Ictus ischemico ed emorragico. Maurizio Paciaroni Stroke Unit University of Perugia

Ictus ischemico ed emorragico Maurizio Paciaroni Stroke Unit University of Perugia

DISCLOSURES Maurizio Paciaroni has participated over the last 5 years for the following speakers bureaus: - Aspen - Bayer - Boehringer Ingelheim - Bristol-Myers Squibb - Daiichi Sankyo - Medtronic - Pfizer - Sanofi Aventis

Secondary prevention of stroke Non Cardioembolic stroke - Lacunar stroke - Cryptogenic stroke Antiplatelets, statins - Atherosclerotic stroke - Carotid atherosclerotic stroke Carotid revascularization Cardioembolic stroke Anticoagulants* * In patients with AF, indication also for primary prevention

Perugia Stroke Registry 2257 patients (Ischemic stroke TIA ICH) - 506 atherosclerosis (22,4%) - 431 small vessels disease (19,1%) - 580 undetermined origin or 1 possible causes (25.7%) - 182 rare causes (8.1%) - 558 Cardioembolic (24.7%) Cardioembolic Stroke: NVAF 428/558 (76.7%) Paciaroni, Unpublished data

Storia di Stroke/TIA

DOACs in secondary stroke prevention Recurrent ischemic stroke Intracranial bleeding Ntaios et al, International Journal of Stroke 2017

Real world: intracranial hemorrhage Ntaios et al, Stroke 2017

Stroke or SE: Patients With or Without Prior Stroke or TIA Probability (%) 10 8 6 4 2 Apixaban vs. warfarin: - Previous stroke or TIA: HR:0.76; 95% CI: 0.56 to 1.03 - No previous stroke or TIA: HR: 0.82; 95% CI: 0.65 to 1.03 Previous stroke or TIA, warfarin (n=1742) Previous stroke or TIA, apixaban (n=1694) No previous stroke or TIA, warfarin (n=7339) No previous stroke or TIA, apixaban (n=7426) 0 0 10 12 18 24 30 Time since randomisation (months) 9 Adapted from Easton et al. Lancet Neurol 2012;11:503-11.

Rischio recidiva precoce IST rischio di recidiva ischemica entro 48 h: 4,8% Trial norvegese rischio recidiva ischemica entro 7 g: 8% Yasaka, 1993 9,2% HAEST rischio di recidiva ischemica entro 14 g: 7,5% CETF 12% Yasaka, 1993 13,7%

Hemorrhagic transformation (HI-1) Small petechiae along the margins of the infarct (HI-2) More confluent petechiae within the infarcted area but without Space-occupying effect (PH-1) Hematoma in <30% of the infarcted area with some slight Space-occupying effect (PH-2) Dense hematoma >30% of the infarcted area with substantial space-occupying effect or as any hemorrhagic lesion outside the infarcted area

Paciaroni et al, Stroke 2008

Combined outcome events Paciaroni et al, Stroke 2015

Inizio della terapia ARISTOTLE: Patients with a previous intracranial haemorrhage (ICH) or any stroke within 7 days before random assignment were excluded. RE-LY: excluded patients with a stroke within 14 days or severe stroke within 6 months before screening ROCKET AF: excluded patients with a severe, disabling stroke within 3 months or any stroke within 14 days before randomization ENGAGE AF-TIMI 48: excluded patients with stroke within the previous 30 days Easton JD et al. Lancet Neurol. 2012;11:503 511.

Derivation cohort (n=854) Validation cohort (n=994) Recurrent ischemic event (at 90 days) Vitamin k antagonist 35/493 (7.1%) 3/62 (4.8%) Direct anticoagulant 4/79 (5.1%) 21/878 (2.4%) Hemorrhagic event (at 90 days) Vitamin k antagonist 15/493 (3.0%) 6/62 (9.6%) Direct anticoagulant 2/79 (2.5%) 21/878 (1.6%) 38/555 (6.8%) 25/957 (2.7%) 21/555 (3.8%) 23/957 (2.6%) Paciaroni et al, Stroke 2017

