Updates on Acute Ischemic Stroke Management

Stephanie Zyck, MD
Julius Gene S. Latorre, MD, MPH*

*Director of Comprehensive Stroke Center
Stroke and Neurocritical Care Division,
Departments of Neurology and Neurosurgery,
SUNY Upstate Medical University

Julius Gene Latorre, MD

Julius Gene Latorre, MD

Significant advances in the management of cerebrovascular diseases have occurred in recent years.  In this update, we will review the most current strategies in the acute and hyper acute management of ischemic strokes. This review highlights the time-sensitive nature of acute stroke intervention, the importance of patient selection using non-invasive imaging to determine vessel patency and tissue viability, and rapid reperfusion of affected vessel.

The Burden of Stroke
Stroke remains a leading cause of death and disability worldwide, claiming over 3.3 million deaths worldwide with over 65.5 million disability-adjusted life years lost in 2013.1 In the US, someone has a stroke every 40 seconds, and one in three are recurrent strokes.2 Over the past few decades, stable incidence rates of stroke and the declining mortality rates have been noted,2 and may in part be explained by improvement in treatment and secondary risk factor control.

Time is Brain
The brain has a very high metabolic activity, consuming energy 10 times the rate of the rest of the body per gram of tissue, and without any energy reserve, it requires continuous energy supply to maintain its function. When stroke happens, sudden loss of focal neurologic function typically occurs due to interruption of blood supply to the affected brain region. If the blood flow is not restored quickly, brain cells die at a rate of 1.9 million cells per minute,3 making it a time-sensitive medical emergency. In patients with large vessel occlusion, for every 30 minute delay in reperfusion, there was an 8.3% reduction in odds of achieving functional independence.4

Intravenous Thrombolysis (IVTPA):  0 to 4.5 hours
Systemic thrombolysis with IVTPA (alteplase, at dose of 0.9mg/kg, not to exceed 90mg and with 10% of dose given as bolus over one minute, and the rest as infusion over 60 minutes) within three hours from last known well (LKW) became the standard of care for acute ischemic stroke treatment after the NINDS landmark trial in 1995.5 The study showed significantly improved chance of recovery to independent function at three months among patients who were treated compared with placebo, despite increase in intracranial hemorrhage. Due to the limited time window for therapy, regional and national stroke systems of care were developed to increase the number of patients who can be treated. Hospital certifications into multiple tiers based on resources and capability to provide acute stroke management were also developed along with regulatory efforts to integrate emergency medical response networks (state and regional 911 systems) with emergency departments of hospitals to streamline pre-hospital processes facilitating identification and rapid transport of suspected stroke patients to stroke-ready receiving centers.6 Public education on recognition of stroke symptoms such as the FAST (Face, Arm, Speech, Time)  campaign encourages the use of 911 as activation of emergency medical service use by patients with strokes, as this has been found to independently correlate with earlier arrival to emergency departments and more rapid treatment.7 In the Get With The Guidelines registry, prehospital notification of a suspected stroke while a patient is en route has been associated with shorter times to therapeutic interventions as hospital resources can be mobilized prior to arrival of the patient.8 After more than ten years of use, time window for IVTPA eligibility was extended to 4.5 hours from LKW after a large study showed benefit of alteplase without significant increase in bleeding complications in carefully selected patients.9

