Endovascular Therapies for Acute Stroke

Incidence of StrokeStroke is the fourth leading cause of death in the United States795,000 new or recurrent events occur annually87% are ischemic, 10% ICH and 3% SAHLeading cause of disability in the United States.

Executive Summary: Heart Disease and Stroke Statistics-2014 Update. A Report From the American Heart Association. Circulation 2014, 129:399-410Heart Disease and Stroke Statistics-2011 Update. A Report From the American Heart Association. Circulation 2011, 123:e18-2309

OutcomesPatient variables associated with worse outcomes and increased health care burden from an ischemic stroke:Occlusions of large intracranial vesselsHigh disease severity scores at presentation (NIHSS)Older age at presentationSuccessful recanalization of the occluded vessel during the acute ischemic stroke (AIS) is associated with:Lower 3-month mortalityImproved functional outcomesWhat Is an Ischemic Stroke?A stroke is infarcted brain tissue that results from inadequate perfusion - blood flow.That means permanent and irreversible damage to the brain tissue because of inadequate blood flow.

Brain Tissue DamageBecause that portion of the brain can not function properly the patient develops neurologic deficits:WeaknessSensory changesVisual changesBalance problemsLoss of speechSomnolence

Patient JF72 year old man PMHX of A-fib, HLD, HTN and CABG 3 weeks prior. He went to take a nap at 1400 and around 1515 his wife heard noises from the bedroom.She found him having trouble getting out of bed and could not understand what he was saying.She called 911, and when EMS arrived, he was not moving his right arm or leg at all. He was taken to Texas Health Presbyterian Plano.

Stroke MechanismsEmbolic materialCardioembolicArtery-artery embolusThrombosisOcclusive process initiated within vessel wallSmall vessel disease

Stroke MechanismsNarrowing of blood vessels cause stroke from hemodynamic failure inadequate blood flowAtherosclerotic stenosisDissectionVasculitisVasospasm

Embolus Occlusion

Cerebral Blood FlowOnce an artery becomes occluded, the factors that determine if the brain tissue becomes permanently damaged include:Regional cerebral blood flow (CBF)Duration of the diminished perfusionWhat does that mean??How much blood is actually getting there And how long has the flow been suboptimalUnderstanding the PhysiologyCBF is the blood supply to the brain in a given time.In an adult this is about 15% of the cardiac output.Equates to 50-54 mL of blood/100 gram of brain tissue/minute.Regional CBF is the blood supply to a specific area.Primate ModelsIn primate models of focal acute ischemic stroke (AIS), the timing of opening the occluded middle cerebral artery (MCA) was strongly correlated with the amount brain tissue injury.Reperfusion of the MCA is associated with minimal damage when it occurs within 20 minutes.50% of brain tissue is spared with reperfusion within 90 minutes.No sparing of brain tissue when reperfusion occurs at 400 minutes (about 6 to 7 hours).Crowell R, Olsson Y, Klatzo I et al. Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke. 1970;1:439-448.Zivin J. Factors determining the therapeutic window for stroke. Neurology. 1998;50:599-603..12What is the PenumbraLandmark study in 1977 changed the way we looked at stroke.Astrup et al., showed that after the onset of focal ischemia, measurements of electrical activity of the brain tissue revealed regions that were dysfunctional but not yet dead.Astrup J, Symon L, Branston N.M. et al. Cortical evoked potential and extracellular K and H at critical levels of brain ischemia. Stroke 8, 51-57 (1977).Summary Critical FactorsCritical factors that influence the fate of hypoperfused tissue the ischemic penumbra:Time elapsed since the onset of ischemiaThe severity of CBF reductionPresence of collateral blood flow to the brain tissue in jeopardyCollateral Blood Flow

Understanding the PenumbraThe brain tissue supplied by an occluded artery is compartmentalized into areas of irreversibly damaged (infarct core) and areas of hypoperfused but viable tissue (ischemic penumbra)

Astrup J, Symon L, Branston N.M. et al. Cortical evoked potential and extracellular K and H at critical levels of brain ischemia. Stroke 8, 51-57 (1977).PET StudiesPET studies in humans suggest that the infarct core corresponds to CBF values of less 7 to 12 mL/100g/minute.The ischemic penumbra corresponds to CBF of 17 to 20 mL/100g/minute. Saving this tissue by restoring its flow to nonischemic levels is the aim of AIS therapy.

Imaging the PenumbraImaging modalities to define the penumbra can be qualitative or quantitative of CBF.No method is clear cut in defining the penumbra region:MRI DWI/PWI mismatchPET scanSPECT Xenon-CTCT perfusionImaging the Penumbra

Goal of AIS Therapy

AIS Therapy GoalsNumerous investigators have shown that the penumbra comprises about 40% of the total ischemic territory at the onset of the occlusion.At times it can persist up to 24 hours from symptom onset.In most cases, ischemic penumbra has a short lifespan, and rapidly converts into the infarct core within hours from onset.

