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Patti G. Vecchi e nuovi anticoagulanti orali a confronto. ASMaD 2013
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  • G02-536 w_script.ppt 03/20/13 10:47 AM
  • G02-536 w_script.ppt 03/20/13 10:47 AM * In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.
  • RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • Patients with atrial fibrillation ( paroxysmal, persistent, or permanent) AF and a CHADS2 score of 2 or greater are eligible for the study, and both patients with or without previous Vitamin K antagonist experience can be included in the trial. Patients will be randomized to one of two dosing regimens of Edoxaban or to the Vitamin K antagonist Warfarin in a 1:1:1 matter. In addition, dose reductions for certain patient groups will apply similarly in both Edoxaban regimens. The primary objective of the study is to demonstrate non-inferiority of either Edoxaban arm versus Warfarin with regard to the primary endpoint, the incidence of stroke and systemic embolic events. The non-inferiority margin for this study for the risk ratio is set at 1.38. The mean follow up of this event driven study is not fixed as ENGAGE AF-TIMI 48 is an event-driven study, but it is expected to be 2 years.
  • Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
  • RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
  • RE-LY ® – Age and renal function subgroup analysis: Stroke and non-CNS embolism There was no significant interaction between either patient age or renal function subgroup and the rate of stroke and non-CNS embolism with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • RE-LY ® – Age and renal function subgroup analysis: Major bleeding There was a significant interaction between patient age and the rate of major bleeding with both doses of dabigatran versus warfarin. 1 For dabigatran 150 mg BID and 110 mg, major bleeding rates were significantly lower compared with warfarin in patients aged <65 years and 65-74 years, whereas in patients aged ≥75 years, major bleeding rates were similar with dabigatran and warfarin. 1 There was no significant interaction between renal function and the rate of major bleeding with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • Reference Patel MR et al. N Engl J Med 10 Aug 2011 (10.1056/NEJMoa1009638).
  • Interaction with age was evident for extracranial bleeding, but not for intracranial bleeding
  • RE-LY ® – Age and renal function subgroup analysis: Haemorrhagic stroke There was no significant interaction between either patient age or renal function and the rate of haemorrhagic stroke with either dose of dabigatran versus warfarin. 1 Reference 1. Healey JS et al. ACC 2010; abstr 1078-120.
  • Compared with warfarin, both doses of dabigatran were associated with lower risks of major bleeding in patients aged <75 years and with similar or higher risks for those aged ≥75 years
  • ISTH criteria: clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2 g per deciliter or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death.
  • Patients with atrial fibrillation ( paroxysmal, persistent, or permanent) AF and a CHADS2 score of 2 or greater are eligible for the study, and both patients with or without previous Vitamin K antagonist experience can be included in the trial. Patients will be randomized to one of two dosing regimens of Edoxaban or to the Vitamin K antagonist Warfarin in a 1:1:1 matter. In addition, dose reductions for certain patient groups will apply similarly in both Edoxaban regimens. The primary objective of the study is to demonstrate non-inferiority of either Edoxaban arm versus Warfarin with regard to the primary endpoint, the incidence of stroke and systemic embolic events. The non-inferiority margin for this study for the risk ratio is set at 1.38. The mean follow up of this event driven study is not fixed as ENGAGE AF-TIMI 48 is an event-driven study, but it is expected to be 2 years.

Patti G. Vecchi e nuovi anticoagulanti orali a confronto. ASMaD 2013 Presentation Transcript

  • 1. Fibrillazione atriale: dall’Epidemiologia alle nuove terapie Roma, 16 Marzo 2013Vecchi e nuovi anticoagulanti orali a confronto Giuseppe Patti Università Campus Bio-Medico di Roma
  • 2. Why a novel anti-thrombotic Rx is needed in AF pts?  No stroke protection with aspirin (with or without clopidogrel)  Warfarin effective for stroke prevention, but - Delayed onset/offset - Unpredictable dose response - Narrow therapeutic index - Drug-drug, drug-food interactions - Problematic monitoring and compliance - High bleeding (especially ICH) - Slow reversibility
  • 3. New Anticoagulants Xa factor inhibitor: Rivaroxaban Apixaban Edoxaban
  • 4. New anticoagulants: advantages Short half-life: - Immediate onset of action - no need for bridging Fixed doses No lab. monitoring A few drug-drug interactions (no food interactions)
  • 5. New oral anticoagulants: how do they compare? Dabigatran Rivaroxaban Apixaban EdoxabanAction Anti-IIa Anti-Xa Anti-Xa Anti-XaProdrug Yes (esterases) No No NoBioavailability (%) 6 80-100 50-66 50Half-life (hrs) 14-17 7-11 8-15 9-11Protein binding (%) 35 95 87 50Onset to peak 2-3 2-4 3 1-1.5action (hrs)Metabolism 80% renal CYP 3A4 CYP 3A4 CYP 3A4 20% glucur. 33% renal 22% renal 23% renalDose 110/150 mg BID 20 mg qD 5 mg BID 30-60 mg qDDrug interaction P-glycoprotein CYP 3A4 CYP 3A4 CYP 3A4 P-glycoprotein P-glycoprotein P-glycoprotein
  • 6. Questions and answers on the use of dabigatran and perpectives on the use ofother new oral anticoagulants in patients with atrial fibrillation Pengo V., Thrombosis and Haemostasis 2011 Predictable drug interactions of the new oral anticoagulants according to the type of metabolism.
