Novel oral Anticoagulants, stroke and intracerebral hemorrhage

Transcription

1 Novel oral Anticoagulants, stroke and intracerebral hemorrhage David Seiffge and Philippe Lyrer on behalf of the Basel Stroke Research Team: Leo Bonati, Gian Marco De Marchis, Stefan Engelter, Henrik Gensicke, Vanessa Grassedonio, Lisa Hert, Nils Peters, Marie- Franciose Ritz, Christopher Traenka

2 Agenda Novel oral anticoagulants in stroke patients (NOACISP) a prospective registry Tranexamic acid in acute intracerebral hemorrhage (TICH-II) Tranexamic acid in intracerebral hemorrhage associated with direct oral anticoagulants (TICH-DOAC)

3 A multi-center registry of new oral anticoagulants in stroke patients NOACISP

4 Background atrial fibrillation (AF) and oral anticoagulation AF one of the leading causes of ischemic stroke Vitamin K-antagonists (VKA) standard treatment and only option for years Novel oral anticoagulants (NOAC) similar effect with lower bleeding rate Approved in Switzerland for prevention of systemic embolism and stroke in atrial fibrillation: Rivaroxaban (Xarelto 04/2012) Dabigatran (Pradaxa 06/2012) Apixaban (Eliquis 11/2013)

5 Open questions for strokologists How do NOAC perform in a real world setting? How to manage intracranial haemorrhage (ICH) in patients taking NOAC, how is the outcome? How to manage acute ischemic stroke in patients taking NOAC (thrombolysis)?

6 Novel oral anticoagulants in stroke patients NOACISP NOACISP LONG-TERM ACUTE «long-term follow-up for secondary prevention in patients with AF and stroke «Stroke and intracerebral haemorrhage in patients under novel oral anticoagulants

7 NOACISP Aims 1) NOACISP LONG-TERM a) safety and efficacy of NOAC in prevention of recurrent stroke among patients with stroke or TIA in a clinical setting 2) NOACISP ACUTE a) management and outcome of intracranial haemorrhage (ICH) among patients treated with NOAC. b) management and outcome of patients with acute ischaemic stroke under NOAC

8 NOACISP Inclusion criteria Consecutive patients who are admitted to the Stroke Unit at a participating center: NOACISP LONG-TERM - Patients with Stroke or TIA, in whom treatment with NOAC or VKA is used for prevention of recurrent stroke NOACISP ACUTE - ICH or - acute ischemic stroke occurring while under treatment with NOAC or VKA for any indication

9 NOACISP Timeline NOACISP ACUTE Baseline If IC fulfilled and signed ICF NOACISP LONG-TERM baseline clinical visite 3 month 6 month 12 month 24 month telephone visite (clinical visite if indicated)

10 NOACISP LONG-TERM Follow-up visits, scope on drug adherence Evaluation of adherence to treamtent: How many NOAC/VKA-dosages were missed since last visit (best guess)? reason mentioned by patient Total number of tablets/caps taken per day VKA/NOAC-drugs administered by (patient him/herself, family member/next-to-kin, health care professional)

11 NOACISP Outcome parameters NOACISP LONG-TERM Primary: stroke (ICH/AIS) or systemic embolism Secondary: any bleeding, adverse events, drug adherence NOACISP ACUTE ICH: mrs at 3 month Hematoma enlargement acute ischemic stroke mrs at 3 month Symptomatic ICH

12 Stroke Center university hospital Basel Pilot and coordinating center Approved by local ethics committee and recruitment started in 04/2013 Amended protocol for NOACISP ACUTE approved by EKNZ 12/2014 Start-up grant from the Swiss heart foundation 2012 for the pilot center in Basel Included January 2015: 300 patients

13 Multicenter registry perspective Grant from the Swiss heart foundation 2013 for the extension of the NOACISP ACUTE to all Swiss Stroke Units: Local ethics committee fee Integration of ecrf in Swiss Stroke Registry planned Negotiations for a grant to expand NOACISP LONGTERM to other Swiss Units

14 Tranexamic acid in intracerebral hemorrhage TICH-II

15 Intracerebral heamorrhage (ICH) hematoma expansion 3h later

16 Hematoma expansion predictor of unfavorable outcome Hematoma expansion (HE) is frequent 26-61% unselected patients 45-54% in VKA-ICH HE is associated with unfavorable outcome Brott T Stroke 1997; Demchuk Lancet Neurology 2012; Flibotte Neurology 2004; Dowlatshahi Stroke 2012

17 Tranexamic acid Tranexamic acid (TA) is a licensed antifibrinolytic drug administered intravenously or orally CRASH-2: 20,000 patients with major bleeding after trauma - TA significantly reduced mortality no increase in vascular occlusive events

18 TICH-2 Trial: Tranexamic acid in IntraCerebral Haemorrhage funded by the NIHR HTA trial opened in March 2013 and will run until February 2017 University of Nottingham is acting as trial sponsor recruitment is ongoing, with 760 participants so far (planned: 2000) Start up phase March 2013 Main phase April 2014 UK, Georgia, Italy, Sweden, Romania

