) 8 (4) 26 (13) 3.76 ( ) CRNMB clinically relevant nonmajor bleeding VTE venous thromboembolism Young AM, et al. J Clin Oncol. 2018;36:

34 SELECT-D Trial Primary Endpoint Outcome Dalteparin n = 203 Rivaroxaban n = 203 HR 95% CI Cumulative VTE, n (%) 22 (11) 8 (4) 0.43 ( ) Secondary Endpoints Major Bleeding, n (%) 8 (4) 12 (6) 1.83 ( ) CRNMB, n (%) 8 (4) 26 (13) 3.76 ( ) GI or urologic most common event CRNMB clinically relevant nonmajor bleeding VTE venous thromboembolism Young AM, et al. J Clin Oncol. 2018;36:

35 Duration of Anticoagulation Treatment Recommendation ASCO (2014) ACCP (2016) NCCN (2018) DVT > 6 months > 3 months > 3 months PE > 6 months > 3 months > 3 months Lyman GH, et al. J Clin Oncol. 2013;31: Kearon C, et al. CHEST. 2016;149(2): National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 35

36 Duration of Anticoagulation Treatment Considerations for Indefinite Therapy Active malignancy Advanced stage Active treatment No contraindications Clot-related symptoms Multiple clots and/or clots not catheter-related Unresolved with AC or catheter removal AC anticoagulation National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). By Videoplasty.com (Patient Care Cartoon.svg), from Wikimedia Commons; License under Creative Commons Attribution ShareAlike

37 Assessment Question PharmD MC is a 55 yo F (5 9 and 90 kg) diagnosed with DVT of left popliteal vein. Her PMH is significant for HTN, metastatic breast cancer, and PE. She is currently receiving treatment for breast cancer and completed 6 months of anticoagulation for her PE 1 year ago. Based on the NCCN 2018 guidelines for VTE disease, which of the following is the most appropriate option for anticoagulation therapy in MC? A. Dalteparin 5000 units subq daily for 6 months B. Enoxaparin 90 mg subq BID for 6 months C. Enoxaparin 90 mg subq BID indefinitely D. Apixaban 10 mg BID x 7 days, then 5 mg BID for total of 6 months E. Aspirin 81 mg daily indefinitely 37

38 Assessment Question PharmD MC is a 55 yo F (5 9 and 90 kg) diagnosed with DVT of left popliteal vein. Her PMH is significant for HTN, metastatic breast cancer, and PE. She is currently receiving treatment for breast cancer and completed 6 months of anticoagulation for her PE 1 year ago. Based on the NCCN 2018 guidelines for VTE disease, which of the following is the most appropriate option for anticoagulation therapy in MC? A. Dalteparin 5000 units subq daily for 6 months B. Enoxaparin 90 mg subq BID for 6 months C. Enoxaparin 90 mg subq BID indefinitely D. Apixaban 10 mg BID x 7 days, then 5 mg BID for total of 6 months E. Aspirin 81 mg daily indefinitely 38

39 Prophylaxis Nonsurgical Multiple myeloma Atrial Fibrillation By Fuzis [CC BY SA 4.0 ( sa/4.0)], from Wikimedia Commons 39

40 Guideline Recommendations ACCP GUIDELINES 2012 NCCN GUIDELINES 2018 ASCO GUIDELINES 2014 ASCO American Society of Clinical Oncology ACCP American College of Chest Physicians NCCN National Comprehensive Cancer Network 40

41 General Primary Prophylaxis for Nonsurgical Patients Summary Therapy Recommendation ACCP (2012) ASCO (2014) NCCN (2018) Inpatient Therapy LMWH UFH Fondaparinux LMWH UFH Fondaparinux LMWH UFH Fondaparinux Outpatient Therapy Not recommended Not recommended High risk patients: 1 mo Not recommended Duration of Therapy Length of hospitalization Length of hospitalization or until fully ambulatory Length of hospitalization or until fully ambulatory Lyman GH, et al. J Clin Oncol. 2013;31: Kahn SR, et al. CHEST. 2012;141(2)(Suppl):e195S e226s National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 41

42 NCCN 2018 Guideline Recommendations General Primary Prophylaxis for Nonsurgical Patients Agent Standard Dosing Obesity Dosing (BMI > 40 kg/m 2 ) Dalteparin 5000 IU subq daily 7500 IU subq daily # Enoxaparin 40 mg subq daily 40 mg subq BID Fondaparinux * 2.5 mg subq daily 5 mg subq daily # UFH 5000 IU subq Q8-12H 7500 units subq Q8H BMI body mass index, UFH unfractionated heparin; #limited data; *Contraindicated in patients with CrCl < 30 ml/min; caution with CrCl ml/min, weight < 50 kg, or age > 75 National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 42

