1. WARFARIN THERAPY Nicolas Novitzky

2. The Ideal Oral Anticoagulant Ideally, an oral anticoagulant would:  Have high efficacy in reducing thromboembolic events  Reach therapeutic levels within several hours  Oral and/or IV administration  Ability to inhibit free and clot bound thrombin  Require no remote monitoring  Have little interaction with food or other drugs  Offer a good safety profile with regard to bleeding risk  Availability of an antidote

3. Antithrombotic Agents: Mechanism of Action  Anticoagulants: prevent clot formation and extension  Heparins, LNWH, huridin  Warfarin  Direct anti thrombin inhibitors Dabigatran  Direct factor Xa inhibitors Rivaroxaban, apixaban  Antiplatelet drugs: interfere with platelet activity  Thrombolytic agents: dissolve existing thrombi

4. Coagulation Cascade

5. Vitamin K-Dependent Clotting Factors

6. Warfarin: Indications  Prophylaxis and /or treatment of:  Venous thrombosis and its extension  Pulmonary embolism  Thromboembolic complications associated with AF and cardiac valve replacement  Prophylaxis of recurrent thrombosis in APS  Post MI, to reduce the risk of death,  recurrent MI,  stroke  Systemic embolization  Prophylaxis of genetic thrombophilia

7. 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

8. The Dilemma of Anticoagulation Management  Narrow therapeutic window of effectiveness & safety.  Frequent monitoring is required to maintain patients in the therapeutic window.  Many factors influence a patient’s stability within that window.  Monitoring is labour intensive and complex  Consequences Increased adverse events with poor management Physicians avoid warfarin use because of its complexity

9. Successful Anticoagulation Team work in monitoring anti- coagulation  Correct indication  Patient education  Compliance  Understanding coagulation results  Diet  Drug interactions  Toxicity, bleeding  Laboratory testing  Point of care testing  Doctor’s office  Patient self testin g

10. Disadvantages of Warfarin  Factors that may influence bleeding risk:  Intensity of anticoagulation  Concomitant clinical disorders  Concomitant use of other medications  Quality of management  Narrow therapeutic index  Need for frequent monitoring  Slow onset & offset of action  Large inter-individual dosing differences  Drug-Drug and drug-food interactions  Genetic polymorphisms  Warfarin skin necrosis  Warfarin embryopathy

11. Conversion from Heparin to Warfarin  Initiate AC with heparin  Heparin bolus dose 5000u 333u / kg and as per aPTT  Enoxaparin (Clexane) 1 mg/kg BD  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 therapeutic range, discontinue heparin  Individualize warfarin dose according to patient response (as indicated by INR)  Use of large loading dose not recommended*  Increases 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.

12. Daily Dose Maintenance Dose Only Loading Dose Then Maintenance Dose

13. Prothrombin Time (PT)  Historically, a most dependable “relied upon” clinical test; but:  Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity)  Many thromboplastin reagents with widely varying sensitivities to low levels of vitamin K-dependent clotting factors available Problem addressed by use of INR (International Normalized Ratio)

14. J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. #687 983. INR: International Normalized Ratio  A mathematical “correction” (of the PT ratio) for variations in the sensitivity of thromboplastin reagents (ISI)  Allows for evaluation of results between labs and standardizes reporting of the PT  Relies upon “reference” thromboplastin  known sensitivity to antithrombotic effects of warfarin INR is the PT ratio obtained if “reference” thromboplastin was used() Patient’s PT in Seconds Mean Normal PT in Seconds INR = ISI INR = International Normalized Ratio ISI = International Sensitivity Index

15. Trusting the INR Result 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Ortho 1.00 BFA DADE 1.03 BFA Behring 1.08 BFA Pacific Hem 1.20 BFA IL Test 1.43 BFA DADE 1.96 BFA Ortho 1.00 ACL DADE 1.03 ACL Behring 1.08 ACL Pacific Hem 1.20 ACL IL Test 1.43 ACL DADE 1.96 ACL Ortho 1.00 MLA DADE 1.03 MLA Behring 1.08 MLA Pacific Hem 1.20 MLA IL Test 1.43 MLA DADE 1.96 MLA Courtesy A. Jacobson Thromboplastin — Reagent combinations and o bserved o bserved variation in INR

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

17. Test Interval vs % In Range % in Range Days Between Tests Summary 18 published studies: PST Coalition Report, July 2000 More Frequent testing increases % in range Optimal Frequency of INR Monitoring*

18. IndicationINR 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)2.5–3.53.0 Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position, NSR2.0–3.02.5 Warfarin: Current Indications/Intensity

19. Optimal INR in AF Adapted from Hylek EM et. al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. NEJM 1996; 335(8):540-6 and Hylek EM and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120(11):897-902.

