Boehringer-Ingelheim satellite symposium Ligue cardiologique belge 13/05/2017

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1 Boehringer-Ingelheim satellite symposium Ligue cardiologique belge 13/05/2017 Dr André Peeters Service de Neurologie Cliniques Universitaires Saint-Luc / U.C.L BRUXELLES

2 Introduction 1. Aim NOACS = preventing AIS without enhancing ICH 2. Real World Data 3. What to do if stroke (ICH, AIS) occurs under NOAC? 4. Conclusions

3 Aim NOACS = preventing AIS without enhancing ICH in AF Lancet 2014;383:955-6

4 Dabigatran 150 mg BID showed a significant reduction of ischemic strokes vs warfarin SPAF Dabigatran 110 mg BID 1 HR % CI Dabigatran 150 mg BID Apixaban 5/2.5 mg BID* Rivaroxaban 20/15 mg OD Edoxaban 60/30 mg OD Edoxaban 30/15 mg OD Favours NOAC Favours warfarin Not head-to-head comparison no clinical conclusions can be drawn adapted from references 1 6. Studies included patients with or without a prior stroke or transient ischaemic attack *Revised data; re-categorized following original publication Edoxaban dose halved (from 60 mg to 30 mg OD in the high-dose group; from 30 mg to 15 mg OD in the low-dose group) if CrCl ml/min, weight 60 kg, or concomitant verapamil, quinidine, or dronedarone 1. Pradaxa : EU SPC, Jan 2015; 2. Lopes R et al. Lancet 2012;380: ; 3. Patel MR et al. N Engl J Med 2011;365:883 91; 4. Giugliano RP et al. N Engl J Med 2013;369: Jan 2015

5 Bleeding rates NOAC versus warfarin (1) ICH reduction under NOACs in AF New Oral Anticoagulants and the Risk of Intracranial Hemorrhage: Traditional and Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials of New Oral Anticoagulants in Atrial Fibrillation JAMA Neurol. 2013;70(12):

6 Courtesy Prof G Lip

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9 Score de propension désigne la probabilité d être exposé à un traitement, selon un ensemble de caractéristiques observables peut être calculé de 2 manières : par régressions logistiques par les arbres de classification et de régression (classification and regression tree analysis CART) Statist. Med. 2013,

10 Practice-based data consistently confirm the favourable safety profile of dabigatran vs warfarin Risk of major bleeding with dabigatran vs VKA Larsen 2016, n= Sponsor Boehringer Ingelheim Other NOAC companies FDA Independent academic centres Chan 2016, n= Larsen 2014, n= Lip 2016, n=9030 Seeger 2015, n= Selected studies of dabigatran vs warfarin, using robust methodologies,* and published between 2014 and 2017 Yao 2016, n= Villines 2015, n= Graham 2015, n= Favours dabigatran Favours warfarin 0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2 HR (95% CI) *Robustness assessed based on sample size, new-user design, use of propensity-score matching, and/or adjustment for patient characteristics. Sample sizes for comparison of dabigatran vs warfarin; Definition of major bleeding may differ across studies. References in notes

11 Practice-based data consistently confirm similar safety profiles for dabigatran and apixaban Risk of major bleeding with dabigatran vs apixaban Lin 2015, n=4478 Sponsor Boehringer Ingelheim Other NOAC companies FDA Independent academic centres Tepper 2015, n= Lip 2016 (standard doses), n=7920 Lip 2016 (all doses), n=8814 Favours dabigatran Favours apixaban 0 0,5 1 1,5 2 2,5 3 Amin 2015, n=9677 Deitelzweig 2016, n= Favours apixaban Favours dabigatran Selected studies of dabigatran vs apixaban, using robust methodologies,* and published between 2014 and ,5 1 1,5 2 2,5 3 HR (95% CI) *Robustness assessed based on sample size, use of propensity-score matching, and/or adjustment for patient characteristics. Sample sizes for comparison of dabigatran vs apixaban; Definition of major bleeding may differ across studies. References in notes

12 Practice-based data consistently confirm the favourable safety profile of dabigatran vs rivaroxaban Risk of major bleeding with dabigatran vs rivaroxaban Lip 2016 (all doses), n=9314 Sponsor Boehringer Ingelheim Other NOAC companies FDA Independent academic centres Gorst-Rasmussen 2015 (D110 vs R15), n=2711 Hernandez 2016 (D150 vs R20), n= Graham 2016 (D150 vs R20), n= Selected studies of dabigatran vs rivaroxaban, using robust methodologies,* and published between 2014 and 2017 Lip 2016 (standard doses), n=8306 Gorst-Rasmussen 2015 (D150 vs R20), n=4980 Favours rivaroxaban Favours dabigatran 0 0,5 1 1,5 2 2,5 3 HR (95% CI) *Robustness assessed based on sample size, use of propensity-score matching, and/or adjustment for patient characteristics. Sample sizes for comparison of dabigatran vs apixaban; Definition of major bleeding may differ across studies. References in notes

