Patients presenting with acute stroke while on DOACs Vemmos Kostas, MD, PhD Stroke Medicine Hellenic Cardiovascular Research Society
Conflicts of interest Honoraria and speaker fees from: BAYER, SANOFI, PFIZER, BOEHRINGER-INGELHEIM, ELPEN, GALENICA
Topics Ischemic stroke Acute phase Secondary prevention Intracerebral hemorrhage (Subarachnoid Hemorrhage Subdural Hematoma) Acute phase Secondary prevention
Case-1 78 years old male History of hypertension and diabetes Known paroxysmal Atrial Fibrillation since 2014 On Dabigatran 110 x 2 At 9:30 pm, he experienced left weakness Presented to ER 2:15 hours later from symptoms onset NIHSS score 13 CT scan available 20 min later
Acute management?
Emergency CT scan and ECG
Reperfusion treatment? 1.Thrombolysis 2.Mechanical thrombectomy
Effect of rt-pa on good stroke outcome (mrs 0 1) 0 by treatment delay, age, and stroke severity Meta-analysis of individual patient data from 6756 patients in 9 RCTs OR (95% CI) 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 Interaction: χ 2 1 =5.80 (P=0.016) Treatment delay (hrs) Age (years) rtpa (n=3391) Control (n=3365) OR (95% CI) 3.0 259/787 (32.9%) 176/762 (23.1%) 1.75 (1.35 2.27) >3.0 to 4.5 485/1375 (35.3%) 432/1437 (30.1%) 1.26 (1.05 1.51) Baseline NIHSS score >4.5 401/1229 (32.6%) 357/1166 (30.6%) 1.15 (0.95 1.40) 80 990/2512 (39.4%) 853/2515 (33.9%) 1.25 (1.10 1.42) >80 155/879 (17.6%) 112/850 (13.2%) 1.56 (1.17 2.08) 0 4 237/345 (68.7%) 189/321 (58.9%) 1.48 (1.07 2.06) 5 10 611/1281 (47.7%) 538/1252 (43.0%) 1.22 (1.04 1.44) 11 15 198/794 (24.9%) 175/808 (21.7%) 1.24 (0.98 1.58) 16 21 77/662 (11.6%) 55/671 (8.2%) 1.50 (1.03 2.17) 22 22/309 (7.1%) 8/313 (2.6%) 3.25 (1.42 7.47) 0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 Treatment delay (hrs) rtpa worse rtpa better 0.5 0.75 1 1.5 2 2.5 mrs, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; rtpa, recombinant tissue plasminogen activator Emberson et al. Lancet 2014
NOACs have a beneficial pharmacological profile compared with warfarin Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Prodrug No Yes No No No Inhibits coagulation Factor II, VII, IX, X IIa Xa Xa Xa Bioavailability (%) ~100 ~6.5 >80 ~50 ~62 Time to peak (hrs) <4 2 2 4 3 4 1 2 Terminal half-life ~1 week 12 14 hrs 11 13 hrs ~12 hrs 9 11 hrs Renal excretion (%) <1 85 ~33 27 ~50 Interactions Multiple P-gp CYP3A4 P-gp CYP3A4 P-gp P-gp P-gp, P-glycoprotein Adapted from Pradaxa : EU SPC, 2015; Xarelto: EU SPC, 2015; Eliquis: EU SPC, 2014; Savaysa: US PI, 2015; Warfarin sodium EU SPC, 2014; Heidbuchel et al. Eur Heart J 2013
Consider differences between NOACs when assessing coagulation status aptt TT, dtt ECT Anti FXa assays PT INR Dabigatran Rivaroxaban Apixaban Edoxaban Patient aptt = 65 sec dtt, diluted thrombin time; ECT, ecarin clotting time; TT, thrombin time Heidbuchel et al. Europace 2013;
Patients presenting with acute ischaemic stroke while on NOACs: EHRA practical guide Assess the time window since last intake of NOAC (>48 hours) In case of uncertainty regarding last dose, prolonged aptt with dabigatran indicates that thrombolysis should not be given For FXa inhibitors, PT may provide quantitative information, but the effect is dependent on the FXa inhibitor and the reagents used If NOACs have been given within 48 hours and coagulation tests are not available or abnormal, consider mechanical recanalization of occluded vessels EHRA, European Heart Rhythm Association Heidbuchel et al. Europace 2013
Intravenous Alteplase in Acute Ischemic Stroke AHA/ASA stroke Guidelines-Febr 2016 The use of intravenous alteplase in patients taking direct thrombin inhibitors or direct factor Xa inhibitors has not been firmly established but may be harmful (Class III; Level of Evidence C). The use of intravenous alteplase in patients taking direct thrombin inhibitors or direct factor Xa inhibitors is not recommended unless laboratory tests such as aptt, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a dose of these agents for >48 hours (assuming normal renal metabolizing function). Stroke. 2016;47:581-641.
Mechanical thrombectomy in acute stroke Solitaire stent Castaño C et al. Stroke 2010;41:1836-1840
Mechanical Thrombectomy in Stroke: Functional Outcomes and All-Cause Mortality (Meta-analysis) analysis) Elgendy, I.Y. et al. J Am Coll Cardiol. 2015; 66:2498 505.
