Reperfusion Therapies in Acute Ischemic Stroke

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Reperfusion Therapies in Acute Ischemic Stroke Leonard L.L. Yeo1, Benjamin Y.Q. Tan1, Wan Yee1, Amit Kulkarni1 and Vijay K. Sharma*1,2 1

Division of Neurology, National University Health System, Singapore; 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore Received: April 27, 2015; Revised: June 29, 2015; Accepted: June 30, 2015

Abstract: Acute Ischemic stroke (IS) remains a leading cause of mortality and long-term disability. Owing to the time-constraints, only a fraction of acute IS patients receive the established and approved thrombolytic therapy and a sizeable proportion of acute IS stroke survivors remain permanently disabled. Rapid advances in various recanalization strategies have aimed at improving functional outVijay K. Sharma come and reducing mortality. Existing literature on various treatment approaches, including the evolution of various thrombolytic agents and interventional devices is presented in this review. In addition to describing intravenous drug trials, continual developments in the field of trials for interventional devices have been described. Additionally, some of the important recent patents filed for various experimental approaches are presented. We strongly believe that the recent therapeutic approaches, including endovascular interventional strategies, based on advanced neuroimaging evaluations appear to have a promising future for acute IS patients.

Keywords: Acute ischemic stroke, interventional therapies, mechanical clot retrievers, thrombolysis, thrombolytics. INTRODUCTION Ischemic stroke (IS) is an important contributor of long term and permanent disability [1]. Nearly half of the stroke survivors suffer from permanently disabilities. Limited therapeutic options were available for acute IS in past and attempts have been made towards developing better therapeutic strategies during past 2 decades. A meta-analysis in 2007 showed that restoration of intracerebral blood flow is the most important determinant of functional outcome and mortality in acute IS [2]. Therefore, the bulk of research in acute IS therapy has aimed at reperfusing the ischemic area through various thrombolytic agents, devices and other innovative methods. In this review we have summarized important failed therapies, currently available strategies as well as future therapies and new technologies. We conducted a comprehensive literature search through the Pubmed, Google Scholar and Scopus to identify all relevant clinical studies that assessed different reperfusion therapies in acute IS. We searched the combination of terms: “ischemic stroke”, “cerebral ischemia”, “thrombolysis”, “thrombectomy”, “sonolysis”, “cerebral reperfusion” and “sonothrombolysis”. Last literature search was conducted on April 10, 2015. DRUG THERAPIES The commonest therapeutic approach for restoring cerebral perfusion in acute IS has been the use of various thrombolytic agent. These agents act through the proteolytic *Address correspondence to this author at the Division of Neurology, Department of Medicine, 5 Lower Kent Ridge Road, National University Hospital, Singapore 119074; Fax: +65 69723566; E-mail- [email protected] 2212-3954/15 $100.00+.00

enzyme plasmin and thrombolysis is achieved by conversion of plasminogen to plasmin that leads to fibrin degradation. The agents have included non-proteolytic (Urokinase and Streptokinase) or proteolytic tissue plasminogen activators (Alteplase, Reteplase and Tenecteplase). Efforts have aimed to increase fibrin specificity and reduce the inhibition by plasminogen activator inhibitor type 1. STREPTOKINASE AND UROKINASE Streptokinase and urokinase were the first thrombolytic agents tested in acute IS. Tillett and Garner (1933) reported the clot dissolving properties of certain strains of hemolytic bacteria. Later, purified streptokinase for intravenous use was obtained by Tillett [3]. Streptokinase is an antigen derived from streptococci bacteria. Urokinase is produced by kidney. The fibrinolytic potential of human urine was described in 1947 by Macfarlane and Pilling. The active component, urokinase (UK) was later isolated by Sobel et al. [4]. UK is a direct activator of plasminogen, without any antigenic activity. The main limitation with these kinases is their poor fibrin specificity. Hence, they produce fibrinogen degradation products from the target thrombus. High saturation of these fibrin degradation products in the blood stream can result in thrombosis, bleeding and tissue swelling. These adverse effect led to cessation of clinical trials with streptokinase [5]. Although, UK is relatively cheaper and still used by some centers, its availability has remained erratic. TISSUE PLASE)

PLASMINOGEN

ACTIVATOR

(ALTE-

Potentially fatal adverse effects of streptokinase and UK led to the development of agents with better thrombus speci© 2015 Bentham Science Publishers

