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Evaluation of Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in the Oncology Population Jessica Hedvat, PharmD PGY-1 Pharmacy Resident Hackensack University Medical Center Hackensack, NJ NJSHP Residency Forum June 9, 2016
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Epidemiology Across all patients with cancer, the risk for VTE is elevated 7-fold as compared to the general population 2nd leading cause of death in oncology patients Cancer is responsible for 18% of all cases of incident VTE With the most profound increases in risk seen in patients with… Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9: Noble S, et al. British Journal of Cancer. 2010; 102: S2-S9.
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Risk Factors VTE Bleeding Antiangiogenics Hormonal therapy
Supportive therapies Central venous catheters Surgery Chemotherapy Radiotherapy Cancer-related changes in hemostasis Liver failure FYI Risk factors for VTE Surgery Chemotherapy (particularly cisplatin – cytotoxic agents cause vessel injury) Hormonal therapy (tamoxifen, letrozole) Angiogenesis inhibitors (thalidomide, lenalidomide, bevacizumab, VEG-F inhibitors: sorafenib, sunitinib) Supportive therapies (steroids, blood transfusions, WBC GF, erythropoiesis stimulating agents) Placement of central venous catheters Radiotherapy Primary site of malignancy Stage (higher stage) Time since diagnosis (risk increased during first 3 – 6 months) Hemostatic changes Reduced hepatic anticoagulant synthesis Decreased hepatic clearance of activated factors TF and factors V, VIII, IX, and XI Tumor cells express cytokines such as TNF-α and IL-1β Deficient activity of von Willebrand’s factor-cleaving protease (ADAMTS13) Risk for Bleeding Tumor local vessel damage and invasion Platelet dysfunction Thrombocytopenia Reduced hepatic clotting factor synthesis Isolated factor defects Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9: Noble S, et al. British Journal of Cancer. 2010; 102: S2-S9.
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Contraindications to Therapeutic Anticoagulation
Intracranial or spinal lesions Active peptic or other gastrointestinal ulceration Active, but non-life threatening bleeding Intracranial bleeding within 4 weeks Major surgery or serious bleeding within 2 weeks Platelets < 50,000/mcL Relative Contraindications Active bleeding Severe, uncontrolled hypertension Surgery or invasive procedure including lumbar puncture, spinal anesthesia, & epidural catheter placement Platelets < 20,000/mcL Absolute Contraindications Anticoagulant management of cancer-associated thrombosis is especially challenging because bleeding rates are also higher in cancer patients Highlight platelet count Lyman GH, et al. J Clin Oncol. 2015; 33.
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Contraindications to Therapeutic Anticoagulation
Intracranial or spinal lesions Active peptic or other gastrointestinal ulceration Active, but non-life threatening bleeding Intracranial bleeding within 4 weeks Major surgery or serious bleeding within 2 weeks Platelets < 50,000/mcL Relative Contraindications Active bleeding Severe, uncontrolled hypertension Surgery or invasive procedure including lumbar puncture, spinal anesthesia, & epidural catheter placement Platelets < 20,000/mcL Absolute Contraindications Most experts agree that therapeutic AC can be administered if PLT count can be maintained over 50,000/mcL Lyman GH, et al. J Clin Oncol. 2015; 33.
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DOAC Dosing for VTE Treatment
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Treatment of VTE 150 mg PO BID after 5 – 10 days of parenteral anticoagulation 15 mg PO BID with food for 21 days, then 20 mg PO daily with food 10 mg PO BID for 7 days, then 5 mg PO BID Renal Adjustment Clcr ≤ 30 mL/min: no dosing recommendation Clcr < 30 mL/min: avoid use None Hepatic Adjustment Moderate or severe hepatic impairment: not recommended Severe hepatic impairment: not recommended Drug Interactions Clcr < 50 mL/min with concomitant P-gp inhibitor: avoid concomitant use P-gp inducers: avoid concomitant use Strong dual CYP3A4/P-gp inhibitors/inducers: avoid concomitant use Strong dual CYP3A4/P-gp inhibitors: ↓ dose by 50% Strong dual CYP3A4/P-gp inducers: avoid concomitant use Clcr = creatinine clearance, CYP = cytochrome P450, P-gp = P-glycoprotein Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; January 2015. Xarelto [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc; January 2015. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; June 2015.
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DOAC Dosing for VTE Treatment
Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Treatment of VTE 150 mg PO BID after 5 – 10 days of parenteral anticoagulation 15 mg PO BID with food for 21 days, then 20 mg PO daily with food 10 mg PO BID for 7 days, then 5 mg PO BID Renal Adjustment Clcr ≤ 30 mL/min: no dosing recommendation Clcr < 30 mL/min: avoid use None Hepatic Adjustment Moderate or severe hepatic impairment: not recommended Severe hepatic impairment: not recommended Drug Interactions Clcr < 50 mL/min with concomitant P-gp inhibitor: avoid concomitant use P-gp inducers: avoid concomitant use Strong dual CYP3A4/P-gp inhibitors/inducers: avoid concomitant use Strong dual CYP3A4/P-gp inhibitors: ↓ dose by 50% Strong dual CYP3A4/P-gp inducers: avoid concomitant use Clcr = creatinine clearance, CYP = cytochrome P450, P-gp = P-glycoprotein Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; January 2015. Xarelto [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc; January 2015. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; June 2015.
