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Review of current and emerging therapies in acute ischemic stroke
  1. R Novakovic1,2,3,4,
  2. G Toth1,2,4,
  3. P D Purdy1
  1. 1Division of Neuroradiology, Department of Radiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  2. 2Division of Stroke, Department of Neurology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  3. 3Division of Neurocritical Care, Department of Neurology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  4. 4Division of Neurointervention, Department of Neurology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  1. Correspondence to
    Roberta (Robin) Novakovic, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-8896, USA; robin.novakovic{at}utsouthwestern.edu

Abstract

The statistics for stroke in the USA reads like a familiar ad slogan cited in most papers pertaining to acute ischemic stroke (AIS). Stroke is the third leading cause of death in the USA. While stroke ranks third among all causes of death, behind diseases of the heart and cancer, it is the leading cause of serious long-term disability in the USA.1 Approximately 795 000 people, 87% of whom are ischemic, suffer from stroke each year in the USA.2 That means that on average, every 40 seconds someone within the USA develops a stroke. For 2009 the combined direct and indirect cost of stroke, from hospitalization and rehabilitation to institutionalization, is estimated at $68.9 billion within the USA.2

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Ischemic stroke is the consequence of varied etiologies. While multiple factors, including comorbidities, may play a role in the length of time and degree of recovery from AIS, the most significant factor is the severity of the stroke itself. Currently, approximately 50–70% of survivors regain functional independence, while 15–30% are permanently disabled and 20% require institutional care 3 months post-stroke.3

Separate from long-term primary and secondary preventive measures, the goal of early management in patients with AIS is to minimize disability and improve functional outcome. The focus of this paper is to review current optimal medical and endovascular therapies; to assess accepted protocols and pathways that optimize and expedite patient access to these therapies and to review emerging therapies in the early management of patients with AIS.

Stroke pathophysiology

The area surrounding an infarct that suffers less severe ischemia is called the ischemic penumbra. It is considered dysfunctional but not irreversibly damaged tissue, and is potentially salvageable should adequate flow be restored.4 Animal studies have shown that the penumbra shrinks as the volume of the infarction expands in the hours following a stroke. Thus, if the ischemic penumbra can be saved, then the ultimate infarct volume and resultant neurological deficits can be minimized.

From a hemodynamic standpoint, a decrease in cerebral perfusion pressure (CPP) (mean arterial pressure (MAP) – intracranial pressure (ICP)) results in a compensatory vasodilation in the affected area.5 This autoregulatory vasodilation, called stage-1 hemodynamic failure, initially preserves normal cerebral blood flow (CBF). The next compensatory strategy, stage-2 hemodynamic failure (or misery perfusion), is characterized by increased oxygen extraction from the available blood supply. The increased oxygen extraction fraction maintains a normal cerebral rate of oxygen metabolism. Brain tissue function will remain intact during these compensatory strategies until perfusion declines further: below 0.55 ml/g/min, protein synthesis diminishes; below 0.35 ml/g/min, anaerobic metabolism is activated; below 0.20 ml/g/min, neurotransmitter release and impaired energy metabolism appear; and below 0.15 ml/g/min, cellular depolarization develops.4

Organized stroke care and primary stroke centers

Over the last decade, new therapeutic options have become available for patients suffering an AIS, ranging from the administration of recombinant tissue plasminogen activator (rt-PA) to newer interventional methods. Acute stroke care has become an increasingly complex and challenging task requiring specific expertise and a multidisciplinary approach. Evidence-based research has demonstrated the benefit of organized stroke care.6 In many cases, obstacles to appropriate stroke services are related to a fragmentation of stroke-related care and inadequate integration of various facilities, departments and professionals. Inadequate patient education, potential risk of legal liability from negative patient outcomes, and suboptimal reimbursement are also thought to be reasons7 for only approximately 3–8.5% of eligible patients receiving rt-PA treatment.8

The concept of an acute stroke center was first presented in a Brain Attack Coalition consensus statement.9 The American Stroke Association (ASA), Brain Attack Coalition, and The Joint Commission aligned to identify criteria for certifying “primary stroke centers”, with resources, organization, and expertise to diagnose and manage patients with AIS. The goal of these centers is to coordinate and promote patient access to the full range of treatments and services associated with stroke prevention, treatment and rehabilitation. Primary stroke centers may function independently, or may refer patients to a “comprehensive stroke center”, typically, the highest link in a hospital network that handles complicated stroke cases, requiring advanced diagnostic, neurointerventional or neurosurgical services.

The key components of primary stroke centers include:

  • Emergency medical services (EMS): first-line response, recognition of symptoms, initial stabilization, possible hyperacute therapies in field and communication with receiving hospitals

  • Emergency Department (ED) for hyperacute stroke care

  • Acute Stroke Team availability within 15 minutes

  • Neuroimaging and laboratory services in-house

  • Stroke Unit, subacute stroke treatment and secondary prevention

  • Neurointerventional and neurosurgical services available on-call or via transfer to another facility

  • Rehabilitation

  • Primary prevention

  • Community education and continuing medical education

  • Outcome and quality improvement activities

  • Written care protocols

Current acute ischemic stroke management

After arriving at the ED, the patient should be evaluated by a designated ED physician. Once a patient with potential AIS is identified, the Acute Stroke Team should be notified. The first goal of the initial evaluation is to confirm that the patient's symptoms are consistent with an ischemic stroke and are not merely secondary to a medical or neurological illness that can mimic an ischemic stroke (table 1). The second goal of the evaluation is to determine whether the patient meets criteria for thrombolysis (table 2). Necessary diagnostic studies and hemodynamic monitoring should follow or run simultaneously as patient care permits. Finally, historical data and other information that provide clues as to the etiology should be ascertained for future decisions regarding prevention of recurrent stroke. The currently recommended acute stroke management algorithm is demonstrated in fig 1.

Table 1

Conditions mimicking stroke

Table 2

Eligibility of patients for IV rt-PA treatment

Figure 1

Acute stroke management algorithm. DVT, deep vein thrombosis; ED, Emergency Department; EMS, emergency medical services; IA; ICP, intracranial pressure; ICU, Intensive Care Unit; IV, intravenous; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale; rt-PA, recombinant tissue plasminogen activator.

Diagnosis and evaluation

History

The patient's history provides invaluable information for determining the time of symptom onset. To establish the 3–6 h window for thrombolytic therapy, the onset is presumed to be when the patient was last known to be symptom-free. Patients with stroke usually present with a history of sudden onset of focal deficit in an anatomical distribution. Some patients may have gradual worsening or waxing and waning of symptoms. Headaches and seizures are infrequent at presentation of AIS; when present, intracerebral hemorrhage (ICH) or subarachnoid hemorrhage must be ruled out. A patient with a seizure at the time of onset of AIS might be eligible for treatment as long as the clinician is convinced that the residual impairments are due to stroke and not to the seizure. Further medical history, history of neurological problems including recent ischemic strokes, home medications including anticoagulation, recent trauma, procedures or surgery must be obtained, as certain variables may contraindicate thrombolytic therapy.

