Prolyse In Acute Cerebral Thromboembolism Research Articles

Safety and Efficacy of Intra-arterial Urokinase After Failed, Unsuccessful, or Incomplete Mechanical Thrombectomy in Anterior Circulation Large-Vessel Occlusion Stroke

Achieving complete reperfusion is a key determinant of good outcome in patients treated with mechanical thrombectomy (MT). However, data on treatments geared toward improving reperfusion after incomplete MT are sparse. To determine whether administration of intra-arterial urokinase is safe and improves reperfusion after failed or incomplete MT. This observational cohort study included a consecutive sample of patients treated with second-generation MT from January 1, 2010, through August 4, 2017. Data were collected from the prospective registry of a tertiary care stroke center. Of 1274 patients screened, 69 refused to participate, and 993 met the observational studies inclusion criteria of a large vessel occlusion in the anterior circulation. Data were analyzed from September 1, 2017, through September 20, 2019. One hundred patients received intra-arterial urokinase after failed or incomplete MT using manual microcatheter injections. Primary safety outcome was the occurrence of symptomatic intracranial hemorrhage (sICH) according to the Prolyse in Acute Cerebral Thromboembolism II criteria. Secondary end points included 90-day mortality and 90-day functional independence (defined as modified Rankin Scale score of ≤2). Efficacy was evaluated angiographically, applying the Thrombolysis in Cerebral Infarction (TICI) scale. After exclusion of patients with posterior circulation strokes and those treated with intra-arterial thrombolytics only, 993 patients were included in the final analyses (median age, 74.6 [interquartile range, 62.6-82.2] years; 505 [50.9%] women). Additional intra-arterial urokinase was administered in 100 patients (10.1%). The most common reason for administering intra-arterial urokinase was incomplete reperfusion (TICI<3) after MT (53 [53.0%]). After adjusting for baseline characteristics underlying case selection, intra-arterial urokinase was not associated with an increased risk of sICH (adjusted odds ratio [aOR], 0.81; 95% CI, 0.31-2.13) or 90-day mortality (aOR, 0.78; 95% CI, 0.43-1.40). Among 53 cases of partial or near-complete reperfusion and treated with intra-arterial urokinase, 32 (60.4%) had early reperfusion improvement, and 18 of 53 (34.0%) had an improvement in TICI grade. Correspondingly, patients treated with intra-arterial urokinase had higher rates of functional independence after adjusting for the selection bias favoring a priori poor TICI grades in the intra-arterial urokinase group (aOR, 1.93; 95% CI, 1.11-3.37). In selected patients, adjunctive treatment with intra-arterial urokinase during or after MT was safe and improved angiographic reperfusion. Systemic evaluation of this approach in a multicenter prospective registry or a randomized clinical trial seems warranted.

State of acute endovascular therapy: report from the 12th thrombolysis, thrombectomy, and acute stroke therapy conference.

Acute endovascular therapy for ischemic stroke is at a pivotal juncture. Until recently, on the basis of randomized trials comparing devices, we knew that endovascular treatment options were effective in quickly restoring blood flow and that successful early recanalization was associated with better functional outcome when compared with sustained occlusion.1,2 We did not have randomized evidence that available acute endovascular therapy improved patient outcomes; the 3 initial randomized controlled trials of endovascular recanalization treatment published in February of 2013—the Phase II Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), Phase III Interventional Management of Stroke (IMS) III, and Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) trials—failed to demonstrate improved clinical outcomes.3–5 Many factors may have contributed to the failure of these 3 initial trials to show endovascular benefits. These trials were performed during a period of rapid evolution of imaging and treatment options, and used intra-arterial thrombolysis, or first-generation device therapies at best, with little use of newer generation devices, such as stent retrievers, demonstrated to achieve significantly higher rates of recanalization.1,2 Patients with mild or moderate stroke severity may have been less likely to benefit from endovascular reperfusion based on IMS III and Prolyse in Acute Cerebral Thromboembolism (PROACT) II post hoc analyses and others.3,6,7 The power of these trials was diluted by including subjects without intracranial vessel occlusions, and post hoc analyses of IMS III suggested a potential treatment effect among stroke patients with baseline computed tomographic (CT) angiographic occlusions.8 Larger vessel occlusions, which are more resistant to recanalization by intravenous recombinant tissue-type plasminogen activator (r-tPA), such as intracranial internal carotid artery (ICA) location or occlusions >8 mm, may have been more likely to show a treatment effect …

Techniques for endovascular treatment of acute ischemic stroke: from intra-arterial fibrinolytics to stent-retrievers.

