clinical case studies in vte: addressing clinical issues...
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Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues
in Special Patient Populations
Presented as a Live Webinar
Wednesday, May 10, 2017 2:00 PM – 3:00 PM ET
On-demand Activity Live webinar recorded and archived to be watched at your convenience
Available after May 25, 2017
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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.
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 venousthromboembolism (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 #: 0204-0000-17-429-L01-P On-demand Activity ACPE #: 0204-0000-17-429-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 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Participants will process CE credit online at http://elearning.ashp.org/my-activities. 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.
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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.
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• 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 ineligibleto claim credit for the corresponding web-based activity)
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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.
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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 2007. In 2013, he was honored with the UNMC campuswide Outstanding Educator Award.
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Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations
Disclosures 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 forBoehringer 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.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 6
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, FCCPUniversity 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
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 7
Learning Objectives
At the conclusion of this educational activity, participants should be able to
• Examine the evidence for use of direct oralanticoagulants (DOACs) with venousthromboembolism (VTE) and kidney disease
• Review the evidence for the use of DOACs in patientswith cancer‐associated VTE
• Review data on the use of DOACs for treatment ofVTE in patients with obesity
• Implement an appropriate strategy for managingpotential drug interactions with DOACs
DOACs in Patients with VTE and Renal Insufficiency
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 8
Case 1
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
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 CrClis 22 mL/min. Which of the following is appropriate oral therapy?
Schulman S et al. N Engl J Med. 2009; 361:2342‐52. Schulman S et al. Circulation. 2014; 129:764‐72. EINSTEIN Investigators et al. N Engl J Med. 2010; 363:2499‐510.
EINSTEIN‐PE Investigators et al. N Engl J Med. 2012; 366:1287‐97. Agnelli G et al. N Engl J Med. 2013; 369:799‐808. HOKUSAI‐VTE Investigators et al. N Engl J Med. 2013; 369:1406‐15.
Renal exclusion criteria in clinical trials
DOAC Renal Clearance
Pivotal Trial(s) Renal Exclusion Criterion
Dabigatran 80% RE‐COVERRE‐COVER II
CrCl < 30 mL/min
Rivaroxaban 36% EINSTEIN DVTEINSTEIN PE
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
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Overall Results
Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124:1968‐75; permission conveyed through Copyright Clearance Center, Inc.
Recurrent VTE Major Bleeding
RR 0.90 (0.77‐1.06)
RR 0.61 (0.45‐0.83)
Results stratified by renal function
Recurrent VTE
Major Bleeding
RR 0.51 (0.26‐0.99)
RR 0.60 (0.40‐0.90)
RR 0.70 (0.43‐1.15)
RR 0.97 (0.83‐1.14)
Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124:1968‐75; permission conveyed through Copyright Clearance Center, Inc.
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Similar results in Phase III non‐valvular atrial fibrillation DOAC trials
GFR Stroke/Systemic EmbolismRR (95% CI)
Major BleedingRR (95% CI)
50‐80 mL/min 0.71 (0.62‐0.81) 0.88 (0.80‐0.97)
< 50 mL/min 0.79 (0.66‐0.94) 0.80 (0.70‐0.91)
Del‐Carpio Munoz F et al. Am J Cardiol. 2016; 117:69‐75.
Real‐world studies: More data to come
Beyer‐Westendorf J et al. Thromb Haemost. 2016; 116(suppl 2):S13‐S23.
Ageno W et al. Thromb Haemost. 2017; 117:415‐21.
