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Stroke Compendium

Acute Ischemic Stroke Therapy Overview

Luciana Catanese, Joseph Tarsia, Marc Fisher
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https://doi.org/10.1161/CIRCRESAHA.116.309278
Circulation Research. 2017;120:541-558
Originally published February 2, 2017
Luciana Catanese
From the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA.
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Joseph Tarsia
From the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA.
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Marc Fisher
From the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA.
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  • Article
    • Abstract
    • Introduction
    • Brain Imaging
    • CT Angiography
    • Magnetic Resonance Imaging
    • Magnetic Resonance Angiography
    • CT Perfusion
    • Acute Ischemic Stroke Therapies
    • Future Directions
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Abstract

The treatment of acute ischemic stroke has undergone dramatic changes recently subsequent to the demonstrated efficacy of intra-arterial (IA) device-based therapy in multiple trials. The selection of patients for both intravenous and IA therapy is based on timely imaging with either computed tomography or magnetic resonance imaging, and if IA therapy is considered noninvasive, angiography with one of these modalities is necessary to document a large-vessel occlusion amenable for intervention. More advanced computed tomography and magnetic resonance imaging studies are available that can be used to identify a small ischemic core and ischemic penumbra, and this information will contribute increasingly in treatment decisions as the therapeutic time window is lengthened. Intravenous thrombolysis with tissue-type plasminogen activator remains the mainstay of acute stroke therapy within the initial 4.5 hours after stroke onset, despite the lack of Food and Drug Administration approval in the 3- to 4.5-hour time window. In patients with proximal, large-vessel occlusions, IA device-based treatment should be initiated in patients with small/moderate-sized ischemic cores who can be treated within 6 hours of stroke onset. The organization and implementation of regional stroke care systems will be needed to treat as many eligible patients as expeditiously as possible. Novel treatment paradigms can be envisioned combining neuroprotection with IA device treatment to potentially increase the number of patients who can be treated despite long transport times and to ameliorate the consequences of reperfusion injury. Acute stroke treatment has entered a golden age, and many additional advances can be anticipated.

  • imaging
  • intervention
  • stroke
  • therapy
  • thrombolysis

Introduction

Acute ischemic stroke (AIS) is a common disorder with almost 700 000 new or recurrent events per year in the United States. The risk of AIS varies by region, with the highest incidence occurring in the so-called stroke belt in the southern part of the country.1 The risk of AIS varies among African Americans, Latinos, and Caucasians, with the highest risk in African Americans. The risk of AIS increases with age, and the ageing of the US population portends an increase in AIS incidence and prevalence over the next several decades, despite increasingly effective efforts to treat stroke risk factors and the use of other preventive strategies.2 The incidence of AIS is also increasing in many other countries, largely related to potentially modifiable risk factors, especially in the developing world.3 The incidence of AIS is also greater among women beginning with an increased risk in the perimenopausal period and continuing into older age groups.4,5 The looming increase in AIS patients in the United States and around the world makes it incumbent that better acute therapies be developed and implemented to improve outcomes of AIS patients.

The pathophysiology of AIS is both simple and complex. Simple in that the initiating event is the occlusion of an intracranial or neck blood vessel that in most cases impairs blood flow to a portion of the brain, leading to infarction of brain tissue in the part of the brain supplied by that blood vessel. The vessel occlusion can occur in relationship to a local vessel occlusion typically in patients with intracranial atherosclerosis, artery to artery embolization typically from an internal carotid artery (ICA) plaque, or secondary to embolization of a clot from the heart to a brain vessel as exemplified by atrial fibrillation. The process of ischemic brain injury is complex because many different cellular consequences occur when cerebral blood flow (CBF) is substantially reduced or absent (Figure 1).6 The ischemic cascade at a cellular level induced by reduced/absent CBF has been studied for decades, and many different pathways have been identified. The consequences of brain ischemia differ in white and gray matter, so the temporal evolution in these brain regions may differ as may approaches to neuroprotection. Some components of the ischemic cascade are activated early after the onset of ischemic injury and others at later time points.7 It must be recognized that the mechanisms of ischemic injury are different in brain regions with little or no residual CBF than in regions with more modest reductions. The temporal evolution of ischemic injury toward irreversibility is also different, with the possibility to salvage ischemic brain tissue in regions with an initially moderate CBF reduction because in that region, infarction may not develop for many hours.8 This potentially salvageable ischemic tissue is termed the ischemic penumbra and is the target of acute stroke therapy because saving all or part of the ischemic penumbra by initiating timely AIS treatment is the basis of acute stroke treatment.9 Conversely, the ischemic region that has already progressed to irreversibility is called the ischemic core. Both regions can be identified and their extent approximated by advanced computed tomography (CT) and magnetic resonance imaging techniques that are clinically available.10 The extent of the ischemic penumbra and core changes over time, with shrinkage of the former and expansion of the latter occurring at varying rates in individual AIS patients with the same location of vascular occlusion. The concept of the ischemic core and penumbra may not be relevant for small-vessel lacunar strokes involving white matter, but seems to be appropriate for both larger vessel occlusions secondary to local atherosclerosis or cardiac embolism. Important factors that affect the evolution of the ischemic core and penumbra include temperature, metabolic factors such as glucose, and collateral blood supply to the affected brain region.11 Interventions such as quickly reestablishing CBF to the ischemic region, enhancing collateral blood flow, and drugs targeted at the ischemic cascade can also affect the evolution of the ischemic penumbra/cascade and form the basis of AIS therapies that have been and will be developed. Currently, AIS has entered a golden age brought about by a confluence of factors, including an enhanced understanding of the basic pathophysiology of focal ischemic brain injury, improved acute stroke imaging, the proven efficacy of both intravenous and intra-arterial (IA) therapies to restore blood flow, and improving care delivery systems to allow for the expeditious treatment of AIS patients.

Figure 1.
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Figure 1.

A schematic representation of the cascade of ischemic injury over time. Courtesy of Dr Won-Ki Kim, Seoul Korea (Illustration Credit: Ben Smith). BBB indicates blood–brain barrier.

Brain Imaging

Noncontrast Head CT

The noncontrast head CT (NCCT) has been a staple of acute stroke imaging for many years. Rapid acquisition time, applicability, and availability to all patients, regardless of comorbidity or setting, and easy detection of intracranial hemorrhage (ICH) has made it a universally invaluable tool. The critical distinction between underlying hemorrhage and ischemia immediately impacts patient management while determining eligibility for acute thrombolytic or endovascular therapy (EVT). With more patients being sent for potential EVT from peripheral centers that lack access to vessel imaging, it is often the NCCT that serves as the only source of radiographic clues for eligibility.