Early recanalization of occluded vessels in acute ischemic stroke (AIS) either by intravenous thrombolysis or endovascular revascularization has been shown to be associated with improved clinical outcome and reduced mortality.1 Initial works on endovascular treatment (EVT) of AIS was published in the 1980s.2,3 Since then, the endovascular techniques for AIS treatment have tremendously improved, advancing from intra-arterial administration of thrombolytic drugs to first-generation mechanical thrombectomy devices (Merci clot retriever and Penumbra clot aspiration) and more recently to second-generation mechanical thrombectomy devices (stent-retrievers; Figure 1). Introduction of various tools and techniques in EVT for AIS will, for obvious reasons, affect the efficacy and safety. Figure 1. Evolution of endovascular techniques for acute ischemic stroke and clinical trials. IMS indicates Interventional Management of Stroke; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; PROACT, Prolyse in Acute Cerebral Thromboembolism; SWIFT, Solitaire With the Intention for Thrombectomy; and TREVO, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke. On the other hand, intravenous thrombolysis was evaluated in several large randomized trials and was shown to improve clinical outcome at 90 days if treatment was initiated within 3 hours of stroke onset.4 Subsequently, the European Cooperative Acute Stroke Study (ECASS) III showed the benefit of intravenous thrombolysis between 3 and 4.5 hours.5 After establishing the efficacy of intravenous recombinant tissue-type plasminogen activator (r-tPA) in the treatment of AIS, EVT had to be evaluated against intravenous treatment. A long time elapsed before the results of the first randomized controlled trials were published in 2013 demonstrating no major difference between intravenous r-tPA treatment and EVT for AIS.6–8 Noteworthy, these trials had several limitations including the fact that all EVT were approved for use.9 …

Early reperfusion and clinical outcomes in patients with M2 occlusion: pooled analysis of the PROACT II, IMS, and IMS II studies.

The role of endovascular therapy in patients with acute ischemic stroke and a solitary M2 occlusion remains unclear. Through a pooled analysis of 3 interventional stroke trials, the authors sought to analyze the impact of successful early reperfusion of M2 occlusions on patient outcome. Patients with a solitary M2 occlusion were identified from the Prolyse in Acute Cerebral Thromboembolism (PROACT) II, Interventional Management of Stroke (IMS), and IMS II trial databases and were divided into 2 groups: successful reperfusion (thrombolysis in cerebral infarction [TICI] 2-3) at 2 hours and failed reperfusion (TICI 0-1) at 2 hours. Baseline characteristics and clinical outcomes were compared. Sixty-three patients, 40 from PROACT II and 23 from IMS and IMS II, were identified. Successful early angiographic reperfusion (TICI 2-3) was observed in 31 patients (49.2%). No statistically significant difference in the rates of intracerebral hemorrhage (60.9% vs 47.6%, p = 0.55) or mortality (19.4% vs 15.6%, p = 0.75) was observed. However, there was a trend toward higher incidence of symptomatic hemorrhage in the TICI 2-3 group (17.4% vs 0%, p = 0.11). There was also a trend toward higher baseline glucose levels in this group (151.5 mg/dl vs 129.6 mg/ dl, p = 0.09). Despite these differences, the rate of functional independence (modified Rankin Scale Score 0-2) at 3 months was similar (TICI 2-3, 58.1% vs TICI 0-1, 53.1%; p = 0.80). A positive correlation between successful early reperfusion and clinical outcome could not be demonstrated for patients with M2 occlusion. Irrespective of reperfusion status, such patients have better outcomes than those with more proximal occlusions, with more than 50% achieving functional independence at 3 months.

