SEARCH

SEARCH BY CITATION

Keywords:

  • outcomes;
  • reperfusion;
  • stroke;
  • thrombectomy;
  • tPA;
  • ultrasound

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

Abstract.  Alexandrov AV (University of Alabama Hospital, Birmingham, AL, USA). Current and future recanalization strategies for acute ischemic stroke (Review). J Intern Med 2010; 267: 209–219.

In a quest for stroke treatment, reperfusion proved to be the first key to the puzzle. Systemic tissue plasminogen activator (tPA), the first and currently the only approved treatment, is also the fastest way to initiate thrombolyis for acute ischemic stroke. tPA works by induction of mostly partial recanalization since stroke patients often have large thrombus burden. Thus, early augmentation of fibrinolysis and multi-modal approach to improve recanalization are desirable. This review focuses on the following strategies available to clinicians now or being tested in clinical trials: (a) faster initiation of tPA infusion; (b) sonothrombolysis; (c) intra-arterial revascularization, bridging intravenous and intra-arterial thrombolysis, mechanical thrombectomy and aspiration; and (d) novel experimental approaches. Despite these technological advances, no single strategy was yet proven to be a ‘silver bullet’ solution to reverse acute ischemic stroke. Better outcomes are expected with faster treatment leading to early, at times just partial flow improvement rather than achieving complete recanalization with lengthy procedures. Arterial re-occlusion can occur with any of these approaches, and it remains a challenge since it leads to poor outcomes and no clinical trial data are available yet to determine safe strategies to prevent or reverse re-occlusion.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

In a quest for stroke treatment, reperfusion proved to be the first key to the puzzle whilst cyto-protection and other treatments still remain elusive. This review will focus on improving blood flow to ischemic areas through established, combinatory, and investigational approaches.

Systemic tissue plasminogen activator (tPA) remains the only approved treatment and the fastest way to initiate thrombolyis for acute ischemic stroke [1]. Selection for this treatment remains simple and expeditious requiring only the presence of a disabling neurological deficit, noncontrast head CT to rule out bleeding, and determination of time from symptom onset as a substitute for a tissue measurement of reversible ischemia [1–3].

When given intravenously (iv), tPA works by induction of mostly partial recanalization since stroke patients often have large thrombus burden [4]. Thus, faster administration of a thrombolytic drug, its delivery to the thrombus and early augmentation of fibrinolysis are desirable goals.

Faster administration of tPA: time is brain = time is reperfusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

A common theme emerges that time matters most whether one correlates clinical outcomes with symptom-onset-to-treatment time or speed of thrombolysis once tPA infusion is initiated [5–7]. With latest advances in extending the timeframe for systemic thrombolysis and improvement in imaging modalities to select patients with reperfusion therapies [8–10], it becomes clear that time from symptom onset matters less than time to treatment in those with salvageable tissues. Shorter time to treatment should translate into faster recanalization, and better clinical recovery. It has been suggested through meta-analysis of studies that evaluated recanalization for stroke treatment [11]. Our collaborative group (CLOTBUST-PRO) set out to prospectively establish this fact, i.e. whether earlier tPA administration translates into faster recanalization and subsequent clinical recovery thereby confirming faster recanalization as a link between earlier treatment initiation and better clinical outcomes after systemic thrombolysis [12].

Intravenous route also remains the fastest way to initiate treatment particularly at a primary stroke centre level. However, there are many obstacles to systemic thrombolysis including that only a minority of stroke patients arrive in time to be eligible for this treatment [13]. Besides patient-related issues, tPA dose is not calculated based on thrombus weight whilst its success is dependent on the presence of residual flow that exposes shallow layers of thrombus to circulating tPA (Fig. 1). Presence of residual flow detectable by ultrasound doubles the chance of tPA induced recanalization [14].

image

Figure 1.  Thrombus appearance on magnetic resonance angiography (top right image), digital subtraction angiography (bottom right), and high resolution microscopy (top left). Digital angiography image also depicts sluggish residual flow around thrombus that will be shown is subsequent images being depicted by real time ultrasound monitoring.