Early Ischemic Changes

These are signs of brain edema that develops in some patients early after onset.12 Hypoattenuation of the x-ray beam occurs as water content increases, which leads to the appearance of a hypodensity and a reduced contrast between adjacent the gray and white matter. The latter phenomenon of blurred distinction between structures, depending on location, leads to radiographic signs, such as the loss of the insular ribbon or obscuration of the lentiform nucleus. These hypodensities are predictive of final infarct volume and demonstrate irreversible tissue damage, despite successful reperfusion.13 Another form of early ischemic changes (EIC) is cortical swelling, which leads to the appearance of sulcal effacement or loss of the subarachnoid spaces between gyri and local mass effect. Cortical swelling, when in isolation, has been correlated with compensatory vasodilation and increased blood volume and has a propensity to be reversed with reperfusion, perhaps representative of penumbral tissue.14

Detection of EICs is difficult and requires training and experience for accurate detection. Adjustments to the CT window and level (eg, W30/L35, W30/L50, etc) can increase the contrast of tissues and may augment the detection of subtle EICs.15 In general, EICs have decreased sensitivity for detecting smaller infarcts, hyperacute infarcts, and infarcts of the brain stem and cerebellum where CT beam artifact is a common confounder. The utility of identifying and quantifying EICs has evolved since the early thrombolytic trials. The Alberta Stroke Program Early CT Score (ASPECTS) was created and validated to help systematically detect and quantify EICs16,17 (Figure 2A). Starting with 10 prespecified areas of the middle cerebral artery (MCA) territory, a point is deducted for each area in which a hypodense or hypoattenuating EIC is present. A lower score indicates more extensive EICs and a larger territory of tissue likely destined for infarction. A posterior circulation ASPECTS was also developed (Figure 2B). The ASPECTS may, therefore, provide a readily available method for determining if the ischemic core is small or large on a noncontrast CT scan that is essentially performed on all AIS patients.

Figure 2.
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Figure 2.

A, Example of an ASPECTS of 3 out of 10, with one point deducted for early ischemic changes in each territory: M2, M3, I (insula), L (lentiform nucleus), IC (internal capsule), M4 and M5 territories with sparing of the M3 and C (caudate) and M1 (not shown). B, pc-ASPECTS score of 4 out of 10. The yellow numbers indicate point deduction for areas of EIC. ASPECTS indicates Alberta Stroke Program Early Computed Tomography Score; EIC, early ischemic changes; and pc-ASPECTS, Posterior Circulation Alberta Stroke Program Early Computed Tomography Score.

Use of the ASPECTS in Clinical Practice and Trials

The ASPECTS has been independently associated with long-term functional outcome. A score of ≤7 is associated with dependent functional status (modified Rankin Scale [mRS] score ≥3), as well as an increased risk for symptomatic intracerebral hemorrhage (sICH).18 Lower scores (0–5) are more useful for prognosis than the scores in the higher range.19 When applied to thrombolytic trial data, intravenous (IV) tissue-type plasminogen activator (tPA) did not have a treatment modification effect on outcome, despite the score.17,20 This is reflected in recent American Heart Association/American Stroke Association (AHA/ASA) guidelines, which conclude that there is no evidence to withhold IV tPA from those with extensive mild-to-moderate EICs and determined that no adequate threshold has been established where EIC within 4.5 hours from symptom onset should preclude the use IV tPA.21 Those with a clear, extensive hypodensity of more than one third of the MCA (≈ASPECTS ≤5) is a class III/A recommendation against therapy.22

Data from the PROACT-II trial (Prolyse in Acute Cerebral Thromboembolism) suggested less benefit for patients with a lower ASPECTS despite recanalization. The MR-CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) did not exclude patients based on EICs but did perform a prespecified subgroup analysis on ASPECTS ranges of 0 to 4, 5 to 7, and 8 to 10. The 8 to 10 subgroup had a primary outcome (shift of mRS) odds ratio of 1.61 (1.11–2.34) and was the only group to maintain statistical significance.23 The ESCAPE trial (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) and the SWIFT PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke) excluded patients with ASPECTS ≤5 and the REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large-Vessel Occlusion Presenting Within 8 Hours of Symptom Onset), excluded patients with ASPECTS ≤6. The ESCAPE, SWIFT-PRIME, and REVASCAT trials all showed better outcomes patients with ASPECTS ≥8.24 A meta-analysis of trial data showed that the subgroup of dichotomized ASPECTS of ≤7 versus >7 had no interaction for improved functional outcome.25 An ASPECTS cutoff of ≥6 is a class IA AHA/ASA recommendation for selecting endovascular candidates. Those with scores <6 are relegated to a class IIb/B-R recommendation because a majority of these patients were excluded from these trials.24 The posterior circulation ASPECTS has been validated and can be useful for predicting futile recanalization in those with acute basilar artery occlusion. Those with posterior circulation ASPECTS of <8 have been shown to independently predict poor functional outcomes (mRS score ≥4), despite complete recanalization.26

Hyperdense Vessel Signs

The NCCT can provide clues to the presence of a large artery occlusion (LAO) when a hyperdense vessel sign is present. These are segments of blood vessels that have high signal attenuation and that represent intraluminal thrombus. The sensitivities and specificities for predicting confirmed vessel occlusion on angiography vary by location, often with high specificity but poor to moderate sensitivities (Table 1).27–34

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Table 1.

Hyperdense Vessel Signs

CT Angiography

CT angiography (CTA) of the head and neck vessels has recently emerged as critical in acute stroke imaging given its ability to confirm large-vessel occlusions and, thus, potential candidates for EVT. It has the benefit of rapidly and accurately delineating the vascular tree from the aortic arch to distal divisions of the intracranial vessels, typically in less than a minute. It also offers an overall assessment of collateral blood flow, which plays a significant role in the evolution of ischemic tissue and planned therapies. The added convenience of obtaining both the NCCT and CTA on the same scanner is another major convenience. It is noninvasive but does confer additional radiation. It requires ≈100 mL of iodinated contrast, which may exclude patients with acute or preexisting renal insufficiency and those with true severe allergies to a contrast agent. Postprocessing that generates 3D reformats and maximal intensity projections are also available in several minutes.

Intracranial LAO

When compared with the gold standard of digital subtraction cerebral angiography, CTA has a sensitivity and specificity of nearly 98% to 100% for detecting intracranial LAO.35,36 CTA is also sufficient for detecting acute intracranial nonocclusive thrombi, a rare though potential predictor of subsequent clinical decline.37 The clot-burden score has been developed to quantify extent of intracranial thrombosis visualized on CTA. It is a 10 point score that is calculated by subtracting points for the presence of occlusive or nonocclusive clot in certain locations: 2 points are deducted for the presence within supraclinoid ICA, proximal MCA trunk/MCA–first segment (M1) or distal M1; 1 point deducted for presence within infraclinoid ICA, anterior cerebral artery or MCA–second segment division (Figure 3).38 A clot burden score of 0 indicates a complete multisegmental vessel occlusion, with lower scores validated to independently predict lower recanalization rates with IV tPA, larger infarcts, poor outcome, and risk of hemorrhagic transformation.38–40 Based on the data acquired from recent endovascular trials, the AHA/ASA has granted a grade I/A recommendation to endovascular candidates only with an occlusion located in the M1 or terminal ICA. The remaining large-vessel arterial locations are designated class IIb/C.24

Figure 3.
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Figure 3.

Example of a left carotid occlusion involving the infra- and supraclinoid carotid artery (left). The Clot Burden Score is 0 out of 10. Infraclinoid ICA =1 (purple), supraclinoid ICA =2 (red), proximal M1 =2 (light green), distal M1 =2 (dark green), A1=1 (yellow), and M2=1+1 (light blue). ICA indicates internal carotid artery.