Proximal Intracranial Arterial Occlusions

Over thepast2decades, the treatmentofacute ischemicstroke has undergone significant changes. The National Institute of Neurological Disorders andStroke tissueplasminogen activator study1 in 1995 followed by the third European Cooperative Acute Stroke Study (ECASS III)2 in 2008heralded major breakthroughs in the hyperacute management of patientswith ischemicstroke. Yet despite the promise of these landmark studies, the overall use of intravenous tissue plasminogen activator remained meager, reaching less than5%ofall strokepatients in theUnited States through 2006.3 Furthermore, for certain stroke subtypes, such as thosewith proximal intracranial arterial occlusions, therateof recanalizationremained low,4 resulting inpoor outcomes when early recanalization was not achieved.5 Over the ensuing years, major excitement was generated in the stroke community about endovascular therapy for ischemic stroke, which logically targeted this population. The Prolyse inAcuteCerebralThromboembolism(PROACT) study6 showed that intra-arterial prourokinase was superior to placebo in achieving recanalization and improving outcomes of stroke patients who were treated within 6 hours of symptom onset. The subsequent advances of new devices and techniques with high recanalization rates resulted in a tide of enthusiasmaseachnewendovascular technologybroughtgreater promise and a better chance of direct, early recanalization for patients with proximal intracranial arterial occlusions. The strokecommunityembracedtheconceptofendovascular treatment because the idea of direct revascularization just made somuch sense. Yet the recanalization rates, which continued to increase asdevices and techniques improved, began tooutstrip clinical outcomes in some studies, bringing into question the assumptions about what the recanalization was ultimately capable of achieving.7 Theexcitementoverdirect recanalizationwasquelled furtherby the results of 3 recent randomizedclinical trials8-10 that failed to show improvedclinical benefit for strokepatientsundergoing endovascular therapy. The Interventional Management of Stroke III (IMS-III) trial8 was an open-label study that randomly assigned 656 patients with a National Institutes of Health Stroke Scale (NIHSS) score of 10 or higher or an NIHSS score of 8 or 9 with vascular imaging evidence of large artery occlusion to thrombolytic therapy alone or thrombolytic therapy plus endovascular therapy. This study8 was stopped earlybecause therewasnodifference inoutcomebetween the 2 arms, and the investigators concluded that the addition of endovascular therapy to intravenous thrombolytic therapydid not improve stroke outcome. The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial10 randomly assigned 118 patients with an anterior circulation large artery occlusionwithin 8hours of symptom onset to undergo mechanical thrombectomy (Merci Retriever or Penumbra System) or to receive the standard of care. This study10 showed no difference in reperfusion rates, and the outcomes between the 2 groups supported the nonsuperiorityofendovascular treatmentover thestandardofcare for acute ischemic stroke. The Endovascular Treatment for Acute Ischemic Stroke (SYNTHESIS) trial9 randomly assigned 362 patients within 4.5 hours of symptom onset to endovascular therapyvs intravenous thrombolytic therapy.This study9 showed that there was no difference in the 3-month outcomes between the 2 study arms, concluding also that endovascular therapy is not superior to intravenous thrombolytic therapy. The findings in these trials8-10 had a sobering effect on the field, limiting the use of endovascular treatment in the stroke community. Althoughallof those recent studieswerewelldesignedand well conducted, valid criticisms were brought to bear on the results.Most of the endovascular devicesusedwereolder and were associatedwith lower recanalization rates thanwere the newerdevices.11 Longer time to treatmentwaspresent in each of the studies compared with the standard treatment arms, with a post hoc analysis of the IMS III trial8 suggesting that thosewhogot earlier interventionshadgreater potential benefits. Could it be that these trialswere inadequate toprove the ultimate failure of endovascular interventions after all?Might there still be a rationale tomove aheadwith additional endovascular trials despite these compelling negative studies? In their article published in this issue of JAMANeurology, Lima et al12 retrospectively analyzed a prospective cohort of stroke patients with proximal intracranial arterial occlusions fromtheScreeningTechnologyandOutcomeProject inStroke (STOPStroke) study. The objective was to evaluate the natural history and outcome of this disease in patients who were not treatedwith intravenous thrombolysis or who did not receive endovascular therapy. In this study,12 the authors demonstrated that theoverallnaturalhistoryofpatientswithproximal intracranial arterial occlusions was poor, withmore than half (56%) not achieving functional independence and about a quarter (22%) dead at 6months. Furthermore, their study12 showed that older age, anNIHSS score of 10orhigher, andevidence of poor collaterals on computed tomography angioAuthor Audio Interview at jamaneurology.com