Thrombectomy in patients receiving anticoagulation If coagulation assays are abnormal or not available, or NOACs have been administered within the last 48 hours, thrombectomy may be considered as an alternative treatment option Data on thrombectomy in patients receiving NOACs is limited, and based on findings from observational studies with small patient numbers Diener et al. Lancet Neurol 2013; Heidbuchel et al. Eur Heart J 2013
Secondary prevention?
CT scan 2nd (7 days later) Hemorrhagic transformation Type I
Early stroke recurrence in patients with Atrial Fibrillation Ntaios G, Vemmos K, Int J Cardiol. 2013
Atrial Fibrillation related ischemic stroke In the presence of high risk for hemorrhagic conversion (ie, large infarct, hemorrhagic transformation on initial imaging, uncontrolled hypertension, or hemorrhage tendency), it is reasonable to delay initiation of oral anticoagulation beyond 14 days (Class IIa; Level of Evidence B). New recommendation Stroke. 2014;45:2160-2236
Initiation or resumption of anticoagulation depends on severity of stroke* Time to re-initiation depends on infarct size: 1 3 6 12 day rule (Diener s Law) Bridging with LMHW not required. TIA Mild stroke Moderate stroke Severe stroke As soon as imaging has excluded a cerebral haemorrhage 3 5 days after symptom onset 5 7 days after stroke onset 2 weeks after stroke onset Day 1 3 6 12 *Mild = NIHSS score <8; moderate = NIHSS score 8 16; severe = NIHSS score >16 NIHSS, National Institutes of Health Stroke Scale Huisman et al. Thromb Haemost 2012; Personal communication, Hans-Christoph Diener, 2015
NOACs are associated with improved outcomes in patients with prior stroke/tia vs warfarin Stroke/SE Haemorrhagic stroke ARISTOTLE RE-LY D150 RE-LY D110 ROCKET AF TOTAL OR (95% CI) 0.76 (0.56 1.03) 0.75 (0.52 1.09) 0.84 (0.58 1.21) 0.94 (0.77 1.17) 0.85 (0.74 0.99) OR (95% CI) 0.42 (0.23 0.77) 0.31 (0.14 0.70) 0.20 (0.08 0.48) 0.73 (0.42 1.25) 0.44 (0.32 0.62) Favours NOAC Favours warfarin Favours NOAC Favours warfarin 0.5 0.7 1 1.5 2 0.1 0.2 0.5 1 2 5 10 This study was not designed to compare NOACs against one another. Comparison between NOACs is not valid because of population differences among the studies. No head-to-head data are available Ntaios et al. Stroke 2012
CHA 2 DS 2 -VASc score and stroke risk in patients with AF Item Previous stroke TIA or systemic embolism Points Age 75 years 2 Congestive heart failure* Hypertension 1 Diabetes mellitus 1 Age 65 74 years 1 Female gender 1 Vascular disease 1 2 1 Add points together CHA 2 DS 2 - VASc 1-year stroke rate 9 23.64% 8 22.38% 7 21.50% 6 High 19.74% 5 15.26% 4 9.27% 3 5.92% 2 3.71% 1 2.01% 0 0.78% *Or moderate-to-severe left ventricular systolic dysfunction (left ventricular ejection fraction 40%) Olesen JB et al. BMJ 2011;342:d124; Camm AJ et al. Eur Heart J 2010;31:2369 2429
HAS-BLED for evaluation of bleeding risk Clinical characteristic Points Hypertension (systolic BP >160 mm Hg) 1 Abnormal renal or liver function 1 + 1 Stroke 1 Bleeding 1 Labile INRs 1 Elderly (age >65 years) 1 Drugs or alcohol 1 + 1 Annual Risk of Major Bleeding (Bleeds/100 Patient-Years) 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 12.50 Maximum score 9 Pisters R et al. Chest 2010;138:1093 1100
Case-1 1 secondary prevention? Dabigatran 150 x 2 Apixaban 5 x 2
Missing diagnosis? If patient compliance and therapeutic effect of coagulation have been assured (i.e. the stroke must have occurred under adequate anticoagulation) Alternative causes for ischemic stroke should be investigated (eg severe carotid stenosis). Patients with AF and significant carotid stenosis, carotid endarterectomy and not stenting recommended to avoid triple therapy. Stroke. 2014;45:2160-2236
WATCHMAN LAA Closure Device in situ PROTECT-AF, Holmes DR, Lancet. 2009 Aug
Atrial Fibrillation related ischemic stroke The usefulness of closure of the left atrial appendage with the WATCHMAN device in patients with ischemic stroke or TIA and AF is uncertain. (Class IIb; Level of Evidence B). New recommendation Stroke. 2014;45:2160-2236
Topics Ischemic stroke Acute phase Secondary prevention Intracerebral hemorrhage (Subarachnoid Hemorrhage Subdural Hematoma) Acute phase Secondary prevention
Types of ICH ICH in RE-LY (n=154) Intracerebral 46% Subdural 45% Subarachnoid 8% Hart et al. Stroke 2012
Case-2 75 years old female History of hypertension and diabetes Known permanent Atrial Fibrillation since 2011 On Dabigatran 110 x 2 At 13:30, Right numbness and weakness Presented to ER 1:30 hours later from symptoms onset NIHSS score 10 CT scan available 25 min later Admission BP 205/115 mmhg
Emergency CT scan 1/3 of patients Hematoma expansion within 24 h
Acute management? Rapid BP reduction in 1 hour <140 mmhg No surgery Class I; Level of Evidence A
N Engl J Med. 2015 Aug 6;373(6):511-20.