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ficity like the tissue plasminogen activator (tPA). Fibrin specificity of tPA is closely related to its affinity to lysine side chain of the thrombus. With the advent of recombinant engineering, tPA was created from human melanoma cells. Owing to its short half life (5 minutes), tPA requires a continuous infusion for one-hour. The landmark trial initiated by National Institute of Neurological Disorders and Stroke (NINDS) established the place of intravenous (IV) tPA for the treatment of acute IS [6]. The pooled analysis of initial six clinical trials with IV-tPA revealed the benefits in acute IS patients, if treatment was initiated within 180 minutes. This analysis predicted that IV-tPA may provide benefit even beyond 3 hours [7-11]. This prediction was later tested in the 3-4.5 hours therapeutic window in the European Cooperative Acute Stroke Study (ECASS III) trial that recruited 821 acute IS from 19 countries. Patients treated with IV-tPA in the extended therapeutic achieved better outcome (52.4%) compared to placebo (45.2%; p=0.04) [12]. Although, IVtPA treated patients developed significantly higher symptomatic intracranial hemorrhage (SICH) as compared to placebo (2.4% versus 0.2%; p=0.008), mortality rates were comparable between the treatment (7.7%) and placebo arm (8.4%; p=0.68). Despite being the standard of care in acute IS treatment, IV-tPA is not effective in all patients. Mokin et al. reported that IV-tPA led to recanalization of only 10-15% of major artery occlusions and 20-40% success rate in general [13]. Another known problem with IV-tPA is the activation of extracellular matrix metalloproteinases and N-methyl-Daspartate (NMDA) receptors. These mechanisms may lead to the disruption in blood brain barrier, SICH and increased cerebral oedema [14]. DESMOTEPLASE Plasminogen activator alpha 1 from the saliva of vampire bat Desmodus rotundas shows considerable similarity to human tPA and has been genetically engineered to Desmoteplase [15]. Compared to tPA, Desmoteplase has a high fibrin specificity. It has low incidence of neurotoxicity and plasmin-dependant disruption of blood brain barrier. The longer half-life of desmoteplase (4 hours) permits its administration as a single IV bolus injection. The ‘Desmoteplase in acute IS (DIAS)’ trial was a dose finding trial that used perfusion-diffusion mismatch on magnetic resonance imaging (MRI) to select patients eligible for treatment [16]. Patients were treated within 3 to 9 hours of symptom-onset. Initially patients were randomized to IV desmoteplase in variable doses (25mg, 37.5mg or 50mg) or placebo. Since the incidence of SICH was high in the desmoteplase arm, the trial reduced the doses according to body-weight (62.5µg/kg, 90µg/kg, and 125µg/kg). Overall 54.3% patients treated in 3-6 hours and 40% in 6-9 hour time window showed reperfusion, that was significantly correlated with favorable clinical outcome (p=0.0028). The ‘Dose escalation of desmoteplase in acute stroke (DEDAS)’ trial treated IS patients within 3 to 9 hours of symptom-onset. Eligible patients were selected with MRI perfusion-diffusion mismatch [17]. DEDAS trial results were

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similar to DIAS. Desmoteplase in a dose of 125µg/kg appeared to improve clinical outcome. Subsequently, a phase III study (DIAS-2) was conducted to confirm the results of the DIAS and DEDAS trials [18]. DIAS-2 trial included 186 patients (randomized into a placebo or 2 doses of desmoteplase- 90µg/kg or 125 µg/kg). There was no significant difference in the outcome among the 3 groups. Various explanations were presented for the failure that included lower National Institute of Health Stroke Scale (NIHSS) score of 9 points, presence of arterial occlusion in only 30% of the recruited patients and small core lesions and the mismatch volumes. Owing to the longer half-life and high fibrin specificity, desmoteplase still holds a theoretical potential in a cohort of carefully selected acute IS patients, especially in an extended therapeutic window. ANCROD Ancrod (viprinex) is obtained the venom of pit viper that demonstrates defibrinating properties. The ‘Stroke Treatment with Ancrod Trial (STAT)’ evaluated 500 acute IS patients, treated within 3-hours of stroke-onset [19]. Study participants were randomized to Ancrod (n=248) or placebo (n=252). More patients treated with Ancrod achieved favorable outcome as compared to the placebo group (42.2% versus 34.4%). However, further trials with Ancrod (ASP I and II) resulted in increased incidence of SICH that led to premature termination of these phase-3 trials [20]. TENECTEPLASE Tenecteplase (TNK) is an improved tPA molecule. Although it has the same amino acid length, it has been modified at theorine-103 to asparagine, asparagines-117 to glutamine, and the amino acids 296-299 to tetra-alanine. These modifications increase its half-life, improve fibrin selectivity and make it resistant to inactivation by endogenous inhibitors. Compared to tPA, TNK has superior therapeutic efficacy in myocardial infarction [21, 22]. The risk benefit profile of TNK is dose dependant [23]. Recently, Parsons et al. conducted a randomized clinical trial of TNK and tPA and showed that both low (0.1mg/kg) and moderate-dose (0.25mg/kg) of TNK were associated with better early as well as delayed outcome, without increasing the incidence of SICH [24, 25]. Comparative properties of streptokinase, urokinase, reteplase and desmoteplase are summarized in Table 1. OTHER AGENTS Argatroban is a direct thrombin inhibitor. It is used as an adjunctive treatment with tPA to enhance recanalization. It’s role and effectiveness in reperfusion is still being studied in an ongoing phase IIb clinical trial [26, 27]. Plasmin is known to be effective in peripheral artery or graft occlusion. It has low risk of bleeding due to rapid neutralization by alpha2-antiplasmin [28, 29]. Marder et al. showed improved recanalization in rabbit models with thrombin induced middle cerebral artery (MCA) stroke [29].

