1. Managing anticoagulation in atrial fibrillation Dr Katy Rice June 2011

2. Atrial fibrillation Commonest chronic arrhythmia Increasing prevalence - ageing population -improved survival from CHD Morbidity/mortality from stroke, heart failure Stroke risk reduced by warfarin

3. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

4. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

5. Burden of disease AF Prevalence per 1000 population in Scotland 2001-2 (Murphy NF et al 2007) Overall8.7 <45 years0.3 65-74 years30.5 >85 years70.7

6. Prevalence of AF in the Renfrew- Paisley study Cohort of men and women aged 45–64 years (n = 15,406) Reproduced with permission of the BMJ Publishing Group from Stewart S et al, Heart 2001: 86:516-21

7. Extrapolating to Sutton and Merton population PCT population392,300 Registered AF patients (QOF 2009-10) 3,959 AF anticoagulated (40%)1,584 Potential AF needing anticoagulation (60%) 2,375 Estimated new AF patients/year 340

8. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

9. Recognition of those at risk of stroke Patients with AF have x 5 risk of stroke AF and no risk factors 1% per year AF and previous stroke/TIA 12% per year Stroke in AF has poorer outcome

10. Annual stroke rates in AF according to CHADS 2 score Score Risk% 01.9 12.8 24.0 35.9 48.5 512.5 618.2

11. Determine stroke/thromboembolic risk High risk: Previous ischaemic stroke/TIA or thromboembolic event Age >75 with hypertension, diabetes or vascular disease Clinical evidence of valve disease, heart failure, or impaired left ventricular function on echocardiography Moderate risk: Age >65 with no high risk factors Age <75 with hypertension, diabetes or vascular disease Low risk: Age <65 with no moderate or high risk factors Patients with AF

12. Determine stroke/thromboembolic risk High risk Moderate risk Low risk Consider anticoagulation or aspirin Aspirin 75 to 300 mg/day if no contraindications Contraindications to warfarin? Warfarin, target INR = 2.5 (range 2.0 to 3.0) Reassess risk stratification whenever individual risk factors are reviewed NO YES Patients with AF

13. New risk scoring systems CHA(2)DS(2)-Vasc (Cong heart failure, Hypertension, Age≥75,Diabetes, Stroke, Vascular disease, Age 65-74, Sex category) HAS-BLED - (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly)

14. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

15. Warfarin and AF Oral anticoagulation reduces stroke risk in AF by 2/3………..but only if time in therapeutic range (INR 2-3) is greater than 65% Oral anticoagulation leads to 2 extra intracranial bleeds per annum per 1000 patients

16. Benefits versus risks Stroke risk Valvular AF CHADS2 Bleeding risk >75 years Uncontrolled hypertension History of bleeding or intracranial haemorrhage Anaemia Polypharmacy History of poor anticoagulation control Anti-platelet drugs

17. Warfarin (relative) contraindications Advanced age Multiple comorbidities Cognitive impairment Visual impairment History of falls Alcohol Previous bleed on warfarin Recent history of GI bleeding Uncontrolled hypertension Recent major surgery Pregnancy Inherited coagulation defect Thrombocytopenia

18. Warfarin preassessment FBC - anaemia (?bleeding) - platelets <100 x 10 9 /l INR or APTT ratio >1.4 needs investigation (liver disease, lupus inhibitor, factor deficiency) Liver function tests

19. Warfarin determinants of dose Genetic e.g. VKORC1, CYP2C9 genes Age Comorbidities (heart, liver disease, poor nutrition) Medication

20. Warfarin induction protocols Slow AF No heparin needed Less likely to ‘overshoot’ Less frequent monitoring Fast Acute DVT or PE Need heparin until INR therapeutic Often results in high INRs Frequent tests

21. AF Induction Protocol Start 3mg daily and check INR after one week If INR <1.4 increase to 5 mg daily and repeat INR in 3 days If INR 1.4-1.8 increase to 4mg daily and repeat in one week If INR 1.9-2.5 continue 3mg daily and repeat INR in one week If INR >2.5 consider dose reduction or omitting dose

22. Cardioversion for persistent AF NICE guidance : INR 2.5 (range 2-3) for 3 weeks prior and 4 weeks after At Epsom & St Helier we aim for target 2.5-3.5 to reduce likelihood of cancellation due to low INR Monitor weekly Cardiologists insist on venous samples (but probably no need if using Coaguchek) For urgent cardioversion give therapeutic LMWH before and warfarin for 4 weeks after

23. Aspirin for AF Alternative to warfarin if contraindications or intolerance or patient preference Less effective than warfarin Reduces stroke risk by 22% compared with placebo (warfarin 68%)

24. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

25. Anticoagulant service provision General practice Secondary care Self monitoring -and various combinations of the above!