Collateral Assessment

Collateral blood flow via leptomeningeal arteries and other vessels during an acute stroke is an important factor in the rate of ischemic tissue evolution and transition from penumbral tissue into irreversible infarct.41 It is highly individualized and is dependent on several factors, including variants of vascular anatomy, clot location, and clot burden. Several scoring methods were used to quantify the presence of collaterals and attempt to validate their ability to predict outcomes. Currently, standardization is lacking regarding the best method. The regional leptomeningeal collateral score assesses the presence and quality of collateral vessels in the 6 MCA cortical ASPECTS locations (M1–M6), parasagittal anterior cerebral artery territory, and the basal ganglia compared with the contralateral side with a maximum score of 20.42 Another example, the collateral score, grades collaterals as either absent (=0), present in <50% of the downstream territory (=1), >50% (=2), or in 100% of the territory (=3). Scores of 0 to 1 are considered poor. Both the regional leptomeningeal collateral and collateral score have been shown to independently predict poor outcome (mRS score >2), infarct volume, and propensity for hemorrhagic transformation in the setting of an acute occlusion.39,42

The aforementioned evaluations of collateral status use a single conventional CTA maximal intensity projection image (single phase). Multiphase CTA is a technique that can be used to increase temporal resolution of collateral blood flow and more accurately depict the process when compared with the opposite hemisphere. This technique uses the initial CTA acquisition followed in rapid succession with 2 additional acquisitions in the midvenous and late venous phases, for a total of 3 maximal intensity projections.43 Scoring collateral status takes into account asymmetry of individual phases and washout of contrast, conveying a particular advantage to single-phase assessments. Multiphase CTA collateral assessment, in addition to the ASPECTS, was used to select patients in the recently successful ESCAPE trial and remains the only collateral score validated in a randomized controlled trial.44 Newer CT scanners capable of whole-brain perfusion allow for time-resolved (ie, 4D) dynamic CTA that allows for a temporally fused maximal intensity projection.45

CTA Source Images ASPECTS

CT angiogram source images can be rewindowed (≈W75/L40) and used for an ASPECTS-like calculation. It has been shown that CT angiogram source images ASPECTS is superior to the NCCT ASPECTS for both the anterior and posterior circulation, can predict final infarct volumes and functional outcomes, and closely represents core lesions on diffusion-weighted imaging (DWI) on magnetic resonance imaging.46–49

Extracranial CTA

The ability to detect an acute symptomatic total occlusion versus 99% stenosis (pseudo-occlusion) of the extracranial carotid artery may make a substantial difference in immediate management. The ability of CTA to detect this subtle difference has good accuracy for detecting a string sign when compared with the standard of digital subtraction cerebral angiography.50 The ability to distinguish dissection rather than traditional atherosclerotic occlusion may also alter acute management and long-term prognosis. The absence of calcification and the appearance of the flame sign may give clues as to the presence of a dissection.

Magnetic Resonance Imaging

Most stroke centers do not use magnetic resonance imaging as a first-line choice for acute stroke imaging. The lack of acute availability, somewhat longer imaging time, expense, contraindications for pacemakers or metal implants, claustrophobia, and other features reduce its use. There are several scenarios, however, in which magnetic resonance imaging is a valuable tool to answer specific questions on a case-by-case basis. The ability to reliably detect early infarction, obtain vessel imaging without the use of contrast for those with renal insufficiency, determine the overall extent of brain stem ischemia in a basilar occlusion, and rule out ischemia in those who have high pretest probability for a stroke mimic are just a few of these scenarios.

DWI and Apparent Diffusion Coefficient

DWI allows for rapid and highly sensitive identification of the acute ischemic tissue with a sensitivity of 77% to 97% and specificity of 95% to 100%.51,52 Sensitivity is lowest for lesions that are hyperacute, small, and located in the brain stem. DWI hyperintensity represents restricted diffusion of water molecules, which are felt to occur as the cytotoxic edema of ischemic tissue traps water intracellularly while increasing the tortuosity and reducing volume of the extracellular space limiting the free motion of water. The apparent diffusion coefficient maps are derived from DWI to give a quantitative assessment of diffusion restriction (ie, increased restriction decreases intensity). Correlating apparent diffusion coefficient hypointensity with DWI hyperintensity increases the specificity for acute ischemia by eliminating artifact created by the T2 component of the original diffusion image (ie, T2 shine through). Apparent diffusion coefficient hypointensity does return to normal between 4 and 7 days (ie, pseudonormalization) and may eventually become hyperintense in chronic lesions. DWI is typically considered the gold standard for identifying infarct core irrespective of reperfusion. There may, however, be some area of reversibility of the DWI lesion with early reperfusion, but not much was seen in both animal data and human case series.53 Apparent diffusion coefficient threshold values of ≤620×10–6 mm2/s have recently been identified as a reasonable (sensitivity 69%/specificity 78%) marker for irreversible infarction.54

Fluid-Attenuated Inversion Recovery

The use of fluid-attenuated inversion recovery/DWI mismatch is currently being studied in randomized controlled trials to identify early (ie, <6 hour) lesions in patients with unknown time of onset. Fluid-attenuated inversion recovery hyperintensity occurs as vasogenic edema develops and is not widely present <6 hours from stroke onset. Patients with mismatch who would normally be excluded from therapy based on unknown onset time may potentially benefit. Vascular hyperintensities on fluid-attenuated inversion recovery can also be indicative of slow-flow areas within an ischemic lesion likely representative of collateral blood flow.55 Given its particularly high sensitivity for blood products and gadolinium in the cerebral spinal fluid space, fluid-attenuated inversion recovery can often detect disruption of the blood–brain barrier and serve a marker of increased risk for hemorrhagic conversion, especially in the setting of reperfusion. This finding of peri-infarct postgadolinium cerebral spinal fluid enhancement has been termed hyperintense acute reperfusion marker.56

T2* or Gradient Echo

Gradient echo may identify the presence of cerebral microbleeds. A recent meta-analysis found that the presence of ≥10 cerebral microbleeds presents a significant increased risk of sICH with IV tPA. This knowledge may provide more informed risk versus benefit analysis in certain patients who are candidates for thrombolytics.57 Prior to this meta-analysis, the last statement from the AHA/ASA did not consider microbleeds as a contraindication to IV tPA (Class IIa/B recommendation).21

T1-Weighted Images and Fat Suppression

T1-weighted images–fat suppression imaging is often ordered if arterial dissection is considered the stroke etiology, either by history or by other angiographic imaging that suggests this process. T1-weighted images axial fat suppression images allow for amplified distinction between surrounding soft tissue of the neck and intramural hematoma, specifically hemoglobin that has transitioned to methemoglobin in the subacute phase.58,59 The confirmation of a dissection alters long-term management and prognosis but may alter acute management decisions depending on the circumstances.