Download figure to PowerPoint

The presence of a proximal arterial occlusion does not necessarily lead to tPA failure since some degree of recanalization can occur even with large thrombi [4, 15]. Figure 2 illustrates the likelihood of complete early recanalization with intravenous tPA treatment dependently on the site of an arterial occlusion [4]. Since intravenous tPA by itself works by induction of mostly partial recanalization of large thrombi [14, 15], early augmentation of fibrinolysis to improve arterial recanalization is desirable. This brings us to the use of ultrasound to detect residual flow and augment tPA induced arterial recanalization.

image

Figure 2.  Thrombus location and likelihood of its recanalization with systemic tPA.

Download figure to PowerPoint

Sonothrombolysis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

Thrombus is a complex formation that captures red blood cells in a mesh of fibrin strands since nature developed this mechanism to prevent blood loss if vessel integrity is compromised. With risk factors leading to atheromatous disease, arrythmias, hypercoagulability, etc, thrombi are formed in various places leading to in situ thrombosis or remote embolism. Natural defences to dissolve these unwelcome thrombi are not effective as evident by the large number of stroke patients with persisting arterial occlusions that arrive to the hospitals. Fibrin strands and activated platelets are at the core of thrombus perseverance and resistance to endogenous and exogenous lytics. Fibrin strands are cross-linked and held by activated platelets (Fig. 1). Once lodged in a vasculature as a plug, the size and structure of thrombo-embolus further create high resistance to antegrade blood flow. Delivery of tPA to the binding sites in the thrombus relies on often-diminished residual blood flow. Mechanical agitation of thrombus-residual flow interface can expose shallow layers of thrombus to circulating tPA and facilitate streaming of plasma through thrombus thus bringing more tPA to binding cites [16, 17, 19, 20].

Ultrasound is a pressure wave that can travel through tissues and deliver this mechanical momentum to stagnant flow areas and thrombus interfaces. Independently of basic science research [16, 17], our group serendipitously uncovered as part of clinical routine that stroke patients treated with systemic tPA and monitored with 2 MHz transcranial Doppler (TCD) can recanalize early into treatment and experience dramatic clinical recovery [21]. Our group further has shown feasibility and safety of thrombolysis monitoring and augmentation at bedside using TCD [22, 23].

We formed a multicenter collaborative group to test this observation in a clinical trial. In the Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic TPA (CLOTBUST) trial [24], 83% of patients achieved any recanalization (46% complete, 27% partial) with tPA+transcranial Doppler vs. 50% (17% complete, 33% partial) with tPA alone within 2 h of treatment, P < 0.001. Sustained complete recanalization at 2 h was 38% vs. 13% respectively, P = 0.03. Symptomatic intracerebral haemorrhage rate was 3.8% in both groups, NS [24]. This trial was the first properly powered clinical trial that confirmed existence of ultrasound enhanced thrombolysis in human subjects, and demonstrated a positive biological effect of diagnostic low power ultrasound.

A recent meta-analysis of six randomized and three nonrandomized clinical studies of sonothrombolysis suggested that any diagnostic ultrasound monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral haemorrhage [25].

In its present form, sonothrombolysis can be performed at bedside using commercially available vascular diagnostic ultrasound systems such as transcranial Doppler [20] or transcranial duplex [26] at no significant increase in the risk of intracerebral haemorrhage [25]. Experimental sonothrombolysis will be covered in a subsequent section.

Whilst early recanalization with systemic tPA is feasible and can be augmented, a substantial number of patients will experience no recanalization or develop re-occlusion [29, 30]. Moreover, the majority of patients still arrive beyond the current timeframe for systemic tPA, and persistence of a proximal arterial occlusion has long been recognized as a poor prognostic sign. These considerations prompted continuing development of catheter-based interventions for acute ischemic stroke.

Intra-arterial revascularization

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

Ever since the invention of invasive angiography, physicians were thinking about its applications in stroke for diagnostic and therapeutic purposes. Development of catheters suitable for navigation into brain vasculature opened the possibility of intra-arterial revascularization with a drug topically delivered to intracranial thrombus or deployment of various mechanical thrombus disruption devices.

