1. Medication Management and Improving Continuity of Care to Reduce Readmissions (and Strokes, Heart Attacks, Major Hemorrhage, Thrombosis, and Death) Texas Partnership for Patients Conference Austin, Texas April 30, 2013 Henry I. Bussey, Pharm.D. President, Genesis Clinical Research (providers of ClotFree Texas); President and Sr. Editor, ClotCare at www.clotcare.org. Co-Developer, ClotFree Disclosures: Dr. Bussey received the 2008 - 2011Chest Foundation’s GSK Distinguished Scholar in Thrombosis Award for a proposal to develop and test a better method for oral anticoagulation management. 1

2. The Plan for Today’s Discussion Review the “connection” between INR control and adverse outcomes. Review traditional methods of anticoagulation management methods and the limitations Analyze what went wrong with two “real world” cases Consider how we can address to current problems and limitations of anticoagulation monitoring and management Discuss the components and projected impact of a new method of anticoagulation monitoring and management

3. Odds Ratio of TE or ICH vs INR in A. Fib < 1.31.4 – 1.72.0 – 2.52.6 – 3.03.1 – 3.53.6 – 4.5> 4.51.8– 1.9 X 7.52 3.72 1.0 X 12.3 3.56 Singer DE, et al. Circ Cardiovasc Qual Outcomes 2009; 2:297-304 1. Witt DM, et al. Chest 2005; 127:1515-1522. 2. Claes N, et al. Eur Heart J 2005; 26:2159-65. From the ATRIA study: n = 9,217 patients, 33,497 patient years 397 TE = 364 Isch strokes, 33 syst. emboli 164 ICH = 83 intracerebral, 55 subdural, 26 “other” TTR 55% to 64% TEV 15% 1 to >20% 2 INRs at extremes ? ? ? ? ? 36% to 45% TTRexp

4. Traditional Methods of Anticoagulation Management Methods and the Limitations “Usual Medical Care” (UMC) – patients followed in a general medical practice without a systematic approach in place. Patient’s lost to follow-up, poor INR control, high rate of major complications. Anticoagulation Clinic (AC) – systematic and close follow up with patient education. Better INR control and reduced major events; but costly, cumbersome, and still sub-optimal care. Self-testing (PST/PSM) – Potential for “lost to follow up”, delayed and incomplete information exchange, potential for miscommunication, financial disincentives, patients “left alone”. Self-test with Online Remote Monitoring and Management – STORM 2 – More later

5. First of Two “Real World” Cases Elderly female, acute anterior MI with initial treatment based on “standared of care”. Warfarin 5 mg daily prescribed by cardiologist on day 4. INR = 2.2 on day 3 of warfarin, and 2.8 at d/c home on day 7 of warfarin. Orders (per cardiologist): repeat INR in 1 week per cardiologist Your thoughts? Any concerns with plan? continued

6. First of Two “Real World” Cases Elderly female, acute anterior MI, warfarin 5 mg daily prescribed by cardiologist. INR = 2.2 on day 3 of warfarin, and 2.8 on day 7 of warfarin. Presents to internist’s office for INR at 1 wk post d/c. Noted order from cardiologist but drew blood and sent to lab INR of 3.2 faxed to PCP office which then faxed to cardiologist Your thoughts, concerns at this point? continued

7. First of Two “Real World” Cases Elderly female, acute anterior MI, warfarin 5 mg daily prescribed by cardiologist. INR = 2.2 on day 3 of warfarin, and 2.8 at d/c on day 7 of warfarin. INR of 3.2 at 1 week post d/c faxed to PCP office which then faxed to cardiologist 2 days later, daughter called internist office asking for report and dosing instructions. Told “if you have not heard, everything is OK; continue same regimen.” Your thoughts and concerns? continued

8. First of Two “Real World” Cases Elderly female, acute anterior MI, d/c on warfarin 5 mg INR = 2.2 and 2.8 after 3 and 7 days of warfarin. INR = 3.2 one wk later, faxed to internist then to cardiologist Daughter 2 days later told “if you have not heard, everything is OK, continue same regimen” 3 more days: patient retired early in the evening “not feeling well”, found dead in bed in AM due to intracranial bleed. Imagine you are her daughter; what would you do? continued

9. First of Two “Real World” Cases Elderly female, acute anterior MI, d/c on warfarin 5 mg INR = 2.2 and 2.8 after 3 and 7 days of warfarin. INR = 3.2 one wk later, faxed to internist then to cardiologist Daughter 2 days later told “if you have not heard, everything is OK, continue same regimen” 3 more days: patient retired early in the evening “not feeling well”, found dead in bed in AM due to intracranial bleed. Imagine you are her daughter; what would you do? continued

10. First of Two “Real World” Cases Elderly female, acute anterior MI, d/c on warfarin 5 mg Miscommunication of INR information at one week post d/c Patient had fatal bleed 12 days after d/c Daughter filed lawsuit – Internist: Not my fault, cardiologist prescribed warfarin and ordered INR – Cardiologist: Local practice is for internist to manage warfarin and I never got the INR of 3.2. – “Resolution”: Both MDs found guilty of negligence, fined, but no remedial action required.

