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Antistolling in AF Het begin van een nieuw tijdperk?

Antistolling in AF Het begin van een nieuw tijdperk?. Dr RG Tieleman Martini Ziekenhuis Groningen. CVA en Atriumfibrilleren: de feiten. CVA is de belangrijkste complicatie van AF AF is geassocieerd met een 5x verhoogde kans op CVA

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Antistolling in AF Het begin van een nieuw tijdperk?

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  1. Antistolling in AF Het begin van een nieuw tijdperk? Dr RG Tieleman Martini Ziekenhuis Groningen

  2. CVA en Atriumfibrilleren: de feiten • CVA is de belangrijkste complicatie van AF • AF is geassocieerd met een 5x verhoogde kans op CVA • AF verdubbeld het risico op CVA wanneer gecorrigeerd voor andere risico factoren • Zonder behandeling is de incidentie van CVA in AF 5% • (incl TIAs en stille CVAs > 7%) • AF is verantwoordelijk voor 1/3 van alle CVAs • AF geassocieerd CVA is 2x vaker dodelijk en meer invaliderend

  3. Warfarin superior in reducing the stroke risk in AF patients Control worse Control better RRR 64% (95% CI: 4974%) Warfarin vs Placebo RRR = 19%(95% CI: –1 to 35%) Aspirin vs Placebo RRR 38%(95% CI: 18–52%) Warfarin vs Aspirin 100 50 0 –50 –100 RRR (%)† Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857–67

  4. VKAs have a narrow therapeutic window Therapeuticrange 20 15 Stroke 10 Intracranial bleed Odds ratio 5 1 0 1 2 3 4 5 6 7 8 International normalized ratio VKAs = vitamin K antagonists ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354& Eur Heart J 2006;27:1979–2030

  5. 100 80 60 40 20 0 3 6 9 12 15 18 21 24 26 Treatment Duration (months) SPORTIF VINR Values – Warfarin Group 68% Time in Range (%) 2.0-3.0 Circulation 2003;108:2723

  6. Bleeding risk with warfarin compared with Aspirin Aspirin Intracranial bleeds 5.0 Warfarin Major bleeds 4.0 3.0 Annual rate (%) 2.0 1.0 0.0 Age 75 yrs Age >75 yrs AFASAK I AFASAK II PATAF SPAF II Major bleeds = transfusion or hospitalization required, or critical anatomic location (e.g. intracranial, perispinal); Within trial differences not statistically significant Albers GW et al. Chest 2001;119:194S–206S

  7. Most strokes occurred in patients who were under-anticoagulated Target range for study 4.0 INR at which stroke event occurred 3.0 INR 2.0 1.0 AFASAK CAFA SPAF BAATAF SPINAF Association of stroke events with intensity of anticoagulation for patientswith AF treated with warfarin in major randomized trials ACC/AHA/ESC recommended INR (2.0–3.0) ACC = American College of Cardiology; AHA = American Heart Association;ESC = European Society of Cardiology; INR = international normalized ratio Levi M et al. Semin Thromb Haemost 2009;35:527–42

  8. Targets for novel antithrombotic agents in the coagulation cascade Vitamin K antagonist: Tecarfarin (Ph II completed)2 Tissue factor/VIIa X IX Indirect factor Xa inhibitors: Idraparinux (Ph III terminated)3 SSR 126517 (withdrawn 2009)4 VIIIa IXa Va Direct factor Xa inhibitors: Apixaban (Ph III ongoing)5,6 Rivaroxaban (Ph III ongoing)7 Edoxaban (Ph III ongoing)8 Betrixaban (Ph II ongoing)9 Xa AT Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed)10 Ximelagatran (withdrawn 2006)11,12 AZD0837 (Ph II completed)13 II Thrombin Fibrinogen Fibrin AT= antithrombin; Ph = Phase 1. Adapted from Turpie AG. Eur Heart J 2008;29:155–65; 2. Ellis DJ et al.Circulation 2009;22:120:1029–35; 3.Bousser MG et al. Lancet 2008;371:315–21; 4. NCT00580216; available at www.ClinicalTrials.gov; accessed Sept 09; 5. Lopes RD et al. Am Heart J 2010;159:331–9; 6. Eikelboom JW et al. Am Heart J 2010;159:348–53; 7. ROCKET-AF Study Investigators. Am Heart J 2010;159:340–47; 8. NCT00781391; available at www.ClinicalTrials.gov; accessed Sept 09; 9. NCT00742859;available at www.ClinicalTrials.gov; accessed Sept 09; 10. Connolly SJ et al. N Engl J Med 2009;361:1139–51;11. Olsson SB et al. Lancet 2003;362:1691–8; 12. Albers GW et al. JAMA 2005;293:690–8;13.Lip GY et al. Eur Heart J 2009;30:2897–907

