M. Edip Gurol, MD, MSc Stroke Service/Neurology, Massachusetts General Hospital, Harvard Medical School

Transcription

1 High Risk of Thromboembolism and ICH: Problems with Medical Management M. Edip Gurol, MD, MSc Stroke Service/Neurology, Massachusetts General Hospital, Harvard Medical School

2 Disclosures Funding from NIH (NS083711) No Other Disclosures

3 Patient 1 69M w/ Hx DM, HTN, HPL, CAD s/p CABG, CMP s/p AICD 2010, AFib 12y, Coumadin 10 years, had ICH in 2014 w/ INR 5.8, coumadin stopped kept on ASA

4 Patient 1 3 years later, he had sudden onset of left sided Sx NIHSS 15 Underwent IAT

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6 Patient 2-86F with slowly progressive memory deficits over the past 3 years (on ASA for primary prevention ) had episodes of word finding difficulty, no other focal deficits -Family member gave her 4 aspirins and brought to ED -No AFib -normal exam other than mild memory and executive dysfunction (MMSE 26)

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8 2 years later

9 Outline High Risk of Intracranial Hemorrhage and Thromboembolism: Definitions and Scope of The problem Problems with Medical Management Does anticoagulation increase the risk of ICH? How are the outcomes of anticoagulation related ICH? Do we have alternatives to anticoagulation? Discussing alternatives with the patients: shared decision making

10 High Intracranial Hemorrhage Risk Survivors of non-traumatic intraparenchymal hemorrhage (IPH) Patients without symptomatic IPH, found to have microbleeds on brain MRI Patients who had traumatic or spontaneous SDH Patients at high fall risk Patients referred for questions of antiplatelet/anticoagulation safety because of neurologic concerns such as presence of severe leukoaraiosis, enlarged perivascular spaces, dementia

11 Ischemic problems that complicate management in High ICH risk population Atrial fibrillation Deep vein thrombosis +/- Pulmonary Embolism Coronary artery disease Congestive Heart Failure Peripheral arterial disease Any hypercoagulable condition Patent foramen ovale + Ischemic stroke

12 Concomitant High ICH Risk & AFib Scope of the problem in the US ~4,000 ICH survivors with AFib per year ~30,000 ischemic stroke survivors with microbleeds and AFib per year ~1,100,000 adults >45 w/ Cerebral Microbleeds & Afib ~5,000 SDH survivors with AFib per year Other conditions requiring antithrombotic use [CDC] Approximately 7.9 million U.S. adults have a history of heart attack, approximately 7 million U.S. adults have a history of stroke, approximately 16 million U.S. adults have received a diagnosis of CAD

13 Etiology of Primary IPH and Recurrence Risk Primary" IPH regardless of the type (lobar cerebral amyloid angiopathy-related VS hypertensive deep ICH) is the most fatal and disabling type of stroke. In many cases it has a relatively high risk of recurrence Other biomarkers can help assess the risk of recurrent hemorrhage in this context Microbleeds Superficial siderosis

14 IPH location as a marker of the etiology Deep HTN IPH Lobar CAA Related IPH Deep HTN IPH and microbleeds Lobar CAA Related microbleeds

15 Hypertensive Deep IPH Hypertensive patient with non-traumatic hemorrhage in deep hemispheric regions Basal ganglia Thalamus brainstem in the absence of other pathology (vascular, neoplastic,...) Annual recurrence risk about 2%

16 Cerebral Amyloid Angiopathy Knudsen Neurology 2001

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18 Risk of Future IPH in CAA with or without IPH at Presentation 70 yo p/w acute symptomatic ICH 72 yo p/w cognitive syx and microbleeds BUT NO symptomatic ICH

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20 Van Etten Stroke 2014 Lobar MB only patients 72M mild HTN, had MRI for depression and memory complaints w/ NL tests, multiple lobar MBs Warfarin use and older age were independent predictors of future IPH in lobar MB-only patients after correction for other covariates

21 Incident IPH in a 85yo patient enrolled w/ lobar MB-only CAA Van Etten Stroke 2014

22 Risk of recurrent IPH in CAA Cortical superficial siderosis Baseline Siderosis 4-year cumulative ICH risk none 25% focal 28.9% disseminated 74% Charidimou, Neurology 2013 Linn J et al. Neurology 2010;74:

23 5,068 patients from 15 studies overall pooled prevalence of CMBs in IS/TIA = 25.3%

24 Microbleeds in Community Dwelling Healthy Elderly Akoudad Circulation % of 4759 HC aged 45 years had MBs (median count 1 [1 111]) Six HC w/ MBs at bline (all 6 had multiple MBs) Developed first-ever ICH during follow-up

25 A A B B C C Probable CAA presenting with ICH ~10% annual ICH recurrence risk Deep Hypertensive ICH ~2% annual ICH recurrence risk Increased risk when Superficial Siderosis (+) Lobar MB only CAA Annual ICH risk ~5% D D E E F F Annual ICH risk in patients with bleeding-prone cerebral pathologies

26 ~ 21% of chronic SDH occur on Warfarin, 42.5x risk then people not on Warfarin Balser J Neurosurg 123: , 2015 Rust J Clin Neuroscience 13: , 2006 Might be related to trauma OR chronic/spontaneous The annual estimated incidence of chronic SDH may reach up to 58.1 per 100,000 persons for patients 65 years of age or older. Estimated chronic SDH patients in 2016: ~ 38,000 Estimated chronic SDH patients in 2030: ~ 60,000

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28 Outline High Risk of Intracranial Hemorrhage and Thromboembolism: Definitions and Scope of The problem Problems with Medical Management Does anticoagulation increase the risk of ICH? How are the outcomes of anticoagulation related ICH? Do we have alternatives to anticoagulation? Discussing alternatives with the patients: shared decision making

29 The reported incidence of OAT-ICH is 7- to 10-fold higher than in patients who are not receiving OAT, and is as high as 1.8% per year in stroke prone patients. OAT-ICH comprise 70% of all OAT-related intracranial hemorrhages, with the remainder being subdural hemorrhages.

30 ICH Risk on Warfarin In controlled trials of patients with nonvalvular atrial fibrillation (from 1990s), a pooled analysis found a 3-fold increase in risk of ICH on warfarin (Arch Intern Med. 1994;154: ). Different studies and meta-analyses found 2-5 folds increase in ICH risk when Warfarin is used

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32 Novel oral anticoagulants (NOAC) NOACs for non-valvular Afib and DVT Emerged as important alternatives to warfarin in general NVAF/DVT populations Lower ICH risk than coumadin overall, but all phase 3 studies excluded patients who had prior ICH, so we do not know how safe these meds are in post-ich patients Multiple concerns Medication compliance Safety in older adults with reduced renal function Efficacy of reversal strategies Cost

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34 Novel oral anticoagulants (NOAC) NOACs for non-valvular Afib and DVT Emerged as important alternatives to warfarin in general NVAF/DVT populations Lower ICH risk than coumadin overall, but all phase 3 studies excluded patients who had prior ICH, so we do not know how safe these meds are in post-ich patients Multiple concerns Medication compliance Safety in older adults with reduced renal function Efficacy of reversal strategies Cost NOACs might be considered in select post-ich patients who have high NVAF related embolic risk and very low ICH risk the uncertainties listed above should be discussed with patient and family and alternatives should also be offered if possible (LAA closure)

35 Outline High Risk of Intracranial Hemorrhage and Thromboembolism: Definitions and Scope of The problem Problems with Medical Management Does anticoagulation increase the risk of ICH? How are the outcomes of anticoagulation related ICH? Do we have alternatives to anticoagulation? Discussing alternatives with the patients: shared decision making

36 Of 435 consecutive patients w/ ICH > 55: (23.4%) were taking warfarin at the time of ICH (50% of them for AFib) Three-month mortality was % for those not taking warfarin % for those taking warfarin

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39 Outline High Risk of Intracranial Hemorrhage and Thromboembolism: Definitions and Scope of The problem Problems with Medical Management Does anticoagulation increase the risk of ICH? How are the outcomes of anticoagulation related ICH? Do we have alternatives to anticoagulation? Discussing alternatives with the patients: shared decision making

40 Left atrial appendage an embryonic remnant of the original left atrium, is a long, tubular, trabeculated structure, in continuity with the left atrial cavity Its unique anatomy predisposes to in-situ thrombus formation, and >90% of atrial thrombi in patients with NVAF are believed to originate in LAA