11. Second of Two “Real World” Cases 64 year old gentleman, retired contractor, hardworking, independent family man with 2 sons and a daughter. History of renal stones, COPD, and is on warfarin for post DVT/PE. Warfarin managed by PCP. Hospitalized briefly for pneumonia/worsening of COPD and treated with “antibiotics” which led to diarrhea. After several days of diarrhea, patient called PCP who prescribed metronidazole (Flagyl) Your thoughts, concerns? continued

12. Second of Two “Real World” Cases 64 year old gentleman, retired contractor, history of renal stones, COPD, and is on warfarin for post DVT/PE. Warfarin managed by PCP. Antibiotic-induced diarrhea treated with metronidazole starting 3 days ago, now presents to urologist with blood in urine. Urologist orders urine analysis and culture, starts “Trim/Sulfa” presumptively Your thoughts, concerns? continued

13. Second of Two “Real World” Cases 64 year old gentleman, retired contractor, history of renal stones, COPD, and is on warfarin for post DVT/PE. Warfarin managed by PCP. On metronidazole for antibiotic-induced diarrhea and “Trim/Sulfa” for presumed UTI Diarrhea persisted, lightheaded, fell 2 days in a row, called sons who found him on floor to weak to stand, soiled with bloody diarrhea Your thoughts, concerns? If you were his son, what would you do? continued

14. Second of Two “Real World” Cases 64 year old gentleman On warfarin, metronidazole, and “Trim/Sulfa” Blood in urine, bloody diarrhea, two falls and to weak to stand Off to ED, labs ordered, developed severe headache, sent for head CT, died in the hospital Your thoughts, concerns? If you were his son, what would you do?

15. Lessons from Two “Real World” Cases Know who is in charge – “too many cooks spoil the soup” (and harm the patient) Have a system to assure on-time follow-up Involve and educate patient and/or care giver Ready access of patient and/or care giver to anticoagulaton clinician Clear, complete, communication (written?) with documentation and confirmation of understanding Centralize oversight and management of all that is happening with the patient Knowledgeable clinician (with or without an expert system), readily available and reliable laboratory Close but efficient monitoring with rapid intervention when needed

16. Clinic STORM 2

17. Our Approach – Self Testing with Online Remote Monitoring and Management (STORM 2 ) CDTM agreement to clearly spell out role of service Face-to-face patient education pluse online (see “New Patient” link on ClotCare.org homepage) Signed “Patient Adherence Agreement” Online system for communication, management, documentation, clinical support continued

18. Our Approach – Self Testing with Online Remote Monitoring and Management (STORM 2 ) Online system for communication, management, documentation, clinical support – Assures on-time follow-up, but communication anytime – Solicits all important information from patient with 20 checkbox questions and free text comments – Patient enters INR and submits – System identifies patients who may need evaluation – Ability to dialogue with patient – Color-coded drug interaction and clinical trends – Instructions provided in writing – Patient must confirm receipt and understanding – All information captured and stored in progress note

19. Self Testing with Online Automated Remote Monitoring and Management (STOARM 2 ) – 1 model (ClotFree) Patient: Answers questions Enters INR System: Compares INR with target range and previous values and evaluates responses to questions Sorts patients, and presents groupings to clinician Clinician Views: Overdue for testing Tested today, stable and no changes Tested today, evaluation needed Clinician Action: Contact overdue pts Automated response to “stable, no change” Evaluate and instruct pts needing evaluation PatientSecure ServerClinician System: Instructions for dosing and re-testing posted back to patient Dialogue possible (start) Patient: Reviews/prints dosage and re-test calendar Confirms understanding Dialogue if needed