  9. Dabigatran RE-LY®: study design R AF with 1 risk factor Absence of contraindications Warfarin 1 mg, 3 mg, 5 mg (INR 2.0–3.0) n=6000 Dabigatran 110 mg BID n=6000 Dabigatran 150 mg BID n=6000 • Primary objective: to establish the non-inferiority of dabigatran to warfarin • Minimum 1 year follow-up, maximum of 3 years and median of 2 years of follow-up • Primary Endpoint: All Strokes (ischemic and hemorrhagic) and systemic embolism Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51

  10. Phase III RE-LY®: time to first stroke or systemic embolism Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID RRR 34% RR 0.91 (95% CI: 0.74–1.11) P<0.001 (NI) P=0.34 (Sup) 0.05 0.04 0.03 Cumulative hazard rates RR 0.66 (95% CI: 0.53–0.82) P<0.001 (NI) P<0.001 (Sup) 0.02 0.01 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Years BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:1139–51

  11. Phase III RE-LY®: major bleeding 3.36 3.11 2.71 RR 0.80 (95% CI: 0.69–0.93) P=0.003 (Sup) RR 0.93 (95% CI: 0.81–1.07) 3.5 P=0.31 (Sup) RRR 20% 3.0 2.5 2.0 Major bleeding (%/yr) 1.5 1.0 0.5 0.0 Dabigatran110 mg BID Dabigatran150 mg BID Warfarin Events/n: 322/6015 375/6076 397/6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:1139–51

  12. Phase III RE-LY®: intracranial bleeding 0.74 0.30 0.23 RR 0.31 (95% CI: 0.20–0.47) P<0.001 (Sup) RR 0.40 (95% CI: 0.27–0.60) 0.9 P<0.001 (Sup) 0.8 0.7 0.6 RRR 60% 0.5 Intracranial bleeding (%/yr) RRR 69% 0.4 0.3 0.2 0.1 0 Dabigatran110 mg BID Dabigatran150 mg BID Warfarin Events/n: 27/6015 36/6076 87/6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:1139–51

  13. Phase III RE-LY®: conclusions Dabigatran etexilate has been shown to concurrently reduce both thrombotic and haemorrhagic events Both doses of dabigatran provide different and complementary advantages over warfarin 150 mg BID has superior efficacy with similar bleeding 110 mg BID has significantly less bleedings with similar efficacy BID = twice daily; INR = international normalized ratio Connolly SJ et al. N Engl J Med 2009;361:1139–51;

  14. Direct and indirect factor Xa (FXa) inhibition Direct FXa inhibitor FXa DIRECT Binds directly to the active site of FXa, blocking substrate interactions (e.g. apixaban, rivaroxaban, edoxaban, betrixaban) INDIRECT Binds to antithrombin (AT) and potentiates the activity of AT against FXa (e.g. idraparinux, SSR 126517) FXa AT AT AT Indirect FXa inhibitor II Thrombin Fibrinogen Fibrin clot Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25

  15. Phase III AVERROES: study design R AF with 1 risk factor and demonstrated or expected unsuitable for VKA Apixaban 5 mg BID (2.5 mg BID in selected patients) Aspirin81–324 mg/d Primary objective: to establish the superiority of apixaban over Aspirin 36 countries, 522 centres, double-blind study. N=5600 pts Study was stopped after interim analysis Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx VKA = vitamin K antagonist; BID = twice daily

  16. AVERROES: stroke or syst embolic event Aspirin Apixaban 0.07 0.06 0.05 RR 0.4695% CI: 0.33–0.64P<0.001 0.04 Cumulative risk 0.03 0.02 0.01 0 0 3 6 9 12 18 21 Months Aspirin 2791 2720 2541 2124 1541 626 329 Apixaban 2809 2761 2587 2127 1523 617 352 RR = relative risk; CI = confidence interval Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