Magnetic Resonance Angiography

Two different magnetic resonance angiography images can be acquired. Time of flight uses no gadolinium and is obtained by using the vascular signal of blood flow velocity and direction to contrast that of the saturated signal of adjacent stationary tissue. This results in a bright signal of blood flow. Three-dimensional circle of Willis reconstructions in a tumble (vertical) or spin (horizontal) plane is most often used. It has a sensitivity of 80% to 90% for occlusions when compared to digital subtraction cerebral angiography.60 Time of flight overestimates the degree of stenosis at highly calcified sites or when severe turbulence occurs. It is also fairly limited in detecting smaller, distal vessels. Contrast-enhanced magnetic resonance angiography can be used to improve the quality of extracranial imaging with shorter acquisition time after gadolinium bolus outlines the vascular anatomy and reduce motion artifact with particular benefit of improved distinction of pseudo-occlusion of the carotid, which may alter acute management.61

CT Perfusion

As an iodinated contrast bolus flows through the parenchyma and feeding arteries, the rise and fall of enhancement in HUs (Hounsfield units) is plotted against time and 2 curves are generated: a parenchymal enhancement curve, Q(t), and an arterial enhancement curve, Ca(t). These curves then undergo mathematical postprocessing called deconvolution (pixel scaling) to create a single residue function enhancement curve, R(t). All variables and final perfusion maps are derived from the data within these curves (Table 2).62 One of the biggest drawbacks and criticisms of CT perfusion (CTP) is the enormous amount of variability and lack of standardization from one vendor or software package to another in both the acquisition of raw perfusion data (eg, scanner slice coverage, automated versus manual arterial input functions, etc) and postacquisition processing (eg, deconvolution algorithms, smoothing, etc). In addition, measures of blood flow parameters may not directly translate to what is occurring at the cellular level.

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Table 2.

Perfusion Imaging Terminology

Despite these shortcomings, certain variables and respective thresholds have shown to be more reliable than others when making this distinction between the ischemic core and penumbra.63 These have also given way to certain profiles and penumbral maps for clinical interpretation (Table 3).63–65 To date, the AHA/ASA gives the use of perfusion imaging a ClassIIb/C recommendation for selecting candidates for EVT with further studies recommended.24

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Table 3.

Thresholds and Pattern Definitions for Clinical Practice

MR Perfusion Imaging

Two different methods exist for perfusion-weighted imaging. The first is dynamic susceptibility contrast imaging, which uses a bolus of gadolinium contrast and uses many of the same principles as CTP. The thresholds and definitions are similar to those of CTP (Table 3). The second method is arterial spin labeling, which uses no contrast, is less available, and less well studied but can provide quantitative CBF data.

Acute Ischemic Stroke Therapies

In a typical large-vessel anterior circulation ischemic stroke, 1.9 million neurons, 14 billion synapses, and 12 km (7.5 miles) of myelinated fibers are destroyed every minute treatment is withheld.66 Brain infarction from stroke leads to functional disability and death, making AIS an emergency that requires hyperacute treatment. Historically, AIS therapies, including thrombolysis and endovascular revascularization, have lagged behind substantially as compared with similar treatments in cardiology. The influx of evidence supporting AIS thrombolytic therapy in 1995 versus 1980s for ST-segment–elevation myocardial infarction and in 2015 for EVT versus 1990s for acute coronary balloon angioplasty serves as some striking examples of the historical gap between these 2 vascular subspecialties (Figure 4). However, with the recent results of several clinical trials, the era of acute stroke endovascular revascularization has begun. Acute stroke therapies use a similar paradigm to acute myocardial infarction: recanalize the occluded artery to restore perfusion to tissue that remains salvageable. Available AIS reperfusion treatments include intravenous thrombolysis (IVT) and EVT.

Figure 4.
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Figure 4.

History of acute ischemic stroke in relation to STEMI therapies. ADMIRAL indicates Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-Up trial; ASSENT, Single-Bolus Tenecteplase Compared With Front-Loaded Alteplase in Acute Myocardial Infarction trial; ASSENT-2, Anglo-Scandinavian Study of Early Thrombolysis; ASSET, Anglo-Scandinavian Study of Early Thrombolysis trial; CADILLAC, the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; ECASS, the European Cooperative Acute Stroke Study trial; ESCAPE, Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke trial; EVT, endovascular therapy; EXTEND-IA, Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial trial; FINESSE, Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events trial; GISSI, Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial; MS, International Management of Stroke trial; INJECT, lnternational Joint Efficacy Comparison of Thrombolytics trial; ISIS, International Study of Infarct Survival Collaborative Group trial; MAST-E, Multicentre Acute Stroke Trial-Europe; MAST-I, Multicentre Acute Stroke Trial-Italy; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial; MR RESCUE, Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy; NOR-TEST, the Norwegian Tenecteplase Stroke trial; RAPID, Reteplase Versus Alteplase Patency Investigation During Acute Myocardial Infarction; ROSIE, ReoPro Retavase Reperfusion of Stroke Safety Study-Imaging Evaluation trial; STEMI, ST-segment -elevation myocardial infarction; SWIFT PRIME, Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke; SYNTHESIS, Local Versus Systemic Thrombolysis for Acute Ischemic Stroke trial; TAPAS, Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction study; TASTE, Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation trial; TNK, tenecteplase; and TPA, tissue-type plasminogen activator.

Intravenous Thrombolysis

The first reports of IVT in ischemic stroke emerged in 1958,67 but stroke remained a condition without a proven treatment until 1995 when the first positive randomized trial was performed by the National Institute of Neurological Disorders and Stroke with recombinant tPA.68 The National Institute of Neurological Disorders and Stroke Group sponsored the first set of phase II pilot studies,69,70 which delineated the final tPA dose (0.9 mg/kg, with 10% administered as a 1-minute bolus and the remaining 90% as an infusion over 60 minutes) that could be safely administered in the treatment of AIS, leading to the pivotal phase 3 National Institute of Neurological Disorders and Stroke trial.68 This 2-part study randomized a total of 624 AIS patients presenting within 3 hours from symptom onset to receive either tPA or placebo in a double-blinded fashion. Although the first part failed to show any significant difference between groups in terms of clinical outcomes at 24 hours, part 2 revealed at least 30% greater likelihood to have minimal or no disability at 3 months in those patients who received tPA versus those who did not (global odds ratio 1.7, 95% confidence interval 1.2–2.6; P=0.008), despite an increased incidence of sICH in the treatment group (6.4% versus 0.6%; P<0.001). No mortality benefit was noted. These results led to the US Food and Drug Administration (FDA) approval of tPA in 1996 and remains one of the most important breakthroughs in the management of AIS.