Mechanical Endovascular Recanalization (MER) Therapy: 0 to 6-8 hours
The recanalization rate with IVTPA, particularly for large vessel occlusions (LVO), the most common cause of severe and fatal strokes, is low (21.3% overall). Since recanalization is the strongest predictor of outcome in ischemic strokes,10 newer therapeutic strategies need to be developed. Intra-arterial infusion of thrombolytics  at the site of occlusion was tested in PROACT II. In this study, patients with acute stroke due to middle cerebral artery occlusion were randomized to intra-arterial pro-urokinase vs. placebo within six hours of LKW. Treated patients had a significantly higher rate of recanalization (66% vs. 18%, p<0.001) and improved functional outcome (40% vs. 25%, p=0.04).11 The data was not deemed sufficient for FDA approval. As such, MER methods for ischemic strokes due to LVO using snares, ultrasound, microcatheters, balloons and embolectomy devices became more common in clinical practice. The Merci™ clot retriever (Stryker Inc.), a corkscrew shaped clot retrieval device, was developed in 2001 as the first generation of mechanical thrombectomy device and was approved by the Food and Drug Administration (FDA) for clinical use in 2005 with the publication of the MERCI trial showing improved recanalization  (48% vs. 18% using historical control, p<0.0001), better functional outcome (46% vs. 10% p<0.0001) and  lower mortality (32% vs. 54%, p=0.01).12 The Penumbra™ system  (Penumbra Inc.), a novel device for clot retrieval by aspiration by an endovascular suction catheter, has been developed13 and eventually approved by FDA in 2008, with a subsequent study confirming its safety and effectiveness for clot removal in intracranial large vessel occlusive disease.14 Third generation devices using retrievable stent technology were approved by FDA in 2012 for treatment of ischemic strokes due to LVO with LKW within eight hours after several studies showed better recanalization rates compared with the Merci retriever (86% vs. 60%, p<0.0001 for superiority) with no difference in procedure-related adverse events (15% vs. 23%, p=0.18),15 increased rate of good functional outcome at three months (58% vs. 33%, p=0.02 for superiority) and lower mortality (17% vs. 38%, p=0.02 for superiority).16

Despite the initial enthusiasm and perceived benefit of MER therapy, three randomized controlled trials presented in 2013 (IMS III, MR RESCUE, and SYNTHESIS) failed to demonstrate significant benefit.17-19 However, several important limitations were noted during the interpretation of these findings, including  the use of first generation devices with lower recanalization rates, suboptimal patient selection not incorporating modern imaging techniques, and prolonged time to initiation of endovascular therapy (381 minutes to groin puncture in MR RESCUE and 208 minutes in IMS III). Addressing these shortcomings by using newer generation devices, sophisticated imaging techniques for patient selection, and decreasing time to groin puncture for interventions, five randomized controlled trials (SWIFT PRIME, MR CLEAN, ESCAPE, REVASCAT, EXTEND-IA) were published in 2015 demonstrating superiority of endovascular therapy over IVTPA alone.20-24 Pooled analysis using patient-level data from these studies  (HERMES Collaboration) with 1287 patients (MER=634, Control=653) showed significant reduction in disability at 90 days (OR=2.49, 95%CI 1.76-3.53, p<0.0001) with a number needed to treat of two to three. More importantly, the benefit was evident even among patients aged 80 and older, among patients randomized more than six hours from LKW, and those not eligible for IVTPA, with no difference in mortality or symptomatic intracranial hemorrhages25 These new findings revolutionized the emergent way that acute ischemic stroke is treated, making MER in addition to IVTPA the new standard of care.

Anesthetic Management During MER
MER can be performed either under monitored anesthesia care (MAC), conscious sedation or general anesthesia (GA). There is much debate over which form of anesthesia is favored, with conflicting concerns over increased time to groin puncture but potentially increased safety with less patient movement under general anesthesia. Earlier studies suggested harm from general anesthesia.26, 27 However, three other randomized controlled trials showed no superiority of MAC or conscious sedation over general anesthesia for clinical outcomes or growth of diffusion weighted area on magnetic resonance imaging.28-30 Currently, our institutional protocol favors GA in cases of inability to maintain oxygen saturations >94%, posterior circulation occlusion, high risk airway, or agitation such that patient movement is a significant concern during MER.

