Extended Treatment Windows for Acute Ischemic Stroke

Educational Objectives

The goal of this program is to improve the management of acute ischemic stroke. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the indications for intra-arterial thrombolysis and mechanical thrombectomy for acute ischemic stroke.
2. Review the results of trials of endovascular treatments for acute ischemic stroke.
3. Explain the importance of appropriate patient selection for thrombectomy in acute ischemic stroke.

Summary

History of interventional stroke therapy: started with intra-arterial (IA) pharmacotherapy (streptokinase, urokinase, and later, recombinant tissue plasminogen activator [tPA]) delivered through catheter directly into arterial system in brain; initial mechanical thrombectomy consisted of inserting microwire and twirling it around to disrupt clot; Mechanical Embolus Removal in Cerebral Ischemia (Merci) Retriever — first mechanical thrombectomy device approved by Food and Drug Administration (FDA); corkscrew-like device; effective in certain situations; first-generation aspiration catheters had some benefit, but not particularly useful for removal of entire clot; stent retrievers and second- and third-generation suction catheters currently used

IA thrombolysis (IAT): cerebral angiography first step; in past, after microcatheter placed (under x-ray guidance) into face of clot and tPA injected, was period of observation; whether clot dissolves and length of time required for it to dissolve depend on composition and size of clot and presence of flow past and around edges of clot; dissolution faster if more surface area exposed to tPA (in clot that is amenable to tPA)

Current practice: treatment starts with thrombectomy or aspiration catheter rather than tPA, unless clot too distal for device to reach or clinically significant stroke has occurred in small vessel, carrying risk that large device may tear vessel; tPA never approved by FDA for IAT because in trial, drugs switched partway through design

Studies: PROACT II study — randomized controlled trial; looked at prourokinase (thought as effective as tPA) in patients with acute stroke caused by occlusion of middle cerebral artery (MCA) who were treated ≤6 hr; showed positive outcomes; 40% of patients had modified Rankin score (mRS) of 0 to 2 at 90 days, compared to 25% in placebo group; recanalization rate 66%, vs 18% for placebo group; IMS II study — dose of IA and intravenous (IV) tPA split (two-thirds of dose given IV and remaining one-third given IA in angiography suite); good outcomes in 45% of cases, vs 39% with IV tPA

Mechanical devices before 2012: only 2 FDA-approved devices (neither used commonly at present), Merci device and first-generation Penumbra suction catheter; Merci Retriever device — delivered through microcatheter past clot; mechanism snares clot physically for removal; studies comparing Merci device with stent retrievers found significantly better outcomes with stent retrievers; trial — extended treatment window to 8 hr and included other vessels (internal carotid artery [ICA], MCA, and basilar artery); adjunct therapy (tPA along with clot retriever device) used in >33% of cases; included nonresponders to IV tPA and used second version of Merci device (with attached sutures); achieving recanalization resulted in better outcomes than failing to achieve recanalization; outcomes deemed favorable in 46% of patients; 90-day mortality significantly decreased; first-generation Penumbra System — came with separator wire to break up clot and device to suction out pieces; available in different sizes and connected to pump; example — occluded internal carotid artery from which embolus traveled to brain; options include angioplasty only, angioplasty plus stenting, or going through occlusion and repairing carotid later; speaker and colleagues usually repair inflow problem first with carotid stent, which then provides conduit for device; suction provides recanalization of MCA; trial — study with treatment window of 8 hr found recanalization rate of 82%; however, definition of recanalization changed to recanalization only where clot initially sat; change in definition negates 82% recanalization rate; rates of recanalization — in PROACT II study, 18% for control group (heparin); Merci device with or without tPA 50% to 60%; at speaker’s institution, successful recanalization rate high, obtaining thrombolysis in cerebral infarction (TICI) score of 2b or 3 in ≈85% of cases with new devices

IMS III, SYNTHESIS Expansion, and MR RESCUE trials: found that IA therapy not beneficial for large-vessel occlusion; comparing IV tPA plus endovascular therapy to IV tPA alone, no difference in proportion of patients with mRS score of 0 to 2; SYNTHESIS trial — endovascular therapy led to slightly lower rate of good outcomes, compared to IV tPA (statistically probably same); MR RESCUE trial — in patients with no penumbra to save, outcomes same (“dismal”) for mechanical embolectomy and standard of care); moreover, even if penumbra present and embolectomy performed, not many patients had good outcomes, even with standard of care of IV tPA; after publication of studies — many clinicians noted that results did not match their experiences; design flaws of studies include use of old technology, poor imaging workup (presence of clot not always confirmed), and questionable enrollment processes at centers in studies; after 2013, number of patients who underwent IA therapy dropped; many large centers stopped offering endovascular therapy