Study Population (n) n
XALIA Patients with VTE treated with rivaroxaban
5723
GARFIELD‐VTE
Patients with VTE treated with DOACs or VKA
10,000 (target)
DresdenNOAC registry
Patients with VTE or NVAF treated withDOACs
2941
RE‐COVERY DVT/PE
Patients with VTE treated with dabigatran or VKA
14,000 (target)
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Evidence in severe renal dysfunction (CrCl < 30 mL/min) or end‐stage renal disease
FDA‐approved DOAC labeling for VTE treatment in renal impairment
DOAC Creatinine Clearance
Dosing Recommendation
Dabigatran > 30 mL/min ≤ 30 mL/min
150 mg BIDNo dosage recommendation
Rivaroxaban ≥ 30 mL/min < 30 mL/min
15 mg BID x 3 wk, then 20 mg dailyNot recommended
Apixaban ≥ 30 mL/min < 30 mL/min
10 mg BID x 7 days, then 5 mg dailyNo dosage recommendation
Edoxaban > 50 mL/min 15‐50 mL/ min< 15 mL/min
60 mg daily*30 mg dailyNot recommended
*30 mg daily if weight ≤ 60 kg or receiving certain P‐glycoprotein inhibitors.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 12
• In patients with CrCl ≥ 30 mL/min…– I use DOACs as first‐line treatment
– If the CrCl is 30‐50 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)
What do I do?
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
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 13
Case 1
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
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 CrClis 22 mL/min. Which of the following is appropriate oral therapy?
DOACs in Patients with Cancer‐associated VTE
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Case 2
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
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.
ACCP Antithrombotic Guideline, 10th edition (AT 10)
Kearon C et al. Chest. 2016; 149:315‐52.
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
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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 (“cancer‐associated 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; 149:315‐52.
VTE Treatment in Cancer Patients: LMWH vs. Warfarin
0%
5%
10%
15%
20%
25%
RecurrentVTE
MajorBleeding
AnyBleeding
8%
6%
14%
17%
4%
19%
Dalteparin
Oral anticoagulant
p=0.002
p=0.27
p=0.09
Lee A et al. N Engl J Med. 2003; 349:146‐53.
• Initial dalteparin dose200 units/kg/day
• Randomized to dalteparin150 units/kg/day orwarfarin (INR 2‐3)
• n = 676• Significant reduction in
VTE at 6 months withdalteparin
• Mortality: dalteparin 39%vs. dalt/warfarin 41% (p =0.53)
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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)
p=0.04
Reproduced with permission from Meyer G et al. Arch Intern Med. 2002; 162:1729‐35. Copyright © 2002 American Medical Association. All rights reserved.
Enoxaparin
Warfarin
ACCP AT 10 Guideline Statement
Kearon C et al. Chest. 2016; 149:315‐52.
AT 10 Choice of anticoagulant for long‐term treatment of DVT and PE:
In patients with DVT of the leg or PE and cancer (“cancer‐associated 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 324‐325. “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
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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
CharacteristicRE‐COVER I & II(dabigatran)
EINSTEIN –DVT & PE
(rivaroxaban)
AMPLIFY(apixaban)
Hokusai –VTE
(edoxaban)
Recurrent VTE 2.4 vs. 2.2 2.1 vs. 2.3 1.9 vs. 2.1 2.8 vs. 2.9
VTE mortality 0.1 vs. 0.1 0.2 vs. 0.3 0.4 vs. 0.6 0.6 vs. 0.6
Total mortality 1.8 vs. 1.8 2.3 vs. 2.4 1.5 vs. 1.9 3.2 vs. 3.1
Major bleeding 1.4 vs. 2.0 1.0 vs. 1.7 0.6 vs. 1.8 1.4 vs. 1.6
Major + CRNM bleeding 5.3 vs. 8.5 9.6 vs. 10.1 4.3 vs. 9.7 8.5 vs. 10
DOAC vs. Warfarin (or VKA)
Dobesh PP et al. Drugs. 2014; 74:2015‐32.
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Acute VTE Treatment: Clinical Trial Comparisons
CharacteristicRE‐
COVER IRE‐
COVER IIEINSTEIN –
DVTEINSTEIN –
PEAMPLIFY
Hokusai ‐VTE
Mean age (yr) 55 57 56 58 57 56
Male sex (%) 58 61 57 53 59 57
Weight (kg) 85 81 82 83 84 82
CrCl 30‐50 mL/min (%) NR NR 6.8 8.2 5.7 6.6
Active cancer (%) 4.8 3.9 6.0 4.6 2.7 2.5
VTE history (%) 26 18 19 20 16 18
DVT only (%) 69 68 99 0 66 60
PE only (%) 21 23 0 75 25 30
DVT + PE (%) 10 9 1 25 9 10
Dobesh PP et al. Drugs. 2014; 74:2015‐32.NR = not reported
Patients with Active Cancer: Primary Efficacy Endpoint
3.5%
5.1%
3.7% 3.7%4.7%
7.1%6.4%
7.1%
0%
2%
4%
6%
8%
RE‐COVER I & II EINSTEIN DVT &PE
AMPLIFY Hokusai‐VTE
DOAC
Standard Care
% of Patients
None of these comparisons are statistically significant
Schulman S et al. Circulation. 2014; 129;764‐72. 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; 369:1406‐15.