19 TICH-2 Trial: Tranexamic acid in IntraCerebral Haemorrhage Inclusion: Adult no upper age limit Spontaneous intracerebral haemorrhage <8 hours symptom onset Exclusion: Secondary ICH (e.g. anticoagulation, AVM, tumour, trauma, SAH) Contra-indication to tranexamic acid (VTE) Pre-morbid disability (mrs >4) Glasgow coma scale <5 Life expectancy < 3 months

20 TICH-2 Trial: Tranexamic acid in IntraCerebral Haemorrhage Primary outcome: Death or dependency (ordinal shift; modified Rankin Scale, mrs) day 90. Secondary clinical outcomes: At day 7 (or discharge if sooner), neurological impairment (NIHSS). At day 90, disability (Barthel index), Quality of Life (EuroQol), cognition. At day 365, mrs, disability (Barthel index, Quality of Life (EuroQol), cognition, cognition and mood (TICS and ZDS). Safety: death, serious adverse events, thromboembolic events, seizures. Costs: length of stay in hospital, re-admission, institutionalisation. Radiological efficacy/safety (CT scan): change in haematoma volume from baseline to 24 hours, haematoma location, and new infarction.

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22 Treating ICH TICH-II or SWITCH? SWITCH TICH-II Key Inclusion Criteria Age: 18 to 75 years Acute stroke syndrome due to a spontaneous ICH Haemorrhage into basal ganglia or thalamus that may extend into cerebral lobes, ventricles or subarachnoid space Glasgow coma scale (GCS) <14 and >7 NIHSS 10 and 30 Surgical treatment within 72 hours after ictus Volume of hematoma 30 ml and 100 ml Key Exclusion Criteria Intracranial aneurysm, brain arteriovenous malformation, brain tumor, brain trauma, stroke thrombolysis Cerebellar or brainstem hemorrhage Exclusive lobar hemorrhage Moribund patients (GCS 3-7) Key Inclusion Criteria: Adult no upper age limit Spontaneous intracerebral haemorrhage <8 hours symptom onset Key Exclusion Criteria: Secondary ICH (e.g. anticoagulation, AVM, tumour, trauma, SAH) Contra-indication to tranexamic acid (VTE) Pre-morbid disability (mrs >4) Glasgow coma scale <5 Life expectancy < 3 months BOTH!

23 Study proposal: TICH-DOAC a multi-center placebo controlled RCT Aim: To test whether treatment with TA reduces HE in DOAC-ICH

24 TICH-DOAC: Treatment of intracerebral haemorrhage in patients on direct oral anticoagulants with tranexamic acid DOAC target selected players in the coagulation cascade. Intracerebral hemorrhage (ICH) is the most feared complication no proven hemostatic treatment for DOAC-ICH.

25 TICH-DOAC: Specific antidots for DOAC Idarucizumab is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo Phase-I/II studies conducted, not yet published Idarucizumab: porcine trauma model (additional treatment with TA) no RCT in DOAC-ICH planned

26 TICH-DOAC Inclusion criteria Acute intracerebral haemorrhage Prior treatment with a novel direct oral anticoagulant (last intake <48hours) Time of onset <12 hours Age >18 years, No upper age limit Informed consent has been received in accordance to local ethics committee requirements

27 TICH-DOAC Exclusion criteria Severe pre-morbid disability (modified Rankin scale >4) Anticoagulation with VKA Secondary intracerebral haemorrhage (e.g., AVM, tumor) Glasgow coma scale <5 Life expectancy < 3 months due to other disease (e.g. advanced metastatic cancer) pregnancy Planned surgery for ICH within 24 hours Recent deep vein thrombosis or pulmonary embolism within 4 weeks

28 TICH-DOAC Treatment and allocation randomized 1:1 via a web-based system either intravenous tranexamic or as comparator placebo administered by identical regimen. best medical treatment as recommended by international guidelines and defined by local standard operating procedures. may include specific antidots for DOAC in the future.

29 TICH-DOAC Primary outcome measure surrogate imaging outcome measure hematoma expansion (HE) defined >33% or 6ml difference between ICH-volume on baseline CT and on follow-up-ct. Any intraventricular haemorrhage (IVH) components will not be included in ICH volumes.

30 TICH-DOAC Secondary outcome measures (I) Categorical shift in mrs at three-months; (II) mrs 0 3 at three-months; (III) modified Rankin Scale (mrs) 0 4 at three-months (IV) Absolute ICH growth volume by 24 ± 3 hours, adjusted for baseline ICH volume; (V) Death due to any cause by three-months; (VI) major thromboembolic events (myocardial infarction, ischemic stroke, pulmonary embolism)

31 TICH-DOAC Sample Size and feasibility Rate of HE (expected): placebo: 61%, TA 30% Interim analysis after 70 patients adjustment of sample size Basel: 10 DOAC-ICH 06/ /2014; 8 <12h from onset Recruitement: 3 patients/year/ center 10 centers and 3 years

32 Thank you for your attention!!! Stroke-Research Team Basel Prof. Philippe Lyrer Prof. Stefan Engelter PD Dr. Leo Bonati PD Dr. Nils Peters Dr. Gian Marco De Marcis Dr. Henrik Gensicke Dr. David Seiffge Dr. Christopher Tränka Dr. Lisa Hert Vanessa Grassedonio Interested? Do not hesitate to contact us for further information!