Reperfusion Therapies in Acute Ischemic Stroke

Table 1.

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Properties of streptokinase, alteplase, reteplase and desmoteplase. Streptokinase

Alteplase

Reteplase

Desmoteplase

Half-life

23 mins

Less than 5 mins

13-15 mins

4 hours

Plasminogen activation

Indirect binding

Direct binding

Direct binding

Direct binding

Fibrin selectivity

No

Yes

Yes

Fibrin specific

Development of Allergy

Yes

No

No

Yes

Intravenous Administration

Infusion

Infusion

Bolus

Bolus

Finally, new clot formation in the acute phase of IS can be prevented by antiplatelet therapy [30]. Endogenous thrombolysis can induce platelet activation via adenosine diphosphate (ADP), which leads to conformational change to glycoprotein IIb/IIIa receptors and then binds with fibrinogen. Hence, glycoprotein IIb-IIIa receptor inhibitors can effectively prevent this process. These agents have been used in acute myocardial infarction and IS. Unlike in the myocardial infarction studies [31], few small case series for acute IS showed low incidence of SICH with the concurrent use of alteplase and glycoprotein IIb-IIIa inhibitors [32, 33]. Abciximab and Tirofiban have been tried in acute IS. Abciximab is a chimeric mouse/human antibody with high affinity for GPIIb-IIIa receptors. An injection blocks about 80% of the receptors and platelet aggregation. They are mostly used as an adjunct to endovascular treatment. Abciximab, administered within 6 hours of stroke-onset (AbESTT), demonstrated a positive profile [34]. However, the ‘Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II)’ of 439 patients (221 randomized to abciximab; 218 placebo), failed to show any benefit in functional outcome. Moreover, Abciximab-treated patients developed more SICH, leading to premature termination of the trial [35]. The ‘Reopro Retevase Reperfusion of Stroke Safety Study (ROSIE)’ study looked into the use of Abciximab (ReoPro) and Reteplase (Retevase) in acute IS within 24 hours of onset [36]. The trial required a severe acute IS (NIHSS score more than 16-points) with perfusion mismatch. Although, Abciximab alone was not effective in reperfusion, it showed acceptable safety and efficacy with reteplase. Due to low affinity for receptors, Tirofiban dissociates faster. Therefore, it requires higher and sustained plasma levels. The ‘Safety of Tirofiban in Acute IS (Sa-TIS)’ trial randomized patients to Tirofiban (n=127) or placebo (n=123) [37]. Non-significantly higher SICH was observed in the Tirofiban treated group. Interestingly, significant lower mortality was noted in the Tirofiban group, at 5 months’ follow-up. INTRA-ARTERIAL THERAPEUTIC APPROACH The initial attempts for enhancing clot recanalization involved the use of a microcatheter and local injection of a thrombolytic agent. This approach was first evaluated in the ‘Prolyse in Acute Cerebral Thromboembolism (PROACT)’ trial [38]. The study included 46 patients with proximal MCA occlusions, who received intraarterial prourokinase or placebo. Patients treated with intraarterial prourokinase

showed better recanalization rates but also developed higher percentage of hemorrhage. Subsequently, the second trial (PROACT-II) randomized 180 patients (within 6-hours of stroke-onset) to intraarterial prourokinase and heparin (n=121) or only IV heparin (n=59) [39]. No mechanical manipulation of the thrombus was allowed. Intraarterial thrombolysis demonstrated better outcome; 40% patients achieved modified Rankin score (mRS) of 2 or less as compared to only 25% in the comparative arm. Although, mortality rates were similar, SICH occurred in more patients treated with intraarterial thrombolysis (10.9% compared to only 2% with placebo). The second randomized trial with intra-arterial thrombolysis was conducted in Japan. The ‘MCA embolism local fibrinolytic intervention trial (MELT)’ utilized intraarterial urokinase [40]. Patients presenting within 6-hours of strokeonset with MCA occlusions were included. Unfortunately, it had to be terminated early with only 114 patients recruited (57 each in intraarterial urokinase and placebo arms) due to approval of IV-tPA by Japanese regulatory authorities. Analyses of the data from recruited cases did not show any statistically significant differences in the functional outcome or SICH between the two treatment arms. However, secondary analysis showed that excellent recovery (mRS ≤1) was commonly seen in the treatment group compared to placebo (42.1 versus 22.8%, p=0.045). Despite these promising preliminary results, delays in the initiation of intra-arterial thrombolysis with resultant loss in efficacy and higher SICH rates proved hurdles for further development and approval of this therapeutic modality. DEVICES FOR RECANALIZATION ISCHEMIC STROKE

IN

ACUTE

IV-tPA induced recanalization in a small proportion of acute IS patients with large-vessel occlusion. While only about 33% MCA occlusions recanalize with IV-tPA, the rate of recanalization of ICA is even more dismal at 811% [41]. Furthermore, patients with thrombi larger than 8 mm rarely achieve recanalization with IV-tPA. Therefore, better therapeutic modalities were being sought. Various device designs have included corkscrews, stents, brushes, baskets, or strand-like filaments with variable sites of deployment. Accordingly, some devices are deployed proximal to the occlusion, some are deployed distal to the thrombus using a microcatheter and others are deployed over the thrombus.