Goal AIS TherapyMain goal is to rapidly restore blood flow and improve perfusion to the affected brain region.Cornerstone of current treatments include:Dissolving the clot with a thrombolytic agent.Or mechanical extraction of the clot.

Current AIS Treatment OptionsTreatment options:Intravenous (IV) thrombolytic therapyUtilized up to 3 sometimes 4.5 hours from onsetIntra-arterial (IA) thrombolytic therapyUp to 6 hours for anterior circulationUp to 12 hours or beyond for basilar occlusionsEndovascular thrombectomy devicesUp to 8 hours

Reality of IV rt-PAUnfortunately, IV rt-PA recanalization rates: 9% for occluded extracranial ICA20-30% for occlusions of the M1Early re-occlusion occurs in 34% of patients treated with rt-PA who had any initial recanalization.

Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M, Delgado-Mederos R, Molina CA. Temporal profile of recanalization after intravenous tissue plasminogen activator: selecting patients for rescue reperfusion techniques. Stroke. 2006;37:1000 1004.Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, Akhtar N, Orouk FO, Salam A, Shuaib A, Alexandrov AV. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948 954.Recanalization Improves OutcomeRecanalization has been shown to be the most important predictor of good clinical outcome after thrombolysis in large vessel occlusive strokes.Cornerstone of treatments include:Dissolving the clot with a thrombolytic agentOr mechanical extraction of the clot with or without IA thrombolytic.

Intra-Arterial TreatmentEndovascular treatment of AIS with IA thrombolytic agents or mechanical thrombectomy is a consideration in patients in whom: IV rt-PA fails or considered likely to failWho are excluded from IV rt-PA treatmentPresent with large vessel occlusion Multisociety Consensus Quality Improvement Guideline: IA TreatmentIA IndicationsSymptom onset up to 8 hoursNIHSS > 8 or severe aphasiaPatients not IV rt-PA candidatesNo improvement after 60 minutes of IV rt-PA and large to medium vessel occlusionVertebrobasilar occlusion extended to 12 hours

IA ThrombolysisIA thrombolysis up to 6 hoursPotential advantage:Better rates of recanalization High-concentration and direct drug delivery into the thrombus. Reduced systemic effects and ICH, Smaller dose of drug can reach a higher local concentration than with an IV infusion. Can be alternative for some patients excluded from IV.Patients with recent surgeries

IA ThrombolysisIA thrombolysis gained validity on the basis of the results from two randomized trials and several case series. The Prolyse in Acute Cerebral Thromboembolism II (PROACT II trial), was a prospective randomized trial to test efficacy and safety of IA prourokinase plus heparin versus heparin alone in patients with occlusion of the MCA who could have initiation of treatment within 6 hours of symptom onset.PROACT IIPartial or complete recanalization was achieved in 67% of patient within the treatment group. Within the treatment group 40% of patients had a mRS 0-2 at 90-days compared with 25% of control subjects (P=0.04). Complete restoration of blood flow (Thromboliysis In Myocardial Infarction [TIMI] 3) was achieved in 20% and an additional 46% had partial recanalization (TIMI 2) in the treatment group versus only 20% TIMI 2-3 in the control group. Symptomatic ICH occurred in 10% of patients within the treatment group compared to 2% of control patients (P=0.06). IA ThrombolysisThe FDA required a confirmatory study prior to approval. Currently not approved.No placebo-controlled, randomized studies have tested the use of IA rt-PA therapy in AIS.Patient JFAt presentation BP was 99/67 and NIHSS score 14. Right facial droop and 0/5 strength in his RUE and RLE, his speech was slurred and he had a hard time thinking of the words he wanted to say. Labs unremarkable. Head CT was negative for bleed and showed a hyperdense left MCA. Not IV rt-PA candidate.He was then transferred UT Southwestern Medical Center for further care.

Territory In Jeopardy

Endovascular Revacularization

The era of endovascular therapy for AIS started over 20 years ago.

Cerebral Arteriogram

Cerebral Circulation

Cerebral Anatomy

Right ICALeft ICALeft MCARight MCAACACerebral Anatomy

Earlier Past Approaches to ERTEarly IA treatmentsIA thrombolysis Endovascular thrombectomy (clot retrieval or suction aspiration devices)Augmented fibrinolysis (catheter-tipped ultrasound and externally applied ultrasonography) Mechanical clot disruption (ie, emergent angioplasty and stenting)

Endovascular Tools

IA Thrombolysis

Complications of ThrombolysisIA thrombolysis is associated with:Reduced and slower rates of recanalizationPotential higher risk of intracerebral hemorrhage

Mechanical EmbolectomyMechanical thromboembolectomy techniques were at first used when there was:Contraindications to thrombolytic therapy.Failed recanalization after thrombolysis. Outside the 6 hour IA thrombolysis window.Mechanical Approaches

The theoretical advantages of mechanical approaches include: Reduced need for thrombolytics Faster rates of recanalization Early studies utilizing endovascular thrombectomy or aspiration devices did not show the anticipated rates of clinical improvement despite achieving higher recanalization rates.

