Il sanguinamento cerebrovascolare Manifestazioni cliniche di sanguinamento: Il sanguinamento cerebrovascolare Giuseppe Micieli Dip. Neurologia d’Urgenza IRCCS Istituto Neurologico C Mondino Pavia

Cerebrovascular Disease Stroke Subtypes Hemorrhagic stroke (17%) Ischemic stroke (83%) Lacunar small vessel disease (25%) Intracerebral hemorrhage (59%) Atherothrombotic disease (20%) Il legame esistente tra valori pressori e patologia cerebrovascolare interessa anche la fase acuta della malattia essendo riportata una frequenza di ipertensione in oltre il 75-80% dei casi di ictus. Ancora controverse sono però le possibili interazioni con le successiva prognosi e anche le modalità e i tempi di un eventuale intervento terapeutico SAH (41%) Embolism (20%) Cryptogenic (30%) Albers GW et al. Chest. 1998;114:683S-698S. Rosamond WD et al. Stroke. 1999;30:736-743. 2

Possible causes of spontaneous nontraumatic ICH Hypertension Hematologic disorders Thrombocytopenia Platelet dysfunction Coagulopathies Blood vessel abnormalities Arteriovenus malformation Aneurism Moyamoya disease Amyloid angiopathy Tumors Primary brain tumor (much less common than metastatic tumor) Metastatic brain tumor (melanoma, choriocarcinoma, thyroid carcinoma, renal cell carcinoma, bronchogenic carcinoma, breast carcinoma) Drugs Illicit drugs (cocaine, amphetamine) Over-the-counter medications (phenylpropanolamine) Prescription medications (warfarin, aspirin, TPA, heparin)

Quality-of-care indicators and accepted reasons for nontreatment Intervention Implementation Acceptable reason far nontreatment Thrombolysis within 3 hours IV-tPA, IA-tPA, tenecteplase Arrival > 3 hours after symptom onset, unknown time of symptom onset, uncontrolled hypertension, rapid improvement, stroke too mild or too severe, seizure at onset, recent surgerv, refusal, history of intracranial bleeding or arteriovenous malformation, on-going bleeding, platelet count <100,000, abnormal aPPT or PT, glucose <50 mg\dL or >400 mg/dL, life expectancy I year, dementia Antithrombotic medication within 48 hours Antiplatelet agents, anticoagulants thrombolysis Bleeding risk, terminal illness D’VT prophylaxis by hospital day 2 Anticoagulants or vascular support hose with paeumatic compression devices Patient ambulatory Smoking cessation counseling Counseling the stop smoking or smoking advice Current nonsmoker, no history of smoking, death in hospital Lipid-lowering medication at discharge Lipid-lowering medications LDL < 100 mg/dL, death in hospital Antithrombotic medication at discharge With atrial fibrillation: anticoagulants; without atrial fibrillation: antiplatelet agents, anticoagulants Bleeding risk (e.g., liver disease, active peptic ulcer disease, fall risk), refusal, terminaI ill, impaired mental status, planned surgery, death in hospital Neurology 2005;65:360–365

ICH after thrombolysis IH1: small petechiae IH2: more confluent petechiae PH1: haematoma in <30% of the infarcted area; slight space-occupying effect PH2: dense haematoma >30% of the infarcted area; substantial

ICH: epidemiology and relationship with antithrombotic treatment Nicolini A et al. Haematologica 2002;87:948-956

Volume of haemorrhage, AC and AP use Stead LG et al. Clin Neurol Neurosurg 2009

AP or OA therapy effect on unfavorable outcome and in-hospital mortality Saloheimo P et al. Stroke 2006;37:129-133

ICH: stima della frequenza assoluta FA: 0.3-0.6% CVD: 0.4-1.0% FA: 0.2% CVD: 0.3% FA: 0.3% CVD: 0.4% 0.15 % 0.5-1.0% Popolazione generale ASA ASA + Clopidogrel Warfarin Warfarin + ASA Hart RG et al. Stroke 2005;36:1588-1593

Da soli o in associazione? 10

Rates of CNS bleeding during antiplatelet therapy with ASA and Clopidogrel Hart RG et al. Stroke 2005;36:1588-1593