The first milestone in this development was achieved by the Prolyse in Acute Cerebral Thromboembolism (PROACT) collaborators who conducted a controlled clinical trial at an extended timeframe up to 6 h from symptom onset in patients with proximal middle cerebral artery occlusions [28]. This trial showed an absolute difference of 15% in good clinical outcomes at 3 month in favour of intra-arterial lytic administration over placebo despite 10% incidence of intracranial hemorrhagic complications with interventions [28]. Despite these highly encouraging results, the US Food and Drug Administration (FDA) did not approve pro-urokinase as a treatment for stroke and required further efficacy trials. Pertinent to the studies discussed below, PROACT investigators also reported an overall 66% recanalization rate at the completion of intra-arterial treatment that is now recognized as one of benchmarks in development of intra-arterial revascularization devices.

In parallel with the primary intra-arterial approach development, a group of investigators now known as the Interventional Management of Stroke (IMS) trialists, started to explore ‘bridging’ therapy, i.e. initiation of treatment with intravenous tPA followed by intra-arterial tPA infusion if occlusion persists beyond the duration of systemic treatment [29, 30]. The phase III IMS trial is now being conducted in the US and Canada and it compares standard intravenous dose of tPA (0.9 mg kg−1 over 1 h infusion) vs. 0.6 mg kg−1 over 30 min followed by intra-arterial administration of up to 22 mg of tPA directly to the intracranial thrombus [30]. Of note, the IMS trial has not been designed to seek US Food and Drug Administration regulatory approval for an intra-arterial approach as a treatment of ischemic stroke. IMS trial bridging arm reflects upon how leading stroke institutions in North America tend to approach persistence of an arterial occlusion. Combinations of drug and devices included in IMS reflect upon the complexity of testing new paradigms in stroke treatment.

The use of intra-arterial revascularization is restricted to centres with skilled operators, usually interventional neuro-radiologists and endovascular neurologists or neurosurgeons. The number of stroke-trained interventionalists is increasing, and other specialties are also looking at cross-training in stroke interventions. This is a rapidly evolving field where procedural success is highly dependent on interventionalists’ skills and improvements in devices they use.

Mechanical thrombectomy emerged in stroke with development of a MERCI™ retriever device [31]. A simple analogy for this device is a corkscrew that we use to open wine bottles. Since thrombus lodges like a plug in a vasculature comparable to its size, a device deploys screw-like wire, engages the thrombus, tracks it towards proximal vessels with larger diameter, and aspirates the retrieved parts of a thrombus (Fig. 3). Several deployments could be attempted during intra-arterial revascularization procedure. The initial studies (MERCI and Multi-MERCI) showed 46–57% recanalization and 7.8–9.8% symptomatic intracranial haemorrhage rates [32, 33]. Furthermore, if an adjunctive therapy was deployed (such as intra-arterial injection of a lytic drug) recanalization rate increased to 69.5% in the Multi-MERCI clinical study [33].

image

Figure 3.  MERCI™ thrombus retriever device (courtesy of Concentric Medical, Inc.).

Download figure to PowerPoint

Despite both MERCI and Multi-MERCI studies lacking concurrent controls and recanalization rates being less of that in PROACT trial, FDA Medical Devices panel granted approval for clinical use in stroke patients [34]. This decision was criticized as the device was approved for thrombus retrieval, not stroke treatment, and the spreading device use in the routine clinical practice further hinders our ability to test new stroke treatments with proper controls [34].

Another device that received a recent FDA approval is aimed to aspirate the thrombus from within the vessel (Fig. 4). The device called Penumbra™ has been tested in phase I-II clinical studies without concurrent controls [35]. The results of the clinical study reported at the 2008 International Stroke Conference in New Orleans are pending final publication at the time of this review. Table 1 summarizes currently available data on recanalization rates, safety, and clinical recovery after systemic treatment, bridging, sonothrombolysis, and currently available catheter interventional options for revascularization. One particular observation emerges from analysing available data: higher recanalization rates at an extended timeframe do not necessarily lead to better clinical outcomes at 3 months.

image

Figure 4.  Penumbra™ thrombus aspiration system (courtesy of Penumbra, Inc.).

