Indications cliniques des nouveaux anticoagulants oraux

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1 Séminaires des services d Urgences Réseau IRIS 14 mai 2013 Indications cliniques des nouveaux anticoagulants oraux Revue de l EBM Pr J-L Vandenbossche CHU StPierre Bruxelles ULB

2 Indications actuelles des «NACO» Prévention de l AVC thrombo-embolique dans la FA Prévention de la maladie thrombo-embolique veineuse après chirurgie orthopédique Traitement de la maladie thrombo-embolique veineuse et prévention de l embolie pulmonaire Prévention après syndrome coronaire aigu

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30 The importance of ischaemic stroke strategies to reduce the clinical burden of AF-related stroke September Sept 2012

31 Stroke is the leading complication of AF AF increases the risk of all types of stroke 5-fold 1 Without prevention, approximately 1 in 20 patients will have a stroke each year 2 AF is responsible for nearly one-third of all strokes 3 1. Savelieva I et al. Ann Med 2007;39:371 91; 2. Atrial Fibrillation Investigators. Arch Intern Med 1994;154: ; 3. Hannon N et al. Cerebrovasc Dis 2010;29: Sept 2012

32 Ischaemic vs. haemorrhagic stroke Ischaemic 1 4 Caused by obstruction within a blood vessel supplying the brain Clot may form directly in blood vessel or travel from another site (e.g. from the left atrium in patients with AF) Haemorrhagic 1 4 Caused by rupture of a weakened vessel and leads to bleeding into or around the brain Intracerebral haemorrhage (bleeding into the brain) causes include: Hypertension Blood vessel abnormalities Antithrombotic therapy Subarachnoid haemorrhage (bleeding into space between brain and skull) usually caused by cerebral aneurysm Bath PMW et al. BMJ 2000;320:920; 4. Donnan G et al. Lancet 2008;371: Sept 2012

33 Most strokes associated with AF are ischaemic Types of stroke in patients with AF Haemorrhagic 8% (n=484) Ischaemic 92% (n=5810) Based on data collected in the Danish National Indicator Project for patients hospitalized for stroke (80% of all stroke admissions in Denmark) including 6294 patients with AF); OAC use not recorded Andersen KK et al. Stroke 2009;40: Sept 2012

34 Ischaemic stroke in AF likely to result in persistent disability or death Proportion of patients (%) Outcomes of first ischaemic stroke in high-risk patients with AF (n=597) % % 0 Persisting disability Modified Rankin scale 2 Death Gladstone DJ et al. Stroke 2009;40: Sept 2012

35 Cumulative probability of recurrence (%) Ischaemic stroke in AF is more likely to recur 10 Recurrent stroke after ischaemic stroke Patients with AF (n=869) Patients without AF (n=2661) 2 P= Months after first stroke 12 Marini C et al. Stroke 2005;36: Sept 2012

36 Impact of ischaemic stroke 36 Sept 2012

37 Limitations of traditional antithrombotics prevent effective stroke prevention ASA: insufficient protection in high-risk patients 1 Limited stroke risk reduction (relative risk reduction 19%) 1 VKAs: narrow therapeutic range, food/drug interactions, slow onset/offset of action, regular coagulation monitoring 2 3 High risk of bleeding 4 Increased risk of major GI bleeding vs. placebo or ASA 5 ASA = acetylsalicylic acid; VKAs = vitamin K antagonists 1. Hart RG et al. Ann Intern Med 2007;146:857 67; 2. Turpie AG. Eur Heart J 2008;29:155 65; 3. Khoo CW et al. Int J Clin Pract 2009;63:630 41; 4. Albers GW et al. Chest 2001;119:194S 206S; 5. Coleman CI et al. Int J Clin Pract 2012;56: Sept 2012

38 ICH is the most feared complication of traditional antithrombotic therapy ICH can be life-threatening 1 Traditional antithrombotics increase the risk of ICH*: 1 ASA use increases risk by 40% Warfarin use doubles risk (INR ; rate is %/yr) Warfarin use also increases the severity of ICH 2 *Compared with placebo ASA = acetylsalicylic acid; ICH = intracranial haemorrhage; INR = international normalized ratio 1. Hart RG et al. Stroke 2005;36: ; 2. Fang MC et al. Stroke 2012;43: Sept 2012

