1. Improving the Outcomes of Oral Anticoagulation: Home Monitoring of Warfarin Therapy Jack Ansell, M.D. Lenox Hill Hospital, NY September 22, 2009 Disclosures Consultant: Roche Diagnostics, ITC, HemoSense

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

3. O RAL ANTICOAGULATION IS ALL ABOUT MANAGEMENT Risks 1,2 Benefits 2,3 Reduction in risk of stroke or venous thromboembolism (VTE) Hemorrhage INR 1. Ansell J et al. Chest. 2004;126:204S-233S. 2. Hirsh J et al. J Am Coll Cardiol. 2003;41:1633-1652. 3. Rothberg MB et al. Ann Intern Med. 2005;143:241-250. The Desired Outcome: Benefits must be greater than Risks Hospital Transition to Outpatient Outpatient

4. 4 Transition from Hospital to Ambulatory Care Settings

5. 5 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”

6. 6 35.3% (123/349) patients were initiated on warfarin in-house for the first time New starts (n=123) 42% 7% 51% Dose too high Dose too low Dose ok Is the correct starting dose used? “Inpatient Warfarin Medication Utilization Evaluation”

7. 7 New starts for VTE indication (n=47) Initial Dose Inappropriate (n=23) Initial Dose Appropriate (n=24) Bleeding events 4 documented bleeds 3 transfusions ≥ 2 u 5 > 2 g/dL decr. Hgb 2 documented bleeds 4 transfusions ≥ 2 u 5 > 2 g/dL decr. Hgb Bleeding risk distribution 15 high risk 6 moderate 2 low 11 high risk 8 moderate 5 low Vitamin K use 4 pts1 pt What is the impact on outcomes? “Inpatient Warfarin Medication Utilization Evaluation”

8. Models of Chronic Anticoagulation Management  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

9. Challenges With Conventional Laboratory Testing 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.

10. Technology Advances: Offers a new paradigm for monitoring since 1987 Use of capillary whole blood 1,2 –Allows fingerstick sampling 2 –Appropriate for self-testing 1 Consistency of INR results 1 Portability 1 –Can be done anywhere Simplicity 1 –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.

12. What are the outcomes with Home Monitoring?

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

14. Thromboembolism with PST or PSM Heneghan et al. Lancet 2006;367:404 Usual Care AMS PSM PST

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

16. Author Year Inter- vention # Patients TTR (% or time in range) Major Hemorrhage Thrombo- embolism PST vs UC Beyth 2000 PST/ams* vs UC 163 vs 162 56 vs 32 p<0.001 5.6% vs 12% p=0.0498.6 % vs 13% p = 0.2 PST vs AMS White 1989 PST/ams* vs AMS 23 vs 24 93 vs 75 p=0.003 00 Kaatz 2001 PST/ams* vs AMS 63 vs 65 p=NS Gadisseur 2003 PST/ams* vs AMS 52 vs 60 63.9 vs 61.3 p=0.14 0 vs 1 event0 THINRS 2009 PST /ams vs AMS ~68% vs 63% p = NS PSM vs UC Horstkotte 1998 PSM vs UC 75 vs 75 92.4 vs 58.8 Sawicki 1999 PSM vs UC 83 vs 82 57 vs 33.8 p=0.006 1 event vs 1 event1 event vs 2 events Fitzmaurice 2002 PSM vs UC 23 vs 26 74 vs 77 p=NS 0 vs 1 event0 Kortke 2001 PSM vs UC 305 vs 295 78.3 vs 60.5 p=<0.001 1.7 % vs 2.6% p=NS1.2% vs 2.1% p=NS Sidhu 2001 PSM vs UC 34 vs 48 76.5 vs 63.8 p<0.0001 1 event vs 0 Sunderji 2004 PSM vs UC 69 vs 70 71.8 vs 63.2 Voller 2005 PSM vs UC 101 vs 101 67.8 vs 58.5 p=0.0061 2 events vs 00 vs 1 event PSM vs AMS Watzke 2000 PSM vs AMS 49 vs 53 84.5 vs 73.8 1 event vs 0 Gadisseur 2003 PSM vs AMS 47 vs 52 66.3 vs 63.9 p=0.14 1 event vs 1 event0 Khan 2004 PSM vs AMS 40 vs 39 71.1 vs 70.4 Menendez- Jandula 2005 PSM vs AMS 368 vs 369 58.6 vs 55.6 p=NS 4 events vs 7 events4 events vs 20 events