  • 7. New oral anticoagulants: trials’ characteristics RELY ROCKET-AF ARISTOTLE (N=18,113) (N=14,264) (N=18,201)Age (yrs, mean) 72 73 70Female (%) 36 40 35Prior stroke/TIA (%) 20 55 19Diabetes (%) 23 40 25Prior CHF (%) 32 62 35VKA naive (%) 50 38 43CHADS2 > 3 (%) 32 87 30CHADS2 (mean) 2.1 3.5 2.1TRR (%) 64 58 62
  • 8. RELY trial – Primary outcome Stroke or Systemic Embolism1.53%/yr vs 1.69%/yr 0.91 (0.74-1.11)1.11%/yr vs 1.69%/yr 0.66 (0.53-0.82) Connolly SJ et al. NEJM 2009
  • 9. RELY trial – Safety outcome P=0.31 P=0.003 4,0 3,5 3,36 3,11Event rate per year (%) 3,0 2,71 2,5 Warfarin 2,0 Dabigatran 110 mg 1,5 Dabigatran 150 mg 1,0 0,5 0,0 Major bleeding Connolly SJ et al. NEJM 2009
  • 10. ROCKET-AF trialPrimary Efficacy Outcome: Stroke and systemic embolism   Rivaroxaban Warfarin     Event Event HR P-value Rate Rate (95% CI) On 0.79 Treatment 1.70 2.15 0.015 (0.65,0.95) N= 14,143 ITT 0.88 2.12 2.42 0.117 N= 14,171 (0.75,1.03) Rivaroxaban Warfarin better better Patel MR et al. NEJM 2011
  • 11. ROCKET-AF trial: Safety outcome Rivaroxaban Warfarin HR Event Rate Event Rate P-value (95% CI)Major and non-major Clinically 14.91 14.52 1.03 (0.96, 1.11) 0.442Relevant Cumulative event rate (%) Patel MR et al. NEJM 2011
  • 12. ARISTOTLE trial: primary efficacy outcome HR 0.79 1.60%/yr (95% CI, 0.66-0.95); P=0.011) 1.27%/yr Granger CB et al. NEJM 2011
  • 13. ARISTOTLE trial: Safety outcome 3.09%/yr HR 0.69 (95% CI, 0.60-0.80); P<0.001 2.13%/yr Granger CB et al. NEJM 2011
  • 14. New oral anticoagulants: main trials’ results Dabigatran Dabigatran Rivaroxaban Apixaban 150 mg 110 mg (N=14,264) (N=18,201) (N=18,113) (N=18,113)Stroke/embol. ↓ = ↓* ↓Ischemic stroke ↓ = = =Major bleed = ↓ = ↓Fatal bleed ↓ ↓ ↓ ↓ (life threath.)IC bleed ↓ ↓ ↓ ↓Minor bleed ↓ ↓ = =GI bleed ↑ = ↑ =Death ↓ (P=0.05) = = ↓
  • 15. NOACS: primary efficacy & safety outcome ESC Working Group on Thrombosis: Task Force on anticoagulants in heart disease position paper MTDe Caterina R. JACC 2012;59:1413
  • 16. Ischemic Stroke ITT : p-valueDabigatran 110 mg 149 1.34% / yr 1.20 0.35Dabigatran 150 mg 111 0.92% / yr 0.76 0.03Warfarin 142 1.20% / yr RELYRivaroxaban 20 mg 149 1.62% / yr 0.99 0.92*Warfarin 161 1.64% / yr ROCKET-AFApixaban 5 mg 162 0.97% / yr 0.92 0.42Warfarin 175 1.05% / yr ARISTOTLE Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
  • 17. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.76 P=0.072<65 1.48 0.69 1.3565–74 1.26 0.98 1.43≥75 1.87 1.43 2.1Creatinine clearance (mL/min) P=0.58 P=0.03630–50 2.26 1.33 2.6551–80 1.65 1.24 1.76>80 0.92 0.72 1 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 18. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.0003 P=0.0001<65 0.76 0.79 2.3265–74 2.12 2.45 3.08≥75 4.21 4.81 4.09Creatinine clearance (mL/min) P=0.1 P=0.09130–50 5.07 4.85 5.1751–80 2.62 3.04 3.44>80 1.36 1.88 2.18 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 19. New anticoagulants and CRF  Longer half-life  Monitoring of renal function  Doses reduction? Connolly SJ et al, NEJM 2009
  • 20. New oral anticoagulants in pts receiving anti-PLT Rx Triple therapy and major bleeding in RE-LY Warfarin Dabigatran Dabigatran RR (95% RR (95% (%) 110 mg BID 150 mg BID CI) CI) (%) (%) Dabigatran Dabigatran 110 mg BID 150 mg BID vs warfarin vs warfarin ASA + 5.2 4.7 4.7 0.77 0.81 clopidogrel (0.50-1.21) (0.52-1.26) No ASA + 3.5 2.8 3.2 0.81 0.95 clopidogrel (0.61-0.94) (0.82-1.10) Connolly SJ et al. N Engl J Med 2009
  • 21. New anticoagulants and risk of CV events MI or ACS  Issues regarding control population  Stroke prevention independent of CAD  Lower protection than warfarin  Ximelagatran reduced CV risk  Studies not powered for MI  No dose-dependent effect  Data not corrected for beta-block., statins  No correlation between CV risk and OR for MIUchino K et al. Arch Intern Med 2012 Hohnloser SH et al. Circulation 2012
