NOVEL ANTICOAGULANTS MAKING EDUCATED GUESSES IN PATIENTS WITH ACUTE ISCHEMIC STROKE IGOR RYBINNIK, M.D. Assistant Professor of Neurology Rutgers Robert Wood Johnson Medical School
DISCLOSURES FINANCIAL DISCLOSURE: No relevant financial relationship exists OTHER DISCLOSURES: I am not a hematologist, pharmacologist or a cardiologist
FIRST, AUDIENCE POLL
How familiar are you with novel anticoagulants (dabigatran, rivaroxaban, apixaban)? 1.Not at all 2.A little bit 3.Somewhat 4.Very much 16% 37% 39% 8% 1 2 3 4
65 year-old man presents with an acute left hemispheric ischemic stroke with witnessed onset 2 hours previously. NIHSS is 15. He has no traditional contraindications to tpa. He is taking dabigatran but the time of his last dose is unknown. 1. Would treat if PTT < 40 sec (assume laboratory normal 34 sec) 36% 2. Would treat if PTT within normal 3. Would treat regardless of PTT 4. Would NOT treat regardless of PTT 5. I am not sure what I would do, and/or I need more information (such as thrombin time) 10% 15% 18% 20% 1 2 3 4 5
65 year-old man presents with acute left hemispheric ischemic stroke with witnessed onset 2 hours previously. He has no traditional contraindications to tpa. He is taking dabigatran. His NIHSS is 15. His PTT is 30 sec (normal). 1. Would treat only if his last dose of dabigatran was > 12h ago 2. Would treat only if his last dose was > 24h ago 3. Would treat only if his last dose was > 48h ago 4. Would treat only if his last dose was > 4 days ago 5. Would treat regardless of time of his last dose 6. Would NOT treat this patient 7. I am not sure what I would do, and/or need more information 17% 26% 12% 3% 23% 10% 9% 1 2 3 4 5 6 7
Which of the following best represents your opinion about the use of catheter based acute stroke therapy in a patient on dabigatran? Assume that patient would otherwise be an appropriate candidate for catheter based intervention and that this intervention is available. 1. Would treat some with IV tpa, but prefer mechanical clot removal only (without any IA tpa) 2. Would treat some with IV tpa, but prefer catheter-based thrombolysis (either mechanical or IA tpa) 3. Would treat some with IV tpa, and consider additional catheter-based interventions as I would for any patient regardless of dabigatran use 4. Would NOT treat patients on dabigatran with IV tpa, and prefer mechanical clot removal only 5. Would NOT treat patients on dabigatran with IV tpa, but prefer catheter based thrombolysis (either mechanical or IA tpa) 6. Would NOT treat patients on dabigatran with any reperfusion therapy 13% 20% 25% 23% 8% 11% 1 2 3 4 5 6
NOACS AND RISK OF ISCHEMIC STROKE
