Nadine Ajzenberg** Marie-Genevieve Huisse** Isabelle Mahé*** Edith Peynaud **** Aurelie Roche* Patricia Esselin* Laurence Auguste-Charlery*

Transcription

1 «new oral anticoagulants and brain specificity» Claire Bal dit Sollier * Ariane Davout * Sun-Young Park* Irène Clavijo* Adeline-Zoe Thoux * Ioana Muller* Ludovic Drouet* Nadine Ajzenberg** Marie-Genevieve Huisse** Isabelle Mahé*** Edith Peynaud **** Aurelie Roche* Patricia Esselin* Laurence Auguste-Charlery* Laboratoire Hématologie hôpital Lariboisière Consultation hémostase thromboses antithrombotiques Institut des Vaisseaux et du Sang (IVS) hôpital Lariboisière Centre de Référence et d Education des AntiThrombotiques d Ile de France (CREATIF) *Lariboisière, **Bichat, ***Louis-Mourier creatif.lrb@lrb.aphp.fr Université Paris 7 Denis- Diderot

2 Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Grant/support Scientific Advisory Board No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare Sanofi, BMS-Pfizer, Lilly-Daiichi, AstraZeneca, Boehringer-Ingelheim, Bayer Sanofi, Lilly-Daiichi Sanofi, BMS-Pfizer, Boehringer-Ingelheim, Lilly- Daiichi, AstraZeneca, Bayer

3

4 Where are we with NOAC in Afib? After three major trials

5 Stroke or systemic embolism indirect meta-analysis

6 Major bleeding indirect meta-analysis

7 NOAC / warfarin in Afib patients (results of 3 major trials) Intracranial Hemorrhages (simple plot of the crude results)

8 Where are we with NOAC in Afib? In real life

9 Dabigatran and Postmarketing Reports of Bleeding Southworth et al, NEJM 2013

10 LarsenT B et al Efficacy and safety of dabigatran etexilate and warfarin in real world patients with atrial fibrillation: A prospective nationwide DK cohort study. JACC2013

11 Where are we with NOAC in Afib? More specific results on ICH From the subgroups in the trials

12 RE-LY ICH subgroup analysis: sites of bleeding 154 ICH events (in 153 pts*) Subarachnoid Intracerebral Subdural *1 patient survived traumatic intracerebral haemorrhage and later died from spontaneous subdural haematoma Classified as haemorrhagic strokes in the RE-LY main results ICH = intracranial haemorrhage Hart RG et al. Stroke 2012;43: Mar 2013

13 Hart R G. Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran : The RE-LY Trial Stroke 2012;43

14 Hart R G. Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran : The RE-LY Trial Stroke 2012;43

15 Where are we with NOAC in Afib? This reduced incidence of ICH is specific among the bleeding events

16 Total bleeding 25 RR 0.78 (95% CI: ) Total bleeding (%/yr) P<0.001 (Sup) RRR 22% RR 0.91 (95% CI: ) P=0.002 (Sup) RRR 9% Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Events/number: 1754/ / /6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2010;363:

17 Intracranial bleeding Intracranial bleeding (%/yr) RR 0.30 (95% CI: ) 0.23 Dabigatran 110 mg BID P<0.001 (Sup) RRR 70% RR 0.41 (95% CI: ) 0.32 Dabigatran 150 mg BID P<0.001 (Sup) RRR 59% 0.76 Warfarin Events/number: 27/ / /6022 BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2010;363:

18 RE-LY ICH subgroup analysis: sites/rates of ICH dabi 110 BID vs warfarin Significantly lower rates of ICH, intracerebral, and subdural haematoma with dabigatran 110 mg BID N/rate (%/yr) Dabigatran 110 mg BID vs warfarin D 110 mg BID Warfarin RR (95% CI); P value All ICH (n=154) 27/ / ( ); P<0.001 Intracerebral (n=71) Subdural (n=70) Subarachnoid (n=13) 14/ / / /0.31 3/0.03 8/ ( ); P< ( ); P< ; P=NS Favours dabigatran Favours warfarin BID = twice daily; D = dabigatran; ICH = intracranial haemorrhage; NS = non-significant; RR = relative risk Hart RG et al. Stroke 2012;43: Mar 2013