13 BMJ 2017;356:j510

14 What to do if an ischemic stroke occurs under NOAC (1)? i. dabigatran normal results of TT exclude a dabigatran-associated bleeding risk with a high sensitivity ii. rivaroxaban / apixaban if factor Xa assay is normal thrombolysis may be considered when aptt and PT are normal Clin Res Cardiol (2013) 102:

15 Specific tests (not all are readily available) & routine tests do not provide a cut-off value, as for VKA

16 Stroke registry St Luc 2016

17 What to do if an ischemic stroke occurs under NOAC (2)? thrombectomy in case of large vessel occlusion RCT thrombectomy: data on NOAC patients? case reports, registries (SITS) Neurology Today. 15:1,16-18

18 What to do if an ischemic stroke occurs under dabigatran?

19 Praxbind a case of life-saving surgery REVERSE-AD

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21 Case EP 85 Medical history AF, R/ dabigatran 110 mg b.i.d. fall at 02:00-03:00 last intake 03:00!, arrival 07:05 Actual condition stroke onset?, NIHSS Ancillary examinations coagulation assays done CT/CTA/CTP

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24 R/ D110 24:00 72:00

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28 National case collection Germany retrospective, 22 centers, jan-aug 2016 AIS: < 4,5 h; 1 wake up aptt normal 68%, TT abnormal 92% 15/19 IVT (1 + TBY) median NIHSS improvement 5 points no SICH 2 bad outcomes (massive BA stroke, DVT + PE) anticoagulation restarted 24h-10 days in all survivors DOI: / First Published March 24, 2017

29 Neurosurgery for ICH Int J Stroke.2014; 9:840-55

30 Neurosurgery for ICH Stroke. 1999;30:

31 What to do if a hemorrhagic stroke occurs under NOAC? ICH : the old recommandations* lowering BP < 140 mmhg discontinue NOAC activated carbon < 2-3 h intake U PCC/kg IV, if no clinical effect apcc or rfviia neurosurgery after correction hemostatic parameters ICH : the new recommandations lowering BP < 140 mmhg discontinue NOAC Pradaxa pat R/ idarucizumab Other NOACs: see old rec neurosurgery after R/ idarucizumab, without awaiting coagulation assays * Clin Res Cardiol (2013) 102:

32 Case MDW 88 Medical history AF, R/ dabigatran 110 mg b.i.d. fall during the night last intake 07:00?, arrival 09:05 Actual condition VII L 1, arm L 2, leg R 3, leg L 3: NIHSS 9 Ancillary examinations coagulation assays done CT

33 29/12/16 10:18 09:34 12:04 15:14 Temps de céphaline Praxbind 25.6 Temps de prothrombine INR Temps de thrombine Fibrinogène

34 29/12/16 10:18 30/12/16 15:35

35 Early hemorrhage growth in ICH Frequency*: 26 % between baseline and 1-hour CT 12 % between 1-hour and 20-hour CT Predictors**: OAC time to initial CT baseline volume lobar/putaminal/thalamic CT angiography spot sign * Stroke. 1997;28:1-5 **JAMA Neurol. 2014;71:

36 Stroke. 2015;46:

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38 National case collection Germany Intracranial hemorrhage: 12 8 intracerebral H; 3 SDH, 1 SAH aptt normal 11/12; TT abnormal 12/12 4 neurosurgery no hematoma growth 10/12 median NIHSS improvement 5,5 points, mrs % 1 death (ICH volume 134,5 ml, herniation) restart ATT (ASA, preventive dose) 12h-36h in 4/12 survivors DOI: / First Published March 24, 2017

39 Conclusions (1) The major objective of OAC is the prevention of AIS, not the prevention of bleeding. For the patients: dabigatran to warfarin in preventing ischemic stroke or systemic embolism and is associated with less intracranial and fatal bleedings. For the neurologist: with a reversal agent, the lack of a clear cut-off value on coagulation tests is not any longer a barrier before IVT whether early R/ of specific antidotes can improve the poor prognosis of NOAC- ICH is? but it allows to achieve hemostasis in case of urgent surgery

40 Conclusions (2) For the GPs: the Real World Data of dabigatran are similar to those of the RCT setting reassure your patients that a reversal agent is available if an urgent intervention is needed stick to the indications/ contra indications! (having a seat-belt and an airbag driving without due care) stick to the right dosage!