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To supplement intra-arterial thrombolytic infusions, clot disruption has been tried. This method involved shaping the microwire into a curved “J” shape and repeatedly pushing it through the occluding thrombus. In more difficult cases, another more forceful method has been used that involved repeated ‘plowing’ of the microcatheter through the thrombus [42]. Early attempts with manipulation of guidewires or local instillation of tPA by microcatheter were met with limited success in achieving arterial recanalization. This led to the designing of devices that could extract the offending clot from intracranial blood vessels. Such devices included the ‘Alligator™ Retrieval Device’ that clamps proximal end of the thrombus to pull it out and the ‘Gooseneck Microsnare Device’, which loops over the thrombus to ensnare and extract it. In 2005, flexible intracranial balloon catheters were introduced for angioplasty and mechanical clot disruption [42]. Interestingly, these early surrogate devices could achieve recanalization rate of up to 80% [43-46]. The ‘Phenox Clot Retriever’ is made up of flexible nitinol-platinum. The polyamide microfilaments are perpendicularly oriented, giving it the look of a brush projecting outwards. Its self-expanding basket-like cage reduces thrombus compression and results in considerably higher rates of recanalization. Another device called “Neuronet” is a wire with a flexible retrieval basket, which was first used for vertebrabasilar occlusions. The self-expanding basket was pushed through a standard microcatheter to extract the offending thrombus [47]. Encouraging recanalization rates achieved by the primitive devices led to the development of a series of devices, aimed at improving the recanalization rates without compromising the safety parameters. ‘Merci Retriever’ was the first device approved by the FDA for clot retrieval in acute IS. It used a balloon guide catheter to temporarily occlude the artery, typically at the carotid bifurcation. This caused flow reversal and delivery of the Merci device to the clot, whereupon the operator would transfix the thrombus with a ‘corkscrew’ wire. The device was then withdrawn into the balloon catheter and allowed extraction of the thrombus in its entirety. Subsequent deflation of the balloon resulted in restoration of perfusion. First MERCI trial included 141 patients, treated within 8-hours of stroke-onset. Arterial recanalization was noted in 48% patients [48]. Peri-procedural complications were noted in 7.1% subjects. Good functional outcome (mRS 0-2) was observed in only 36% patients. The Merci device faced some technical challenges. First, distal MCA occlusion required a long distance to be traveled and the device often lost its grip on the thrombus. Second, the vector force applied on the thrombus was along the axis of the carotid artery rather than horizontally along the MCA vector, which caused considerable torqueing of the parent vessel. Interestingly, Merci Retriever was approved by the FDA despite these shortcomings and led to a lot of debate among the stroke community. Subsequently, the Outreach Distal Access Catheter (DAC; Concentric Medical) was designed to overcome the issues faced by the Merci device and approved for use in 2010. The DAC improved access for the Merci thrombectomy device and optimize the forces involved in retracting the clot back into the DAC. The development of large diameter flexible catheters that could reach into the intracranial