MATCH: life-threatening and major bleeding Type of Bleeding Events (%) Placebo + Clopidogrel (n=3,781) ASA + Clopidogrel (n=3,759) % Absolute Difference (95% CI) p value Defined as Life-threatening Events (%) 49 (1.3) 96 (2.6) 1.26 (0.64, 1.88) <0.001 Gastrointestinal 21 (0.6) 51 (1.4) Intracranial 25 (0.7) 40 (1.1) Major Bleeding Events (%) 22 (0.6) 73 (1.9) 1.36 (0.86, 1.86) 11 (0.3) 42 (1.1) Life threatening: any fatal bleeding event, or a drop in haemoglobin of 5g/d, or significant hypotension with the need of inotropes (hemorrhagic shock) or, symptomatic intracranial haemorrhage, or requiring transfusion of  4 units of RBC or equivalent amount of whole blood Major bleeding: significantly disabling (with persistent sequelae), or intraocular bleeding leading to significant loss of vision or, requiring transfusion of  3 units of RBC or equivalent amount of whole blood Diener HC, et al. Lancet 2004;364:331-337

CHARISMA: Overall Population Safety Results Endpoint* - N (%) Clopidogrel + ASA (n=7802) Placebo + ASA (n=7801) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 0.17 Primary ICH 27 (0.3) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) <0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006 – In press

ASA and ER-Dipyridamole versus Clopidogrel for recurrent stroke: primary and secondary outcomes Sacco R et al. NEJM 2008;359:1-14

Prasugrel vs Clopidogrel in Acute Coronary Syndromes Wiviott SD et al. NEJM 2007;357:2001-2015

Platelet antiaggregants and anticoagulants within 48 hours of acute ischemic stroke Coull BM et al, Stroke 2002

SPREAD: Terapia anticoagulante in prevenzione secondaria 2003 2007 (&2010) Raccomandazione 10.12 Grado D In pazienti con qualunque eziologia cardioembolica, escludendo i casi a rischio emboligeno molto elevato, qualora vi sia una lesione estesa alla TC a 48 ore, è indicato procrastinare di almeno 14 giorni l’inizio del trattamento anticoagulante, per il maggior rischio di trasformazione emorragica sintomatica. Qualora una TC abbia documentato una lesione minore del 30% dell’emisfero colpito senza trasformazione emorragica in forma di ematoma, il trattamento può essere iniziato precocemente. Raccomandazione 10.10 Grado D            In pazienti con qualunque etiologia cardioembolica, in assenza delle controindicazioni elencate al Capitolo 5, è indicato iniziare il trattamento anticoagulante orale tra 48 opre e 14 giorni tenendo conto di: Gravità clinica Estensione della lesione alle neuroimmagini Comorbosità cardiologica (definita anche con ecocardiografia)

ECASS study: ICH following thrombolysis Derex L, Nighoghossian N. JNNP 2008;79:1093-1099

Thrombolysis-related ICH Acute Myocardial Infarction: 0.6% Pulmonary Embolism: 3% Ischaemic Stroke*: 6-11% Intravenous thrombolytic therapy 6% Intra-arterial thrombolytic therapy 11% * ICH in brain areas outside the vascular distribution of the ischaemic stroke: 20% Mac Carron MO & Nicol JAR, Lancet Neurology 2004;3(8):484

Tissue Plasminogen Activator – Possible Reasons for Temporal Restriction rt-PA Multi-tasking: Additional physiological functions of tPA turn deleterious in the ischemic setting tPA , a neurotoxic agent: Endogenous glutamate can cause neurotoxicity, e.g. under ischemic conditions; tPA is able to aggravate this toxicity. Benchenane et al, Trends Neurosci 27: 155 (2004) Second Generation: Recombinant Proteins Cleavage rt-PA Plasmin ogen Plasmin Fibrin

Caso clinico: maschio, 71 anni, emiparesi sinistra, esordita da circa 45’ Plavix 75 mg cp 1 cp dopo pranzo Cardioaspirin 100 mg cp 1 cp dopo cena Torvast 10 mg cp 1 cp alla sera Triatec 5 mg cp 1 cp al mattino Bisoprololo 2.5 mg cp 1 cp al mattino Dopo circa 2 h dalla trombolisi