43 Treatment & Prophylaxis Summary Drug Treatment Prophylaxis Dalteparin Enoxaparin Heparin Fondaparinux Warfarin --- (Combination with LMWH) Dabigatran --- (combination with LMWH) Apixaban --- Rivaroxaban --- Edoxaban (combination with LMWH) --- NCCN Guidelines 2018; excludes multiple myeloma, LMWH low molecular weight heparin National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 43

44 Multiple Myeloma (MM) 9-fold increased risk of developing VTE compared to general population Healthy Bone Marrow Disease-related pathological risk factors Increased blood viscosity High immunoglobulin levels Procoagulant activity of monoclonal protein Inflammatory cytokines Plasma Cell Myeloma Treatment-related Individual risk factors Red blood cell By すじにくシチュー [CC0], from Wikimedia Commons Plasma cell By A. Rad, Mikael Häggström, Spacebirdy, RexxS, domdomegg (File:Hematopoiesis (human) diagram en.svg) [CC BY SA 4.0 ( sa/4.0)], via Wikimedia Commons Diagram of a white blood cell CRUK 028 By Cancer Research UK (Original from CRUK) [CC BY SA 4.0 ( sa/4.0)], via Wikimedia Commons Sanfilippo KM, et al. Blood. 2016;128:

45 Risk Factors Individual Risk Factors Obesity (BMI > 30 kg/m 2 ) Prior VTE CVAD/pacemaker Comorbidities: o Cardiac disease o Chronic renal disease o Diabetes o Acute infection o Immobilization Surgery, use of erythropoietin, blood clotting disorders Risk Assessment Model for Prevention of VTE in MM MM-related Risk Factors Diagnosis of myeloma / hyperviscosity MM Therapy IMiD in combination with: o High dose dexamethasone (> 480 mg/month) o Doxorubicin o Multiagent chemotherapy National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). Palumbo A, et al. Leukemia. 2008;22: Recommendation No risk factor or only 1 individual/myeloma risk factor: Aspirin mg once daily > 2 individual/myeloma risk factors: LMWH 40 mg subq daily (or equivalent) Warfarin (INR 2-3) LMWH 40 mg subq daily (or equivalent) Warfarin (INR 2-3) INR international normalized ratio, LMWH low molecular weight heparin, IMiD immunomodulatory imide drug, VTE venous thromboembolism, CVAD cardiovascular assist device, BMI body mass index, MM multiple myeloma 45

46 DOACs for VTE Prophylaxis in MM? Why a DOAC? 5-11% VTE occurrence despite thromboprophylaxis; limited efficacy Practical barriers with current recommended thromboprophylaxis agents Storrar et al. Retrospective study evaluating apixaban 2.5 mg BID x 4 months (max of 6 months) in 70 patients with MM treated with IMiD-containing therapy Outcome: No VTE within 6 months of treatment initiation 1 major bleeding event 5 died during follow-up (unrelated to VTE) VTE venous thromboembolism IMiD immunomodulatory drug Storrar NPF, et al. Br J Haematol. 2018; 46

47 Assessment Question PharmD SH is a 65 yo F (5 7 and 80 kg) recently diagnosed with MM. Her PMH is significant for hypothyroidism and hyperlipidemia. She has not yet started IMiD or chemotherapy. Per NCCN 2018 guidelines, which of the following is the most appropriate option for thromboprophylaxis in SH? A. Aspirin 81 mg daily B. Warfarin 5 mg daily C. Dabigatran 150 mg BID D. Apixaban 5 mg BID E. Enoxaparin 40 mg subq daily 47

48 Assessment Question PharmD SH is a 65 yo F (5 7 and 80 kg) recently diagnosed with MM. Her PMH is significant for hypothyroidism and hyperlipidemia. She has not yet started IMiD or chemotherapy. Per NCCN 2018 guidelines, which of the following is the most appropriate option for thromboprophylaxis in SH? A. Aspirin 81 mg daily B. Warfarin 5 mg daily C. Dabigatran 150 mg BID D. Apixaban 5 mg BID E. Enoxaparin 40 mg subq daily 48

49 DOACs for Thromboprophylaxis in AF? Little published evidence on efficacy and safety of anticoagulation for AF in cancer Traditional scoring systems for stroke prediction not validated in cancer Patell, et al. showed a positive correlation between CHADS2 and CHAD2DS2-VASc with increased risk of ischemic stroke CHADS2 more predictive than CHA2DS2-VASc 1 point increase = 40% greater risk of stroke Primary cancer site as a cancer specific risk factor 3 retrospective studies assessing warfarin, rivaroxaban, apixaban, and dabigatran DOACs showed lower incidence of stroke compared to warfarin Apixaban associated with less bleeding AF atrial fibrillation DOAC direct oral anticoagulant Shah S, et al. Blood Advances. 2018;2(3): Kim K, et al. Korean Circ J. 2018;48(5): Laube ES, et al. Am J Cardiol. 2017;120(92): Patell R, et al. Am J Cardiol. 2017;120:

