Anticoagulation Problems, Pitfalls & Possibilities

1. Anticoagulation Problems, Pitfalls & Possibilities George A. Davis, PharmD, BCPS University of Kentucky HealthCare April 16, 2014 georgedavis@uky.edu

2. Disclosures • I have no financial conflict of interest related to this presentation.

3. Objectives • Describe dosing protocols for initiation of therapy and management dosing of anticoagulants. • Illustrate the indications for use of the new oral anticoagulants. • Evaluate the management of the in's and out's of the INR.

4. Outline • Basics of Anticoagulant Drug Pharmacology • Review of Warfarin (VKA) and Target-Specific or Novel Oral Anticoagulants (TSOAC or NOAC) • Dosing recommendations and monitoring of oral anticoagulation

5. Hemostatic System • Preserves integrity of circulatory system • A highly complex system • Vessel wall (endothelial cells) • Soluble plasma proteins (clotting factors) • Cellular components (platelets) • Microparticles (tissue factor) • Activated by tissue injury or changes in the endothelial surface

6. Hemostasis Overview • Hemostasis is the arrest of bleeding following blood vessel damage • Rapid formation of impermeable platelet and fibrin plug at site of injury • Localized to site of injury • Fibrin within clot triggers its own dissolution (fibrinolysis) • Pathologic thrombus = normal regulatory controls overwhelmed Furie B, Furie BC. N Engl J Med 2008;359:938-949.

7. Response to Vascular Injury Endothelial disruption (may not involve actual damage) Two pathways of platelet activation Exposed collagen triggers accumulation of activated platelets Exposed tissue factor initiates generation of thrombin Generates fibrin Activates platelets Furie B, Furie BC. N Engl J Med 2008;359:938-949.

8. Cellular Model of Coagulation Process ThrombHaemost2013; 110: 859–867; ActaAnaesthesiolScand2014

9. Oral Anticoagulants in Coagulation Cascade Rivaroxaban Apixiban Warfarin Dabigatran Anticoagulants Protein C, S ClinPharmacokinet(2013) 52:69–82

10. Warfarin • Developed in 1930s at the University of Wisconsin • Hemorrhagic death in cattle after eating spoiled sweet clover • First used clinically in 1941 • Most widely used OAC • Good bioavailability (>90%) • Absorbed in upper GI tract • Peak absorption 60-120 min • Predictable onset • Predictable duration of action

11. Warfarin: Racemic Mixture of Two Enantiomers

12. Warfarin Pharmacology • By suppressing the production of clotting factors, warfarin prevents the initial formation and propagation of thrombus • NOTE: Has no direct effect on previously circulating clotting factors or previously formed thrombus • Antithrombotic effect delayed until circulating vitamin K-dependent factors (II, VII, IX, X) are cleared from the blood

13. Vitamin K Dependent Proteins and Monitoring of Warfarin Effect (INR) • Time to reach therapeutic INR is determined by the half-lives of the clotting factors • Initial increase in INR due to decline in factor VII • Full antithrombotic effect of warfarin due primarily to inhibition of factor II • Anticoagulant vs. Antithrombotic effect • Full antithrombotic effect may take 1 week or more • Possible thrombogenic state in the intial 1-2 days of therapy • Early INR > 2.0 may not indicate adequate antithrombotic protection

14. Vitamin K Dependent Proteins and Monitoring of Warfarin Effect (INR) Ann Pharmacother2004;38:2115-21.

15. Initiation of Warfarin with Parenteral Anticoagulant • Required due to warfarin’s delayed onset of action • Recommended to overlap parenteral anticoagulant and warfarin for at LEAST 5 days • INR should be in range and stable before discontinuation of parenteral anticoagulant • Warfarin does NOT affect existing clotting factors • Consider UFH/LMWH when clinical appropriate • TSOACs are not recommended to bridge warfarin but there are ongoing studies Chest. 2012 Feb;141(2 Suppl):e44S-88S.

16. Warfarin-Induced Skin Necrosis • Ischemia-related skin necrosis • 1 in 10,000 patients • Secondary to rapid decline in Protein C when warfarin is initiated • Risk factors • High warfarin dose • Obesity • Female gender • Manifestation • Plaques, hemorrhagic blisters, or scars Ann Dermatol26(1) 96-98, 2014; J Gen Intern Med 29(1):248–9, 2013

17. Warfarin-Induced Skin Necrosis • Avoidance • Avoid warfarin loading doses • Adequate parenteral anticoagulation • Treatment • Reversal of warfarin effect with vitamin K • Administration of heparin • Re-challenge? MUST be very careful!

