5The brain ages 3.6 years each hour without treatment during an ischemic stroke.
6Epidemiology Annually, 15 million people worldwide suffer a stroke One-third of these individuals die and another one- third are left permanently disabledThe World Health Organization (WHO) estimates that a stroke occurs every 5 seconds
7EpidemiologyIn the United States, approximately 795,000 people have a new or recurrent stroke each yearAbout 600,000 are new strokes and 195,000 are recurrent strokesA stroke occurs approximately every 40 seconds, which is 2160 strokes per day
8EpidemiologyIn the U.S., stroke is the primary cause of long term disability with an estimated 6.5 million survivors among adults age 20 and older (2.6 million males and 3.9 million females)The estimated 2015 direct and indirect cost of stroke is $95 billion
9Epidemiology Stroke mortality extends beyond 150,000 people annually Stroke is now the fifth leading cause of death in the U.S., and the second leading cause of death globallyStroke accounts for nearly 1 out of every 16 deaths in the U.S. and approximately 10% of all deaths worldwide
10EpidemiologyStroke can either be ischemic (an occlusion of a blood vessel) or hemorrhagic (a rupture of a blood vessel)Hemorrhagic strokes include intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)
12EpidemiologyOf all strokes in the U.S., 87 percent are ischemic, 10 percent are ICH and 3 percent are SAHIschemic strokes are further classified into subtypes according to the mechanism of injury
13PathophysiologyThe degree of damage is dependent on duration of ischemia and degree of collateral flowNormal cerebral blood flow is greater than 50mL/100mg/min, but if blood flow is decreased to less than 10mL/100mg/min, irreversible neuronal death occurs quickly
14PathophysiologyBlood flow between 11 and 20 mL/100mg/min is thought to represent the ischemic penumbraThis is an area of neurons that are ischemic, but still viable if blood flow is restoredThe ischemic penumbra is the target of most acute stroke interventions in which recanalization of a vessel should theoretically restore perfusion to the penumbra
16Acute management: thrombolysis IV thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the only FDA approved drug treatment for acute ischemic strokeEndogenous tissue-plaminogen activators convert plasminogen to plasmin, an enzyme that catalyzes fibrin breakdownFibrinolysis is strongly enhanced by rt-PA
18Acute management: thrombolysis Double blinded placebo-controlled trial with 624 patients randomized to IV rt- PA or placeboPatients who received rt-PA within 3 hours had more favorable outcomes and were 30% more likely to have minimal or no disability at 3 months (odds ratio 1.7, 95% CI 1.2 to 2.6)
19Modified Rankin Scale (mRS) The scale runs from 0-6, running from perfect health without symptoms to death.0 - No symptoms.1 - No significant disability. Able to carry out all usual activities, despite some symptoms.2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.3 - Moderate disability. Requires some help, but able to walk unassisted.4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.6 - Dead.
20Acute management: thrombolysis Only a select group of patients are eligible to received rt-PAThe major adverse affect of rt-PA is hemorrhageThe symptomatic intracranial hemorrhage rate in the NINDS trial was 6.4%Symptomatic ICH was seen primarily from hemorrhagic transformation of the ischemic infarct
21Acute management: thrombolysis An additional landmark study was the European Cooperative Acute Stroke Study (ECASS) III published in the New England Journal of Medicine in September 2008It is a double-blinded placebo-controlled study with 821 patients randomized to IV rt-PA or placebo
22Acute management: thrombolysis Patients who received intravenous rt-PA administered between 3 and 4.5 hours after the onset of symptoms had statistically significant improved clinical outcomes compared with placebo (52.4% vs. 45.2%; P=0.04)The incidence of symptomatic ICH was higher with rt- PA than placebo (2.4% vs. 0.2%; P=0.008), but mortality did not significantly differ between the two groups
23Acute management: thrombolysis In May 2009, the American Heart Association/ American Stroke Association released a Science Advisory recommending the expansion of the time window for treatment of acute ischemic stroke with rt-PA from 3 hours to 4.5 hours after onset of symptoms
24Acute management: thrombolysis However, the FDA has declined to extend the approved time window for IV-tPA administration beyond 3 hours
25Acute management: endovascular thrombolysis Endovascular therapy for acute ischemic stroke includes intra-arterial fibrinolysis, mechanical clot retrieval or a combination of the twoThere has been a 6 fold increase in endovascular treatment from 2004 to 2009 (0.1% vs 0.6%; P<0.001)Mortality decreased (OR=0.7; P=0.007), but moderate to severe disability increased from (OR=1.4; P=0.0002)
26Acute management: endovascular thrombolysis 4 mechanical devices with FDA clearance: Merci Retrieval System (2004), the Penumbra System (2007), the Solitaire Flow Restoration Device (2012), and the Trevo Retriever (2012)Devices are cleared as mechanical means for recanalization of acutely occluded arteries based on studies without noninterventional control groups
31Acute Management: endovascular thrombolysis 3 endovascular thrombectomy trials were highlighted at the International Stroke ConferenceIMS IIIMR RESCUESYNTHESIS Expansion
32Acute Management: endovascular thrombolysis All 3 trials failed to show a statistically significant difference between the endovascular therapy group and the best medical management group (which could include IV-tPA) as measured by an mRS of 2 or less
33MR CLEAN: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the NetherlandsPublished January 1, 2015500 patients with large vessel occlusion(LVO) confirmed by CTA were randomized to intra-arterial treatment (n=233) or medical management (n=267) within 6 hours of symptom onset32.6% of patients who received endovascular treatment achieved a good functional outcome (mRS 0-2) compared to 19.1% of patients who received medical managementBerkhemer OA et al. N Engl J Med 2015;372:11-20.