AP treatment and thrombolysis: distribution of the mRS scores at 3 months Diedler J et al. Stroke 2010;41:288-294

AP treatment and thrombolysis: causes of death Diedler J et al. Stroke 2010;41:288-294

Cerebral microbleeds Prevalence: No CVD: 4.7% Ischemic CVD: 40% Ischemic CVD with cerebral microangiopathy: 57% Hemorrhagic CVD: 68% Location: Cortical-subcortical area Koennecke HC, Neurology 2006;66(2):165

Leukoaraiosi e ICH TAO-relata Presenza: OR: 12.9 (95%CI: 2.8-59.8) Grado 3-4: OR: 24.9 (95% CI: 4.5-137.4) Pz in prevenzione secondaria per pregresso stroke ischemico Valori espressi in n(%) Smith EE et al, Neurology 2002

Anticoagulant-related ICH Hart R, Stroke 1995;26:1471

Anticoagulant-related ICH Anticoagulation to conventional intensities increases the risk of intracranial hemorrhage 7- to 10-fold, to an absolute rate of nearly 1%/y for many stroke-prone patients. Most (70%) anticoagulant-related intracranial hemorrhages are intracerebral hematomas (approximately 60% are fatal); the bulk of the remainder are subdural hematomas. Predictors of anticoagulant-related intracerebral hematoma are advanced patient age (>75 yrs), race, prior ischemic stroke, hypertension (systolic BP >160 mmHg), intensity of anticoagulation, concomitant use of antiplatelet drug, and cerebral amyloid angiopathy. In approximately half of anticoagulated patients with intracerebral hematoma the bleeding evolves slowly over 12 to 24 hours, and emergency reversal of anticoagulation is crucial Hart R mod, Stroke 1995;26:1471

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

The increasing incidence of anticoagulant-associated intracranial haemorrhage 1988 1993-1994 1999 All ischemic stroke NA 140.0 (133.2-146.8) 142.6 (135.8-149.3) Cardioembolic stroke NA 31.1 (27.9-34.3) 30.4 (27.3-33.5) Cardioembolic ischemic stroke due to AF NA 22.0 (19.3-24.8) 20.6 (18.1-23.2) All ICH 16.5 (14.1-18.9) 22.1 (19.4-24.8) 24.6 (21.8-27.4) AAICH 0.8 (0.3-1.3) 1.9 (1.1-2.7) 4.4 (3.2-5.5) Flaherty ML et al. Neurology 2007;68:116-121

Racial/ethnic differences in the risk of ICH among patients with AF Shen A Y-J et al. J Am Coll Med 2007;50:309-315

Predittori di ICH durante TAO Età Fang MC et al, Ann Intern Med 2004

Predittori di ICH durante TAO Ipertensione arteriosa PROGRESS trial Pressione arteriosa sistolica Il rischio assoluto passava da 0.6%/anno a 0.3%/anno e 0.2%/anno rispettivamente Chapman N et al, Stroke 2004

Rischio emorragico e valori di INR 40% Aumento rischio ICH di 2-5 volte, direttamente correlato ai valori di INR. Buona parte delle ICH occorrono, tuttavia, con INR in range terapeutico Cantalapiedra A et al, J Thromb Thrombolysis 2006

Risk analysis of thrombo-embolic and recurrent bleeding events in AC-related ICH Recurrent ICH: 8/108 pts (before restarting OAC) TE risk: 0,66/1000 pts-day at risk (8/11590 pts-day) De Vleeschouwe S et al, Acta Chir Bel 2005;105:268-274

Discontinued anticoagulation for intracranial haemorrhage In a patient who is taking warfarin and experiences an intracranial haemorrhage, warfarin should be stopped and its effects reversed fully with vitamin K orally, subcutaneously or intravenously and clotting factor replacement. The timing of recommencing anticoagulation will depend on the risk of embolisation and on the risk of rebleeding. It is possible to resume warfarin therapy quite early, even within the first 7-14 days, without high risk of recurrent bleeding in patients with a high risk of re-embolisation and a small intracranial bleed.

Avoiding CNS bleeding during antithrombotic therapy Hart RG et al. Stroke 2005;36:1588-1593