Epidemiology. Epidemiology 6/1/2015. Cerebral Ischemia

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1 Presenter Disclosure Information Paul Nyquist MD/MPH FCCM FAHA Updates on the Acute Care of Ischemic Stroke and Intracranial Hemorrhage Updates on the Acute Care of Ischemic Stroke Paul Nyquist MD/MPH, FAHA, Associate Professor Neurology, Anesthesiology-Critical Care, General Internal Medicine, and Neurosurgery NCCU and Cerebrovascular Division Johns Hopkins School of Medicine Funding Sources: Principal Investigator 1R01NS A1, GRANT , Occult Small Vessel Cerebrovascular Disease in High Risk Families. Investigator / InteventionalManagement of Stroke (IMS) III NIH Sponsored Clinical Trial Principal Investigator/ Clinical Trial of rfviia (Novoseven) in Patients with Intracerebral Hemorrhage at Johns Hopkins University, Sponsored by NOVONORDISK Principal Investigator/ Desmotaplase in Acute Stroke at Johns Hopkins University (DIAS), Sponsored by Forest Pharmaceuticals Investigator, CLEAR, Use of rt-pa for the Resolution of Clot in Intraventricular Hemorrhage, Sponsored by FDA Orphan Drug Program Investigator / CREST, Carotid Revascularization Endarterectomy vs. Stent Trial, NIH Sponsored Clinical Trial Principal Investigator/ Siblings with Ischemic Stroke Study Stroke, INOVA Fairfax Hospital Educational Grants: Pulsion, The Medicines Co., Codman Inc., and Hospira Inc. DISCLOSURE INFORMATION Grant Support From NOVO Seven, NINDS, JANs Medical Epidemiology 700,000 acute ischemic strokes a year 500,000 Ischemic 30,000 60,000 are Intracranial Hemorrhages Epidemiology 4.1 million Stroke Survivors Estimated 22 million Silent Strokes a year Stroke is the third leading cause of death in the USA Leading cause of disability in the elderly Stroke incidence is increasing with the aging of the population Stroke Centers and Comprehensive Stroke Centers JHACO Certified Stroke Center AHA is developed Guidelines for the Establishment of Comprehensive Stroke centers Centralized Specialized Cerebrovascular Care Specialized Cerebrovascular Neurosurgical Care Specialized Cerebrovascular Interventional Neuroradiology Specialized Neurocritical Care Penumbral Viability Cerebral Ischemia Core Penumbral Viability ml/100g/min 1

2 Ischemically Intact Irreversible Ischemia Cerebral Blood flow greater than 30mls/100g/min. Mean Transit Time less the 3.5 sec. Cerebral Blood flow less than 10mls/100g/min. Mean Transit Time greater the 6 sec. Ischemic Penumbra Outcome at 90 Days for NINDS Part 2 Cerebral Blood flow less than 22mls/100g/min. Mean Transit Time greater the 4 sec. New England Journal of Medicine: 1996, 334 Mortality Placebo vs. rt-pa NINDS Part 2 Early stroke treatment associated with better outcome: The NINDS rt PA Stroke Study 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum NEUROLOGY 2000;55: New England Journal of Medicine: 1996, 334 2

3 Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt PA stroke trials Patients treated 0 to 90 minutes from stroke onset with rt-pa have an increased odds of improvement at 24 hours and favorable 3-month outcome 2775 patients Odds of a favourable 3 month outcome were 2 8 (95% CI ) for 0 90 min 1 6 ( ) for min 1 4( ) for min 1 2 ( ) for min Hemorrhage(5 9%) rt PA,(1 1%) controls Haemorrhage was not associated with OTT Lancet 2004; 363: Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke New England Journal of MedicineVolume 359: September 25, 2008 Number patients 418 to the alteplase 403 to the placebo group Median treatment time 3 hours 59 minutes Good outcome (52.4% vs. 45.2%) Odds ratio, 1.34 (1.02 to 1.76; P=0.04) The incidence of intracranial hemorrhage was higher with alteplase than with placebo Any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001 Symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008 Mortality Similiar Distribution of Scores on the Modified Rankin Scale. The distribution of scores is shown for the intention-to-treat population (Panel A) and The per-protocol population (Panel B) at the 3-month visit (90 days plus or minus 14 days). New England Journal of MedicineVolume 359: September 25, 2008 Number 13 Frequency distribution of delay time for patients hospitalized for acute stroke, with calculated delay times (n = 1334) and approximated delay times (n = 561) Prioritizing interventions to improve rates of thrombolysis for ischemic stroke California Acute Stroke Pilot Registry (CASPR) Investigators Smith, M. A. et. al. Ann Intern Med 1998;129:

4 Important Thrombolytic Studies Tissue Plasminogen Activator for Acute Ischemic Stroke. The National Institute of Neurological Disorders and Stroke rt PA Stroke Study Group Intravenous Thrombolysis With Recombinant Tissue Plasminogen for Acute Hemispheric Stroke. The European Cooperative Acute Stroke Study (ECASS) 6 hours of onset vs. 3 hours onset Randomized Double blinded Placebo controlled Trial of Thrombolytic Therapy With Intravenous Alteplase in Acute Ischemic Stroke (ECASS II) Recombinant Tissue type Plasminogen Activator (Alteplase) for Ischemic Stroke 3 5 Hours After Symptom Onset. The ATLANTIS Study: A Randomized Controlled Trial Intravenous Ancrod for Treatment of Acute Ischemic Stroke: the STAT Study: a Randomized Controlled Trial Intra arterial Pro urokinase for Acute Ischemic Stroke: the PROACT II Study: a Randomized Controlled Clinical Trial Diffusion Perfusion Mismatch Hypothesis: Ischemic Penumbra = PWI DWI DWI, PWI & MRA 8 hours after onset of global aphasia & right hemiplegia PROACT II: Infarct and Recanalization After Pro-Urokinase JAMA: 1999, 282 PROACT II: Reperfusion after Pro-Urokinase 1hr vs. 2hr Patients, % P < P = r-prouk, 1 hr (n=102) r-prouk, 2 hr (n=108) Control (n=50) 4 2 TIMI 2+3 TIMI 3 Perfusion Flow Grades JAMA: 1999, 282 4

5 Embolectomy Merci clot retriever Possis neurojet 3F /angiojet Oasis BSC Snares, Microsnare, Ensnare, Intime retriever, neuronet Merci 2 Post procedure 50/81 (62%) Major device complication rate 3.7% 125 pts from 25 sites Pre RX NIHSS 20 (10 40) Duration of symptoms 7.32 Hrs Alexandrov et al., Stroke, Nov Middle cerebral artery recanalization and serial NIHSS scores Recanalization rates in the in the CLOTBUST after tpa bolus. Alexandrov et al., Stroke, Nov Graph depicts total cumulative complete grade 3 AOL recanalization at each 15-minute interval for the EKOS Primo sonography microcatheter (n = 29) and the standard microcatheter in IMS II (n = 14). Standard microcatheter recanalization data points at 60 and 120 minutes are also depicted. IMS I data are incomplete at 60 minutes, with 23 confirmed control arteriograms. Sixty- and 120-minute IMS I data points closely approximate the line of IMS II microcatheter recanalization. The open circle emphasizes an early equivalence of standard microcatheter to the sonography (US) microcatheter. The greatest recanalization effect (>20%) is within the first 15 minutes of microcatheter placement. American Journal of Neuroradiology 29: , March

6 The Interventional Management of Stroke IMS 1 3 study aka Drip and Ship NINDS RO1 Study 0 3 Hrs NIHSS 10 IV rtpa 0.6mg/kg IA rtpa up to 22mg IA IMS 3 Devices Drug: IV rt PA Drug: IA rt PA (Investigational) Device: Standard Microcatheter Infusion Device: EKOS Micro Infusion (NeuroWave Infusion) System Device: Concentric Merci Retriever Device: The Penumbra System Device: Solitaire FR Revascularization Device American Journal of Neuroradiology 29: , March 2008 IMS 3 Endpoints Within 3 months Primary Outcome Measures: Efficacy: modified Rankin Scale score, dichotomized to 0 2 verses greater than 2. Safety: (1) death due to any cause (2) presence of symptomatic ICH (6 24hrs) IMS 3 Secondary Outcome Measures: Barthel Index NIHSSS Trail Making Test at 3 months; early response to treatment as determined by NIHSSS of 0 2 at 24 Dichotomized mrs score (0 2): 6, 9, and 12 months from Incidence of parenchymal Type II (PH2) hematomas and any asymptomatic ICH 6

7 EKOS catheter The Penumbra System Solitaire IMS 3 Status Stopped after mid term review No safety issues Efficacy Issues IMS3 Interventions Thrombectomy with the Merci retriever [Concentric Medical] Penumbra System [Penumbra] Solitaire FR revascularization device [Covidien] Endovascular delivery of t PA by means of the MicroSonic SV infusion system [EKOS] Standard microcatheter 7

8 Adjusted Relative Risk for Predefined Subgroups, as Assessed According to the Primary Outcome of a Modified Rankin Score of 0 to 2 at 90 Days. Distribution of Modified Rankin Scores, According to Study Group and Score on the National Institutes of Health Stroke Scale (NIHSS). Broderick JP et al. N Engl J Med 2013;368: Broderick JP et al. N Engl J Med 2013;368: Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. in the DEFUSE Study 72 patient Intention to Treat 64 patients Occlusion Treated with Iv r TPA 3 6 hours Any perfusion/diffusion mismatch (odds ratio, 5.4; p = 0.039) Target Mismatch profile (odds ratio, 8.7; p = 0.011) Modified Rankin Scale measurement at 30 days. The statistical comparison of the outcomes was performed with the Mantel-Haenszel test using all seven categories of the modified Rankin Scale (mrs). The p value is for the Target Mismatch group (more favorable outcomes with early reperfusion) and 0.04 for the No Mismatch group (less favorable outcomes with early reperfusion). The mrs score 0-1 indicates no disability, 2-3 slight to moderate disability, 4-5 severe disability, and a score of 6 indicates death. Annals of Neurology Volume 60, Issue 5, Pages MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study Figure 1 Examples of output from RAPID An example of the output of the automated MRI processing software (RAPID) for a patient with the target mismatch profile (A); the volume of irreversibly injured ischaemic tissue on the diffusion-weighted MRI map is e... Maarten G Lansberg, Matus Straka, Stephanie Kemp, Michael Mlynash, Lawrence R Wechsler, Tudor G Jovin, Micha... MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study The Lancet Neurology, Volume 11, Issue 10, 2012,

