1. AHA QCOR in CVD and Stroke 2010: Controversies in Atrial Fibrillation “Introduction: Contemporary Epidemiology of AF, Stroke Rates, and the Effectiveness of Warfarin” Daniel E. Singer, MD

2. Presenter Disclosure Information Daniel E. Singer, MD “Introduction: Contemporary Epidemiology of AF, Stroke Rates, and the Effectiveness of Warfarin” FINANCIAL DISCLOSURE: Research Grant: Daiichi Sankyo, significant. Consultant/Advisory Board: Boehringer Ingelheim, significant; Daiichi Sankyo, significant; Johnson and Johnson, modest; Medtronic, significant; Merck and Co., modest; Sanofi Aventis, modest; St. Jude Medical, modest. Honorarium/Symposium Presentation: Bristol-Myers Squibb, Pfizer, modest. Executive Committee: ROCKET-AF trial of rivaroxaban in AF. UNLABELED/UNAPPROVED USES DISCLOSURE: None

3. AF: The importance of Stroke AF can cause distressing symptoms and inefficient cardiac function which lead to increased rates of hospitalization. It has been associated with higher mortality rates. But the most important complication of AF is ischemic stroke.

4. AF and Stroke: Epidemiology 1.AF is the most common significant arrhythmia 2.AF prevalence strongly age-dependent 10% of age 80+ years 3.RR for stroke = 5 4.VKA (e.g., warfarin): RRR ~67% 5. ASA: RRR 21% (0-38%) Arch Intern Med 1987;147:1561-1564 Arch Intern Med 1994;154:1449-1457

5. Prevalence of Diagnosed AF by Age and Sex Go AS et al. JAMA 2001;285:2370–2375

6. Projected Number of Adults with AF in the US, 1995-2050 *JAMA. 2001;285:2370-2375 2.94 2.66 2.44 2.26 2.08 3.33 3.80 4.34 4.78 5.16 5.42 5.61 0.0 1.0 2.0 3.0 4.0 5.0 6.07.01990199520002005201020152020202520302035204020452050 Year Adults with Atrial Fibrillation, millions

7. Lifetime Risk of Developing AF* Lifetime risk of developing AF for men and women ages 40 and over*Lifetime risk of developing AF for men and women ages 40 and over* Overall: about 1 in 4 *Lloyd-Jones D, et al. Circulation 2004;110:1042-1046. Based predominantly on data from white individuals.

8. AF and Stroke: Framingham Study, 30-Year Follow-up* Strokes Age Prev AF per 1000py o per 1000py AF RR 60-691.8%4.5 21 4.7 70-794.7%9.0 49 5.4 80-8910.2%14 71 5.0 * Wolf PA, Abbott RD, Kannel WB, Arch Intern Med 1987;147: 1561- 1564; adjusted for BP

9. AF: Putative Mechanism for Stroke AF loss of atrial contraction LA thrombus embolism

10. Left atrial appendage thrombus LA LAA-Thrombus

11. RCTs of VKA vs Control to Prevent Stroke in AF Go AS et al. Progr Cardiovasc Dis 2005;48:108–124 *p<0.05 AFASAKBAATAFSPAF-ICAFASPINAFEAFT Annual stroke rate (%) 0 2 4 6 8 10 12 14 Control Warfarin –71%*–86%*–69%*–52%–79%* –66%* 5.5 1.6 3.0 0.4 7.4 2.3 5.2 2.5 4.3 0.9 12.3 3.9

12. Efficacy of Anticoagulation for AF Trial Target Ranges: INR ~ 1.8-4.2 RelativeAbsolute Risk ReductionRisk Reduction Pooled 1° RCTs 68% (50-79%)3.1% per year EAFT 66% (43-80%)8.4% per year Arch Intern Med 1994;154:1449-1457 Lancet 1993;342:1255-1262

13. Safety of Anticoagulation for AF Pooled 1° RCTs 0.3% per yr 0.1% per yr Intracranial Hemorrhage: Anticoagulation Control Absolute Rates of

14. Efficacy of Aspirin for AF Pooled 3 trials versus placebo: AFASAK75 mg daily SPAF I325 mg daily EAFT300 mg daily Relative Risk Reduction: 21% (0-38%) No signif impact on severe/fatal stroke *JAMA 2002;288:2441-2448 (AFASAK I &II, EAFT, PATAF, SPAF I-III)

15. The Optimal INR For an anticoagulant where toxicity results from an exaggeration of the beneficial effect, choosing the right “dose,” here INR, is crucial.