  • 22. Reduced LOS with dabigatranEnd point  Standard Dabigatran, n=18  p  anticoagulation, n=18 Duration of in- 4.0 2.0 <0.001hospitalanticoagulation(median days) Hospital length of 86 60.4 <0.05stay (mean hours) Hospital length of 75.5 49.4 <0.01stay (median hours)  David A Vorchheimer, ACC Congress 2013
  • 23. NAO e Cardioversione: raccomandazioni Nei pazienti con FA in corso da ≥48 ore o quando la durata di FA èsconosciuta, la terapia anticoagulante orale (es. AVK con INR 2-3 o I BDabigatran) è raccomandata per ≥3 settimane prima e per ≥4settimane dopo cardioversione, indipendentemente dalla tipologia(elettrica o farmacologica orale/endovenosa) Non ci sono dati pubblicati relativi alla cardioversione con Rivaroxaban o Apixaban
  • 24. Practical issues with new anticoagulants  Is bridging Rx needed?  Stop before surgery  Switching from warfarin  Switching from LMWH  Switching from UFH
  • 25. How to manage a bleeding event while on Rx with new anticoagulants? Discontinue the anticoagulant Investigate and treat the source of bleeding Maintain diuresis Blood volume replacement with/without fresh-frozen plasma Prothrombin complex concentrates, recombinant factor VIIa Platelet concentrates in case of Rx with long-acting antiplatelet drugs Use of activated charcoal Rx Dialysis for dabigatran
  • 26. New anticoagulants Warfarin Economic issues  Excellent efficacy Unresolved issues  Low cost - No standardized monitoring  Long track record - Adherence to Rx  Centralized anticoag. clin. - Lack of antidote  Point of care testing - Long-term safety (real world) - No head-to-head comparison  INR q 12 w if stable
  • 27. New anticoagulants: Summary Superior to aspirin At least non-inferior to warfarin for ischemic thrombo-embolicend-point Significant reduction of ICH and fatal bleed Consistent data according to history of previous stroke and CHADSscore, but dabigatran reduced ischemic stroke Possibility to choice the dabigatran dose according to bleeding risk Selection/prioritization of pts for these agents: pts unwilling to takewarfarin, new pts, pts with unstable INR or events while on warfarin;pts with stable INR? Evaluation in other settings of pts requiring anticoagulation
  • 28. D 110 R D 150 Anti-PLT Rx CYP CYP (high bleeding) (low bleeding)High bleeding risk Older age CRF GI bleed GP drugs Good INR Valve prosthesis/ Other indication for OAC A W
  • 29. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.76 P=0.072<65 1.48 0.69 1.3565–74 1.26 0.98 1.43≥75 1.87 1.43 2.1Creatinine clearance (mL/min) P=0.58 P=0.03630–50 2.26 1.33 2.6551–80 1.65 1.24 1.76>80 0.92 0.72 1 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 30. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.0003 P=0.0001<65 0.76 0.79 2.3265–74 2.12 2.45 3.08≥75 4.21 4.81 4.09Creatinine clearance (mL/min) P=0.1 P=0.09130–50 5.07 4.85 5.1751–80 2.62 3.04 3.44>80 1.36 1.88 2.18 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 31. Study design AF on Electrical N = 21,107 Recording < 12 mo Intended oral A/C CHADS2 > 2 R Low Exposure High Exposure Active Control Strategy Strategy Warfarin Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0) Median duration of follow up 24-months Primary Objective Edoxaban: Therapeutically as good as Warfarin 1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EPs = Major Bleeding, Hepatic FunctionSEE=systemic embolic eventRuff CT et al. Am Heart J. 2010;160:635-41
  • 32. Other issues regarding new anticoagulants Results of these drugs in pts with older age? Compliance? Need for monitoring? Anti-thrombotic Rx in pts with AF receiving coronary stents?
