Outline• Epidemiology• Intracranial Hemorrhage • Spontaneous • Risk of anticoagulation • Treatment• Ischemic Stroke • Vascular Disease in the Brain • Cardioembolic Source • Treatment Strategies
Epidemiology• Stroke is almost as important as ischemic heart disease • Here are the numbers • Acute coronary syndrome - 1.2 million per year in the US • Transient Ischemic Strokes - 750,000 per year in the US • Ischemic strokes - 200,000 to 500,000 per year in the US • Intracerebral hemorrhage - 37,000 to 52,400 per year in the US • Eighty percent of strokes are caused by focal cerebral ischemia due to arterial occlusion • Remaining twenty percent are caused by hemorrhages • Mortality rates • For ischemic strokes mortality rates range from 10 to 17 percent at one year • Wide variability ranging from 2.5% for lacunar infarcts to 78% in patients with space-occupying hemispheric infarction • For hemorrhagic strokes, mortality rates are 62% surviving the ﬁrst year Brott T NEJM 2000
Intracerebral Hemorrhage• Classiﬁcation • Primary • Accounts for 78 to 88 percent • Originates from spontaneous rupture of small vessels damaged by chronic hypertension or amyloid angiopathy • Secondary • Occur from vascular abnormalities (i.e. AV malformations or aneurysm) • Tumors • Impaired coagulation• Incidence • Worldwide - 10 to 20 cases per 100,000 population • More common in men than women • African-Americans and Japanese have high incidence (50 per 100,000 population) Qureshi NEJM 2001
Intracerebral Hemorrhage associated with oral anticoaguation• Mortality at one year is much higher in this population close to 67 %• Patients receiving anticoagulation have a 7 to 10 fold increased in developing ICH• Underlying cause of spontaneous versus anticoagulation associated ICH are likely the same • Anticoagulation, however, may act as an exacerbating factor• Hematoma expansion in patients on anticoagulation occurs for a longer period of time• Treatment Strategies • Vitamin K • Takes at least 2 to 6 hrs to take effect • Allows for a more sustained reversal of anticoagulation • IV Vitamin K has a low risk of allergic or anaphylactic reaction in one study 3 per 10,000 doses  • FFP • Contains all factors in a non concentrated form requiring large volume to have effective hemostasis • Ideally, 1mL of FFP/kg body weight is required to bring INR down 1 to 2 IU/dL • ? Novoseven 1 Steiner, T Stroke 2006
Vascular Disease and the Brain• The incidence of silent strokes • On serial MRI approximately 6 to 7 % at age 60 which increases to 28% at age 80• Presence of silent brain infarct more than doubles the risk of dementia with a hazard ratio 2.26 • Silent thalamic infarcts in particular were responsible for a decrease memory performance • Occur due to obstruction of end vessels which have no collateral supply• Small vessel disease is likely a global phenomenon affecting the brain, heart, retina, kidneys and other organs with high blood ﬂow• Affected the vascular risk factors such age, hypertension, diabetes, and renal disease • There may be a possibility that small vessel disease in one organ may precipitate progression in other organ Vermeer SE Lancet Neurology 2007 Vermeer SE, NEJM 2003
Transient Ischemic Attack - the unstable angina of the brain• Deﬁned as a neurologic deﬁcit lasting less than 24 hrs that is attributed to focal cerebral or retinal occlusion • There is much controversy over how to deﬁne TIAs • Rapid recovery may be the most important characteristic in deﬁning a distinct clinic entity • But this may portend a more unstable pathophysiology• Diagnosis is difﬁcult because it is usually based on clinical history alone relying on the memories of patients who were neurlogically impaired. • Broad differential include migraine, seizure, vasovagal, syncope, arrhythmia, compressive neuropathy, anxiety, and conversion disorder• Risk of stroke after a TIA • Study of 1707 patients given diagnosis of TIA were studied for a 90-day period  • Roughly 1 in 9 patients had a stroke after diagnosis • Half of all strokes happened within two days of diagnosis • 2.6 percent of patients had a cardiac event • 2.6 percent died • Patients with atrial ﬁbrillation had an 11 percent chance of stroke at 90 days Johnston, SC NEJM 2002
The subtypes of ischemic stroke • In a study of 5,017 patients with acute ischemic stroke • Cardioembolism was the most common 25.6% • Large artery atherosclerosis 20.9% • Small vessel 20.5% • Neurological deﬁcit on admission was most severe in cardioembolism • Mortality was highest in cardioembolic stroke (22.6%) compared to large vessel (9.3%) and microangiopathy (3.3%) Grau Stroke 2001
