1. ANTICOAGULATION ISSUES In Geriatric Population Ann McBride, M.D. UW Anticoagulation Service

2. No financial disclosuresNo financial disclosures

3. Underuse of Anticoagulation for Atrial FibrillationUnderuse of Anticoagulation for Atrial Fibrillation –Balance of Stroke vs. Bleeding Risks –Alternatives Warfarin Initiation and MaintenanceWarfarin Initiation and Maintenance Bridging TherapyBridging Therapy

4. Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines CHEST Supplement, September 2004CHEST Supplement, September 2004

5. Overall CVA Risk for AF 4.5% per yearOverall CVA Risk for AF 4.5% per year Risk increases with AgeRisk increases with Age –1.5% per year 50-59 yo –10% per year 80-89 yo –20% per year 90 yo

6. C H A D S2 Gage et al, Circulation 2004

7. Congestive Heart Failure Hypertension -Treated; untreated >140/90 mmHg Age -Older than 75 Diabetes Stroke - 2

8. CHADS2 CVA risk/yr on ASA Low = 0 0.8 Med = 1-2 2.7 High = 3 or more 5.3

9. Adjusted dose warfarin—Target INR 2.5— reduces CVA risk 60%Adjusted dose warfarin—Target INR 2.5— reduces CVA risk 60% ASA reduces CVA risk 20%ASA reduces CVA risk 20%

10. Warfarin Also Decreases Severity INR 2.0-3.0INR 2.0-3.0 Associated with reduced severity of strokeAssociated with reduced severity of stroke Greater likelihood of survivalGreater likelihood of survival

11. INR Intensity & CVA Severity 596 strokes/13,559 pts w/ NVAF596 strokes/13,559 pts w/ NVAF –32% warfarin –27% ASA –42% neither Hylek, et al, N Engl J Med 2003

12. 1.Risk for CVA sharply increased INR < 2 2.CVA severity & fatality with INR 1.5 – 1.9 ~ INR < 1.5 3.With INR 2-3, CVA more likely to be “minor”

13. Bleeding Risk Warfarin increases risk of major hemorrhageWarfarin increases risk of major hemorrhage 1.7 x risk associated with ASA 1.7 x risk associated with ASA

14. Bleeding Risk 65 yo and older65 yo and older Hx of noncardioembolic CVAHx of noncardioembolic CVA Hx of GI BleedHx of GI Bleed > 1 Comorbid Conditions> 1 Comorbid Conditions –Recent MI –Hct less than 30 –Creatinine > 1.5 –Diabetes Beyth et al. Am J Med 1998

15. SCORE MAJOR BLEED Low = 0 Less than 3% Moderate = 1-2 12% High = 3 48% (First 12 mos) 250 Patients with AF or VTE

16. Overall incidence of major bleed 6.5%Overall incidence of major bleed 6.5% Greatest risk for bleed first 30 daysGreatest risk for bleed first 30 days Most were avoidable maintaining therapeutic INR range and avoiding NSAIDsMost were avoidable maintaining therapeutic INR range and avoiding NSAIDs

17. Other Risk Factors Excess Warfarin Anticoagulation APAP intake 9100 mg/wk or moreAPAP intake 9100 mg/wk or more New medication known to increase warfarin effectNew medication known to increase warfarin effect (Note: antibiotic, PPI, amiodarone, SSRI) (Note: antibiotic, PPI, amiodarone, SSRI) Bleed vs. CVA riskBleed vs. CVA risk Recent diarrheal illnessRecent diarrheal illness Decreased oral intakeDecreased oral intake Incorrectly taking higher dose of warfarin than prescribedIncorrectly taking higher dose of warfarin than prescribed Hylek et al. JAMA 1998

18. STROKE RISK vs. Bleeding Risk -CHF Hx GI Bleed -Hypertension -75 yo & Older 65 yo & Older -DM -Stroke Hx CVA Comorbid > 1 Recent MI Recent MI Hct 30 or less Hct 30 or less Cr > 1.5 Cr > 1.5 DM DM

19. 145 pts w/ ICH on warfarin145 pts w/ ICH on warfarin 870 pts on warfarin w/o ICH870 pts on warfarin w/o ICH Increasing Age (especially > 85)Increasing Age (especially > 85) Increasing INR (especially > 3.5)Increasing INR (especially > 3.5) Fang et al. Annals of Internal Medicine 2004