n=221 n=597 n=159 n=208
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Patients with Active Cancer: Safety Endpoints
15.2%12.6%
18.3%
2.8% 2.3%
15.8%
22.5%25.3%
5.8% 5.0%
0%
5%
10%
15%
20%
25%
30%
EINSTEIN DVT& PE
AMPLIFY Hokusai‐VTE EINSTEIN DVT& PE
AMPLIFY
DOAC
Standard Care
% of Patients
None of these comparisons are statistically significant
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; 369:1406‐15.
Major + CRNM Bleeding Major Bleeding
VTE Treatment in Cancer Patients: LMWH vs. Warfarin
0%
5%
10%
15%
20%
25%
RecurrentVTE
MajorBleeding
AnyBleeding
8%
6%
14%
17%
4%
19%
Dalteparin
Oral anticoagulant
p=0.002
p=0.27
p=0.09
Lee A et al. N Engl J Med. 2003; 349:146‐53.
• 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)
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 20
Case 2
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
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.
DOACs in Patients with VTE and Obesity
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Case 3
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
A 42‐year‐old morbidly obese woman (124 kg, BMI 47.0 kg/m2) 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?
Schulman S et al. N Engl J Med. 2009; 361:2342‐52. Schulman S et al. Circulation. 2014; 129:764‐72. EINSTEIN Investigators et al. N Engl J Med. 2010; 363:2499‐510. EINSTEIN‐PE Investigators et al. N Engl J Med. 2012; 366:1287‐97. Agnelli G et al. N Engl J Med. 2013; 369:799‐808. HOKUSAI‐VTE Investigators
et al. N Engl J Med. 2013; 369:1406‐15. Martin K et al. J Thromb Haemost. 2016; 14:1308‐13.
Weight‐based enrollment in clinical trials
DOAC Volume of distribution
Pivotal Trial(s)
Weight categories
Enrollment (%)
Dabigatran 50‐70 L RE‐COVER
RE‐COVER II
≥ 100 kgBMI ≥ 35 kg/m2
> 100 kgBMI > 35 kg/m2
502/2539 (20%)306/2539 (12%)438/1280 (34%)302/1280 (24%)
Rivaroxaban ~50 L EINSTEIN DVTEINSTEIN PE
> 90 kg> 90 kg
245/1731 (14%)345/2419 (14%)
Apixaban ~21 L AMPLIFY ≥ 100 kgBMI > 35 kg/m2
522/2691 (19%)349/2691 (13%)
Edoxaban 107 L HOKUSAI‐VTE > 100 kg 611/4118 (15%)
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Overall Results
Recurrent VTE Major Bleeding
RR 0.90 (0.77‐1.06)
RR 0.61 (0.45‐0.83)
Republished with permission of American Society of Hematology from van Es N et al. Blood. 2014; 124:1968‐75; permission conveyed through Copyright Clearance Center, Inc.
Results in high body weight* subgroup
Di Minno MN et al. Ann Med. 2015; 47:61‐8.Permission by Copyright Clearance Center Inc., on behalf of Taylor & Francis Ltd. www.informaworld.com
Recurrent VTE
Bleeding, M+CRNM
*Cut‐off for defining high BW was 100 kg in 4 trials and 90 kg in 2 trials.
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PK/PD data
Parameter 70‐80 kg (n=12) >120 kg (n=12)
AUC (ng mL‐1 hr) 1029 1155
Cmax (ng/mL) 143.4 149.0
t1/2 (hr) 7.2 7.3
Rivaroxaban 10 mg single dose study in healthy volunteers
Kubitza D et al. J Clin Pharmacol. 2007; 47:218‐26. Upreti VV et al. Br J Clin Pharmacol. 2013; 76:908‐16.