18. Warfarin: Dose / Response Relationships VKORC1 Haplotype CYP2C9 Genotype

19. Warfarin: Major Drug-Drug Interactions Arch Intern Med. 2005;165:1095-1106c

20. Warfarin Dose: Genetic Influence • Genetic polymorphisms account for up to 50% of individual variation in dose responsiveness Warfarin product labeling. Rev. October 2011.

21. Warfarin: Genetics vs. Dosing Algorithm • Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. N Engl J Med 2013;369:2283-93; N Engl J Med 2013; 369:2294-2303

22. Warfarin Dosing/Monitoring Considerations • Must consider long half-life • Every dose for last 5-7 days should be considered in making dosing considerations • Dose from last 2-3 days will most effect on current INR • Should allow dose changes sufficient time for INR changes to occur • Changes should not be made more than ever 3 days • Small dose changes may not become evident for 5-7 days

23. Warfarin Dosing/Monitoring Considerations • Usual maintenance dose is 2.5 – 7.5 mg/day but can range from 0.5 – 30 mg/day • Zero order kinetics – small dose changes can result in large changes in INR • Alterations of 5-20% of WEEKLY dose are recommended • Simplified dosing regimens should be implemented to promote adherence

24. Target-Specific Oral Anticoagulants (TSOACs) • Approved in the US • Dabigatran (Pradaxa) • Rivaroxaban (Xarelto) • Apixaban (Eliquis) J Thromb Thrombolysis (2013) 36:133–140

25. Pharmacology of TSOACs

26. TSOACs: Clinical Trials in AFib P&T. 2014 Jan;39(1):54-64

27. TSOACs: Clinical Trials in VTE Best Practice & Research Clinical Haematology 26 (2013) 151–161

28. Pharmacology of TSOACs Adapted from J Thromb Thrombolysis (2013) 36:133–140

29. TSOACs: Clinical Implications of Onset of Anticoagulation Effect for VTE Warfarin Bridging LMWH, UFH Warfarin Dabigatran Switching LMWH Dabigatran 150mg BID Day 1 Day 6-11 At least 3 months Rivaroxaban Apixaban Rivaroxaban 15mg BID X 3 weeks, then 20mg QD Apixiban 10mg BID X 1 week, then 5mg BID At least 3 months Single Drug Approach Day 1

30. TSOACs: Potential for Drug Interactions *Does not include every potential drug-drug interaction Adapted from J Thromb Thrombolysis (2013) 36:133–140

31. TSOACs: Different Mindset for Evaluating Drug Interactions Warfarin TSOACs Drug interactions are contraindications or precautions No ability to monitor and adjust dose based on response Less drug-food interactions versus warfarin • Interacting drugs are NOT contraindicated • Drug interactions can be managed through increased INR monitoring and dose adjustment

32. TSOACs: Formulation Issues, Food Effects

33. TSOACs: Dosing Regimens

34. TSOACs: Timing of interruption of before surgery or invasive procedures Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

35. TSOACs: Monitoring versus Measuring • Monitoring: Implies dose adjustment according to test result (e.g., warfarin/INR) • Measuring (or quantifying) the drug or drug effect may be useful in: • Over dosage • Questionable compliance • Urgent surgery, interventions, thrombolysis • Extreme body weights • Renal insufficiency

36. Measuring the Effect of TSOACs Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

37. Reversal of Oral Anticoagulants A The intervention may need to be modified based on changes in the patient’s clinical status (e.g., if status worsens, expedited or emergent treatment options should be considered). INR = International Normalized Ratio, PCC4 = four-factor prothrombin complex concentrate, PCC3 = three-factor prothrombin complex concentrate, rFVIIa= recombinant factor VIIa, aPCC = activated prothrombin complex concentrate, FFP = fresh frozen plasma. B Contraindicated in the setting of gastrointestinal bleeding. Am J Health-Syst Pharm—Vol 70 Nov 1, 2013

38. Checklist during following up on TSOACs Europace (2013) 15, 625–651

39. Summary • Warfarin is still mainstay of oral anticoagulation • New oral anticoagulants are emerging as an alternative to warfarin in select patients • Less lab testing but still need to monitor response and safety • Drug-drug interactions and renal function are important • Understanding current guidelines will be important to inpatient or outpatient management

40. Questions? George A. Davis, PharmD, BCPS University of Kentucky HealthCare georgedavis@uky.edu