Mechanical Approaches

Three uncontrolled trials led to 2 early generation devices, the Merci Retriever (in 2004) and the Penumbra System (in 2008), to achieve FDA approval for the indication of intracranial clot retrieval in patients with AIS. Merci Retriever (in 2004) Penumbra System (in 2008)MerciThe Mechanical Embolus Removal in Cerebral Ischemia (MERCI) system is an embolectomy device (Concentric Medical, Inc., Mountain View, California, USA) approved by the FDA in 2004.

MerciThe device has a flexible tapered wire with helical loops that can be embedded in the thrombus for retrieval of clot.

Penumbra CatheterThe Penumbra system (Penumbra, Inc., Alameda, California, USA) is another device approved by the FDA in 2008. It was designed to mechanically disrupt thrombus and aspirate clot fragments through a catheter.

Images courtesy of Penumbra, Inc.Penumbra Device

Images courtesy of Penumbra, Inc.Penumbra Device Clot Extraction

Complications of Embolectomy DevicesIn a retrospective multicenter study, the Penumbra device achieved recanalization rate of 83%.IA adjunctive thrombolytic therapy was used in 68.6% of patients.The MERCI Retriever System achieved recanalization rate of 55% and 68% after adjunctive thrombolytic therapy.

Endovascular strategies Early studies of pharmacological and mechanical endovascular strategies showed recanalization rates on 66-81%.Unclear whether translated to better clinical outcome. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:20032011.Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal Stroke Trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:27612768.IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II study. Stroke. 2007;38:21272135.Bridging TherapyIt is understandable that there are inherent delays in performing endovascular procedures, which is why IV rt-PA therapy remains first line treatment. Ideally, bridging therapy combines the rapidity of administration by the IV route with the better efficacy of the IA approach.

Bridging TherapyPrevious studies evaluating the combined approach have shown better recanalization rates, however, they have shown only trends toward better outcomes as compared with the IV rt-PA treated subjects in the NINDS rt-PA Stroke Trial. The Interventional Management of Stroke (IMS) III study compared IV and multimodal approach IA therapy to IV rt-PA.

IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II study. Stroke. 2007;38:21272135.Fields JD, et al. Mechanical thrombectomy for the treatment of acute ischemic stroke. Expert Rev Cardiovasc Ther. 8:581592.Mazighi M, et al. Comparison of intravenous alteplase with a combined intravenous endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol. 2009;8:802 809.IMS IIIPhase III, randomized, multi-center, open label clinical trial designed to examine whether a combined IV and IA approach is superior to standard IV rt-PA alone when initiated within 3 hours of AIS.Halted on May 2, 2012 by the DSMB. Decision was based upon the primary outcome in the study, the mRS at 3 months, meeting the threshold for futility.There were no serious safety concerns. The data showed that the study had a very low likelihood of demonstrating clinical significance between the treatment arms of the study.Potential IMS III FlawsStrong influence on the trials results is inherent in its early conception.Trial started enrollment in August 2006A time where experience and technology used in ERT was primitiveThe IA therapy arm consisted of one of five possible treatment modalities and modalities could not be combined. These treatment modalities consisted of 1) IA rt-PA up to 22 mg 2) the Merci Retriever 3) EKOS catheter 4) Penumbra aspiration system added in 2009 5) Solitaire FR thrombectomy device added in April 2012Not a single device was usedRetrievable StentsThe limitations of those therapies drove the pursuit of devices that could further expedite and improve the degree of flow restoration. 3rd generation devices - Stentrievers (RS) offer the advantage of immediate flow restoration after deployment and the ability to retrieve the stent during mechanical embolectomy.Mechanical Approaches

2 randomized controlled trials have led to 2 devices to achieve FDA approval for the indication of intracranial clot retrieval in patients with AIS. Solitaire retrievable stent (April 2012)Trevo retrievable stent (August 2012)Solitaire Flow Restoration DeviceThe Solitaire Device (Covidien Neurovascular, Irvine, CA)Was designed to immediately restore flow and extract thrombus by embedding it in through the stents

SWIFT TrialIn SWIFT trial was a multicenter randomized, parallel-group, non-inferiority trial, Solitaire vs Merci. 58 patients in Solitaire group and 55 patients in Merci; mean NIHSS 17 both groups; 33% Solitaire group represented IV rt-PA failures versus 47% Merci group60.7% versus 24.1% achieved recanalization (TIMI 2 or 3) without sICH (pnon-inferiority