META-ANALYSIS: NOACS VS WARFARIN STROKE OR SYSTEMIC EMBOLISM ISCHEMIC STROKE HEMORRHAGIC STROKE ICH ALL-CAUSE MORTALITY MAJOR HEMORRHAGE GI HEMORRHAGE 30 (+1, +55) 20 25 RELATIVE RISK TO WARFARIN (%) 10 0-10 -20-30 p<0.0001-19 (-31, -2) -8 (-17, +2) p<0.0001 p<0.0001 p=0.0003-10 (-15, -5) p=0.06-14 (-17, 0) p=0.04 ~20% -40 RR REDUCTION OF ISCHEMIC STROKE COMPARED TO WARFARIN (RE-LY TRIAL) -51-50 ~60% RR REDUCTION OF ISCHEMIC STROKE COMPARED -55TO (-62, -36) ASPIRIN (AVERROES TRIAL) -60 (-61, -41) Adapted from Ruff CT, et al. Lancet 2013 Online; S0140-6736(13)62343-0
IS WARFARIN OUTCLASSED? Warfarin
PHARMACOLOGY OF NOACS
DABIGATRAN: PHARMACOKINETICS Peak Half life Clin Pharmacokinet 2008;47(5):285
DABIGATRAN: CLOTTING ASSAYS Just right Not sensitive enough Too sensitive Provides qualitative assessment Clin Pharmacokinet 2008;47(5):285
RIVAROXABAN: PHARMACOKINETICS Peak Half life NOTE THAT THROMBIN GENERATION REMAINS INHIBITED FOR 24 HOURS AFTER RIVAROXABAN ADMINISTRATION 1 1 J Clin Pharmacol 2007;47:1398 Clin Pharmacokinet 2011;50(10):675
RIVAROXABAN: CLOTTING ASSAYS Effect on clotting assays: Prolongs both PT and aptt in dose-dependent manner. PT may be more sensitive but agentdependent Eur J Clin Pharmacol. 2005;61:873 J Thromb Haemost 2011;9:133
APIXABAN: PHARMACOKINETICS Peak Half life Br J Clin Pharmacol. 2012;75(2):476
APIXABAN: COAGULATION ASSAYS mpt improved sensitivity INR aptt Br J Clin Pharmacol. 2012;75(2):476
EDOXABAN: PHARMACOKINETICS Peak Half life J Cardiovasc Pharmacol 2012;60(4):335
EDOXABAN: COAGULATION ASSAYS aptt INR Anti-FXa THERE IS SIGNIFICANT REAGENT VARIABILITY Samama MM, et al. Thromb Res 2012;129:e77
NOACS AND COAGULATION ASSAYS DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Peak concentration 2-3 hours 2-4 hours 1.5-3 hours 1-2 hours Half-life 12-17 hours (19-28 hours with impaired renal function) 5-9 hours (11-13 hours with moderate renal impairment or age 75) 8-15 hours (17-18 with CrCl <50 ml/min) 8-11 hours (if normal GFR) aptt to to PT/INR - TT ECT Anti-Xa activity to Peak value aptt Anti-Xa activity (PT, aptt) Trough value Thrombin time Anti-Xa activity Specific test system Hemoclot test Calibrated anti-xa activity
NOACS AND COAGULATION ASSAYS DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN Peak concentration 2-3 hours 2-4 hours 1.5-3 hours 1-2 hours Half-life 12-17 hours (19-28 hours with impaired renal function) 5-9 hours (11-13 hours with moderate renal impairment or age 75) 8-15 hours (17-18 with CrCl <50 ml/min) 8-11 hours (if normal GFR) aptt to to PT/INR - TT ECT Anti-Xa activity to Peak value aptt Anti-Xa activity (PT, aptt) Trough value Thrombin time Anti-Xa activity Specific test system Hemoclot test Calibrated anti-xa activity
NOACS AND REPERFUSION IN ACUTE STROKE
TO REPERFUSE OR NOT, THAT IS THE QUESTION?