Cardioembolic Stroke• Background • These strokes are generally severe and prone to early recurrence • Due to their large size, cardiac emboli have a predilection for the middle cerebral artery• What clinical signs make a cardioembolic source more likely? • Sudden onset • Hemorrhagic transformation of an ischemic infarct • Visual ﬁeld abnormalities • Neglect • Neurological defect involving multiple brain areas • Wernicke aphasia, or global aphasia without hemiparesis are common• The issue of hemorrhagic transformation • About 20 to 40% of all patients with stroke • Increased on cardioembolic stroke - occurs in up to 71% of patients. • Possible explanation that the hemorrhage is a result of local vascular spasm which leads to reperfusion injury Ferro, J The Lancet Neurology 2003
Cardioembolic stroke - when do you start anticoagulation?• Purpose - To see if early anticoagulation (<48 hrs) is 426 Stroke February 2007 beneﬁcial compared to other treatments (placebo or aspirin)• Methods - Seven studies were included in the meta analysis of these 3792 patients had atrial ﬁbrillation and 827 had other cardioembolic sources• Results • Anticoagulation was associated with a non signiﬁcant difference in death or disability (73.5% vs 73.8%, OR 1.01, p 0.9) • Anticoagulation was associated with a signiﬁcant Figure 2. Death or disability in trials comparing anticoagulants with other treatments (a, anticoagulants versus placebo or aspirin; b, anticoagulants versus aspirin; c, anticoagulants versus placebo) for the initial treatment of acute cardioembolic stroke. increase in symptomatic ICH analysis (none in CESG, HAEST, and Camerlingo; 11 in significant (OR 1.18; 95% CI: 0.74 to 1.88, P 0.49, P for (2.5 vs 0.7%, OR 2.9, P 0.02 TAIST; 25 patients overall in TOAST without specific heterogeneity 0.25). Anticoagulants were associated with a Paciaroni Stroke 2007 information about the number of patients with cardioem- nonsignificant reduction in recurrent stroke within 7 to 14 bolic stroke; 99.99% completed for 14 days outcome and days (3.0% versus 4.9%, OR 0.68; 95% CI: 0.44 to 1.06, 99.2% completed 6-month outcome in IST). P 0.09, number needed to treat 53) but were associated
Cardiac Catheterization and Stroke• Prevalence of Aortic Atherosclerosis • In a study of 588 patients enrolled at random (average age 66.9 years) who underwent TEE, • Aortic plaque was present 43.7% • Complex plaque was present in 7.6% • Ascending aortic plaque was present 8.4%• Iatrogenic Embolization from Aortic Plaque • Overall rate is low from 0.2% to 0.4% • More frequent with DM, HTN, prior stroke, or renal failure • Procedural Characteristics • Longer procedure time • Larger contrast load • More likely urgent procedure • More likely to have IABP Kronzon I Circulation 2007 Hamon M Circulation 2008
Cardiac Catheterization thrombolytic bolus of 20 mg of recom- by recent literature is that stroke oc- the case study described above, binant tissue plasminogen activator. curring during cardiac catheterizationcause the stroke occurred during the As soon as patency of the vertebral is the most treatable of neurological Periprocedural Stroke in PCI First aim: clinical confirmation With NIHSS rating Consider sedation reversal, assess glycemia & O2 saturation Per-procedure Timing? Post-procedure Experience in selective cerebral angiography? Brain Imaging required: - MRI (DWI/PWI/MRA/T2*) YES NO - or Plain CT, CT perfusion/CTA Proceed with selective No evidence Acute cerebral angiography of acute haemorrhage haemorrhage No Ischemic stroke confirmed thrombolysis with arterial occlusion found? Significant PWI-DWI mismatch No significant mismatch YES NO or CT perfusion mismatch Hypoperfusion No Hypoperfusion Consider endovascular Consider IA or combined IV/IA Intervention thrombolysis or endovascular No extensive Extensive No and/or IA thrombolysis Intervention especially DWI lesion DWI lesion thrombolysis for distal ICA ‘’T’’occlusion Consider Consider brain thrombolysis decompression ure 2. Algorithm for the management of periprocedural stroke in the setting of cardiac catheterization. IA indicates intra-arterial; ICA,ernal carotid artery; CTA, computed tomography angiography; DWI, diffusion-weighted imaging; IV, intravenous; MRA, magnetic res-ance angiography; MRI, magnetic resonance imaging; and PWI, perfusion-weighted imaging.
