Stroke
Outline•   Epidemiology•   Intracranial Hemorrhage    •   Spontaneous    •   Risk of anticoagulation    •   Treatment•   I...
Epidemiology•   Stroke is almost as important as ischemic heart disease    •   Here are the numbers        •   Acute coron...
Intracerebral Hemorrhage•   Classification    •   Primary        •   Accounts for 78 to 88 percent            •   Originate...
MEDICAL PROGRESS    Spontaneous                                                                       AIntracerebral Bleed...
Intracerebral Hemorrhage associated               with oral anticoaguation•   Mortality at one year is much higher in this...
original article                                          Efficacy and Safety of Recombinant Activated                    ...
PERSPECTIVE                                                                                                   small vessel...
Vascular Disease and the Brain•   The incidence of silent strokes    •   On serial MRI approximately 6 to 7 % at age 60 wh...
Transient Ischemic Attack - the unstable angina of                        the brain•   Defined as a neurologic deficit lasti...
Objectives                                              combination of antiplate                                       Thi...
The subtypes of ischemic stroke •   In a study of 5,017 patients with acute ischemic     stroke     •   Cardioembolism was...
Cardioembolic Stroke•   Background    •   These strokes are generally severe and prone to early recurrence    •   Due to t...
Cardioembolic stroke - when do you start anticoagulation?•   Purpose - To see if early    anticoagulation (<48 hrs) is    ...
Cardiac Catheterization and Stroke•    Prevalence of Aortic Atherosclerosis    •   In a study of 588 patients enrolled at ...
Cardiac Catheterization                            thrombolytic bolus of 20 mg of recom-                          by recen...
Management of Acute Stroke•   Making the diagnosis    •   Common things being common atherosclerosis and cardioembolic    ...
Figure 3 gives the results of an intention-to-treat analysis                                                              ...
The Fibrinolytic Cascade
Recombinant Tissue Plasminogen           Activator - the NINDS trial• Study Design •   Alteplase given to patient with a c...
Results of the NINDS•   Part 1 (291 patients) looked at    clinical improvements at 24 hours    •   No sig difference at 2...
ECASS-3•   Prospective, multicenter, randomized study looking at the tPA    treatment (n 418) versus placebo (n 403) in 3 ...
Pushing the envelope    NANDS ECASS-3   IST-3                Zoppo GJ Stroke 2009
International Stroke Trial 1997  International Stroke Trial     Recurrent Stroke at 14 daysRecurrentN =Stroke Within 14 Da...
The Acute Hypertensive             Response post-stroke•   Prevalence    •   In the International Stroke Trial, mean systo...
Algorithm for treating hypertension178      Circulation          July 8, 2008                                             ...
In Summary•   Majority of strokes are ischemic (80%) compared to hemorrhagic (20%)    •   Though hemorrhagic strokes have ...
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    1. 1. Stroke
    2. 2. Outline• Epidemiology• Intracranial Hemorrhage • Spontaneous • Risk of anticoagulation • Treatment• Ischemic Stroke • Vascular Disease in the Brain • Cardioembolic Source • Treatment Strategies
    3. 3. 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
    4. 4. 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
    5. 5. MEDICAL PROGRESS Spontaneous AIntracerebral Bleed B C• D E Risk Factors • Hypertension • Excessive alcohol intake Figure 2. Most Common Sites and Sources of Intracerebral Hemorrhage. Intracerebral hemorrhages most commonly involve cerebral lobes, originating from penetrating cortical bran middle, or posterior cerebral arteries (A); basal ganglia, originating from ascending lenticulostriate branches o artery (B); the thalamus, originating from ascending thalmogeniculate branches of the posterior cerebral arter • inating from paramedian branches of the basilar artery (D); and the cerebellum, originating from penetrating Serum cholesterol less <160 mg/dl (particular in patients terior inferior, anterior inferior, or superior cerebellar arteries (E). with HTN) consciousness.59 Patients with a supratentorial intra- Secondary Deterioration cerebral hemorrhage involving the putamen, caudate, In one fourth of patients with intr and thalamus have contralateral sensory-motor defi- rhage who are initially alert, a deterio cits of varying severity owing to the involvement of of consciousness occurs within the • the internal capsule. Abnormalities indicating higher- ter onset of the hemorrhage.64,65 T Mutations in Factor XIII (involved in the formation of fibrin) level cortical dysfunction, including aphasia, neglect, gaze deviation, and hemianopia, may occur as a result of the disruption of connecting fibers in the subcor- large hematoma and ventricular blo risk of subsequent deterioration an pansion of the hematoma is the mo • tical white matter and functional suppression of over- of underlying neurologic deterioratio lying cortex, known as diaschisis.60 Amyloid angiopathy (caused by the deposition of beta three hours after the onset of hemo In patients with an infratentorial intracerebral hem- ing cerebral edema is also implicated orrhage, signs of brain-stem dysfunction include ab- terioration that occurs within 24 to normalities of gaze, cranial-nerve abnormalities, and onset of hemorrhage.65 Infrequently, amyloid protein in the blood vessels) contralateral motor deficits.61 Ataxia, nystagmus, and dysmetria are prominent when the intracerebral hem- is associated with progression of ed second and third weeks after the on orrhage involves the cerebellum.61 Common nonspe-• cific symptoms include headache and vomiting due to Outcome Occur in the cerebral lobes, basal ganglia, thalamus, the brain increased intracranial pressure and meningismus result- ing from blood in the ventricles.57,62,63 The mortality rate six months a intracerebral hemorrhage ranges fro stem, or the cerebellum N Engl J Med, Vol. 344, No. 19 · May 10, 2001 · ww Downloaded from www.nejm.org by RAJ M. KHANDWALLA MD on June 7, 2010 . Copyright © 2001 Massachusetts Medical Society. All rights reserved.