17. Improving AC Outcomes at the Time of Discharge Discharge Day 8 Home Monitoring UC Monitoring Home Monitoring UC Monitoring p value Sub-therapeutic49%47%29%33% Therapeutic42%45%67%41% <0.01 Supra-therap9%8%4%26% Home Monitoring (n=59) Usual Care Monitoring (n=68) Major Bleeding210 0.05 Total Bleeding1536 0.009 Embolic Event910 NS Readmit due to AC Complication38 0.32 Death78 NS Jackson et al. J Intern Med 2004:256:137 128 patients randomized to home POC monitoring (n= 60) or UC (n=68) after discharge. POC testing on d 2,4,6,8 vs UC on d 8 Adverse events up to day 90

18. Who is able to perform Home Monitoring?

19. 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

20. The THINRS Trial: Design Purpose: Compare HQACM with PST to HQACM alone on major health outcomes Patient population: Atrial fibrillation or mechanical heart valve Participating Centers 28 VA Med Ctrs with ACC of > 100 patients Two parts: Part 1: Training and home testing for 2-4 weeks Part 2: Competency assessment and, if capable, randomization to HQACM every 4 weeks or PST every week Matchar. Amer J Med 2002;113:42-51 = ACC

21. A key attribute of this trial is that “everyone” was trained for PST and those who were deemed capable, then randomized to either PST or ACC management The THINRS Trial: Design Matchar. Amer J Med 2002;113:42-51

22. Interventions: HQACM (monthly INR) Designated, trained staff person Local standard management algorithm PST (Weekly INR) Interactive value response reporting system with web-based local monitoring Outcomes: Primary time to first major event (stroke, major bleed, death) Secondary time in range, satisfaction, quality of life The THINRS Trial: Intervention & Outcomes Matchar. Amer J Med 2002;113:42-51 Anticoag Clinic Dose management Anticoag Clinic Dose management

23. 3,644 Trained 3,566 home with meter for 2-4 weeks 3,058 competency assessment 2,922 randomized 78 did not pass training 508 dropped out 136 did not pass assessment or dropout 2,922 / 3,644 = 80% Passed Competency The THINRS Trial: Participants Matchar. Amer J Med 2002;113:42-51

24. Summary from THINRS: Outcomes 80% of screened subjects demonstrated PST competency and were randomized –approx. 4 out of 5 pass Patients were less likely to pass PST, if –Older, h/o CVA, poor cognition, low literacy, poor manual dexterity Matchar. Amer J Med 2002;113:42-51

25. Summary from THINRS: Outcomes: Stroke, Bleed, Death Event Type 4,235 pt yrs HQACM Rate per pt-yr 4,495 pt yrs PST Rate per pt-yrTotal Rate per pt-yr Stroke 320.76%310.69%630.72% Major Bleed 1894.46%1733.85%3624.15% Death 1573.71%1523.38%3093.54% Total 3788.93%3567.92%7348.41% HQDM PST

28. Summary from THINRS 80% of screened subjects demonstrated PST competency and were randomized –approx. 4 out of 5 pass Patients were less likely to pass PST, if –Older, h/o CVA, poor cognition, low literacy, poor manual dexterity Outcomes (TTR & AEs) were improved to a small degree with PST

29. How Does Home Monitoring Achieve Good Outcomes ? Access to testing Frequency (convenience), timeliness Greater Time-in-Range Consistency of testing Instrument & thromboplastin Consistent Results Awareness of test results Knowledge, empowerment, compliance Greater Time-in-Range

