The case for switching to the emerging oral anticoagulants in Atrial Fibrillation

1. The case for switching to the emerging oral anticoagulants in Atrial Fibrillation Dr Neil Baldwin Consultant Physician & Clinical Lead for Stroke North Bristol NHS Trust Bristol neil.baldwin@nbt.nhs.uk

2. AF prevalence increases with age 9 8 7 6 5 AF prevalence (%) 4 3 2 1 0 General population >60 years >80 years Age 3. Go AS, et al. JAMA 2001;285:2370-2375

3. Treatment options for Atrial Fibrillation Anti-platelet Treatments • Aspirin • Clopidogrel • Anticoagulants • Warfarin • Dabigatran • Riveroxiban • Apixaban • Mechanical Left Atrial Appendix occluder

4. Aspirin v placebo Aspirin is generally regarded as An ineffective treatment But its safer Or is it?

5. Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT RRR 64%*(95% CI: 49–74%) All trials 100 50 0 –50 –100 RRR (%)† Warfarin has been hard to beat Random effects model; Error bars = 95% CI;* p>0.2 for homogeneity; † Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857–67

6. Frenchay AF Thromboprophylaxis ESSC project Aliya Rahman N Baldwin 2010

7. How are AF patients at risk of stroke currently being managed? Preadmission medications in patientswith known Atrial fibrillation who were admitted withacute ischemic stroke (high-risk cohort, n=597) No antithrombotic29% Therapeuticwarfarin, 10% Dual antiplatelettherapy, 2% Sub-therapeuticwarfarin, 29% Single antiplateletagent, 29% Gladstone, D. J. et al. Stroke 2009;40:235–240

8. Warfarin and its challenging therapeutic window 20 Therapeuticrange Requires dose adjustmentand regular monitoring Stroke 15 Intracranial bleed 10 Odds ratio 5 1 0 1 2 3 4 5 6 7 8 International normalized ratio (INR) ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354and Eur Heart J 2006;27:1979–2030

9. Why time in therapeutic range (TTR) matters Warfarin group 1.0 71–100% 61–70% 51–60% 0.9 41–50% 31–40% <30% Cumulative survival 0.8 Non warfarin 0.7 0.6 0 500 1000 1500 2000 Survival to stroke (days) Morgan CL et al. Thrombosis Research 2009;124:37–41

10. Individual TTR: main determinant of quality of anticoagulation and predictor of clinical outcome Black – above range Light Grey – within range Dark grey – below range Veeger et al: Brit J Haematol 2005;128:513

11. Warfarin is not widely used

12. Waited over 50 years for a new oral anticoagulant....

13. SPAF trials versus Warfarin Date of preparation: January 2012 Ezekowitz et al. Am Heart J 2009;157 and Connolly et al, N Eng J Med 2009; 361 Rocket investigators, Am Heart J 2010; 159 and Patel et al, N Eng J Med 2011; 365 Lopes et al. Am Heart J 2010; 159 and Granger et al, N Eng J Med 2011; 365

14. Dabigatran - Time to first stroke / SSE RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) p=0.34 (Sup) 0.05 Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.04 RRR 35% 0.03 Cumulative hazard rates RR 0.65 (95% CI: 0.53–0.82) p<0.001 (NI) p<0.001 (Sup) 0.02 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ et al.NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

15. RE-LY (dabigatran): Time to first intra-cranial bleed 0.02 Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RRR 59% RRR 69% RR 0.41 (95% CI: 0.27–0.60) p<0.001 (Sup) Cumulative hazard rates 0.01 RR 0.31 (95% CI: 0.20–0.47) p<0.001 (Sup) 0.0 0 0.5 1.0 1.5 2.0 2.5 Years RR, relative risk; CI, confidence interval; Sup, superior Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientswith Atrial fibrillation Connolly SJ et al.NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

16. Major bleeding risk compared to warfarin RR 0.80 (95% CI: 0.70–0.93) p=0.003 (sup) RR 0.93 (95% CI: 0.81–1.07) 4.0 p=0.32 (sup) 3.5 3.57 3.0 3.32 RRR 7% ARR 0.25% RRR 20% ARR 0.70% 2.87 % per year 2.5 2.0 1.5 1.0 0.5 0 D110 mg BID D150 mg BID Warfarin 342 / 6,015 399 / 6,076 421 / 6,022 19. Connolly SJ et al.N Engl J Med 2009; 361:1139–1151 20. Connolly et al. N Engl J Med 2010; 363:1875–1876

17. Most common adverse events *Occurred more commonly on dabigatran p<0.001 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientswith Atrial fibrillation Connolly SJ et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

18. Rivaroxaban - primary endpoint Date of preparation: January 2012 Patel et al, N Eng J Med 2011; 365 *SSE (Stroke, Systemic Embolism)

19. Rivaroxaban - safety endpoint Date of preparation: January 2012 Patel et al, N Eng J Med 2011; 365

20. Apixaban – primary endpoint Date of preparation: January 2012 Granger et al, N Eng J Med 2011; 365 *SSE (Stroke, Systemic Embolism)

21. Apixaban – safety endpoints Date of preparation: January 2012 Granger et al, N Eng J Med 2011; 365

22. New agents versus warfarin Stroke, Systemic Embolism Haemorrhagic stroke Date of preparation: January 2012 Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19 Patel et al, N Eng J Med 2011; 365 Granger et al, N Eng J Med 2011; 365