16. SPAF III: INR 1.2-1.5 plus ASA versus INR 2.0-3.0 RRR favoring INR 2-3: 74% (50-87%) RRR favoring INR 2-3: 74% (50-87%) No reduction in risk of ICH No reduction in risk of ICH Lancet 1996; 348: 633–38

17. Figure 1b Thromboembolism Intracranial Hemorrhage = 10.19 = 11.12 12812173411419TE cases 132389544280114122TE controls 102445341536ICH cases 411442521196841ICH controls Circ CV Qual and Outcomes 2009;2:297-304

18. Antithrombotic Trials in AF: Core Findings Anticoag. at INR 2.0-3.0 very effective - Generally safe - Moderately burdensome Aspirin is much less effective

19. Anticoagulation for AF: For Whom? Guideline perspective: Anticoagulate AF patients whose risk of stroke is high enough to “merit” the burden and risk of warfarin therapy Anticoagulate AF patients whose risk of stroke is high enough to “merit” the burden and risk of warfarin therapy ASA for others ASA for others

20. Pooled Analysis of AF Trials: Risk Factors for Stroke* Relative Risk (RR) Relative Risk (RR) Variable Multivariate Variable Multivariate Prior stroke/TIA 2.5 Prior stroke/TIA 2.5 Hx HBP 1.6 Hx HBP 1.6 Age** 1.4 Age** 1.4 Hx Diabetes 1.7 Hx Diabetes 1.7 **RR per decade * Arch Intern Med 1994;154:1449-1457 * Arch Intern Med 1994;154:1449-1457

21. Echo Risk Factors for Stroke With AF: Pooled Analysis of Control Arms of 3 RCTs* Feature RR p value LV dysfunction mod-severe3.04<0.001 mod-severe3.04<0.001 *Arch Intern Med 1998;158:1316-1320, univariate

22. CHADS 2 AF Stroke Risk Score* C = CHF1 point H = Hypertension1 point A = Age >75 years1 point D = Diabetes1 point S = Prior Stroke/TIA2 points NB: Applies to persistent or paroxysmal AF *Gage, et al. JAMA 2001; 285(22): 2864-70

23. CHADS 2 AF Stroke Risk Score CHADS 2 Score No. of Patients (n = 1733) No. of Strokes (n = 94) NRAF Crude Stroke Rate per 100 Patient- Years 012021.2 1463172.8 2523233.6 3337256.4 4220198.0 56567.7 65244.0 Risk of Stroke in National Registry of Atrial Fibrillation (NRAF) Participants, Stratified by CHADS 2 Score* *C=CHF, H=HBP, A=age >75, D=diabetes, S=prior stroke/TIA. Gage, et al. JAMA 2001; 285(22): 2864-70

24. Risk of Stroke in AF: Impact of Paroxysmal AF From pooled trials (~25% had PAF) From pooled trials 1 (~25% had PAF) RR (PAF/Sust AF) = 0.9 (univar) From ACTIVE W (18% had PAF) From ACTIVE W 2 (18% had PAF) RR (PAF/Sust AF) = 0.94 (multivar) 1 Arch Intern Med 1994;154:1449-1457 2 JACC 2007;50:2156-61

25. AF Stroke Prevention Guidelines* Clinical Profile (Applies to PAF, as well) Treatment Recommendation Prior stroke/TIA (CHADS 2 ≥ 2) Warfarin, INR 2-3 ≥ 2 of the following RFs: CHF, HTN, age ≥ 75, DM (CHADS 2 ≥ 2) Warfarin, INR 2-3 1 RF (not prior stroke) (CHADS 2 =1) ASA or warfarin 0 RF (CHADS 2 =0) ASA Anticoagulation recommendation assumes: 1) patient is not a bleeding risk, and 2) high quality of anticoagulation will occur. * ACCP 8 (Chest 2008; 133:546S-592S); ACC/AHA/ESC 2006 (Europace 2006;8:651-745.)