Physical examination

The initial evaluation by an ED physician can quickly identify the main features of a stroke and serves as a baseline when the Acute Stroke Team arrives. The National Institutes of Health Stroke Scale (NIHSS) is a widely accepted standardized measure of neurological deficits related to AIS.10 Usually performed in less than 10–15 minutes, the NIHSS can assist in prognostication. Favorable outcome was seen in 60–70% of patients at 1 year with scores <10,11 12 while hemorrhagic transformation and worse outcome had a higher incidence in patients with scores >20.13

Initial testing

An initial battery of tests should be performed upon arrival at the ED for patients with AIS. The diagnostic tests establish suitability for thrombolytic therapy as well as exclude metabolic disorders that can mimic stroke symptoms. The recommended screening tests include complete blood count with platelets, electrolytes, renal and hepatic function tests, cardiac enzymes, prothrombin time, and activated partial thromboplastin time.14 As time is critical, thrombolytic therapy should not be delayed while waiting for the results of coagulation studies unless there is clinical suspicion of a bleeding abnormality or anticoagulant use. Determination of platelet count, serum glucose and coagulation studies, in patients taking warfarin or equivalent, are required prior to administering thrombolytic therapy.14 Hypoglycemia can mimic stroke symptoms and therefore must be excluded.

A 12-lead ECG should be obtained to rule out concomitant myocardial infarction (MI), atrial fibrillation or other cardiac complications, because these conditions are common in patients with stroke. Continuous cardiac monitoring may also be necessary in patients with suspected paroxysmal arrhythmias. A toxicology screen should be considered if the history and examination are suggestive of substance abuse. A pregnancy test is necessary for women of child-bearing age.14

General supportive care

Ventilatory support

Adequate oxygenation during AIS is vital because tissue hypoxia can worsen neurological injury. Patients with AIS should be monitored with pulse oximetry to keep oxygen saturation level ≥ 92%. Arterial blood gas need only be drawn if the possibility of hypoxia is raised.14 Supplemental oxygen is recommended for patients with hypoxemia. Routine use of supplemental O2 in patients with normal arterial oxygen saturation has not been shown to be beneficial.15

Airway support and ventilatory assistance is recommended for patients with reduced consciousness or a compromised airway. Patients with stroke may develop decreased level of consciousness, impaired oropharyngeal motility and loss of protective reflexes.16 Endotracheal intubation can result in a hyperdynamic state and may worsen ICP or decrease CPP; hemodynamic stability is essential during this procedure. Elective intubation should be considered in cases of elevated ICP and brain edema.17 Patients with stroke who require intubation have a poor prognosis with up to 50% mortality at 30 days.18 19

Hypertension

Elevated blood pressure in stroke may occur secondary to the acute event, stress, pain, bladder distension or increased ICP. The appropriate management of hypertension in the setting of AIS is not well established. Lowering blood pressure may decrease the risk of hemorrhagic transformation, prevent vascular damage and reduce brain edema. However, aggressive treatment of hypertension may lead to expansion of the ischemic area by causing reduced flow and tissue hypoxia.20 It has been shown that blood pressure reduction will occur without pharmacological intervention in most cases.21

In patients not eligible for thrombolytic therapy and without evidence of end-organ dysfunction or damage, treatment is not recommended for systolic blood pressure (SBP) <220 mmHg and diastolic blood pressure (DBP) <120 mmHg.14 20 When treatment is indicated, intravenous agents such as labetalol, which are easily titrated and have minimal vasodilatory effects on cerebral blood vessels, are preferred. A reasonable goal is to lower the blood pressure by 15% during the first 24 h after AIS.14

Thrombolytic agents should only be administered to patients with SBP <185 mmHg and DBP <110 mmHg at the time of treatment.14 If reasonable efforts fail to lower the blood pressure, the patient cannot receive thrombolytic therapy. Blood pressure should be maintained below 180/105 mmHg for at least the first 24 h,14 22 due to increased risk of ICH.13 23 24

Hypotension

Hypotension is infrequently seen in patients with AIS. The most likely etiologies include cardiac arrhythmias, MI, aortic dissection, volume depletion and gastrointestinal bleeding. Inadequate CPP places the ischemic penumbra at risk for conversion to infarction. Therefore, in the first few hours of AIS, persistent hypotension threatens potentially viable brain tissue. As such, the search for an etiology and initiation of treatment should not be delayed.

Fever and hypothermia

Fever has been associated with increased morbidity, mortality and unfavorable outcome in the setting of AIS.25 Possible contributing mechanisms to worse outcomes include increased neurotransmitter release, enhanced free radical production and increased metabolic demand.25 26 27 The source of fever should be sought and adequately treated. Treating a fever with cooling devices and antipyretic medications might improve patient outcome.28 29

Cardiac arrhythmias

Potential complications of AIS include MI,30 cardiac arrhythmias,30 31 32 and sudden death.31 33 The likely mechanism for myocardial damage is increased catecholamine outflow.30 33 34 Atrial fibrillation is the most commonly detected arrhythmia,31 32 however QT prolongation, inverted T waves, prominent U waves and ST depression are also frequently seen on ECG.31 35 Right hemispheric strokes may be associated with a higher risk of arrhythmias, possibly secondary to dysfunction of the autonomic nervous system.33 34 36 To detect these potentially life-threatening abnormalities, cardiac monitoring is recommended during the initial evaluation of patients with AIS.14

Hypoglycemia and hyperglycemia

Hypoglycemia may mimic the symptoms of AIS with focal neurological signs, while hyperglycemia is associated with an unfavorable outcome.37 38 Thus, prompt measurement and rapid treatment of the serum glucose is an important step in the early evaluation of a patient with AIS. Finger glucose scan provides an efficient method to assess baseline serum levels rapidly in suspected patients with stroke arriving at the ED.

Hyperglycemia can be a consequence of a severe stroke, even in non-diabetic patients, and is possibly related to the stress of the event. While hyperglycemia can be a marker of a severe vascular event, it has also been demonstrated to have detrimental effects.39 Hyperglycemic patients have a higher regional lactic acid production, which is associated with decreased survival of penumbral tissue and increased blood–brain barrier permeability.40 Furthermore, in several thrombolysis trials, hyperglycemia was found to be associated with hemorrhagic events, a finding that was reconfirmed in a re-analysis of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study.38 Therefore, euglycemia should be maintained and glucose-containing intravenous fluids in patients with stroke should be avoided, even in the absence of nutritional feeding.14

Correction with rapidly acting insulin is recommended in most published guidelines (European Stroke Initiative guidelines >10 mmol/l, ASA guidelines >300 mg/dl).14 41 In spite of the evidence supporting the negative effects of hyperglycemia, clear benefit of rigorous glucose control is yet to be proven in clinical trials. To date there is still no clinical evidence to prove that reversal of hyperglycemia improves the prognosis, as it has been demonstrated to do in acute MI and in critically ill postsurgical patients. Nonetheless, based on the known detrimental effects of hyperglycemia it is advisable to maintain euglycemia.14