19 RE-LY ICH subgroup analysis: sites/rates of ICH dabi 150 BID vs warfarin Significantly lower rates of ICH and intracerebral haemorrhage with dabigatran 150 mg BID N/rate (%/yr) Dabigatran 150 mg BID vs warfarin D 150 mg BID Warfarin RR (95% CI); P value All ICH (N=154) 37/ / ( ); P<0.001 Intracerebral (n=71) 11/ / ( ); P<0.001 Subdural (n=70) Subarachnoid (n=13) 24/ /0.31 2/0.02 8/ ( ); P= ( ); P= Favours dabigatran Favours warfarin BID = twice daily; D = dabigatran; ICH = intracranial haemorrhage; RR = relative risk Hart RG et al. Stroke 2012;43: Mar 2013

20 Where are we with NOAC in Afib? Are the factors modulating the risk/benefit of ICH among the patients in the trials depending on:? -The patient -The diseases -The treatments -The doctors

21 CHADS 2 subgroup analysis: intracranial bleeding Effect of dabigatran was consistent (no significant interaction with treatment) Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin CHADS 2 score D 110 mg BID Annual rate (%) D 150 mg BID Warfarin P=0.70* P=0.82* *P values for interaction BID = twice daily; D = dabigatran Oldgren J et al. Ann Int Med 2011;155: Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin 21 Mar 2013

22 CHADS 2 subgroup analysis: major bleeding Effect of dabigatran was consistent (no significant interaction with treatment) Dabigatran 110 mg BID vs warfarin Dabigatran 150 mg BID vs warfarin CHADS 2 score D 110 mg BID Annual rate (%) D 150 mg BID Warfarin P=0.26* P=0.14* *P values for interaction BID = twice daily; D = dabigatran Oldgren J et al. Ann Int Med 2011;155: Favours dabigatran Favours warfarin Favours dabigatran Favours warfarin 22 Mar 2013

23 Age and bleeding subgroup analysis: intracranial and extracranial bleeding Interaction with age for extracranial bleeding (but not intracranial bleeding) Annual rate (%) D110 vs warfarin D150 vs warfarin D110 D150 Warfarin RR (95% CI) P value* RR (95% CI) P value* Intracranial ani bleeding <75 yrs ( ) 0.43 ( ) ( ) ( ) 0.91 Extracranial bleeding <75 yrs ( ) 0.78 ( ) ( ) ( ) <0.001 *P value for interaction D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RR = relative risk Eikelboom JW et al. Circulation 2011;123: Mar 2013

24 Prior stroke subgroup analysis: intracranial bleeding Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.20 ( ) 0.41 ( ) No prior stroke/tia Annual rate, % RR (95% CI) vs warfarin 0.35 ( ) 0.43 ( ) P value for interaction BID = twice daily; TIA = transient ischaemic attack Diener HC et al. Lancet Neurol 2010;9: Mar 2013

25 Time to first intracranial bleed 0.02 Warfarin Dabigatran 110 mg BID Cumulative hazard rates 0.01 Dabigatran 150 mg BID RR 0.41 (95% CI: ) P<0.001 (Sup) RRR 59% RRR 70% 0.00 RR 0.30 (95% CI: ) P<0.001 (Sup) Time (years) BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ. ESC oral presentation #181; Connolly SJ et al. N Engl J Med 2010;363:

26 VKA-naïve vs VKA-experienced: time to first intracranial bleed Cumulative hazard rate Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID All patients Years of follow-up P value for interaction * Years of follow-up *Interaction between treatment group and VKA status BID = twice daily; VKA = vitamin K antagonist Connolly SJ. ESC 2009; session 181 available at: accessed March 2012; Ezekowitz M et al. Circulation 2010;122: Cumulative hazard rate Cumulative hazard rate VKA-naïve Years of follow-up VKA-experienced 27

