Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations

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1 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Presented as a Live Webinar Wednesday, May 10, :00 PM 3:00 PM ET On-demand Activity Live webinar recorded and archived to be watched at your convenience Available after May 25, This activity is sponsored and planned by the American Society of Health-System Pharmacists (ASHP). Supported by an educational grant from the Bristol-Myers Squibb and Pfizer Alliance Copyright 2017, American Society of Health-System Pharmacist, Inc. All rights reserved.

2 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Activity Overview Clinical case studies will be used to illustrate approaches for addressing clinical issues related to the use of direct oral anticoagulants (DOACs) for managing venous thromboembolism in three patient populations: patients with cancer-associated thrombosis, kidney disease, and obesity. Strategies for managing potential drug interactions with DOACs will also be discussed. Learning Objectives At the conclusion of this application-based educational activity, participants should be able to Examine the evidence for use of direct oral anticoagulants (DOACs) with venous thromboembolism (VTE) and kidney disease Review the evidence for the use of DOACs in patients with cancer-associated VTE Review data on the use of DOACs for treatment of VTE in patients with obesity Implement an appropriate strategy for managing potential drug interactions with DOACs Continuing Education Accreditation The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU no partial credit) of continuing pharmacy education credit. Live Activity ACPE #: L01-P On-demand Activity ACPE #: H01-P The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Health-System Pharmacists designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Participants will process CE credit online at For pharmacist participants, CPE credit will be reported directly to CPE Monitor. Per ACPE, CE credit must be claimed no later than 60 days from the date of the live activity or completion of a home-study activity. 2

3 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations List of Abbreviations For a list of abbreviations used in this activity, please see page 36. Webinar Information Visit to find Webinar registration link Group viewing information and technical requirements CE webinar processing information Additional Educational Activities in this Initiative On-demand activities Web-based activities for the 3-part webinar series available in May 2017 (1 hour CE each, please note that individuals who claim CE credit for a live webinar are ineligible to claim credit for the corresponding web-based activity) 3

4 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Faculty Adam C. Cuker, M.D., M.S. Assistant Professor of Medicine and Pathology & Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Adam C. Cuker, M.D., M.S., is Assistant Professor of Medicine and of Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia. He also serves as Director of the Penn Comprehensive Hemophilia and Thrombosis Program and Associate Director of the Penn- CHOP Blood Center for Patient Care and Discovery. Dr. Cuker received his Doctor of Medicine degree from Yale University in New Haven and completed an internship and residency in internal medicine at Brigham and Women s Hospital and Harvard Medical School in Boston. He continued his postgraduate training as a fellow in hematology/oncology at the Hospital of the University of Pennsylvania. Dr. Cuker also holds a Master of Science in Translational Research degree from the University of Pennsylvania. He is board certified in internal medicine and hematology and is a fellow of the American College of Physicians. Dr. Cuker conducts patient-oriented research on heparin-induced thrombocytopenia, venous thromboembolism, and anticoagulation funded by the National Institutes of Health. He is Chair of the forthcoming American Society of Hematology (ASH) guidelines on venous thromboembolism and Chair of the ASH panel on heparin-induced thrombocytopenia. 4

5 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Paul P. Dobesh, Pharm.D., BCPS-AQ Cardiology, FCCP Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska Paul P. Dobesh, Pharm.D., BCPS-AQ Cardiology, FCCP, is Professor of Pharmacy Practice at the University of Nebraska Medical Center (UNMC) College of Pharmacy in Omaha, Nebraska. Dr. Dobesh earned both his Bachelor of Science in pharmacy and Doctor of Pharmacy degrees from South Dakota State University. He completed a specialty residency in internal medicine at the University of Texas at Austin at Brackenridge Hospital. He is a board-certified pharmacotherapy specialist with added qualifications in cardiology. Dr. Dobesh currently maintains clinical practice with cardiology services at Nebraska Medical Center. He is responsible for teaching pharmacy and medical students, as well as pharmacy and medical residents. His main lecture topics include ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. Dr. Dobesh has conducted research on antiplatelet and antithrombotic therapy, focusing on the real-world use of these therapies and healthcare economics. He has also published book chapters and several manuscripts in this area. Dr. Dobesh was awarded the Distinguished Educator of the Year Award at the UNMC College of Pharmacy in 2015, an award he received four times since In 2013, he was honored with the UNMC campuswide Outstanding Educator Award. 5