39 Proportion of eligiible patients using warfain (%) Warfarin is used in only half of eligible AF patients Underuse greatest in elderly patients (who are at highest risk of stroke) % 58% 61% 57% Overall use = 55% (n= ) 35% 20 0 < Age (yrs) Go A et al. Ann Intern Med 1999;131: Sept 2012

40 Most ischaemic strokes occur in patients who are sub-optimally anticoagulated Pre-admission medications in high-risk* AF patients admitted for first ischaemic stroke Data from a prospective stroke registry of 597 patients with AF at high risk of stroke (*1 high-risk factor or 1 moderate-risk factor according to ACCP guidelines); INR = international normalized ratio Gladstone DJ et al. Stroke 2009;40: Sept 2012

41 New-generation agents have the potential to optimize stroke protection Developed to overcome limitations of traditional agents 1 Dabigatran etexilate and rivaroxaban approved for stroke prevention in AF in several countries 2,3 Other agents in clinical development include: Apixaban (Phase III completed) 4,5 Edoxaban (Phase III) 6 1. Lip GY et al. Eur Heart J Suppl 2005;7:E21 5; 2. Pradaxa : SmPC, 2012; 3. Xarelto : SmPC, 2012; 4. Granger CB et al. N Engl J Med 2011;365:981 92; 5. Connolly SJ et al. N Engl J Med 2011;364:806 17; 6. NCT ; available at accessed March 2012 Disclaimer: Apixaban and edoxaban are not approved for clinical use in stroke prevention in AF. Rivaroxaban is approved in this indication only in the USA and EU. Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 41 Sept 2012

42 Goals for anticoagulation therapy in AF Prevent ischaemic stroke Minimize haemorrhagic stroke (minimize risk of ICH) 42 Sept 2012

43 The importance of ischaemic stroke prevention in patients with AF summary AF increases the risk of stroke 1 Most strokes associated with AF are ischaemic 2 Likely to result in permanent disability or death 3 Traditional agents for stroke prevention in AF have limitations, including the risk of ICH 4 Many patients receive suboptimal anticoagulation 3 Goal of antithrombotic therapy in AF should be to prevent ischemic stroke and minimize the risk of haemorrhagic stroke (ICH) New-generation OACs could optimize stroke protection in AF Dabigatran, rivaroxaban and apixaban all significantly reduce the risk of haemorrhagic stroke and ICH vs warfarin 4 7 Only dabigatran 150 mg BID significantly reduced the risk of ischaemic stroke vs warfarin 4,5 ICH = intracranial haemorrhage; OACs = oral anticoagulants 1. Savelieva I et al. Ann Med 2007;39:371 91; 2. Andersen KK et al. Stroke 2009;40: ; 3. Gladstone DJ et al. Stroke 2009;40:235 40; 4. Hart RG et al. Stroke 2005;36: ; 4. Connolly SJ et al. N Engl J Med 2009;361: ; 5. Connolly SJ et al. N Engl J Med 2010;363:1875 6; 6. Granger CB et al. N Engl J Med 2011;365:981 92; 7. Patel MR et al. N Engl J Med 2011;365: Sept 2012

44 Risk factors for stroke and thrombo-embolism in non-valvular AF AF= atrial fibrillation; EF = ejection fraction (as documented by echocardiography, radionuclide ventriculography, cardiac catheterization, cardiac magnetic resonance imaging, etc.); LV = left ventricular; TIA = transient ischaemic attack. European Heart Journal (2010) 31,

45 CHADS 2 score and stroke rate *The adjusted stroke rate was derived from the multivariable analysis assuming no aspirin usage; these stroke rates are based on data from a cohort of hospitalised AF patients, published in 2001, with low numbers in those with a CHADS 2 score of 5 and 6 to allow an accurate judgement of the risk in these patients. Given that stroke rates are declining overall, actual stroke rates in contemporary non-hospitalised cohorts may also vary from these estimates. Adapted from Gage BF et al. AF = atrial fibrillation; CHADS 2 = cardiac failure, hypertension, age, diabetes, stroke (doubled). European Heart Journal (2010) 31,

46 Adjusted stroke rate according to CHA 2 DS 2 -VASc score European Heart Journal (2010) 31,

47 Risk factor-based point-based scoring system - CHA 2 DS 2 -VASc *Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates. European Heart Journal (2010) 31,