Additional trials were performed subsequently that focused on pushing the limits of the IV tPA time window. ATLANTIS trial (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) Part A and B,71 EPHITET (Echoplanar Imaging Thrombolysis Evaluation Trial),72 and ECASS trials (European Cooperative Acute Stroke Studies) 173 and 274 were not successful. A subsequent meta-analysis published in 2004 confirmed the strong association between rapid treatment and favorable outcomes and suggested a potential benefit of tPA infusion ≤270 minutes after stroke onset.75 In 2008, the ECASS 3 trial randomized 821 AIS patients to receive IV tPA versus placebo within 3 to 4.5 hour from symptom onset, demonstrating a modest but significantly higher rate of functional independence at 3 months (odds ratio 1.34, 95% confidence interval 1.02–1.76; P=0.04), while the risk of ICH was comparable with prior tPA trials.76 Despite a subsequent robust meta-analysis supporting these findings,77 the FDA failed to approve the extended therapeutic window beyond the 3-hour mark, leaving IV tPA for AIS patients presenting within 0 to 3 hours as the only FDA-approved pharmacological AIS treatment in the United States. The AHA/ASA guidelines, however, have recommended the extended time window ever since. The IST (International Stroke Trial)-3 randomized the largest cohort of patients (3035) to IV tPA versus placebo and showed that despite early hazards from an increased risk of ICH, thrombolysis within 6 hours improved functional outcomes even in patients aged >80 years.78 Although some studies have suggested that genetic polymorphisms,79,80 race, and sex may influence the efficacy of tPA,81,82 only certain comorbidities such as hypertension and hyperglycemia have been found to significantly and negatively impact thrombolytic response in AIS patients.83,84

Other Approaches to IVT

Although tPA is the mainstay of AIS therapy, it has several limitations, including a short half-life (4–8 minutes), low recanalization rate of 30% to 40% for proximal occlusions and of <5% for distal ICA occlusion,85 effects on the blood–brain barrier and neurotoxicity, risk of ICH, time-sensitive administration, and a long list of absolute contraindications. The shortcomings of tPA have stimulated researchers to explore other thrombolytic agents. Clinical trials of tenecteplase began in 1999 after promising results in the acute myocardial infarction ASSENT-2 trial (Anglo-Scandinavian Study of Early Thrombolysis) emerged.86 Early phase IIB87,88 and a pilot studies’89 data reported tenecteplase safety for the treatment of AIS within 3 hours at smaller doses compared with those used in cardiology, as well as its efficacy with increased early reperfusion rates measured by perfusion/diffusion scans and improved functional outcome (National Institute of Health Stroke Scale at 24 hours) when compared with tPA. These led to the ongoing phase III trials, TASTE (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation Trial) and NOR-TEST (The Norwegian Tenecteplase Stroke Trial).90,91 Desmoteplase, a fibrin-specific thrombolytic drug with a longer half-life and less neurotoxicity compared with tPA, was initially tested in 2 phase II trials (DIAS [Desmoteplase in Acute Ischemic Stroke]92 and DEDAS [Dose Escalation of Desmoteplase for Acute Ischemic Stroke]93) that documented reperfusion efficacy within a 9-hour window and safety at lower doses. Unfortunately, the subsequent phase III studies (DIAS-394 and DIAS-495) failed to show efficacy. Finally, the combination of tPA with other treatment modalities such as hypothermia, epifibatide, activated protein C, and extend alteplase therapeutic window ≤9 hours using novel imaging modalities are being studied with the hope of improving IV thrombolytic therapy in this dynamic, time-sensitive, and complex disease process.

Endovascular Therapy

EVT for AIS has undergone a major evolution since its origins back in the 1980s when it was purely based on the IA administration of thrombolytic agents directly into the clot. Potential benefits from this treatment were shown initially in nonrandomized studies, but it was not until the 1990s that the PROACT-I trial randomized patients with angiographically documented M1 and MCA–second segment occlusions to receive either IA recombinant prourokinase or placebo within 6 hours from stroke symptom onset.96 IA recombinant prourokinase was associated with higher recanalization rates than placebo without a significantly increased incidence of ICH. A subsequent phase III study (PROACT-II) randomized 180 patients with AIS of <6 hours’ duration and angiographically proven proximal MCA occlusion to receive IA recombinant prourokinase plus heparin versus heparin alone.97 Despite an increased incidence of early sICH (10.2%), patients treated with recombinant prourokinase had higher recanalization rates (66% versus 18%; P<0.001) and were significantly more likely to be independent at 90 days (40% versus 25%; P=0.04). The positive results of this trial stimulated the exploration of other EVT recanalization approaches. Some of the proposed approaches included microwire manipulation of the clot, balloon angioplasty, manual aspiration of the clot, and the combination of IV, IA tPA, and low energy ultrasound, but none of them succeeded.

Initial EVT Approaches

The era of clot retrievers was launched with the FDA approval of the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) retriever in 2004. This approval was supported by the MERCI and multi-MERCI trials, a set of prospective, nonrandomized, multicenter, and single-arm trials designed to test the safety and efficacy of this device in large-vessel AIS patients with ≤8 hours of stroke symptoms.98,99 Successful recanalization rates (Thrombolysis in Myocardial Infarction score 2 and 3) were lower than expected, with percentages ranging from 48 to 57 with MERCI only and 60 to 69 with MERCI in combination with adjunctive therapies. Although the proportion of favorable clinical outcomes tended to be higher and mortality rates lower with better degrees of recanalization, no significant difference was found when compared with controls from PROACT-2.97 The FDA cleared a second first-generation device for AIS, the Penumbra Clot Aspiration system, in 2008 based on the results of the Penumbra Pivotal Stroke Trial.100 This prospective multicenter single-arm study evaluated the safety and effectiveness of the penumbra system in the revascularization of large-vessel AIS patients presenting within 8 hours from symptom onset. Thrombolysis in Myocardial Infarction 2 or 3-reperfusion was achieved in 81.6% of patients without an increased risk of sICH (11.2%) when compared with historical controls, documenting both device efficacy and safety. However, despite the higher revascularization rates, only 27.7% were clinically independent at 90 days compared with 40% in the control arm of PROACT II.

Stent Retrievers

Uncertainty as to whether such recanalization could translate in better neurological outcomes in AIS led to the development of second-generation devices, the stent retrievers. The 2 main retrievable stent systems developed are the Solitaire (Medtronic) and Trevo (Stryker Neurovascular), both FDA approved in 2012. Unlike the detachable stents widely used in cardiology, the stent retrievers are characterized by being nondetachable, allowing for stent deployment within the clot for thrombus embedment and quick restoration of flow and subsequent clot removal. The safety and efficacy of this new technology was rapidly tested in several randomized trials that compared it directly to the first-generation devices.101–105 The recanalization rates in these trials ranged from 61% to 87.5% for Solitaire and 91.7% to 92% for Trevo.106 Both of these devices demonstrated high rates of good clinical outcomes as measured by the mRS at 90 days, 40% and 58% for Trevo and Solitaire, respectively.101,104 Concomitantly, several landmark endovascular trials tested first- and, to a lesser extent, second-generation devices versus medical therapy in large populations of IV tPA–eligible patients. The IMS-III trial (Interventional Management of Stroke III) enrolled 656 participants to IV tPA within 3 hour from stroke onset with or without additional EVT ≤7 hours. As CTA and newer generation devices became more readily available in stroke centers, these technologies were implemented later in the course of the study to improve patient selection and treatment. Unfortunately, premature halting of the trial occurred, and no significant difference in clinical outcomes at 90 days was found across treatment groups (38.7% for IVT only and 40.8% IVT and EVT, P=0.25). SYNTHESIS (Synthesis Expansion: A Randomized Controlled Trial on IA Versus IV Thrombolysis in Acute Ischemic Stroke) randomized 362 AIS patients within 4.5 hours from symptom onset to receive IVT or EVT, which included IA tPA, mechanical clot disruption, or retrieval or a combination of these. At 3 months, only 30.4% of patients in the EVT group versus 34.8% treated medically had little or no disability (adjusted odds ratio 0.71; P=0.16). MR-RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots using Embolectomy) randomized patients with anterior circulation LAO presenting within 8 hours from onset of symptoms to receive either EVT or IVT. Patients were also stratified based on favorable or nonpenumbral pattern. The recanalization rates were low, likely related to the use of first-generation devices, and no significant difference in functional outcomes at 90 days was appreciated, even after stratification. Although valuable preliminary data for the assessment of EVT in AIS was obtained, these trials had several limitations, including treatment delays, unstructured workflow, minimal use of stent retrievers, and lack of imaging-based selection to prove LAO, as well as to exclude patients with large areas of irreversible brain damage. As a consequence of these trials, pessimism spread in the stroke community.