26. Trends in Warfarin Use and Outcomes in AF patients Lakshminarayan K, et al., Atrial Fibrillation and Stroke in the General Medicare Population. Stroke 2006;37:1969-1974.

27. BAFTA: Warfarin vs. Aspirin in Elderly AF Patients* RCT of Warfarin, INR 2-3, vs ASA, 75mg/dRCT of Warfarin, INR 2-3, vs ASA, 75mg/d PopulationPopulation –N=973, age >=75: mean age = 81.5 yrs –Recruited Apr 2001 – Nov 2004 *Mant JM, et al. Lancet 2007; 370: 493-503.

28. BAFTA Study Outcomes Relative risk=0.48, (95% CI 0.28-0.80)* –Annual risk on warfarin = 1.8% –Annual risk on aspirin = 3.8% –Bleeding rates ~same on warfarin and aspirin in this elderly cohort. *Analysis by intention to treat

29. Problem: The risk schemes are not very predictive.

30. Percent of patients with and without stroke by CHADS 2 stroke risk score National Registry of Atrial Fibrillation (NRAF) cohort (n=1733) Data from Gage et al. JAMA 2001;285:2864-2870.

31. AF Stroke Risk Schemes: ROC Curves* *Fang et al. JACC 2008;51:810-5

32. Problem (?): Stroke rates in AF appear to be declining.

33. Decreasing Stroke Rates: CHADS 2 =1, Off Warfarin Study Time Period Stroke rate AFI RCTs: ASA 1 1987-96 2.2 (1.6-3.1) ATRIA: +/- ASA 2 1996-2003 1.2 (1.0-1.4) BAFTA: ASA 3 2003-2006 1.4 (0.6-2.9) 1 Circulation. 2004;110(16):2287-92. 2 Ann Intern Med. 2009;151:297-305 3 cited in Stroke 2009;40:2607-2610

34. Anticoagulation for AF in the “Real World”

35. AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study Massachusetts General Hospital Kaiser Permanente Division of Research

36. ATRIA Cohort Outcomes N=13,559, 1996-2003N=13,559, 1996-2003 Median follow-up of 6.0 yearsMedian follow-up of 6.0 years 66,754 person-years of observation,66,754 person-years of observation, –~50% on warfarin; 532,000 INR tests 1,092 validated TE events (1017 ischemic strokes)1,092 validated TE events (1017 ischemic strokes) 299 validated ICH events299 validated ICH events

37. “Net Clinical Benefit” in AF TEs prevented minus ICHs induced (TE rate off warfarin - TE rate on warfarin) minus 1.5x minus 1.5x (ICH rate on warfarin - ICH rate off warfarin)

38. -0.25 0.11 1.00 2.34 -0.65 -0.37 0.44 1.29 0.08 0.40 1.40 3.30 Age <65 Age 65-74 Age 75-84 Age ≥ 85 Warfarin worseWarfarin better -0.500.511.522.533.5 The net clinical benefit of warfarin by age group Net Clinical Benefit (events per 100 person years) Ann Intern Med 2009;151:297-305

39. -0.11 0.19 0.97 2.07 2.22 -0.44 -0.27 0.43 1.21 0.58 0.20 0.45 1.41 2.79 3.75 CHADS 2 =0 CHADS 2 =1 CHADS 2 =2 CHADS 2 =3 CHADS 2 =4-6 Net Clinical Benefit (events per 100 persons per years) Warfarin worseWarfarin better -0.500.511.522.533.5 *CHADS 2 is a widely used stroke risk classification scheme for patients with AF. 6 C=congestive heart failure; H=hypertension; A=age>75 years; D=diabetes; and S=prior ischemic stroke. The presence of each clinical feature confers one point except for S which confers 2 points. The net clinical benefit of warfarin by CHADS 2 score* Ann Intern Med 2009;151:297-305