50 Reversal Agents By Fuzis [CC BY SA 4.0 ( sa/4.0)], from Wikimedia Commons 50

51 Anticoagulant Half-Life Reversal Agent Precautions/Considerations UFH 1 hr Protamine 1 mg/100 U of UFH Max dose: 50 mg 5-7 hr < 8 hours since last dose given Infuse 5 mg/min o Protamine 1 mg/mg of enoxaparin Anaphylaxis LMWH o Protamine 1 mg/100 U of dalteparin > 8 hours since last dose given o Decrease by 50% Warfarin Reversal Agents for Life-Threatening Bleeding or Emergent Surgery (per NCCN 2018 Guidelines) hr Dependent on clinical scenario and INR o Hold dose o Oral / IV vitamin K (phytonadione) o FFP, PCC, rfviia Avoid vitamin K subq erratic absorption and delayed onset Vitamin K IV infuse 1 mg/min History of HIT 3-factor PCC Fondaparinux hr Discontinue drug; limited evidence for rfviia Thromboembolic events UFH unfractionated heparin, LMWH low molecular weight heparin, FFP fresh frozen plasma, PCC prothrombin complex concentrate, rfviia activated recombinant human factor VII, HIT heparin induced thrombocytopenia National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 51

52 Reversal Agents for Life-Threatening Bleeding or Emergent Surgery (per NCCN 2018 Guidelines) DOAC Half-life Reversal Agent Precautions/Considerations hr Discontinue drug Dabigatran Idarucizumab (5 g IV) Similar precautions as previously stated Oral charcoal Rivaroxaban 9-12 hr Discontinue drug Apixaban 12 hr PCC, rfviia Oral charcoal Edoxaban hr PCC prothrombin complex concentrate, rfviia activated recombinant human factor VII National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 52

53 Andexanet Alfa (Andexxa ) Approved 2018 Indication: rivaroxaban and apixaban reversal Dose: Low dose: 400 mg bolus (30 mg/min), followed by 4 mg/min infusion for up to 120 mins High dose: 800 mg bolus (30 mg/min), followed by 8 mg/min infusion for up to 120 mins Drug Last Dose < 8 hours or unknown > 8 hours Rivaroxaban < 10 mg Low dose Rivaroxaban > 10 mg / unknown High dose Apixaban < 5 mg Low dose Apixaban > 5 mg / unknown High dose Low dose Andexanet alfa (Andexxa) [package insert]. Portola Pharmaceuticals, Inc., South San Francisco, CA:

54 Andexanet Alfa (Andexxa ) Pharmacological activity obinds and sequestrates rivaroxaban and apixaban oincreases tissue factor-initiated thrombin generation Pharmacodynamics orapid decrease in anti-fxa activity within 2 minutes after completion of bolus oreturn of anti-fxa activity within 2 hours after completion of bolus / continuous infusion Storage and handling Store intact vials at 2 o C to 8 o C Reconstituted vials stable at room temperature for < 8 hours 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter is required Allocated to specific sites Andexanet alfa (Andexxa) [package insert]. Portola Pharmaceuticals, Inc., South San Francisco, CA:

55 Andexanet Alfa (Andexxa ) Pharmacological activity obinds and sequestrates rivaroxaban and apixaban oincreases tissue factor-initiated thrombin generation Pharmacodynamics orapid decrease in anti-fxa activity within 2 minutes after completion of bolus oreturn of anti-fxa activity within 2 hours after completion of bolus / continuous infusion Storage and handling Store intact vials at 2 o C to 8 o C Reconstituted vials stable at room temperature for < 8 hours 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter is required Allocated to specific sites Low Dose (9 vials): $25,000 High Dose (18 vials): $50,000 Andexanet alfa (Andexxa) [package insert]. Portola Pharmaceuticals, Inc., South San Francisco, CA:

56 Assessment Question PharmD Andexanet alfa (Andexxa ) is a recombinant factor Xa inhibitor approved for reversal of rivaroxaban, apixaban, and dabigatran. True False 56

57 Assessment Question PharmD Andexanet alfa (Andexxa ) is a recombinant factor Xa inhibitor approved for reversal of rivaroxaban, apixaban, and dabigatran. True False 57