Time of initiating therapy for NOACs. Paciaroni et al, JAHA in press

Outcome events (ischemic and hemorrhagic) depending on the time between onset and initiation of therapy with NOACs. 12.4% 2.1% 9.1% Risk of combined outcome events based upon the day of initiating NOAC Paciaroni et al, JAHA in press

Grandezza della lesione

Lesion size and outcome Paciaroni et al, Thromb Hemost 2016

Lesion size: recurrent stroke and severe bleeding Chisq= 0.8 on 1 degrees of freedom, p= 0.379 Chisq= 2.6 on 1 degrees of freedom, p= 0.109 Paciaroni et al, JAHA in press

Paciaroni et al, Thromb Hemost 2016

Perugia Stroke Registry 2257 patients (Ischemic stroke TIA ICH) - 506 atherosclerosis (22,4%) - 431 small vessels disease (19,1%) - 580 undetermined origin (25.7%) - 182 rare causes (8.1%) - 558 Cardioembolic (24.7%) Cardioembolic Stroke: NVAF 428/558 (76.7%) Paciaroni, Unpublished data

Ictus da causa indeterminata Non si possono effettuare tutti gli esami diagnostici: - severità dell ictus (morte precoce) - rifiuto del paziente Esami diagnostici effettuati in tempi impropri Paziente con 2-3 cause potenziali Tutti gli esami fatti ma tutti risultati negativi

Fibrillazione atriale Parossistica Persistente Permanente

Sottotipi di ictus ischemico e recidive 30 giorni 1 anno 5 anni Aterotrombotico (%) 18.5 21.4 24.4 Cardioembolico (%) 5.3 13.7 31.7 Lacunare (%) 1.4 7.1 24.8 Criptogenico (%) 3.3 13.2 33.2 p 0.0006 ns ns Petty et al, Stroke 2000

M Evoluzione degli strumenti per la registrazione ECG Norman Holter Holter ECG 1950s Contemporary Holter ECG Implantable recorders since 2000s

Sanna et al, 2014 N Engl J Med

Stroke risk is evident in subclinical AF Subclinical AF* is associated with a 2.5-times greater risk of ischaemic stroke or systemic embolism 4.2% vs 1.7% with no arrhythmia (P=0.007) 0.08 Risk of ischaemic stroke or systemic embolism Cumulative hazard 0.06 0.04 0.02 0 0 0.5 1.0 1.5 2.0 2.5 Years of follow-up *Subclinical atrial tachyarrhythmias detected by implanted devices (n=2580) Healey JS et al. N Engl J Med 2012;366:120 9 Subclinical atrial tachyarrhythmias present Subclinical atrial tachyarrhythmias absent 29 Apr 2012

Caratteristiche suggestive di stroke cardioembolico Cliniche Riduzione dello stato di coscienza all inizio dei sintomi Rapida regressione dei sintomi (shrinking syndrome) Improvvisa comparsa del massimo deficit (<5 min.) Disturbi visivi campimetrici, neglect o afasia Embolia in distretti extracerebrali Palpitazioni all onset.

Lacunar versus non lacunar stroke

arteria perforante: ictus lacunare

Sanna et al, 2014 N Engl J Med

Embolic Stroke of Undetermined Source (ESUS)

1. Hart et al. Lancet Neurol. 2014;13:429 438. Embolic Stroke of Undetermined Source (ESUS): Criteri diagnostici proposti e iter diagnostico Panel 2: Criteria for diagnosis of embolic stroke of undetermined source* Stroke detected by CT or MRI that is not lacunar Absence of extracranial or intracranial atherosclerosis causing 50% luminal stenosis in arteries supplying the area of ischaemia No major-risk cardioembolic source of embolism No other specific cause of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse) *Requires minimum diagnostic assessment (panel 3). Lacunar defined as a subcortical infarct smaller than or equal to 1.5 cm ( 2.0 cm on MRI diffusion images) in largest dimension, including on MRI diffusion-weighted images, and in the distribution of the small, penetrating cerebral arteries; visualisation by CT usually needs delayed imaging greater than 24 48 h after stroke onset. Permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis. Panel 3: Proposed diagnostic assessment for embolic stroke of undetermined source* Brain CT or MRI 12-lead ECG Precordial echocardiography Cardiac monitoring for 24 h with automated rhythm detection Imaging of both the extracranial and intracranial arteries supplying the area of brain ischaemia (catheter, MR, or CT angiography, or cervical duplex plus transcranial doppler ultrasonography) *Imaging of the proximal aortic arch is not needed; special blood tests for prothrombotic states only if the patient has a personal or family history of unusual thrombosis or associated systematic signs or disorder. Cardiac telemetry is not sufficient.

