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

3. Treatment options for Atrial Fibrillation Anti-platelet Treatments AspirinClopidogrel  Anticoagulants Warfarin Warfarin Dabigatran Dabigatran Riveroxiban Riveroxiban Apixaban 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. Random effects model; Error bars = 95% CI; *p>0.2 for homogeneity; † Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Warfarin has been hard to beat Hart RG et al. Ann Intern Med 2007;146:857–67 Warfarin better Placebo better RRR (%) † 100–100500–50 AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% * (95% CI: 49–74%)

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

7. DBG2919 | August 2011 How are AF patients at risk of stroke currently being managed? Gladstone, D. J. et al. Stroke 2009;40:235–240 Preadmission medications in patients with known Atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597) Therapeutic warfarin, 10% Sub-therapeutic warfarin, 29% Single antiplatelet agent, 29% Dual antiplatelet therapy, 2% No antithrombotic 29%

8. DBG2919 | August 2011 Warfarin and its challenging therapeutic window ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 and Eur Heart J 2006;27:1979–2030 1 International normalized ratio (INR) Odds ratio 2 15 8 10 5 0 1 34567 Intracranial bleed Therapeutic range 20 Requires dose adjustment and regular monitoring Stroke

9. Why time in therapeutic range (TTR) matters 0500100015002000 Survival to stroke (days) 0.6 0.7 0.8 0.9 1.0 Cumulative survival 71–100% Warfarin group 61–70% 51–60% 41–50% 31–40% <30% Non warfarin Morgan CL et al. Thrombosis Research 2009;124:37–41

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

11. Warfarin is not widely used

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

13. SPAF trials versus Warfarin DabigatranRivaroxabanApixaban DabigatranRivaroxabanApixaban StudyRELYRocketAristotle DesignPROBEDouble Blind Follow up2 yrs1.5yrs Population size>18,000>14,000>18,000 InclusionNon valvular AF + 1 risk factor Non valvular AF + 2 risk factor (i.e. moderate to high risk) Non valvular AF + 1 risk factor Inclusion (CHADs) 2.13.52.1 Primary Endpoint Stroke and systemic embolism Warfarin comparator INR control (mean TTR) 64%55%62% 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 Date of preparation: January 2012

14. 0.01 0.02 0.03 0.05 0.04 Cumulative hazard rates RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) p=0.34 (Sup) RR 0.65 (95% CI: 0.53–0.82) p<0.001 (NI) p<0.001 (Sup) Years 00.51.01.52.02.5 0.0 Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Dabigatran - Time to first stroke / SSE Connolly SJ et al. NEJM published online on Aug 30 th 2009. DOI 10.1056/NEJMoa0905561 RRR35%

15. RR 0.41 (95% CI: 0.27–0.60) p<0.001 (Sup) RR 0.31 (95% CI: 0.20–0.47) p<0.001 (Sup) Cumulative hazard rates Years 0.0 0.01 0.02 00.51.01.52.02.5 RE-LY (dabigatran): Time to first intra-cranial bleed RRR59%RRR69% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg Connolly SJ et al. NEJM published online on Aug 30 th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with Atrial fibrillation RR, relative risk; CI, confidence interval; Sup, superior

16. Major bleeding risk compared to warfarin RR 0.93 (95% CI: 0.81–1.07) RR 0.80 (95% CI: 0.70–0.93) % per year RRR 7% ARR 0.25% RRR 20% ARR 0.70% 0 1.0 2.0 4.0 342 / 6,015 2.87 D110 mg BID 399 / 6,076 3.32 D150 mg BID 421 / 6,022 3.57 Warfarin p=0.32 (sup) p=0.003 (sup) 3.0 3.5 2.5 1.5 0.5 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 Dabigatran 110 mg % Dabigatran 150 mg %Warfarin% Dyspepsia*11.811.35.8 Dyspnoea9.39.59.7 Dizziness8.18.39.4 Peripheral edema 7.97.97.8 Fatigue6.66.66.2 Cough5.75.76.0 Chest pain 5.26.25.9 Arthralgia4.55.55.7 Back pain 5.35.25.6 Nasopharyngitis5.65.45.6 Diarrhoea6.36.55.7 Urinary tract infection 4.54.85.6 Upper respiratory tract infection 4.84.75.2 *Occurred more commonly on dabigatran p<0.001 Connolly SJ et al. NEJM published online on Aug 30 th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with Atrial fibrillation

18. Rivaroxaban - primary endpoint Patel et al, N Eng J Med 2011; 365 RivaroxabanWarfarinRivaroxaban vs. Warfarin SSE* #No. / 100 pts yrs # ARRHRP = Safety, as treated 1891.72432.20.50.79 (0.65-0.95) 0.02 (sup) Intention to treat 2692.13062.40.30.88 (0.75-1.03) 0.12 (sup) *SSE (Stroke, Systemic Embolism) Date of preparation: January 2012

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

20. Apixaban – primary endpoint ApixabanWarfarinApixaban vs. Warfarin #%/YR# ARRHRP = SSE*2121.272651.600.330.790.01(sup) Granger et al, N Eng J Med 2011; 365 *SSE (Stroke, Systemic Embolism) Date of preparation: January 2012

21. Apixaban – safety endpoints Granger et al, N Eng J Med 2011; 365 ApixabanWarfarinApixaban vs. Warfarin #%/YR# ARRHRP = Major Bleeding 3272.134623.090.960.69 (0.60-0.80) <0.001 Major + Clinical relevant Bleeding 6134.078776.011.940.68 (0.61-0.75) <0.001 GI Bleeding 1050.761190.860.100.89 (0.70-1.15) 0.37 Date of preparation: January 2012