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circulation proved to be a big technological leap [49, 50]. DAC increased the proximal strength and axial load-bearing characteristics with a more flexible distal end. It allowed the catheter to overcome ophthalmic curve and could also be used as an aspiration device to reduce distal emboli during clot retrieval [51]. The ‘Multi-MERCI’ trial used an improved version (with microfilaments) of the ‘Merci’ device. This trial recruited 164 subjects treated within 8-hours of stroke-onset [52]. The study enrolled patients in whom IVtPA treatment could not recanalize the offending intracranial artery and required salvage treatment or patients with largevessel occlusion ineligible for IV-tPA treatment. While the Merci Retriever alone achieved 57.3% recanalization rates, better results (recanalization rate of 69.5%) were observed if it was used in conjunction with tPA. Importantly, complications rates with the new Merci device were lower than the original MERCI trial (5.5%) [48, 52-54]. The Original Penumbra aspiration system (Penumbra, Oakland, California, USA) was first used in 2008. This initial version used a relatively large-bore catheter (up to 5F) which was placed at proximal end of the blood clot and a separator fragmented the occluding thrombus, which was always under direct aspiration to prevent embolization of fragments [55]. The company produced several catheters with varying internal diameters from 0.026 inches to 0.041 inches and the corresponding separators to fit various vessels of the brain and optimize the aspiration forces. The separator design was supposed to engage at the center of the vessel lumen rather than in an actual stent. One of the major advantages of the Penumbra aspiration system was that no additional passes were required once the catheter system was delivered to the occlusion [56]. The first trial using the device, Penumbra Pivotal Stroke Trial, included 125 patients with moderately severe acute IS (mean NIHSS 17.6 points) [57]. Most of the patients were pre-treated by IV- thrombolysis. Although, arterial recanalization was achieved in 81.6% patients, clinical outcomes did not show a commensurate improvement (mortality 32.8%, good outcome 25% and SICH 11.2%). Overall, the technological achievements of the Penumbra system were not effective. This was because the largest device at that time only had a lumen diameter of 0.041 inches preventing it from generating enough aspiration force to suck the thrombus. Moreover it could not reach distal occlusions and required an unacceptable median of 45 minutes to achieve recanalization. Nonetheless, the introduction of these very flexible catheters coated with lubricious polymers was considerably easier while maintaining good hoop strength to prevent collapse under suction. It eventually paved the way for further technological advancements and placement of larger catheters directly into the distal cerebral vasculature. The aspiration force is proportional to the square of the diameter of the catheter, which can happen only when the largest size aspiration catheter is used. In 2009, the 054 Reperfusion Catheter became available that could provide 4 times greater suction as compared to the 041catheter [58]. However, the 054 catheter needed more difficult navigation. A coaxial catheter was still mandatory for delivery to the distal MCA. Another technical issue with the penumbra catheter was a significant ledge when used with the guidewire, which could get stuck at the origin of ophthalmic

Reperfusion Therapies in Acute Ischemic Stroke

artery. This was overcome with a coaxial technique using smaller 032 or 026 reperfusion catheters over the guidewire followed by delivery of the larger 054 catheter. Another approach used the Merci retriever system to improve the trackability of larger penumbra catheter by gently altering the angle of the vessel and engaging the ophthalmic artery origin using a ‘grappling hook’ technique [59]. Direct aspiration and removing the clot in its entirety became possible due to further improvements in catheter technology that allowed large-caliber aspiration catheters to be advanced faster [58]. In 2012, the next iteration of the Penumbra catheter were introduced (named 5Max, 4Max and 3Max). They were unique for larger inner diameters (to reduce the resistance) and ramp up the aspiration power. An increased number of transition zones in the catheter allowed these catheters to be delivered over either a 0.014 or 0.016 inch microwire past the ophthalmic artery origin. Finally, it was made of polymers, which rendered it more lubricious, more flexibile and with extra braid/ring reinforcement. The latest version, 5Max ACE, was introduced in June 2013 with 12 transition zones and an inner diameter of 0.060 with 0.068 proximal end for larger aspiration force. The penumbra Max series of catheters were advanced to the occlusion over guidewire and a microcatheter. Aspiration force was applied on the thrombus by either a 60 mL syringe or the accompanying Penumbra aspiration pump. Lack of blood on aspiration confirmed the presence of thrombus in the device opening. The penumbra catheter was then withdrawn while maintaining aspiration in the penumbra and the side port of the guide catheter to prevent dislodging the thrombus, as it was withdrawn into the sheath. When successful, this technique did not require a stent retriever or Penumbra separator devices, therefore reducing the overall procedure/ device cost [60]. If unsuccessful, the large-bore penumbra catheters could still function as a direct distal conduit for other devices such as stent retrievers and reduced the procedure time. The initial experience with 10 patients was very promising and showed 100% recanalization rate. Although good recovery was noted by day 30, 2 patients suffered from SICH [61]. The introduction of intracranial stents presented another modality for thrombectomy [62]. In the early phase, these devices were used in acute IS in an ‘off-label’ fashion. The ‘Stent Assisted Recanalization in acute Ischemic Stroke (SARIS)’ trial used such stents in occluded intracranial arteries and showed high recanalization rates with improved functional outcome [63]. However, leaving the stent in-situ required the use of long-term combination anti-platelet therapy, thus increasing the risk of SICH. Initial promising results set the stage for developing dedicated cerebrovascular stent devices that were designed to be removed after entangling the clot. The stent-retrievers were made of nitinol. Being a self-expanding material, nitinol exerted a low radial force on the arterial wall. The stent was attached to the delivery microwire and recaptured after partial deployment. The stent-retriever was deployed across the blood clot by a microcatheter. Withdrawal of the microcatheter unsheathed the stent-retriver so that it lied over the thrombus. Struts of the stent integrated into the blood clot and the outward radial force partially restored cerebral blood flow as well as helped in engaging the clot. This was left for a set period of time specified by the manufacturer and once the stent retriever

