Boehringer-Ingelheim satellite symposium Ligue cardiologique belge 13/05/2017 Dr André Peeters Service de Neurologie Cliniques Universitaires Saint-Luc / U.C.L. 1200 BRUXELLES
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
Aim NOACS = preventing AIS without enhancing ICH in AF Lancet 2014;383:955-6
Dabigatran 150 mg BID showed a significant reduction of ischemic strokes vs warfarin SPAF Dabigatran 110 mg BID 1 HR 1.13 95% CI 0.89 1.42 Dabigatran 150 mg BID 1 0.76 0.59 0.98 Apixaban 5/2.5 mg BID* 2 1.02 0.81 1.29 Rivaroxaban 20/15 mg OD 3 0.94 0.75 1.17 Edoxaban 60/30 mg OD 4 1.00 0.83 1.19 Edoxaban 30/15 mg OD 4 1.41 1.19 1.67 Favours NOAC Favours warfarin 0.0 0.5 1.0 1.5 2.0 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 30 50 ml/min, weight 60 kg, or concomitant verapamil, quinidine, or dronedarone 1. Pradaxa : EU SPC, Jan 2015; 2. Lopes R et al. Lancet 2012;380:1749 58; 3. Patel MR et al. N Engl J Med 2011;365:883 91; 4. Giugliano RP et al. N Engl J Med 2013;369:2093 104 4 Jan 2015
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):1486-1490
Courtesy Prof G Lip
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, 32 3388 3414
Practice-based data consistently confirm the favourable safety profile of dabigatran vs warfarin Risk of major bleeding with dabigatran vs VKA Larsen 2016, n=48 137 Sponsor Boehringer Ingelheim Other NOAC companies FDA Independent academic centres Chan 2016, n=19 853 Larsen 2014, n=21 189 Lip 2016, n=9030 Seeger 2015, n=44 672 Selected studies of dabigatran vs warfarin, using robust methodologies,* and published between 2014 and 2017 Yao 2016, n=28 614 Villines 2015, n=25 586 Graham 2015, n=134 414 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
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=29 748 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=44 542 Favours apixaban Favours dabigatran Selected studies of dabigatran vs apixaban, using robust methodologies,* and published between 2014 and 2017 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
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=13 121 Graham 2016 (D150 vs R20), n=118 891 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
BMJ 2017;356:j510
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) 102:399 412
Specific tests (not all are readily available) & routine tests do not provide a cut-off value, as for VKA
Stroke registry St Luc 2016
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
What to do if an ischemic stroke occurs under dabigatran?
Praxbind a case of life-saving surgery REVERSE-AD
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 17 11 Ancillary examinations coagulation assays done CT/CTA/CTP
R/ D110 24:00 72:00
National case collection Germany retrospective, 22 centers, jan-aug 2016 AIS: 19 18 < 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: 10.1177/1747493017701944 First Published March 24, 2017
Neurosurgery for ICH Int J Stroke.2014; 9:840-55
Neurosurgery for ICH Stroke. 1999;30:905-915
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 30-50 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) 102:399 412
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
29/12/16 10:18 09:34 12:04 15:14 Temps de céphaline 25.1-36.5 29.2 Praxbind 25.6 Temps de prothrombine 9.35-14.30 12.7 12.3 INR 0.80-1.20 1.09 1.06 Temps de thrombine 10.0-18.0 33.5 13.5 Fibrinogène 150-450 401 432
29/12/16 10:18 30/12/16 15:35
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;71:158-164
Stroke. 2015;46:376-381
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 0-3 67% 1 death (ICH volume 134,5 ml, herniation) restart ATT (ASA, preventive dose) 12h-36h in 4/12 survivors DOI: 10.1177/1747493017701944 First Published March 24, 2017
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
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!