27 RE-LY ICH subgroup analysis: patient characteristics Patients with ICH vs those without ICH: Older, lower CrCl, had heart failure less often, had prior stroke/tia more often, more likely to take aspirin, assigned to warfarin more often No ICH (n=17 960) Any ICH (n=153) P value Mean age, yrs <0.001 Mean CrCl, ml/min <0.001 Heart failure, % Prior stroke/tia, % Assigned warfarin, % <0.001 Aspirin use prior to haemorrhage, % 32 * Characteristics not significantly different between groups are not shown * Fraction using Aspirin at any follow-up visit prior to the mean time to ICH CrCl = creatinine clearance; ICH = intracranial haemorrhage; TIA = transient ischaemic attack Hart RG et al. Stroke 2012;43: Mar 2013

28 RE-LY ICH subgroup analysis: independent predictors of ICH Age, prior stroke/tia, assignment to warfarin, and aspirin use predicted ICH Aspirin use also a predictor in the warfarin group Only age was a significant predictor in the dabigatran group Feature Relative risk P value All patients (n=153) Age (per year) White race Prior stroke/tia Assigned warfarin Aspirin use < < Warfarin patients (n=90) Age (per year) White race Prior stroke/tia Aspirin use TTR Dabigatran patients (n=64) * Age (per year) * Aspirin use was associated with a relative risk of 1.5 (95% CI: ); Multivariate analysis ICH = intracranial haemorrhage; TIA = transient ischaemic attack; TTR = time in therapeutic range Hart RG et al. Stroke 2012;43: Mar 2013

29 Intracranial bleeding according to cttr cttr Dabi 110 mg Rate per 100-person yrs Dabi 150 mg Rate per 100-person yrs Warfarin Rate per 100-person yrs Dabigatran 110 mg vs warfarin HR (95% CI) P* (interacti on) Dabigatran 150 mg vs warfarin HR (95% CI) P* (interact ion) <57.1% ( ) 0.53 ( ) % ( ) 0.45 ( ) % ( ) 0.35 ( ) >72.6% ( ) ( ) 0.89 *Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variable TTR = time in therapeutic range; cttr = centre mean TTR; HR = hazard ratio Wallentin L et al. Lancet 2010;376:

30

31

32

33

34 Concomitant antiplatelet therapy subgroup analysis: dabigatran 110 mg BID vs warfarin Stroke/embolism All stroke Haemorrhagic Ischaemic Non-inferiority margin = 1.46 No antiplatelet Antiplatelet CV death Major bleed Minor bleed All bleed Intracranial Extracranial BID = twice daily; CV = cardiovascular Dans AL et al. Presented at ESC 2011; Session ; e-slides available at: accessed Sept Mar 2013

35 Concomitant antiplatelet therapy subgroup analysis: antiplatelet vs no antiplatelet Haemorrhagic stroke Major bleed Minor bleed Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Major/minor bleed Intracranial Extracranial Dans AL et al. Presented at ESC 2011; Session ; e-slides available at: accessed Sept Mar 2013

36 What are the putative explanations for the lower rate of ICH in patients treated with NOAC vs warfarin? The trans-cellular permeability of the blood-brain barrier depends on p-gp

37

38 E. Aronica et al. / Advanced Drug Delivery Reviews 2011

39 What are the putative explanations for the lower rate of ICH in patients treated with NOAC vs warfarin? The trans-cellular permeability of the blood-brain barrier depends on p-gp A pro-hemorrhagic effect specific of VKA at the blood-brain barrier level

40

41 Fernández-Fernández et al. Thromb Haemost 2008; 100: Effect of GAS6 interaction with Axl

42

43 Where are we with NOAC in Afib? Lower incidence of ICH among the Afib patients treated with NOAC This lower incidence is modulated -The patient -The diseases The net incidence depend on - The treatments (NOAC/warf, APA ) -The doctors (treatment, education, surveillance.. )