    6. 6. 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 [4] • 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
    7. 7. original article Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage Stephan A. Mayer, M.D., Nikolai C. Brun, M.D., Ph.D., Kamilla Begtrup, M.Sc., Joseph Broderick, M.D., Stephen Davis, M.D., Michael N. Diringer,h M.D., e ng l a n d T e ne w j o u r na l of m e dic i n e Brett E. Skolnick, Ph.D., and Thorsten Steiner, M.D., for the FAST Trial Investigators* Table 2. Hemorrhage Volumes at Baseline and Follow-up.* A BS T R AC T rFVIIa, rFVIIa,• 20 µg/kg 80 µg/kg Placebo Background Variable (N = 276) (N = 297) (N = 268) Volume of intracerebral hemorrhage Background • At baseline — ml 24±26 23±26 22±24 Intracerebral hemorrhage is the least treatable form of stroke. We performed this From the Departments of Neurology and Activated Factor VIIa directly activates phase 3 trial to confirm a previous study in whichAtrecombinant activated factor VII Neurosurgery, Columbia University Col- 24 hr — ml 28±30 25±28 28±31 Factor Xa on the surface reduced growth of the hematoma and improved survival and functional (S.A.M.); Novo Nordisk, Bagsvaerd, to 17) (rFVIIa) of activated P value vs. placebo lege of Physicians(13 toSurgeons, New York Estimated percent increase from baseline — mean (95% CI) 18 and 24) 0.09 11 (6 Den- <0.001 26 (20 to 32) — outcomes. platelets resulting in a burst of thrombin mark (N.C.B., K.B.); the University of Cin- Estimated milliliters of increase from baseline — mean (95% CI) 4.9Center, 7.0) 3.7 (1.7 to 5.7) cinnati Medical (2.9 to Cincinnati ( J.B.); 7.5 (5.4 to 9.6) and acceleration of Methods coagulation P value vs. placebo the Royal Melbourne Hospital, University 0.08 0.009 of Melbourne, Melbourne, Australia (S.D.); — We randomly assigned 841 patients with intracerebral of intraventricular hemorrhage pla- Washington University School of Medi- Volume hemorrhage to receive cebo (268 patients), 20 µg of rFVIIa per kilogram of body weight (276 patients), or cine, St. Louis (M.N.D.); Novo 5.3±11.7 At baseline — ml 3.6±8.0 Nordisk, 2.7±7.5• Methods 80 µg of rFVIIa per kilogram (297 patients) withinAt 24 hr — ml Princeton, NJ (B.E.S.); and the University 5.8±17.2 4 hours after the onset of stroke. of Heidelberg, Heidelberg, Germany (T.S.). Estimated milliliters of increase from baseline — mean (95% CI) 2.0 (0.6 to 3.3) The primary end point was poor outcome, defined as severe disability or death ac- Address reprint requests to Dr. Mayer at 5.4±10.8 1.0 (−0.2 to 2.3) 4.6±10.3 1.6 (0.3 to 3.0) cording to the modified Rankin scale 90 days aftervalue vs. placebo P the Neurological 0.74 Institute, 710 W.0.51 — • the stroke. 168th Multicenter, randomized double-blind, St., Box 39, New York, NY 10032, or at Volume of intracerebral hemorrhage plus intraventricular hemorrhage plus edema sam14@columbia.edu. placebo controlled trial Results At baseline — ml 46±45 46±49 42±47 Treatment with 80 µg of rFVIIa per kilogram resultedhrin a significant reduction in *The institutions71±69 T h e in 65±66 e ng l68±67 d j o u r n At 72 — ml participating the Fac- ne w an tor Seven for Acute Hemorrhagic Stroke growth in volume of the hemorrhage. The mean estimated increase in volume of themean (95% CI) are (21 to 31) the Appendix.27) • Estimated milliliters of increase from baseline — (FAST) trial 26 listed in 22 (17 to 29 (23 to 34) Inclusion - Patients over 18 intracerebralyears oldat 24 hours was 26% inP the placebo group, as compared hemorrhage value vs. placebo 0.53 0.06 — with 18% in the group receiving 20 µg of rFVIIa per kilogram (P= 0.09) and 11% in N Engl J Med 2008;358:2127-37. who had a spontaneous intracerebral(P<0.001). The growth*in volumevaluesintracerebral For estimatedCopyrightincreases, 95% confidence intervals (CIs) are derived from a the group receiving 80 µg Plus–minus of are means ±SD. hemor- mean © 2008 Massachusetts Medical Society. 