INR AND RISK OF sich AFTER IV TPA TREATMENT OF PATIENTS WITH ISCHEMIC STROKE WHO WERE GIVEN WARFARIN AT SUBTHERAPEUTIC INR VALUES ( 1.7) IS PROBABLY SAFE INR 1.7 PROSPECTIVE, OBSERVATIONAL STUDY FROM GWTG REGISTRY (>20,000 PATIENTS). ADMISSION INR WAS NOT STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH SICH AFTER IV TPA (AFTER ADJUSTMENT FOR BASELINE RISK FACTORS). Xian Y, et al. JAMA 2012;307(24):2600
NOACS AND IV TPA: ANIMAL DATA Positive experience with IV TPA in patients receiving dabigatran and rivaroxaban in animal studies 1-3 1 Ann Neurol 2012;71(5):624 2 J Cereb Blood Flow & Metab 2014;34:495 3 Thromb Haemost 2013;110(1):153
DABIGATRAN AND IV TPA: CASE REPORTS AGE/ GENDER LAST DOSE INITIAL NIHSS COAGS TIME TO TPA OUTCOME CITATION 75/W 2.5 h 8 Unknown Withheld NIHSS 2 62/M 3 h 18, >2/3 left MCA 76/W 15 h 4, left MCA 46/W 7 h 19, right MCA, ICA dissection 51/M 15.8 h 5, right MCA 64/M Unknown 8, left MCA 73/M 7 h 14, right MCA 56/M Unknown 8, left hemispheric 77/M Unknown 15, left M1 occlusion PT 14.6 INR 1.29 aptt 37.1 PT 11.4 INR 1 aptt 30.6 INR 1.2 aptt 34.8 INR 1.07 aptt 30.7 TT 26.4 INR 1.1 aptt 37.6 INR 1.13 aptt 38 INR 1.1 TT 69.2 aptt 35.6 INR 1.08 aptt 20 TT 20 190 min ICH in 12 h Death in 48 h 120 min NIHSS 0 just <270 min NIHSS 12 in 24 h 153 min mrs 1 in 6 months 205 min Asympt. arm ecchymosis Unknown Asympt. at day 7 Withheld 90 min NIHSS 5 in 24 h mrs 2 at 90 d Chong et al. 2010 Naranjo, et al. 2011 Matute, et al. 2011 De Smedt, et al. 2010 Sangha, et al. 2012 Lee, et al. 2012 Marrone, et al. 2012 Folyovich, et al. 2013 Pfeilschifter, et al. 2013
DABIGATRAN AND IV TPA: CASE REPORTS AGE/ GENDER LAST DOSE INITIAL NIHSS COAGS TIME TO TPA OUTCOME CITATION 75/W 2.5 h 8 Unknown Withheld NIHSS 2 62/M 3 h 18, >2/3 left MCA 76/W 15 h 4, left MCA 46/W 7 h 19, right MCA, ICA dissection 51/M 15.8 h 5, right MCA 64/M Unknown 8, left MCA 73/M 7 h 14, right MCA 56/M Unknown 8, left hemispheric 77/M Unknown 15, left M1 occlusion PT 14.6 INR 1.29 aptt 37.1 PT 11.4 INR 1 aptt 30.6 INR 1.2 aptt 34.8 INR 1.07 aptt 30.7 TT 26.4 INR 1.1 aptt 37.6 INR 1.13 aptt 38 INR 1.1 TT 69.2 aptt 35.6 INR 1.08 aptt 20 TT 20 190 min ICH in 12 h Death in 48 h 120 min NIHSS 0 just <270 min NIHSS 12 in 24 h 153 min mrs 1 in 6 months 205 min Asympt. arm ecchymosis Unknown Asympt. at day 7 Withheld 90 min NIHSS 5 in 24 h mrs 2 at 90 d Chong et al. 2010 Naranjo, et al. 2011 Matute, et al. 2011 De Smedt, et al. 2010 Sangha, et al. 2012 Lee, et al. 2012 Marrone, et al. 2012 Folyovich, et al. 2013 Pfeilschifter, et al. 2013
RIVAROXABAN AND IV TPA: CASE REPORTS AGE/ GENDER LAST DOSE 83/M 21 h 9 83/W 22 h INITIAL NIHSS COAGS/LABS TIME TO TPA OUTCOME CITATION 18 (left MCA syndrome) aptt 41.9 TT 18.9 (normal) INR 1.41 Anti-FXa activity absent Platelets normal CrCl 28.2 aptt 36.9 PT 10.7 INR 0.9 Plat 211 CrCl 46 210 min 240 min NIHSS 1 at discharge NIHSS 2 in 24 hours, mrs 2 at discharge (9 days) Fluri et al. 2013 Kawiorski et al, 2013