Management of cryptogenic stroke ESUS Patient education Risk factors control Anti-hypertensives Statins Antiplatelet drugs

Management of cryptogenic stroke ESUS Patient education Risk factors control Anti-hypertensives Statins Antiplatelet drugs Randomized studies

NAVIGATE-ESUS: trial design 475 sites in 31 Countries Prospective, randomised, double blind, active-comparator, event-driven, superiority, phase III trial Patients with recent ischemic stroke and: 1. visualized by brain CT or MRI that is not lacunar 2. absence of cervical carotid atherosclerotic artery stenosis 50% or occlusion 3. no AF after 24 hrs cardiac rhythm monitoring 4. no intra-cardiac thrombus on transthoracic on echocardiography 5. no other specific etiology for cause of stroke (eg. arteritis, dissection, migraine/vasospasm, drug abuse N = 7.000 R Rivaroxaban 15 mg OD n = 3.500 - Target RRR 30%; superiority; 90% power α=0.05 - Enrollment 24 months; minimum treatment 12 months; study duration 36 months - Estimated mean treatment duration 18-24 months ASA 100 mg OD n = 3.500 1 month post study drug observation period Age 18 years (max 10% patients < 60 years Day 1 Randomization Randomization 7 days to 6 months after acute ESUS Efficacy Cut off date 30 ± 7 days EOS Two substudies: MRI substudy assessing covert strokes Biomarker/genetics substudy to identify biomarkers linked with ESUS, recurrent stroke and treatment response Expected timelines: Recruitment started Dec 2014 Topline result Q1 2018 Study number NCT02227550. Details available from www.clinicialtrials.gov.

To evaluate the efficacy and safety of Dabigatran for secondary stroke prevention in patients with an embolic stroke of undetermined source (ESUS) 6,000 patients who had an ESUS within six months prior to enrollment ASA 100 mg vs Dabigatran 150 mg BID or 110 mg BID for pts older than 75 or who have reduced renal function Clinicaltrials.gov

ATTICUS: : Apixaban for Treatment of Embolic Stroke of Undetermined Source Phase III, multicentre, prospective, randomised, parallel-group, open-label, active-controlled trial* Includes a dynamic treatment protocol implementing conversion from ASA arm to apixaban arm in case of detection of relevant episodes of AF during the study Patients with ESUS and 1 suggestive risk factor for cardiac embolism Countries: Germany FPFV: Sep 2015 R N=500 APIXABAN 5 mg twice daily ASA 100 mg once daily 12 MONTHS FOLLOW- UP FOR 30 DAYS AFTER LAST STUDY DRUG INTAKE Study sponsor: University Hospital Tübingen, Germany Principal investigator: Tobias Geisler (Germany) *Investigator-initiated research, not company-sponsored Apixaban 2.5 mg twice daily in selected patients AF, atrial fibrillation; ASA, acetylsalicylic acid; ESUS, embolic stroke of undetermined source; R, randomisation Study number NCT02427126: https://clinicaltrials.gov/show/nct02427126

Hemorrhagic stroke

Santosh, Stroke 2017

Risk of recurrence Weimar et al; Cerebrovascular Dis 2011; 32: 283-288

ICH location in patients treated with anticoagulants Pezzini et al, Neurology 2014

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

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

Risk of thromboembolic events CHADS-Vasc score rate (% year) 1 1.3 2 2.2 3 3.2 4 4.0 5 6.7 6 9.8 >6 >10

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