Management of Oral Anticoagulant Therapy

2. Management of Oral Anticoagulant Therapy Principles & Practice

3. Prepared for thePostgraduate Education Committee,Council on Clinical CardiologyAmerican Heart Associationby Jack Ansell, M.D. Jack Hirsh, M.D. Nanette K. Wenger, M.D. Supported by an Educational Grant from DuPont Pharmaceuticals The content of these slides is current as of October, 1999. Future revisions will be posted on the American Heart Association website (www.americanheart.org)

4. Endorsed by The Anticoagulation Forum The American Heart Association Council on Atherosclerosis, Thrombosis, and Vascular Biology

5. Clotting Cascade

6. Vitamin K-Dependent Clotting Factors Vitamin K VII Synthesis of Functional Coagulation Factors IX X II

7. Vitamin K Mechanism of Action

8. Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII Synthesis of Non Functional Coagulation Factors IX X II Warfarin

9. Warfarin Mechanism of Action

10. Virchow’s Triad

11. Antithrombotic Agents: Mechanism of Action • Anticoagulants: prevent clot formation and extension • Antiplatelet drugs: interfere with platelet activity • Thrombolytic agents: dissolve existing thrombi

12. Warfarin: Indications • Prophylaxis and/or treatment of: • Venous thrombosis and its extension • Pulmonary embolism • Thromboembolic complications associated with AF and cardiac valve replacement • Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization • Prevention and treatment of cardiac embolism

13. Warfarin: Major Adverse Effect—Hemorrhage • Factors that may influence bleeding risk: • Intensity of anticoagulation • Concomitant clinical disorders • Concomitant use of other medications • Quality of management

14. Special Considerations in the Elderly—Bleeding • Increased age associated with increased sensitivity at usual doses • Comorbidity • Increased drug interactions • ? Increased bleeding risk independent of the above

15. Mean Warfarin Daily Dose (mg) Patient Age <50 50–59 60–69 70–79 >80 Gurwitz, et al, 1992 6.4 5.1 4.2 3.6 ND (n=530 patients total study) James, et al, 1992 6.1 5.3 4.3 3.9 3.5 (n=2,305 patients total study) Warfarin Dosing in Elderly Patients Increasing age has been associated with an increased response to the effects of warfarin Gurwitz JH, et al. Ann Int Med 1992; 116(11): 901-904. James AH, et al. J Clin Path 1992; 45: 704-706.

16. Prothrombin Time (PT) • Historically, a most reliable and “relied upon” clinical test However: • Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred • Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity) • Problem addressed by use of INR (International Normalized Ratio)

17. INR: International Normalized Ratio • A mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastin reagents • Relies upon “reference” thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants • INR is the PT ratio one would have obtained if the “reference” thromboplastin had been used • Allows for comparison of results between labs and standardizes reporting of the prothrombin time J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983.

18. INR Equation ( ) ISI Patient’s PT in Seconds Mean Normal PT in Seconds INR = INR = International Normalized Ratio ISI = International Sensitivity Index

19. How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient Patient’s PT (Seconds) Mean Normal (Seconds) ThromboplastinReagent PTR ISI INR 16 A 12 1.3 18 B 12 1.5 21 C 13 1.6 24 D 11 2.2 E 38 14.5 2.6

20. How Different Thromboplastins Influence the PT Ratio and INR Blood from a single patient Patient’s PT (Seconds) Mean Normal (Seconds) Thromboplastinreagent PTR ISI INR 16 A 12 1.3 3.2 2.6 18 B 12 1.5 2.4 2.6 21 C 13 1.6 2.0 2.6 24 D 11 2.2 1.2 2.6 E 38 14.5 2.6 1.0 2.6

21. Relationship Between PT Ratio and INR Adapted from: Poller L. Thromb Haemost vol 60, 1988.

22. Limitations Unreliable during induction Loss of accuracy with high ISI thromboplastins Incorrect ISI assignment by manufacturer Incorrect calculation of INR due to failure to use proper mean normal plasma value to derive PT ratio Solutions Use thromboplastin reagents with low ISI values (less than 1.5) Use thromboplastin reagents with low ISI values Use thromboplastin reagents with low ISI values and use plasma calibrants with certified INR values Use “mean normal” PT derived from normal plasma samples for every new batch of thromboplastin reagent Potential Problems with the INR

23. Warfarin: Dosing Information • Individualize dose according to patient response(as indicated by INR) • Use of large loading dose not recommended* • May increase hemorrhagic complications • Does not offer more rapid protection • Low initiation doses are recommended for elderly/frail/liver-diseased/malnourished patients *Harrison L, et al. Ann Intern Med 1997;126:133-136.