40. The Importance of “TTR” in Achieving the Net Benefit of Warfarin in AF

41. Stroke and Systemic Emboli (SE) Outcomes by INR Control Category: Results from SPORTIF III and V* *White, HD et al. Comparison of Outcomes Among Patients Randomized to Warfarin Therapy According to Anticoagulant Control. Arch Intern Med. 2007; 167:239-245. <60%60-75%>75% TTR = % of time spent at INR 2.0-3.0

42. ACTIVE-W VKA arm: Time in Therapeutic Range (TTR) Country Mean TTR South Africa 46.3 Brazil47.1 Russia53.4 Poland55.3 Belgium58.7 United States 62.9 Netherlands64.0 Argentina64.5 Czech Republic 66.8 Italy67.2 Canada68.5 Germany69.3 Australia74.5 United Kingdom 74.8 Sweden77.8 Circ 2008;118:2029-37

43. ACTIVE-W VKA arm: Time in Therapeutic Range (TTR) Country Mean TTR South Africa 46.3 Brazil47.1 Russia53.4 Poland55.3 Belgium58.7 United States 62.9 Netherlands64.0 Argentina64.5 Czech Republic 66.8 Italy67.2 Canada68.5 Germany69.3 Australia74.5 United Kingdom 74.8 Sweden77.8 Circ 2008;118:2029-37 “In medicine, geography is destiny.”

44. The Importance of “TTR” in Achieving the Net Benefit of Warfarin in AF “Do the right thing” “Do the right thing right”

45. Problems with Warfarin Much inter- and intra-individual variation in dosing: Monitoring is crucial (17 INRs/yr) Much inter- and intra-individual variation in dosing: Monitoring is crucial (17 INRs/yr) Drug and diet interactions ~4 day lag in effect, both on and off ~4 day lag in effect, both on and off Much physician and patient burden; significant discontinuation rates Much physician and patient burden; significant discontinuation rates

46. Response of Industry Increasing prevalence of AF and dissatisfaction with warfarin have prompted extraordinary investment in novel anticoagulants, primarily Xa-I and DTIs. Multiple non-inferiority megatrials Multiple non-inferiority megatrials ~40,000+ AF patients in RCTs ~40,000+ AF patients in RCTs

47. Stroke Prevention in AF: The Future 1.Optimizing warfarin 2. Replacing warfarin – “Breaking the warfarin barrier” 3. True cure for AF: initiator: ablation/isolation of PVinitiator: ablation/isolation of PV substrate: “maze” proceduresubstrate: “maze” procedure

48. Stroke Prevention in AF: The Future 4. “Rx” of LAA: surgery, Watchman catheter approach 5. **Better risk stratification: stroke, ICH**

49. Trends in publications on AF Source: PubMed May 2010; Search limits: atrial fibrillation in title, human, English language. Year Number of Publications

50. END

51. Warfarin?

52. Warfarin and Vitamin K: Pharmacogenetics Common gene variants for warfarin sensitivity: -CYP2C9: S-warfarin metabolism -VKORC1: warfarin effect 2 genes account for ~25% variability in warf dose Clinical impact: ??

53. Risk Factors for ICH Clinical AgeAge HypertensionHypertension Prior strokePrior stroke Anticoagulation (esp. VKA with INR>3.5)Anticoagulation (esp. VKA with INR>3.5)Genetic Apolipoprotein ε2 or ε4 (RR ~2 for “lobar” ICH)

54. Imaging for Cerebral Small Vessel Disease Radiographic manifestations of cerebral small vessel disease.* Left, T2*GRE MRI with left occipital ICH and multiple microbleeds (arrows) in a patient with probable CAA. Left, T2*GRE MRI with left occipital ICH and multiple microbleeds (arrows) in a patient with probable CAA. Right, FLAIR sequence demonstrates extensive leukoaraiosis. *Rost et al., Stroke. 2008; 39:2166-2173

55. Atritech, Inc., WATCHMAN

57. Left Atrial Appendage Casts* *Anat Rec 1995;242:553-61