1. Cost effectiveness of AF monitoring strategies in a post-stroke population LAUREN E. CIPRIANO JEFF HEALEY OMAR AKHTAR KAREN LEE LUCIANO A. SPOSATO APRIL 12, 2016

2. Disclosures Funding: CADTH Conflicts: None to report

3. Atrial fibrillation in patients with a history of stroke or TIA ~ 20% of stroke patients have a known history of AF ~ 20 - 25% of stroke patients without a prior AF diagnosis, have AF History of stroke & AF  10-15% risk of recurrent stroke in year 1 2

4. Oral anticoagulation treatment Reduce the risk of recurrent stroke (HR = 0.3-0.65) Increase the risk of bleeding (HR = 1.5-3.0) NOAC lower the risk of ICH but increase the risk of non- brain bleeding compared to warfarin Warfarin is inexpensive, but has many contraindications and requires regular visits for patients NOACs are expensive, similarly effective to warfarin, and require less follow-up visits to ensure safety /efficacy 3

5. Post discharge AF monitoring 4 Patient with stroke or TIA ECG Hospital discharge Age 70 CHADS-VASC ~4 24+ hr monitoring (sometimes) Focus of our analysis 24 hr – 7 days monitoring? 30 days monitoring? 2-3 years monitoring? (implantable device)

6. Objective To evaluate the cost effectiveness of outpatient cardiac monitoring devices for the evaluation of atrial fibrillation in discharged patients with a recent history of stroke or TIA Variation in clinical evaluations of monitoring strategies made many desired comparisons difficult to evaluate. 5

7. Research Question Three separate cost effectiveness analyses 6 StudyHiggins et al. (2013)Gladstone et al. (2014)Sanna et al. (2014) Cohort: Ischemic stroke or TIA within 7 days Cryptogenic stroke or TIA within 6 months Cryptogenic stroke or TIA within 90 days Prior AF monitoring: 12-lead ECG 12-lead ECG and ≥ 24-hour Holter 12-lead ECG and ≥ 24-hour Holter Intervention: 7 day cardiac event monitoring (ELR) 30-day event triggered recorder (ELR) 3-yr insertable cardiac monitor (ILR ) Comparator: Standard practice (60% received 24-hour Holter) 24-hour Holter Standard practice (30% ≥ 1 ECG and 8% 24-hour Holter)

8. Markov Model 7 Undiagnosed AF / No AF Diagnosed AF May initiate OAC May discontinue OAC + GI bleed (any cycle)

9. Model assumptions Monthly cycles & Lifetime horizon Perspective: Public payer and Soceital Input parameters Medical literature Expert opinion Validated to Oxford Vascular Study Life-expectancy, QALYs, and 5-year recurrent strokes 8

10. OAC assumptions 61% of patients initiate OAC after diagnosis 16% of patients on OACs quit each year OACs reduce the risk of recurrent stroke Warfarin: 36% reduction compared to aspirin Apixiban: 45% reduction compared to aspirin Annual CostDisutilityPatient time* Warfarin$396 - 0.0132 hours every 3 weeks Dabigatran$1288 - 0.006- Rivaroxaban$1157 - 0.006- Apixaban$1288 - 0.006- * Assume a caregiver attends all visits; patient and caregiver time @ $25/hr

11. Model-based outcomes 10 Outcomes AF without diagnosis AF with diagnosis Warfarin Apixaban Within 2 years (per 10,000) Recurrent IS, severe or fatal1,087709636 Recurrent stroke, any1,7241,2231,093 ICH479942 GI bleed171276264 AF diagnosis: Non-fatal strokes Fatal strokes Bleeds

12. Model-based outcomes 11 Outcomes AF without diagnosis AF with diagnosis Warfarin Apixaban LE4.314.534.60 Discounted LY3.593.753.80 Discounted QALYs2.302.392.45 Costs Baseline229,025238,458241,473 OAC08432,870 Acute events19,87617,22315,952 Total248,901256,525260,294 Life expectancy Quality-adjusted life expectancy AF diagnosis: Costs

13. Minimum diagnostic yield to be cost effective 12 61% of AF patients initiate OAC100% of AF patients initiate OAC

14. Minimum diagnostic yield to be cost effective 13 61% of AF patients initiate OAC100% of AF patients initiate OAC 7d 30d

15. Evaluation 1: 7-day monitoring vs standard practice Patients: Stroke and TIA patients within 7 days of discharge Previous evaluation: ECG Comparison: 7-day ELR vs Standard practice (60% 24-hr Holter)  diagnostic yield (sustained AF) = 16% (4.7% - 27.3%) Results: ICER $50,000 - $80,000 per QALY gained 14