48 The HAS-BLED bleeding risk score *Hypertension is defined as systolic blood pressure > 160 mmhg. INR = international normalized ratio. European Heart Journal (2010) 31,

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55 RE-LY FA avec 1 facteur de risque Absence de contre-indications R Pradaxa 150 mg, 2 fois/jour N = (prévu) Pradaxa 110 mg, 2 fois/jour N = (prévu) Warfarine 1 mg, 3 mg, 5 mg (INR 2,0 3,0) N = (prévus) Objectif principal : Démontrer la non-infériorité du Pradaxa par rapport à la warfarine Connolly SJ, et al. N Engl J Med 2009; 361: Ezekowitz MD, et al. Am Heart J 2009;157: BIBE FR 07/

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57 TTR subgroup analysis: stroke and systemic embolism, and intracranial bleeding CTTR status,% Favours dabigatran Favours warfarin Stroke and systemic embolism: D110 mg BID < > Stroke and systemic embolism: D150 mg BID < > Intracranial bleeding: D110 mg BID < > Intracranial bleeding: D150 mg BID < > Hazard ratio P value Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variable BID = twice daily; D =dabigatran; TTR = time in therapeutic range Wallentin L et al. Lancet 2010;376:975 83

58 Dabigatran is the only new-generation agent to also reduce the risk of ischaemic stroke vs warfarin In addition to a significant reduction in stroke/se, haemorrhagic stroke, and ICH Event rate (%/yr) Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin D110 D150 Warfarin RR (95% CI) P value RR (95% CI) P value Stroke/SE <0.001 (NI) <0.001 (Sup) Ischaemic stroke (Sup) RRR=25% Haemorrhagic stroke <0.001 (Sup) <0.001 (Sup) ICH Favours dabigatran Favours warfarin <0.001 (Sup) <0.001 (Sup) Favours Favours dabigatran warfarin ICH = intracranial haemorrhage; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; SE = systemic embolism; Sup = superiority Connolly SJ et al. N Engl J Med 2010;363:1875 6; Pradaxa : EU SmPC, 2012 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 59 Sept 2012

59 Taux annuel (%) CRITÈRE D'EFFICACITÉ PRINCIPAL AVC OU EMBOLIE SYSTÉMIQUE RR 0.65 (IC 95% : 0,52 0,81) P < (supériorité) 1,8 1,5 1,2 RRR 35% 1,71 0,9 0,6 1,11 0,3 0 Accidents / n : D150 mg 2 x/j Warfarine 134 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

60 RE-LY EN PERSPECTIVE Warfarine versus placebo Warfarine versus dose faible de warfarine Warfarine versus AAS Warfarine versus AAS + clopidogrel Warfarine versus ximélagatran Méta-analyse de l AVC ischémique ou de l embolie systémique Warfarine versus dabigatran 150 mg 2 fois/jour 0 0,3 0,6 0,9 1,2 1,5 1,8 2,1 En faveur de la warfarine En faveur de l autre traitement Camm J. Oral presentation at ESC on 30 Aug BIBE FR 07/

61 MEILLEURE PRÉVENTION DES AVC AVEC PRADAXA 150 MG 2X/J VERSUS WARFARINE Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

62 Taux annuel (%) CRITÈRES D EFFICACITÉ SECONDAIRES MORTALITÉ VASCULAIRE RR 0,85 (95% CI: 0,72 0,99) P=0.04 (supériorité) 3,0 RRR 15% 2,0 2,28 2,43 2,69 1,0 0 D150 mg 2x/j warfarine 274 / / 6022 Connolly SJ, et al. N Engl J Med 2009;361: BIBE FR 07/

63 Taux annuel (%) HÉMORRAGIES MAJEURES 5,0 RR 0.93 (IC 95% : 0,81 1,07) P = ,0 3,0 2,0 3,32 3,57 1,0 0 Accidents / n : D150 mg 2 x/j Warfarine 399 / / 6022 Connolly SJ, et al. N Engl J Med 2009;361: BIBE FR 07/

64 Nombre d évènements HÉMORRAGIES INTRACRÂNIENNES RR 0.41 (95% CI: 0,28 0,60) P < (supériorité) RRR 59% 90 0,76% ,32% 0 Accidents / n : D150 mg 2 x/j Warfarine 38 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