ENDOVASCULAR THERAPY IN PATIENTS ON OAC CHARACTERISTICS PREVIOUS USE OF OAC ADMISSION INR 1.7 NO PREVIOUS USE OF OAC No. of patients 28 20 686 <0.0001 ICH, n (%) sich aich Clinical outcome, n (%) mrs 3-6 Mortality 2 (7.1) 3 (10.7) 19 (67.9) 5 (17.9) 1 (5.0) 2 (10.0) 13 (65.0) 6 (30.0) 41 (6.0) 119 (17.4) 349 (50.9) 148 (21.6) RETROSPECTIVE STUDY OF 714 PATIENTS WITH ACUTE STROKE TREATED WITH ENDOVASCULAR APPROACH IN 6 H P 0.80 0.30 0.11 0.58 4% PRETREATED WITH ORAL ANTICOAGULANTS AT ONSET OF ACUTE STROKE OF WHOM ½ HAD INR <1.7 NO SIGNIFICANT INCREASE OF sich RECANALISATION STRATEGY ADAPTED TO INR (DOSE OF IA TPA, MECHANICAL ONLY OPTION) Adapted from De Marchis GM, et al. Stroke 2011;42:3061
MODERN ENDOVASCULAR THERAPY MODERN STENT RETRIEVER THERAPY HAS 2-4% RISK OF sich Nogueira RG, et al. Lancet 2012; 380: 1231 Saver JL, et al. Lancet 2012; 380: 1241
DE AND ENDOVASCULAR: CASE REPORTS AGE/ GENDER LAST DOSE INITIAL NIHSS 77/M 30 min 18 COAGS INR 1.3 aptt 33 TIME TO ENDOVASC. OUTCOME CITATION 255 min (Solitaire) mrs 1 at 90 days Moye et al. 2012 66/W 72 h M1 occlusion (global aphasia, hemiparesis) aptt 32 TT 84 (4x normal) 540 min (mech.) NIHSS 2 in 24 hours Freeman et al. 2012
SURVEY OF US STROKE NEUROLOGISTS 221/809 STROKE NEUROLOGISTS SURVEYED 88% REPORTED THEY WERE SOMEWHAT OR VERY FAMILIAR WITH DABIGATRAN
SURVEY: COAGULATION ASSAY QUESTION 65 year-old man with acute left hemispheric stroke, symptom onset 2 hours ago, unremarkable head CT and no traditional contraindications to TPA. Time from last DE dose is unknown. Would you treat if? APTT <40 8.6% NORMAL APTT 27.6% WOULD TREAT REGARDLESS OF APTT 3.6% WOULD NOT TREAT REGARDLESS OF APTT 49.0% NOT SURE MOST PEOPLE COMMENTED THAT THEY WOULD NEED THROMBIN TIME 11.3% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% Rybinnik I, et al. J Stroke Cerebrovasc Dis. 2013;22(8):1312
SURVEY: STROKE SEVERITY QUESTION 65 year-old man with acute left hemispheric stroke, witnessed symptom onset 2 hours ago, unremarkable head CT and no traditional contraindications to TPA. Time from last DE dose is unknown, but His PTT is absolutely normal. Would you treat if? ONLY SEVERE STROKE (NIHSS>20) 0.9% AT LEAST MODERATE STROKE (NIHSS>10) 7.7% MILD-MODERATE STROKE (NIHSS>4) 30.3% WOULD NOT TREAT REGARDLESS OF NIHSS 47.5% NOT SURE 13.6% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% Rybinnik I, et al. J Stroke Cerebrovasc Dis. 2013;22(8):1312
SURVEY: TIME FROM LAST DE DOSE QUESTION 65 year-old man with acute left hemispheric stroke (NIHSS 15), symptom onset 2 hours ago, unremarkable head CT, normal aptt and no traditional contraindications to TPA. When would you treat? LAST DE DOSE >12H LAST DE DOSE >24H LAST DE DOSE > 48H 13.6% 13.1% 14.9% LAST DE DOSE > 96H 5.4% WOULD TREAT REGARDLESS OF TIME FROM 20.8% WOULD NOT TREAT 14.5% NOT SURE PARTICIPANTS ASKED FOR THROMBIN TIME, ECARIN CLOTTING TIME, INFORMED CONSENT NEED FROM MORE INFORMATION PATIENT/FAMILY, CRCL, VESSEL STATUS 8.1% 9.5% 0.0% 10.0% 20.0% 30.0% Rybinnik I, et al. J Stroke Cerebrovasc Dis. 2013;22(8):1312