Imaging

Non-contrast head computed tomography (CT) remains the recommended and most utilized imaging modality in the acute stroke setting.14 42 It has been shown to identify ICH with high accuracy; however, identification of early ischemia may be more challenging. Early CT signs of acute cerebral infarction may be detected within 6 h of symptom onset and include: blurring of the internal capsule; loss of the insular ribbon; loss of differentiation between the cortical gray and subjacent white matter; and swelling of the cortical gyri with sulcal effacement.43 44 A hyperdense middle cerebral artery (MCA) may also be present, suggestive of a thrombus or embolus occluding the vessel.45 The presence of these early signs in patients with a well-established stroke onset within the window for thrombosis does not preclude treatment with intravenous rt-PA.23 46 However, some experts believe that larger than one-third of MCA territory stroke, increased hypoattenuation or early edema may suggest less beneficial effect and possible higher risk of hemorrhage.13 24 47 According to current recommendations from the ASA, a non-contrast head CT should be completed within 25 minutes of arrival, with interpretation by a skilled physician within an additional 20 minutes.14 A repeat CT after rt-PA administration should be obtained 24 h after thrombolytic therapy or if the patient clinically worsens, to rule out hemorrhagic transformation.14

Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) is used increasingly in some institutions, because it has been shown to be better than CT for accurate identification of acute ischemic areas within 30 minutes of symptom onset.48 49 However, limited availability, higher cost, longer examination time and contraindications, such as cardiac pacemakers, may delay the widespread use of this imaging modality. Newer perfusion MRI and CT studies, transcranial Doppler (TCD), and CT, MRI or conventional angiography are available in many centers and may be useful in selected patients. At this time these studies are not utilized on a routine basis and should not delay acute treatment.

Current acute ischemic stroke medical therapy

One of the main goals of AIS therapy is to restore blood flow and improve perfusion to the affected brain region. The cornerstone of this treatment is rapid recanalization of the parent vessel via removing or dissolving an obstructive blood clot and preventing further clot propagation.

The currently available and accepted non-invasive medical therapies predominantly aim to achieve rapid recanalization or improve blood flow by dissolving existing clots, and preventing platelet aggregation and/or further thrombus formation in the cerebral vasculature. Antiplatelet agents, anticoagulation and fibrinolytics have been used alone or in combination for this purpose.

Thrombolytics

Intravenous tissue plasminogen activator

In 1996, the Federal Drug Administration (FDA) approved intravenous rt-PA for patients with AIS based on the results of the NINDS rt-PA Stroke Study, in which 624 patients with ischemic stroke were treated with placebo or rt-PA within 3 h of symptom onset.50 Tissue plasminogen activator was demonstrated to be beneficial with a global odds ratio (OR) of 1.7 for a favorable outcome (95% CI 1.2 to 2.6). Patients who received rt-PA were at least 30% more likely to have minimal or no disability at 3 months than placebo, representing an absolute benefit of approximately 11–13%. The benefit was similar at 1 year after stroke. Symptomatic ICH occurred in 6.4% of patients given rt-PA versus 0.6% of patients given placebo (p < 0.001), but this did not offset the overall benefit of rt-PA. Mortality at 3 months was 17% in the rt-PA group and 21% in the placebo group (p = 0.30).

Pooled analysis of the NINDS trial, the European Cooperative Acute Stroke Studies (ECASS-I and -II) and Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS A and B) trials further confirmed the efficacy of intravenous rt-PA, and demonstrated that the odds of favorable outcome increased with faster administration times of the drug, the highest being 2.8 (95% CI 1.8 to 4.5) for 0–90 minutes and the lowest being 1.2 (95% CI 0.9 to 1.5) for 271–360 minutes.51 Symptomatic ICH was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Interestingly, benefit of rt-PA administration was still found in the 181–270-minute interval with an OR of 1.4 (95% CI 1.1 to 1.9). This finding was confirmed in the ECASS-III trial52 showing that more patients had a favorable outcome at 90 days with alteplase than with placebo in the 3–4.5 h treatment window (52.4% vs 45.2%, respectively; p = 0.04). Based on available data, new guidelines published in May 2009 by the American Stroke Association approved expansion of the time window for treatment of acute ischemic stroke with IV t-PA. In addition to patients presenting within the 3-hour window who should be treated as recommended in the 2007 guidelines, IV t-PA now should also be administered to eligible patients in the time period of 3–4.5 hours after stroke.52a The eligibility criteria are the same as for the 0–3 hour window, with any one of the additional exclusion criteria listed in table 2.

Phase IV studies examining outcomes with intravenous rt-PA in broad clinical practice settings included the Standard Treatment with Alteplase to Reverse Stroke (STARS) from 57 medical centers in the USA,53 the Canadian Activase for Stroke Effectiveness Study (CASES) from 60 centers in Canada,54 and the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) from 285 centers in Europe.55 All three studies demonstrated efficacy of intravenous rt-PA comparable with prior large clinical studies. The proportion of patients with minimal or no disability was 54.8% in SITS-MOST at 90 days, 43% in STARS at 30 days and 36.8% in CASES at 90 days, compared with 49.0% (95% CI 44.4 to 53.6) in the pooled analysis of large randomized controlled intravenous rt-PA trials. Acceptable safety profile was also confirmed with a symptomatic ICH rate of 3.3% in STARS, 4.6% in CASES and 7.3% in SITS-MOST, compared with 8.6% (95% CI 6.3 to 11.6) in the pooled data of large randomized trials.

Intra-arterial thrombolysis

The potential advantage of intra-arterial administration of thrombolytic agents is high-concentration local drug delivery into the clot with reduced systemic effects. Majority of data on intra-arterial thrombolytics originates from studies with recombinant pro-urokinase (rpro-UK). The Prolyse for Acute Cerebral Thromboembolism I trial (PROACT-I) enrolled 40 patients to evaluate the potential benefit of intra-arterial recombinant rpro-UK with heparin versus heparin alone in patients with MCA occlusion within 6 h of symptom onset.56 Recanalization rates were 58% in the rpro-UK group and 14% with placebo (p = 0.017). Early symptomatic ICH occurred in 15.4% with rpro-UK and 7.1% in the placebo group, but this difference was non-significant (2p = 0.64). Good outcomes (30.8% vs 21.4%, respectively) and 90-day mortality rates (26.9% vs 42.9%, respectively) favored rpro-UK, but the results did not reach statistical significance.

PROACT-II was a prospective, randomized, placebo-controlled phase III trial, which treated 180 patients.57 The study demonstrated markedly higher recanalization rates in the rpro-UK group as compared with the placebo group (66% vs 18%, respectively; p < 0.001). Despite higher incidence of symptomatic ICH (10% for pro-UK vs 2% for controls; p = 0.06), there was no evidence of increased mortality (25% vs 27%, respectively), and 40% of rpro-UK treated patients versus 25% of placebo patients achieved a modified Rankin Scale score (mRS) of 2 or less (p = 0.04) at 90 days. Despite these favorable results, rpro-UK is currently not available for routine clinical use.

Another thrombolytic agent, urokinase (UK), was tested in the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) for MCA occlusion within 6 h of stroke symptoms.58 This study was stopped after the approval of intravenous rt-PA in Japan, but it still enrolled 114 patients. The recanalization rate was 73.7%. There was a trend for favorable outcome (mRS ≤ 2) at 90 days in the UK-treated group (49.1% UK group vs 38.6% placebo group), but this did not reach statistical significance. The secondary endpoint, excellent functional outcome (mRS ≤ 1) at 90 days, was seen in more patients in the UK group (42.1% vs 22.8% placebo group, p = 0.045). There were no statistically significant differences in mortality (5.3% vs 3.5%, respectively) and symptomatic ICH (9% vs 2%, respectively) between the UK and placebo group. Similarly to rpro-UK, UK is currently not approved for AIS therapy in the USA.