34MR CLEAN: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke Berkhemer OA et al. N Engl J Med 2015;372:11-20.
35Acute Management: endovascular thrombolysis 3 endovascular thrombectomy trials were highlighted at the February International Stroke Conference in Nashville, TNESCAPEEXTEND-IASWIFT PRIME
36Acute Management: endovascular thrombolysis All 3 trials showed a statistically significant difference between the endovascular therapy group and the best medical management group (which could include IV-tPA) as measured by an mRS of 2 or less
37ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke Published February 11, 2015Trial was stopped early because of efficacy316 patients with proximal large vessel occlusion (LVO) and good collateral circulation confirmed by CTA were randomized to endovascular intervention (n=165) or medical management (n=150) within 12 hours of symptoms onsetRates of functional independence (mRS 0-2) at 90 days was statistically significant for the endovascular intervention group compared to the control group (53.0% vs. 29.3%; p< 0.001)Endovascular intervention was associated with reduced mortality (10.4% vs 19.0%; p=0.04)Goyal M et al. N Engl J Med DOI: /NEJMoa
38ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke Goyal M et al. N Engl J Med DOI: /NEJMoa
39EXTEND-IA: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection Published February 11, 2015Trial was stopped early due to efficacy70 patients with internal carotid or middle cerebral artery occlusion, salvageable brain tissue, and ischemic core < 70 ml confirmed by CTP were randomized to endovascular thrombectomy with the Solitaire FR stent retriever (m=35) or alteplase alone (n=35) within 4.5 hours of symptom onsetThe endovascular reperfusion group achieved greater reperfusion at 24 hours (median, 100% vs. 37%; p,0.001) and increased early neurologic improvement at 3 days (80% vs. 37%, p=0.002) as measured by the NIHSSNo significant difference in mortality or symptomatic ICHCampbell BC et al. N Engl J Med DOI: /NEJMoa
40EXTEND-IA: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection Campbell BC et al. N Engl J Med DOI: /NEJMoa
41SWIFT PRIME Results presented at ISC on February 11, 2015 Trial was stopped early due to efficacy196 patients with large vessel occlusion (LVO) confirmed by CTA or MRA were randomized to endovascular treatment with the Solitaire FR stent retriever (n=98) or alteplase alone (n=98) within 6 hours of symptom onsetThe OR for mRS shift at 90 days in the endovascular treatment group compared to the alteplase alone group was statistically significant (p=0.0002), and good functional outcome (mRS 0-2) was achieved in 60.2% of the patients in the endovascular treatment group compared to 35.5% of the patients in the control group (p=0.0008)Saver J. International Stroke Conference 2015 Invited Presentation. Presented February 11, 2015.
42SWIFT PRIME: Secondary Endpoints Endovascular TreatmentControlP ValuemRS score of at 90 d (%)60.235.5.0008Mortality (%)220.127.116.11Mean improvement in NIHSS score at 27 h (points)8.53.9<.0001Saver J. International Stroke Conference 2015 Invited Presentation. Presented February 11, 2015
43Impact on acute stroke treatment All 4 trials showed statistically significant evidence of endovascular treatment in select acute ischemic stroke patientsSelection of patients should be confirmed by vascular imagingIV rt-PA should always be the first line treatment for eligible acute ischemic stroke patientsOn average approximately 5% of stroke patients receive acute stroke treatmentWe need to continue to improve community and physician awareness
44Mobile Stroke UnitsMobile Stroke Units debuted in Cleveland and Houston during the past yearUnits resemble a typical ambulance, but are equipped with a portal CT scanner, lab testing capabilities and the ability to administer IV-tPAMobile Stroke Units cost about $1 million and are staffed with a critical care nurse, a paramedic and CT technology expertPhysicians are able to remotely evaluate a patient with two-way video conferencing
45Mobile Stroke UnitsIn Cleveland, the stroke unit operates from 8 am to 8 pm dailyResearchers found that on average patients received a CT scan 20 minutes faster than through the ECThere was also a significant reduction in average treatment time for the mobile stroke unit (64 minutes) compared to the emergency room (104 minutes)Hussain MS. International Stroke Conference 2015.
46More research is needed to determine if Mobile stroke units lead to overall better stroke outcomes and if they are cost effective in different locations.
47Conclusion Every minute 1.9 million neurons die during a stroke Just because we have 4.5 hours to administer IV rt-PA, does not mean that we should wait 4.5 hours to give IV rt-PAEndovascular reperfusion therapy is beneficial for appropriately selected stroke patientsTime is brain!