Management of Acute Stroke• Making the diagnosis • Common things being common atherosclerosis and cardioembolic sources are leading causes, but • Ptosis and miosis on the contralateral side of the deﬁcit may indicate carotid-artery dissection • Fever and cardiac murmur - endocarditis • Headache and elevated ESR in pt >50 yo may indicate giant cell arteritis• Imaging • CT and MRI have a sensitivity for acute intracranial bleed, but MRI has a much high sensitivity for acute ischemic changes esp in the posterior fossa and early in the evolution of a stroke • MRI can detect cytotoxic edema within minutes after the onset of ischemia Worp HB NEJM 2007
Figure 3 gives the results of an intention-to-treat analysis of data pooled from randomized trials of rtPA for ischemic Time lost is brain lost stroke (NINDS, ECASS-I, ECASS-II, and ATLANTIS) that included 2775 patients treated up to 6 hours after symptom onset at more than 300 hospitals located in 18 countries.20 The analysis supports the primary finding of the NINDS trial Goldstein Acute Stroke Treatment in that treatment within 3 hours (and possibly up to 4.5 hours) 1505 of symptom onset is associated with a greater chance of aFigure 1. Relationship between cerebral blood ﬂow, time, func- favorable outcome at 3 months. Moreover, as expected on thetional impairment, and infarction. Even within 3 hours, ischemic basisnous rtPA included the European Cooperative Acute Stroke of the principles illustrated in Figure 1, the likelihood oftissue might go on to infarction or be viable if reperfused.Reproduced from Jones et al3 with permission from the Journalof Neurosurgery. Copyright 1981, American Association of Neu- What to consider when administering t- benefit diminishes as time after used a onset dose of rtPA and Study (ECASS)-I, which symptomhigher elapses (ie, the chances of benefit decrease hours after the onset of symp- randomized patients up to 6 as time to reperfusionrological Surgeons. toms. PA increases).17 In the negative ECASS-II, the dose of tissue plasmin- A ogen activator was identical to that used in thestroke second concern was that a baseline imbalance in NINDS trial,treatment, and because the overall benefit in the NINDS trialincluded a 10-fold increase in the proportion of treated > Onset of symptoms less than 3 h severity between the rtPA- and placebo-treated groups in the patients but there was a 6-hour treatment window, with most NINDS trial after 3explain18 The Alteplase Thrombolysis for Acute treated might hours. the observed benefit. An indepen-patients having symptomatic intracerebral hemorrhage (6.4%versus 0.6%), which could compromise the benefit when used before beginning treatment dent Noninterventionalthe trial dataIschemic Stroke (ATLANTIS) group reanalyzed Therapy in and found a clinically important and statistically significant treatment to the NINDS trial study used a treatment protocol identical benefit de-outside a clinical trial setting. Negative thrombolytic studies differed from the NINDS > No head trauma or previous stroke in spitebut randomized patients 3 baseline stroke severity.21 subgroup imbalances in to 5 hours after stroke.19 Multiple exploratory analyses failedof an intention-to-treat analysis Figure 3 gives the results to identify any subgrouptrial in fundamental and important ways (eg, different of ischemic pooled patients who wouldtrialsmore likely to of data stroke from randomized be of rtPA for ischemicthrombolytic drugs, different doses of rtPA, and longerintervals between symptom onset and treatment). Trials of the previous 3 m either benefit from treatment or be harmed by it. stroke (NINDS, ECASS-I, ECASS-II, and ATLANTIS) that A third concern has been that the benefits of intravenousanother thrombolytic, streptokinase, included patients treatedbeyond 3 hours of symptom onset and generally incorporated > No MI in previous 3 m included 2775 patients treated up to 6 hours after symptom rtPA found