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Conclusion in Cancer Patients
Previous Trials DOAC Clinical Trial Cancer Subjects Conclusion in Cancer Patients Dabigatran RE-COVER (Treatment of VTE; ~70% DVT & ~30% PE) 121/2539 (4.8%) Similar rates of recurrent VTE (3.1% dabigatran vs. 5.3% warfarin); bleeding rates not available Rivaroxaban EINSTEIN-DVT (Treatment of DVT) 207/3449 (6%) Similar rates of recurrent VTE (3.4% rivaroxaban vs. 5.6% warfarin) & CRB (14.4% vs. 15.9%) EINSTEIN-PE (Treatment of PE) 223/7251 (4.6%) Similar rates of recurrent VTE (1.8% rivaroxaban vs. 2.8% warfarin) & CRB (12.3% vs. 9.3%) Apixaban AMPLIFY (Treatment of VTE) 143/5395 (2.7%) No data available Rates similar to conventional therapy (warfarin) CRB = clinically relevant bleeding, DVT = deep vein thrombosis, PE = pulmonary embolism Schulman S, et al. N Engl J Med. 2009; 361: ; Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9: Bauersachs R, et al. N Engl J Med. 2010; 363: ; Buller HR, et al. N Engl J Med. 2010: 366: Agnelli G, et al. N Engl J Med. 2013; 369:
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Conclusion in Cancer Patients
Previous Trials DOAC Clinical Trial Cancer Subjects Conclusion in Cancer Patients Dabigatran RE-COVER (Treatment of VTE; ~70% DVT & ~30% PE) 121/2539 (4.8%) Similar rates of recurrent VTE (3.1% dabigatran vs. 5.3% warfarin); bleeding rates not available Rivaroxaban EINSTEIN-DVT (Treatment of DVT) 207/3449 (6%) Similar rates of recurrent VTE (3.4% rivaroxaban vs. 5.6% warfarin) & CRB (14.4% vs. 15.9%) EINSTEIN-PE (Treatment of PE) 223/7251 (4.6%) Similar rates of recurrent VTE (1.8% rivaroxaban vs. 2.8% warfarin) & CRB (12.3% vs. 9.3%) Apixaban AMPLIFY (Treatment of VTE) 143/5395 (2.7%) No data available Rates similar to conventional therapy (warfarin) CRB = clinically relevant bleeding, DVT = deep vein thrombosis, PE = pulmonary embolism Schulman S, et al. N Engl J Med. 2009; 361: ; Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9: Bauersachs R, et al. N Engl J Med. 2010; 363: ; Buller HR, et al. N Engl J Med. 2010: 366: Agnelli G, et al. N Engl J Med. 2013; 369:
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Conclusion in Cancer Patients
Previous Trials DOAC Clinical Trial Cancer Subjects Conclusion in Cancer Patients Dabigatran RE-COVER (Treatment of VTE; ~70% DVT & ~30% PE) 121/2539 (4.8%) Similar rates of recurrent VTE (3.1% dabigatran vs. 5.3% warfarin); bleeding rates not available Rivaroxaban EINSTEIN-DVT (Treatment of DVT) 207/3449 (6%) Similar rates of recurrent VTE (3.4% rivaroxaban vs. 5.6% warfarin) & CRB (14.4% vs. 15.9%) EINSTEIN-PE (Treatment of PE) 223/7251 (4.6%) Similar rates of recurrent VTE (1.8% rivaroxaban vs. 2.8% warfarin) & CRB (12.3% vs. 9.3%) Apixaban AMPLIFY (Treatment of VTE) 143/5395 (2.7%) No data available Rates similar to conventional therapy (warfarin) CRB = clinically relevant bleeding, DVT = deep vein thrombosis, PE = pulmonary embolism Schulman S, et al. N Engl J Med. 2009; 361: ; Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9: Bauersachs R, et al. N Engl J Med. 2010; 363: ; Buller HR, et al. N Engl J Med. 2010: 366: Agnelli G, et al. N Engl J Med. 2013; 369:
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VTE Treatment in Patients with Active Cancer
ACCP 2012 ASCO 2014 NCCN 2015 Initial treatment Not addressed in oncology patients LMWH is preferred Use of DOACs is not currently recommended Long-term Treatment Across 3 major guidelines, they are not recommended 2 organizations do make specific comments addressing the use of DOACs FYI NCCN = expert opinion, certain cancer centers – MDs and PharmDs from committees, more updates ASCO = better, society-driven, directly from evidence, less updates LMWH vs. heparin Data extrapolated from subgroup analyses showed no difference in efficacy between LMWH and UFH in cancer patients However, a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing LMWH vs. warfarin CLOT trial (N Engl J Med 2003, 676 patients): dalteparin vs. warfarin Warfarin is less effective in patients with cancer, with rates of recurrent VTE being 3X higher than in patients without cancer, despite maintenance of the INR within therapeutic range A meta-analysis confirmed this finding, reporting a relative risk reduction of 53% Similar rates of bleeding ACCP = American College of Chest Physicians, ASCO = American Society of Clinical Oncology, LMWH = low-molecular-weight heparin, NCCN = National Comprehensive Cancer Network Kearon C, al. Chest. 2012; 141 (2 Suppl): e419S-94S. NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33.