SURVEY: IV TPA IN EXTENDED WINDOW QUESTION How would your decision be affected if the time of witnessed onset was 4 hours instead of 2 hours previously? WOULD NOT TREAT IN 3-4.5H WINDOW 17.2% LESS LIKELY TO TREAT IN 3-2.5H WINDOW 25.8% EQUALLY LIKELY TO TREAT IN 3-4.5H WINDOW 26.2% WOULD NOT TREAT AT ALL 24.4% NOT SURE 6.3% 0.0% 10.0% 20.0% 30.0% Rybinnik I, et al. J Stroke Cerebrovasc Dis. 2013;22(8):1312
SURVEY: ENDOVASCULAR THERAPY QUESTION Assume that the patient is an appropriate candidate for catheter-based intervention. Which best represents your opinion? WOULD TREAT SOME WITH IV TPA, BUT PREFER MECHANICAL THROMBECTOMY ONLY WOULD TREAT SOME WITH IV TPA, BUT PREFER IA TPA OR MECHANICAL 11.8% 11.8% WOULD TREAT SOME WITH IV TPA, AND CONSIDER ENDOVASCULAR AS PER USUAL 30.3% WOULD USE MECHANICAL CLOT RETRIEVAL ONLY 19.9% WOULD USE MECHANICAL OR IA TPA 16.3% WOULD NOT TREAT AT ALL 9.0% 0.0% 10.0% 20.0% 30.0% 40.0% Rybinnik I, et al. J Stroke Cerebrovasc Dis. 2013;22(8):1312
DABIGATRAN AND IV TPA There is a remarkable lack of consensus among vascular neurologists regarding the assessment and treatment of acute stroke patients on dabigatran.
NOVEL ANTICOAGULANTS AND IV TPA I m not deploying my parachute until scientists get more certain about this gravity stuff and prove the parachute s effectiveness. A TRIAL OF REPERFUSION THERAPIES IN THE SETTING OF NOVEL ANTICOAGULANTS IS NOT LIKELY TO BE FEASIBLE
NOVEL ANTICOAGULANTS AND IV TPA DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN t1/2 12-17 hrs (20-30 with renal impairment) Clotting assays: aptt, TT, ECT t1/2 5-9 hrs (11-13 with mod renal impairment or age 75) Clotting assays: PT/aPTT, anti-fxa t1/2 8-15 hrs (17-18 with renal impairment) Clotting assays: mpt, anti-fxa t1/2 6-11 hrs (17-18 with renal impairment) Clotting assays: PT/aPTT, anti-fxa It is reasonable to consider IV/IA tpa if: >24 hours since last dose (~25% anticoagulant effect after 2 half lives) in patient with CrCl >50 ml/min and completely normal sensitive coagulation testing Dabigatran: normal aptt, TT <4x upper normal range, ECT <2x upper normal range, or Hemoclot test <50 ng/ml Rivaroxaban, Apixaban, Edoxaban: normal PT/INR, aptt, anti-fxa absent (if available)
AHA/ASA GUIDELINES The use of intravenous rtpa in patients taking DTIs or direct FXa inhibitors may be harmful and is not recommended unless sensitive laboratory tests such as aptt, INR, platelet count, and ECT, TT, or appropriate direct factor Xa activity assays are normal, or the patient has not received a dose of these agents for >2 days (assuming normal renal metabolizing function). Similar consideration should be given to patients being considered for intra-arterial rtpa. (Class III; Level of Evidence C). Further study is required.