20. What might be the clinical impact of better anticoagulation management? – Clinical pharmacist-run anticoagulation clinics reduce major events, hospitalizations, and ED visits by as much as 60% to 80% vs “usual care” or “other” clinic 1-3 – Self-testing or self-management reduces major events and deaths more than clinic management. – Self-testing and online remote monitoring and management (STORM 2 ) provides even better INR control (with improved efficiency) (continued) 1.Chiquette, et al. Arch Intern Med. 1998; 158:1641-1647 2.Rudd, et al. Pharmacotherapy. 2010; 30:330-338 3.Hall, et al. Pharmacotherapy. 2011; 31:686-694 14

21. What might be the clinical impact of better anticoagulation management? (continued) – Self-testing or self-management (SM) reduces major events and deaths more than clinic management. 1.Bloomfield HE, Ann Intern Med. 2011; 154:472-482. 2.Menendez-Jandula, et al. Ann Intern Med. 2005; 142:1-10. EventControl GpPST/SM GpDiff Meta-analysis of 22 randomized trials, n = 8,413 patients 1 Maj. TE4.0%2.5%42% dec. p < 0.001 Maj. Bleed7.9%7.0%12% dec. (NS) Death12%9.2%26% dec. p, 0.001 Randomized trial SM vs hematology clinic management n = 737 patients Maj TE5.4% (n=20)1.1% (n=4)80% dec., p < 0.05 Maj. Bleed1.9% (n=7)1.1% (n=4)26% dec. (NS) Maj Combined7.2% (n=27)2.2% (n=8)70% dec. p<0.05 Death4.1% (n=15)1.6% (n=6)61% dec. (NS) 15

22. Outcome Quartile 1, n=14 Quartile 2, n=14 Quartile 3, n=14 Quartile 4, n=13 †,‡ Combined, n=55 %TTR 6 mo pre- Intervention (iTTR range) 22.9 (0-34) 48.0 (35-59) 68.5 (60-74) 87.2 (75-100*) 56.0 (0-100) Patient Sources: * Group A Group B Group C Group D Group E 2441324413 3142431424 3500635006 6231162311 14 12 11 4 14 %TTR mo 4-1276.382.382.085.381.1 Percentage point change+ 53.4+ 34.3+ 13.5(-1.9)+ 25.1 Patients by % iTTRexp mo 4 – 12, n (%) < 65% 65-75% 75-80% 80-90% 90-100% Combined 0 4 10 14 0 1 3 10 14 0 2 1 11 14 0 1 12 13 0 3 9 43* 55

23. RE LY Event Rates (%/yr) vs iTTR # Event (%/yr) 25% with iTTR < 53.6% 50% with iTTR > 67.2% Warf TTR=64% N = 6022 Dabig 110 n = 6015 Dabig 150 n = 6076 Stroke + SEE2.341.341.711.54 (NI)1.11** Maj Bleed4.952.823.522.87**3.32 M.I. ## na 0.530.720.74 # Totalna5.584.96 Death7.482.464.133.753.64 Comp.12.325.487.647.096.91 NNT- - -14.62319.118.5 Connolly SJ, et al. N Engl J Med 2009; 361:1139-1151. Gage BF. N Engl J Med 2009; 361:1200-1202. Wallentin L, et al. Lancet 2010; 376:975-83. and http://www.fda.gov/downloads # iTTR = Individual’s INR time in the therapeutic range. *”Stroke” includes hemorrhagic stroke, **stat. sig. vs total warfarin group. Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. NNT = number needed to treat for 1 year to prevent a composite event vs warf. 4 th quartile. ## MI diff. initially stat. sig but not with later updated values (p < 0.07); lack 2 MIs/12,000 pats. if dabi. gps combined. 13

24. Events Prevented and $ Saved per 1,000 patient-years Event Better TTR 1,2 Savings +Self Testing 3 Savings Stroke11$1,762,83816$2,564,688 Maj Bleed23 $367,72426$415,688 M.I.8$1,298,82411$1,784,508 Sub Total42$3,428,38653$4,764,324 Deaths48$2,400,00060$3,000,000 Total$5,828,386$7,764,324 Event rates calculated from the RE LY 1 (dabigatran v warfarin in A Fib) and SPORTIF 2 (ximelagatran v warfarin in A Fib) with est. TTR of 78.4%. Death ($50,000) and Major Bleed ($15,988) counted as a one-time event; Stroke ($160,258) and MI ($162,228) calculated as life time cost. 1.Wallentin L, et al. Lancet 2010; 376:975-83 2.White HD, et al. Arch Intern Med 2007;167(3):239-45. 3.Bloomfield HE, et al., Ann Intern Med 2011;154(7):472-82.