Other thrombolytics

Alternative thrombolytic agents may offer benefits over rt-PA with potentially improved half-life, higher target specificity and better safety profile. A few older medications showed no benefit in previous studies, while research on novel agents is ongoing.

Pooled analysis59 of the Australian Streptokinase (ASK), Glasgow Trial, Multicenter Acute Stroke Trial-Europe (MAST-E) and Multicenter Acute Stroke Trial-Italy (MAST-I) studies utilizing high dose (1.5 million units) of streptokinase up to 6 h after onset demonstrated increased death rate at 3 months with streptokinase compared with placebo (relative risk (RR) 1.46; 95% CI 1.24 to 1.73; p < 0.001) and more hemorrhagic transformations (RR 1.85; 95% CI 1.58 to 2.17; p < 0.001). Streptokinase has no proven utility in AIS therapy at this time.

Desmoteplase, a highly fibrin-specific plasminogen activator, showed promising results in two phase II trials60 61: Desmoteplase in Acute Ischemic Stroke (DIAS) and Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS). Doses of 90 µg/kg and 125 µg/kg desmoteplase, administered up to 9 h after symptom onset in patients with perfusion/diffusion mismatch on brain imaging, showed acceptable safety profile, better reperfusion rate than placebo and improved clinical outcome at 90 days. However, DIAS-2, a phase III trial62 that included 186 patients, failed to confirm the beneficial effect of desmoteplase treatment on clinical response at day 90. The study investigators postulated that a high response rate in the placebo group, likely secondary to mild strokes and small mismatch volumes without vessel occlusions, possibly reduced the potential to detect any effect of desmoteplase.

Tenecteplase (TNK) is a genetically engineered variant of rt-PA with a longer half-life, more fibrin specificity and more resistance to plasminogen activator-1 than rt-PA.63 A pilot study for this promising new thrombolytic agent demonstrated safety at 0.1–0.4 mg/kg doses administered within 3 h of symptom onset.64 A recent trial compared patients receiving TNK between 3 and 6 h to patients treated with rt-PA within 3 h.65 The TNK patient group was selected based on MR or CT perfusion imaging criteria. Limited results were encouraging with more patients demonstrating reperfusion, major neurologic improvement at 24 h and less ICH in the TNK group. Trials utilizing Ancrod given within 6 h of AIS showed no benefit66 67 or were halted secondary to futility following an interim analysis.68 Reteplase, a recombinant peptide with longer plasma half-life allowing bolus intravenous dosing, is undergoing testing in combination with abciximab in the ROSIE and ROSIE-CT trials (see “Combined medical therapies” section). Several other novel thrombolytic agents (microplasmin, V10153 etc) are currently being studied for AIS of up to 12 h duration.

Antiplatelet agents

Oral medications inhibiting platelet function are widely used for secondary stroke prevention based on proven efficacy in numerous large-scale controlled trials. However, data on the potential benefit of these drugs for AIS intervention are limited. The two largest studies that evaluated the benefit of aspirin in AIS are the International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST). Patients were randomized and treated within 48 h in both studies. In CAST,69 small but statistically significant reduction in early mortality was seen with aspirin compared with placebo (3.9% vs 3.3%, respectively; p = 0.04). There were fewer recurrent ischemic strokes in the aspirin group (1.6% vs 2.1%, respectively; p = 0.01). The IST70 also demonstrated that patients receiving aspirin had fewer recurrent ischemic strokes (2.9% vs 3.8%, respectively, 2p = 0.005) and slightly decreased mortality at 14 days (9.0% vs 9.4%, respectively). There was a non-significant trend toward decreased mortality or dependence at discharge in CAST, and at 6 months in IST. Combined analysis of these two trials71 confirmed the small but statistically significant benefit of prompt aspirin administration to decrease early stroke recurrence (1.6% aspirin vs 2.3% control, 2p<0.00001). In a recent meta-analysis72 of 12 trials (94% of data obtained from IST and CAST), antiplatelet therapy was associated with a significant reduction in death or dependence (OR 0.95, 95% CI 0.91 to 0.99; p = 0.008) and recurrent ischemic strokes (OR 0.77, 95% CI 0.68 to 0.86; p < 0.00001). The results demonstrated that for every 1000 patients treated with aspirin, 13 patients would avoid death or dependency (number needed to treat (NNT): 79), and seven patients would avoid recurrent ischemic stroke (NNT: 140).

The randomized controlled Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER) pilot trial73 had a factorial design and investigated the effects of simvastatin and clopidogrel started within 24 h of transient ischemic attack (TIA) or minor stroke with a 90-day follow-up. All patients received aspirin. The study closed early because of failure to enroll. A potential benefit of aspirin and clopidogrel therapy together to prevent recurrent stroke was suggested by the authors based on trends in the study, but this was not supported by any statistically significant result. In addition, there was evidence of significantly increased risk of intracranial and extracranial hemorrhage with the combination of aspirin and clopidogrel in the trial.

Another modality of antiplatelet therapy is represented by the group of intravenous platelet glycoprotein IIb/IIIa receptor inhibitors. One of the available therapeutic agents has been evaluated in the Abciximab in the Emergency Treatment of Stroke (AbESTT-II) trial.74 This phase III study was terminated prematurely due to an unfavorable benefit–risk profile after enrolling 808 patients instead of the planned 1800. Patients were treated with abciximab within 5 h of symptom onset. There was no significant difference in favorable response to treatment between the abciximab and placebo group (33% vs 32%, respectively; p = 0.944) at 3 months. There was an increased risk of symptomatic or fatal ICH within 5 days in the abciximab group (5.5% vs 0.5%, respectively; p = 0.002).

Although several other large studies have evaluated the role of different antiplatelet agents in secondary stroke prevention (MATCH, CAPRIE, CHARISMA, ESPS-2, ESPRIT, PROFESS etc), no other randomized controlled trial has assessed the efficacy of platelet function inhibitors or combination thereof in the AIS setting. A few smaller feasibility and pilot trials provide limited data that should be interpreted with caution. The Loading of Aspirin and Clopidogrel in Acute Ischemic Stroke and Transient Ischemic Attacks (LOAD) study75 was a non-randomized pilot study of only 40 patients with matched historical controls, evaluating the use of aspirin 325 mg and clopidogrel 375 mg loading dose in patients with AIS within 36 h of symptom onset. Most patients (97.5%) had no deterioration and 57.5% had neurologic improvement by discharge. One case (2.5%) of symptomatic ICH occurred. The authors concluded that neurologic deterioration may be decreased in treated patients when compared with matched controls. A small report of 20 patients loaded with 600 mg clopidogrel within 25 h of AIS symptoms76 showed no increased hemorrhage or neurologic deterioration. The Study of Efficacy of Tirofiban in Acute Ischemic Stroke (SETIS) is investigating the utility of the glycoprotein IIb/IIIa inhibitor tirofiban versus aspirin given for 3 days, started within 6 h of stroke symptom onset.77

Although these trials do not establish efficacy and/or safety of dual antiplatelet therapy or loading doses of clopidogrel in patients with AIS at this time, they further emphasize the need for larger-scale, randomized controlled clinical trials to assess for potential benefit.