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entangled the thrombus, it was withdrawn into a guide catheter. During this time, suction force could aid in clot purchase and reduced distal embolic showers. The next generation of stent retrievers were designed for thrombectomy in acute IS and comprised of the Solitaire and Trevo Pro. The ‘Solitaire AB neurovascular remodeling device was a self-expanding stent that bridged the neck of aneurysms for multiple retrievals. This allowed adjustments and optimal positioning even after full deployment. It was approved by the FDA in March 2012 for thrombectomy in acute IS [64]. Solitaire AB’s design helped in exerting an optimal radial force that maximized the chances of trapping the blood clot. Other manufacturers produced similar stent retrievers with variations in cell design, lubricity and end portion variations. The solitaire could be resheathed and withdrawn after deployment. In the first study with ‘Solitare’ device, 20 patients were treated within 8-hours of stroke-onset [65]. Two patients had failed intra-arterial tPA and three had failed recanalization with Merci retriever. Recanalization was achieved in 90% of patients, 45% achieved mRS ≤2 at 3-months and SICH occurred in 10%. Similar results were reported from several small studies and led to proper randomized controlled trials [63, 66]. The Solitaire device was compared to the Merci Retriever in SWIFT [64] and TREVO [66, 67] trials. Patients treated with Trevo achieved significantly better recanalization rates than Merci (86% versus 60%) and functional outcomes (58% versus 33%). However, complications and mortality rates were similar (33% versus 24%) [67]. In the ‘SWIFT’ trial, Solitaire device (n=58) was compared with Merci retriever (n=55). The trial was terminated prematurely due to significantly better recanalization rates (69% versus 30%), clinical outcomes (58% versus 33%) and less SICH (2% versus 11%). with the Solitaire device. As a result, mortality at 90 days was less in the Solitare arm (17%) as compared to the Merci arm (38%) [64]. Importantly, the SWIFT trial showed that the stent retrievers achieve recanalization at a faster speed than devices (36 minutes versus 52 minutes). Higher recanalization rates and reduced mortality with the use of retrievable stent-like devices for large-vessel occlusions led to their rapid and widespread adoption [64 68]. Despite improvements in the designs of stent retrievers, a small but significant proportion of acute IS patients developed reocclusion after recanalization, when the device was pulled back. This was most likely due to underlying atherosclerosis with plaque rupture. Furthermore, such cases required multiple attempts at crossing the occlusion and resulted in distal embolization. One of the early stents, Enterprise vascular reconstructive device (Codman, Raynham, Massachusetts, USA), used in aneurysm coiling also, provided the therapeutic option in such cases. It was based on a closed-cell nature that could be expanded within the thrombus to achieve both mechanical disruption and restore blood flow while being retrievable [69, 70]. It was initially employed for acute IS on compassionate grounds after other devices had failed. The ‘Enterprise-assisted Recanalization in Acute Ischemic Stroke (ERAIS)’ study used an investigational device and tested the safety of the Enterprise stent as the primary revascularization device in acute IS. The principal benefits of this self-expanding closed-cell stent included

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ease of delivery and less radial force compared with other self-expanding stents designed for intracranial use [71]. The ‘Revive SE Clot retrieval device’ trapped the clot to reduce distal embolization. It was designed with narrow and taller struts for better penetration and engagement of the clot. In the preliminary trials, complete recanalization was reported in a high proportion of patients [61]. The ‘pREset thrombus retriever’ was a self-expanding nitinol stent with laser-cut slit within its wall. Its closed-ring design helped to maintain a constant radial outward force. It was non-detachable and fully resheathable at any point during the procedure. It was intended to be used in acute IS with occlusion in intracranial arteries (with diameters of 2-4 mm) [72]. Interventionalists occasionally used an additional aspiration with the Solitaire device to improve recanalization. The balloon-guide catheter was deployed in the internal carotid artery to stop antegrade blood flow during withdrawal of the stent retriever and minimized distal embolization. To minimize the distance, the stent retriever must travel while engaging the thrombus and reducing the possibility of losing the clot. The 5 Max had a large inner diameter that provided further aspirational force when the Solitaire stent was withdrawn. Both were removed together in a similar way as the Merci retriever device was removed with a DAC [73]. In early 2013, three acute IS trials were presented that compared endovascular treatment against the best medical treatment [74-76]. The ‘Interventional Management of Stroke (IMS) 3’ trial included acute IS patients (n=656) treated within 3-hours of stroke-onset. Patients were randomized to either IV-tPA plus intervention techniques or IV-tPA only. Most of the thrombectomy devices used in the IMS 3 trial were from the earlier generations and relatively few stent retrievers were used. The trial was prematurely terminated when a planned interim analysis showed futility in the primary outcome of mRS ≤2 at 90 days. Despite higher recanalization rates in the endovascular treated group, only 40.8% had good functional outcomes as compared with 38.7% in the IV-tPA arm, which was not statistically significant [74]. In the ‘MR RESCUE’ trial, patients were treated with either best medical therapy or thrombectomy within 8 hours of stroke-onset [75]. The patients (n=47) were randomized to the treatment arms depending on the penumbral pattern seen on the pre-treatment CT or MRI. In this study, a favorable penumbral pattern was not able to differentiate which patients would benefit from endovascular therapy. Moreover in the same study, embolectomy failed to show benefit over best medical therapy. In the ‘SYNTHESIS expansion’ trial [76], acute IS patients treated within 4.5-hours of stroke-onset were randomly assigned to endovascular treatment or IV-tPA alone. Again, this trial reported that endovascular treatment was not better than IV-tPA (mRS 0-1 at 3 months, 30.4% versus 34.8%) [76]. Finally, positive signals of efficacy of interventional therapy in acute IS have started to evolve. The ‘MRCLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands)’ trial treated patients within 6-hours of onset. Patients with anterior circulation stroke and arterial occlusions were randomly assigned to intraarterial treatment plus medical care (n=233) or medical care alone (n=267). IV-tPA was administered to 89.0% cases. Stent retrievers were used in 81.5% cases in the