  • 33. CTRs vs. real world observations CRTs Real worldAge 30% 65%CRF 20% 58%Low body weight 30% 50% Harper P et al. N Engl J Med 2012
  • 34. Effects of Apixaban vs Warfarin Among PatientsUsing and Not Using Aspirin in ARISTOTLE HR ASA HR No ASA Stroke or 0.55 0.80 embolism Major bleeding 0.77 0.65 Hemorrhagic 0.40 0.51 stroke Granger CB et al. N Engl J Med 2011
  • 35. Messages from trials according to patients age and renal function Reduction of the benefit on the efficacy endpoint with 150 mg Dabigatran over the spectrum of ages. Maintained improvement on the efficacy endpoint with 150 mg Dabigatran in pts with CRF (real world?) Trend towards increase in major bleeding in older pts with 150 mg Dabigatran. No reduction of bleeding in older pts and in pts with CRF with 110 mg Dabigatran Consistent reduction in the efficacy endpoint with Apixaban and Rivaroxaban over the spectrum of ages (possibly higher in older pts) and of renal function Monitoring of renal function? Dose modification? 15-30 ml/min Dabi 75 mg x 2; 30-50 ml/min Riva 15 mg; creat. >1.5 mg/dl Api 2.5 mg x 2
  • 36. ROCKET AF – primary efficacy endpoint subgroup analysis Hazard ratio and 95% CIs Rivaroxaban Warfarin n/N (%) n/N (%) p-value* Overall 189/7,061 2.7 243/7,082 3.4 Sex 0.92 Male 103/4,270 2.4 136/4,283 3.2 Female 86/2,791 3.1 107/2,799 3.8 Age (years) 0.11 <75 107/3,988 2.7 119/4,005 3.0 ≥75 82/3,073 2.7 124/3,077 4.0 Weight (kg) 0.78 ≤70 63/2,004 3.1 78/2,008 3.9 70–≤90 92/3,022 3.0 129/3,133 4.1 >90 34/2,033 1.7 36/1,940 1.9 CrCl (ml/min) 0.72 <50 50/1,485 3.4 60/1,456 4.1 50–80 91/3,290 2.8 128/3,396 3.8 >80 47/2,278 2.1 54/2,221 2.4*p-value for interaction 0.1 0.2 0.5 1 2 5 10Safety population – on-treatment analysis Favours Favours rivaroxaban warfarinPatel MR et al, 2011
  • 37. Apixaban vs Warfarin in ARISTOTLEGranger NEJM 2011
  • 38. Dabigatran Anti-Xa Inhibition of both No effect on pre-existingfree and bound thrombin thrombin Better stroke prevention? Lower bleeding? NNT Stroke Major bleed Dabigatran 150 172 333 Dabigatran 110 625 143 Rivaroxaban 222 500 Apixaban 303 100
  • 39. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.76 P=0.072<65 1.48 0.69 1.3565–74 1.26 0.98 1.43≥75 1.87 1.43 2.1Creatinine clearance (mL/min) P=0.58 P=0.03630–50 2.26 1.33 2.6551–80 1.65 1.24 1.76>80 0.92 0.72 1 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 40. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.0003 P=0.0001<65 0.76 0.79 2.3265–74 2.12 2.45 3.08≥75 4.21 4.81 4.09Creatinine clearance (mL/min) P=0.1 P=0.09130–50 5.07 4.85 5.1751–80 2.62 3.04 3.44>80 1.36 1.88 2.18 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 41. ROCKET AF – primary efficacy endpoint subgroup analysis Hazard ratio and 95% CIs Rivaroxaban Warfarin n/N (%) n/N (%) p-value* Overall 189/7,061 2.7 243/7,082 3.4 Sex 0.92 Male 103/4,270 2.4 136/4,283 3.2 Female 86/2,791 3.1 107/2,799 3.8 Age (years) 0.11 <75 107/3,988 2.7 119/4,005 3.0 ≥75 82/3,073 2.7 124/3,077 4.0 Weight (kg) 0.78 ≤70 63/2,004 3.1 78/2,008 3.9 70–≤90 92/3,022 3.0 129/3,133 4.1 >90 34/2,033 1.7 36/1,940 1.9 CrCl (ml/min) 0.72 <50 50/1,485 3.4 60/1,456 4.1 50–80 91/3,290 2.8 128/3,396 3.8 >80 47/2,278 2.1 54/2,221 2.4*p-value for interaction 0.1 0.2 0.5 1 2 5 10Safety population – on-treatment analysis Favours Favours rivaroxaban warfarinPatel MR et al, 2011
  • 42. Apixaban vs Warfarin in ARISTOTLEGranger NEJM 2011
  • 43. Messages from trials according to patients age Consistent reduction of the efficacy endpoint with 150 mg Dabigatran over the spectrum of ages Trend towards reduction of major bleeding with 110 mg Dabigatran confined to younger pts (no reduction of bleeding in older pts); trend towards increase in bleeding with 150 mg Dabigatran in older pts Consistent (and possibly higher in older pts) reduction in the efficacy endpoint with Apixaban and Rivaroxaban
  • 44. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BID Age (yrs) P=0.76 P=0.072 <65 1.48 0.69 1.35 65–74 1.26 0.98 1.43 ≥75 1.87 1.43 2.1 Creatinine clearance (mL/min) P=0.58 P=0.036 30–50 2.26 1.33 2.65 51–80 1.65 1.24 1.76 >80 0.92 0.72 1 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better betterBID = twice daily; D = dabigatran; P values for interaction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Healey JS, et al. ACC 2010; abstr 1078-120.
  • 45. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BID Age (yrs) P=0.0003 P=0.0001 <65 0.76 0.79 2.32 65–74 2.12 2.45 3.08 ≥75 4.21 4.81 4.09 Creatinine clearance (mL/min) P=0.1 P=0.091 30–50 5.07 4.85 5.17 51–80 2.62 3.04 3.44 >80 1.36 1.88 2.18 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better betterBID = twice daily; D = dabigatran; P values for interaction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Healey JS, et al. ACC 2010; abstr 1078-120.
  • 46. ROCKET AF – primary efficacy endpoint subgroup analysis Hazard ratio and 95% CIs Rivaroxaban Warfarin n/N (%) n/N (%) p-value* Overall 189/7,061 2.7 243/7,082 3.4 Sex 0.92 Male 103/4,270 2.4 136/4,283 3.2 Female 86/2,791 3.1 107/2,799 3.8 Age (years) 0.11 <75 107/3,988 2.7 119/4,005 3.0 ≥75 82/3,073 2.7 124/3,077 4.0 Weight (kg) 0.78 ≤70 63/2,004 3.1 78/2,008 3.9 70–≤90 92/3,022 3.0 129/3,133 4.1 >90 34/2,033 1.7 36/1,940 1.9 CrCl (ml/min) 0.72 <50 50/1,485 3.4 60/1,456 4.1 50–80 91/3,290 2.8 128/3,396 3.8 >80 47/2,278 2.1 54/2,221 2.4*p-value for interaction 0.1 0.2 0.5 1 2 5 10Safety population – on-treatment analysis Favours Favours rivaroxaban warfarinPatel MR et al, 2011.