Tissue vs. Time Window: 0 to 24 hours
Initial trials only supported the use of mechanical thrombectomy within six-eight hours from LKW. Until very recently, patients presenting after this timeframe were considered ineligible for treatment. While the “time is brain” dogma holds true and studies continue to confirm that earlier revascularization by pharmacologic and endovascular therapies directly leads to better clinical outcomes, it is known that individuals vary in how quickly their strokes progress, presumably related to availability of collateral blood supply. Assessment of infarct volume and remaining tissue at risk, known as penumbra, that can be salvaged with recanalization therapy became the critical information necessary for optimal patient selection. Imaging techniques assessing these parameters were tested in several studies looking at efficacy of MER on patients presenting outside the time window of zero-eight hours from LKW, using the concept of tissue window for recanalization. Patients with a target mismatch profile (i.e. small core infarct and large penumbra or tissue at risk, Figure 2) were selected for treatment while patients with a malignant profile (i.e. large core infarct and small penumbra, Figure 3) were not subjected to MER. In 2018, the DAWN and DEFUSE-3 trials, using the RAPID software© (iSchemaView, Stanford, CA, USA), were published providing evidence to extend the window for MER for up to 24 hours. The DAWN trial enrolled patients presenting between six to 24 hours from LKW. The trial was stopped early when the prespecified interim analysis showed significant superiority of MER over control group in 90-day good functional outcome (49% vs. 13%, posterior probability of superiority >0.999)  with no difference in rate of symptomatic intracranial hemorrhage (6% vs. 3%, p=0.5) or mortality (19% vs. 18%, p=1.0).(31) The DEFUSE-3 trial also used similar imaging perfusion methods, and included patients with anterior circulation LVO presenting within six-16 hours from LKW. The trial was stopped early after the publication of the DAWN trial with interim analysis also showing better functional outcome (45% vs. 17%, p<0.001), lower mortality (14% vs. 26%, p=0.05), and no difference in symptomatic intracranial hemorrhage (7% vs. 4%, p=0.75).(32) With these findings, mechanical thrombectomy up to 24 hours has been accepted as a standard of care in carefully selected patients based on clinical and imaging data.33

Despite the newly expanded treatment window of up to 24 hours, it is estimated that as much as 70% of patients may not qualify for either IVTPA or MER34 for various reasons, including presence of one or more exclusion criteria in the strict trial screening (large infarct size, unknown LKW or LKW >24 hours) or lack of necessary expertise where the patient is located. In another study looking at consecutive stroke admissions at a single stroke center, less than 2% of patients met the eligibility criteria for either DAWN or DEFUSE 3.35 Studies looking at outcomes of patients undergoing MER with less restrictive selection criteria are promising, with results showing similar outcomes compared with patients treated on trial protocol.34, 36 Other studies looking at expansion of the IVTPA window beyond 4.5 hours or in patients with an unwitnessed stroke onset are being done. It has been determined that lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and mismatch between diffusion-weighted MRI with FLAIRmight indicate stroke duration within guideline-recommended thrombolysis. This concept was tested in MR WITNESS trial and result showed that IVTPA in patients with MRI-DWI to FLAIR mismatch with wake-up stroke is safe.37 In WAKE-UP trial, patients with MRI-DWI to FLAIR mismatch with strokes of unknown onset were randomized to IVTPA or placebo. Patients who received IVTPA had better outcomes (53% vs. 42%, p=0.02) with no significant increase in mortality (4.1% vs. 1.2%, p=0.07) or symptomatic intracranial hemorrhage (2.0% vs. 0.4%, p=0.15).(38)

Future Directions:
Availability of stroke care across wide range of expansive geographic distances to stroke centers are improving with the use of modern telecommunication technologies within the telestroke networks, allowing instant access of patients in remote areas to specialists who may be hundreds of miles away, providing acute stroke care locally. Urban centers are beginning to use specially fitted mobile stroke units that can be deployed on the field and  meet the patients where they are when the stroke occurred, allowing for very fast evaluation and IVTPA treatment. Newer thrombolytics are being tested as an alternate to alteplase. Tenecteplase is a genetically engineered tissue plasminogen activator, modified using recombinant DNA technology resulting in longer half-life,  increased fibrin specificity and greater resistance to inactivation by  plasminogen activator inhibitor 1(PAI-1). In a multicenter study with 1100 patients, tenecteplase at a dose of 0.4mg/kg not to exceed 40 mg as a single bolus had safety and efficacy similar to standard dose of alteplase.39 In another study on stroke due to large vessel occlusion,  patients treated with tenecteplase prior to mechanical thrombectomy had higher reperfusion rates and better functional outcomes than  patients treated with standard dose of alteplase.40