65 Taux annuel (%) HÉMORRAGIES MENACANT LE PRONOSTIC VITAL RR 0,80 (95% CI: 0,66 0,98) P=0.03 (supériorité) 2,0 RRR 20% 1,5 1,85 1,0 1,49 0,5 0 Accidents / n : D150 mg 2x/j warfarine 179 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

66 HÉMORRAGIES MAJEURES ET COMPOSANTS Caractéristique Dabigatran 150 mg 2x/j Warfarine Valeur P D150 versus W Nombre de patients Taux d hémorragie majeure (% annuel) 3,32 3,57 0,32 Menaçant le pronostic vital 1,49 1,85 0,03 Pas menaçant le pronostic vital 2,06 1,92 0,39 Gastro-intestinale 1,56 1,07 0,001 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

67 Taux annuel (%) HÉMORRAGIES TOTALES RR 0,91 (95% CI: 0,85 0,96) P=0.002 (supériorité) RRR 9% ,56 18, Accidents / n : D150 mg 2x/j warfarine 1993 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

68 Taux annuel (%) CRITÈRE D'EFFICACITÉ PRINCIPAL AVC OU EMBOLIE SYSTÉMIQUE 1,8 RR 0,90 (95% CI: 0,74 1,10) P<0.001 (non-infériorité) 1,5 1,2 1,54 1,71 0,9 0,6 0,3 0 Accidents / n : D110 mg 2x/j warfarine 183 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

69 Taux annuel (%) HÉMORRAGIES MAJEURES 5,0 RR 0,80 (95% CI: 0,70 0,93) P=0.003 (supériorité) 4,0 RRR 20% 3,0 2,0 3,32 2,87 3,57 1,0 0 Accidents/n: D110 mg 2x/j warfarine 342 / / 6022 Connolly SJ, et al. N Engl J Med 2009;361: BIBE FR 07/

70 Nombre d évènements HÉMORRAGIES INTRACRÂNIENNES RR 0,30 (95% CI: 0,19 0,45) P<0,001 (supériorité) RRR 70% 90 0,76% ,23% 0 Accidents/n: D110 mg 2x/j warfarine 27 / / 6022 Connolly SJ, et al. N Engl J Med 2010;363: BIBE FR 07/

71 RE-LY RÉSUMÉ DES RÉSULTATS Pradaxa 150 mg, 2 x/jour, versus warfarine Efficacité Réduction significative de l AVC/embolie systémique Sécurité Taux d hémorragies majeures comparable Réduction significative de: Hémorragies intracrâniennes, Hémorragies menaçant le pronostic vital Hémorragies totales Pradaxa 110 mg, 2 x/jour, versus warfarine Efficacité Taux comparable d'avc/embolie systémique Sécurité Réduction significative de : Hémorragies majeures Hémorragies intracrâniennes, Hémorragies menaçant le pronostic vital Hémorragies totales Connolly SJ, et al. N Engl J Med 2009;361: BIBE FR 07/

72 Dabigatran is the only new-generation agent to also reduce the risk of ischaemic stroke vs warfarin In addition to a significant reduction in stroke/se, haemorrhagic stroke, and ICH Event rate (%/yr) Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin D110 D150 Warfarin RR (95% CI) P value RR (95% CI) P value Stroke/SE <0.001 (NI) <0.001 (Sup) Ischaemic stroke (Sup) RRR=25% Haemorrhagic stroke <0.001 (Sup) <0.001 (Sup) ICH Favours dabigatran Favours warfarin <0.001 (Sup) <0.001 (Sup) Favours Favours dabigatran warfarin ICH = intracranial haemorrhage; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; SE = systemic embolism; Sup = superiority Connolly SJ et al. N Engl J Med 2010;363:1875 6; Pradaxa : EU SmPC, 2012 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 75 Sept 2012

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82 Rivaroxaban reduces the risk of haemorrhagic stroke and ICH with similar rates of stroke/se vs warfarin Event rate (per 100 patient-yrs) Rivaroxaban Warfarin Rivaroxaban vs warfarin HR (95% CI) P value Stroke/SE ITT OT Ischaemic stroke Haemorrhagic stroke ICH Favours rivaroxaban HR = hazard ratio; ICH = intracranial haemorrhage; ITT = intention-to-treat; OT = on-treatment; SE = systemic embolism Enrolled patients were at moderate-to-high risk of stroke (CHADS 2 score 2) Patel MR et al. N Engl J Med 2011;365: Disclaimer: Rivaroxaban is only approved for clinical use in stroke prevention in atrial fibrillation in the USA and EU. Please check local prescribing information for further details Favours warfarin 85 Sept 2012