  • 47. Apixaban and renal functionHohonloser EHJ 2012
  • 48. Messages from trials according to renal function Consistent (and possibly higher in pts with CRF) reduction of the efficacy endpoint with 150 mg Dabigatran over the spectrum of renal function Trend towards lower reduction of major bleeding with 110 mg Dabigatran in pts with CRF Consistent reduction in the efficacy endpoint with Apixaban and Rivaroxaban over the spectrum of renal function Monitoring of renal function? Dose modification? Dabigatran 15-30 ml/min 75 mg x 2; Riva 30-50 ml/min 15 mg
  • 49. CHADS2 subgroup analysis: stroke and systemic embolism  Effect of dabigatran 150 mg was consistent Dabigatran 110 mg BID Dabigatran 150 mg BID vs. warfarin vs. warfarin Annual rate (%) D 110 D 150 P=0.37 P=0.84CHADS2 mg mgcore BID BID Warf.0–1 1.06 0.65 1.082 1.45 0.84 1.383–6 2.12 1.88 2.73 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction Oldgren J et al. Ann Int Med 2011;155:660−9
  • 50.  History of stroke, TIA or non-CNS SE OR ≥2* of the following:  CHF  Hypertension  Age ≥75 years  Diabetes Effect of Rivaroxaban was consistent
  • 51. Apixaban vs warfarin in ARISTOTLE  Effect of Apixaban was consistentGranger NEJM 2011
  • 52. Prior stroke subgroup analysis: major clinical outcomes in patients with or without previous stroke or TIA Rate (% per year) Dabigatran 110 mg 150 mg Warfarin Interaction P Interaction P Stroke Previous stroke or TIA 2.23 1.91 2.53 0.85 0.28 No previous stroke or TIA 1.24 0.78 1.34chaemic or unknown stroke Previous stroke or TIA 2.19 1.75 1.75 0.46 0.12 No previous stroke or TIA 1.12 0.71 1.08 Death from any cause Previous stroke or TIA 3.24 4.39 4.58 0.06 0.50 No previous stroke or TIA 3.87 3.45 4.02 Haemorrhagic stroke Previous stroke or TIA 0.08 0.20 0.77 0.09 0.97 No previous stroke or TIA 0.13 0.07 0.29 0.5 1.0 1.5 0.5 1.0 1.5 Favours Favours Favours Favours 110 mg warfarin 150 mg warfarin dabigatran dabigatran  Effect of dabigatran was consistent with regard to reduction of the efficacy endpoint (150 mg) as well as to reduction of ICH (both doses) Diener HC et al. Lancet Neurol 2010;9:1157–63
  • 53. Apixaban vs Warfarin in ARISTOTLE (Eastone et al. Lancet Neurology 2011)Effect of Apixaban was consistent (and possibly higher) for reduction of the safety endpoints in pts with previous strokeEastone et al. Lancet Neurology 2011
  • 54. Nuovi Anticoagulanti Orali non VK Antagonisti Vantaggi Dose – risposta prevedibile : dose fissa giornaliera Non necessità di monitoraggio dell’anticoagulazione Elevata efficacia e sicurezza Significativa riduzione del rischio emorragico Inizio e termine d’azione rapidi: non necessità di bridge con eparina Minime interazioni farmacologiche Assenza di interazioni alimentari Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
  • 55. Nuovi Anticoagulanti Orali non VK Antagonisti Svantaggi Aggiustamento empirico del dosaggio Necessità di nuovi test laboratoristici da eseguire in caso di eventi emorragici o trombotici Difficoltà di valutare l’aderenza del paziente alla terapia Mancanza di antidoto in caso di sovradosaggio o emorragie Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti con bassa aderenza terapeutica Possibile ridotta consapevolezza della terapia da parte del paziente Costo elevato Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65
  • 56. Nuovi farmaci anticoagulantiProblemi Aperti Aderenza/persistenza Come monitorare Range terapeutico Antidoto Gestione dell’emorragia Safety a lungo termine
  • 57. Possible reasons to AF keep pts on warfarin (1)  GOOD LEVEL OF CONTROL - Because of the twice daily dosing (D, A) and greater risk of nonhemorrhagic side effects (D) patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran. Patient values and preferences should influence the decision to initiate dabigatran.  RENAL FAILURE - Warfarin remains the treatment of choice for patients with a calculated creatinine clearance close to or less than 30 mL/min.  MECHANICAL HEART VALVE REPLACEMENT Schulman and Crowther 2012
  • 58. Possible reasons to keep AF patients on warfarin (2) GI DISEASE AND ELDERLY - When extracranial bleeding is of particular concern, for example in patients over 75 yrs with a history of recurrent extracranial bleeding or with preexisting coagulopathy, warfarin may be preferable vs D because this drug is rapidly reversible. This concern may not be true for the factor Xa inhibitors (?) Patients with intestinal angiodysplasia, IBD, or diverticulosis, or those with a history of other forms of GI bleeding may experience a deterioration on treatment with D or R Discontinuation of D was more frequent as a result of GI distress, and over 11% of pts complained of dyspepsia (attributed to both tartaric acid contained in the capsule and to a high concentration of active drug in the colon). Schulman and Crowther 2012