1.00 linear mixed model with the patient and the reader as random effects and baseline volume of the hemorrhage, time hemorrhage documented on a CT2.6 ml (95% confidence interval [CI], symptoms 5.5;patientsCT scan, and time fromreceiving 20 µg of rFVIIa (recombined activated CT scans at rhage was reduced by scan from onset of −0.3 to to baseline P = 0.08) in Placebo baseline CT scan to treatment as fixed effects. factor VII) In th the group receiving 20 µg of rFVIIa per kilogram 24 hours were missing for 12 0.9 to 6.7; placebo, 17 and by 3.8 ml (95% CI, receiving within 3 hours afterPonsetin thesymptoms 80 µg, as compared with0.95 placebo group. Despite = 0.009) of group receiving per kilogram, and 12 receiving 80 µg of rFVIIa per kilogram. the 20 µg/kg of rFVIIa 80 µg/kg of rFVIIa the o this reduction in bleeding, there was no significant difference among the three rhag • CLINICAL OUTCOMES groups in the proportion of patients with poor treated within 3 hours after the onset of symp- clinical outcome (24% in the pla- Exclusion - Glasgowcebo group, 26% in the group receiving 20 µg of rFVIIa0.90 kilogram,−8.0 to −1.0) and was Mortality at 3 months was approximately 20% in toma Score<5, toms (−4.5 ml; 95% CI, per and 29% in greater still among those treated within 2 hours the three groups (Table 3 and Fig. 2). The primary hemorrhage secondary to receiving 80 µg). The overall frequencyafter onset (−5.6 ml; 95% CI, −13.1 to −2.0). How- outcome measure (the proportion of patients outco the group trauma, AV of thromboembolic serious adverse malformation, known the was similar in the80 µg groups; however,ever, thereeventsand themorefrom onset of symp- who died or were severelythree groups (Table 3). the c events in anticoagulant use, of rFVIIa than inarterial0.85 nogrouptime interaction between significantly among the disabled) did not differ group receiving three the placebo was were treatment effect significant frequent (9% vs. 4%, myocardial infarction= 0.04). P toms to treatment. 0.80 Similarly, the distribution of outcomes on the trial, Although the intraventricular-hemorrhage vol- modified Rankin scale (Fig. 3) and the median ume at 24 hours doubled in the placebo group scores on the Barthel index were similar among tive r • Conclusions Three treatment arms - Low dose 20 and was essentially unchanged in the group re- the three groups. The NIHSS scores were sig- Hemostatic therapy with rFVIIa reduced growthceiving 80 µg of rFVIIa per kilogram, the differ- nificantly lower in the group receiving 80 µg of of the 0.75 hematoma but did not im- plana micrograms/kg, High dose 80 prove survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials. ence between the groups was not statistically rFVIIa per kilogram than in the placebo group, rand 0.00 gov number, NCT00127283.) significant. Growth in volume 20 the total lesion but the magnitude of 70 difference was small of this rial t micrograms/kg, placebo 0 10 30 40 50 (intracerebral hemorrhage, intraventricular hem- (Table 3). 60 80 90 the i orrhage, and edema) was 7 ml less in the group In a series of exploratory post hoc analyses,
    8. 8. PERSPECTIVE small vessels, big problems Big versus Small A B Cerebral amyloid Arteriolosclerosis angiopathy Vessels Thromboembolism Saccular aneurysm C• Diseases of the big vessels (>0.1 mm) • Account for two-thirds of symptomatic strokes Atherosclerosis • Large-Vessel and Small-Vessel Brain Disease. Atherosclerotic narrowing and occlusion of large neck vessels The sites of the most common forms of cerebrovascular disease are shown in Panel A. Arteriolosclerosis typically affects small vessels that penetrate the white matter and the deep gray nuclei, whereas cerebral amyloid angiopathy preferentially involves the small arteries and arterioles of the cerebral cortex and gray–white-matter junction. Axial MRI with the use of gradient-echo technique (Panel B) and fluid-attenuated inversion recovery (Panel C) highlight two prominent radiographic features of small-vessel brain disease: hemorrhages (Panel B, dark lesions [examples • shown by arrowheads]) and changes in white matter (Panel C, bright lesions). The images are of a 71-year-old man with probable cerebral amy- Aneurysmal rupture and subarachnoid bleeds loid angiopathy. vessel brain disease: type IV col- host of microvascular abnormali- type IV collagen also appear to lagen. Type IV collagen α1 and α2 ties. Among the prominent find- be responsible for some familial • chains, assembled as a heterotri- ings in the mice were increased forms of intracerebral hemorrhage, Thromboembolic occlusion of major vessel branches mer, are a major component of the vascular basement membrane in the brain and elsewhere. Us- fragility of brain microvessels in response to stressors such as birth trauma and hypertension, tortu- white-matter lesions, and retinal- vessel tortuosity. These studies do not provide ing random mutagenesis in