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endovascular group. Significantly higher rates of functional independence were observed in the interventional treatment group (32.6% compared to 19.1% in medically treated). Mortality and SICH were comparable in the two groups [77]. Similar positive and encouraging results were reported recently by the ‘Randomized assessment of rapid endovascular treatment of ischemic stroke (ESCAPE)’ trial (careful selection of patients with multiphasic CT angiography) [78] as well as by the ‘Endovascular therapy for ischemic stroke with perfusion-imaging selection (EXTEND-IA)’ trial (careful selection of patients with MRI diffusion-perfusion mismatch) [79]. ULTRASOUND ENHANCED THROMBOLYSIS Thrombolytic activity of IV-tPA can be potentiated using ultrasound energy, which results in increasing the surface area of the thrombus that gets exposed to tPA and increases its dissolution. The ‘Combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic tPA (CLOTBUST)’ trial included 126 patients who were treated within 3-hours of stroke-onset. It showed that continuous exposure of the occluded intracranial artery by the routine diagnostic 2-MHz transcranial Doppler (TCD) improved arterial recanalization [80]. During the same period, the ‘Transcranial low- frequency ultrasound-mediated thrombolysis in brain ischemia (TRUMBI)’ trial used 300 kHz transcranial duplex probe to enhance penetration of the ultrasound waves into the skull. Overwhelming incidence of SICH, which occurred even at sites remote from the ischemic lesion in the ultrasound arm, led to premature termination of the trial [81]. Recently, CLOTBUST-ER trial was launched to evaluate the efficacy of a hands-free ultrasound device, using 2-MHz pulsed wave non-directed ultrasound Doppler during IV-tPA infusion (ClinicalTrials.gov, NCT01098981). The control arm receives sham insonation using the same hands-free head frame [82]. Another approach of improving the thrombolytic activity of IV-tPA is to add microbubbles in conjunction with 2-MHz TCD monitoring. Microbubbles may facilitate ultrasoundinduced clot-dissolution by inducing acoustic cavitation. A multicenter international study, the ‘Transcranial ultrasound in clinical sonothrombolysis (TUCSON)’ trial was a dose escalation study for determining the optimal dose of the 3rd generation lipid microspheres [83]. The trial was stopped by the sponsors due to increased rates of SICH in the higher microbubble dose tier. Another novel method of ultrasound delivery during IV thrombolysis was employed in the IMS-3 trial [84]. The catheter used for delivering ultrasound directly into the intracranial clot was known as the EKOS NeuroWave catheter. Earlier studies employed a 2.5F infusion catheter with an ultrasound-generating 2mm transducer ring [84]. Later version was EndoWave System (Bothwell), a 5.2 F device using ultrasonic waves delivered via core wire [85]. One novel approach aims at targeted tPA delivery through shear-activated nanotherapeutics (SA-NTs). The nanoparticles break up into its nanoscale components during high fluid shear-stress and deliver the therapeutic compo-

Reperfusion Therapies in Acute Ischemic Stroke

Recent Patents on CNS Drug Discovery, 2015, Vol. 10, No. 1 51

nents hidden within. When coated with tPA and administered intravenously in mice, these SA-NTs can rapidly dissolve the clot and restore normal blood flow. This novel biophysical strategy for drug targeting requires lower doses of tPA and reduces unwanted side effects [86]. Baseline stroke severity, recanalization rates and outcome measures in various trials are summarized in Table 1. CURRENT & FUTURE DEVELOPMENTS The quest for rapid and effective clot dissolution and restoration of arterial patency in acute IS continues. The next wave of technology consists of low profiled devices that are deployed through small microcatheters. These microcatheters can help in gaining access through distal tortuous vessels and include ‘Capture LP’ and ‘Flow LP’ thrombus aspiration devices (MindFrame, Irvine, California). They have improved tensile strength, are kink resistant and possess better traceability for precise control [87]. Another recently applied Table 2.

