1. Safety Considerations for TSOACs (Target Specific Oral Anticoagulants): An Overview
Christopher Malabanan, Pharm.D., BCPS, CACP
Jenny Park, Pharm.D.
St. Joseph’s Regional Medical Center

2. Learning Objectives
After the presentation, pharmacists will be able to
Describe basic principles in changing to/from anticoagulants
Define appropriate dosing for idarucizumab to reverse dabigatran
After the presentation, pharmacy technicians will be able to
Name four TSOACs used in the outpatient setting
Describe safe packaging and handling of the TSOACs

3. Patient Case
AB is a 65 year old female on dabigatran 150 mg po BID as an outpatient for non-valvular AF. She is admitted to the ICU for severe sepsis secondary to pneumonia. She is intubated and is receiving enteral feeding and medication through a nasogastric tube. The following are options regarding anticoagulant administration, Scr 1.0, Wt 76 kg
Open capsules and administer dabigatran through NGT
Discontinue dabigatran and initiate IV UFH protocol
Discontinue dabigatran and convert to apixaban 5 mg po BID
Either B or C

4. Target Specific Oral Anticoagulants
Warfarin (Vitamin K antagonist) has been conventional anticoagulant agent
TSOACs are classes of “newer” anticoagulant agents
Anticoagulants = “Blood Thinners”
Indications
Atrial fibrillation
Venous thromboembolism (VTE)
Treatment
Prophylaxis
Images retrieved on March 28, 2016 from:

5. Target Specific Oral Anticoagulants
Advantages
Fixed dose
No INR monitoring
No food interactions
Fewer drug interactions (vs warfarin)
Disadvantages
Cost
No antidote for FXa inhibitors
Assessment of compliance
Renal monitoring/dose adjustment

6. High Risk Medications Institute for Safe Medication Practices (ISMP)
All TSOACs are listed as high risk medication
High alert medications
↑ risk of causing significant harm when they are used in error
ADE can be significant
Bleeding
Limited reversal agent
Variable indication and dosing
Administration/dosing is not simple!
Ways to reduce the risk of errors
Standardize the ordering/storage
Auxiliary labels
Limit access to high-alert medication
Pradaxa® Plavix

7. TJC National Patient Safety Goal 03.05.01
Reduce the likelihood of patient harm associated with the use of anticoagulant therapy
Use approved protocols
Use authoritative resources to manage potential food and drug interactions for patients receiving warfarin
Written policy addressing baseline and ongoing laboratory tests
Evaluate anticoagulation safety practices, take action to improve practices, and measure
Provide education to prescribers, staff, patients, and families. Patient/family education includes:
Importance of follow-up monitoring
Compliance
Drug-food interactions
Adverse drug reactions and interactions

8. Mechanism of action Rivaroxaban Dabigatran Apixaban Edoxaban
Clotting Cascade Intrinsic (Damaged surface) Extrinsic (Trauma)
XII
XIIa
VIIa
VII XI
XIa
Rivaroxaban
Apixaban
Edoxaban IX
IXa
Dabigatran X Xa X
Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16(1):11-17.
Prothrombin (II)
Thrombin (IIa)
Fibrinogen (I)
Fibrin (Ia)
Cross-linked fibrin clot
Harter K, et al..West J Emerg Med. 2015; 16(1):11-17.

9. Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban
Brand name
Available strength
Eliquis®
2.5, 5
Xarelto®
10,15,20
Pradaxa®
75,110,150
Savaysa®
15,30,60
Indication/Dose
NVAF
5mg BID
20mg QD
150mg BID
60mg QD
VTE treatment
10mg BID x 7D  5mg BID
15mg BID x21D  20mg QD
Reduction of risk of VTE recurrence
2.5mg BID X
DVT Prophylaxis (hip/knee surgery)
10mg QD
220mg QD
Parenteral lead-in
5 – 10 days
Reversal agent
Praxbind®
Package insert of pradaxa, rivaroban, apixaban, endoxaban
Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015.
Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015.
NVAF: nonvalvular atrial fibrillation; VTE: venous thromboembolism; DVT: Deep venous thrombosis
Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]
Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

10. Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban
Renal Dose Adjustment
NVAF
2.5mg: Scr >1.5 +
Age ≥ 80 or
≤ 60kg
15mg: CrCl 15-50
75mg:
CrCl 15-30
Dronedarone
Ketoconazole
Avoid use:
CrCl P-gp inhibitor
30mg: CrCl 15-50
CrCl >95
CrCl < 15
VTE
None
CrCl < 30
CrCl ≤ 30
CrCl < P-gp inhibitor
Extreme Weight
Not affected
Affected
Unknown
APS X
Package insert of pradaxa, rivaroban, apixaban, endoxaban
Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015.
Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015.
Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]
Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

11. Comparison of TSOACs Apixaban Rivaroxaban Dabigatran Edoxaban
Pregnancy B C
Lactation X
Split/Crush O
Unknown
GI tolerability
Dyspepsia
Storage
Original container
Discard after 4 months
Co-pay assistance & patient assistance programs (PAP)
$10 savings card for eligible patients
PAP available via BMS
$0 savings card for eligible patients
PAP available via J&J
PAP available via Boehringer Ingelheim
$4 savings card for eligible patients
Package insert of pradaxa, rivaroban, apixaban, endoxaban
Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015.
Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015.
Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]
Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

12. TSOACs- Drug interactions
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
↑ drug effect
Other AC
Antiplatelets
NSAIDS
P-gp inhibitors
CYP3A4 inhibitors
↓ drug effect
P-gp inducers
Antacids?
CYP3A4 inducers
Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]

13. Safe Medication Handling: Pradaxa®
Blue-white capsule
Cannot open capsule
Increases AUC by 75%
Available
Blister packs
Plastic medication bottle
Cannot remove Pradaxa capsules
Unit-dosing from bottle is unsafe
Medication stability
Medication efficacy
Image retrieved from

14. Importance of Accurate Medication Reconciliation
Increased prescriptions for TSOACs
Pharmacist or pharmacy technician driven medication reconciliation
There can be change in the choice of anticoagulation
Warfarin  TSOAC
TSOAC  TSOAC
TSOAC  Warfarin
Important to identify duplicate therapy!
Obtaining the accurate medication and dose is crucial
Medication error can cause severe adverse event

15. Dabigatran (Pradaxa®)
PLAVIX®
PRADAXA®
Anticoagulation
Antiplatelet
Used to prevent stroke/heart attack

16. Anticoagulation conversion
Warfarin
LMWH
UFH
Apixaban
D/C warfarin
Start when INR is < 2.0
D/C LMWH
Start when next LMWH is due
D/C infusion
Start at same time
Dabigatran
Start 0-2 hours prior to next scheduled evening LMWH
Edoxaban
Start when INR is < 2.5
Start 4 hours later
Rivaroxaban
Start when INR is < 3.0
Start 0-2 hours prior to next scheduled evening administration
Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration
Pradaxa®, Xarelro®, Eliquis®, Savaysa® [package insert]

17. Anticoagulation conversion
From To
Dabigatran
Warfarin
CrCl 50 mL/min, start warfarin 3 days before discontinuing dabigatran.
CrCl mL/min, start warfarin 2 days before discontinuing dabigatran.
CrCl mL/min, start warfarin 1 day before discontinuing dabigatran.
CrCl <15 mL/min, no recommendations can be made.
LMWH/UFH
CrCl >30 mL/min, wait 12 hours after last dose of dabigatran to initiate parenteral anticoagulant
CrCl <30 mL/min, wait 24 hours after last dose of dabigatran to initiate parenteral anticoagulant
Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration
Hellerslia V, et al. Transition of Anticoagulants Hospital Pharmacy

18. Anticoagulation conversion
From To
Rivaroxaban
LMWH/UFH
Wait 24 hours after rivaroxaban (treatment dose) discontinuation to initiate parenteral anticoagulant.
Warfarin
Initiate warfarin when next dose of rivaroxban is due
Consider use of parenteral anticoagulant until INR is therapeutic
Apixaban
Wait 12 hours after last dose of apixaban to initiate parenteral anticoagulant.
Initiate warfarin when next dose of apixaban is due
Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration
Hellerslia V, e al. Transition of Anticoagulants Hospital Pharmacy

19. Anticoagulation conversion
From To
Edoxaban
Warfarin
Oral option
edoxaban 60 mg/day reduce dose to 30 mg/day and begin warfarin at the same time
edoxaban 30 mg/day reduce dose to 15 mg/day and begin warfarin at the same time
INR must be measured at least weekly
When INR ≥2, discontinue edoxaban and continue warfarin
Parenteral option
Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose
When INR ≥2 , discontinue the parenteral anticoagulant and continue warfarin
LMWH/UFH
Discontinue edoxaban and start the parenteral anticoagulant at the time of the next dose of edoxaban
Now that we know what agents are more optimal for specific population – we also need to take the conversion method into consideration
Savaysa® [package insert]