Anticoagulation

The use of anticoagulation remains a controversial field of AIS therapy. Anticoagulation has shown benefit or has been accepted for primary or secondary stroke prevention in certain conditions (eg, atrial fibrillation, left atrial thrombus, venous sinus thrombosis, hypercoagulable state, mechanical heart valves, arterial dissection etc), but routine use of heparin, low-molecular-weight heparin, or heparinoids with the goal of improving neurologic outcome or preventing early recurrent stroke has not been proven in AIS. The major risk associated with anticoagulation use is symptomatic hemorrhagic transformation, which appears greater with larger infarct size, elevated blood pressure and higher anticoagulation doses. The risk of hemorrhage is thought to be between that associated with thrombolytic therapy and antiplatelet agents.

Interestingly, in the Hong Kong trial78 patients receiving nadroparin within 48 h of stroke onset for 10 days appeared to have reduced risk of death or dependency at 6 months. Patients with large-artery atherosclerotic stroke, a predefined subgroup of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) study,79 demonstrated benefit in favorable outcome from danaparoid at 3 months (68.1% vs 54.7%, respectively; p = 0.04). However, several other similarly designed studies (FISS bis,80 FISS tris,81 TAIST82 and TOPAS83) were unable to reproduce these favorable results or show benefit of other low-molecular-weight heparins.

Interesting to note that intravenous heparin was used in the PROACT trials56 57 in both the rpro-UK treatment and non-treatment arms. Heparin was administered to the majority of patients as a 2000-unit bolus, followed by 500 unit/h dose for 4 h. Symptomatic ICH was seen in 7.1% (PROACT-I) and 2% (PROACT-II) of heparin-only patients, compared with 15.7% and 10% in the heparin + rpro-UK treatment groups, although these differences were non-significant. Beneficial treatment effect was only observed in patients receiving rpro-UK, independent of heparin administration.

A recent comprehensive meta-analysis of 24 trials involving 23 748 participants84 showed no benefit of anticoagulation with regards to death and dependency or death alone in patients with AIS. A reduction in recurrent ischemic stroke during the treatment period was offset by a proportional increase in ICH. According to the current ASA guidelines, urgent anticoagulation to prevent early recurrent stroke or neurological worsening is not recommended for patients with AIS at this time.

Combined medical therapies

The rationale for using combination therapies is to achieve clot lysis with thrombolytics, and then potentially prevent clot reformation and vessel reocclusion with agents that inhibit platelet function or thrombus formation. As with all antiplatelet and thrombolytic treatments, the major safety concern remains the potential increase in bleeding. No large randomized controlled trials are available to assess efficacy at this time, but studies are ongoing to address the potential benefits and risks of these combined therapies.

The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (CLEAR) dose-escalation and safety trial included 94 patients with AIS within 3 h of symptom onset.85 The rate of symptomatic ICH, the primary safety endpoint of the study, was 1.4% in the eptifibatide + rt-PA combination group and 8.0% in rt-PA treated patients (p = 0.17). The study was halted when further enrollment was statistically unlikely to indicate inadequate safety for the combination group.

The ReoPro Retavase Reperfusion of Stroke Safety Study Imaging Evaluation (ROSIE/ROSIE-CT) trial is evaluating the safety and efficacy of abciximab and reteplase in patients presenting within 3–24 h of AIS with perfusion deficit on MRI or CT. All patients receive abciximab in addition to placebo or four different reteplase doses. Interim results of 34 patients demonstrated complete reperfusion in 33% of the abciximab monotherapy group, 40% of the 2.5 units of the reteplase group, 45% in the group given 5 units, 58% of patients treated with 7.5 units, and 50% of patients administered 10 units of reteplase.86

The goal of the ongoing Combination Anti-platelet and Anti-coagulation Treatment after Lysis of Ischemic Stroke Trial (CATALIST; previously ROSIE-2) is to determine an acceptable dose of eptifibatide in combination with aspirin, low-molecular-weight heparin tinzaparin, and standard rt-PA therapy in AIS. All patients receive rt-PA, aspirin and tinzaparin. Patients are assigned to one of five dosing groups for eptifibatide. The rt-PA must be administered within 3 h; the study drug will be given no later than 6 h from symptom onset.87

Limited data from small, non-randomized, non-controlled studies on the combination of tirofiban and low doses of rt-PA showed 68% MCA recanalization, greater rescue of tissue-at-risk based on perfusion MRI, and more neurological improvement in recanalized versus non-recanalized patients, with no significant increase in symptomatic ICH.88 89

Based on the promising preliminary observations in a previous small, open-labeled, dose-escalation study, the argatroban rt-PA stroke study90 investigates the rate of ICH and arterial recanalization with intravenous argatroban for 48 h after standard rt-PA dose administration.91

Current acute ischemic stroke mechanical embolectomy

Mechanical thromboembolectomy techniques are typically utilized in patients with contraindications to thrombolytic therapy or failed recanalization after thrombolysis. Currently there are only two FDA-approved devices for catheter-based mechanical embolectomy.

MERCI devices

The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) system is an embolectomy device (Concentric Medical, Inc., Mountain View, California, USA) approved by the FDA as a Humanitarian Device Exemption (HDE) device in 2004. The device has a flexible tapered wire with helical loops that can be embedded in the thrombus for retrieval (fig 2). The MERCI92 and multi-MERCI93 were prospective, single-arm, multicenter trials evaluating the efficacy of the device within 8 h of symptom onset in 141 and 164 patients, respectively. In the original MERCI trial, only patients ineligible for intravenous rt-PA were included, but patients could be enrolled in multi-MERCI even if they had received rt-PA but failed to recanalize on a subsequent angiogram. The multi-MERCI trial also included a newer version of the retriever device (L5) in addition to the older models (X5 and X6). The acceptable international normalized ratio (INR) range was extended to <3.0 from <1.7 in MERCI part II and multi-MERCI.

Figure 2

The Merci Clot Retriever (Concentric Medical, Inc., Mountain View, CA) third generation V series, a corkscrew device extracts clot endovascularly.

The revascularization rate of a Thrombolysis in Myocardial Infarction (TIMI) grade 2–3 in the MERCI trial was achieved in 68/141 (48%) patients. Adjuvant therapy (intra-arterial rt-PA, alligator, snare) was used in 51/141 (36%) patients. Thirty-eight (27%) enrolled patients were within 3 h of symptom onset, but were ineligible for intravenous rt-PA. Procedural complications occurred in 18/141 (13%) patients, and in 10/141 (7.1%) these were clinically significant. Eleven subjects (7.8%) experienced symptomatic ICH within 24 h, and 27.7% had asymptomatic ICH. At 90 days, the overall mortality was 43.5%, with 31.8% in the recanalized group and 54.2% in the non-recanalized group (p = 0.0101). Good outcome (mRS ≤ 2) was reached by 27.7% of patients, 46.0% in the recanalized group and 10.4% in the non-recanalized group (p<0.00001). Revascularization was independently associated with good neurological outcome (mRS ≤ 2) using multivariate logistic regression.