26. Anticoagulant service provision

28. Anticoagulation service at St Helier Estimated AF patients on books new AF patients per month Pressure to reduce ‘new:follow-up ratios’ Need to work with GPs to transfer patients to primary care

30. Themes of talk 1.AF - the burden of disease 2.Recognition of those at risk of stroke 3.Warfarin - current standard of care 4.Anticoagulant service provision 5.New oral anticoagulants

31. The new anticoagulants Oral Wide therapeutic index Predictable pharmacokinetics and dynamics negating need for monitoring Rapid onset of action Antidote Minimal non-anticoagulant side-effects Minimal interactions with other drugs and food

32. The new oral anticoagulant drugs Dabigatran (Pradaxa - Boehringer-Ingelheim) Rivaroxaban (Xarelto - Bayer) - both licensed in UK for thromboprophylaxis post knee and hip replacement. Dabigatran licence for AF expected late June 2011. Apixaban (Pfizer)- awaiting FDA approval

33. Dabigatran Dabigatran etexilate, a pro-drug, is rapidly converted to dabigatran 80% excreted by kidney Half-life of 12-17 hours Phase 2 data identified 110 mg BID and 150 mg BID as viable doses

34. RE-LY: A Non-inferiority Trial Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Warfarin adjusted (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000 Blinded Event Adjudication. Open Blinded

35. Trial Execution Performed December 2005-March 2009 Median Follow up 2.0 years Follow up 99.9% complete Mean time in therapeutic range = 64% (patients on warfarin)

36. Ischaemic/Unspecified Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR =1.11 95% CI = 0.89- 1.40 P = 0.35 RR = 0.76 95% CI = 0.60- 0.98 P = 0.03 Years of Follow-up Cumulative Hazard Rates 0.0 0.02 0.04 0.06 0.08 00.51.01.52.02.5 Dabigatran110 Dabigatran150 Warfarin

37. Hemorrhagic Stroke D 110 mg vs. Warfarin D 150 mg vs. Warfarin RR = 0.31 95% CI =0.17- 0.56 P <0.001 RR =0.26 95% CI =0.14-0.49 P <0.001 Years of Follow-up Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 00.51.01.52.02.5 Dabigatran110 Dabigatran150 Warfarin

38. Bleeding D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrateAnnualrateRR 95% CI pRR p Total14.6%16.4%18.2% 0.78 0.74-0.83 <0.001 0.91 0.86-0.97 0.002 Major2.7 %3.1 %3.4 % 0.80 0.69-0.93 0.003 0.93 0.81-1.07 0.31 Life- Threatenin g major 1.2 %1.5 %1.8 % 0.68 0.55-0.83 <0.001 0.81 0.66-0.99 0.04 Gastro- intestinal Major 1.1 %1.5 %1.0 % 1.10 0.86-1.41 0.43 1.50 1.19-1.89 <0.001

39. MI, Death and Net clinical Benefit D 110mgD 150mg warfari n D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrate Annual AnnualrateRR 95% CI pRR p MI0.7% 0.5 % 1.35 0.98-1.87 0.07 1.38 1.00-1.91 0.048 Death3.8 %3.6 %4.1 % 0.91 0.80-1.03 0.13 0.88 0.77-1.00 0.05 Net Clinical Benefit 7.1 %6.9 %7.6 % 0.92 0.84-1.02 0.10 0.91 0.82-1.00 0.04 Net Clinical Benefit includes vascular events, death and major bleed

40. Dabigatran 150 mg vs. 110 mg Dabigatran 110mg Dabigatran 150mg D 150mg vs. D 110 mg Numberrate/yrNumberrate/yr Relative Risk 95% CI p Stroke and systemic embolism 1.5%1.1 % 0.73 0.58-0.91 0.005 Hemorrhagic stroke 0.1% 0.85 0.39-1.83 0.67 Major Hemorrhage2.7 %3.1 % 1.16 1.00-1.34 0.05 Net Clinical Benefit7.1 %6.9 % 0.98 0.89-1.08 0.66 *Net Clinical Benefit includes vascular events, death and major bleed

41. Permanent Discontinuation Years of Follow-up Stopping Rates 0.0 0.1 0.2 0.3 0.4 00.51.01.52.02.5 Dabigatran110 Dabigatran150 Warfarin

42. Adverse events occurring in >5% of any group Dabigatran 110 mg% Dabigatra n 150 mg% Warfarin% Dyspepsia *11.811.35.8 Dyspnea9.39.59.7 Dizziness8.18.39.4 Peripheral edema7.9 7.8 Fatigue6.6 6.2 Cough5.7 6.0 Chest pain5.26.25.9 Arthralgia4.55.55.7 Back pain5.35.25.6 Nasopharyngitis5.65.45.6 Diarrhea6.36.55.7 Atrial fibrillation5.55.95.8 Urinary tract infection4.54.85.6 Upper respiratory tract infection 4.84.75.2 Common Adverse Events *Occurred more commonly on dabigatran p<0.001

43. RE-LY Study Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses reduced intra-cerebral, life-threatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

44. Conclusions Both Dabigatran doses offer advantages over warfarin Dabigatran 150 is more effective and dabigatran 110 has a better safety profile Taken twice daily No reversal agent

45. Dabigatran - financial impact £2.50/day £912.50/year Warfarin cost £383/year(NICE)? Annual cost pressure for S London £6 - 10.3 million Planned introduction needed

46. S & M implementation scenarios ScenarioCost (£) All patients switch from warfarin (minus warfarin costs) 839k New patients only at 60% rate186k Out of range on warfarin only (,65% TTR) 479k Currently untreated only (assuming 50% identified) 593k Warfarin contraindicated only (11%) 159-238k

47. Key issues Can a budget be identified from June 2011? Can subgroups be specified pending NICE HTA? How can clinicians be encouraged to comply with guidance? Can money be released from anticoag services for 2012/13? How should public pressure be dealt with if no money for widespread use?

48. Recommendations from S London Cardiac and Stroke Network Warfarin to remain agent of choice in short term Dabigatran in patients with contraindications to warfarin Establish S London working group to ensure consistent approach and develop prescribing guidance Develop communication plan and patient information strategy