Stroke: new horizons in treatment

Intra-arterial therapy (IAT) has been used for three decades to promote recanalisation after stroke. Whereas results of the Prolyse in Acute Cerebral Thromboembolism-II trial (PROACT-II) 1 Furlan A Higashida R Wechsler L et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003-2011 Crossref PubMed Scopus (2720) Google Scholar showed significant improvement in clinical outcome with intra-arterial fibrinolysis, the stroke specialty received some disturbing news in 2013. Results of the Interventional Management of Stroke-III (IMS-III), 2 Broderick JP Palesch YY Demchuk AM et al. for the Interventional Management of Stroke (IMS) III InvestigatorsEndovascular therapy after intravenous t-PA vs t-PA alone for stroke. N Engl J Med. 2013; 368: 893-903 Crossref PubMed Scopus (1421) Google Scholar SYNTHESIS, 3 Ciccone A Valvassori L Nichelatti M et al. for the SYNTHESIS Expansion InvestigatorsEndovascular treatment for acute ischemic stroke. N Engl J Med. 2013; 368: 904-913 Crossref PubMed Scopus (357) Google Scholar and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) 4 Kidwell CS Jahan R Gornbein J et al. for the MR RESCUE InvestigatorsA trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013; 368: 914-923 Crossref PubMed Scopus (1091) Google Scholar studies failed to show an increased benefit for IAT compared with intravenous alteplase (t-PA) or as an adjunctive approach to intravenous alteplase. All three studies were randomised controlled trials: IMS-III assessed the adjunctive benefit of IAT with intravenous alteplase, SYNTHESIS tested IAT efficacy against intravenous alteplase, and MR RESCUE tried to identify patients most likely to benefit from IAT on the basis of a favourable imaging profile showing a penumbral pattern. IAT advocates have pointed out that newer devices than those used in these studies might achieve more rapid and complete recanalisation and better outcomes. A post-hoc analysis from IMS-III showed that patients treated within 4 h from symptom onset have potential to benefit most from IAT. Furthermore, new data showing improved reperfusion rates and times with the introduction of stent retrievers could result in improved clinical outcomes. 5 Saver JL Jahan R Levy EI et al. for the SWIFT TrialistsSolitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012; 380: 1241-1249 Summary Full Text Full Text PDF PubMed Scopus (1051) Google Scholar , 6 Nogueira RG Lutsep HL Gupta R et al. for the TREVO2 trialistsTrevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012; 380: 1231-1240 Summary Full Text Full Text PDF PubMed Scopus (889) Google Scholar

Commentary

Commentary

Off-Label Use of Drugs and Devices in the Neuroendovascular Suite

The off-label use of drugs and devices in neuroendovascular procedures is common. Neurointerventionalists should be well aware of the level of evidence available in support of the off-label use of drugs and devices in their practice and some of the potential adverse events associated with them. These uses are categorized as I or II if they have been evaluated as primary or ancillary interventions in prospective trials/registries of neuroendovascular procedures and III if they were evaluated in case series. Category IV use is based on evaluation as primary or ancillary interventions in prospective trials/registries of non-neuroendovascular procedures. Physicians are allowed to use off-label drugs and procedures if there is strong evidence that they are beneficial for the patient. The neurointerventional professional societies agree that off-label use of drugs and devices is an important part of the specialty, but practicing providers should base their decisions on sound evidence when using such drugs and devices.

Endovascular acute ischemic stroke therapy

Over 15 years ago, the US Food and Drug Administration (FDA) approved the use of tissue plasminogen activator (tPA) for acute ischemic stroke (AIS) within 3 hours of symptom onset.1 Since then, additional landmark advancements in AIS included the results of the Prolyse in Acute Cerebral Thromboembolism (PROACT) trial and the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT), which showed improved clinical outcome following local intra-arterial therapy, in comparison with placebo, and expanded the therapeutic treatment window of AIS.2,3 Because of the limited rate of recanalization by systemic and local chemical thrombolysis, mechanical thrombectomy became the next area of interest with the hope of achieving safer and faster recanalization. In the past decade, 4 major prospective studies of single-arm devices have yielded high rates of recanalization and FDA approval of 2 devices for thrombectomy.4,–,8 To take advantage of both early treatment initiation with systemic thrombolysis and the high rate of recanalization with endovascular therapy, the Interventional Management of Stroke (IMS) II feasibility trial evaluated the safety and potential clinical …