Data including both first- and second-generation devices in the multi-MERCI trial showed that the revascularization rate increased to 55% with device alone, and to 68% with device plus adjunctive therapy, although 48 patients (29.3%) also received intravenous rt-PA before angiography. Procedural complications occurred in 9.8% patients, and in 5.5% these were clinically significant. Symptomatic ICH rate was 9.8%, and 30.5% had asymptomatic ICH. No significant increase in ICH or clinically significant procedure complications were seen associated with pre-procedural intravenous rt-PA use. At 3 months, the overall mortality was 34%, with 25% in the recanalized group and 52% in the non-recanalized group (p<0.001). Good outcome (mRS ≤ 2) was reached by 36% of patients, 49% in the recanalized group and 9.6% in the non-recanalized group (p < 0.001). The multi-MERCI data support the results of the previous MERCI trial by demonstrating increased survival and improved outcome associated with recanalization, but none of the two studies included a control arm to conclusively show that thrombectomy improves stroke outcomes.

Mechanical embolectomy with the MERCI device is undergoing further analysis in the MR and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) and Interventional Management of Stroke (IMS) III trials.

Penumbra device

The Penumbra system (Penumbra, Inc., Alameda, California, USA) is another embolectomy device approved by the FDA as an HDE device in 2008. It was designed to mechanically disrupt intravascular thrombus and aspirate clot fragments through a reperfusion catheter (fig 3). Limited results of a recently published, prospective, multicenter, single-arm phase I trial utilizing this device are promising.94 The study enrolled 23 patients who presented within 8 h of symptom onset and were ineligible for or refractory to treatment with intravenous rt-PA. The access rate was 87%, because three patients had tortuous vessels that could not be treated. Among the 20 treated subjects, 45% had an NIHSS > 20, 50% presented over 3 h, and 43% of occlusions involved the posterior circulation. The primary endpoint, TIMI grade ≥ 2 revascularization, was achieved in 21 out of 21 treated vessels (100%). The secondary endpoint, a mRS score ≤ 2 or a 4-point improvement on the NIHSS at 30 days, was achieved in 45% of treated patients. The all-cause mortality was 45%, but none were related to procedural complications and given the severity of stroke symptoms and/or posterior circulation occlusions, this was still lower than originally expected. The rate of symptomatic ICH was 10%. Two periprocedural adverse events were reported: one groin hematoma treated with transfusion, and one intraprocedural subarachnoid hemorrhage without neurological deterioration. It is important to consider that 7 of 8 ICHs occurred when adjunctive rt-PA was used to treat vessel occlusion distal to the recanalized target vessel.

Figure 3

The Penumbra System (Penumbra, Inc., Alameda, CA) uses a microcatheter and Separator™ based thrombus debulking approach to intracranial revascularization.

Preliminary results of the Penumbra POST, a retrospective multicenter study representing a review of worldwide experience with the Penumbra System, were presented at the 2009 International Stroke Conference.95 The study included over 100 patients from international centers. Preliminary data suggested similar results to the prior trial with a recanalization rate of 83.3% and mortality of 21%. Intra-arterial adjunctive thrombolytic therapy was used in 68.6% of patients. The final results are yet to be officially published.

The preliminary results of the small phase I trial and retrospective study appear promising. The system appears to have a potential for treating thromboembolic large-vessel occlusions with a good recanalization rate, but further investigation is needed.

Emerging acute ischemic stroke therapies

Evolving therapies for AIS have been plodding along without dramatic advancement since the concept of early recanalization-limiting infarct extent. Progress in AIS therapies is partly hampered by the heterogeneity of stroke and the limitation of narrow treatment windows. However, bridging therapies such as collateral flow augmentation and neuroprotection are expanding the conceptual approach to AIS treatment. Neuroprotective therapies, with the potential advantage of being administered by EMS, have great allure but have thus far failed to live up to the expectation. Newer therapies targeted at early recanalization have focused on interventional techniques, ultrasound-enhanced systemic drug treatment or combined systemic and endovascular approaches. Furthermore, imaging techniques such as CT perfusion and multimodal MRI are being utilized for detection of preserved penumbra, with attempts to justify treatment beyond the window for thrombosis.

Bridging therapies

Ultra-early neuroprotective therapies

Bridging therapies, like neuroprotective strategies, in theory would improve neuronal survivability by maintaining tissue salvageability during the additional time required for recanalization approaches. These bridging therapies would require ultra-early initiation, ideal for the EMS setting. However, inadvertent treatment of non-stroke patients would be inevitable, necessitating very safe therapies with a low toxicity profile. Limited studies of combination neuroprotective and reperfusion therapies in AIS have been preformed, such as with lubeluzole,96 clomethiazole97 and hypothermia; however, until randomized clinical efficacy trials are completed these therapies remain experimental. Thus far, neuroprotective treatments in AIS have failed for a variety of reasons. The complex multipathway nature of the ischemic cascade gives a single drug limited ability to significantly halt the rapid process, especially when given late in the excitotoxicity course.

Ultra-early therapies spawn hope from the recent clinical trial showing benefit from early hypothermia-based neuroprotective therapy after cardiac arrest.98 99 The Field Administration of Stroke Therapy-Magnesium (FAST-Mag) trial now in phase III is the first ambulance-based clinical trial for AIS.100 Other potential neuroprotective therapies under investigation in AIS, such as high-flow oxygen therapy (hyperoxia), Minocycline101 and statin therapy102 seem well suited for ultra-early bridging therapies.

Hypothermia is one of the best-studied and most highly effective modes of neuroprotection studied.103 Hypothermia slows cerebral metabolism and protects neurons in the setting of ischemia. While feasibility of moderate hypothermia in AIS has been demonstrated in two clinical trials from the Cooling for Acute Ischemia Brain Damage (COOL-AID) study group; to date there are no completed, prospective, randomized controlled trials of hypothermia in patients with stroke.104 105 Nonetheless, induced hypothermia is one of the most promising neuroprotective therapies. This modality seems ideal for an ambulance-based setting, perhaps even in combination with other neuroprotective strategies.

Augmentation therapies

In the setting of an arterial occlusion, penumbral tissue is sustained by the presence of collaterals. The extent of collateral circulation should therefore influence the salvageability of the ischemic penumbra. Several studies have established the degree of collateral circulation with infarct volume and functional outcome.106 107 In a retrospective review of the PROACT-II trial, patients with collaterals treated with intra-arterial thrombolysis had a better outcome compared with the control group. In the absence of collaterals, rpro-UK did not improve outcome compared with control.108 Thus, robust collateralization appears to be the underlying precondition for survival of ischemic tissue until successful recanalization can be achieved. Therefore, strategies to augment leptomeningeal collateral flow have become the focus of some emerging therapies.

Induced hypertension is one method to increase collateral flow. In normal individuals CBF remains constant within a range of 50–150 mmHg of MAP secondary to the effects of autoregulation. In the setting of AIS cerebral autoregulation is impaired; resulting in a linear increase in CBF with increases in MAP.109 Markedly elevated blood pressure after AIS may increase the risk of hemorrhagic conversion of the ischemic lesion, worsen cerebral edema or induce other detrimental systemic effects. Nonetheless, preliminary studies suggest that induced hypertension may have a role in the treatment of AIS.110 111 In a study by Rordorf et al, 13 patients outside the window for thrombolytic therapy were treated within the first 12 h of AIS with intravenous phenylephrine, which was used to raise the SBP by 20% from admission. Improvement in NIHSS by at least two points was seen in seven patients. The induced hypertension was continued between 1 and 6 days. Neurological status at discharge was improved in those who had responded to the therapy and no systemic or hemorrhagic complications were noted.112 Preliminary and small clinical studies suggest that drug-induced hypertension could be used in management of AIS; however, data from large clinical trials are not available to establish efficacy of this treatment.

