Giuseppe Micieli Dipartimento di Neurologia d Urgenza IRCCS Fondazione Istituto Neurologico Nazionale C Mondino, Pavia

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1 Giuseppe Micieli Dipartimento di Neurologia d Urgenza IRCCS Fondazione Istituto Neurologico Nazionale C Mondino, Pavia

2

3 Charidimou et al, 2012

4 Pathogenesis of spontaneous and anticoagulationassociated ICH Charidimou A et al. Front Neurol 2012;3(133):1-13

5 Kaplan-Meier estimate of rate of hemorrhage expansion Flibotte Neurology, 2004;63(6):1059

6 ICH expansion in patients treated with warfarin and clinical outcome CHANT Investigators, Stroke 2009

7 Significant hematoma growth despite INR correction with PCC The patient was treated with 1000 U of PCC and 10 mg vitamin K 98 minutes after baseline CT scan Dowlatshahi D et al. Stroke 2012;43:

8 Canadian PCC Registry (CanPro) 141 cases of TAO related ICH treated with PCC 79.5% INR<1.5 within 1 h Mortality 42.3% Re-bleedings 45.5% Thromboembolic complications 3/141 (2%) within 7 days Dowlasthaki D et al Stroke 2012; 43:

9 Etiology of intracranial hemorrhage Primitive Hemorrhages (78-88%): Secondary Hemorrhages : - Lipoialinosis due to hypertension (Deep) - Cerebral amyloid angiopathy (Lobar) - Vascular malformation - Tumor - Coagulation disorders - Therapy with antiplatelets, anticoagulants or thrombolytics - Granulomatous Angitiis and other vasculitis - Drugs (simpaticomimetics) - Mieloproliferative disease - Eclampsya - Moyamoya - Hemorrhagic transformation due to reperfusion of an ischemic lesion - Trauma

10 Location of ICH Typical Atypical

11 Most common sites of intracerebral haemorrhage Cerebral lobes Basal ganglia Pons Thalamus Cerebellum Symptoms: headache abnormality in sensory or motor function (e.g. weakness on one side of the body) inability to speak problems with balance comatose aphasia Qureshi et al. N Engl J Med 2001;344:

12 Anatomical location of ICH and INR Pezzini A et al. Neurology 2014;82:

13 Schematic diagram of the basal ganglia and superficial perforating arterioles Wardlaw et al, Lancet Neurology 2013

14 Cerebral amyloid angiopathy and focal cisternal microbleeds

15 Mortality of intracerebral hemorrhage Sacco et al, Stroke 2009

16 Risk of recurrence in general intracerebral hemorrhage Weimar et al; Cerebrovascular Dis 2011; 32:

17 Intracranial bleeding and anticoagulants in patients with atrial fibrillation Reinitiating warfarin therapy is a difficult proposition and the pertinent question for any physician Competing risks include: the risk of recurrent intracranial bleeding if warfarin therapy is restarted versus the risk of recurrent thromboembolism without warfarin therapy

18 234 ICH patients (177 survived the first week) Median follow up: 69 weeks HR for recurrent ICH with W resumption: 5.6 (95% CI, ) HR for ischemic stroke: 0.11 (95% CI, ) Recurrent ICH and ischemic stroke nadir occurs when W is resumed after weeks Warfarin resumption after Warfarinassociated ICH Majeed A et al. Stroke 2010;41:

19 Three Danish nationwide registries in the period between 1997 and ,752 pts 1 year follow-up Nielsen et al, Circulation 2015

20 Incidence rate of ischemic and hemorrhagic complications during 1-year follow-up in patients with and without OAC resumption 19 Germany terziary care centers 1176 individuals 853 for analysis of hematoma enargement 719 for analysis of OAC resumption Kuramatsu JB et al. JAMA 2015;313(8):

21 INR reversal or combined INR reversal, SBP (<160 mmhg) and timing (4 hrs) with hematoma enlargement Kuramatsu JB et al. JAMA 2015;313(8):

22 Chao et al, Circulation 2016

23 The risk of recurrent intracranial bleeding Deep hemorrhage for 1000 anticoagulated patients for 1 year: - 31 fewer thromboembolic strokes - 19 additional ICHs Lobar hemorrhage for 1000 anticoagulated patients for 1 year: - 31 fewer thromboembolic strokes additional ICHs Eckman et al. Stroke 2003

24 Can patients be anticoagulated after intracerebral hemorrhage? Lobar hemorrhage Eckman et al. Stroke 2003

25 Can patients be anticoagulated after intracerebral hemorrhage? Deep hemorrhage: Eckman et al. Stroke 2003

26 New anticoagulants: hemorrhagic risk Ntaios et al, Stroke 2012

27 Mortalità dopo un sanguinamento maggiore 0.2 Warfarin Dabigatran Mortality rate (%) Time (days) Kaplan Meier analysis indicated a reduced risk of death with dabigatran* vs warfarin during 30 days from the bleeding (P=0.052) *Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major bleed included. Analysis not adjusted for covariates Majeed A et al. Circulation 2013

28 Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran The RE-LY Trial Mortality Dabigatran Dabigatran Warfarin 150 mg 110 mg All intracranial 36% (32/90) 35% (13/37) 41% (11/27) Intracerebral 41% (19/46) 64% (7/11) 64% (9/14) Hart RG et al, Stroke 2012

29 Aspirin and recurrent lobar cerebral hemorrhage Neurology 2010; 75:

30 Apixaban versus aspirin Connolly et al, N Engl J Med 2011

31 Cerebral microbleeds (CBM)

32 Cerebral microbleeds and age Yamada S et al. Eur J Neurol 2012;19:98-104

33 RRs for subsequent ICH among patients with CMBs versus those without CMBs Wang D-N et al. J Stroke Cerebrovasc Dis 2015;

34 New CMBs significantly correlated with: Age Leukoaraiosis Increase of CMBs in patients with CMBs at baseline during warfarin therapy Necioglu Orken D et al. Clin Neurol Neurosurg 2013;115:

35 Annual incidence of stroke in heart prosthetic valves without anticoagulation Double disk aortic mechanic prosthesis 12.3% Double disk mitral mechanic prosthesis 22.2% Double mechanic prosthesis 91.0% Biologic prosthesis (at 3 months) 17.0%* *mitral valve prosthesis

36 Restarting anticoagulation after ICH in different clinical conditions Becattini C et al. Vasc Pharmacol 2016;84:15-24

37 Can patients be anticoagulated after intracerebral hemorrhage? Patients with lobar haemorrhage or cerebral amyloid angiopathy remain at higher risk for anticoagulant-related ICH recurrence than thromboembolic events and, therefore would be best managed without anticoagulants. Patients with deep hemispheric ICH and a baseline risk of ischaemic stroke >6.5% per year, that corresponds to CHADS2 4 or CHA2DS2-VASc 5, may receive net benefit from restarting anticoagulation. To date, a reasonable recommendation regarding time to resumption of anticoagulation therapy would be after 10 weeks.

38 Can patients be anticoagulated after intracerebral hemorrhage? Available data regarding the role of MRI on the risks of both ICH and warfarin-related ICH do not support the use of this test for excluding anticoagulation in patients with atrial fibrillation. In patients having both atrial fibrillation and an unfavourable risk/benefit profile for restarting anticoagulation, antiplatelet therapy should not be considered as a valid alternative. Due to the reduction of ICH in patients treated with the new anticoagulants compared to warfarin, it could be reasonable to consider these new anticoagulants for restarting anticoagulation in patients who suffered from ICH during warfarin therapy.

39 Vincent Van Gogh Notte stellata sul Rodano (1888)

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