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VTE Treatment in Patients with Active Cancer
ACCP 2012 ASCO 2014 NCCN 2015 Initial treatment Not addressed in oncology patients LMWH is preferred Use of DOACs is not currently recommended Long-term Treatment Across 3 major guidelines, they are not recommended 2 organizations do make specific comments addressing the use of DOACs FYI NCCN = expert opinion, certain cancer centers – MDs and PharmDs from committees, more updates ASCO = better, society-driven, directly from evidence, less updates LMWH vs. heparin Data extrapolated from subgroup analyses showed no difference in efficacy between LMWH and UFH in cancer patients However, a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing LMWH vs. warfarin CLOT trial (N Engl J Med 2003, 676 patients): dalteparin vs. warfarin Warfarin is less effective in patients with cancer, with rates of recurrent VTE being 3X higher than in patients without cancer, despite maintenance of the INR within therapeutic range A meta-analysis confirmed this finding, reporting a relative risk reduction of 53% Similar rates of bleeding ACCP = American College of Chest Physicians, ASCO = American Society of Clinical Oncology, LMWH = low-molecular-weight heparin, NCCN = National Comprehensive Cancer Network Kearon C, al. Chest. 2012; 141 (2 Suppl): e419S-94S. NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33.
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Study Rationale Identify the dosing patterns of DOACs for VTE treatment in patients with active cancer Limited data evaluating the safety of DOACs for VTE treatment in patients with active cancer There's a need to evaluate the dosing of DOACs because of complexity of patient population (bleeding risk, procedures, thrombocytopenia, etc)… Due to ease of administration, still used We noticed an increased trend and we wanted to look further
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Study Objective To evaluate the practice and safety patterns of the DOACs when used for VTE treatment in the oncology population at Hackensack University Medical Center
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Study Endpoints Primary endpoints Secondary endpoints
Percentage of patients who were receiving a DOAC dosage consistent with that of the package insert Percentage of patients who experienced clinically significant bleeding Secondary endpoints Percentage of patients who had their DOAC held for thrombocytopenia Percentage of procedures when patients had their DOAC appropriately held The primary endpoints are… the secondary endpoints are…
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Clinically significant bleeding
Definitions Clinically significant bleeding A decrease in Hgb of ≥ 2 g/dL and transfusion of ≥ 2 units of packed RBCs Bleeding that occurs in at least one critical site (intracranial, intraspinal, intra-ocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal) Bleeding that was fatal Minor bleeding All acute clinically overt bleeding events not meeting the criteria for clinically significant bleeding Thrombocytopenia Platelets < 50,000/mcL or or Major bleeding Non-life-threatening Reduction in Hgb ≥ 2 g/dL AND transfusion of 2 units of PRBC Symptomatic bleeding in a critical area/organ Life threatening Fatal bleeding, symptomatic intracranial bleeding, reduction in Hgb ≥ 5 g/dL, bleeding requiring transfusion of ≥ 4 units of PRBCs or inotropic agents or necessitating surgery Agnelli G, et al. N Engl J Med. 2013; 369: Connolly SJ, et al. N Engl J Med 2009; 361(12): Hgb = hemoglobin, RBCs = red blood cells
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Study Design IRB-approved Retrospective review of medical records
Computer generated report of DOACs Included patients on all inpatient adult oncology floors January 2013 – October 2015 Hackensack University Medical Center 775-bed teaching hospital 4 oncology floors (75 beds)
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Inclusion/Exclusion Criteria
≥ 18 years of age Admitted to an oncology floor Received a DOAC for VTE treatment for ≥ 48 hours Active malignancy Hemodialysis Receiving a DOAC exclusively for atrial fibrillation
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Patients Screened 87 Patients Excluded 126 Patients Screened
26: Atrial fibrillation only 17: DOAC used for < 48 hours 15: No active malignancy 10: Outpatient orders 9: Atrial fibrillation only & DOAC used for < 48 hours 4: Atrial fibrillation only & no active malignancy 2: No active malignancy & DOAC used for < 48 hours 2: DOAC used for primary VTE prophylaxis 1: Patient on hemodialysis 1: Unknown DOAC indication 39 Patients Included Highlight fact that majority = rivaroxaban First one that got the VTE indication (Nov 2012; dabigatran April 2014; apixaban August 2014) Started first and more comfort Once daily Good coupon program from mfg n = 0 dabigatran (0%) n = 35 rivaroxaban (90%) n = 4 apixaban (10%)
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Patient Demographics Characteristic n = 39 Median age, years 61
Gender, n (%) Male 20 (51) Female 19 (49) DOAC indication, n (%) DVT 32 (82) PE 2 (5) DVT and PE 5 (13) Concomitant atrial fibrillation, n (%) Yes 7 (18) No
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Patient Demographics Reflective of our inpatient population at HUMC
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Primary Endpoint – DOAC Dosing
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Dosing Not Adherent to Package Insert
Not mutually exclusive, if met > 1 reason for being incorrect was counted > 1x Total 15 times incorrect dose No drug-drug interactions Note: a patient may be counted in > 1 category Clcr calculated according to the Cockcroft-Gault equation
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Primary Endpoint – Clinically Significant Bleeding
No patients experienced clinically significant bleeding
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Dose According to Package Insert DOAC Held/Discontinued
Minor Bleeding Patient # Type of Cancer Site of Bleed Dose According to Package Insert DOAC Held/Discontinued 1 Leukemia GI Yes Held for ~ 3 days & dose was reduced 2 NHL GU No (higher dose) Discontinued (also anticipated thrombocytopenia) 3 Solid GI & GU (lower dose) Held for ~ 3 days, no dose reduction 4 MM (also had renal/liver dysfunction, & thrombocytopenia) Patient 2: Clcr < 30, PLT 59 and anticipating thrombocytopenia Patient 4: thrombocytopenic platelet count 39 GI = gastrointestinal, GU = genitourinary
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Thrombocytopenia
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Secondary Endpoint – Thrombocytopenia
None of those 4 had a bleed
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Secondary Endpoint – Procedures
Total of 11 procedures Chest tube placement Thoracentesis EGD Lumbar puncture Bronchoscopy Adherent to holding DOAC for all 11 procedures EGD = esophagogastroduodenoscopy
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Conclusions Dosing Safety
26% of patients were receiving a DOAC dose that was not according to the package insert Majority were receiving a DOAC dose that is not approved for VTE treatment (rivaroxaban 15 mg PO daily) Safety No patients experienced clinically significant bleeds, and 10% of patients experienced a minor bleed 1 out of 14 thrombocytopenic patients experienced a minor bleed This is a very high risk population, these patients probably wouldn’t be included in a randomized controlled trial Last line – in a patient where it was appropriately held
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Study Limitations Retrospective analysis Small sample size
Only included inpatients Not compared to standard of care Rates of recurrent VTE were not analyzed Small sample size – LMWH standard of care, only a limited comfort using DOACs still Inpatients only – 90% cancer treated as outpatient Last line – future direction!