6 Disclosures Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations In accordance with the Accreditation Council for Continuing Medical Education s Standards for Commercial Support and the Accreditation Council for Pharmacy Education s Standards for Commercial Support, ASHP requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g. employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on the content. All faculty and planners for ASHP education activities are qualified and selected by ASHP and required to disclose any relevant financial relationships with commercial interests. ASHP identifies and resolves conflicts of interest prior to an individual s participation in development of content for an educational activity. Anyone who refuses to disclose relevant financial relationships must be disqualified from any involvement with a continuing pharmacy education activity. Paul P. Dobesh, Pharm.D., BCPS-AQ Cardiology, FCCP, declares that he has served as a consultant for Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb and Pfizer Alliance, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., and Portola Pharmaceuticals, Inc. (Faculty) Alpesh Amin, M.D., MBA, FACC, MACP, SFHM, declares that he has served as a consultant for Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb and Pfizer Alliance, and Portola Pharmaceuticals, Inc. (Steering Committee) Toby C. Trujillo, Pharm.D., BCPS-AQ Cardiology, FAHA, FCCP, declares he has served as a consultant for Bristol-Myers Squibb and Pfizer Alliance and Janssen Pharmaceuticals, Inc. (Steering Committee) All other faculty and planners report no financial relationships relevant to this activity. 6

7 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Adam C. Cuker, M.D., M.S. University of Pennsylvania, Perelman School of Medicine Philadelphia, Pennsylvania Paul P. Dobesh, Pharm.D., BCPS AQ Cardiology, FCCP University of Nebraska Medical Center, College of Pharmacy Omaha, Nebraska Disclosures of Faculty and Planners Paul P. Dobesh, Pharm.D., BCPS AQ Cardiology, FCCP, declares that he is a consultant for Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers Squibb and Pfizer Alliance, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., and Portola Pharmaceuticals, Inc. (Faculty) Toby C. Trujillo, Pharm.D., BCPS AQ Cardiology, FAHA, FCCP, declares that he has served as a consultant for the Bristol Myers Squibb and Pfizer Alliance and Janssen Pharmaceuticals, Inc. (Steering Committee) Alpesh Amin, M.D., MBA, FACC, MACP, SFHM, declares that he has served as a consultant for Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers Squibb and Pfizer Alliance, and Portola Pharmaceuticals, Inc. (Steering Committee) All other faculty and planners report no financial relationships relevant to this activity 7

8 Learning Objectives At the conclusion of this educational activity, participants should be able to Examine the evidence for use of direct oral anticoagulants (DOACs) with venous thromboembolism (VTE) and kidney disease Review the evidence for the use of DOACs in patients with cancer associated VTE Review data on the use of DOACs for treatment of VTE in patients with obesity Implement an appropriate strategy for managing potential drug interactions with DOACs DOACs in Patients with VTE and Renal Insufficiency 8

9 Case 1 A 78 year old man with chronic kidney disease is admitted for pulmonary embolism. He is stabilized on heparin and is ready to be transitioned to an oral anticoagulant. His CrCl is 22 ml/min. Which of the following is appropriate oral therapy? a. Apixaban 10 mg BID x 1 week, then 5 mg BID b. Apixaban 10 mg BID x 1 week, then 2.5 mg BID c. Dose adjusted warfarin (INR goal = 2 3) d. Edoxaban 60 mg daily e. Rivaroxaban 15 mg BID x 3 wk, then 15 mg daily Renal exclusion criteria in clinical trials DOAC Renal Clearance Pivotal Trial(s) Renal Exclusion Criterion Dabigatran 80% RE COVER RE COVER II Rivaroxaban 36% EINSTEIN DVT EINSTEIN PE CrCl < 30 ml/min CrCl < 30 ml/min Apixaban 25% AMPLIFY CrCl < 25 ml/min or SCr > 2.5 mg/dl Edoxaban 35% HOKUSAI VTE CrCl < 30 ml/min Schulman S et al. N Engl J Med. 2009; 361: Schulman S et al. Circulation. 2014; 129: EINSTEIN Investigators et al. N Engl J Med. 2010; 363: EINSTEIN PE Investigators et al. N Engl J Med. 2012; 366: Agnelli G et al. N Engl J Med. 2013; 369: HOKUSAI VTE Investigators et al. N Engl J Med. 2013; 369:

10 Overall Results Recurrent VTE Major Bleeding RR 0.90 ( ) RR 0.61 ( ) Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124: ; permission conveyed through Copyright Clearance Center, Inc. Results stratified by renal function Recurrent VTE RR 0.70 ( ) RR 0.97 ( ) Major Bleeding RR 0.51 ( ) RR 0.60 ( ) Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124: ; permission conveyed through Copyright Clearance Center, Inc. 10

11 Similar results in Phase III non valvular atrial fibrillation DOAC trials GFR Stroke/Systemic Embolism RR (95% CI) Major Bleeding RR (95% CI) ml/min 0.71 ( ) 0.88 ( ) < 50 ml/min 0.79 ( ) 0.80 ( ) Del Carpio Munoz F et al. Am J Cardiol. 2016; 117: Real world studies: More data to come Study Population (n) n XALIA GARFIELD VTE Dresden NOAC registry RE COVERY DVT/PE Patients with VTE treated with rivaroxaban Patients with VTE treated with DOACs or VKA Patients with VTE or NVAF treated with DOACs Patients with VTE treated with dabigatran or VKA ,000 (target) ,000 (target) Beyer Westendorf J et al. Thromb Haemost. 2016; 116(suppl 2):S13 S23. Ageno W et al. Thromb Haemost. 2017; 117:

12 Evidence in severe renal dysfunction (CrCl < 30 ml/min) or end stage renal disease DOAC Dabigatran Rivaroxaban Apixaban Edoxaban FDA approved DOAC labeling for VTE treatment in renal impairment Creatinine Clearance > 30 ml/min 30 ml/min 30 ml/min < 30 ml/min 30 ml/min < 30 ml/min > 50 ml/min ml/ min < 15 ml/min Dosing Recommendation 150 mg BID No dosage recommendation 15 mg BID x 3 wk, then 20 mg daily Not recommended 10 mg BID x 7 days, then 5 mg daily No dosage recommendation 60 mg daily* 30 mg daily Not recommended *30 mg daily if weight 60 kg or receiving certain P glycoprotein inhibitors. 12

13 What do I do? In patients with CrCl 30 ml/min I use DOACs as first line treatment If the CrCl is ml/min, I have a slight preference for a factor Xa inhibitor over dabigatran In patients with CrCl < 30 ml/min I avoid DOACs I use warfarin In patients with CrCl > 95 ml/min I use another DOAC in preference to edoxaban (based on experience in non valvular atrial fibrillation) Key Takeaways DOACs have non inferior efficacy and superior safety compared with warfarin in patients with VTE and CrCl 30 ml/min Therefore, DOACs should be considered first line treatment in this population DOACs have not been studied in patients with VTE and CrCl < 30 ml/min Therefore, DOACs should be avoided in this population 13

14 Case 1 A 78 year old man with chronic kidney disease is admitted for pulmonary embolism. He is stabilized on heparin and is ready to be transitioned to an oral anticoagulant. His CrCl is 22 ml/min. Which of the following is appropriate oral therapy? a. Apixaban 10 mg BID x 1 week, then 5 mg BID b. Apixaban 10 mg BID x 1 week, then 2.5 mg BID c. Dose adjusted warfarin (INR goal = 2 3) d. Edoxaban 60 mg daily e. Rivaroxaban 15 mg BID x 3 wk, then 15 mg daily DOACs in Patients with Cancer associated VTE 14

15 Case 2 HW is a 60 year old man who was diagnosed with stomach cancer about 6 months ago. Today he presents with a proximal DVT in his left leg. He has normal hepatic and renal function. He would like to avoid injectable therapy. Which of the following is the best treatment for HW s DVT? a. Warfarin for 6 months b. Apixaban 10 mg twice daily x 21 days, then 5 mg twice daily c. Edoxaban 30 mg once daily d. Rivaroxaban 15 mg twice daily x 21 days, then 20 mg daily e. Dabigatran 150 mg twice daily ACCP Antithrombotic Guideline, 10 th edition (AT 10) AT 10 Choice of anticoagulant for long term treatment of DVT and PE: In patients with DVT of the leg or PE and no cancer, as long term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over VKA therapy (Grade 2B) Remarks: Acute therapy with parenteral anticoagulation is given before dabigatran and edoxaban In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the first 3 months (Grade 2C). ACCP = American College of Chest Physicians Kearon C et al. Chest. 2016; 149:

16 ACCP AT 10 Guideline Statement AT 10 Choice of anticoagulant for long term treatment of DVT and PE: In patients with DVT of the leg or PE and cancer ( cancerassociated thrombosis ), as long term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). Remarks: Acute therapy with parenteral anticoagulation is given before dabigatran and edoxaban. See text for factors that influence choice of therapy. Kearon C et al. Chest. 2016; 149: VTE Treatment in Cancer Patients: Initial dalteparin dose 200 units/kg/day Randomized to dalteparin 150 units/kg/day or warfarin (INR 2 3) n = 676 Significant reduction in VTE at 6 months with dalteparin Mortality: dalteparin 39% vs. dalt/warfarin 41% (p = 0.53) LMWH vs. Warfarin 25% 20% 15% 10% 5% 0% Dalteparin Oral anticoagulant p=0.09 p= % 17% 8% Recurrent VTE p=0.27 6% 4% Major Bleeding 14% Any Bleeding Lee A et al. N Engl J Med. 2003; 349:

17 VTE Treatment in Cancer Patients: LMWH vs. Warfarin Enoxaparin 1.5 mg/kg/day vs. warfarin (INR 2 3) n = 146 (cancer and VTE) Duration: 3 months Primary outcome: recurrent VTE and/or major bleeding, warfarin 21.1% vs. enoxaparin 10.5% (p = 0.09) Fatal bleeding: warfarin 8% vs. enoxaparin 0% (p = 0.03) Mortality: warfarin 22.7% vs. enoxaparin 11.3% (p = 0.07) Enoxaparin p=0.04 Warfarin Reproduced with permission from Meyer G et al. Arch Intern Med. 2002; 162: Copyright 2002 American Medical Association. All rights reserved. ACCP AT 10 Guideline Statement AT 10 Choice of anticoagulant for long term treatment of DVT and PE: In patients with DVT of the leg or PE and cancer ( cancerassociated thrombosis ), as long term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). Remarks: Acute therapy with parenteral anticoagulation is given before dabigatran and edoxaban. See text for factors that influence choice of therapy. Pages In patients with VTE and cancer who are not treated with LMWH, we do not have a preference for either a NOAC or VKA. There is no preference of one NOAC over another NOAC Kearon C et al. Chest. 2016; 149:

18 DOAC VTE Trials and Dosing RECOVER I and II At least 5 days of injectable anticoagulation followed by dabigatran 150 mg twice daily EINSTEIN DVT and PE Rivaroxaban 15 mg twice daily for 21 days, then 20 mg daily AMPLIFY Apixaban 10 mg twice daily for 7 days, then 5 mg twice daily Hokusai VTE At least 5 days of injectable anticoagulation followed by edoxaban 60 mg once daily Acute VTE Treatment: Clinical Trial Comparisons DOAC vs. Warfarin (or VKA) Characteristic RE COVER I & II (dabigatran) EINSTEIN DVT & PE (rivaroxaban) AMPLIFY (apixaban) Hokusai VTE (edoxaban) Recurrent VTE 2.4 vs vs vs vs. 2.9 VTE mortality 0.1 vs vs vs vs. 0.6 Total mortality 1.8 vs vs vs vs. 3.1 Major bleeding 1.4 vs vs vs vs. 1.6 Major + CRNM bleeding 5.3 vs vs vs vs. 10 Dobesh PP et al. Drugs. 2014; 74:

19 Characteristic Acute VTE Treatment: Clinical Trial Comparisons RE COVER I RE COVER II EINSTEIN DVT EINSTEIN PE AMPLIFY Hokusai VTE Mean age (yr) Male sex (%) Weight (kg) CrCl ml/min (%) NR NR Active cancer (%) VTE history (%) DVT only (%) PE only (%) DVT + PE (%) NR = not reported Dobesh PP et al. Drugs. 2014; 74: Patients with Active Cancer: Primary Efficacy Endpoint % of Patients 8% 6% 4% 2% 0% None of these comparisons are statistically significant DOAC 7.1% 7.1% 6.4% Standard Care 4.7% 5.1% 3.5% 3.7% 3.7% RE COVER I & II EINSTEIN DVT & AMPLIFY Hokusai VTE PE n=221 n=597 n=159 n=208 Schulman S et al. Circulation. 2014; 129; Prins MH et al. Thromb J. 2013; 11:21. Agnelli G et al. Poster at European Society of Cardiology (ESC) Congress. Barcelona, Spain; 2014 Sep 2. The Hokusai VTE Investigators. N Engl J Med. 2013; 369:

20 % of Patients 30% 25% 20% 15% 10% 5% 0% Patients with Active Cancer: Safety Endpoints 15.2% 15.8% 12.6% EINSTEIN DVT & PE None of these comparisons are statistically significant 22.5% 18.3% 25.3% DOAC Standard Care 5.8% 5.0% 2.8% 2.3% AMPLIFY Hokusai VTE EINSTEIN DVT & PE AMPLIFY Major Bleeding Major + CRNM Bleeding Prins MH et al. Thromb J. 2013; 11:21. Agnelli G et al. Poster presented at ESC Congress. Barcelona, Spain; 2014 Sep 2. The Hokusai VTE Investigators. N Engl J Med. 2013; 369: VTE Treatment in Cancer Patients: Initial dalteparin dose 200 units/kg/day Randomized to dalteparin 150 units/kg/day or warfarin (INR 2 3) n = 676 Significant reduction in VTE at 6 months with dalteparin Mortality: dalteparin 39% vs. dalt/warfarin 41% (p = 0.53) LMWH vs. Warfarin 25% 20% 15% 10% 5% 0% Dalteparin Oral anticoagulant p=0.09 p= % 17% 8% Recurrent VTE p=0.27 6% 4% Major Bleeding 14% Any Bleeding Lee A et al. N Engl J Med. 2003; 349:

21 Case 2 HW is a 60 year old man who was diagnosed with stomach cancer about 6 months ago. Today he presents with a proximal DVT in his left leg. He has normal hepatic and renal function. He would like to avoid injectable therapy. Which of the following is the best treatment for HW s DVT? a. Warfarin for 6 months b. Apixaban 10 mg twice daily x 21 days, then 5 mg twice daily c. Edoxaban 30 mg once daily d. Rivaroxaban 15 mg twice daily x 21 days, then by 20 mg daily e. Dabigatran 150 mg twice daily DOACs in Patients with VTE and Obesity 21

22 Case 3 A 42 year old morbidly obese woman (124 kg, BMI 47.0 kg/m 2 ) is on indefinite anticoagulation with warfarin for a history of recurrent unprovoked VTE. She asks if she can switch to one of the new drugs. How do you advise her? a. Switch to a DOAC safer and more convenient than warfarin b. Switch to apixaban more effective than warfarin in patients of her size when weight based dose is used c. Do not switch DOACs less effective than warfarin in patients of her size d. Do not switch paucity of evidence on DOAC use in patients of her size Weight based enrollment in clinical trials DOAC Volume of distribution Pivotal Trial(s) Weight categories Enrollment (%) Dabigatran L RE COVER RE COVER II Rivaroxaban ~50 L EINSTEIN DVT EINSTEIN PE 100 kg BMI 35 kg/m 2 > 100 kg BMI > 35 kg/m 2 > 90 kg > 90 kg 502/2539 (20%) 306/2539 (12%) 438/1280 (34%) 302/1280 (24%) 245/1731 (14%) 345/2419 (14%) Apixaban ~21 L AMPLIFY 100 kg BMI > 35 kg/m 2 522/2691 (19%) 349/2691 (13%) Edoxaban 107 L HOKUSAI VTE > 100 kg 611/4118 (15%) Schulman S et al. N Engl J Med. 2009; 361: Schulman S et al. Circulation. 2014; 129: EINSTEIN Investigators et al. N Engl J Med. 2010; 363: EINSTEIN PE Investigators et al. N Engl J Med. 2012; 366: Agnelli G et al. N Engl J Med. 2013; 369: HOKUSAI VTE Investigators et al. N Engl J Med. 2013; 369: Martin K et al. J Thromb Haemost. 2016; 14:

23 Overall Results Recurrent VTE Major Bleeding RR 0.90 ( ) RR 0.61 ( ) Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124: ; permission conveyed through Copyright Clearance Center, Inc. Recurrent VTE Results in high body weight* subgroup Bleeding, M+CRNM *Cut off for defining high BW was 100 kg in 4 trials and 90 kg in 2 trials. Di Minno MN et al. Ann Med. 2015; 47:61 8. Permission by Copyright Clearance Center Inc., on behalf of Taylor & Francis Ltd. 23