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87 Apixaban reduces the risk of stroke/se, haemorrhagic stroke, and ICH vs warfarin Apixaban Event rate (%/yr) Warfarin Stroke/SE Apixaban vs warfarin HR (95% CI) P value Ischaemic or uncertain stroke Haemorrhagic stroke <0.001 ICH < Favours apixaban 1.5 Favours warfarin HR = hazard ratio; ICH = intracranial haemorrhage; SE = systemic embolism Granger CB et al. N Engl J Med 2011;365: Disclaimer: Apixaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only. 90 Sept 2012

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98 Score CHA 2 DS 2 VASc (évaluation du risque de stroke) BIBE FR 07/

99 RECOMMANDATIONS EUROPÉENNES POUR LA PRÉVENTION DE L AVC LIÉ À LA FA Score CHA 2 DS 2 VASc = 0 Aucun antithrombotique Score CHA 2 DS 2 VASc 1 * : 1e choix: nouveaux anticoagulants oraux: Inhibiteur de la thrombine directe (Pradaxa) Inhibiteur facteur Xa (rivaroxaban, apixaban) 2e choix: antagonistes de la Vitamine K * Quand le score CHA 2 DS 2 VASc = 1, les anticoagulants oraux (nouvel anticoagulant ou AVK) sont à envisager en fonction du risque de saignement et des préférences du patient BIBE FR 07/

100 Score HASBLED (évaluation du risque hémorragique) BIBE FR 07/

101 Rivaroxaban reduces the risk of haemorrhagic stroke and ICH with similar rates of stroke/se vs warfarin Event rate (per 100 patient-yrs) Rivaroxaban Warfarin Rivaroxaban vs warfarin HR (95% CI) P value Stroke/SE ITT OT Ischaemic stroke Haemorrhagic stroke ICH HR = hazard ratio; ICH = intracranial haemorrhage; ITT = intention-to-treat; OT = on-treatment; SE = systemic embolism Enrolled patients were at moderate-to-high risk of stroke (CHADS 2 score 2) Patel MR et al. N Engl J Med 2011;365: Disclaimer: Rivaroxaban is only approved for clinical use in stroke prevention in atrial fibrillation in the USA and EU. Please check local prescribing information for further details Favours rivaroxaban Favours warfarin BIBE FR 07/

102 Apixaban reduces the risk of stroke/se, haemorrhagic stroke, and ICH vs warfarin Apixaban Event rate (%/yr) Warfarin Stroke/SE Apixaban vs warfarin HR (95% CI) P value Ischaemic or uncertain stroke Haemorrhagic stroke <0.001 ICH < Favours apixaban 1.5 Favours warfarin HR = hazard ratio; ICH = intracranial haemorrhage; SE = systemic embolism Granger CB et al. N Engl J Med 2011;365: Disclaimer: Apixaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only. 105 Sept 2012

103 Rivaroxaban reduces the risk of haemorrhagic stroke and ICH with similar rates of stroke/se vs warfarin Event rate (per 100 patient-yrs) Rivaroxaban Warfarin Rivaroxaban vs warfarin HR (95% CI) P value Stroke/SE ITT OT Ischaemic stroke Haemorrhagic stroke ICH Favours rivaroxaban HR = hazard ratio; ICH = intracranial haemorrhage; ITT = intention-to-treat; OT = on-treatment; SE = systemic embolism Enrolled patients were at moderate-to-high risk of stroke (CHADS 2 score 2) Patel MR et al. N Engl J Med 2011;365: Disclaimer: Rivaroxaban is only approved for clinical use in stroke prevention in atrial fibrillation in the USA and EU. Please check local prescribing information for further details Favours warfarin 106 Sept 2012

104 Cumulative probability of recurrence (%) Ischaemic stroke in AF is more likely to recur 10 Recurrent stroke after ischaemic stroke Patients with AF (n=869) Patients without AF (n=2661) 2 P= Months after first stroke 12 Marini C et al. Stroke 2005;36: Sept 2012