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Recommendations Increase education and awareness on the oncology floors on how to Dose the DOACs according to the package insert Adjust the DOACs based on hematologic parameters Utilize monitoring program for DOACs Implement electronic DOAC order sets
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Acknowledgements Christina Howlett, PharmD, BCOP
Ruchi Jain, PharmD, BCPS James McCloskey, MD
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Self-Assessment Question
What percentage of patients experienced clinically significant and minor bleeding in this study? 10% of patients experienced a clinically significant bleed and no patients experienced a minor bleed No patients experienced a clinically significant bleed and 10% of patients experienced a minor bleed No patients experienced a clinically significant or minor bleed 10% of patients experienced a clinically significant bleed and 10% of patients experienced a minor bleed
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Self-Assessment Question
What percentage of patients experienced clinically significant and minor bleeding in this study? 10% of patients experienced a clinically significant bleed and no patients experienced a minor bleed No patients experienced a clinically significant bleed and 10% of patients experienced a minor bleed No patients experienced a clinically significant or minor bleed 10% of patients experienced a clinically significant bleed and 10% of patients experienced a minor bleed
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Evaluation of Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in the Oncology Population Jessica Hedvat, PharmD PGY-1 Pharmacy Resident Hackensack University Medical Center Hackensack, NJ NJSHP Residency Forum June 9, 2016
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Supplemental Slides
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Clinically relevant bleeding
Definitions Clinically relevant bleeding Major bleeding (bleeding that was clinically overt and associated with a fall in Hgb of ≥ 2 g/dL, resulted in the need of ≥ 2 units of red cells, bleeding was intracranial or retroperitoneal, involved a critical site, or was fatal) Clinically relevant non-major bleeding (overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study drug, or discomfort or impairment of activities of daily life) AND Bauersachs R, et al. N Engl J Med. 2010; 363: Buller HR, et al. N Engl J Med. 2010: 366:
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Definitions Major bleeding Non-life-threatening Life threatening
Reduction in Hgb ≥ 2 g/dL AND transfusion of 2 units of PRBCs Symptomatic bleeding in a critical area/organ Life threatening Fatal bleeding, symptomatic intracranial bleeding, reduction in Hgb ≥ 5 g/dL, bleeding requiring transfusion of ≥ 4 units of PRBCs or inotropic agents or necessitating surgery Connolly SJ, et al. N Engl J Med 2009;361(12):
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Cockcroft-Gault Equation
(140 −age) × Weight (kg) 72 × SCr (mg/dL) Clcr (mL/min) = For females, multiply Clcr by 0.85 If actual body weight < ideal body weight (IBW) Used actual body weight If actual body weight > IBW Used adjusted body weight IBW Males = 50 kg + (2.3 x inches above 5 feet) Females = 45.5 kg + (2.3 x inches above 5 feet) Adjusted body weight = IBW + 0.4(actual body weight – IBW)
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Concomitant Medications
Antiplatelet Aspirin / Dipyridamole / Cilostazol / Clopidogrel / Prasugrel / Ticagrelor Anticoagulant Argatroban / Bivalirudin / Desirudin / Heparin / Warfarin P-gp inducer Carbamazepine / Dexamethasone / Fosphenytoin / Phenytoin / Phenobarbital / Pentobarbital / Primidone / Rifampin / St. John’s wort / Tipranavir P-gp inhibitor Itraconazole / Lopinavir/ritonavir / Clarithromycin / Ritonavir / Ketoconazole / Indinavir/ritonavir / Conivaptan / Cyclosporine / Tacrolimus Strong CYP3A4 inducer Carbamazepine / Phenobarbital / Phenytoin / Rifampin / St. John’s wort Strong CYP3A4 inhibitor Boceprevir / Clarithromycin / Conivaptan / Indinavir / Itraconazole / Ketoconazole/ Lopinavir/ritonavir / Nefazodone / Nelfinavir / Posaconazole / Ritonavir / Saquinavir / Telaprevir / Telithromycin / Voriconazole Drug Interactions & Labeling. U.S. Food and Drug Administration, 28 July Web. 24 Dec Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. Dec
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Data Collection Form
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Data Collection Form
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Data Collected Patient demographics Type of cancer
DOAC order information Hematologic safety parameters Renal function Procedures that require withholding anticoagulation Concurrent antiplatelets, anticoagulants, P-gp or CYP3A4 inducers or inhibitors Patient demographics Age, sex, weight, height Type of cancer Hematological (HSCT vs. non-HSCT), solid DOAC usage Indication, dose, dates used, frequency administered Hematologic safety parameters Hemoglobin, platelets Renal function SCr, Clcr Invasive procedures that require withholding anticoagulation Type of procedure undergone, date of procedure Concurrent medications Antiplatelet, anticoagulant, P-gp and/or CYP3A4 inducer or inhibitor