  17. Phase III AVERROES: major bleeding Aspirin Apixaban 0.025 0.020 RR 1.1495% CI: 0.74–1.75P=0.56 0.015 Cumulative risk 0.010 0.005 0 0 3 6 9 12 18 21 Months No. at risk Aspirin 2791 2744 2572 2152 1570 642 340 Apixaban 2809 2763 2567 2123 1521 622 357 RR = relative risk; CI = confidence interval Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

  18. Ongoing Phase III trials with direct factor Xa inhibitors for the prevention of stroke in patients with AF *Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily

  19. Who should we treat with what? Individual ‘cost-benefit analysis’ to determine therapeutic strategy

  20. Stroke risk assessment with CHA2DS2-VASc *Theoretical rates without therapy corrected for the % of patients receiving Aspirin within each group,assuming 22% reduction in risk with Aspirin TE = thromboembolism Lip GYH et al. Chest 2010;137:263-72

  21. 2010 ESC guidelines on antithrombotic therapy in AF recommendations based on the CHA2DS2-VASc score: Score of ≥2: Oral anticoagulation (INR 2.0–3.0) Score of 1: Oral anticoagulation (INR 2.0–3.0) (preferred option) or Aspirin (81–325 mg/day) Score of 0: Aspirin (81–325 mg/day) or no therapy (preferred option) ESC = European Society of Cardiology; INR = international normalized ratio ESC guidelines: Camm J et al. Eur Heart J 2010

  22. Bleeding risk assessment with HAS-BLED INR=international normalized ratio *P value for trend = 0.007 Pisters R et al. Chest. 2010; ESC guidelines: Camm J et al. Eur Heart J 2010

  23. Percutane Left Atrial Appendage Closure Devices PLAATO AMPLATZER CARDIAC PLUG WATCHMAN

  24. Future guidelines on Antithrombotic therapy in Atrial Fibrillation All AF pts receive Direct Thrombin Inhibitor or Direct Factor Xa Inhibitorexcept: Male lone AF patients < 65 yrs No therapy HAS-Bled Score of ≥ 4: LAA Closure device? No indication for vitamin K antagonists or Aspirin R.G. Tieleman, (personal opinion) GetRhythm Symposium Utrecht 2010

  25. Back-up Slides

  26. Dabigatran etexilate Oral prodrug, converted to dabigatran, which is a potentand reversible direct thrombin inhibitor (DTI) Inhibits both clot-bound and free thrombin 6.5% bioavailability Peak plasma levels of dabigatran achieved within 2 hours after administration in healthy volunteers Half-life of 12–17 hours ~80% renal excretion Most advanced DTI in Phase III development for stroke prevention in patients with AF Recently demonstrated superiority to warfarin in the Phase III RE-LY® study Pradaxa: SmPC, 2009; Connolly SJ et al. N Engl J Med 2009;361:1139–51

  27. Dabigatran etexilate has key features that make it an effective antithrombotic for stroke prevention 1. Pradaxa: SmPC, 2009; 2.Stangier J et al. Clin Pharmacokinet 2008;28:47–59; 3. Stangier J Clin Pharmacokinet 2008;47:285–95; 4. Stangier J et al. Br J Pharmacol 2007;64:292–303; 5. Blech S et al. Drug Metab Dispos 2008;36:386–99; 6. Stangier J et al. J Clin Pharmacol 2005;45:555–63 Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation.This information is provided for medical education purposes only.

  28. Phase III RE-LY®: largest AF outcomes trial 18113 patients randomized during 2 years1,2 50% of enrolled patients are naïve to previous oral anticoagulant Median treatment duration: 2 years 951 centres in 44 countries December 2005 to March 2009 Results first presented at ESC congress 2009 and published online in New England Journal of Medicine on 30 Aug 2009 RE-LY®:Randomized Evaluation of Long-term anticoagulant therapy ESC = European Society of Cardiology 1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51

  29. Baseline characteristics ASA = acetylsalicylic acid (aspirin); BID = twice daily; CHF = congestive heart failure; MI = myocardial infarction; TIA = transient ischaemic attack Connolly SJ et al. N Engl J Med 2009;361:1139–51

  30. Phase III RE-LY®: study inclusion and exclusion criteria Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51

  31. Phase III RE-LY®: risk of stroke or systemic embolism Non-inferiority P value Superiority P value Dabigatran110 mg BID vs. warfarin <0.001 0.34 Margin = 1.46 Dabigatran150 mg BID vs. warfarin <0.001 <0.001 0.50 0.75 1.00 1.25 1.50 Hazard ratio Error bars = 95% CI; BID = twice daily Connolly SJ et al. N Engl J Med 2009;361:1139–51

