clinical case studies in vte: addressing clinical issues...

Clinical Case Studies in Venous Thromboembolism: Addressing Clinical Issues

in Special Patient Populations

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Wednesday, May 10, 2017 2:00 PM – 3:00 PM ET

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Copyright © 2017, American Society of Health-System Pharmacist, Inc. All rights reserved.

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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.

Copyright © 2017, American Society of Health-System Pharmacists, Inc. All rights reserved. 2

http://elearning.ashp.org/my-activities


List of Abbreviations For a list of abbreviations used in this activity, please see page 36.

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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.



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.



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.



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


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


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


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)



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)


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.


• 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


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


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


ACCP AT 10 Guideline Statement


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.


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)



• 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



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


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.


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


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


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)


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


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%)


Overall Results

Recurrent VTE Major Bleeding

RR 0.90 (0.77‐1.06)

RR 0.61 (0.45‐0.83)


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.


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


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.


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


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.


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


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


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


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



Xarelto (rivaroxaban) prescribing information. 2017 Mar.


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%



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



Savaysa (edoxaban) prescribing information. 2017 Apr.


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.


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


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



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



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


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