Merci mechanical thrombectomy retriever for acute ischemic stroke therapy

Mechanical thrombectomy is a promising adjuvant or stand-alone therapy for acute ischemic stroke (AIS) caused by occlusion of a large vessel in patients beyond the systemic thrombolysis therapeutic window. This review focuses on the clinical and angiographic outcomes of mechanical thrombectomy with use of the Merci retriever device. Available literature published to date on the major trials and observational studies involving the Merci retriever was reviewed. In addition to the review, results from studies involving the Merci retriever were compared to results from Prolyse in Acute Cerebral Thromboembolism II (PROACT II) and the Penumbra device studies. The predictors for favorable outcome following revascularization with the Merci device were reviewed on the basis of published stratified analyses. Favorable clinical outcome was defined in the Merci experience by a modified Rankin Scale (mRS) score of ≤ 2 at 90 days following AIS. Presented in this review are a total of 1,226 patients treated with the Merci device; 305 patients are from 2 pivotal trials involving the device, and the remaining 921 patients are from observational studies in the Merci registry. The 90-day mRS of ≤ 2 was achieved in 32% of the patient group, with an overall mortality rate of 35.2%. Symptomatic intracerebral hemorrhage was identified in 7.3% of patients treated with Merci retriever, a result comparable to that in the PROACT II and Penumbra thrombectomy trials. Successful recanalization, lower NIH Stroke Scale score, and younger age were identified as the strongest predictors of favorable outcomes. Mechanical thrombectomy with the Merci retriever device is a safe treatment modality for AIS patients presenting with a large-vessel occlusion within 8 hours of symptom onset. Although the Merci retriever showed a good recanalization rate, there are currently no randomized clinical trials to assess its clinical efficacy in comparison with systemic thrombolysis within a window of 3 to 4.5 hours or with standard of care beyond a 4.5-hour window.

Periprocedural management of acute ischemic stroke intervention

Periprocedural medical management is an important aspect in optimizing the outcome of patients who undergo endovascular treatment for acute ischemic stroke. Blood pressure, fluid hydration, and antithrombotics are some of the elements that need to be tailored carefully to the patient according to the patency of his or her cerebral vasculature, the extent of his or her infarct, and the potential for hemorrhagic transformation. This article reviews the medical care of acute stroke patients before and after endovascular therapy.

Thromobolysis for Acute Ischemic Stroke: Is Intra-arterial Better than Intravenous? A Treatment Effects Model

Three randomized trials of intra-arterial thrombolysis (IAT) for acute ischemic stroke ≤ 6 hours were conducted without intravenous tissue plasminogen activator (IV-tPA) treatment of patients in the control groups now known to benefit. The effect of IV-tPA treatment on 130 control subjects in the Prolyse in Acute Cerebral Thromboembolism (PROACT), PROACT II, and Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) studies was modeled using linearly weighted time-dependent odds ratios (ORs) from pooled IV-tPA trials. In the PROACT trials, the model assumed that 50% (36/73) were treated at 4.5 hours, the median time to arteriography. For MELT, the model assumed treatment at arrival plus 90 minutes based on hospital arrival times obtained from the principal investigator. The OR of 1.31 for all 130 controls (91 presumed treated ≤ 4.5 hours; OR 1.44) was applied to the original control data to derive the adjusted control outcome, and this was compared to the IAT group. Sensitivity analyses were performed. Meta-analysis of the original data revealed a statistically significant benefit for IAT (P = .03). After adjustment for the effect of IV-tPA in controls, there was no longer a significant treatment benefit for IAT (P = .26). Loss of significant IAT treatment benefit persisted if either the OR for benefit of IV-tPA or the number of treated controls was more than halved. These 3 randomized trials of IAT for acute ischemic stroke ≤ 6 hours would not likely have shown a benefit if eligible controls had been treated with IV-tPA. Whether IAT is superior to IV-tPA in IV-tPA-eligible patients or better than placebo in IV-tPA-ineligible patients remains to be determined.

Endovascular Treatment of Acute Ischemic Stroke: Ready to Go?