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Resident’s Role Aug 2015 Literature review Sept 2015
Background presentation to pharmacy team Nov 2015 Submitted expedited IRB approval Dec 2015 ASHP Midyear poster presentation Mar 2016 Received IRB approval Apr 2016 Retrospective chart review Data analysis May 2016 Eastern States Conference
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Solid Cancers
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Hematopoietic Stem Cell Transplant (HSCT)
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DOAC Dosing Patient Number Admission Type of Cancer DOAC
Administered Dose Package Insert Dose Rationale 3 2 NHL Rivaroxaban 15 mg PO daily 20 mg PO daily - 4 1 Solid 15 mg PO BID Should have received 12 more days of 15 mg PO BID dosing. 19 Had already received 21 days of 15 mg PO BID dosing. contraindicated Clcr 25 mL/min. 20 MM New DVT. Clcr 26 mL/min. 27 Apixaban 5 mg PO BID 10 mg PO BID 29 32 Should have received 2 more days of 15 mg PO BID dosing. 33 34 39 No new DVT.
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Dose According to Package Insert DOAC Held/Discontinued
Minor Bleeding Patient Number Admission Type of Cancer Bleed Dose According to Package Insert DOAC Held/Discontinued 1 2 ALL Blood in stool Yes Held for ~ 3 days & dose was reduced 19 3 NHL Blood in urine No (on 20 mg PO daily, Clcr < 30 mL/min) Discontinued (also thrombocytopenic) 29 Solid Transfused with 2 units packed RBC’s Yes – blood in urine & vomit No (on 15 mg instead of 20 mg PO daily) 33 MM No (on 20 mg PO daily instead of 15 mg PO BID) Discontinued (also had renal & liver dysfunction, & thrombocytopenia)
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Platelet Count (x103/mcL)
Thrombocytopenia 14 patients experienced thrombocytopenia during admission 10/14 patients (71%) had their DOAC held for thrombocytopenia Patient Number Admission Held Platelet Count (x103/mcL) 3 2 Yes 34, 28, 35 4 1 No 39, 45, 44 8 36 10 37, 13, 7, 29 14 38 16 18, 11, 10, 23, 34 17 37, 18, 8, 23, 15, 16, 19 23 39, 39, 36, 44 24 36, 16, 12, 5, 28, 26, 34, 39, 48 27 7 30 40 33 Yes (discontinued) 39 35 37, 21 37 36, 36, 33 2 units RBC minor bleeding (stool)
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Bleeding Risk Assessment
NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version
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Safety Rivaroxaban Apixaban Elective surgery or invasive procedures
Discontinue 24 hours prior Apixaban Moderate or high risk of unacceptable or clinically significant bleeding Discontinue 48 hours prior Low risk of bleeding or where the bleeding would be non-critical in location and easily controlled Xarelto [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc; January 2015. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; June 2015.
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Procedures Invasive procedures: chest tube placement and LP
Patient Number Minor Bleed Procedure DOAC Held 1 Yes (GI) Chest tube placed Rivaroxaban 2 days 5 No Thoracentesis 1 day 6 EGD 12 LP > 2 days 21 22 25 27 Bronchoscopy 28 Invasive procedures: chest tube placement and LP Chest tube placed: blood in stool (held) Non-invasive procedures: 4 major bleeding EGD (held) PICC exchange (not held) Port-a-cath placed (not held) Port-a-cath removed (not held, patient with bleeding coffee-ground vomit/urine) EGD = esophagogastroduodenoscopy, LP = lumbar puncture,
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Contact activation (intrinsic) pathway
DOACs Contact activation (intrinsic) pathway Tissue factor (extrinsic) pathway Tissue factor rivaroxaban apixaban edoxaban Tissue factor Didn’t include edoxaban from now on because it is not on our formulary dabigatran XIIIa Sabir I, et al. Nat Rev Cardiol. 2014; 11:
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Balancing the Risks All patients require an individualized assessment of their bleeding risk before the initiation of anticoagulation NCCN 2015 ASCO 2014 Absolute Contraindication to Therapeutic Anticoagulation for VTE Recent intracranial or spinal lesion at high risk for bleeding Active bleeding (> 2 units transfused in 24 hours) Active bleeding Severe, uncontrolled hypertension Severe platelet dysfunction or inherited bleeding disorder Platelets < 20,000/mcL Surgery or invasive procedure including lumbar puncture, spinal anesthesia, & epidural catheter placement Relative Contraindication to Therapeutic Anticoagulation for VTE Chronic, measureable bleeding > 48 hours Platelets < 50,000/mcL Recent major operation Underlying hemorrhagic coagulopathy High risk for falls (head trauma) Neuraxial anesthesia/lumbar puncture Intracranial or spinal lesions Active peptic or other gastrointestinal ulceration Active, but non-life threatening bleeding Intracranial bleeding within 4 weeks Major surgery or serious bleeding within 2 weeks Anticoagulant management of cancer-associated thrombosis is especially challenging because bleeding rates are also higher in cancer patients Most experts agree that therapeutic AC can be administered if PLT count can be maintained over 50,000/mcL NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33.