20. Signs of Warfarin Over-dosage  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

21. Current Daily Dose (mg) 2.5 5.0 7.510.012.5 Warfarin INRDose Adjustment* Adjusted Daily Dose (mg) 1.0-2.0Increase x 2 days5.07.510.012.515.0 2.0-3.0No change—— — — — 3.0-6.0Decrease x 2 days1.252.55.07.510.0 6.0-10.0 † Decrease x 2 days01.252.55.07.5 10.0-18.0 § Decrease x 2 days00002.5 >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). Dosage Adjustment Algorithm

22. 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 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 K 1 (1.0 to 2.5 mg orally) Patients requiring more rapid reversal before urgent surgery or dental extraction: vitamin K 1 (2–4 mg orally); if the INR remains high at 24 h, an additional dose of 1–2 mg INR >5.0 but <9.0, no clinically significant bleeding

23. Managing Patients with High INR Values & 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 K 1 Guidelines Vitamin K 1 (3–5 mg orally); closely monitor the INR; if the INR is not substantially reduced by 24 h, the vitamin K 1 dose can be repeated Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K 1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K 1 injections may be needed q12h Prothrombin complex concentrate, with vitamin K 1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR Heparin, until the effects of vitamin K 1 have been reversed, and patient is responsive to warfarin

24. 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, ifosfamide, ketoprofen, simvastatin, 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.

25. 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

26. 26 Treatment decisions involving inappropriate assessment of response Total = 647 decisions 8% 1% 10% 1% 10% 69% Initial dose too high (52 decisions) Initial dose too low (9 decisions) Different dose from home therapy (63 decisions) Continued home dose but should have been changed (6 decisions) Continued home dose but should have been held (4 decisions) Held dose when therapy should have been restarted (66 decisions) PK/PD not taken into account (447 decisions) 349 records reviewed and assessed by established criteria 647/2030 (31.8%) warfarin treatment decisions were deemed inappropriate How well does a University Hospital do in managing warfarin therapy? “Inpatient Warfarin Medication Utilization Evaluation”

27. Challenges With Conventional Laboratory Testing Challenges for patients’ compliance  Patient issues  Time for traveling to office or laboratory  Ability to travel  Need for venous access  Labor-intensive and higher costs  Scheduling visits  Proper handling and delivery of sample  Documentation at several time points  Potential for communication delays  Laboratory to contact provider with results  Provider to contact patient with dosage adjustments Jacobson AK. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy. 2nd ed. St. Louis, Mo: Facts and Comparisons; 2003;45:1-6.

28. Models of Chronic Anticoagulation Management Laboratory based Vs Patient self testing  Routine Medical Care (Usual Care) AC managed by physician or office staff w/o any systematic program for education, follow-up, communication, and dose management. May use POC device or laboratory INR  Anticoagulation Clinic (ACC) AC managed by dedicated personnel (MD, RN or pharmacist) with systematic policies in place to manage and dose patients. May use POC device or laboratory INR  Patient Self-Testing (PST) Patient uses POC monitor to measure INR at home. Dose managed by UC or ACC  Patient Self-Management (PSM) Patient uses POC monitor to measure INR at home and manages own AC dose

29. Home Monitoring  Willing to:  Learn and perform testing procedure  Keep accurate written records  Communicate results in timely fashion  Able to:  Participate in a training program to acquire  skills/competencies to perform self-testing  Generate an INR  Understand implications of test result  Maintain records  Reliable to:  Perform procedure with acceptable technique to obtain accurate results Considerations for Patient Selection

30. www. ASmartWayToTest.com

31. Technology Advances: Offers a new paradigm for monitoring since 1987  Use of capillary whole blood  Allows fingerstick sampling  Appropriate for self-testing  Consistency of INR results  Portability  Can be done anywhere  Simplicity  Patient can easily perform test 1. Leaning KE, Ansell JE. J Thromb Thrombolysis. 1996;3:377-383. 2. Ansell JE. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy. 2nd ed. St. Louis, Mo: Facts and Comparisons; 2003;44:1-6.