22. New agents versus warfarin SSE* vs. Warfarin (ITT population) ARRHR D1500.600.65 (0.52-0.81) D1100.170.90 (0.74-1.10) Rivaroxaban0.300.88 (0.75-1.03) Apixaban0.330.79 (0.66-0.95) Haemorrhagic stroke vs. Warfarin ARRHR D1500.280.26 (0.14-0.49) D1100.260.31 (0.17-0.56) Rivaroxaban0.180.59 (0.37-0.93) Apixaban0.230.51 (0.35-0.75) 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 Stroke, Systemic Embolism Date of preparation: January 2012 Haemorrhagic stroke

23. New agents versus warfarin Intracranial Bleeding ARRHR D1500.440.41 (0.28-0.06) D1100.530.30 (0.19-0.45) Rivaroxaban0.200.67 (0.47-0.93) Apixaban0.470.42 (0.30-0.58) 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 Major BleedingARRHR D1500.250.93 (0.81-1.07) D1100.700.80 (0.70-0.93) Rivaroxaban-0.201.04 (0.90-1.20) Apixaban0.960.69 (0.60-0.80) Date of preparation: January 2012 Major Bleeds Intracranial bleeding

24. Benefits of New Agents Dabigatran 150 mg bd and Apixaban 5mg bd have superior efficacy to Warfarin. 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. 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. 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 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 Warfarin in avoiding major bleeds All three drugs are oral agents All three drugs are oral agents Short half life means rapid onset of action Short half life means rapid onset of action All three do not require monitoring (Major perceived benefit for patients) All three do not require monitoring (Major perceived benefit for patients) Few known drug interactions 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 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 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 a test of coagulation may be a problem if patients present with acute bleeding Lack of an agreed protocol for managing acute bleeding Lack of an agreed protocol for managing acute bleeding Differences in the proposed management of bleeding complications Differences in the proposed management of bleeding complications

27. “The Cost is greater than Warfarin” Dabigatran £2.52/day Dabigatran £2.52/day Riveroxiban £2.10/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 No RxASAW re-ly IS -960-280-37 ICH 12-82-206 ECH 341-95-44 AMI -48-2450 Cost/QALY £6,334£15,643£16,072 Annual cost £228£308£266

29. Difference in the estimated number of events over 5 yr if 10,000 patients over 80 switched to dabigatran ASAW re-lyW 50- 60% W 40- 50% IS -2803715-14 ICH -82-206-230-239 ECH -95-44-216-329 AMI -24504743 Cost/QALY £15,643£16,072£12,604£10,719 Annual cost £308£266£245£230 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 Characteristic Dabi 110 mg Dabi 150 mg Warfarin P-value 110 vs. W P-value 150 vs. W Number of patients (n)601560766022 Net Clinical Benefit7.347.117.910.090.02 - Stroke / SSE - Death - MBE - PE - MI 1.54 3.75 2.87 0.12 0.82 1.11 3.64 3.32 0.15 0.81 1.71 4.13 3.57 0.10 0.64 <0.001 (NI) 0.30 (sup) 0.13 0.003 0.71 0.09 <0.001 (NI) <0.001 (sup) 0.051 0.32 0.30 0.12 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 with Atrial Fibrillation and at least a CHADS score of 1. Patients who are documented to be allergic or intolerant to Coumarins 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 Failure to maintain adequate time in therapeutic range Patients who continue to need INR monitoring more frequently than every two weeks Patients who continue to need INR monitoring more frequently than every two weeks Patients in whom the practicality of INR monitoring is burdensome Patients in whom the practicality of INR monitoring is burdensome

34. Warfarin and its challenging therapeutic window ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 and Eur Heart J 2006;27:1979–2030 1 International normalized ratio (INR) Odds ratio 2 15 8 10 5 0 1 34567 Intracranial bleed Therapeutic range 20 Requires dose adjustment and regular monitoring Stroke

35. Stroke / SSE 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 % per year 183 / 6,015134 / 6,076202 / 6,022 RRR 35% ARR 0.60% RRR 10% ARR 0.17% 1.54 0 0.3 0.6 0.9 1.2 1.5 1.8 D110 mg BID 1.11 D150 mg BID 1.71 Warfarin RR 0.65 (95% CI: 0.52–0.81) RR 0.90 (95% CI: 0.74–1.10) p<0.001 (sup) p<0.001 (NI)

36. RR, Relative risk; CI, confidence interval; Sup, superior Time to first intra-cranial bleed RRR 70% ARR 0.53% RR 0.41 (95% CI: 0.28–0.60) p<0.001 (Sup) RR 0.30 (95% CI: 0.19–0.45) p<0.001 (Sup) Cumulative hazard rates Years 0.0 0.01 0.02 00.51.01.52.02.5 RRR 59% ARR 0.44% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 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 Patients with recent TIA High risk of early stroke recurrence High risk of early stroke recurrence Immediate prescription will lead to immediate cover compared to delayed cover with Warfarin Immediate prescription will lead to immediate cover compared to delayed cover with Warfarin Patients with recent cardio embolic stroke > 14 days 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. The rate of myocardial infarction was higher with both doses of dabigatran than with warfarin. Definition not reported in Re-ly but adjudicated Definition not reported in Re-ly but adjudicated Enzyme rise / ECG change Enzyme rise / ECG change No difference in mortality 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. 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. 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. The explanation for this finding is therefore uncertain.

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