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VTE Treatment in Patients with Cancer
CHEST 2012 NCCN 2015 ASCO 2014 Initial treatment Not addressed in oncology patients LMWH is preferred Use of direct oral anticoagulants is not currently recommended Long-term Treatment In patients not treated with LMWH, warfarin therapy is preferred over dabigatran or rivaroxaban Warfarin INR goal 2 – 3 Warfarin INR goal 2 -3 Duration of Treatment Extended anticoagulant therapy is preferred over 3 months of treatment Minimum of 3 months Indefinite if active cancer, under treatment, or persistent risk factors exist At least 6 months Extended treatment may be considered for patients with metastatic disease or receiving chemotherapy Kearon C, al. Chest. 2012; 141 (2 Suppl): e419S-94S. NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33.
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VTE Treatment in Patients with Cancer
LMWH vs. heparin Data extrapolated from subgroup analyses showed no difference in efficacy between LMWH and UFH in cancer patients However, a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing LMWH vs. warfarin Warfarin is less effective in patients with cancer, with rates of recurrent VTE being 3X higher than in patients without cancer, despite maintenance of the INR within therapeutic range A meta-analysis confirmed this finding, reporting a relative risk reduction of 53% NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33. Lee, et al. N Engl J Med. 2003; 349(2): 146‐53.
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RE-COVER Results % % % % ¶
HR 1.1 (95% CI, 0.65 – 1.84) p < 0.001*, non-inferior % HR 0.82 (95% CI, 0.45 – 1.48) % % % Major Bleeding = clinically overt and if it was associated with a fall in the Hgb of at least 20 g/L, resulted in the need for transfusion of 2 or more units of red cells, involved a critical site, or was fatal. Since noninferiority was established, they tested for superiority but it was not reached. Usually INR range 62%, so study achieved therapeutic anticoagulation w warfarin – applicable yes (rate that is consistent w good quality management of warfarin dosing) Study should technically always be symptomatic – yes. Only previously available direct thrombin inhib – ximelagatran >90% had Clcr>50 Median 9 days parenteral AC before started dabigatran, higher than typical duration Ximelagatran alone appeared to be associated w a higher early rate of recurrent VTE than did tx with warfarn/enox *P-value is for non-inferiority; p<0.001 for predefined upper limits of the 95% CI for both HR (<1.80) & difference in risk (<3.6%). ¶Major bleeding = bleeding that was clinically overt and associated with a fall in Hgb of ≥ 20 g/L, resulted in the need of ≥ 2 units of red cells, involved a critical site, or was fatal. INR was in therapeutic range 60% of the time (below therapeutic range 21% of the time, above therapeutic range 19% of the time). Schulman S, et al. N Engl J Med. 2009; 361:
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RE-COVER Subgroup Analysis – Cancer
Patients with cancer at baseline Dabigatran: 64/1273 (5%) vs warfarin: 57/1266 (4.5%), p = 0.60 Bleeding rates not available RR 0.59 (95% CI, 0.10 – 3.43) % % Conclusion in cancer patients Similar rates of recurrent VTE Schulman S, et al. N Engl J Med. 2009; 361: Gomez-Outes A, et al. Vasc Health Risk Manag. 2013; 9:
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EINSTEIN-DVT Results % % % % ¶
HR 0.97 (95% CI, 0.76 – 1.22) p = 0.77 % % HR 0.68 (95% CI, 0.44 – 1.04) p < 0.001*, non-inferior % % DVT -Excluded if had received therapeutic dose of LMWH, fonda, or UFH >48 hrs, more than a single dose of vka before randomization, treated w thrombectomy, vena cava filter, or fibrinolytic -Clcr < 30, sig liver disease, ALT > 3xuln, bacterial endocarditis, active bleeding, SBP >180, DBP>110 -Concomittant strong 3a4 inhibitors: PROTEASE INHIBITORS, KETOCONAZOLE or inducers: RIFAMPRIN, CBZ, PHENYTOIN -life expectancy < 3mon -major bleeding: 0.8 vs 1.2 (p0.21) -antiplatelets /nsaids discouraged, up to 100ASA and 75clopidogrel ok *P-value is for non-inferiority; p < for predefined upper limits of the 95% CI for HR (<2).Superiority was not found (p = 0.08). ¶CRB = clinically relevant bleeding = major bleeding (bleeding that was clinically overt and associated with a fall in Hgb of ≥ 20 g/L, resulted in the need of ≥ 2 units of red cells, bleeding was intracranial or retroperitoneal, involved a critical site, or was fatal) + clinically relevant non-major bleeding (overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study drug, or discomfort or impairment of activities of daily life). INR was in therapeutic range 57.7% of the time (below therapeutic range 24.4% of the time, above therapeutic range 16.2% of the time). Bauersachs R, et al. N Engl J Med. 2010; 363: Buller HR, et al. N Engl J Med. 2010: 366:
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EINSTEIN-PE Results % % % % ¶
HR 0.90 (95% CI, 0.76 – 1.07) p = 0.23 % % HR 1.12 (95% CI, 0.75 – 1.68) p = 0.003*, non-inferior % % 1.1 vs 2.2 major bleeding (any) *P-value is for non-inferiority; p = for predefined upper limits of the 95% CI for HR (<2).Superiority was not found (p = 0.57). ¶CRB = clinically relevant bleeding = major bleeding (bleeding that was clinically overt and associated with a fall in Hgb of ≥ 20 g/L, resulted in the need of ≥ 2 units of red cells, bleeding was intracranial or retroperitoneal, involved a critical site, or was fatal) + clinically relevant non-major bleeding (overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study drug, or discomfort or impairment of activities of daily life). INR was in therapeutic range 62.7% of the time (below therapeutic range 21.8% of the time, above therapeutic range 15.5% of the time). Bauersachs R, et al. N Engl J Med. 2010; 363: Buller HR, et al. N Engl J Med. 2010: 366:
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EINSTEIN-DVT/PE Subgroup Analysis - Cancer
Patients with cancer at baseline EINSTEIN-DVT Rivaroxaban 118/1731 (6.8%) vs enoxaparin/warfarin 89/1718 (5.2%) EINSTEIN-PE Rivaroxaban 114/2419 (4.7%) vs enoxaparin/warfarin 109/2413 (4.5%) % % % % % % EINSTEIN-DVT EINSTEIN-PE Bauersachs R, et al. N Engl J Med. 2010; 363: Buller HR, et al. N Engl J Med. 2010: 366:
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AMPLIFY Results % % % % ¶ RR 0.84 (95% CI, 0.60 – 1.18)
p < 0.001*, non-inferior % % RR 0.31 (95% CI, 0.17 – 0.55) p < 0.001§ % % Exclusion -High risk bleeding -Cancer and long-term tx w LMWH planned -less than 6 months tx planned -ASA>165 -Potent cyp inhibitors -hgb<9, PLT<1000,000, Scr>2.5, Clcr<25 *P-value is for non-inferiority; p<0.001 for predefined upper limits of the 95% CI for both relative risk (<1.80) and difference in risk (<3.5%). ¶Major Bleeding = bleeding that was clinically overt and associated with a fall in Hgb of ≥ 20 g/L, resulted in the need of ≥ 2 units of red cells, involved a critical site, or was fatal. §P-value is for superiority. INR was in therapeutic range 61% of the time (below therapeutic range 23% of the time, above therapeutic range 16% of the time) Apixaban adherence to therapy was ≥ 80% in 96% of patients Agnelli G, et al. N Engl J Med. 2013; 369:
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AMPLIFY Subgroup Analysis – Cancer
Patients with cancer at baseline Apixaban: 66/2691 (2.5%) vs enoxaparin/warfarin: 77/2704 (2.8%) No data available for cancer subgroup Of the 5395 patients, 169 (3.1%) had active cancer Recurrent VTE Apixaban group: 3/81 (3.7%) patients Conventional-therapy group: 5/78 (6.4%) RR, 0.56; 95% CI, 0.13 – 2.37 Major bleeding Apixaban group: 2/87 (2.3%) Conventional-therapy group: 4/80 (5%) RR, 0.45; 95% CI, 0.08 – 2.46 Although the number of cancer patients was small, results in subgroup are consistent with overall findings and suggest that apixaban is as effective as conventional therapy in VTE patients with active cancer, and is associated with less bleeding Agnelli G, et al. N Engl J Med. 2013; 369:
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Prophylactic treatment for 3 months
ADVOCATE Population Receiving 1st or 2nd line chemotherapy for advanced or metastatic cancer Excluded patients at moderate or high risk of bleeding (prolonged coagulation times, receiving antiplatelet therapy, or other therapies with potential cause to bleeding), and prior history of DVT/PE Study design Phase II, randomized, double-blind, placebo-controlled study Interventions Study drug began within 4 weeks of the start of chemotherapy apixaban 5 mg PO daily vs apixaban 10 mg PO daily apixaban 20 mg PO daily placebo PO daily -Receiving 1st or 2nd line chemotherapy for advanced or metastatic lung, breast, GI, bladder, ovarian, or prostate cancer, myeloma or selected lymphomas, and cancer of unknown origin -Patients at moderate or high risk of bleeding (patients with prolonged coagulation times, receiving antiplatelet therapy, or other therapies with potential to cause bleeding) -Prior history of DVT/PE Intervention Study drug began within 4 weeks of the start of chemotherapy 125 patients randomized to receive one-daily doses of apixaban 5 mg (n = 32), 10 mg (n = 30), 20 mg (n = 33), or placebo (n = 30) in a double-blind manner for 12 weeks Prophylactic treatment for 3 months Levine MN, et al. J Thromb Haemost. 2012; 10:
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ADVOCATE Results Primary outcomes No fatal bleeding episodes
Apixaban 5 mg (n = 32) Apixaban 10 mg (n = 30) Apixaban 20 mg (n = 33) Placebo Major Bleed* 2 (drop in Hgb with overt bleeding, lower GI) 1 (upper GI) CRNM Bleeding¶ 1 (epistaxis) 1 (urogenital) 2 (gingival, urogenital) *Major bleed = clinically overt and associated with a fall in Hgb of ≥ 20 g/L, resulted in the need of ≥ 2 units of red cells, bleeding in a critical site – intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; or bleeding that contributed to death. ¶CRNM bleeding = clinically relevant non-major bleeding = bleeding that did not meet the criteria for major but that in routine clinical practice would be considered relevant and not trivial by a patient and physician. Such bleeding satisfied criteria defined a priori, which included for example, epistaxis if it lasted for more than 5 min,, if it was repetitive (2 or more in 24 hrs) or if it led to an intervention (packing or electrocoagulation) or hematuria, if it was macroscopic and either spontaneous or lasted for more than 24 h after instrumentation (catheter placement or surgery) of the urogenital tract. Death Apixaban groups: 1 death in apixaban 5 mg (heart failure) Placebo: 2 deaths (heart failure, progressive cancer) 5 mg and 10 mg doses of apixaban were well tolerated and associated with a low risk for VTE in patients with metastatic or advanced cancer Small sample size Had postulated that the target sample size of 140 patients would be accrued in < 12 months Enrollment began in 2006, but a decision was made by the Steering Committee and BMS to close the trial in September 2008 because of slow rate of accrual Lack of screening for asymptomatic events Only selected patients at low risk of bleeding Enrollment started in In September 2008, a decision was made by the Steering Committee and BMS to close the trial because of the slow rate of accrual. But it was felt that the main study objectives could be met despite not reaching the intended sample size. one reason for the slow rate was the exclusion of patients receiving bevacizumab, bec of its potential to cause bleeding Exclusion of patients at moderate to high bleeding risk No fatal bleeding episodes Symptomatic DVT Apixaban groups: no patients Placebo: 3 (10.3%) patients Levine MN, et al. J Thromb Haemost. 2012; 10:
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VTE Treatment in Patients with Cancer
CHEST 2012 NCCN 2015 ASCO 2014 Initial treatment -Not addressed in cancer patients. -LMWH is preferred. -Fondaparinux or UFH can also be used. -Use of novel oral anticoagulants is not currently recommended. -LMWH is preferred over UFH for initial 5 – 10 days of treatment in patients with Clcr > 30 mL/min. Long-term Treatment -In patients not treated with LMWH, VKA therapy is preferred over dabigatran or rivaroxaban. Patients receiving extended therapy should continue with the same agent used for the first 3 months of treatment. -LMWH is preferred for first 6 months as monotherapy without warfarin in patients with VTE and metastatic or advanced cancer. -Warfarin 2.5 – 5 mg PO daily initially with subsequent dosing based on INR value 2 – 3. -VKAs (target INR 2 – 3) are acceptable for long-term therapy if LMWH is not available. Duration of Treatment -Extended anticoagulant therapy is preferred over 3 months of treatment. -Minimum of 3 months. -Indefinite anticoagulant if active cancer, under treatment, or persistent risk factors exist. -At least 6 months. -Extended treatment may be considered for patients with metastatic disease or those receiving chemotherapy. NCCN = expert opinion, certain cancer centers – MDS and PHARMDs from committees, more updates ASCO = better, society-driven, directly from evidence, less updates WHY ENOXAPARIN PREFERRED -Data extrapolated from subgroup analysis of trials in unselected patients showed no difference in efficacy between LMWH andd UFH in cancer patients -However, SS reduction in MORTALITY RISK w LMWH at 3 months of follow-up has been noted. The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing -In addition to better efficacy, LMWH provides other advantages vs UFH: lower cost (bec hospitalization and lab monitoring are not required), simple dosing (bec total daily dose is based on weight), and associated with lower risk for heparin-induced thrombocytopenia (HIT). -Fondaparinux vs enoxaparin: Matisse trials, the 3 month rate for symptomatic recurrent VTE was higher for fondaparinux vs enoxaparin for DVT tx BUT lower for fonda vs UFH for PE tx. -However, UFH can be used in those with severe renal impairment (Clcr <30) given its shorter half-life, reversibility with protamine, and dependence on hepatic clearance. Fonda is a reasonable choice in patients with a history of HIT. -VKAs are less effective in patients with cancer, with rates of recurrent VTE 3x higher than in patients without cancer, despite maintenance of the INR within therapeutic range. -Trials show improved efficacy of LMWH vs VKA in the prevention or recurrent VTE in patients with cancer-associated VTE, meta-analysis confirmed this finding, reporting a RR reduction of 53%. -Also adv over warfarin = no lab mon, shorter t1/2, limited drug interactions, no food interactions or reliance on oral intake or GIT absorption. Major barriers: COST and daily SC injections Kearon C, al. Chest. 2012; 141 (2 Suppl): e419S-94S. NCCN. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Lyman GH, et al. J Clin Oncol. 2015; 33.
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NOAC Advantages & Disadvantages
Oral Once or twice daily dosing Do not require laboratory monitoring Limited studies in oncology population No specific antidote Drug-drug interactions with chemotherapy and immunosuppressant drugs used in oncology population Interaction Effect Dabigatran P-gp Rivaroxaban P-gp & CYP3A4 Apixaban NOAC plasma levels Cyclosporine Tacrolimus Tamoxifen Lapatanib Nilotinib Sunatinib Imatinib NOAC plasma levels Dexamethasone Doxorubicin Vinblastine Apixaban is minor substrate of CYPs 1A2, 2C19, 2C8, and 2C9 Lee AYY, et al. Blood. 2013; 122:
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References Gomez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. Vasc Health Risk Manag. 2013; 9: Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. British Journal of Cancer. 2010; 102: S2-S9. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Practice Guideline Update J Clin Oncol. 2015;33. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; January 2015. Xarelto [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc; January 2015. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; June 2015. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361: Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2010; 363: Buller HR, Prins MH, Lensin AW, et al; EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2010: 366: Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Supp): e419S-94S. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease. Version Available at: Accessed August 28, 2015.
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