  • 59. Possible reasons to keep AF patients on warfarin (3) POOR COMPLIANCE (?) – However, with novel agents, the first marker of noncompliance is probably stroke or other thrombotic complications. COSTS (?) - Many patients who do not have drug coverage will probably remain on warfarin, despite evidence that from a broader perspective novel agents are cost-neutral or cost-effective in many settings Schulman and Crowther 2012
  • 60. Possible reasons to keep AF patients on NOAs UNEXPLAINED POOR WARFARIN CONTROL - Warfarin-experienced patients who continue to have variable INR results, corresponding to a TTR of less than 65%, have lower rates of stroke and other complications when treated with D 150 mg twice daily POOR LEVEL OF CONTROL BECAUSE OF UNAVOIDABLE DRUG- DRUG INTERACTION – frequent need for antibiotic treatment, chemotherapy, amiodarone, frequent use of acetaminophen, azathioprine, or a large number of concomitant medications, particularly if the exposure to these medications varies HISTORY OF INTRACRANIAL BLEEDING NEW PATIENTS ON AF OR PATIENTS NEVER PRESCRIBED AVK LOGISTIC PROBLEMS PTS WILLING TO RECEIVE NOA Modified from Schulman and Crowther 2012
  • 61. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran) JACC 2011
  • 62. stroke risk reduction with antithrombotic therapy in AF MTGranger CB, Circulation 2012
  • 63. Exclusion criteria in AF trials
  • 64. Apixaban vs Warfarin in ARISTOTLE  Effect of Apixaban was consistent with regard to reduction of the safety endpointGranger NEJM 2011
  • 65. CHADS2 subgroup analysis: intracranial bleeding  Effect of dabigatran was consistent (no significant interaction with treatment) Dabigatran 110 mg BID Dabigatran 150 mg BID vs. warfarin vs. warfarin Annual rate (%) D 110 D 150 P=0.70 P=0.82CHADS2 mg mg Warfariscore BID BID n0-1 0.20 0.20 0–12 0.22 0.26 0.693–6 0.26 0.52 1.07 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction Oldgren J et al. Ann Int Med 2011;155:660−9
  • 66. New anticoagulants and CRF  Longer half-life  Monitoring of renal function  Doses reduction?  Drug interaction? Connolly SJ et al, NEJM 2009
  • 67. Age and bleeding subgroup analysis: intracranial and extracranial bleeding Annual rate (%) D110 vs. warfarin D150 vs. warfarin Warfari P P D110 D150 RR (95% CI) RR (95% CI) n value* value* Intracranial bleeding 0.22 (0.11– 0.43 (0.25– <75 yrs 0.14 0.26 0.61 0.45) 0.74) 0.37 (0.21– 0.42 (0.25– ≥75 yrs 0.37 0.41 1.00 0.28 0.91 0.64) 0.70) Extracranial bleeding 0.72 (0.57– 0.78 (0.63– <75 yrs 1.76 1.91 2.44 0.90) 0.98) 1.20 (0.97– 1.39 (1.13– ≥75 yrs 4.10 4.68 3.44 0.001 <0.001 1.48) 1.70) *P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RR = relative risk Eikelboom JW et al. Circulation 2011;123:2362–72 Dec 2011
  • 68. Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation Lip GYH, JACC 2012
  • 69. Prior stroke subgroup analysis: major clinical outcomes in patients with or without previous stroke or TIA Rate (% per year) Dabigatran 110 mg 150 mg Warfarin Interaction P Interaction P Total bleeding Previous stroke or TIA 14.49 16.90 18.53 0.57 0.65 No previous stroke or TIA 14.71 16.33 18.15 Major bleeding Previous stroke or TIA 2.74 4.15 4.15 0.15 0.51 No previous stroke or TIA 2.91 3.10 3.43 Intracranial bleeding Previous stroke or TIA 0.25 0.53 1.28 0.26 0.91 No previous stroke or TIA 0.22 0.27 0.63Gastrointestinal major bleed Previous stroke or TIA 1.39 2.32 1.41 0.68 0.53 No previous stroke or TIA 1.35 1.73 1.23 0.5 1.0 1.5 0.5 1.0 1.5 Favours Favours Favours Favours 110 mg warfarin 150 mg warfarin dabigatran dabigatran No significant interactions between primary and secondary outcomes in patients with and without a history of prior stroke TIA = transient ischaemic attack Diener HC et al. Lancet Neurol 2010;9:1157–63 Dec 2011
  • 70. SUBGROUP ANALYSIS: HAEMORRHAGIC STROKE Annual rate (%) D 110 D 150 D 110 mg BID D 150 mg BID Warfarin vs. warfarin vs. warfarin mg BID mg BIDAge (yrs) P=0.51 P=0.75<65 0.05 0.05 0.3865–74 0.08 0.08 0.31≥75 0.2 0.15 0.47Creatinine clearance (mL/min) P=0.67 P=0.430–50 0.26 0.12 0.5851–80 0.12 0.09 0.47>80 0.03 0.08 0.13 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Dabigatran Warfarin Dabigatran Warfarin better better better better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.