Download figure to PowerPoint

Table 1.   Recanalization rates, risks and outcomes in major reported clinical studies
Revascularization StrategyPartial and Complete RecanalizationSymptomatic ICHmRS 0–2 at 3 month
IV tPA <3 h CLOTBUST Control arm [24]50%3.8%37%
Merci™ <8 h Multi-Merci Study [33]57%9.8%36%
Penumbra™ <8 h  as reported at ISC 200882%7.2%20%
IV tPA <3 h + i.a. TPA IMS II trial [37]64%9.9%38%
Sonothrombolysis <3 h CLOTBUST tPA+TCD arm [24]83%3.8%51%

This seemingly counter-intuitive finding is linked to two facts. First, there is no consistency in stroke literature what is reported and when in terms of recanalization and reperfusion of tissues. Second, the terms revascularization and reperfusion are defined through different aspects of vascular end-points of treatment. Recanalization refers to restoration of flow through arterial occlusive lesions (AOL) whilst reperfusion means restoration of flow to tissues supplied by the occluded vessel often described by the Thrombolysis in Myocardial Infarction (TIMI) flow grades [36, 37]. In the IMS I trial, there was only a modest correlation between the two scores whilst only 49–54% of patients with good-to-excellent recanalization (AOL II/III) or reperfusion (TIMI II/III) achieved good clinical outcomes [36]. Not surprisingly, if a similar recanalization or reperfusion level is achieved hours later, one might expect even less recovery or doubt the link between recanalization and recovery from stroke [38]. Key differences between intra-arterial technologies and clinical study designs can be found elsewhere [38]. Nevertheless, this underscores the need for better patient selection at a timeframe past 3 h of symptom onset to justify costly and risky intra-arterial procedures. On the other hand one might argue that if a patient with a proximal arterial occlusion has a favourable brain scan at more than 3 h of symptom onset, this patient has developed reasonable collaterals and stroke outcome would depend less on recanalization of a proximal lesion but rather on maintenance of sufficient tissue perfusion whilst the primary lesion is recanalized slowly and at times just partially. In any case, these considerations should be taken into account when further clinical trials at an extended timeframe are planned to test novel approaches to brain reperfusion.

Novel experimental approaches

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

Main venues of ongoing clinical research in reperfusion therapies for stroke are as follows:

  • 1
     augmentation of systemic tPA-induced recanalization;
  • 2
     bridging intravenous and intra-arterial tPA thrombolysis;
  • 3
     primary intra-arterial interventions; and
  • 4
     multi-modal approaches to reperfusion.

Augmentation of systemic tPA treatment can be accomplished with low power ultrasound and gaseous microspheres [39–44]. Since human application of frequencies below diagnostic range (i.e. kHz) resulted in increased symptomatic bleeding rates [45] whilst low power 2 MHz diagnostic ultrasound showed a strong signal of efficacy and safety [24], the latter is combined with gaseous microspheres for testing in clinical trials [42, 44, 46].

Molina et al. pioneered the use of gaseous microspheres in combination with CLOTBUST monitoring methods and reported safety and recanalization rates with the first generation air-filled microspheres (Levovist, Schering AG) as well as newer diagnostic microspheres (Sonoview, Bracco) [39, 41]. These microspheres were designed for diagnostic purposes to be given as boluses in order to enhance returned echoes and improve quality of ultrasound images. Regardless of a microsphere type, they share the same mechanism by which they respond to ultrasound pressure waves (Fig. 5). Being injected intravenously, microspheres circulate thru the whole body effectively crossing the lung barrier due to their size and stability [47, 48]. When intercepted intracranially by an ultrasound beam aimed at thrombus-residual flow interface, these micropsheres undergo expansion in size followed by transient oscillation or complete break up (Fig. 5). This transmits energy momentum to areas with stagnant flow and further promotes penetration of tPA into the thrombus as well as its own mechanical agitation and dissolution [49, 50].