25. Clinic New Agents

26. Events Prevented and $ Saved per 1,000 patient-years vs New Agents Events and CostsSTORM 2 Savings Stroke 9.2$1,474,374 Maj Bleed14.0$223,832 MI 5.7$924,700 Sub Total28.9$2,622,906 Deaths30.2$1,510,000 Total$4,132,906 Difference in Drug Cost*$2,850,000 Monitoring Cost*(-$1,640,000) Net Savings$5,310,000 Drug costs: $240/mo vs $2.52/mo and monitoring cost based on CMS total reimbursement for patient self-testing

28. Disadvantages of New Agents Higher GI bleeding rate (P-gp efflux, poor absorption) Short half-life = rapid offset = clotting risk (noted with Riva.) No reversal agent for bleeding, emergent procedures No laboratory monitoring required – No way to monitor adherence – Can not “titrate” dose for individuals with renal dz, liver dz, extremes of size, – No way to monitor for drug interactions (known and unknown) {FDA discounts interaction if not = 2.5 fold inc in conc.} – No way to assess drug concentration in bleeding, “bridging”, TPA, etc. – Still need to monitor for sn/sx bleeding or clotting – Reduces opportunities for ongoing patient education and frequent evaluation Product stability prohibits use of “weekly pill boxes” with dabigatran – and limited stability in original container once opened. 3

29. New Agents = New Problems = New Need Develop online system to serve patients and/or clinicians – Educate patients on importance of adherence and self- monitoring for evidence of bleeding or clotting – Track adherence – Report evidence of bleeding or clotting – Questions and alerts for drug and/or supplement interactions – Questions and alerts for periodic renal fx evaluation, hemoglobin/hematocrit measurements, LFTs, etc. – All areas of above updated as new information becomes available – Capabilities to send online warnings as needed

30. Questions? Discussion?

31. Event Rates (%/yr) vs iTTR # 7.5* 0.96 2.58 2.46 1.5 Est. mean for VKA n = 3587 4.966.0311.53Total 0.620.891.38M. I. 1.691.844.2Mortality no diff*1.581.963.85Maj. Bleed 1.6** 1.07 1.34 2.1 Stroke + SEE Ximelag. One-third iTTR>75% n = 1190 One-third iTTR 60%- 75% n = 1207 One-third iTTR<60% n = 1190 # iTTR = Individual’s INR time in the therapeutic range. * NNT 1 yr = 15 vs poor control. **In the 2 studies the stroke + SEE event rates with warfarin were 2.3% and 1.2%, major bleeding was not different with warfarin vs. ximelagatran White HD, et al. Arch Intern Med. 2007; 167:239-245 5

32. TIA/CVA with Intracranial Stenosis – WASID (Warfarin vs Aspirin, no Difference Overall) INR (pat-yrs) Maj Bld- %/yr (n) Isc CVA- %/yr (n) Maj Card- %/yr (n) Comb- %/yr (n) < 2 (92.5)1.1 (1)24.9 (23)10.8 (10)36.8 (34) 2 – 3 (256.9)*3.5 (9)5.1 (13)0.4 (1)9.0 (23)* 3.1 – 4.4 (52.6)15.2 (8)5.7 (3) 26.6 (14) > 4.5 (4.9)123.3 (6)20.6 (1)0 (0)143.9 (7) All groups (406.9)5.9 (24)9.8 (40)3.4 (14)19.2(78)* Chimowitz MI, et al. N Engl J Med 2005; 352:1305-1316. http://www.clotcare.com/clotcare/aspirinfortia.aspx *TTR = 63.1%, Comb rate of 9%/yr when INR was in range was 63% lower than the 19.2%/yr

33. Meta-analysis of Warfarin + ASA post-MI 1 10 Trials, 11,000 patient-years 45% to 55% Relative Risk Reduction in stroke, MI In “high risk” patients with low bleeding risk 83 MIs averted per 1,000 patient-years 43 Strokes averted per 1,000 patient-years 6 More major bleeds per 1,000 patient-years NNT for 3 months: 16 NNH for 3 months: 333 Benefit persist for up to 5 years 1.Rothberg MB, et al. Annals Internal Medicine. 2005; 143:241-250.

34. ASA +/- Mod, High Dose Warfarin Post-M.I. Regimen ASPECT–2 1 (ST Dep. n=993 WARIS-II 2 (AMI n=3630) Death, MI, StrokeMaj. Bld Death, MI, StrokeMaj Bld. ASA 80/160 ASA + INR 2-2.5 INR 3 – 4 9.2 5.1 5.2 0.9 2.1 0.9 20.0 15.0 16.7 0.81 2.75 2.16 1.van Es RF, et al. Lancet 2002; 360:109-13 2.Hurlen, M, et al. N Engl J Med 2002; 347:969-74.