16. Base case analysis 15 Health economic outcomes OAC treatment Warfarin Apixaban Lifetime Costs Cost of FN diagnosis $151,148$151,435 Cost of TP diagnosis $153,490$155,140 Incr. cost of correct diagnosis $2,342$3,705 Incr. cost of monitoring $139 Lifetime benefits QALYs of FN diagnosis 2.302.31 QALYs of TP diagnosis 2.362.40 Incr. QALYs of correct diagnosis 0.0550.088 Incr. cost effectiveness ratio (ICERs) ($/QALY gained) $58,800$52,200

17. Sensitivity analysis 7-day monitoring ICER <$100,000 / QALY gained with incremental diagnostic yield as low as 5% Patient characteristics that increase cost effectiveness Higher risk of recurrent stroke (>10% py) Lower baseline risk of bleeding Healthier / Fewer comorbidities (lower baseline mortality risk; lower baseline health care costs; higher baseline utility) Higher likelihood of OAC uptake if diagnosed Societal perspective (apixaban) ICER $75,000 – 85,000 / QALY gained ICER <$70,000 if OAC if patient is above average baseline health 16

18. Cost effectiveness improves with connection to OAC treatment 17

19. Cost of monitoring is critical factor influencing cost effectiveness 18

20. Summary: 7-day monitoring vs standard practice ICER likely between $40,000-$80,000 per QALY gained Patient population Unselected stroke and TIA patients within 7 days Prior monitoring: only ECG Targeted patient populations ICER <$50,000 per QALY gained > 20% incremental diagnostic yield high rate of connection to OAC treatment low OAC discontinuation rate selection of relatively healthy patients Unable to evaluate 7-day monitoring vs. universal 24-hour monitoring Optimal duration of monitoring is unknown 19

21. Evaluation 2: 30-day ELR vs 24-hour Holter Patients: Cryptogenic stroke patients within 6 months Previous evaluation: ECG and at least 24-hrs of Holter Comparison: 30-day ELR vs 24-hr Holter Incremental diagnostic yield = 12.9% (8.0% - 17.6%) Results: ICER $90,000 - $120,000 per QALY gained 20

22. Base case analysis 21 Health economic outcomes OAC treatment Warfarin Apixaban Lifetime Costs Cost of FN diagnosis $151,148$151,435 Cost of TP diagnosis $153,490$155,140 Incr. cost of correct diagnosis $2,342$3,705 Incr. cost of monitoring $508 Lifetime benefits QALYs of FN diagnosis 2.302.31 QALYs of TP diagnosis 2.362.40 Incr. QALYs of correct diagnosis 0.0550.088 Incr. cost effectiveness ratio (ICERs) ($/QALY gained) $ 114,979 $ 87,130

23. Sensitivity analysis 30-day monitoring followed by treatment with warfarin and apixaban has an ICER < 100,000 per QALY gained Incremental diagnostic yield > 20% Incremental cost of monitoring < $300 OAC uptake > 85% Patients with above average baseline health Patient and system factors alone insufficient to make 30-day monitoring cost effective compared to 24-hour Holter without greater diagnostic yield and/or lower incremental cost Societal perspective: base case >$110,000 per QALY gained 22

24. Cost effectiveness improves with connection to OAC treatment 23

25. Summary 30-day ELR vs 24-hour Holter Unlikely to be cost effective (ICER > $100,000/QALY gained) Patient population Cryptogenic stroke and TIA patients within 6 months Prior monitoring: ECG and 24-hour Holter Unable to compare 24-hour Holter to no monitoring Unclear if any monitoring after ECG and 24-hour Holter is cost effective Unable to evaluate whether evaluating patients sooner (within 30 or 90 days of stroke) would improve cost effectiveness 24

26. Evaluation 3: 3-years of ILR vs standard practice Patients: Cryptogenic stroke patients within 90 days Previous evaluation: ECG and at least 24-hrs of Holter Comparison: 3-years of ILR vs. standard practice (38% ECG or 24-hour Holter within 6 months) 30% of patients in ILR group diagnosed with AF vs. 3% in the standard practice group Incremental cost: EV ~$3400 ($2800 implantation + monitoring) Results: ICER > $250,000 per QALY gained 25

27. Connection to OAC treatment is important but not sufficient No single or reasonable combination of factors achieves ICER < $100,000 per QALY gained 26

28. Summary 3-years of ILR vs standard practice 3-year ILR is not cost effective compared to standard care Patient population Cryptogenic stroke and TIA patients within 90 days Prior monitoring: ECG and 24-hour Holter 27

29. Post discharge AF monitoring Evaluation 1: 7-day ELR vs. standard care 28 Patient with stroke or TIA ECG in Hospital Hospital discharge Age 70 CHADS-VASC ~4 7-day ELR Standard care Conclusion: Likely cost effective $40,000-80,000/QALY gained ∆ diagnostic yield > 10-20% Patient factors ↑risk of stroke; ↓risk of bleeding Relatively healthy ↑ connection to OAC ∆ diagnostic yield = 16% ∆ cost = $140