in the NINDS trial would be not be generalizable onset at more than 300 hospitals located in 18 countries.20 to nonstudy settings. Several observational studies reinforcedthe concomitant use of other antithrombotic drugs, which wasprohibited in the NINDS trial.14 –16 Negative trials of intrave- > No GI bleed in previous 21 days this The analysis supportsratesprimary finding of the NINDS trial fear, because higher the of bleeding complications occurred more commonly when treatment protocols were hours) in that treatment within 3 hours (and possibly up to 4.5 favorable outcome at 3 months. Moreover, as expected on the in previous 14 days > No major surgery of symptom onset is associated with a greater chance of aFigure 1. Relationship between cerebral blood ﬂow, time, func-tional impairment, and infarction. Even within 3 hours, ischemic benefit diminishes > time afterarterial puncture at a non as No symptom onset elapses (ie, basis of the principles illustrated in Figure 1, the likelihood oftissue might go on to infarction or be viable if reperfused.Reproduced from Jones et al3 with permission from the Journal the chances of benefit decrease as time to reperfusionof Neurosurgery. Copyright 1981, American Association of Neu-rological Surgeons. increases). compressible site in previous 7 days A second concern was that a baseline imbalance in stroketreatment, and because the overall benefit in the NINDS trial severity between the rtPA- and<185/110 in the > BP placebo-treated groupsincluded a 10-fold increase in the proportion of treated NINDS trial might explain the observed benefit. An indepen-patients having symptomatic intracerebral hemorrhage (6.4% dent group reanalyzed No active bleeding or trauma > the trial data and found a clinically Figure 2. Algorithm for the managementversus 0.6%), which could compromise the benefit when used of patients with acute ischemic stroke. important and statistically significant treatment benefit de-outside a clinical trial setting. > Not taking oral anticoagulant or INR IV-tPA indicates intravenous tissue plas- spite subgroup imbalances in baseline stroke severity. minogen activator; Rx, treatment. 21 Negative thrombolytic studies differed from the NINDS Multiple exploratory analyses failed to identify any subgrouptrial in fundamental and important ways (eg, different of ischemic stroke<1.7 who would be more likely to patientsthrombolytic drugs, different doses of rtPA, and longer either benefit from treatment or be harmed by it.intervals between symptom onset and treatment). Trials of A third concern > been that the benefits of intravenous has PTT in normal rangeanother thrombolytic, streptokinase, included patients treated rtPA found in the NINDS trial would be not be generalizablebeyond 3 hours of symptom onset and generally incorporatedthe concomitant use of other antithrombotic drugs, which was > Plt greater 110k Goldstein LB Circulation 2007 to nonstudy settings. Several observational studies reinforced this fear, because higher rates of bleeding complicationsprohibited in the NINDS trial.14 –16 Negative trials of intrave- occurred more commonly when treatment protocols were
Recombinant Tissue Plasminogen Activator - the NINDS trial• Study Design • Alteplase given to patient with a clear clinical diagnosis of stroke • Within 3 hours of onset of symptoms • Following CT head to conﬁrm no hemorrhage present • Patients aged 18-80 • Symptoms present for at least 30 minutes • Large number of other exclusion criteria
Results of the NINDS• Part 1 (291 patients) looked at clinical improvements at 24 hours • No sig difference at 24 hours• Part 2 (333 patients) looked at functional outcomes at 3 month New England Journal, 1995• Alteplase associated with an NINDS tPA Stroke Trial increase in intracranial hemorrhage (6.4% vs. 0.6%)• 30 Hemorrhage Alteplase associated with a 30% 30 p < .05 increase in chance of either none 20 20 or minimal disability (mRS of 31 0-1) 9 20• 20 Alteplase associated with small 10 10 non-signiﬁcant reduction in 0 0 8 1 mortality (p=0.30) tPA Placebo tPA Placebo NIHSS Excellent Total Death NINDS study group NEJM 1995 Recovery (%) Rate (%)