32. Thromboembolism with PST or PSM vs Control Heneghan et al. Lancet 2006;367:404 psm pst What is the control group

33. Major Hemorrhage with PST & PSM vs Control Heneghan et al. Lancet 2006;367:404

34. Oral Anticoagulation Patient Self-Testing: Consensus Guidelines for Practical Implementation. Managed Care 2008;17(#10, Suppl 9):1-9 Communication with patient doing home monitoring

35. Management of Warfarin During Invasive Procedures  For sub-therapeutic or normal INR: Hold warfarin for 3–5 days pre- procedure  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  Enoxaparin (Clexane) 1 mg/kg  Full Dose Heparin (FDH): full doses of heparin, IV continuous infusion, to achieve a therapeutic aPTT (~1.5–2x control); implement as for LDH  Enoxaparin (Clexane 1 mg / kg B. D.)  Restart heparin or warfarin post-op when considered safe to do so

36. Mean Warfarin Daily Dose (mg) Patient Age 80 Gurwitz, et al, 19926.45.14.2 3.6ND (n=530 patients total study) James, et al, 19926.15.34.33.93.5 (n=2,305 patients total study) 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. Warfarin Dosing in Elderly Patients

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

38. Special Considerations in the Elderly: Bleeding  Older age associated with increased sensitivity at usual doses  Comorbidity  Increased drug interactions  ? Increased bleeding risk independent of the above

39. Barriers to Warfarin Use  Reasons why physicians don’t use coumadin:  Risk of hemorrhage:2.0  Risk of embolus too low:3.4  Patient Refusal:3.6  Inconvenience of monitoring:5.2  Impairs quality of life:5.2  Belief that aspirin is superior:5.2  Cost:5.6  Doubt effectiveness:6.8 McCrory, et al. Arch Int Med, 1995

40. Management Recommendations  Heparin: For patients starting IV UFH, the initial bolus and the initial rate of the continuous infusion be weight adjusted  Bolus 80 units/kg followed by 18 units/kg per h for VTE;  Bolus 70 units/kg followed by 15 units/kg per h for cardiac or stroke patients)  Use of a fixed dose (bolus 5,000 units followed by 1,000 units/h) rather than alternative regimens (Grade 2C).  For outpatients with VTE treated with SC UFH, weight-adjusted dosing (first dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weight-adjusted dosing with monitoring (Grade 2C) suggested.  For patients receiving therapeutic LMWH who have severe renal insufficiency (calculated creatinine clearance < 30 mL/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C).  For OPD start therapy with warfarin 10 mg daily for 1-2 days followed by dosing based on INR measurements  Recommend against the routine use of pharmacogenetic testing for guiding doses of VKA (Grade 1B).  In acute VTE, start VKA therapy on day 1 or 2 of LMWH or low-dose unfractionated heparin (UFH) therapy (Grade 2C).  For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (Grade 2B).  For patients with previously stable therapeutic INRs  a single out-of-range INR of ≤ 0.5 below or above therapeutic, continuing the current dose and testing INR within 1 to 2 weeks (Grade 2C).  a single subtherapeutic INR value, not to routinely administering bridging heparin (Grade 2C).  For patients taking VKAs, we suggest against routine use of vitamin K supplementation (Grade 2C).  For patients treated with VKAs who are motivated and can demonstrate competency in self-management strategies, including the self-testing equipment, we suggest patient self-management rather than outpatient INR monitoring (Grade 2B).  For dosing decisions, we suggest using validated decision support tools (paper nomograms or computerized dosing programs) rather than no decision support (Grade 2C).  For patients taking VKAs, avoid concomitant treatment with nonsteroidal antiinflammatory drugs, and certain antibiotics (Grade 2C).  For patients taking VKAs, we suggest avoiding concomitant treatment with antiplatelet agents except patients with mechanical valves, patients with acute coronary syndrome, or patients with recent coronary stents or bypass surgery (Grade 2C).  A therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) rather than a lower (INR < 2) or higher (INR 3.0-5.0) range (Grade 1B) is recommended.  For patients with APS with previous thromboembolism, warfarin therapy titrated to a moderate-intensity INR range (INR 2.0-3.0) rather than INR 3.0-4.5 (Grade 2B) recommended.  Discontinuation of VKA, should be abrupt rather than tapering of the dose (Grade 2C).

41. Anticoagulants (oral and parenteral) top the list for adverse events. Management of warfarin therapy is often poor, even in the best of circumstances. The transition from inpatient to outpatient anticoagulation requires labor intensive systems and processes for successful implementation. Anticoagulation management models include Routine or Usual Care, Anticoagulation Clinics, and PST/PSM (home monitoring) Point-of-care provides an alternative to laboratory testing that is easy, portable, and accurate and allows for testing either by physician or patient Home monitoring requires systems in place to implement and manage results. IDTFs can perform much of the implementation and follow up tracking of results Conclusions...