24. Loading Dose then Maintenance Dose Daily Dose

25. Maintenance Dose Only Daily Dose

26. Loading Dose thenMaintenance Dose Maintenance Dose Only Daily Dose Daily Dose

27. Conversion from Heparin to Warfarin • May begin concomitantly with heparin therapy • Heparin should be continued for a minimum of four days • Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR) • When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)

28. Warfarin: Dosing & Monitoring • Start low • Initiate 5 mg daily* • Educate patient • Stabilize • Titrate to appropriate INR • Monitor INR frequently (daily then weekly) • Adjust as necessary • Monitor INR regularly (every 1–4 weeks) and adjust * Elderly, frail, liver disease, malnourished: 2 mg/day

29. Relative Contraindications to Warfarin Therapy • Pregnancy • Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy • Uncontrolled alcohol/drug abuse • Unsupervised dementia/psychosis

30. Signs of Warfarin Overdosage • Any unusual bleeding: • Blood in stools or urine • Excessive menstrual bleeding • Bruising • Excessive nose bleeds/bleeding gums • Persistent oozing from superficial injuries • Bleeding from tumor, ulcer, or other lesion

31. Managing Patients with High INR Values/Minor or No Bleeding Clinical Situation INR >therapeutic range but <5.0, no clinically significant bleeding, rapid reversal not indicated for reasons of surgical intervention Guidelines Lower the dose or omit the next dose; resume warfarin therapy at a lower dose when the INR approaches desired range If the INR is only minimally above therapeutic range, dose reduction may not be necessary INR >5.0 but <9.0, no clinically significant bleeding Patients with no additional risk factors for bleeding; omit the next dose or two of warfarin, monitor INR more frequently, and resume warfarin therapy at a lower dose when the INR is in therapeutic range Patients at increased risk of bleeding: omit the next dose of warfarin, and give vitamin K1 (1.0 to 2.5 mg orally) Patients requiring more rapid reversal before urgent surgery or dental extraction: vitamin K1 (2–4 mg orally); if the INR remains high at 24 h, an additional dose of 1–2 mg

32. Managing Patients with High INR Values/Serious Bleeding Clinical Situation INR >9.0, no clinically significant bleeding Life-threatening bleeding or serious warfarin overdose Continuing warfarin therapy indicated after high doses of vitamin K1 Guidelines Vitamin K1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 24–24 h, the vitamin K1 dose can be repeated Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K1 injections may be needed q12h Prothrombin complex concentrate, with vitamin K1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR Heparin, until the effects of vitamin K1 have been reversed, and patient is responsive to warfarin

33. Relationship Between INR and Efficacy/Safety • Low-intensity treatment: • Efficacy rapidly diminishes below INR 2.0* • No efficacy below INR 1.5 • High-intensity treatment: • Safety compromised above INR 4 * Effective below 2.5

34. Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding. Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:897-902

35. Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996;335:540-546.

36. Indication INR Range Target Prophylaxis of venous thrombosis (high-risk surgery) 2.0–3.0 2.5 Treatment of venous thrombosis Treatment of PE Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) Valvular heart disease Atrial fibrillation Mechanical prosthetic valves (high risk) 2.5–3.5 3.0 Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position, NSR 2.0–3.0 2.5 Warfarin: Current Indications/Intensity