30. Post discharge AF monitoring Evaluation 2: 30-day ELR vs. 24-hr Holter 29 Patient with cryptogenic stroke or TIA ECG in Hospital Hospital discharge Age 70 CHADS-VASC ~4 30-day ELR 24-hour Holter Conclusion: Not cost effective $90,000-120,000 / QALY gained 20% <$100,000 if ∆ cost < $300 Patient or system factors alone are unlikely to be sufficient ∆ diagnostic yield = 13% ∆ cost = $476 24-hr Holter

31. Post discharge AF monitoring Evaluation 3: ILR vs. standard care 30 Patient with cryptogenic stroke or TIA ECG in Hospital Hospital discharge Age 70 CHADS-VASC ~4 3-year ILR Standard care Conclusion: Not cost effective ICER > $250,000 / QALY gained ∆ diagnostic yield = 27% ∆ cost = $3400 24-hr Holter

32. Summary In a stroke or TIA patient who received ECG in hospital 7-days of monitoring is likely cost effective compared to standard care Unclear if cost effective vs. universal 24-hour monitoring Unclear if 7-days is the optimal duration of monitoring Unlikely to be cost effective in a patient who has received in-patient Holter/CICT/cECG monitoring (needs large incremental diagnostic yield) In a cryptogenic stroke or TIA patient who received ECG and 24-hr Holter 30-day monitoring is unlikely cost effective compared to 24-hr Holter ILR is not cost effective compared to standard care Unclear 24-hour Holter is cost effective compared to no further monitoring Unclear if 30-days of monitoring is cost effective compared to 7-days in a patient cohort without prior 24-hr Holter 31

33. Limitations Many comparisons of interest were not evaluated Optimal sequence of monitoring technologies remains unknown Many simplifying structural assumptions Assume a constant rate of recurrent stroke AF diagnosis after subsequent event OAC adherence, quitting after a bleeding event, and re-starting after a clotting event Model considers patients at average risk Explored the influence of patient factors on cost effectiveness of monitoring Do not consider correlation between patient factors Do not consider the incidence of AF after stroke Incident AF will be captured by longer-monitoring technologies (ILR) 32

34. 33

35. Evaluation 1: 7-day ELR vs. standard care OAC Adherence 34

36. Evaluation 2: 30-day ELR vs. 24-hr Holter OAC Adherence 35

37. Comparisons to other models Kamel et al. Cost effectiveness of dabigatran, apixaban vs. warfarin in post-stroke patients with AF 36 Kamel et al. QALY CADTH Base case OAC discontinuation No OAC discontinuation QALY LY QALY LY Dabigatran4.272.574.012.644.12 Apixaban4.192.634.082.744.24 Warfarin3.912.564.022.634.14 * 3% annual discount rate Utility weight for initial health state = 0.994-0.987 vs. 0.68

38. Comparisons to other models Coyle et al. Cost effectiveness of NOACs vs. warfarin in post-stroke patients with AF Lifetime QALYs with warfarin Coyle et al. Mild stroke (utility = 0.75): 4.45 QALYs Coyle et al. Severe stroke (utility = 0.33): 2.2 QALYs Our model Mixed cohort (utility = 0.68): 2.4 QALYs (3.75 LY) 37 * 5% annual discount rate Our rate of recurrent stroke on warfarin is greater. Coyle et al. = 0.035 (base rate of 0.016 x HR of 2.2) Our model = 10.2% annual rate on aspirin x HR of 0.63 = 0.068

39. Model-based outcomes 38 Outcomes AF without diagnosis AF with diagnosis Warfarin Apixaban Within 2 years (per 10,000) Recurrent IS, severe or fatal1,087709636 Recurrent stroke, any1,7241,2231,093 ICH479942 GI bleed171276264 Within 5 years (per 10,000) Recurrent IS, severe or fatal2,0021,4551,345 Recurrent stroke, any3,1892,4592,266 ICH8717080 GI bleed316487471 LE4.314.534.60

40. Model-based outcomes 39 Outcomes AF without diagnosis AF with diagnosis Warfarin Apixaban LE4.314.534.60 Discounted LY3.593.753.80 Discounted QALYs2.302.392.45 Costs Baseline229,025238,458241,473 OAC08432,870 Acute events19,87617,22315,952 Total248,901256,525260,294

41. Model Validation 40

42. Comparison to Oxford Vascular Study Oxford vascular study 440 TIA and 748 stroke patients (2002-2007) followed up for 5-10 years 17% prior history of stroke 18% prior diagnosis of AF 41 Life yearsQALYs TIA4.33.3 Stroke3.62.5 Mild4.12.9 Moderate2.81.7 Severe1.40.7 Overall3.82.7 Adjusted (12%)4.43.1 Life yearsQALYs No AF7.24.73 AF without diagnosis4.32.75 AF with diagnosis Warfarin4.52.88 Apixaban4.62.95 Our modelOxford Vascular Study