58 Assessment Question CPhT Which of the following is true of the proper storage and handling of Andexanet alfa (Andexxa )? A. Store in freezer B. Reconstituted product is stable at room temperature for < 8 hours C. Manufactured as multidose vials D. Filter required for IV infusion E. B and D 58

59 Assessment Question CPhT Which of the following is true of the proper storage and handling of Andexanet alfa (Andexxa )? A. Store in freezer B. Reconstituted product is stable at room temperature for < 8 hours C. Manufactured as multidose vials D. Filter required for IV infusion E. B and D 59

60 Special Considerations By Fuzis [CC BY SA 4.0 ( sa/4.0)], from Wikimedia Commons 60

61 Considerations for Selecting an Appropriate Regimen Renal / hepatic function Absorption Cost Reversal ability Considerations Administration / Adherence Bleeding Risk Drug interactions Monitoring 61

62 Anticoagulant Administration Drug Interactions Renal Elimination Renal/Hepatic Adjustments Dalteparin SubQ Enoxaparin Agents increasing 100% CrCl < 30 ml/min Heparin SubQ / IV bleeding / nephrotoxicity < 1% -- Fondaparinux SubQ 100% CrCl < 30 ml/min Contraindicated Warfarin Oral CYP1A2, CYP2C19, CYP2C9, CYP3A4 Dabigatran Oral P-glycoprotein 80% Apixaban Rivaroxaban Oral Oral BCRP, CYP1A2, CYP2C19, CYP2C8, CYP2C9, CYP3A4 BCRP, CYP3A4, p- glycoprotein 92% Liver dysfunction 27% 66% Edoxaban Oral P-glycoprotein 50% CrCl < 30 ml/min (excluded from trial) CrCl < 25 ml/min, liver dysfunction (excluded from trial) CrCl < 30 ml/mi, liver dysfunction (excluded from trial) CrCl < 30 ml/min, liver dysfunction (excluded from trial) National Comprehensive Cancer Network. Cancer Associated Venous Thromboembolic Disease (Version ). 62

63 Summary of Anticoagulants Considerations Dabigatran Apixaban Rivaroxaban Edoxaban Enoxaparin Fondaparinux Route of Administration Oral Oral Oral Oral Subcutaneous Subcutaneous Storage Room temp with limited moisture Original container Room temp Room temp Room temp Room temp Room temp Discard within 4 months of opening Crushable N Y Y Y Gastric tube N Y Y Y Special Instructions Dispense in original container Do no express air bubble Sharps disposal Lovenox [package insert]. Bridgewater, NJ. Sanofi Aventis, LLC.; 2009 Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2015 Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2001 Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014 Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011 Eliquis [package insert]. Princeton, NJ: Bristol Myers Squibb Company;

64 Cost of Anticoagulants $5, $4,000 $3, $2, $1, $0 4 Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Enoxaparin Fondaparinux Dalteparin Average cost for 30 day supply Expanded access for edoxaban 64

65 Cost of Anticoagulants $5, $4,000 Patient Assistance $3, $2,000 Savings Card 1791 $1, $0 4 Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Enoxaparin Fondaparinux Dalteparin Average cost for 30 day supply Expanded access for edoxaban 65

66 $25,000 Cost of Reversal Agents 25,000 $20,000 $15,000 13,600 $10,000 $5,000 5,700 7,000 $ Protamine 50 mg Phytonadione PO Phytonadione Syr 4-PCC 50 IU/kg rfviia Idarucizumab 5 g Andexanet alfa (low dose) rfviia activated recombinant human factor VII (90 mcg/kg dose for 70 kg patient) 4-PCC 4-factor prothrombin complex concentrate (50 IU/kg dose for 70 kg patient) 66

67 Assessment Question CPhT Which of the following oral anticoagulants cannot be crushed? A. Dabigatran B. Rivaroxaban C. Apixaban D. Edoxaban E. Warfarin 67

68 Assessment Question CPhT Which of the following oral anticoagulants cannot be crushed? A. Dabigatran B. Rivaroxaban C. Apixaban D. Edoxaban E. Warfarin 68

69 Assessment Question CPhT Savings cards and patient assistance programs are ways to mitigate cost of anticoagulants for patients? True False 69

70 Assessment Question CPhT Savings cards and patient assistance programs are ways to mitigate cost of anticoagulants for patients? True False 70

71 Summary VTE Treatment ASCO Guidelines ACCP Guidelines NCCN Guidelines Prophylaxis General nonsurgical patients Multiple myeloma Atrial fibrillation Future directions: CASSINI and AVERT Trial Special Considerations Efficacy & Safety Affordability Patient-specific factors 71

72 Questions? By Fuzis [CC BY SA 4.0 ( sa/4.0)], from Wikimedia Commons 72