image

Figure 5.  (a) Upper images show microphotography of a single microsphere destruction by an ultrasound pulse. Time axis is in microseconds. Lower images show microspheres permeation around or through the MCA thrombo-embolic material to areas of no flow pretreatment (middle bottom image ‘initial permeation’). It was possible to detect this phenomenon in our clinical feasibility study [51] due to initial dilution of microspheres and the ability of TCD to detect a single microsphere in the intracranial circulation. Bottom right image shows partial recanalization detected by TCD at 7 min of treatment with tPA+microspheres+TCD. This finding was confirmed by repeat CTA (image insert above ‘thrombus’) (Images modified from references 41 and 47). (b) The TCD probe and head gear monitor used in the CLOTBUST trial.

Download figure to PowerPoint

Our pilot multi-centre feasibility study showed that the new generation perflutren-lipid micropsheres reached intracranial thrombi in all patients, and in 75% of them they immediately permeated through or around thrombi and reach areas with no detectable flow (Fig. 5) [51]. Our pilot study and subsequent Transcranial Ultarsound in Clinical SONothrombolysis (TUCSON) trial showed that a 1.4 mL dose of perflutren-lipid microspheres can be safely co-administered during tPA infusion causing no symptomatic intracerebral haemorrhage [42, 44]. As a signal-of-efficacy, the combination of perflutren-lipid microspheres, TCD and tPA lysed 50–67% of proximal MCA occlusions [42, 44]. This finding that favourably compares to concurrent and historic controls receiving tPA alone [24, 42, 44].

Specifically, TUCSON trial [44] evaluated stroke patients receiving 0.9 mg kg−1 tPA with pretreatment proximal intracranial occlusions on TCD that were randomized in a 2 : 1 ratio to μS (MRX-801) infusion over 90 min (Cohort1 1.4 mL, Cohort2 2.8 mL) with continuous TCD-insonation whilst Controls received tPA and brief TCD-assessments. Primary safety end-point was symptomatic intracerebral haemorrhage (sICH) within 36 h post-tPA.

Amongst 35 patients (Cohort1 = 12, Cohort2 = 11, Controls = 12) no sICH occurred in Cohort1 and Controls whilst three (27%, with 2 fatal) sICH’s occurred in Cohort2 (P = 0.028). A trend towards greater stroke severity in Cohort 2 may have contributed to these findings (and also to lower recanalization/recovery rates than in Cohort 1 as shown below). Pretreatment median NIHSS scores were 10 in Cohort 1 (range 2–19, mean 10), 16 (range 6–25, mean 15) in Cohort 2, and 12 in Controls (range 4–22, mean 12; P = 0.080. Another potential con-founding factor could have been poor blood pressure control in those who had symptomatic bleeding. Although patients with sICH had similar screening and pretreatment SBP levels in comparison to the rest, higher SBP levels were documented in sICH(+) patients at 30 min, 60 min, 90 min and 24–36 h following tPA-bolus. During this period, the most significant SBP (mm Hg) difference was seen at 60 min if treatment: sICH(+) 182 ± 11 vs. 149 ± 21 sICH(−), P = 0.012 [44].

Sustained complete recanalization rates at the end of TCD-monitoring were 67% Cohort1, 46% Cohort2, and 33% Controls (P = 0.255). The median-time-to-any-recanalization tended to be shorter in Cohort 1 (30 min/IQR = 6) and Cohort 2 (30 min/IQR = 69) compared to controls (60 min, IQR 5; P = 0.054). Functional recovery at 3 months tended to be better in both treatment Cohorts 1 and 2 compared to Controls: modified Rankin score 0–1 75%, 50%, and 36% respectively, P = 0.167 [44].

Our collaborative group concluded that perflutren-lipid μS can be safely combined with systemic tPA and ultrasound at a dose of 1.4 mL. Safety concerns in the second dose tier may necessitate extended enrolment and further experiments to determine the mechanisms how microspheres interact with tissues. An encouraging finding emerged that despite baseline imbalances, sonothrombolysis with μS and tPA showed a trend towards higher early recanalization and clinical recovery rates in both group tiers compared to standard iv tPA therapy [44].