ECASS-3• Prospective, multicenter, randomized study looking at the tPA treatment (n 418) versus placebo (n 403) in 3 to 4.5 hour window from the onset of symptoms • Trial excluded persons older than 80 yo, baseline NIHSS>25, patients taking anticoagulants or who had previous history of stroke• Intracranial hemorrhage was increased in the arm that received tPA (7.9%) vs placebo (3.5%; OR 2.38 p 0.006)• Primary efﬁcacy outcome (Rankin Score 0 to 1) was signiﬁcantly increased with tPA (52.4%) than with placebo (45.2% risk ratio 1.16 p 0.04) • This beneﬁt was smaller than NINDS as ECASS-3 OR for global favorable outcome 1.28 compared to 1.9 for NINDS Zoppo GJ Stroke 2009
International Stroke Trial 1997 International Stroke Trial Recurrent Stroke at 14 daysRecurrentN =Stroke Within 14 Days 19,435 patientsRecurrent Stroke Within 14 Days (N = 19,435)
The Acute Hypertensive Response post-stroke• Prevalence • In the International Stroke Trial, mean systolic BP was 160.1 mmHg and 82% of patients had high BP at enrollment• Pathophysiology • Stroke involves transient or permanent damage or areas involved in the regulation of CV functioning • These areas are diffusely distributed in the brain • Increased BP may also be a sign of increased ICP • In acute stroke, autoregulation is impaired for a given region • After an stroke the core region has a severe reduction in ﬂow eventually leading to necrosis, while the penumbra has a moderate reduction • The penumbra remains viable for hours because of some degree of blood ﬂow is sustained through collateral ﬂow
Algorithm for treating hypertension178 Circulation July 8, 2008 Clinical diagnosis of acute stroke Reduce BP if >185/110 mm Hg using short acting IV medication* Ischemic Emergent computed tomographic scan Intracerebral stroke hemorrhage Candidate for Not a candidate for Suspect Do not suspect thrombolysis thrombolysis high ICP high ICP Reduce BP if Reduce BP if Reduce BP if Reduce BP if >185/110 mm Hg >220/120 mm Hg SBP >180 mm Hg SBP >180 mm Hg using short acting using short acting or MAP >130 mm Hg or MAP >130 mm Hg IV medication. α IV medication. using short acting using short acting Avoid and treat IV medication; IV medication. hypotension ICP monitoring Monitor neurological (<100/70 mm Hg).α recommended to examination every maintain 15 minutes. β CPP >60 mm Hg. β Treat with thrombolysis. Maintain BP <180/105 mm Hg using short acting IV medication or Oral antihypertensive agents may be considered after 24 hours; BP goal ≈160/110 mm Hg. infusions for 24 h. α Titrate to more aggressive goals after neurological stability is achieved. αFigure. Algorithm for treatment of acute hypertensive response among patients with stroke and stroke subtypes. IV indicates intrave-
In Summary• Majority of strokes are ischemic (80%) compared to hemorrhagic (20%) • Though hemorrhagic strokes have much higher mortality rates• Common sites of spontaneous hemorrhagic strokes are cerebral lobes, basal ganglia, thalamus, the brain stem, or the cerebellum • Anticoagulation increases risk and administration of activated Factor VII has not been shown to have a mortality beneﬁt• Small vessel disease plays an important role in silent stroke • These silent strokes are associated to the development of dementia• TIA portend worse outcomes esp., in patients with atrial ﬁbrillation • Anticoagulation has not been shown to be superior to antiplatelet therapy• Cardioembolic stroke has a high rate of mortality and disability • Early anticoagulation does not lead to better outcomes• tPA for ischemic stroke is the mainstay of treatment • The longer you wait the worse the outcome • Administration > 4.5 hours has not been shown to be beneﬁcial
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