24 PK/PD data Rivaroxaban 10 mg single dose study in healthy volunteers Parameter kg (n=12) >120 kg (n=12) AUC (ng ml 1 hr) C max (ng/ml) t 1/2 (hr) Apixaban 10 mg single dose study in healthy volunteers Parameter kg (n=16) >120 kg (n=19) AUC (ng ml 1 hr) C max (ng/ml) t 1/2 (hr) Kubitza D et al. J Clin Pharmacol. 2007; 47: Upreti VV et al. Br J Clin Pharmacol. 2013; 76: FDA approved DOAC labeling for VTE treatment in obesity DOAC Dosing for VTE in patients with obesity Dabigatran No dosage recommendation Rivaroxaban No dosage recommendation Apixaban Edoxaban No dosage recommendation No dosage recommendation 24

25 International Society on Thrombosis and Haemostasis recommendations We suggest that DOACs should not be used in patients with a BMI > 40 kg/m 2 or a weight > 120 kg. IfaDOACisusedinapatientwithaBMI>40kg/m 2 or a weight > 120 kg, we suggest checking a peak and trough drug level. If the level falls within the expected range, continuation of the DOAC seems reasonable. If the level is found to be below the expected range, we suggest changing to a VKA rather than adjusting the dose of the DOAC. Martin K et al. J Thromb Haemost. 2016; 14: Key Takeaways DOACs appear to have a non inferior efficacy and safety profile compared with VKA in patients with body weight of kg and/or BMI of kg/m 2. Therefore, DOACs may be considered as a first line treatment option in this population. Very few data are available on DOAC use in patients with body weight > 120 kg and/or BMI > 40 kg/m 2. Therefore, DOACs should be avoided in this population. If a DOAC is used, measurement of drug levels should be considered. 25

26 Case 3 A 42 year old morbidly obese woman (124 kg, BMI 47.0 kg/m 2 ) is on indefinite anticoagulation with warfarin for a history of recurrent unprovoked VTE. She asks if she can switch to one of the new drugs. How do you advise her? a. Switch to a DOAC safer and more convenient than warfarin b. Switch to apixaban more effective than warfarin in patients of her size when weight based dose is used c. Do not switch DOACs less effective than warfarin in patients of her size d. Do not switch paucity of evidence on DOAC use in patients of her size Drug Interactions with DOACs 26

27 Case 4 TS is a 50 year old man with a history of multiple DVTs. He has been receiving apixaban 5 mg twice daily for about 5 months. He falls acutely ill and is diagnosed with invasive aspergillosis and needs to be started on voriconazole. He has a CrCl of 60 ml/min and normal hepatic function. What is the best approach to managing his anticoagulation therapy? a. Continue on apixaban 5 mg twice daily b. Change to rivaroxaban 15 mg once daily c. Change to dabigatran 75 mg twice daily d. Change to apixaban 2.5 mg twice daily e. Change to warfarin 7.5 mg daily DOAC Drug Interaction Potential Dabigatran IIa inhibitor Esterase mediated hydrolysis when absorbed Absorption dependent on P glycoprotein Minimal (20%) hepatic metabolism not CYP3A4 Approximately 80% renal elimination Rivaroxaban Xa inhibitor Absorption dependent on P glycoprotein Approximately 65% metabolized by hepatic CYP3A4 and CYP2J3 Approximately 35% renal elimination Apixaban Xa inhibitor Absorption dependent on P glycoprotein Approximately 73% metabolized by hepatic CYP3A4 Approximately 27% renal elimination Edoxaban Xa inhibitor Absorption dependent on P glycoprotein Approximately 50% hepatic metabolism, but only 4% CYP3A4 Approximately 50% renal elimination Heiduchel H et al. Europace. 2015; 17:

28 P Glycoprotein (P gp): A Drug Transport Protein Substrate Intestinal lumen Intestinal wall P-gp Plasma Normal activity of the P gp efflux mechanism in the GI tract Present in liver, kidney, brain, capillaries, placenta, and GI tract Functions as an efflux pump to prevent absorption of certain drugs that are P gp substrates Adapted from DuBuske LM. Drug Safety. 2005; 28: Mechanism of P Glycoprotein Drug Interactions Substrate Intestinal lumen Intestinal wall Inhibitor P-gp Plasma Effect of inhibition on the P gp efflux mechanism Drugs that inhibit P gp will increase absorption of a substrate, increasing its serum concentrations Drugs that induce P gp will decrease absorption of a substrate, reducing its serum concentrations Adapted from DuBuske LM. Drug Safety. 2005; 28:

29 Interplay Between CYP3A4 and P gp Bailey DG et al. CMAJ. 2004; 170: Copied under license from Access Copyright. Further reproduction, distribution, or transmission is prohibited, except as otherwise permitted by law. P Glycoprotein Drug Interactions Inducers clotrimazole St. John s wort midazolam nifedipine phenobarbital phenytoin rifampin Inhibitors amiodarone cefoperazone ceftriaxone clarithromycin cyclosporine diltiazem dipyridamole erythromycin hydrocortisone itraconazole ketoconazole nicardipine nifedipine propranolol quinidine quinine tacrolimus tamoxifen verapamil 29

30 CYP3A4 Drug Interactions Inducers carbamazepine efavirenz glucocorticoids nevirapine phenobarbital phenytoin primidone rifampin rifapentine ritonavir St. John s wort Inhibitors amiodarone amprenavir aprepitant atazanavir cimetidine clarithromycin cyclosporine diltiazem erythromycin fluconazole fluoxetine fluvoxamine grapefruit juice indinavir itraconazole ketoconazole lopinavir nefazodone nelfinavir quinidine quinupristin and dalfopristin ritonavir saquinavir verapamil voriconazole DOAC Drug Interactions More drugs interact with DOACs than outlined in the DOAC product labeling EHRA guidelines provide useful information on increases in AUC of DOACs based on available data Clinical trial exclusion criteria for concomitant drugs with interaction potential are an important consideration when reviewing product labeling EHRA: European Heart Rhythm Association Heidbuchel H et al. Europace. 2015; 17: January CT et al. J Am Coll Cardiol. 2014; 64:e1 e76. 30

31 Dabigatran Drug Interactions Mechanism Interacting Medication P gp induction rifampin P gp inhibition with CrCl ml/min ketoconazole dronedarone Effect Recommendation stroke risk, avoidcombination bleeding risk, consider dose reduction to 75 mg BID P gp inhibition with CrCl ml/min amiodarone, verapamil, ketoconazole, bleeding risk, avoid combination dronedarone, diltiazem, clarithromycin Pharmacodynamic interaction aspirin, clopidogrel, NSAIDs bleeding risk, assess risks and benefits Pradaxa (dabigatran etexilate mesylate) prescribing information Nov. Rivaroxaban Drug Interactions Mechanism Interacting Medication Strong dual CYP 3A4 & P gp induction rifampin, phenytoin, carbamazepine St. John s wort Strong dual CYP 3A4 & P gp inhibition conivaptan, HIV protease inhibitors, itraconazole, ketoconazole Weak to moderate CYP 3A4 & P gp inhibition & CrCl ml/min amiodarone, verapamil, diltiazem, erythromycin, dronedarone, cimetidine Pharmacodynamic interaction aspirin, clopidogrel, NSAIDs Effect Recommendation stroke risk, avoidcombination bleeding risk, avoid combination bleeding risk, avoid combination unless benefit exceeds risk, concurrent administration was allowed in ROCKET AF Trial bleeding risk, assess risks and benefits Xarelto (rivaroxaban) prescribing information Mar. 31

32 Apixaban Drug Interactions Mechanism Interacting Medication Strong dual CYP 3A4 & P gp induction rifampin, phenytoin, carbamazepine, St. John s wort Strong dual CYP 3A4 & P gp inhibition itraconazole, ketoconazole, ritonavir, clarithromycin Effect Recommendation stroke risk, avoidcombination If on 2.5 mg BID: bleeding risk, avoid combination If on > 2.5 mg BID: bleeding risk, reduce dose by 50% Pharmacodynamic interaction aspirin, clopidogrel, NSAIDs bleeding risk, assess risks and benefits Eliquis (apixaban) prescribing information Apr. Edoxaban Drug Interactions Mechanism Interacting Medication P gp induction rifampin P gp inhibition atrial fibrillation P gp inhibition VTE verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole Pharmacodynamic interaction aspirin, clopidogrel, NSAIDs Effect Recommendation stroke risk, avoidcombination No dose reductions; dose reduction in those on P gp inhibitors in trial resulted in lower than expected concentrations bleeding risk, reduce dose to 30 mg daily; adjust dose upward after short term P gp inhibitor administration if no other indication for dose decrease present bleeding risk, assess risks and benefits Savaysa (edoxaban) prescribing information Apr. 32