43. Comparison to Oxford Vascular Study Oxford vascular study 440 TIA and 748 stroke patients (2002-2007) followed up for 5-10 years 17% prior history of stroke 18% prior diagnosis of AF 42 5-year risk of recurrent stroke TIA16% Stroke20% 5-year risk of recurrent stroke No AF8.1% AF without diagnosis31.9% AF with diagnosis Warfarin24.6% Apixaban22.7% Our modelOxford Vascular Study

44. Inputs: Natural history Recurrent stroke MIICHGI bleed Annual risk of event No AF2.2%2.6%0.3%1.1% AF no OAC10.2%5.1%0.3%1.1% HR with OAC (compared to aspirin*) Warfarin 0.380.892.602.50 Dabigatran 0.381.421.084.11 Rivaroxaban 0.360.721.743.65 Apixaban 0.350.781.092.23 43

45. Inputs: Costs and Utilities Recurrent stroke DeathGI bleedMIICHTIA/Mild*Mod-Sev Month of Mortality (no OAC/OAC)0%11%31%/44%39% / 29% Cost$43,600$9,975$18,400$36,000$16,200$55,000 QOL- 0.03- 0.01- 0.05- 0.02- 0.13 History of Annual mortality (no AF/AF)12 % / 16 %16 % / 22 % Direct health costs18,400 30,900 Unpaid caregiver costs15,000 25,000 QOL0.650.620.680.31

46. Minimum diagnostic yield to be cost effective (100K) 45 61% of AF patients initiate OAC100% of AF patients initiate OAC 7d 30d

47. Comparison to Yong et al. Cost effectiveness of 30-day ELR vs 24-hr Holter 46 * 5% annual discount rate ** assumes 16.1% AF prevalence Key differences Yong et al. are modeling a healthier cohort Annual mortality rate = 5.4% per year vs. 12.1% per year Baseline utility = 0.93 vs. 0.68 Baseline costs associated with history of stroke = $9301 vs. $43,200 Yong et al.CADTH 30-day ELR LE = 8.158 yearsLE = 6.8 years 24-hr Holter LE = 8.138 yearsLE = 6.2 years ICER Cost saving $151,208 / QALY gained

48. AF diagnosis occurs over time Assumed 30% AF prevalence While undiagnosed, patients (with and without AF) may die or have recurrent stroke Considered censored Calculated the rate of AF identification in undiagnosed patients to match KM curves in Sanna (NEJM 2014) 47

49. Cohort with 30% AF prevalence 48 Outcomes Warfarin Standard practice ILR Apixaban Standard practice ILR Within 2 years (per 10,000) Recurrent IS, severe or fatal 475449474443 Recurrent stroke, any 780746777735 ICH 51545049 GI bleed 183190183189 LE 6.316.336.316.34 Discounted LY 4.824.834.824.84 Discounted QALY 3.183.193.183.19

50. Cohort with 30% AF prevalence 49 Outcomes Warfarin Standard practice ILR Apixaban Standard practice ILR Costs Baseline $292,815$293,792$292,959$294,14 Testing $40$1,129$40$1,129 OAC $41$118$138$402 Acute Events $11,651$11,404$11,591$11,227 TOTAL $304,547$306,443$304,727$306,971 Incr. cost of ILR monitoring $1,896 $2,244 Incr. QALYs 0.0090.015 Incr. cost effectiveness ratio (ICERs) ($/QALY gained) $205,169 $151,208

51. Sensitivity analysis ILR monitoring vs. standard care ICER > 100,000 per QALY gained is robust Doubling the diagnosis rate (diagnosing patients faster) W: $175,400 per QALY gained A: $132,600 per QALY gained Immediate diagnosis in ILR arm W: $154,300 per QALY gained A: $120,500 per QALY gained Cost of implantation = $0  ICER > $100,000 per QALY gained Cost of monitoring =$0  ICER > $100,000 per QALY gained ICER < 100,000 per QALY gained  Cost of implantation and monitoring 25% of base case 50

52. Comparison to Diamantopoulos et al. Cost effectiveness of ILR vs standard care 51 * 3.5% annual discount rate ** 5% annual discount rate Key differences Baseline mortality rate in Diamantopoulos et al. is based on UK life tables (no increase in mortality rate for history of stroke) Baseline utility = 0.76 vs. 0.68 Low costs of long-term care e.g., £578 per year after a mild stroke (vs. $43,200) e.g., £1,712 per year after a recurrent major stroke (vs. $65,000) Diamantopoulos et al.*CADTH** ILR7.367 QALY4.84 QALY Standard care7.216 QALY4.82 QALY ICER£ 17,175 / QALY gained $151,208 / QALY gained