35. Aspect – 2 (Acute MI) ASA 80mg vs. (ASA 80 + INR 2 - 2.5) vs. INR 3 – 4 van Es RF, et al. Lancet 2002; 360:109-13 Deaths

36. Patient GroupAmount Saved Atrial Fib. currently on “usual” warfarin (1 stroke, 0.8 MI, 2.2 Maj bleed, 2.5 deaths)$400,000 Atrial Fib. not on anticoagulation (4.2 strokes, 0.8 MI)$750,000 ACS/MI (not stented), “high risk” vs aspirin (6 MIs and strokes) 1 $840,000 TIA due to intracranial disease vs aspirin (4.7 strokes, 3 “major cardiovascular events) 2 $1,078,000 Expanded Projections of STOARM 2 and Health Care Costs (per 100 patients per year) 1.http://www.clotcare.com/warfarinandaspirinforacs.aspxhttp://www.clotcare.com/warfarinandaspirinforacs.aspx 2.http://www.clotcare.com/aspirinfortia.aspxhttp://www.clotcare.com/aspirinfortia.aspx 7

37. Extreme INRs and TTR Values Belgium Anticoagulation Improvement Study (TTR < 63%) 1 – 41 – 44% INRs less than 2 – 7 – 19 % INRs greater than 5 Alere, Inc. self-testing 1 – 4x /mo. (TTR 62 to 67%) 2 – 8% - 16% INRs 5 n = 4,500 Kaiser Permanente, Colorado (TTR 63.5%) 3 – 15.1% clinic vs 20.4% usual care % INRs 4 ClotFree (TTR 80%) 4 – 0.40% time < 1.5 – 0.07% time > 5 1.Claes N, et al. Eur Heart J 2005; 26:2159-65. 2.Liska G, et al. poster at Anticoagulation Forum, Boston, MA.,May, 2011. 3.Witt DM, et al. Chest 2005; 127:1515-1522. 4.Bussey HI, J Thromb Thrombolysis 2011; 31:265–274 n = 743 n = 6,645 N = 55 11

38. Same Site Studies Showing Reduced Major Events Three Pharm.D. clinics reduced major events, hospitalizations, and ED visits by 60% to 80% 1-3 Randomized trial of 737 patients; weekly INR self-testing & self management vs hematologist’s clinic: 4 – Reduced mortality 61% [6 (1.6%) vs 15 (4.12%)] – Reduced major events 70% [8 (2.2%) vs 27 (7.3%)] – TTR: 64.3% vs 64.9% – % INRs 5 = 5.6% in both groups ClotFree = better INR control than any of the above 5 Therefore, presume at least a 60% reduction in events 1.Chiquette, et al. Arch Intern Med. 1998; 158:1641-1647 2.Rudd, et al. Pharmacotherapy. 2010; 30:330-338 3.Hall, et al. Pharmacotherapy. 2011; 31:686-694 4.Menendez-Jandula, et al. Ann Intern Med. 2005; 142:1-10 5.Bussey HI, J Thromb Thrombolysis 2011; 31:265–274 12

39. New Agents vs Warfarin in A. Fib. (% per 100 pat-yrs) End PointRiv. vs Warf 1 Apix. vs Warf 2 Dabi. vs Warf 3 SSE2.1 v 2.41.27 v 1.601.11 v 1.69 Stroke1.65 v 1.961.19 v 1.511.01 v 1.57 Hem. Stroke0.26 v 0.440.24 v 0.470.10 v 0.38 Isch. Stroke1.34 v 1.420.97 v 1.050.92 v 1.20 Maj. Bld3.6 v 3.42.13 v 3.093.11 v 3.36 ICH0.5 v 0.70.33 v 0.800.30 v 0.74 Death4.5 v 4.93.52 v 3.943.64 v 4.13 Comp.Na6.13 v 7.206.91 v 7.64 Comp. = total of stroke, SEE, Maj. Bleed, Death (+ MI, PE in Dabi) 1.Patel, et al. N Engl J Med 2011; DOI: 10.1056/NEJMoa1009638 2.Granger, et al. N Engl J Med 2011; DOI: 10.1056/NEJM0a1107039 3.Connolly, et al. N Engl J Med 2009;361:1139-51. 14