37. Mechanical Prosthetic Heart Valves Patient Characteristics Recommendation Bileaflet mechanical valve in the aortic position, Goal INR 2.5; range, 2.0–3.0left atrium of normal size, NSR, normal ejection fraction Tilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, 2.5–3.5*the mitral position Bileaflet mechanical aortic valve and AF Goal INR 3.0; range, 2.5–3.5* Caged ball or caged disk valves Goal INR 3.0; range, 2.5–3.5; and aspirin therapy (80–100 mg/d) Additional risk factors Goal INR 3.0; range, 2.5–3.5; and aspirin therapy (81 mg/d) Systemic embolism, despite adequate therapy Goal INR 3.0; range, 2.5–3.5;with oral anticoagulants and aspirin therapy (81 mg/d) * Alternative: goal INR 2.5; range, 2.0–3.0; and aspirin therapy (80–100 mg/d)

38. Examples of Low & High Risk InvasiveProcedures & Clinical Conditions Risk of Bleeding Low High Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy AF; valvular heart disease ±aortic prosthesis; old DVT/PE Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy Prosthetic valves, esp. in mitral position;AF + history of CVA; very recent DVT/PE Dental; cutaneous biopsies;open procedures; cataracts AF; valvular heart disease ±aortic prosthesis; old DVT/PE Dental; cutaneous biopsies;open procedures; cataracts Prosthetic valves, esp. in mitral position; AF + history of CVA; very recent DVT/PE Low Risk of Thrombosis High

39. Management of Warfarin for Invasive Procedures Risk of Bleeding Low High Do procedure at:subtherapeutic INR range or lower Do procedure at:normal INR range; use no alternative or use LDH, AdjDH or FDH Low Risk of Thrombosis Do procedure at:therapeutic or subtherapeutic INR range Do procedure at:normal INR range; use FDH High LDH = Low dose heparin AdjDH = Adjusted dose heparin FDH = Full dose heparin

40. Management of Warfarin During Invasive Procedures • For subtherapeutic or normal INR: Hold warfarin for 3–5 days pre-procedure • Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID); hold warfarin 3–5 days pre-procedure and begin LDH therapy 1–2 days pre-procedure • Adjusted Dose Heparin (AdjDH): Same as LDH but higher doses of heparin (between 8,000–10,000 IU BID or TID) to achieve an aPTT in upper range of normal or slightly higher midway between doses • Full Dose Heparin (FDH): full doses of heparin, IV continuous infusion, to achieve a therapeutic aPTT (~1.5–2x control); implement as for LDH • Restart heparin or warfarin post-op when considered safe to do so

41. 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Warfarin Dosing Schedule Total Weekly Dose Mon Tue Wed Thu Fri Sat Sun 35 mg 30 mg 2.5 2.5 27.5 mg 2.5 2.5 2.5

42. Dosage Adjustment Algorithm Current Daily Dose (mg) 2.0 5.0 7.5 10.0 12.5 Warfarin INR Dose Adjustment* Adjusted Daily Dose (mg) 1.0-2.0 Increase x 2 days 5.0 7.5 10.0 12.5 15.0 2.0-3.0 No change — — — — — 3.0-6.0 Decrease x 2 days 1.25 2.5 5.0 7.5 10.0 6.0-10.0† Decrease x 2 days 0 1.25 2.5 5.0 7.5 10.0-18.0§ Decrease x 2 days 0 0 0 0 2.5 >18.0§ Discontinue warfarin and consider hospitalization/reversal of anticoagulation † Consider oral vitamin K, 2.5–5 mg § Oral vitamin K, 2.5–5 mg * Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).

43. Drug Interactions with Warfarin: Potentiation Level of Evidence Potentiation Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition) Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccine Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole I II III IV †In a small number of volunteer subjects, an inhibitory drug interaction occurred.

44. Drug Interactions with Warfarin: Inhibition Level of Evidence Inhibition Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate Dicloxacillin Azathioprine, cyclosporine, etretinate, trazodone I II III IV

45. Drug Interactions with Warfarin: No Effect Level of Evidence No Effect Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡ Ibuprofen, ketoconazole Diltiazem, tobacco, vancomycin I II III IV

46. Effective Patient Education • Teach basic concepts of safe, effective anticoagulation • Discuss importance of regular INR monitoring • Counsel on use of other medications, alcohol • Develop creative strategies for improving compliance

47. Factors Influencing Variability Patient/Disease State Process of Care Warfarin: drug with a narrow therapeutic index

48. The content of these slides is current as of October, 1999. Future revisions will be posted on the American Heart Association website (www.americanheart.org)