33 DOAC Drug Interactions DOACs are substrates of P gp and CYP 450 system Dependence on CYP 3A4 for metabolism rivaroxaban > apixaban > edoxaban Despite similar mechanisms of drug interactions, considerable variability in product labeling May need to consider renal function along with concomitant drugs Labeling for managing drug interactions varies across international regulatory agencies Aspirin significantly increases bleeding risk with all DOACs, evaluate concomitant indication Case 4 TS is a 50 year old man with a history of multiple DVTs. He has been receiving apixaban 5 mg twice daily for about 5 months. He falls acutely ill and is diagnosed with invasive aspergillosis and needs to be started on voriconazole. He has a CrCl of 60 ml/min and normal hepatic function. What is the best approach to managing his anticoagulation therapy? a. Continue on apixaban 5 mg twice daily b. Change to rivaroxaban 15 mg once daily c. Change to dabigatran 75 mg twice daily d. Change to apixaban 2.5 mg twice daily e. Change to warfarin 7.5 mg daily 33

34 Which of these practice changes will you consider making? Select all that apply. a. Share info about DOACs in challenging situations with interprofessional team b. Include DOACs as option after LMWH for CAassociated thrombosis c. Review regimens to consider potential DOAC drug interactions d. Educate patients above DOAC weight cutoffs about VTE options e. If lack of evidence, educate patients to facilitate informed decision Selected Resources DOACs in Patients with VTE and Renal Insufficiency van Es N, Coppens M, Schulman S et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014; 124: Del Carpio Munoz F, Gharacholou SM, Munger TM et al. Meta analysis of renal function on the safety and efficacy of novel oral anticoagulants for atrial fibrillation. Am J Cardiol. 2016; 117: DOACs in Patients with Cancer associated VTE Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease. CHEST Guideline and Expert Panel Report. Chest. 2016; 149: Dobesh PP, Fanikos J. New oral anticoagulants for the treatment of venous thromboembolism: understanding differences and similarities. Drugs. 2014; 74:

35 DOACs in Patients with VTE and Obesity Di Minno MN, Lupoli R, Di Minno A et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta analysis of randomized controlled trials. Ann Med. 2015; 47:61 8. Martin K, Beyer Westendorf J, Davidson BL et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14: Drug Interactions with DOACs Selected Resources Heidbuchel H, Verhamme P, Alings M et al. Updated European Heart Rhythm Association practical guide on the use of non vitamin K antagonist anticoagulants in patients with non valvular atrial fibrillation. Europace. 2015; 17:

36 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Abbreviations Used in Presentation ACCP AUC BID BMI BW CI CrCl CRNM DOAC DVT EHRA ESRD FDA GFR INR ISTH LMWH M M+CRNM NOAC NSAIDs P-gp PE PK/PD RR t 1/2 VKA VTE American College of Chest Physicians area under curve twice daily body mass index body weight confidence interval creatinine clearance clinically relevant nonmajor direct oral anticoagulant deep vein thrombosis European Heart Rhythm Association end-stage renal disease Food and Drug Administration glomerular filtration rate International Normalized Ratio International Society on Thrombosis and Haemostasis low molecular weight heparin mortality major + clinically relevant nonmajor non-vitamin K oral anticoagulant nonsteroidal antiinflammatory drugs P-glycoprotein pulmonary embolism pharmacokinetic/pharmacodynamic relative risk half-life vitamin K antagonist venous thromboembolism 36

37 Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations Self-assessment Questions 1. Which of the following direct oral anticoagulants is most dependent on the kidneys for clearance? a. Apixaban b. Dabigatran c. Edoxaban d. Rivaroxaban 2. Based on current evidence, which of the following statements regarding the data with DOACs in treating cancer-associated VTE is TRUE? a. DOACs have significantly better efficacy compared with warfarin. b. DOACs have demonstrated similar safety compared with LMWH. c. DOACs have demonstrated similar efficacy compared with warfarin. d. DOACs have significantly worse safety compared with warfarin. e. DOACs are preferred to LMWH as a first-line treatment option. Also see the polling questions within the activity. Answers 1. b 2. c 37