20. Risk of ICH was NOT lower in elderly pts w/ AF when INR < 2.0 compared to INR 2.0-3.0Risk of ICH was NOT lower in elderly pts w/ AF when INR < 2.0 compared to INR 2.0-3.0 EVEN FOR PTS OLDER THAN 75EVEN FOR PTS OLDER THAN 75

21. ACCP Recommendations No Risk Factors ASA 325 mg/day 0-1 risk factor Warfarin (INR=2.5) or ASA 325 mg/day More than 1 risk factor Warfarin (INR = 2.5) Atrial Flutter & Paroxysmal AF recommendations same as for sustained NVAF

22. Bottom Line Stroke RiskStroke Risk Bleeding RiskBleeding Risk Patient Functional & Cognitive StatusPatient Functional & Cognitive Status incl. falls risk incl. falls risk Patient Compliance Patient PreferencePatient Preference

23. Suggest: 1.INR 2.5 (2.0 - 3.0) 2.Attention to risk factors for bleeding If bleed occurs, target INR 2.2 (1.8 - 2.5) 3.More frequent monitoring 4.Attention to Rx med or OTC med change Role of Anticoagulation ClinicRole of Anticoagulation Clinic

24. Patient Sample #1

25. Initiating Warfarin ElderlyFrailMalnourishedCHF Liver Disease Concurrent Medications (cytochrome P450 isoenzymes mutation)

26. Lower Dose In Elderly “…starting dose of less than 5 mg might be appropriate in the elderly…”“…starting dose of less than 5 mg might be appropriate in the elderly…” Nomograms available, but few geriatric patients representedNomograms available, but few geriatric patients represented

27. Daily Warfarin Dose (in AF) AgeMaleFemale 50-59 5.4 mg 5.0 mg 60-69 4.6 mg 4.0 mg 70-79 4.3 mg 3.5 mg 80-89 3.9 mg 3.0 mg > 90 3.6 mg 3.0 mg Garcia et al, CHEST June 2005

28. In each age group, median daily dose for afib pts less than for VTE ptsIn each age group, median daily dose for afib pts less than for VTE pts Older women require lowest dosesOlder women require lowest doses

29. When warfarin initiated, 5 mg/day will lead to overanticoagulation for manyWhen warfarin initiated, 5 mg/day will lead to overanticoagulation for many geriatric patients geriatric patients Lower initiation and maintenance doses for elderly patientsLower initiation and maintenance doses for elderly patients

30. Warfarin Initiation (hospitalized*) 4 mg daily x 3 days @ dinnertime4 mg daily x 3 days @ dinnertime INR – Morning 4 th DayINR – Morning 4 th Day INR1.0 to < 1.35 mgINR1.0 to < 1.35 mg 1.3 to < 1.54 mg 1.5 to < 1.73 mg 1.7 to < 1.92 mg 1.9 to < 2.51 mg > 2.5 daily INRhold until INR 2.5 daily INRhold until INR < 2.5 resume @ 1 mg/day Otherwise, INR repeated every 2-3 daysOtherwise, INR repeated every 2-3 days Siguret et al. Am J Med 2005;118:137-142

31. Other Options ??? For NVAF pts – ACTIV StudyFor NVAF pts – ACTIV Study –Warfarin vs. ASA/Clopidigrel XimelagatranXimelagatran

32. Ximelegatran Oral Direct Thrombin InhibitorOral Direct Thrombin Inhibitor Fixed DoseFixed Dose Fast onset and offset activityFast onset and offset activity Very few food/drug interactionsVery few food/drug interactions No laboratory monitoringNo laboratory monitoring

33. Ximelegatran, cont. Adverse EffectsAdverse Effects 1.Liver enzyme elevation 2.Risk for CAD

34. AstraZeneca EXANTA® (ximelagatran) Tablets NDA 21-686 FDA Advisory Committee Briefing Document 10 September 2004 pg. 109

35. Bridging Therapy Anticoagulation Perioperative Interruption of Warfarin VTE Risk vs. Hemorrhage Risk

36. Chest 2001, September Supplement

37. Cleveland Clinic Journal of Medicine, 2005;72(Suppl 1)

38. Chest 2004;126(3):September 2004 Supplement, pg. 215S