Even though intra-arterial fibrinolysis has shown a significantly better outcome in the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial, this treatment option was not approved by the US Food and Drug Administration (FDA), whereas intravenous fibrinolysis was approved as a standard therapy. New mechanical endovascular approaches, such as the Merci device or the Penumbra system were initially seen with great enthusiasm in the neuro-interventional community as high recanalization rates of up to 80% were achieved. Nevertheless, clinical results were disappointing which is why these techniques were increasingly critically viewed by stroke neurologists. In recent years a new technique with stent-like retrievers, has changed the practice in many stroke centers. In single center experiences even higher recanalization rates have been reported which were also associated with improved outcome in a substantial number of patients. This is a posi

Use of a vascular reconstruction device to salvage acute ischemic occlusions refractory to traditional endovascular recanalization methods

Acute revascularization has been associated with improved stroke outcomes. The Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial achieved recanalization rates of 66%. The Multi Mechanical Embolus Removal in Cerebral Ischemia (Multi MERCI) trial achieved recanalization in 70% of patients. However, these interventional tools are not always successful. The Enterprise vascular reconstruction device was recently introduced for treatment of cerebral aneurysms previously untreatable with endovascular techniques. The authors evaluated a multicenter experience using this stent as a salvage revascularization tool for acute stroke treatment. Four medical centers participated in a retrospective review of endovascularly treated patients with acute stroke for cases treated with the Enterprise stent after routine interventions had been unsuccessful. Data collected included preprocedure information, intraprocedure findings, and outcomes. Twenty patients with acute stroke (mean age 61.6 +/- 22 years) were treated with the Enterprise stent. Ten patients received intravenous recombinant tissue plasminogen activator before catheter intervention, without improvement. Intraarterial interventions attempted unsuccessfully before Enterprise deployment included the Merci retriever (12 patients), angioplasty (7 patients), glycoprotein IIb-IIIa inhibitor administration (12 patients), intraarterial nitroglycerin (1 patient), Wingspan stent deployment (3 patients), and Xpert stent deployment (1 patient). The mean preintervention National Institutes of Health Stroke Scale (NIHSS) score was 17 +/- 6 (median 17). All patients presented with a Thrombolysis in Myocardial Infarction (TIMI) score of 0 or 1. Revascularization was achieved in all patients (75% with a TIMI score of 3, 25% with a TIMI score of 2). Improvement (> or = 4 points on the NIHSS) was documented in 75% of patients. Mean NIHSS improvement from intervention to discharge was 8 +/- 7 points (median 9 points). These preliminary data suggest a potential benefit to the use of the Enterprise stent when routine intervention methods fail.

Intra-Arterial Thrombolysis Within Three Hours of Stroke Onset in Middle Cerebral Artery Strokes

The Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial showed improved outcomes in patients with proximal middle cerebral artery (MCA) occlusions treated with intra-arterial (IA) thrombolysis within 6 h of stroke onset. We analyzed outcomes of patients with proximal MCA occlusions treated within 3 h of stroke onset in order to determine the influence of time-to-treatment on clinical and angiographic outcomes in patients receiving IA thrombolysis. Thirty-five patients from three academic institutions with angiographically demonstrated proximal MCA occlusions were treated with IA thrombolytics within 3 h of stroke onset. Outcome measures included outcomes at 30-90 day follow-up, recanalization rates, incidence of symptomatic intracranial hemorrhage, and mortality in the first 90 days. The endpoints were compared to the IA treated and control groups of the PROACT II trial. The median admission National Institutes of Health Stroke Scale (NIHSS) score was 16 (range 4-24). The mean time to initiation of treatment was 106 min (range 10-180 min). Sixty-six percent of patients treated, had a modified Rankin Scale (mRS) score of 2 or less at 1-3 month follow-up compared to 40% in the PROACT II trial. The recanalization rate was 77% (versus 66% in PROACT II). The symptomatic intracranial hemorrhage rate was 11% (versus 10% in PROACT II) and the mortality rate was 23% (versus 25% in PROACT II). Time-to-treatment is just as important in IA thrombolysis as it is in IV thrombolysis, both for improving clinical outcomes and recanalization rates as well.