23. New agents versus warfarin Major Bleeds Intracranial bleeding Date of preparation: January 2012 Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19 Patel et al, N Eng J Med 2011; 365 Granger et al, N Eng J Med 2011; 365

24. Benefits of New Agents • Dabigatran 150 mg bd and Apixaban 5mg bd have superior efficacy to Warfarin. • Dabigatran 110mg bd and Riveroxiban 20mg od are non inferior to Warfarin. • All four agents and doses are superior to Warfarin in reducing Intracranial haemorrhages. • Dabigatran 110mg bd and Apixaban 5mg bd are superior to Warfarin in avoiding major haemorrhage

25. Benefits of New Agents Warfarin in avoiding major bleeds All three drugs are oral agents Short half life means rapid onset of action All three do not require monitoring (Major perceived benefit for patients) Few known drug interactions

26. Disadvantages of the new agents • Short half life means concordance of treatment regime is important otherwise patients will be undertreated • Lack of monitoring will prevent patients concordance being checked • Lack of a test of coagulation may be a problem if patients present with acute bleeding • Lack of an agreed protocol for managing acute bleeding • Differences in the proposed management of bleeding complications

27. “The Cost is greater than Warfarin” Dabigatran £2.52/day Riveroxiban £2.10/day Have we really understood the true cost of anticoagulation with Warfarin? Frequency of INR Tests Need for District Nurse visits for phlebotomy Full cost of bleeding complication ICH Major bleeding Admissions with high INR Urgent clinic attendances Have we understood the cost of increased stroke for patients not ant coagulated because of “Fear of Warfarin?

28. Difference in the estimated number of events over 5 yr if 10,000 patients over 80 switched to dabigatran

29. Difference in the estimated number of events over 5 yr if 10,000 patients over 80 switched to dabigatran • As TTR falls the • incremental benefits of introducing Dabigatran are • Reductions in the number of Ischaemic stroke • Reductions in ICH • Reduction in ECH • Fall in net cost

30. Net clinical benefit and components All data represents %/year Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.

31. What about other preventative treatments Proteos for Osteoporosis £312 per year Candesartan 32 mg £ 192 per year HRT patches £384 per year

32. Where should we focus the use of new agents? • Patients with Atrial Fibrillation and at least a CHADS score of 1. • Patients who are documented to be allergic or intolerant to Coumarins

33. Where should we focus the use of new agents? Failure to maintain adequate time in therapeutic range Patients who continue to need INR monitoring more frequently than every two weeks Patients in whom the practicality of INR monitoring is burdensome

34. Warfarin and its challenging therapeutic window 20 Therapeuticrange Requires dose adjustmentand regular monitoring Stroke 15 Intracranial bleed 10 Odds ratio 5 1 0 1 2 3 4 5 6 7 8 International normalized ratio (INR) ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354and Eur Heart J 2006;27:1979–2030

35. Stroke / SSE RR 0.90 (95% CI: 0.74–1.10) p<0.001 (NI) RR 0.65 (95% CI: 0.52–0.81) 1.8 p<0.001 (sup) 1.71 1.5 1.54 RRR 35% ARR 0.60% 1.2 RRR 10% ARR 0.17% % per year 1.11 0.9 0.6 0.3 0 D110 mg BID D150 mg BID Warfarin 183 / 6,015 134 / 6,076 202 / 6,022 19. Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151 20. Connolly et al. N Engl J Med 2010; 363:1875-1876

36. Time to first intra-cranial bleed 0.02 Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RRR 59% ARR 0.44% RRR 70% ARR 0.53% RR 0.41 (95% CI: 0.28–0.60) p<0.001 (Sup) Cumulative hazard rates 0.01 RR 0.30 (95% CI: 0.19–0.45) p<0.001 (Sup) 0.0 0 0.5 1.0 1.5 2.0 2.5 Years RR, Relative risk; CI, confidence interval; Sup, superior 19. Connolly SJ et al.N Engl J Med 2009; 361:1139–1151 20. Connolly et al. N Engl J Med 2010; 363:1875–1876

37. Should we focus the use of new agents on patients with recent TIA? Patients with recent TIA High risk of early stroke recurrence Immediate prescription will lead to immediate cover compared to delayed cover with Warfarin Patients with recent cardio embolic stroke > 14 days

38. The ‘pitch’ • Newly diagnosed, treatment-naïve AF patients should be offered a new oral anticoagulants • Its more effective than Warfarin • Its rapid onset ensures early protection • Its is simpler to use • Its much easier for patients

39. The ‘pitch’ Patients stable on warfarin should be switched to a new oral anticoagulant?

40. Thank you

41. Myocardial infarction The rate of myocardial infarction was higher with both doses of dabigatran than with warfarin. Definition not reported in Re-ly but adjudicated Enzyme rise / ECG change No difference in mortality It may be that warfarin provides better protection against coronary ischemic events than dabigatran, and warfarin is known to reduce the risk of myocardial infarction. Rates of myocardial infarction were similar between patients with Atrial fibrillation who received warfarin and those on ximelagatran, another direct thrombin inhibitor. The explanation for this finding is therefore uncertain.

42. Use of dabigatran in clinical "real world" practice Non-adherence is likely to undermine therapeutic outcomes in "real world" practice because of a reduction in patient adherence Drug interactions. Although identified drug interactions are few at this point, it can be anticipated that at least some additional medications will interact with dabigatran Safety vs efficacy at extremes of body weight Renal and/or hepatic disease Other adverse effects may be identified as wide-spread use occurs Medico-legal issues may arise when major bleeding occurs with this drug that cannot be monitored or reversed. Cost