  32. Warfarin reduces the risk of stroke in patients with AF Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials 100 50 0 –50 –100 RRR (%)† RRR 64%*(95% CI: 4974%) 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

  33. Limited efficacy of Aspirin in reducing the risk of stroke in patients with AF Aspirin better Placebo better AFASAK SPAF EAFT ESPS II LASAF 125 mg/d 125 mg QOD UK-TIA 300 mg/d 1200 mg/d JAST RRR = 19%*(95% CI: –1 to 35%) All trials 100 50 0 –50 –100 RRR (%)† Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR)for all strokes (ischaemic and haemorrhagic); QOD = every other day Hart RG et al. Ann Intern Med 2007;146:857–67

  34. Warfarin compared with Aspirin for stroke prevention in AF Warfarin better Aspirin better AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II Age 75 yrs Age >75 yrs RRR 38%(95% CI: 18–52%) All trials 100 50 0 –50 –100 RRR (%)* 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

  35. Congestive heart failure (1 point) (History of) Hypertension (1 point) Age > 75 years (1 point) Diabetes Mellitus (1 point) Prior Stroke/TIA (2 points) Risk factors for stroke in AF: CHADS2 OAC in case score > 1 Cage et al JAMA 2001

  36. Stroke risk assessment with CHADS2 0 1 2 3 CHADS2 score 4 5 6 0 5 10 15 20 25 30 Annual stroke rate (%)* • Congestive heart failure (1 point) • (History of) Hypertension (1 point) • Age > 75 years (1 point) • Diabetes Mellitus (1 point) • Prior Stroke/TIA (2 points) Error bars = 95% CI; *Adjusted stroke rate = expected stroke rate per 100 patient-years based on exponential survival model, assuming Aspirin not taken Gage BF et al. JAMA 2001;285:2864–70

  37. 2010 ESC guidelines for antithrombotic Rx in AF ESC guidelines: Camm J et al. Eur Heart J 2010

  38. 2010 ESC guidelines for antithrombotic therapy in AF CHADS2 score ≥2† †Congestive heart failure,Hypertension, Age ≥75 yrs, Diabetes, Stroke/TIA/thrombo-embolism (doubled) *Other clinically relevant non-major risk factors: age 65–74 yrs, female sex, vascular disease No Yes Consider other risk factors* Age ≥75 years No Yes ≥2 other risk factors* No Yes OAC 1 other risk factor* Yes OAC (or Aspirin) No Nothing (or Aspirin) ESC = European Society of Cardiology; OAC = oral anticoagulation; TIA = transient ischaemic attack ESC guidelines: Camm J et al. Eur Heart J 2010; [Epub ahead of print]

  39. SPAF III: adjusted-dose warfarin compared with low-intensity warfarin plus Aspirin n= 521 378 265 166 61 n= 523 397 273 173 65 Ischaemic stroke or systemic embolism 15 Similar Bleeding Risk Combination therapy Fixed-dose warfarin (INR 1.2–1.5)*+ Aspirin (325 mg/d) 10 Cumulative event rate (% per year) RRR 74%(95% CI: 5087%) P<0.0001 5 Adjusted-dose warfarinWarfarin (INR 2.0–3.0) 0 0 0.5 1.0 1.5 2.0 Years *Warfarin dose adjusted between 0.5 and 3.0 mg/day to achieve international normalized ratio (INR) 1.21.5 when initiating therapy and then fixed for rest of study; RRR = relative risk reduction SPAF Investigators. Lancet 1996;348:633–8

  40. ACTIVE trials: dual antiplatelet therapy for stroke prevention in AF Documented AF and 1 risk factor*for stroke Suitable for VKA Unsuitable for VKA ACTIVE A Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d) vs. Aspirin (75–100 mg/d) ACTIVE W Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d) vs. VKA (target INR = 2.0–3.0) No exclusion criteria for ACTIVE I ACTIVE I Irbesartan (300 mg/d) vs. placebo Partial factorial design Connolly SJ et al. Am Heart J 2006;151:1187–1193

  41. ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF n= 3335 3168 2419 941 n= 3371 3232 2466 930 Stroke 0.05 Dual antiplatelet therapy Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d) 0.04 RR 1.72(95% CI: 1.242.37) P=0.001 0.03 Oral anticoagulationVKA (target INR = 2.0–3.0) Cumulative hazard rates 0.02 0.01 0.00 0 0.5 1.0 1.5 Years INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist ACTIVE Investigators. Lancet 2006;151:1903–12