Atherosclerotic Peripheral Vascular Disease Symposium II

Stroke is the third leading cause of death and a leading cause of adult disability in the United States.1 From a global perspective, stroke is also a leading cause of death and disability. The past 20 years have seen significant improvements in stroke prevention, yet each year, >700 000 people have a new or recurrent stroke.2,3 The medical and societal costs of stroke exceed $62 billion in the United States alone.4 Any intervention that could reverse or limit the effects of a stroke would have dramatic medical, societal, and public health benefits. This section will focus on treatment of acute ischemic stroke, which accounts for 80% to 85% of all strokes. Other recent publications have focused on therapies for intracerebral hemorrhage. Acute interventions to reduce the effects of an ischemic stroke can be organized into several main approaches: (1) reperfusion strategies (lytics, endovascular/mechanical); (2) neuroprotection; and (3) restoration, regeneration, and rehabilitation. ### Medical Therapies Thrombolytic therapies for acute ischemic stroke have been used or under study for 30 to 40 years, yet only recently has an agent been approved by the US Food and Drug Administration (FDA) and included in the treatment guidelines. Intravenous recombinant tissue plasminogen activator (rtPA) is the only FDA-approved medical therapy proven to reduce the effects of an ischemic stroke.5,6 Its main mechanism of action is to lyse a clot that is occluding a cerebral vessel, thereby reperfusing distal ischemic brain tissue and preventing or limiting the area of cell death and tissue necrosis. The efficacy of intravenous rtPA was proven in the pivotal National Institute of Neurological Disorders and Stroke (NINDS) rtPA study, which showed improved outcomes for patients treated within 3 hours of stroke onset.7 The NINDS tissue plasminogen activator (tPA) trial had an efficacy end point that was equivalent to the …

Interventional Management of Stroke

See related article, pages 1770–1773 . Intravenous thrombolysis has become generally accepted and is currently the only FDA approved medical therapy for treatment of patients with acute ischemic stroke. Its use is associated with improved outcomes of patients who can be treated within 3 hours of stroke onset.1 A higher concentration of thrombolytic agents delivered directly into the thrombus has led to the promotion of intra-arterial thrombolysis, although the possible clinical benefits may be counterbalanced by delays to initiating treatment.2,3 With the evolving concept of interventional management of stroke, several options of multimodal reperfusion therapy are being evaluated. Options include emergency angioplasty and stenting as well as mechanical disruption or extraction of the thrombus.4–6 …

Localized therapeutic hypothermia in the brain for the treatment of ischemic stroke

stroke is, according to the World Health Organization ([10][1]), the third most common cause of death in the developed countries, exceeded only by coronary heart disease and cancer. Annually, 15 million people worldwide suffer a stroke. Of these 15 million people, 5.5 million die and 5 million are

Does the Merci Retriever Work?

In a decade after approval of IV rt-PA for acute stroke, treatment leads to good outcomes in less than half of patients, and hemorrhage rates have not been reduced. Recanalization improves outcome1 but is often delayed and incomplete. Devices offer the promise of rapid recanalization with a greater proportion of good outcomes and fewer hemorrhages. The Merci retrieval system was introduced with hopes of fulfilling this promise. The FDA recently approved this device for removal of thrombus from intracranial arteries in patients with stroke. Despite this approval, the question of whether the device works remains unsettled. The recently published Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial2 using the Merci retriever claims efficacy based on a recanalization rate that is greater than the spontaneous recanalization rate observed in the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial control group.3 Recanalization …

Does the Merci Retriever Work?

Section Editors: Geoffrey A. Donnan MD, FRACP Stephen M. Davis MD, FRACP Technically, it works. And remarkably so. The Merci Retriever is a mechanical embolectomy device designed to reopen occluded vessels by extracting occlusive thrombi from the cerebral vasculature. In the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial (parts I and II combined), among 151 patients enrolled in the intention-to-treat group; partial or complete recanalization by use of the device alone was achieved in 46%.1 This rate substantially exceeded that in the prespecified comparator group—patients enrolled in the control arm of the Prolyse in Acute Cerebral Thromboembolism (PROACT-II) trial (18%). The associated probability value of <0.0001 indicates a less than 1 in 10 000 chance that this result occurred by chance. The Merci Retriever indeed works. And it works well where we most need it to work: on proximal occlusions for which there was previously no good therapy. Proximal carotid terminus and M1 middle cerebral artery thrombi respond poorly to IV or intra-arterial fibrinolytic therapy, likely attributable in large part to the sheer volume of the clot burden requiring enzymatic digestion. The average volume of carotid terminus thrombi (0.4 ml) is more than an order of magnitude larger than that of M2 middle cerebral artery division thrombi …