The main limitation of current sonothrombolysis technology (applied with or without microspheres) remains operator-dependency of ultrasound to target intracranial occlusions and residual flow [20, 48]. Skilled sonographers able to perform transcranial Doppler or duplex are largely unavailable to the emergency departments outside a few centres worldwide. Therefore, our collaborative group now set out to develop an operator-independent and easy-to-use sonothrombolysis technology applicable to emergency settings [46].

Even as systemic treatment options improve, one might still expect a substantial number of patients have persisting arterial occlusions or re-occlusions [27]. Bridging 0.6 mg kg−1 intravenous and intra-arterial (i.v.-i.a.) tPA thrombolysis is feasible [29, 37], and IMS III clinical trial is currently underway in the United States and Canada (NCT00359424) [30]. The goal of this trial is to compare i.v.-i.a. approach to standard systemic tPA treatment with 0.9 mg kg−1 dose. Of note, there are no data currently available to determine if primary intra-arterial interventions are any better than systemic tPA initiated within the same timeframe, i.e. sub 3 h from symptom onset. There is still an equipoise and a randomized trial is needed to see if primary i.a. approach is any better than systemic tPA in patients with proximal arterial occlusions and if primary i.a. is better than placebo if administered after the timeframe for iv tPA. The latter is being addressed in an ongoing Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR-RESCUE) clinical trial (NCT00094588) [52]. Of note, this trial uses MERCI™ retriever in the treatment arm and compares this first FDA approved device for thrombus removal in stroke patients to standard-of-care such as oral aspirin and no other intervention or active reperfusion medication in patients ineligible for tPA treatment within 8 h after symptom onset. Unlike the ongoing MERCI™ open-label use registry (NCT00478478) [53], MR RESCUE has a control arm and attempts to answer the question if primary i.a. intervention is any better than conservative standard-of-care management.

Furthermore, IMS III trial evaluates intra-arterial ultrasound catheter (EKOS™) [54] that currently uses 1.7 MHz emitting frequency and 400 mW power settings to agitate thrombus from within the vessel lumen [37]. Interestingly, these ultrasound parameters chosen for EKOS™ catheter are similar to 2 MHz and average power settings used in the CLOTBUST trial for noninvasive transcranial insonation of thrombus-residual flow interface [24, 55]. EKOS™ catheter shortened time necessary to achieve recanalization with intra-arterial lytic infusions [37, 54]; findings that parallel noninvasive observations and further point to feasibility of sonothrombolysis with i.a. approach.

Intra-arterial approach for stroke may not be viewed as a one-device-solves-all-problems intervention. i.a. procedures are generally lengthy and often require application of different catheters, several devices, stents or drug-device combinations [56, 57]. Recently, a combination of externally applied transcranial Doppler and intra-arterial catheter delivered gaseous microspeheres was used during i.a. procedures in an attempt to augment thrombolysis [58]. With complexity of stroke, large thrombus burden, and difficulties with anatomical access [59, 60], there is a need for further evolution of i.a. technologies. Aside from a specific situation of persisting basilar artery occlusion that carries 80% mortality risk where randomized trial of i.a. approach is considered un-ethical [18, 61], we need better imaging for patient selection [62] and testing multi-modality combinatory strategies through randomized clinical trials. Similar to other technologies in medicine, our available data indicate that no single approach can reverse all strokes.

Conflict of interest statement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References

Dr. Alexandrov reports having served as consultant to ImaRx Therapeutics, Inc., having received grant support from Genentech, Inc. and NINDS for the CLOTBUST trial. Dr Alexandrov has a US patent ‘Therapeutic methods and apparatus for use of sonication to enhance perfusion of tissue’ (6 733 450) and he is a founder of Vitason Technologies. Dr Alexandrov is a Co-Investigator in the SPOTRIAS Program, NINDS.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Faster administration of tPA: time is brain = time is reperfusion
  5. Sonothrombolysis
  6. Intra-arterial revascularization
  7. Novel experimental approaches
  8. Conflict of interest statement
  9. References