20. Example: Anticoagulation Algorithm
Is patient at ↑ risk of bleed? (HAS-BLED score = ____) No
Yes
Consider apixaban
Only TSOAC superior to warfarin for major bleeding event
Alternative: rivaroxaban
Renal impairment?
Yes No
Consider apixaban
Portion of renal elimination: Dabigatran>rivaroxaban>edoxaban>apixaban
Is CrCl > 95 ml/min?
Yes No
Consider apixaban
Edoxaban should NOT be used if CrCl>95
Does patient have dyspepsia?
Yes
Consider apixaban, rivaroxaban, or edoxaban
Dabigatran is associated with dyspepsia No
Yes
Is patient > 75 y/o?
Consider apixaban
Edoxaban should NOT be used if CrCl>95 No
Consider apixaban
Alternatives: rivaroxaban, dabigatran, or edoxaban
Adapted from SJHMC TSOAC Protocol by Shannon Tellier, Pharm.D.

21. Back to our patient!
AB is a 65 year old female on dabigatran 150 mg po BID as an outpatient for non-valvular AF. She is admitted to the ICU for severe sepsis secondary to pneumonia. She is intubated and is receiving enteral feeding and medication through a nasogastric tube. The following are options regarding anticoagulant administration, Scr 1.0, Wt 76 kg
Open capsules and administer dabigatran through NGT
Discontinue dabigatran and initiate IV UFH protocol
Discontinue dabigatran and convert to apixaban 5 mg po BID
Either B or C

22. Reversal agents for TSOACs
Four factor PCC not FDA approved for reversal of TSOACs
Idarucizumab (Praxbind®) FDA approved for urgent reversal of dabigatran
No current reversal agent for Factor Xa inhibitors
Andexanet (ANNEXA-R, ANNEXA-A, ANNEXA-4)- biologics license application filed in early 2016
Aripazine (PER977, ciraparantag)- broad activity among many anticoagulants
Ansell J, et al. NEJM 2014; 371:
Siegal DM, et al. NEJM 2015; 373:
Pollack CV, et al. NEJM 2015; 373:
Praxbind® [package insert]

23. Idarucizumab (Praxbind®)
Humanized monoclonal antibody fragment, reversal of dabigatran for emergent/urgent surgery or life-threatening/uncontrolled bleeding
Dosed as 5 grams IV (given as 2 separate infusions of 2.5 grams/50ml)
Interim analysis of REVERSE-AD
Almost complete reversal of anticoagulant effect based on dTT or ECT
LASA: Idarubicin (ISMP alert)
Image retrieved from
Pollack CV, et al. NEJM 2015; 373:
Praxbind® [package insert]

24. Question 1
True or false
When converting dabigatran (Pradaxa®) to warfarin, one has to consider patient’s creatinine clearance.
True
False
Pharmacists

25. Question 2
Which of the following is NOT a TSOAC used in outpatient setting?
Dabigatran
Rivaroxaban
Apixaban
Enoxaparin
Edoxaban

26. Question 3
What is the appropriate dose of idarucizumab (Praxbind®) to administer for reversal of dabigatran (Pradaxa®)?
Administer 2.5mg IV x1, repeat if bleeding persists
Administer 2.5mg IV x2 (more than 15 minutes apart)
Administer 2.5mg IV x2 (no more than 15 minutes apart)
Administer 5mg IV

27. Question 4
Which of the following TSOACs cannot be removed from original container for storage?
Dabigatran
Rivaroxaban
Apixaban
Edoxaban

28. References
Ansell J, Bakhru SH, Laulicht BE, et al. Use of PER977 to Reverse to Anticoagulant Effect of Edoxaban. N Engl J Med. 2014;371:
Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015
Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16(1):11-17.
Hellerslia V, et al. Transition of Anticoagulants Hospital Pharmacy
Pollack CV, Reilly PA, Eikelbloom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511-20
Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
Praxbind® [package insert]. Ridgefield, CT: Boerhinger Ingelheim Pharmaceuticals; 2015
Savaysa® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015.
Siegal DM, et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity". N Engl J Med :
Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2015.