NOACS AND TIMING OF INITIATION AFTER ACUTE STROKE
HEPARIN AFTER ACUTE ISCHEMIC STROKE IV HEPARIN WITHIN 48 HOURS AFTER ACUTE STROKE % PATIENTS IN 14 DAYS WITH RECURRENT STROKE 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 1.4 2.9 HEPARIN 0.4 3.8 AVOID HEPARIN Ischemic Hemorrhagic International Stroke Trial. Lancet. 1997;349(9065):1569
META-ANALYSIS OF EARLY ANTICOAGULATION POST STROKE Study or subcategory Anticoagulants (n/n) Aspirin (n/n) OR (random) 95% CI ALL STROKES (ANTICOAGULANTS VS ASPIRIN) HAEST (Dalteparin) 25/224 21/225 1.22 (0.66, 2.25) IST heparin any dose 28/772 24/837 1.27 (0.73, 2.22) TAIST (Tinzaparin) 11/256 2/112 2.47 (0.54, 11.33) Total (95% CI) 1252 1174 1.31 (0.88, 1.95) MORTALITY OF DISABILITY (ANTICOAGULANTS VS ASPIRIN) IST heparin any dose 611/772 646/837 1.12 (0.89, 1.42) HAEST 148/224 146/225 1.05 (0.71, 1.55) TAIST 192/247 78/110 1.43 (0.86, 2.38) Total (95% CI) 1243 1172 1.14 (0.95, 1.38) 0.1 0.2 0.5 1 2 5 10 Favors anticoagulation Favors aspirin ANTICOAGULANTS ASSOCIATED WITH NON-SIGNIFICANT REDUCTION IN RECURRENT STROKE WITHIN 7-14 DAYS, BUT ALSO SIGNIFICANT INCREASE IN SYMPTOMATIC INTRACRANIAL BLEEDING Adapted from Stroke 2007;38:423
RATES OF HEMORRHAGIC TRANSFORMATION POST STROKE 29% HT (CI 1-51%) IN 48H 76% HT (CI 39-100%) IN 4 DAYS Hemorrhagic infarction No evidence of hemorrhagic infarction Adapted from Lodder J, Stroke 1988;19:1482
NOACS TRIALS EXCLUDED RECENT STROKE DAYS FROM MOST RECENT STROKE/TIA 180 3 90 14 14 7 PATIENTS WITH PRIOR STROKE/TIA IN FOLLOWING TIME PERIODS EXCLUDED FROM TRIALS: 10 30 RE-LY ROCKET-AF ARISTOTLE AVERROES ENGAGE-AF TIMI 48 Any Ischemic Stroke Severe Ischemic stroke (mrs 4-5) TIA
STARTING NOACS AFTER ISCHEMIC STROKE FACTORS TIA (without DWI positivity) TIME TO STARTING NOAC Immediately Small ischemic strokes Controlled BP, absence of microbleeds on MRI Within 3-5 days Moderate ischemic strokes Controlled BP, absence of microbleeds on MRI Large strokes, or hemorrhagic transformation Within 5-7 days 2 weeks (imaging to verify stability) Adapted from McGrath ER, et al. International J Stroke 2014;9:71
SUMMARY
SUMMARY Remarkable lack of consensus among vascular neurologists regarding acute reperfusion therapies in patients on dabigatran, despite reported familiarity Animal data suggest IV TPA is safe in patients on novel anticoagulants It is reasonable to consider IV/IA tpa in patient receiving NOAC if: >24 hours since last dose (although guidelines are more conservative, choosing >48 hour cutoff) CrCl >50 ml/min Completely normal sensitive coagulation testing It is reasonable to start novel anticoagulants after stroke: Within 2-5 days after small stroke 5-7 days after moderate stoke 2 weeks after large ischemic stroke or stroke with HT
WARFARIN WHO WOULD HAVE THOUGHT THAT I WOULD BE EATING RAT POISON TO PRESERVE MY HEALTH? I LOVE MY RAT POISON.
NOVEL ANTICOAGULANTS AND IV TPA
NOACS AND COAGULATION ASSAYS Dabigatran aptt TT Hemoclot Rivaroxaban PT/INR Anti-FXa activity Apixaban mpt/inr Anti-FXa activity Edoxaban PT/INR, aptt Anti-FXa activity