  • 71. Stroke prevention: Anticoagulant effect Meta-analysis of stroke or systemic embolism ICH Relative Hazard Ratio (95% CI) W vs Dabiga 110 W vs Placebo W vs Rivaroxa W vs W low dose W vs Dabiga 150 W vs Aspirin W vs Apixaban 5W vs Aspirin+ClopW vs Ximelagatran W vs Dabiga 110 Major bleeding W vs Rivaroxa W vs Dabiga 150 W vs Dabiga 110 W vs Apixaban 5 W vs Rivaroxa W vs Dabiga 150 Favours Warfarin Favours other RX W vs Apixaban 5 Favours Warfarin Favours other RX
  • 72. Age and bleeding subgroup analysis: major bleeding Annual rate (%) D110 vs. warfarin D150 vs. warfarin RR P RR P D110 D150 Warfarin (95% CI) value* (95% CI) value* 0.62 0.70<75 yrs 1.89 2.12 3.04 (0.50–0.77) (0.57–0.86) <0.001 <0.001 1.01 1.18≥75 yrs 4.43 5.10 4.37 (0.83–1.23) (0.98–1.42) *P value for interaction; CI = confidence interval; D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RR = relative risk Eikelboom JW et al. Circulation 2011;123:2362–72 Dec 2011
  • 73. New Anticoagulants ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX IXa APC (drotrecogin alfa) VIIIa sTM (ART-123) Va Rivaroxaban AT Fondaparinux Apixaban Xa Idraparinux Edoxaban II DX-9065aDabigatran IIa THROMBIN Fibrinogen Fibrin Weitz & Bates, J Thromb Haemost 2005
  • 74. Safety outcome Patel MR et al, NEJM 2011
  • 75. Dabigatran versus Warfarin in Patients with Atrial Fibrillation: RE-LY trial Dabigatran 110 mg BID (N=6013) BlindedPatients with Primary study outcome: Dabigatran 150 stroke or systemicNVAF and ≥ 1 mg BID F.U. embolism risk factors R (N=6075) 2 years Primary safety outcome: (N=18113) major bleeding Open Warfarin adjusted (N=6013) Connolly SJ et al, NEJM 2009
  • 76. Rivaroxaban versus Warfarin in Nonvalvular atrial fibrillation: ROCKET AF trial Rivaroxaban 20 mg/die (or 15 mg/die if Cr Cl Primary study outcome: Patients with 30-49 ml/min) stroke or systemic NVAF at F.U. embolismmoderate-to-high R (N=7131) risk of stroke Primary safety outcome: Warfarin adjusted major and nonmajor (N=14.264) (N=7133) clinically relevant bleeding Patel MR et al, NEJM 2011
  • 77. Apixaban versus Warfarin in Patients with AtrialFibrillation: ARISTOTLE trial Apixaban 5 mg BID (2.5 mg BID if age≥80 ys, body weight<60 Kg,Patients with AF Crea>1.5 mg/dl) Primary study outcome: and ≥ 1 risk (N=9120) F.U. stroke or systemic factors R embolism (N=18.201) Primary safety outcome: Warfarin adjusted major bleeding according to the ISTH criteria (N=9081) Granger CB et al, NEJM 2011
  • 78. Bleeding P<0.001 % 20 P=0.002 15 10 P=0.03 P<0.01 P=0.43 P=0.31 5 P=0.04 P<0.001 0 g g g g in in in in eed e ed e ed ed bl bl bl le al or g a lb t aj in in To M en t t t es ea in hr ro fe -T a st Li G Dabigatran 110 mg Dabigatran 150 mg Warfarin Connolly SJ et al, NEJM 2009
  • 79. Primary Efficacy Outcome: Stroke and systemic embolism 6 Rivaroxaban Warfarin 5 Warfarin Event Cumulative event rate (%) Rate 1.71 2.16 4 Rivaroxaban 3 HR 0.79 (95% CI; 0.66-0.96) 2 P-value Non-Inferiority: <0.001 1 0 0 120 240 360 480 600 720 840 960 Days since randomization Patel MR et al, NEJM 2011
  • 80. Study design AF on Electrical N = 21,107 Recording < 12 mo Intended oral A/C CHADS2 > 2 R Low Exposure High Exposure Active Control Strategy Strategy Warfarin Edoxaban 30 mg QD Edoxaban 60 mg QD (INR 2.0 – 3.0) Median duration of follow up 24-months Primary Objective Edoxaban: Therapeutically as good as Warfarin 1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EPs = Major Bleeding, Hepatic FunctionSEE=systemic embolic eventRuff CT et al. Am Heart J. 2010;160:635-41