Parameter 65‐85 kg (n=16) >120 kg (n=19)
AUC (ng mL‐1 hr) 2024 1561
Cmax (ng/mL) 207 144
t1/2 (hr) 12.0 8.8
Apixaban 10 mg single dose study in healthy volunteers
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 No dosage recommendation
Edoxaban No dosage recommendation
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Martin K et al. J Thromb Haemost. 2016; 14:1308‐13.
International Society on Thrombosis and Haemostasis recommendations
We suggest that DOACs should not be used in patients with aBMI > 40 kg/m2 or a weight > 120 kg.
If a DOAC is used in a patient with a BMI > 40 kg/m2 or aweight > 120 kg, we suggest checking a peak and trough druglevel. If the level falls within the expected range, continuationof the DOAC seems reasonable. If the level is found to bebelow the expected range, we suggest changing to a VKArather than adjusting the dose of the DOAC.
Key Takeaways
• DOACs appear to have a non‐inferior efficacy and safety
profile compared with VKA in patients with body weight of
100‐120 kg and/or BMI of 35‐40 kg/m2.
• 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/m2.
• Therefore, DOACs should be avoided in this population. If
a DOAC is used, measurement of drug levels should be
considered.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 25
Case 3
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
A 42‐year‐old morbidly obese woman (124 kg, BMI 47.0 kg/m2) 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?
Drug Interactions with DOACs
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 26
Case 4
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
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.
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; 17:1467‐507.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 27
P‐Glycoprotein (P‐gp): A Drug Transport Protein
• 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; 28:789‐801.
Substrate Intestinallumen
Intestinalwall
Plasma
P-gp
Normal activity of the P‐gp efflux mechanism in the GI tract
Mechanism of P‐Glycoprotein Drug Interactions
• 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; 28:789‐801.
Substrate Intestinallumen
Intestinalwall
Plasma
Effect of inhibition on the P‐gp efflux mechanism
Inhibitor
P-gp
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Interplay Between CYP3A4 and P‐gp
Bailey DG et al. CMAJ. 2004; 170:1531‐2. Copied under license from Access Copyright. Further reproduction, distribution, or transmission is prohibited, except as otherwise permitted by law.
P‐Glycoprotein Drug Interactions
Inducers
clotrimazoleSt. John’s wortmidazolamnifedipinephenobarbitalphenytoinrifampin
Inhibitors
amiodarone itraconazolecefoperazone ketoconazoleceftriaxone nicardipineclarithromycin nifedipinecyclosporine propranololdiltiazem quinidinedipyridamole quinineerythromycin tacrolimushydrocortisone tamoxifen
verapamil
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CYP3A4 Drug Interactions
Inducers
carbamazepineefavirenzglucocorticoidsnevirapinephenobarbitalphenytoinprimidonerifampinrifapentineritonavirSt. John’s wort
Inhibitors
amiodaroneamprenaviraprepitantatazanavircimetidineclarithromycincyclosporinediltiazemerythromycinfluconazolefluoxetinefluvoxaminegrapefruit juice
indinaviritraconazoleketoconazolelopinavirnefazodonenelfinavirquinidinequinupristin and dalfopristinritonavirsaquinavirverapamilvoriconazole
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
Heidbuchel H et al. Europace. 2015; 17:1467‐507. January CT et al. J Am Coll Cardiol. 2014; 64:e1‐e76.
EHRA: European Heart Rhythm Association
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 30
Dabigatran Drug InteractionsMechanism‐ Interacting Medication Effect – Recommendation
P‐gp induction
rifampin ↑stroke risk, avoid combination
P‐gp inhibition with CrCl 30 – 50 mL/min
ketoconazoledronedarone
↑bleeding risk, consider dose reduction to 75 mg BID
P‐gp inhibition with CrCl 15 – 30 mL/min
amiodarone, verapamil, ketoconazole, dronedarone, diltiazem, clarithromycin
↑bleeding risk, avoid combination
Pharmacodynamic interaction
aspirin, clopidogrel, NSAIDs ↑bleeding risk, assess risks and benefits
Pradaxa (dabigatran etexilate mesylate) prescribing information. 2015 Nov.