Second-Generation Stent Retriever Trials

Several new trials were initiated, and the first to be completed in 2014 was MR CLEAN.107 In this study, 500 patients with documented anterior circulation LAO on CTA presenting within 6 hours from stroke onset were enrolled to receive EVT or usual care alone. Stent retrievers were used in 81.5% patients, and tPA was administered in 90.6% of patients assigned to the EVT group and control group, respectively. An absolute difference of 13.5% points (adjusted odds ratio 1.67) in the rate of mRS score 0 to 1 at 90 days in favor of intervention was found, whereas mortality and sICH rates did not significantly differ between groups. The positive results precipitated an early interim analysis of the remaining 4 EVT trials: ESCAPE,44 REVASCAT,108 EXTEND-IA trial (Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial),109 and SWIFT-PRIME,110 which were subsequently prematurely stopped because of positive outcomes. Uniquely, the ESCAPE and EXTEND-IA trials used pre-enrollment imaging to identify a favorable penumbral pattern. Although the ESCAPE investigators used multimodal CT to estimate the degree of adequate collateral circulation as a marker of salvageable penumbra, the EXTEND-IA group used CTP analyzed by the Rapid Processing of Perfusion and Diffusion software. Overall, median onset to groin puncture ranged from 200 to 260 minutes, with a successful revascularization rate of 59% to 88%. A 50% reduction in mortality was noted in the EXTEND-IA and ESCAPE trials, although this finding was not universal (Table 2). The HERMES trial (Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke), a recently published patient-level meta-analysis including 1287 individuals from the 5 EVT landmark trials, confirmed the stunning results. Disability at 90 days was significantly reduced compared with the control group (cOR 2.49, 95% confidence interval 1.76–3.53; P<0.0001). The number needed to treat to reduce disability by at least one level on mRS for each patient undergoing EVT is 2.6, one of the largest effect sizes across all disciplines in medicine. Benefit was irrespective of patients characteristics (elderly, time from onset to randomization >300 min, individuals not receiving recombinant tPA) and mortality, and sICH did not differ between groups.111 Two additional EVT trials (THERAPY [The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke] and THRACE [Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke])112,113 with promising results presented at the European Stroke Conference in 2015 remain to be published, and others (POSITIVE [Perfusion Imaging Selection of Ischemic Stroke Patients for Endovascular Therapy] and DAWN [Diffusion Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention]) are ongoing with the hope to extend the therapeutic time window ≤12 and 24 hours, respectively. On the basis of available trials data, IV tPA remains the initial treatment for AIS patients presenting within 4.5 hours from symptoms onset. If an LAO is documented by expedited imaging while the ischemic core remains small, immediate EVT should be pursued ≤6 hours from stroke onset. Overall, <10% of patients with AIS receive stroke recanalization therapies in the United States, even in communities with highly organized stroke centers.114 Some challenges to treatment include small-vessel strokes, strokes in evolution, severe strokes from large-vessel occlusion, and the so-called wake-up strokes. Patients who wake up with stroke symptoms or wake-up strokes represent an undertreated subgroup of AIS patients (≈20%) who are generally excluded for recanalization therapies because of the unknown time of symptom onset.115 A series of DEFUSE trials (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution)116,117 have explored the role of perfusion imaging in assessing reversibility of brain ischemia in patients who present at a later time window. DEFUSE-3 is currently enrolling selected AIS patients ≤16 hours from symptom onset. For those stroke patients who are unable to receive any acute IV or IA therapies, a pivotal element for their care are the so-called stroke units. These organized inpatient stroke wards are staffed by a multidisciplinary team of experts specialized in stroke care and are dedicated to care for AIS patients. Individuals who receive care in stroke units are more likely to be independent, alive, and living at home at 1 year when compared with those who are admitted to alternative forms of care while the duration of hospital stays remain unchanged.118 Although AIS therapies had lagged behind those in cardiology, AIS treatment has finally gained momentum.

New AIS Therapy Guidelines

The recent influx of randomized trials has forced a recent AHA/ASA AIS guideline update, which took place in December 2015 for IV thrombolysis and in June 2015 for EVT.21,24 The EVT AHA/ASA Guidelines recommend pursuing EVT with stent retrievers in all AIS patients who present within 6 hours from symptom onset, are ≥18 years of age, have minimal or no disability at baseline (prestroke mRS score 0–1), have a National Institute of Health Stroke Scale score and ASPECTS ≥6 on arrival, and a documented LVO on admission angiogram (Class I). The guidelines highlight the need for expedited treatment to ensure EVT benefit but recommend against either withholding IV tPA while EVT is being considered or prolonged observation of potential EVT candidates after IV tPA infusion to assess for clinical improvement. As with IV tPA, the EVT guideline is likely to become more inclusive with time, in particular with the advancement of perfusion imaging and devices. The main recommendations for EVT in AIS are summarized in Table 4.

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Table 4.

Summary of the Principal AHA/ASA Guideline Recommendations for Endovascular Therapy in Acute Ischemic Stroke