2015 trials: HERMES col laboration pooled data from MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-IA trials; showed that significantly more patients in intervention group had better outcomes (mRS score of 0-2) than in control group (IV tPA); 46% in endovascular group had good outcomes (mRS score of 0-2), compared to 26.5% in control group; determined number needed to treat of 2.6; combined recanalization rate of 71%; one reason for difference in outcomes between older and newer trials that earlier trials were reporting on devices no longer being widely used (ie, Merci, first-generation Penumbra); newer trials reflected growing use of stent retrievers

Stent retrievers: stent attached to wire and can be opened and closed as desired; deployed across clot and left for 3 to 5 min, then withdrawn with clot attached; discussion ongoing as to whether to use balloon occlusion in carotid artery when removing stent retriever; some type of protection necessary for fragmentation of clot, whether aspirating locally with suction catheter at back of stent or, if carotid occluded, aspirating while pulling out

Suction catheters: goal for catheter to be as large as possible; current generation large and flexible, with enough aspiration power and large enough inner diameter to insert into MCA

DAWN and DEFUSE-3 trials (2018): in older trials, window for intervention through catheter ≈6 hr, and patients with wake-up strokes excluded; wake-up strokes common; 2014 study showed that with mechanical clot retrieval, possibility of positive outcome decreases linearly with time; 2015 study also showed linear decline as time from stroke onset to reperfusion increased

Reasons for success of trials in spite of linear decline: inclusion of wake-up strokes (many actually early-onset strokes) and use of imaging to help determine which patients had good collateral circulation (imaging criteria not used in other trials); HERMES data on defined time window of 0 to 6 hr showed that 46% of endovascular treatment group had good outcomes, vs 27% in control group; in DAWN and DEFUSE-3 trials, late-window presenters (6 hr to 24 hr) showed good outcomes in 47% of those in treatment group; reasons for differences among trials include different designs and patient selection criteria; thought to be differences in rate of progression to significant ischemic core volume (volume of brain not salvageable), depending on presence of good collateral circulation; in newer trials, positive outcomes related to good collateral circulation or occur because patients in early-onset time window from wake-up stroke; new trials used specific computed tomography (CT) perfusion technique to look for presence of salvageable brain tissue, so able to intervene and obtain good outcomes (otherwise, patients will not improve); in trials looking at 0- to 6-hr window, patient population larger, with typical collateral pattern in which brain tissue dies faster

Reperfusion outcomes with penumbral tissue: if reperfusion achieved <6 hr, mRS score of 0 to 2 seen in 60% of cases; if treatment given >6 hr and penumbral tissue present, can still achieve good outcomes; key is to find patients in delayed-onset time window with salvageable tissue; trials used diffusion-weighted imaging and perfusion (requires time, and less available at most centers on rapid basis) or CT perfusion (easier, faster, less cumbersome) used for determining amount of nonsalvageable brain tissue and amount of tissue at risk

Extended time-window trials: highly select group of patients; in real world, far fewer patients in delayed time window are candidates; however, if patients appropriately selected and clot removed promptly, same likelihood of obtaining good outcomes as with patient who presents ≤1 hr of stroke; potential criticism of DAWN and DEFUSE-3 trials that results interpreted to validate RAPID software imaging as only correct approach; trials not designed to measure that, however; might be better way to determine core infarct; historically, speaker’s institution used source images from CT angiography to determine global at-risk brain tissue and core infarct

DAWN trial: baseline National Institutes of Health Stroke Scale (NIHSS) score of ≥10 required, and patients had to be randomized within 6 to 24 hr of time last known well; those with significant prestroke disability excluded (mRS score had to be 0-1); infarct had to involve <33% of territory of MCA on CT or magnetic resonance imaging (MRI), and actual vessel occlusion had to be diagnosed; mismatch required between severity of clinical deficit (per NIHSS score) and infarct volume; in thrombectomy group (6- to 24-hr window), almost 50% had good outcomes