REVERSE-AD group A 51 patients who had serious bleeding (18 had ICH)
Could idarucizumab be used in RE-VERSE AD TM in the acute phase of ICH to prevent haematoma expansion? ICH could be covered by the proposed indication lifethreatening or uncontrolled bleeding at the discretion of treating physician No data yet on use of idarucizumab in patients with ICH regarding clinical outcome Reduced haematoma volume with idarucizumab treatment has been demonstrated in a mouse model of ICH
AHA/ASA: Guidelines for the Management of Spontaneous Intracerebral Hemorrhage Stroke. 2015;46:2032-2060. For patients with ICH who are taking dabigatran, rivaroxaban, or apixaban, Treatment with FEIBA*, other PCCs, or rfviia might be considered on an individual basis. Hemodialysis might be considered for dabigatran (Class IIb; Level of Evidence C). (New recommendation) It has been suggested that FEIBA or rfviia may be better for the direct thrombin inhibitor dabigatran, Whereas other PCCs may be better for the factor Xa inhibitors rivaroxaban and apixaban *Factor Eight Inhibitor Bypassing Activity
AHA/ASA: Guidelines for the Management of Spontaneous Intracerebral Hemorrhage Stroke. 2015;46:2032-2060. Patients with ICH should have intermittent pneumatic compression for prevention of venous thromboembolism beginning the day of hospital admission (Class I; Level of Evidence A). (Revised from the previous guideline) After documentation of cessation of bleeding, low dose subcutaneous LWMH or unfractionated heparin may be considered for prevention of venous thromboembolism in patients with lack of mobility after 1 to 4 days from onset (Class IIb; Level of Evidence B).
Recommendation (acute phase) In the absence of RCTs, we cannot make strong recommendations about how, when, and for whom to normalize coagulation for patients with acute spontaneous ICH who had been on anticoagulant drugs. Recommendation (secondary prevention) In the absence of RCTs to address these treatment dilemmas, we cannot make firm recommendations about whether and when to resume antithrombotic drugs after ICH. Int J of Stroke.2014, 840 855
Only observational data Secondary prevention?
Case-2: CT scan 16 days later
Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation 3 Danish nationwide registries Five-year Kaplan Meier survival curve Circulation. 2015;132:517-525
12,917 patients with a history of ICH Annual rates per year ICH Ischemic Antiplatelets 5.3 5.2 Warfarin 5.9 3.4 The annual risk of recurrent ICH increased from 4.2% for patients left untreated to 5.9% when treated with warfarin The NNT was lower than NNH for patients with a CHA2DS2-VASc score > 6 receiving warfarin treatment (37 versus 56),
Other considerations: cerebral microbleeds are a marker for the severity and type of small vessel disease CMBs located in cortical subcortical regions are presumably caused by CAA A. Cerebral amyloid angiopathy CMBs located in deep brain regions result from hypertensive arteriopathy B. Hypertensive arteriopathy CAA, cerebral amyloid angiopathy; CMB, cerebral microbleed A: axial susceptibility-weighted imaging; B: axial; T2*-weighted gradient-recalled echo (T2*-GRE) MRI Charidimou et al. Front Neurol. 2012
Anticoagulation following ICH is based on assessment of risk Initiation or resumption of OAC Source of bleeding can be removed or treated Small basal ganglia bleed Subdural haematoma after surgery SAH with clipped or coiled aneurysm Lobar bleed 1 Severe small vessel disease High number of microbleeds Uncontrolled hypertension Future anticoagulation not recommended Subdural haematoma in a patient with chronic alcoholism Re-initiation of oral anticoagulation after 4 8 weeks SAH, subarachnoid haemorrhage Personal communication, Hans-Christoph Diener, 2015 1. Morgensten et al. Stroke 2010
Case-2 2 secondary prevention? Risk assessment CHA 2 DS 2 -VASc = 6 (19.74% year rate for ischemic stroke) HAS-BLED = 4 (8.4% year rate for bleeding Basal ganglia bleeding Microbleeds (MRI needed) Control hypertension Left atrial appendix closure (Watchman device) DOACs?
Summary More evidence data are necessary for patients presenting with acute stroke while on DOACs In patients with ischemic stroke while on DOACs thrombolysis could be implemented on those discontinued medications > 48 hours Mechanical thrombectomy has been suggested Restart DOACs based on empirical recommendations In patients with acute ischemic stroke while on DOACs New promising agents (praxbind, andexanet) Watchman device could be considered Careful selection for restart anticoagulation