Organizing and Implementing Systems of Care

The recently proven efficacy of IA therapy with stent retrievers and other devices is the most important advance for AIS treatment in 20 years. To best deliver IA therapy to as many AIS patients as possible will require careful planning, and the best approach will vary among cities, regions, and states depending on many factors. For the foreseeable future, the availability of IA device therapy will remain restricted to larger tertiary medical centers because the number of interventionalists capable of performing the procedure is limited, the establishment of an endovascular treatment center requires resources that many smaller hospitals will not have available, and as with many other procedures, there seems to be a relationship between successful performance and case volume.119 Regional AIS care delivery paradigms will need to be established based on available resources, including the number of endovascular centers, the number and distribution of primary stroke care centers where the initial evaluation and treatment of AIS patients with IV tPA can be done, and the local emergency medical transport system. A key question is what should be the preferred destination for AIS patients with an LAO appropriate for IA device therapy when both primary stroke centers and tertiary centers can both be reached relatively quickly.120 In such a setting, it would be useful for ambulance crew to assess the severity of the AIS and the LAO likelihood by using currently available stroke rating scales and if it is determined that the stroke is likely caused by LAO to proceed directly to the endovascular center.121 The ambulance crew can be aided by developing technologies, such as telemedicine, that would allow them to interact with a physician remotely who can see the patient with them and help to determine stroke severity by guiding them through an examination such as the National Institute of Health stroke scale.122 Another developing technology is mobile stroke units that contain a CT scan and sophisticated personnel who interact with a hospital base station.123 Currently, head CT scans can be performed and IV tPA can be started quickly in such units. It is unlikely that they will be widely available. A balance must be considered between choosing to route the patient to a primary stroke center and starting therapy with IV tPA with an inherent delay in reaching an endovascular center for patients with LAO versus bypassing the primary stroke center and proceeding directly to the endovascular center.124 Factors that will need to be considered by the EMS system beyond distance and transport time include the rapidity of clinical and imaging evaluation at the primary stroke center, the door-to-needle time, and the door in door out time. If these time metrics are excessive, then routing patients with suspected LAO to an endovascular center and not to a closer primary stroke center may be the appropriate course of action. The development of regional AIS care plans will need to be done individually in different locales, but the basic concept will be to get the patients to the most appropriate treatment center as quickly as possible based on the likelihood of LAO and the other factors that will influence routing decisions.

For centers performing IA device therapy, it be incumbent on them to try to emulate the work flow paradigms as performed in the clinical trials so that appropriate AIS patients are treated as quickly as possible.25 The best approach to imaging remains to be established but should at least include a head CT scan, CTA, and in some centers CTP.125 A large ischemic core can be identified by the CT ASPECTS score, excluding patients with scores of ≤5 as was done in the clinical trials or a large ischemic core volume on CTP. Important time metrics that endovascular treatment centers should monitor will include time from emergency department arrival to imaging, time from imaging to start of the endovascular procedure, and time to reperfusion. The trials with the best outcome results also performed the best regarding these treatment metrics. Clinical centers will not replicate the trial results if they do not include patients similar to those in the trials and fail to establish reperfusion in a timely manner.

In other situations, the distance to an endovascular center is much greater, and all AIS patients will initially have to be taken to a primary stroke center or smaller hospital for initial assessment and treatment. Again the use of telemedicine technology will be useful because stroke expertise at a large center can be used to help evaluate the patient and make treatment decisions at the outlying medical center. Currently, most smaller hospitals do not routinely perform CT angiography, but now that EVT is of proven value for proximal vessel occlusions, the availability of CTA will need to increase because a vessel occlusion potentially amenable to endovascular treatment should initiate the rapid transfer of such patients to a center capable of performing the procedure. The telemedicine consultant can help to evaluate the CTA and the head CT scan performed at the outlying hospital to help local personnel decide if there is a proximal vessel occlusion amenable to IA therapy if the ASPECTS score on the head CT scan is compatible with a small to moderate ischemic core, supporting the suitability of the patient for IA therapy. For patients who are not candidates for IA therapy, transfer to a tertiary medical center may not be necessary in many cases, and the patient can then be managed locally with IV tPA in some cases. A transfer if deemed to be appropriate can be done either by helicopter or ambulance, but a major concern is that if the transfer will take several hours and that by the time the patient arrives at the endovascular center, the ischemic core will have enlarged to such an extent that the patient will no longer benefit from IA therapy. From a system-of-care perspective, patients who may be appropriate for IA therapy will need to be rapidly identified and transport times minimized as much as possible so that as many patients as possible will remain candidates for IA therapy. As will be discussed, the development of therapies to impede ischemic core growth that could be used during transfer is an exciting possibility that may substantially increase the percentage of AIS patients subject to long transfer times who might still benefit from IA therapy.

Future Directions

The positive endovascular trials raise many questions regarding the next steps to be taken for expanding the indications of IA therapy and for the development of adjunctive therapies that may be useful with device-induced reperfusion. The 5 positive IA device trials necessarily focused on specific patient populations that were selected based on prior studies that included patients most likely to respond to treatment. The results of the trials leave unanswered whether device IA therapy will be beneficial in other patients who were not studied or who were ineligible for the trials.126 Table 5 provides an overview of the types of patients who were either not included in the trials or included with insufficient numbers to provide definitive information about treatment efficacy. Trials are either under way or planned to determine if treatment efficacy can be established in these patient groups. One important concept that needs further trial exploration is how late after stroke onset will IA device therapy still be beneficial in AIS patients who still have evidence of a small to moderately sized ischemic core identified by the ASPECTS score, CTP, or DWI. A large National Institute of Health–funded trial is exploring this question. Other trials are being done in wakeup stroke patients in whom the last time they were known to be well was when they went to sleep.127 In these trials, imaging selection is also a key component. Another unresolved question irrespective of time from onset to treatment is how large can the core be before IA treatment is ineffective. For the ASPECTS score on a head CT, what is the lowest score pretreatment that will identify AIS patients who no longer derives benefit from IA device treatment? The recent meta-analysis of the IA device trials did confirm that a baseline ASPECTS score of 6 to 7 was associated with treatment benefit, but few patients with scores of ≤5 were treated, so it is uncertain if scores in this range absolutely predict a lack of treatment response. Similarly, for the ischemic core volume determined by CTP, the upper threshold for lesion volume that predicts a lack of treatment response remains to be established. Future trials exploring these imaging predictors of treatment response need to be performed.

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Table 5.

Types of Stroke Patients Not Studied or Inadequately Studied in the Prior IA Trials

The IA device trials suggest that device therapy can be combined with neuroprotective interventions to potentially maximize benefit. A major problem for IA device therapy in many locations is the long transport time required to reach a tertiary center capable of performing this treatment. A well-known maxim is time is brain, and it was estimated that in a proximal brain vessel occlusion, ≈2 million neurons die per minute.66 During long transport times, many AIS patients will likely have their ischemic core expand to the extent that they will no longer be eligible for IA device treatment based on the currently available data. An exciting possibility to explore is could neuroprotection initiated in the ambulance during transport or at the initial primary stroke center of smaller outlying hospital slow the evolution of the ischemic core and allow more patients to remain candidates for IA device therapy.128 Animal stroke modeling studies suggest that this may be possible and has been shown that the treatment window for IV tPA in a rat embolic model could be extended with high flow oxygen.129 Two potential types of clinical trials can be envisioned to explore this treatment strategy. The first would be to randomize AIS patients with moderate or severe strokes to a neuroprotective drug or gas in the ambulance with guidance by a stroke physician from the tertiary center, as was done in the FAST-MAG trial (Field Administration of Stroke Therapy–Magnesium) of IV magnesium.130 On arrival at the tertiary center, the extent of the ischemic core in the prespecified target population of AIS patients can be assessed by CTP or DWI to determine if it is significantly smaller than in the control group and also if treatment increases the percentage of patients who remain eligible for IA device treatment, despite transport times of up to several hours. Another type of trial would randomize patients at primary stroke centers or smaller hospitals again with the help of stroke physicians at the tertiary center via telemedicine. Such a trial could be more focused because if CTA is required at the time of initial evaluation, for inclusion, the number of excluded patients would be dramatically smaller. When patients arrive at the tertiary center, the extent of the ischemic core could be compared between the active treatment and control groups, as well as the percentage of patients who remain candidates for IA device therapy. Potential therapeutic candidates to use in such trials remain to be determined, but based on animal modeling, a PSD-95 inhibitor and high-flow normobaric oxygen should be considered.131 Another potentially interesting approach would be to perform paraconditioning in the ambulance with intermittent inflation of blood pressure cuffs on both arms as was done in a Danish trial.132 This trial did show effects on the ischemic lesion severity on DWI performed on hospital arrival, and a larger follow-up study is being initiated.