  42. ACTIVE A: dual antiplatelet therapy superior to Aspirin alone for stroke prevention in AF 3772 3491 3229 2570 1203 n= n= 3782 3458 3155 2517 1186 Stroke 0.15 Aspirin aloneAspirin (75–100 mg/d) Dual antiplatelet therapy Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d) 0.10 But 1.5-2.0x more bleeding Cumulative incidence HR 0.72(95% CI: 0.62–0.83) P<0.0001 0.05 0.00 0 1 2 3 4 Years Reasons for considering patients inappropriate for vitamin K antagonist included specific risk of bleeding (22.9%), physician’s judgement in absence of specific bleeding risk (49.7%) and patient preference alone (26.0%);HR = hazard ratio ACTIVE Investigators. N Engl J Med 2009;360:2066–78

  43. Safety and efficacy of idraparinux for stroke prevention in AF: Phase III AMADEUS Idraparinux (n=2283) Warfarin (n=2293) 19.7% 20 1.5 1.3% 15 0.9% 1.0 11.3% 10 Incidence (%) Incidence (%) 0.5 5 0 0 Clinically relevant bleeding Stroke and embolism P<0.0001 P=0.007 (for non-inferiority) Bousser MG et al. Lancet 2008;371:315–21

  44. Rivaroxaban Highly selective and potent inhibitor of factor Xa Bioavailability of 60–80%1 Half-life of up to 9 hours in healthy young subjects and 11–13 hours in the elderly2 Approved in Europe and Canada for the prevention of venous blood clots in patients undergoing elective hip- or knee-replacement surgery3 Compound has no direct effect on platelet aggregation4 Well-tolerated in healthy human subjects5,6 Rapid onset of action5,6 Dose-proportional pharmacokinetics/pharmacodynamics5,6

  45. Rivaroxaban and stroke prevention in AF: Phase III ROCKET-AF Randomized, double-blind, non-inferiority study1 Approximately 14000 patients with AF Comparing the efficacy and safety of rivaroxaban 20 mg ODwith warfarin for the prevention of stroke Patients with moderate renal impairment (creatinine clearance 30–49 mL/min) will receive a fixed dose of 15 mg OD rivaroxaban Primary outcomes: Any stroke or non-CNS systemic embolism Composite of major and clinically relevant non-major bleeding events Secondary outcomes: Each category of bleeding events and adverse events Composite of stroke, non-CNS systemic embolism and vascular death

  46. Phase III ROCKET-AF: study inclusion criteria ECG = electrocardiogram; LVEF = left ventricular ejection fraction ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

  47. ROCKET-AF: study exclusion criteria VTE = venous thromboembolism ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

  48. Summary: direct factor Xa inhibitors Apixaban, rivaroxaban and edoxaban are highly selective and potent inhibitors of factor Xa Several Phase III studies are comparing the efficacy and safety of direct factor Xa inhibitors with warfarin for stroke prevention in AF: ARISTOTLE (apixaban) ROCKET-AF (rivaroxaban) ENGAGE-AF TIMI-48 (edoxaban) For patients with AF who are unsuitable or have failed warfarin therapy, the efficacy and safety of direct factor Xa inhibitors have been compared with those of Aspirin AVERROES has reported that apixaban significantly reduces the risk of stroke or systemic embolism over Aspirinwith no significant increase in risk of major haemorrhage1 1. Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

  49. Biotinylated version of idraparinux: SSR 126517 No antidote for idraparinux to reverse its anticoagulant activity SSR 126517 developed to offer the same pharmacological featuresas idraparinux Addition of biotin allows the rapid removal of the drug following intravenous injection of avidin1 The bioequipotency of SSR 126517 compared with an equimolar dose of idraparinux has been evaluated for the treatment of deep vein thrombosis2 The Phase III BOREALIS-AF study compared SSR 126517 with warfarin for the prevention of stroke in AF3 SSR 126517 was withdrawn from development for stroke prevention in AF in December 2009 as it did not appear to significantly improve the care of patients4

  50. Summary: indirect factor Xa inhibitors Idraparinux has a long half-life of 80 hours that subsequently enables weekly dosing The Phase III AMADEUS study was terminated due to excess bleeding SSR 126517, the biotinylated version of idraparinux, was withdrawn from development for stroke prevention in AF in December 2009

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