40. With 60% Reduction in Warfarin-related Event Rates (% per 100 pat-yrs) End PointRiv. vs Warf 1 Apix. vs Warf 2 Dabi. vs Warf 3 SSE2.1 v 0.961.27 v 0.641.11 v 0.68 Stroke1.65 v 0.781.19 v 0.61.01 v 0.63 Hem. Stroke0.26 v 0.180.24 v 0.190.10 v 0.15 Isch. Stroke1.34 v 0.570.97 v 0.420.92 v 0.48 Maj. Bld3.6 v 1.42.13 v 1.243.11 v 1.34 ICH0.5 v 0.280.33 v 0.320.30 v 0.30 Death4.5 v 1.963.52 v 1.583.64 v 1.65 Comp.Na6.13 v 2.886.91 v 3.06 Comp. = total of stroke, SEE, Maj. Bleed, Death (+ MI & PE in Dabi) 1.Patel, et al. N Engl J Med 2011; DOI: 10.1056/NEJMoa1009638 2.Granger, et al. N Engl J Med 2011; DOI: 10.1056/NEJM0a1107039 3.Connolly, et al. N Engl J Med 2009;361:1139-51. Avg # of fewer events per 1,000 patients/yr (range per study) SSE: 7.3 (4.3 to 11.4)Maj Bld: 16.2 (8.9 to 22), Deaths: 21.6 (19.4 to 25.4), Comp: 35.5 (32.5 to 38.5) 15

41. Other Aspects of STORM 2 Patient satisfaction and quality of life – Preferred by most patients (> 90% preferred STORM 2 ) 1,2 – Willing to pay out of pocket 2 – “Would recommend to a friend” 62% increased to 100% 2 – Freedom to travel – Eliminate frequent lab or clinic visits (time, costs) – No need to miss work 1.Ferrando F, et al. Thromb Haemost 2010; 103:1091-1101 2.Forcade NA, et al. Poster #113E Am Coll Clin Pharm meeting, Oct. 19, 2010

42. Other Aspects of STORM 2 Efficiency of management – Patient: 10 min per “visit” from “anywhere” 1 – Clinician: < 10 min per patient per 4 “visits” per month 1,2 – Automatic documentation and reappointment 1 – Documented confirmation of receipt and understanding of instructions 1 – Dosing calendar – printable and available online 1 continued 1.Bussey HI, et al AHA-10-A-341-QCOR (Am Heart Assoc mntg on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke 2010, May 21, 2010. 2.Harper PL, et al Blood 2008; 112:Abstract 1278.

43. Obstacles and Solutions to STORM 2 Patient does not have internet access – 75% to 82% of US households do 1 – Available in local library, at work, other locations Patient does not “do” internet – 50% of US population in 2001 1 – 77% of US population in 2010 1 – Family member, neighbor, care giver Patient can not do fingerstick test – Family member, neighbor, care giver – Testing stations (CMS coverage?) – Home health Ref: Bussey HI. J Thromb Thrombolysis. 2011; 31:265-274

44. Considerations in Implementing STORM 2 (cont’d) Avoid dosing nomograms – Mediocre TTR (66.8%) 1 – Supervising expert to over ride dose in 27+% of instances 1 Avoid telephone and/or fax management – Incomplete data collection – Miscommunication or misunderstanding – Poor documentation – “Non-stable” patients had TTR < 50% in Kaiser studies 2,3 – THINRS: 62.4% vs. 66.2 TTR 4 1.Poller, et al. Thromb Haemost 2009; 101:487-94 2.Witt DM, et al Blood 2009; 114(5):952-6 3.Witt DM et al J Thromb Haemost 2010; 8:744-9 4.Matcher DB, et al. N Engl J Med 2010; 363:1608-20

45. Poor Warfarin Management in Studies of New Agents in Atrial Fibrillation vs Events – TTR = 55% to 64% (more useful measures like extreme INRs not reported) – High bleeding rate with warfarin – 7 to 8 ICH/1,000 patients/yr vs 1 to 5 in other large trials in Finland, 1 US, 2 and many earlier INR-based A. Fib trials. 3 – Major Bleeding > 3%/yr in each study vs < 2%/yr in almost all other INR-based A. Fib trials. 3 – What would be the impact of a > 60% reduction in major events? 1.Huhtakangas, et al. Stroke 2011 (DOI: 10.1161/STROKEAHA.111.615260 2.Singer, et al. Circulation Cardiovasc Qual Outcomes. 2009; 2:297-304 3.Singer, et al. Chest 2008; 133:546S-592S 13