mice, osity of the retinal vessels, and evidence that nonfamilial small-• Gould and colleagues found that albuminuria. Completing the con- vessel disease is caused by ab- Diseases of the small vessels the deletion of an exon in the gene encoding type IV collagen α1 (Col4a1) prevented the normal nections from molecule to mouse to clinical disease, the authors made the striking observation that normalities of type IV collagen or the vascular basement mem- brane, but this intriguing hypoth- assembly and secretion of vascu- mutations in the human COL4A1 esis seems worthy of testing. The • lar type IV collagen, resulting in a gene that affect the assembly of basement membrane is not only Small arteries and arterioles that penetrate the brain cortex and reach the white and deep gray matter 1452 n engl j med 354;14 www.nejm.org april 6, 2006 • Arteriosclerosis Downloaded from www.nejm.org by RAJ M. KHANDWALLA MD on June 8, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved. • Cerebral Amyloid Angiopathy • These diseases can lead to occlusion causing lacunar brain infarctions or intracerebral hemorrhage • Cause silent strokes that can eventually lead to dementia • Rotterdam Scan Study found that the rate of dementia was more than doubled in the 20 percent of healthy adults who had evidence of lacunar infarcts [1] Vermeer, NEJM 2003
    9. 9. 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
    10. 10. 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 [5] • 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
    11. 11. Objectives combination of antiplate This review aimed to (1) compare the efficacy of oral antico- agulants and antiplatelet therapy in the secondary prevention of Data Col Managing a Transient Ischemic Attack vascular events after cerebral ischemia of presumed arterial origin and (2) compare the safety of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular Two reviewers selected and extracted details o of treatments and asse events after cerebral ischemia of presumed arterial origin. analysis is possible • In a meta-analysis of five trials withSearch Strategy a total of 4076 patients treatment groups are prognostic risk factor comparing antiplatelet versusStroke Review the searcha strategy Relevant trials were Cochrane anticoagulation therapy for the This review draws on Group as whole. developed tients who are exclude outcomes, and entry a Figur strok Schr Koud Anticoagulation antip vasc attac offers no benefit rial o Coch Updawith an increase in Algra et al Heparin Use in Selected Patients Wit Softw bleeding Received October 28, 2002; accepted October 28, 2002. From the Department of Neurology (A.A., E.L.L.M.D.S., J.v.G., L.J.K.) and the Julius Center for Health Sciences an Utrecht, the Netherlands; and the Department of Neurology (P.J.K.), Erasmus Medical Center Rotterdam, the Nethe Figure 2. O Correspondence to Ale Algra, University Medical Centre Utrecht, Julius Center for Health Sciences and Primary(F plication. Utrecht, Netherlands. E-mail A.Algra@neuro.azu.nl Schryver E (Stroke. 2003;34:234-235.) Koudstaal © 2003 American Heart Association, Inc. antiplatelet vascular ev Stroke is available at http://www.strokeaha.org attack or m rial origin [C Algra Stroke 2003 234 Downloaded from stroke.ahajournals.org by on June 9, 201 Cochrane L Update So Software, O
    12. 12. 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
    13. 13. 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
    14. 14. 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
    15. 15. 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
    16. 16. 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.
    17. 17. 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
    18. 18. 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
    19. 19. The Fibrinolytic Cascade
    20. 20. 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
    21. 21. 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 (%)
    22. 22. 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
    23. 23. Pushing the envelope NANDS ECASS-3 IST-3 Zoppo GJ Stroke 2009
    24. 24. 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)
    25. 25. 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
    26. 26. 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-
    27. 27. 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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