Rivaroxaban Drug InteractionsMechanism‐ Interacting Medication Effect – Recommendation
Strong dual CYP 3A4 & P‐gp induction
rifampin, phenytoin, carbamazepine St. John’s wort
↑stroke risk, avoid combination
Strong dual CYP 3A4 & P‐gp inhibition
conivaptan, HIV protease inhibitors, itraconazole, ketoconazole
↑bleeding risk, avoid combination
Weak to moderate CYP 3A4 & P‐gpinhibition & CrCl 15‐80 mL/min
amiodarone, verapamil, diltiazem, erythromycin, dronedarone, cimetidine
↑bleeding risk, avoid combination unless benefit exceeds risk, concurrent administration was allowed in ROCKET‐AF Trial
Pharmacodynamic interaction
aspirin, clopidogrel, NSAIDs ↑bleeding risk, assess risks and benefits
Xarelto (rivaroxaban) prescribing information. 2017 Mar.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 31
Apixaban Drug InteractionsMechanism‐ Interacting Medication Effect – Recommendation
Strong dual CYP 3A4 & P‐gp induction
rifampin, phenytoin, carbamazepine, St. John’s wort
↑stroke risk, avoid combination
Strong dual CYP 3A4 & P‐gp inhibition
itraconazole, ketoconazole, ritonavir, clarithromycin
• 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. 2017 Apr.
Edoxaban Drug InteractionsMechanism‐ Interacting Medication Effect – Recommendation
P‐gp induction
rifampin ↑stroke risk, avoid combination
P‐gp inhibition‐ atrial fibrillation
No dose reductions; dose reduction in those on P‐gp inhibitors in trial resulted in lower than expected concentrations
P‐gp inhibition‐ VTE
verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole
↑bleeding risk, reduce dose to 30 mg daily; adjust dose upward after short term P‐gpinhibitor administration if no other indication for dose decrease present
Pharmacodynamic interaction
aspirin, clopidogrel, NSAIDs ↑bleeding risk, assess risks and benefits
Savaysa (edoxaban) prescribing information. 2017 Apr.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 32
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
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
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.
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 33
Which of these practice changes will you consider making? Select all that apply.
a. Share info about DOACs in challenging situations withinterprofessional team
b. Include DOACs as option after LMWH for CA‐associated thrombosis
c. Review regimens to consider potential DOAC druginteractions
d. Educate patients above DOAC weight cutoffs aboutVTE options
e. If lack of evidence, educate patients to facilitateinformed decision
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; 124:1968‐75.
• 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; 117:69‐75.
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; 149:315‐52.
• Dobesh PP, Fanikos J. New oral anticoagulants for the treatment of venous
thromboembolism: understanding differences and similarities. Drugs. 2014;
74:2015‐32.
Selected Resources
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 34
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;14:1308‐13.
Drug Interactions with DOACs
• 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;
17:1467‐507.
Selected Resources
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Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues in Special Patient Populations
Abbreviations Used in Presentation ACCP American College of Chest Physicians AUC area under curve BID twice daily BMI body mass index
BW body weight CI confidence interval CrCl creatinine clearance CRNM clinically relevant nonmajor
DOAC direct oral anticoagulant DVT deep vein thrombosis EHRA European Heart Rhythm Association ESRD end-stage renal disease FDA Food and Drug Administration
GFR glomerular filtration rate INR International Normalized Ratio ISTH International Society on Thrombosis and Haemostasis LMWH low molecular weight heparin
M mortality M+CRNM major + clinically relevant nonmajor NOAC non-vitamin K oral anticoagulant NSAIDs nonsteroidal antiinflammatory drugs
P-gp P-glycoprotein PE pulmonary embolism PK/PD pharmacokinetic/pharmacodynamic RR relative risk
t1/2 half-life VKA vitamin K antagonist VTE venous thromboembolism
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 36
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. Apixabanb. Dabigatranc. Edoxaband. 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. b2. c
Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 37