Multiple scientific advances are underway to improve neurologic outcomes in acute ischemic stroke. These include the use of stem cell transplantation, neuroprotective agents, and pharmacogenomics. One recent meta-analysis suggested that stem cell transplantation can significantly improve neurologic deficits and the quality of life in patients with ischemic stroke.41 Neuroprotection, or the ability to protect ischemic brain from injury before reperfusion and then protect it from reperfusion injury, has also gained significant attention. The concept of neuroprotection is to interrupt or reverse the cascade of cellular and molecular events seen during cerebral ischemia. Targets for therapy have included preventing and minimizing the effects of excitatory amino acids, transmembrane calcium influx, free radical damage, intracellular enzymes, and inflammation.42 Other non-pharmacologic methods include transcranial magnetic stimulation, and transcranial laser therapy to alter the cascade of cellular apoptosis in penumbral tissue. Hyperbaric oxygen therapy has also been used to maximize patients’ oxygen concentrations in plasma and minimize the extraction of oxygen from circulating hemoglobin, but multiple studies show conflicting data.43 Despite initial enthusiasm regarding therapeutic hypothermia,44 multiple subsequent trials have not shown any evidence of clinical benefit45 but higher rate of pneumonia.46 Other interventions for improving neurologic recovery have included acupuncture, hands on therapy, speech therapy for aphasia, and vagal nerve stimulation paired with upper limb rehabilitation. The study of pharmacogenomics, how an individual’s genetic composition affects responses to drugs, has also become an important area of study for acute ischemic stroke, especially in antithrombotic management for secondary stroke prevention.

Needless to say, care of patients with acute ischemic stroke has been revolutionized over the past decade and continues to evolve in an exponential fashion. The use of advanced neuroimaging to select patients who may benefit from  intervention, the use of modern technology for faster diagnosis and delivery of care will continue to dominate the future development of acute stroke treatment. It is important to maintain awareness of these ongoing developments in order to provide the best care at an individual, institutional, regional, and global level.

Figure 1. Illustration of different approaches to intra-arterial (IA) treatment of patients with acute stroke due to large-vessel occlusion. An intracranial vessel with occlusive thrombus is shown. A: Intra-arterial pharmacological thrombolysis is doneby injecting a thrombolytic agent through a microcatheter directly into the clot. B: Microwire manipulation breaks down theclot into smaller particles. C: Mechanical thrombectomy with the Merci retriever works by wrapping around and capturing theclot. D: Aspiration thrombectomy using the Penumbra aspirator and separator breaks down the clot under constant negativepressure. E: A stent retriever (examples: Solitaire©, Medtronic, Minneapolis, MN, USA or Trevo©, Stryker, Kalamazoo, MI, USA) allows capture of the thrombus and instant restoration of blood flow. Both thestent and clot are then retrieved together. Copyright University at Buffalo Neurosurgery. Adapted from Mokin M et al. Neurosurg Focus 2014;36(1):E5. Used with permission.

Figure 1

Figure 2. Target mismatch profile. Commercially available automated perfusion mapping software enable accurate quantification of viable tissues at risk of infarction (mismatch volume), allowing optimal patient selection during acute stroke evaluation. This figure is an example of a patient with  target mismatch profile, the ideal candidate for mechanical thrombectomy. At the time the multimodal CT scan images were obtained, despite the prolonged presentation with last known well 15 hours prior to CT scan, the patient’s infarct core was only six cc (CBF<30%) with large area of hypoperfusion (82 ml) and a mismatch volume of 76 ml. The patient was recanalized and had improvement in neurologic function, with modified Rankin scale of one at discharge.

Figure 2

Figure 3.  Malignant profile. Automated CT perfusion map of a  67F who presented at 10 hours from last known well. The patient had severe stroke symptoms due to occlusion of R MCA main trunk. Due to large estimated infarct core (83 cc)  and small remaining viable tissues (mismatch volume 23 cc), the patient did not undergo mechanical thrombectomy. This pattern of mismatch is referred to as malignant profile. Mechanical thrombectomy in this case is not only without benefit, but may even be harmful due to increased risk of hemorrhagic transformation and cerebral edema.

Figure 3



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