30. Managing Home Monitoring?

31. Trusting the INR Result

32. Trusting the INR Result Thromboplastin — Reagent Combinations and o bserved variation in INR 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

33. % 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* Test Interval vs % In Range

34. 1. 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. 2. Roche Diagnostics. CoaguChek System: Why Use? Available at: http://www.coaguchek-usa.com/ information_for_professionals/why_use/content.html. Accessed May 12, 2006. 3. Wittkowsky AK et al. Pharmacotherapy. 2005;25:265-269. Barriers to PST/PSM Lack of physician awareness or acceptance 1,2 Fear it will lead to unintended self-management 3 Implementation of PST/PSM 3 Reimbursement 3

35. Barriers to INR Patient Self-Testing (PST): National Survey of Anticoagulation Practitioners 1 Cost of Device Main Barrier 1. Wittkowsky AK et al. Pharmacotherapy. 2005;25:265-269. Provider Barriers to PST Survey Respondents (%)

36. Willingness to Pay for PST is low Few patients are willing to pay for self-testing, despite the benefits of weekly testing. Those willing to pay for PST stated an average of $18 per month as the acceptable out-of-pocket expense for home testing with a POC device. Amount Willing to Pay Out-of- Pocket Per Month Percent Respondents n=71 $035% $5 - $3051% $35 - $10014% Proprietary information

37. CMS did the right thing by approving reimbursement, but they did it the wrong way As of March 19, 2008 CMS expanded coverage to patients with VTE and chronic AF

38. Medicare National Coverage Policy for Home PT/INR Testing (as of July 2008) Medicare will cover the use of home INR monitoring for chronic, oral anticoagulation management for patients with mechanical heart valves (non-porcine), chronic atrial fibrillation, or venous thromboembolism. The monitor and the home testing must be prescribed by a treating physician and all of the following must be met: Patient anticoagulated for at least 3 months Patient must undergo face-to-face educations program and demonstrate correct use of device Patient continues to correctly use device Self-testing no more frequently than once per week More information at: http://www.cms.hhs.gov/MLNMattersArticles/downloads/MM6313.pdf

39. Oral Anticoagulation Patient Self-Testing: Consensus Guidelines for Practical Implementation. Managed Care 2008;17(#10, Suppl 9):1-9

40. What is an IDTF ? CMS defined a new entity independent of a hospital or physician’s office in which diagnostic tests are performed by licensed or certified non-physician personnel under appropriate physician supervision. This entity is called an Independent Diagnostic Testing Facility (IDTF). The IDTF may be a fixed location, a mobile entity, or an individual non-physician practitioner and in all cases must comply with the applicable laws of any state in which it operates.

41. IDTF’s… How They Work Doctor Patient CMS Device Manufacturer IDTF Manages INR Inst order Inst sent Rx Inst teach Tech fee $140/mon Serv + Inst Prof fee $9/mon Train fee $191

42. 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

43. PST dosed by internet expert system vs AMS CriteriaAMSSupervised PSTP - value # INRs /pt (mean)10.7 (+ 5.2)41.7 (+ 6.6)<0.001 Freq of testing (mean)19.6 days4.6 days<0.001 Time in range58.6%74%<0.001 Extreme INRs6 %1.7 %<0.001 INRs < 1.545.9 %33.3 %<0.001 INRs > 5.0 (%)54.1 %66.7 %0.006 RCT (cross-over) of 162 patients, followed for 6 months; mean age 59 yr (16-91), 80% male with diverse indications. Daily time to manage 80 patients 10-45 min (mean 23.2 min) Ryan et al. J Thromb Haemost 2009;7:1284

44. 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 is a critical transition that requires labor intensive systems and processes for successful implementation. POC INR technology can play an important role in facilitating such care. Anticoagulation management models include Routine or Usual Care, Anticoagulation Clinics, and PST/PSM (home monitoring) Point-of-care (POC) provides an alternative to laboratory testing that is easy, portable, and accurate and allows for testing either by physician or patient POC home monitoring can be done either with physician management or patient self-management 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...