The high rate of substantial reperfusion observed in the recent IA device trials that used a stent retriever raises the possibility that reperfusion injury could affect patient outcomes. Reperfusion injury has been observed in animal stroke models, as well as with reperfusion in animals of other organs.133 Many potential mechanisms could contribute to reperfusion injury, including, free radical generation, inflammation related to white blood cell recruitment, cell–matrix deterioration, and microvascular occlusion/edema.134,135 It remains uncertain to what extent secondary brain injury after reperfusion contributes to clinically evaluated patient outcomes at 90 days and beyond. Additionally, it will be difficult to detect the benefits of a treatment targeting reperfusion injury because of the substantial rate of good to excellent outcomes observed in the recent IA device trials. A trial targeting reperfusion injury can be envisioned for an anti-inflammatory drug or free radical scavenger in AIS patients who are documented to have reperfusion at the end of the IA device procedure. They would then be randomized active treatment or placebo with delivery of the study agent locally via the catheter used for IA treatment or systemically via an IV infusion. Such a trial will likely have to include a large number of patients to detect an ≈10% greater rate of favorable 90-day outcome than the placebo group because the control group will by definition have undergone successful reperfusion, a treatment documented to have a high rate of good-to-excellent clinical outcomes.

Another adjunctive therapeutic target to consider with IA device therapy is enhancement of collateral blood flow. It is well documented that AIS patients with a favorable collateral status have better outcomes with IA device therapy because good collaterals are associated with initially smaller ischemic cores and slower evolution of the ischemic penumbra into the ischemic core.136 These observations imply that if collateral flow could be enhanced acutely, more ischemic tissue could be salvaged in more patients by IA device therapy. Possible approaches to enhancing collateral flow include induced hypertension, volume expansion, external counterpulsation, temporary partial aortic obstruction, and stimulation of the sphenopalatine ganglion.137 All of these approaches entail potential side effects that may adversely affect outcome, and some have inherent time delays. They could be considered for patients who will have long time delays before reaching the tertiary center for IA device therapy as was discussed for neuroprotective strategies to delay ischemic core expansion. Pharmacological approaches could also be considered such as with glyceryl trinitrate, a prodrug of nitric oxide used to treat angina pectoris by vasodilitation that demonstrated apparent benefit in AIS patients treated within 6 hours of stroke onset in the ENOS trial (Efficacy of Nitric Oxide in Stroke) when given transdermally.138 Glyceryl trinitrate did lower blood pressure, so this effect may be concerning, but blood pressure and collateral blood flow effects could be titrated. This is an exciting time for treating AIS patients with IV tPA or IA device therapy. Many potential therapies can be envisioned that can be developed in conjunction with these proven therapies.

Disclosures

None.

Footnotes

  • Circulation Research Compendium on Stroke

  • Introduction to the Stroke Compendium

  • Global Burden of Stroke

  • Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

  • Stroke Risk Factors, Genetics, and Prevention

  • Stroke Caused by Extracranial Disease

  • Stroke Caused by Atherosclerosis of the Major Intracranial Arteries

  • Cardioembolic Stroke

  • Cryptogenic Stroke: Research and Practice

  • Acute Ischemic Stroke Therapy Overview

  • Heart–Brain Axis: Effects of Neurologic Injury on Cardiovascular Function

  • Vascular Cognitive Impairment

  • Marc Fisher, Costantino Iadecola, and Ralph Sacco, Editors

  • Nonstandard Abbreviations and Acronyms
    AIS
    acute ischemic stroke
    ASPECTS
    Alberta Stroke Program Early Computed Tomography Score#8232;
    ASSENT
    Anglo-Scandinavian Study of Early Thrombolysis
    ATLANTIS
    Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke
    CBF
    cerebral blood flow
    CT
    computed tomography
    CTA
    computed tomographic angiography
    CTP
    computed tomography perfusion
    DAWN
    Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention
    DEDAS
    Dose Escalation of Desmoteplase for Acute Ischemic Stroke
    DIAS
    Desmoteplase in Acute Ischemic Stroke
    DWI
    diffusion-weighted imaging
    ECASS
    European Cooperative Acute Stroke Studies
    EICs
    early ischemic changes
    EPHITET
    Echoplanar Imaging Thrombolysis Evaluation Trial
    ESCAPE
    Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke
    EVT
    endovascular therapy
    FAST-MAG
    Field Administration of Stroke Therapy–Magnesium
    FDA
    Food and Drug Administration
    IA
    intra-arterial
    ICA
    internal carotid artery
    ICH
    intracranial hemorrhage
    IMS
    Interventional Management of Stroke
    IST
    International Stroke Trial
    IV
    intravenous
    IVT
    intravenous thrombolysis
    LAO
    large artery occlusion
    M1
    middle cerebral artery–first segment
    MCA
    middle cerebral artery
    MI
    myocardial infarction
    MIPs
    maximal intensity projections
    MR-CLEAN
    Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands
    mRS
    modified Rankin Scale
    NCCT
    noncontrast computed tomography
    NOR-TEST
    The Norwegian Tenecteplase Stroke Trial
    pc-ASPECTS
    Posterior Circulation Alberta Stroke Program Early Computed Tomography Score
    POSITIVE
    Perfusion Imaging Selection of Ischemic Stroke Patients for Endovascular Therapy
    PROACT
    Prolyse in Acute Cerebral Thromboembolism
    REVASCAT
    Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large-Vessel Occlusion Presenting Within 8 Hours of Symptom Onset
    sICH
    symptomatic intracerebral hemorrhage
    SWIFT PRIME
    Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke
    TASTE
    Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial
    THERAPY
    The Randomized, Concurrent Controlled Trial to Assess the Penumbra System’s Safety and Effectiveness in the Treatment of Acute Stroke
    THRACE
    Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke
    tPA
    tissue-type plasminogen activator

  • Received June 10, 2016.
  • Revision received July 30, 2016.
  • Accepted August 14, 2016.
  • © 2017 American Heart Association, Inc.

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Circulation Research
February 3, 2017, Volume 120, Issue 3
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    Acute Ischemic Stroke Therapy Overview
    Luciana Catanese, Joseph Tarsia and Marc Fisher
    Circulation Research. 2017;120:541-558, originally published February 2, 2017
    https://doi.org/10.1161/CIRCRESAHA.116.309278

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    Acute Ischemic Stroke Therapy Overview
    Luciana Catanese, Joseph Tarsia and Marc Fisher
    Circulation Research. 2017;120:541-558, originally published February 2, 2017
    https://doi.org/10.1161/CIRCRESAHA.116.309278
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