Collateral flow augmentation through partial aortic occlusion is another emerging therapy currently in phase II studies evaluating efficacy as a stand-alone or adjuvant therapy. The NeuroFlo™ (CoAxia, Inc., Maple Grove, Minnesota, USA) device partially restricts blood flow in the descending aorta, enhancing cerebral perfusion by diverting blood flow from the lower extremities (fig 4). It has been proposed that a persistent therapeutic effect may be evident long after treatment is completed. A pilot feasibility study of the device deployed for 1 h in 17 patients with AIS treated up to 12 h from symptom onset demonstrated an improvement in NIHSS >3 in 67% at the time of treatment and at 24 h after. CBF velocities increased in excess of 15% for 12 of 16 patients.113 The Safety and Efficacy of NeuroFlo™ for Treatment of Ischemic Stroke (SENTIS), a prospective, controlled, randomized, multicenter phase III clinical trial designed to demonstrate the safety and efficacy of the NeuroFlo treatment relative to medical management is currently underway.

Figure 4

NeuroFlo (CoAxia, Maple Grove, MN) device partially restricts blood flow in the descending aorta. The device is a multilumen catheter with two separate balloons that are sequentially inflated to produce occulsions of approximately 70% at each location for 45 minutes and then removed.

A similar non-invasive approach to collateral flow augmentation utilizes an external counterpulsation treatment. Sequential inflation of air-filled cuffs on the lower extremities induces retrograde blood flow in the descending aorta during diastole, with resultant increases in the mean diastolic CBF velocity as measured by TCD.114

Emerging recanalization therapies

Recanalization approaches have taken the form of medical thrombolysis, endovascular thrombectomy (clot retrieval or suction aspiration devices), augmented fibrinolysis (catheter-tipped ultrasound and externally applied ultrasonography) and mechanical clot disruption (ie, emergent angioplasty and stenting). Currently, some novel strategies aimed at improving and expediting the rates of recanalization are utilizing a combination of these therapies.

Combined intravenous and intra-arterial thrombolytic therapies

The combination of intravenous and intra-arterial thrombolytic therapy enables the relative speed and widespread availability of intravenous thrombolysis to initiate recanalization while assuming the inherent delays of the more effective intra-arterial thrombolysis. In recent clinical trials intra-arterial thrombolytic monotherapy achieved partial to complete recanalization in 58–73% of patients, however, complete recanalization was achieved in only 5–18% of patients in the PROACT-II and MELT studies.56 57 58 115 116 Several studies have assessed the combined approach of both intravenous and intra-arterial rt-PA treatment.117 118

The IMS I study was a multicenter, open-labeled feasibility trial comparing 18 patients with baseline NIHSS >10, treated with combined intravenous/intra-arterial rt-PA protocol to historical subjects in the NINDS rt-PA Stroke Study. The rate of symptomatic ICH (6.3%) in IMS I subjects was similar to that of historical subjects in the treatment arm (6.6%). IMS I subjects had similar 3-month primary and secondary outcomes as rt-PA-treated NINDS patients (mRS 0–2; 45% vs 39%, respectively) and significantly better outcome at 3 months than NINDS placebo-treated subjects for all outcome measures.116

The IMS II protocol was identical to that of IMS I, except the EKOS Micro-Infusion Catheter (EKOS Corporation, Bothell, Washington, USA) was used to deliver the rt-PA into the thrombus in 41% of the patients. The introduction of the EKOS Micro-Infusion Catheter, an ultrasound-assisted catheter, into the IMS II trial was to study its potential effectiveness in recanalization. Patients enrolled in the IMS studies received combined intravenous rt-PA (0.6 mg/kg, 60 mg maximum, over 30 minutes) and intra-arterial rt-PA therapy (up to 22 mg over 2 h). Intravenous and intra-arterial rt-PA was to be initiated within 3 and 5 h of stroke onset, respectively. Heparin was administered as a 2000-unit bolus before intra-arterial rt-PA therapy and continued as a low-dose infusion 450 units/h during intra-arterial therapy. In the IMS II trial, the 73 patients treated with combined therapy showed a trend toward better outcomes than rt-PA-treated NINDS patients (3-month mRS 0–2; 45% in IMS II patients). There was a 1.65-fold higher likelihood of patients to be independent at 3 months in the IMS II study compared with NINDS patients after adjustment for baseline NIHSS, age and time to treatment (median times; 140 minutes IMS I vs 141 minutes IMS II vs 90 minutes NINDS). Identical mortality rates were seen in the IMS I and IMS II (16%) despite a higher symptomatic ICH rate in IMS II (9.9%). With regards to the ultrasound catheter, a higher rate of recanalization was achieved in IMS II (69%) compared with IMS I (51%).119

IMS III is a randomized, multicenter, open-label, 900-patient phase III clinical trial currently underway. The IMS III is the first randomized trial comparing standard intravenous therapy with a combined intravenous/intra-arterial interventional treatment approach. For patients receiving endovascular therapy the MERCI device can also be utilized for mechanical clot removal.120

Combined intravenous thrombolysis and ultrasound therapies

TCD ultrasonography studies suggest only a 30% complete recanalization rate for MCA occlusion, a 48% partial recanalization rate, and a 27% reocclusion rate after intravenous rt-PA monotherapy.121 External ultrasound has been shown to enhance the thrombolytic properties of intravenous rt-PA in the Combined Lysis of Thrombus in Brain Ischemia Using 2 MHz Transcranial Ultrasound and Systemic tPA (CLOT-BUST) study, a phase II clinical trial of 126 patients with MCA occlusion presenting within 3 h of symptom onset. Half of the patients were randomized to continuous 2 MHz TCD ultrasonography targeted at the occluded vessel and the remaining half to the placebo group.122 Complete MCA recanalization or dramatic clinical recovery within 2 h was observed in 49% of patients receiving intravenous rt-PA combined with transcranial ultrasound versus 30% of patients who received intravenous rt-PA alone (p = 0.03). Favorable outcome (mRS 0–1) was observed in 42% of the ultrasound group and 29% of the control group at 3 months (p = 0.20).122 Currently, a randomized controlled multicenter phase III clinical trial, to assess safety and efficacy of this combined therapy for MCA occlusion is due to complete enrollment in June of 2009.

Mechanical clot disruption therapies

There are concerns that intra-arterial pharmacological thrombolysis is associated with reduced and slower rates of recanalization as well as potential for higher risk of ICH. Likewise, FDA-approved mechanical thromboembolectomy techniques still have suboptimal rates of recanalization. The MERCI Retriever System achieved recanalization rates in only 55% of patients and 68% after adjunctive thrombolytic therapy (intra-arterial rt-PA, alligator, snare) in the multi-MERCI trial.123 Thus, emerging endovascular therapies have targeted at safer techniques to improve the rate and speed of recanalization.