patent uses a dual apparatus to remove the clot from an obstructed blood vessel. This aims at reducing the risk of distal embolization during the clot removal procedure by using a proximal expandable stent that can evert to enfold a distal expandable stent [88]. Thus the clot is secured prior to pulling it into the catheter. The proximal expandable member covers portions of the clot stuck to or extending from the outside of the distal expandable member, and helps to prevent the clot from being scraped off when the clot is pulled into the catheter. The close proximity of the two expandable members also allows the captured clot to be covered almost immediately, which reduces the possibility of fragmentation and distal embolization. The development of acute stroke interventional treatment devices takes the leads from cardiac devices. Accordingly, it is not surprising that a new patent has been applied for the use of drug eluting stents in acute IS patients [89]. This device is designed for local delivery of antiplatelet medications via the coating (embedded with an antiplatelet drug, preferably GPIIb/IIIa receptor inhibitor

Baseline stroke severity, recanalization rates and outcome measures reported in various clinical trials.

STUDY

Year

Number

NIHSS

Treatment

OTT

TIMI/ TICI 2-3

(hour) 6

SICH

mRS 0-2

(%)

Mortality (%)

NINDS

1995

312

14

IV tPA

1.5

NR

6.4

31

17

PROACT II39

1999

90

17

IA pro-UK

4.7

66

10

40

27

IMS III74

2013

222

17

IV

2

NR

5.9

38.7

21.6

434

16

IV/IA device

2

81

6.2

40.8

19.1

2005

151

20

MERCI

4.3

60.3

7.8

27.7

43.5

2008

123

19

MERCI

NR

69

9.8

36

34

Penumbra Pivotal57

2009

125

17.6

Penumbra

4.3

81.6

11

25

32.8

SARIS71

2011

20

14

SES

5.2

100

5

55

35

64

2012

58

17.3

Solitaire

4.9

89

2

58

17

55

17.4

MERCI

5.3

67

11

33

28

88

19

TREVO

4.7

86

4

40

33

90

18

MERCI

4.2

60

2%

22%

24

181

13

IV

3.8

NR

6

46

6

181

13

IA device

2.8

NR

6

42

8

32

16

No Device + mismatch

5.8

92

6

23

21

32

16

IA Device + Mismatch

5.3

67

9

14

18

19

20.5

No Device No Mismatch

5.7

78

0

10

30

30

19

IA Device No Mismatch

5.2

77

0

9

20

2015

196

17

IA Device

4.3

80

6

33

21

2015

150

17

IV

2.08

NR

2.7

29.3

19

165

16

IV+endovascular

2.68

72.4

3.6

53

10.4

35

13

IV

2.4

43*

2

30

7

35

17

IV+endovascular

3.5

94*

0

71

3

48

MERCI

52

Multi-MERCI

SWIFT

Trevo 2

67

2012

SYNTHESIS76

75

MR- RESCUE

MR CLEAN ESCAPE

77

78

EXTEND-IA

79

2013

2013

2015

52 Recent Patents on CNS Drug Discovery, 2015, Vol. 10, No. 1

such as abcixmab) and optionally comprises a polymeric binder that functions as a drug modulating polymer. A novel approach for accessing a cerebral artery in acute IS comprises of forming a transcervical puncture through a wall of a common carotid artery and inserting an arterial access sheath system directly, without previously inserting an introducer [90]. This allows direct delivery of intraarterial thrombolytic therapy. It can also be used to perfuse the cerebral vasculature distal to the site of a proximal occlusion with autologous arterial blood, oxygenated solution, neuroprotective agents or even hypothermic solutions. A recently proposed assembly uses a bundle of unwoven fibers to trap the clot. This bundle of fiber design allows the device to be effectively delivered into the distal tortuous cerebral arteries by conforming to the changing inner perimeter during clot removal. The filtration matrix offers an additional advantage by trapping any break-off of the clot during the removal process [91]. Localized mechanical percussion delivery to the chest wall, upper back, head or neck of a patient can be used to enhance clearance of acute thrombosis. A non-invasive localized low frequency mechanical percussion at a frequency between 1-1000 Hz accelerates the emergency clearance of the acute thrombotic arterial obstruction [92]. Another interesting approach in acute IS induces vasodilatation by a system that stimulates carotid chemo- and baro-receptor. The system increases blood flow in the area and enhance recanalization [93]. Another device is largely an assembly for cerebral perfusion therapy which uses an outer catheter with multiple apertures for perfusion of diagnostic agents or thrombolytic agents as well as a tapered distal tip to transverse the clot. Furthermore, it has an inner slidable coaxial catheter configured for delivering thrombolytic and other neurorestorative/neuroprotective agents [94]. With improving healthcare standards and increasing life expectancy, the incidence of acute ischemic stroke is bound to rise. Exciting developments are happening in the field of acute stroke treatment that are expected to ensure better survival and functional recovery. CONFLICT OF INTEREST

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The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none.

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