41 New approaches in AFib that might obviate the need for long-term anticoagulation Endovascular left atrial appendage (LAA) closure procedures WATCHMAN (only FDA approved device) AMPLATZER (2 nd gen) AMULET LAmbre device Combined endovascular and epicardial LAA closure procedures LARIAT procedure Surgery for LAA closure AtriClip Primary ligation/excision/amputation New procedures to treat AFib?? Endovascular ablation Mini Maze procedure

42 WATCHMAN FDA approval On March 13, 2015, the FDA issued an approval for the WATCHMAN device. The approval specified indications for use in patients with NVAF who are: 1) at increased risk of stroke and systemic embolism on the basis of CHADS2 or CHA2DS2-VASc scores 2) deemed by their physicians to be suitable for warfarin therapy 3) have an appropriate rationale to seek a nonpharmacological alternative to warfarin, taking into account the safety and efficacy of the device compared with warfarin

43 Outline High Risk of Intracranial Hemorrhage and Thromboembolism: Definitions and Scope of The problem Problems with Medical Management Does anticoagulation increase the risk of ICH? How are the outcomes of anticoagulation related ICH? Do we have alternatives to anticoagulation? Discussing alternatives with the patients: shared decision making

44 Consider risks/benefits when anticoagulation needed in pts at high ICH risk What is the risk of ICH for this patient? Does anticoagulation cause an unacceptably high risk/benefit ratio in this particular situation? Are there any alternatives to long-term anticoagulation that might be considered for this particular patient? left atrial appendage closure for non-valvular AFib What are the potential benefits of anticoagulation for this particular patient? valvular atrial fibrillation and mechanical heart valves are strong indications for coumadin and there is not really much of an alternative approach for these situations Many questions do not have evidence-based answers so an honest and comprehensive discussion with patient/family is very important! Shared-decision making approaches needed in every encounter that involves pts with high ischemic & hemorrhagic risk

45 Patient 3 73M HTN, DM2; HPL, CAD s/p 2V CABG; CHF, PAFib, s/p cardioversion, on Coumadin TIA? 1997

46 TIA? 1997 TND 2003 Patient 3

47 Patient 3 TIA? 1997 TND

48 Thank you

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52 Based on annual 4.5% embolic risk from AFib and 68% warfarin efficacy If prior lobar ICH, withholding anticoagulation therapy strongly preferred, improving quality-adjusted life expectancy by 1.9 QALYs If prior deep hemispheric ICH, withholding anticoagulation resulted in a smaller gain of 0.3 QALYs. Anticoagulation could be preferred if the risk of thromboembolic stroke is particularly high.

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54 Secondary prevention measures Regardless of the decision to anticoagulate (or not), always take all precautions for secondary prevention of ICH in all patients Good blood pressure control Avoiding all unnecessary blood thinners Manage other risk factors (no smoking, no excessive alcohol, no illicit drugs at all) Correct any hematologic or other systemic medical problem that might increase the ICH risk Consider risk/benefit ratio and use alternatives, if possible, for medications that might theoretically increase ICH risk (NSAIDs, statins, SSRIs,...)

55 Healthy life style and preventive measures are very important to keep the brain normal for as long as possible

56 Etiology of ICH and Recurrence Risk Different types of intracranial hemorrhage exist and each one has different recurrence risk Intracerebral (parencymal) hemorrhage Subdural Hematoma Subarachnoid hemorrhage brainbleeds.com

57 Cerebral Microbleeds Small foci of chronic blood products in normal (or near normal) brain tissue correspond pathologically to clusters of hemosiderinladen macrophages primarily a radiological construct small MRI signal voids visible on T2* MRI sequences

58 Cortical superficial siderosis a distinct pattern of bloodbreakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord a key feature of cerebral amyloid angiopathy associated with a high risk of future IPH

59 Superficial Siderosis Score Charidimou 2016 ISC

60 Superficial Siderosis Score Charidimou 2016 ISC

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66 Recurrence Risk of Secondary ICH? Recurrence risk of ICH related to trauma (SDH), gross vascular pathologies (SAH) or mass lesions is less well known and depends on many factors that are not easily predictable such as fall/trauma risk, longterm success of coiling/clipping of an aneurysm, type/prognosis of malignancy Multidisciplinary approach depending on underlying pathology Neurosurgery Interventional Neuroradiology Oncology/NeuroOncology