9 Figure 2 Study profile *Because of absence of large vessel occlusion on magnetic resonance angiography (n=8), large diffusionweighted MRI lesion (n=12), clinical improvement (n=4), and other reasons (n=4). Of the 28 patients who did not undergo an endova... Figure 3 Functional outcome according to mrs at 90 days For patients with (A) and without (B) target mismatch. p=0 04 for the comparison of good functional outcome (score 0 2) between patients with and without reperfusion in the target mismatch group. Goo... Maarten G Lansberg, Matus Straka, Stephanie Kemp, Michael Mlynash, Lawrence R Wechsler, Tudor G Jovin, Micha... Maarten G Lansberg, Matus Straka, Stephanie Kemp, Michael Mlynash, Lawrence R Wechsler, Tudor G Jovin, Micha... MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study The Lancet Neurology, Volume 11, Issue 10, 2012, The Lancet Neurology, Volume 11, Issue 10, 2012, Enrollment and Outcomes. MR Rescue Kidwell CS et al. N Engl J Med 2013;368: Functional Outcome at 90 Days in Four Subgroups of Patients, According to Score on the Modified Rankin Scale. Figure 3 Functional outcome according to mrs at 90 days For patients with (A) and without (B) target mismatch. p=0 04 for the comparison of good functional outcome (score 0 2) between patients with and without reperfusion in the target mismatch group. Goo... Maarten G Lansberg, Matus Straka, Stephanie Kemp, Michael Mlynash, Lawrence R Wechsler, Tudor G Jovin, Micha... MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study The Lancet Neurology, Volume 11, Issue 10, 2012, Kidwell CS et al. N Engl J Med 2013;368:

10 New clinical trials ISC 2015 MR CLEAN Berkhemer OA, et al. N Engl J Med 2015;372:11 20 ESCAPE GoyalM, et al. N Engl J Med 2015, February 11 EXTEND IA Campbell BCV, et al. N Engl J Med 2015, February 11 SWIFT PRIME Saver J, et al. Presented at ISC 2015 REVASCAT Davalos, et al. Presented at ISC 2015 Solitaire MR CLEAN Inclusion criteria Acute ischemic stroke Intracranial anterior circulation occlusion (confirmed by CTA) IA treatment within 6 hours from onset feasable Age 18 NIHSS 2 Intervention Arterial catheterization with a microcatheter to the level of occlusion Mechanical treatment, delivery of a thrombolytic agent, or both Mechanical treatment: use of a retrievable stent thrombus retraction aspiration wire manipulation Intervention N=233 IV rtpa and Embolectomy 81% Solitaire Control N=267 IV rtpa 10

11 Safety Variables and Serious Adverse Events within 90 Days after Randomization. Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population. Berkhemer OA et al. N Engl J Med 2015;372: Berkhemer OA et al. N Engl J Med 2015;372: Solitaire Swift 11

12 Solitaire 12

13 Original Article Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke (ESCAPE) the ESCAPE Trial Investigators In this randomized trial involving patients who had moderate-to-severe acute ischemic stroke with proximal vessel occlusion and a small infarct core, endovascular treatment improved functional outcomes. Randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group) Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded N Engl J Med Volume 372(11): March 12,

14 Scores on the Modified Rankin Scale at 90 Days in the Intention-to-Treat Population. Goyal M et al. N Engl J Med 2015;372: Subgroup Analyses. Primary and Secondary Efficacy Outcomes. Goyal M et al. N Engl J Med 2015;372: Goyal M et al. N Engl J Med 2015;372: Reported Serious Adverse Events. Comparison of trials Trial Age Time (LSN) ESCAPE > 18 years 0 12 hours >5* CT/CTA ac 50% col EXTEND IA No age limit h/tpa NIHSS Selection CS/GA Device No lim. MR CLEAN > 18 years 0 6 hours >1 CTA/MRI/angio ac SWIFT PR y h/tpa 90.9/9.1% 86.1% st CT/CTA ac RAPID 64/36% solitaire 8 29 CTA or MR md2 ac 62.2/37/8 % NA 81.5% st solitaire REVASCAT y 0 8hrs > 5 CTA/MRIaspects NA solitaire Goyal M et al. N Engl J Med 2015;372:

15 Implications rtpa and mechanical thrombectomy should be the new standard of care Systems re organization and cooperation with large stroke refferal networks Selection paradigm and imaging criteria are in constant state of change Number of Patients Screened 25% of rtpa patients will meet criteria for treat ment Say average IV rtpa yearly treatment of 50 patients means 12.5 candidates yearly. 15