The theory has been proposed that mechanical disruption of the clot may facilitate pharmacological thrombolysis, in part by increasing the surface area for thrombolysis. Strategies that achieve higher rates of recanalization may minimize the need for escalating dose of thrombolytic therapy, thus potentially reducing the ICH complication rate. Thus, mechanical methods such as microcatheter and microwire manipulations,124 balloon angioplasty,125 stenting, snare devices,126 and intra-arterial ultrasound127 have been reported as alternative approaches to recanalization. A Swiss study of 350 patients with AIS treated with intra-arterial thrombolytic therapy found recanalization rates of more than 75% when additional endovascular techniques such as mechanical fragmentation of the thrombus, thromboaspiration, percutaneous transluminal angioplasty (PTA) and implantation of stents were used.128

In the largest case series reported, Nakano et al describe 36 patients with acute MCA occlusion treated with intra-arterial UK alone and 34 patients with PTA and subsequent thrombolytic therapy if needed for distal embolization. Between the two groups there was no significant difference in NIHSS or duration of ischemia. Partial to complete recanalization rates were achieved in 91.2% of patients treated with PTA and 63.9% (p < 0.01) with thrombolytic monotherapy. The rate of massive symptomatic ICH was 2.9 and 19.4% (p = 0.03), respectively. Functional independence (mRS < 2) was achieved in 73.5% of the PTA group compared with 50% in the thrombolysis-alone group (p = 0.04).129 The technique of rescue angioplasty may be effective and safe for adjuvant to intra-arterial thrombolysis. Potential complications of intracranial angioplasty include arterial dissection or rupture, distal embolism and occlusion or shearing of associated perforating vessels.

Limited data are available about the use of angioplasty and stenting in the emergent treatment of intracranial or extracranial lesions in patients with AIS. Small case series have shown trends for aggressive mechanical clot disruption as adjunct to thrombolytic therapy to achieve earlier and better overall rates of recanalization with potential for low rates of periprocedural complications and better outcomes.125 130 131 132 133 Gupta et al retrospectively reviewed 168 consecutive patients treated with multimodal endovascular therapies. Independent predictors of recanalization included combination intra-arterial thrombolytics and glycoprotein IIb/IIIa inhibitors (p<0.048), intracranial stent placement and angioplasty (p<0.001) or extracranial stent placement with angioplasty (p<0.014).134

There have been several reports of successful balloon-mounted coronary stent implantation for recalcitrant acute occlusions.133 134 135 A comparison of self-expanding and balloon-mounted stents in an animal model of acute embolic occlusion showed no difference in respect to the rates of recanalization,136 however, the self-expanding stents performed better in navigability, had lower rates of vasospasm and side-branch occlusion. Self-expanding stents are designed specifically for the cerebrovasculature with an increased safety profile in deliverability, likely because the stents are deployed at lower pressures than balloon-mounted coronary stents. A retrospective review of 19 patients treated with self-expanding stents for recanalization of acute cerebrovascular occlusions demonstrated feasibility and safety with partial to complete recanalization rates of 79%. However, the best rate of recanalization was achieved when self-expanding stent delivery was combined with multimodality therapy, including PTA, MERCI clot retrieval and adjunctive pharmacologic therapy.136

Rates of recanalization have shown to vary based on location of clot as well as maneuvers utilized to recanalize the artery. Retrospective case series have demonstrated single-vessel lesions are more amenable to recanalization than dual-vessel occlusions (ICA to MCA clot) or carotid terminus occlusions utilizing PTA and stenting.133 134 137 It is difficult to directly compare results of limited studies and case series as to the most efficacious modality of revascularization. While preliminary and small clinical studies suggest that PTA and stenting could be used in management of recalcitrant lesions in AIS, data from large clinical trials and long-term follow-up are not available. As such, the efficacy of this treatment has not been established. Furthermore, utilization of self-expanding intracranial stents and GP IIb/IIIa inhibitors to prevent acute in-stent thrombosis for recanalization in acute intracerebral artery occlusion is considered an off-label application.

Acute ischemic stroke beyond conventional time windows

It is probable that a salvageable penumbra is present in up to 80% of patients at the time of symptom onset. Within the first 6–12 h the penumbral territory either progresses to infarct or improves flow.138 Thus, some patients who present outside of the therapeutic window may still have small infarct cores with large areas of ischemic penumbra that could benefit from thrombolysis. Many studies have investigated the use of CT and MR perfusion hemodynamic parameters (such as cerebral blood volume, CBF, and mean transit time) to identify ischemic penumbra and collateral reserves.139 140 A popular penumbral paradigm uses multimodal MRI to define the ischemic penumbra as the mismatch zone between the areas of perfusion-weighted MRI (PWI) abnormality that do not have corresponding diffusion-weighted MRI (DWI) changes.

The hypothesis of an extended therapeutic window for patients with persistent ischemic penumbra has been assessed in recent clinical trials including DIAS I and II, DEDAS, Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET).60 61 62 141 142 The DEFUSE and EPITHET randomized studies were designed to determine whether intravenous rt-PA given 3–6 h after symptom onset would reduce infarct growth in patients with PWI/DWI mismatch.141 142 In the DEFUSE study of 74 patients, early reperfusion was associated with significantly increased odds of achieving a favorable clinical response in patients with a PWI/DWI mismatch (odds ratio 8.7; p = 0.011). Patients with no PWI/DWI mismatch did not appear to benefit from early reperfusion.142 However, in the EPITHET study of 101 patients, non-significantly lower rates of infarct growth were seen in PWI/DWI mismatch patients who received rt-PA.141

The DIAS study was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Intravenous desmoteplase given 3–9 h after AIS onset in patients with PWI/DWI mismatch was associated with a higher rate of reperfusion, better clinical outcome and a low rate of symptomatic ICH compared with placebo.60 Likewise, the results of the DEDAS generally supported the results of DIAS.61 The follow-up study DIAS II, a phase III trial that included 186 patients, failed to confirm the beneficial effect of desmoteplase treatment on clinical response at 3 months. The study investigators postulated that a high response rate in the placebo group, likely secondary to mild strokes and small mismatch volumes without vessel occlusions, possibly reduced the potential to detect any effect of desmoteplase.62

Theoretically, patients with a large PWI/DWI mismatch would have the most to gain from recanalization. Perhaps one day the window for thrombolytic therapy may extend beyond an arbitrary time limitation and instead be defined by quantifiable evidence of salvageable tissue, the PWI/DWI mismatch. However, at this time efficacy of this treatment has not been established.

Conclusion

The development of acute stroke centers and systems of care may revolutionize the medical community's ability to treat patients with stroke. Specialized stroke services have been effective in improving acute and long-term outcome measures. Focusing clinical resources in neurocritical care units and stroke units provides greater specialist care, enhances knowledge in the field, and may also facilitate data collection and enrollment in clinical trials. Ideally, these measures will optimize patient access to the best of current medical and endovascular therapies. In the foreseeable future, a combination of bridging therapies and recanalization strategies may evolve for therapeutic approaches for AIS. Furthermore, with the integration of safe extended treatment windows for AIS therapies in patients with salvageable penumbra, the future may hold better neurological outcomes for patients with stroke.

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View Abstract

Footnotes

  • Competing interests None.

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