DEFUSE-3 trial: inclusion criteria included stroke in anterior circulation, patients 18 to 85 yr of age, NIHSS score ≥6; able to obtain MR or CT perfusion; 6 to 16 hr between last known normal and time of puncture; mRS score of 0 to 2; occlusion of ICA or MCA (M1); target mismatch on penumbral imaging protocol used (RAPID software); initial infarct volume <70 mL and mismatch ratio of ≥1.8 (almost twice as much penumbra as core); statistical significance for primary and secondary efficacy outcomes of independence at 90 days and mRS score; safety profile similar to earlier treatment

Timing of tPA and angiography: if patient eligible, IV tPA given within 3 to 4.5 hr of symptom onset; no waiting to determine whether patient improving on IV tPA before being brought to angiography suite; speaker performs angiography to ensure no clot present even if patient seems to have improved significantly

Timing of imaging: within 0 to 6 hr, CT perfusion imaging not necessary; beneficial from 6 to 24 hr, based on standard of care evidence; >24 hr — patient presentation at >24 hr rare; at speaker’s institution, even if patient may be >24 hr (ie, not known), imaging may be obtained and patient treated if salvageable tissue present; outcomes sometimes positive; for basilar artery occlusion, imaging may also be performed at >24 hr; outcomes almost always poor (usually fatal); at speaker’s institution, MRI often performed to assess posterior circulation, and treatment may be attempted if present

Experience: more is better (more experience results in decreased mortality and better outcomes); essentially linear correlation between volume of procedures performed at thrombectomy center and good patient outcomes

Conclusions: endovascular treatment of acute stroke is standard of care and can have significant benefit ≤24 hr with appropriate patient selection; triage as if emergency and provide rapid treatment if salvageable brain tissue present regardless of last time seen normal

Readings

Balami JS et al: A systematic review and meta-analysis of randomized controlled trials of endovascular thrombectomy compared with best medical treatment for acute ischemic stroke. Int J Stroke, 2015 Dec;10(8):1168-78; Bracco S et al: Wake-up (or wake-up for) stroke: a treatable stroke. Neuroradiol J, 2013 Oct;26(5):573-8; Chen C et al: Influence of penumbral reperfusion on clinical outcome depends on baseline ischemic core volume. Stroke, 2017 Oct;48(10):2739-45; Ciccone A et al: SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med, 2013 Mar 7;368(10):904-13; Goyal M et al: HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet, 2016 Apr 23;387(10029):1723-31; Josephson SA et al: Merci and Multi Merci Investigators. Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II. Neurocrit Care, 2009;10(1):43-9; Jovin TG et al: Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods. Int J Stroke, 2017 Aug;12(6):641-52; Khatri P et al: IMS III Trialists. Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial. Lancet Neurol, 2014 Jun;13(6):567-74; Kidwell CS et al: MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med, 2013 Mar 7;368(10):914-23; Liebeskind DS et al: IMS III Investigators. Collaterals at angiography and outcomes in the Interventional Management of Stroke (IMS) III trial. Stroke, 2014 Mar;45(3):759-64; Messé SR et al: Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry. Neurology, 2016 Oct 11;87(15):1565-74; Sallustio F et al: CT angiography-based collateral flow and time to reperfusion are strong predictors of outcome in endovascular treatment of patients with stroke. J Neurointerv Surg, 2017 Oct;9(10):940-3; Sheinberg DL et al: DEFUSE-3 Trial: Reinforcing evidence for extended endovascular intervention time window for ischemic stroke. World Neurosurg, 2018 Apr;112:275-6; Shindo A et al: Treatment of acute cerebral artery occlusion using the Penumbra system: our early experience. Neurol Med Chir (Tokyo), 2014 Jun 17;54(6):441-9; Yamamoto S et al: Correlation of middle cerebral artery tortuosity with successful recanalization using the Merci retrieval system with or without adjunctive treatments. Neurol Med Chir (Tokyo), 2014;54(2):113-9.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Layton presents information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Layton was recorded at Baylor Scott & White Neuroscience Symposium, held June 22-23, 2018, in Bastrop, TX, and presented by Baylor Scott & White Health, A. Webb Roberts Center for Continuing Medical Education. For information about upcoming CME activities from this sponsor, please visit their website at bswhealth.med/cme/. The Audio Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

NE092001

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.