Reperfusion Therapy For Acute Stroke Research Articles

Reperfusion-Related Intracerebral Hemorrhage.

The efficacy of intravenous thrombolysis (IVT) for acute ischemic stroke patients has been well established worldwide, with endovascular therapy performed in patients who have failed or are ineligible for IVT and who have major vessel occlusion. The most feared complication of acute stroke reperfusion therapy is intracerebral hemorrhage (ICH), as these patients have a poor clinical outcome and high mortality. The fundamental mechanisms responsible for reperfusion-related ICH include increased permeability and disruption of the blood-brain barrier. Recombinant tissue plasminogen activator may exacerbate the blood-brain barrier disruption through its pharmacological action during IVT. Furthermore, interactions between the device and the vessel walls and contrast intoxication may also be related to ICH, which includes the occurrence of subarachnoid hemorrhage after endovascular therapy. Numerous factors have been reported to be associated with or to be able to predict ICH, and several scoring systems have been developed for predicting symptomatic ICH (sICH) after IVT. However, a scoring system with enough power to detect an unacceptably high risk of sICH or to provide information on when to withdraw IVT has yet to be definitively established. In current clinical practice, acute stroke patients without contraindications for IVT who have been identified by conventional computed tomography scans normally undergo IVT, irrespective of any clinical predictors of ICH after IVT. Strategies that have been suggested for preventing reperfusion-related ICH in high-risk patients include intensive blood pressure control, tight glycemic control, and the avoidance of early aggressive antithrombotic therapy. If sICH, and especially massive parenchymal hematoma, does occur, hematoma expansion needs to be prevented through the use of tight blood pressure control and other methods. Although evidence of efficacy has yet to be established, surgical removal is performed not only for the purpose of saving lives but also for improving the functional outcome. In order to develop therapeutic strategies for reperfusion-related ICH that will lead to an improved stroke prognosis, further studies are warranted.

Multimodal Computed Tomography Based Definition of Cerebral Imaging Profiles for Acute Stroke Reperfusion Therapy (CT-DEFINE): Results of a Prospective Observational Study.

To prospectively evaluate the prognostic impact of multimodal computed tomography-based imaging in ischemic stroke patients potentially eligible for reperfusion therapy. Anterior circulation stroke patients underwent non-contrast CT (NCCT), CT-angiography, and CT-perfusion within 12 h from symptom-onset. Patients could be treated with intravenous-tissue plasminogen activator (IV-tPA), endovascular or combined reperfusion therapies. Cerebral imaging profiles (IP) were NCCT-Alberta Stroke Program Early CT Score (ASPECTS) > 7 (IP1); NCCT-ASPECTS > 5 and proximal occlusion on CT-angiography (IP2); CT-perfusion mismatch between cerebral blood volume (CBV)-ASPECTS, and cerebral blood flow (CBF)-ASPECTS ≥ 2 (IP3). Favorable outcome was defined as modified Rankin Scale ≤ 2 at 3 months. Of 102 included patients, 62 (61%) received any reperfusion therapy. In IP2 and IP3, favorable outcome was more frequent in patients with reperfusion therapy than in those without; however, this did not reach statistical significance (IP2: 39% vs 15%, p = 0.26; IP3: 50% vs 17 %; p = 0.31). No difference was seen in IP1 (58% vs 58%, p = 1.0). In IP2, patients with IV-tPA alone achieved better functional outcome (50% vs 11%, p = 0.03) and lower mortality (0% vs 28%, p = 0.045) than those without. Our results suggest a benefit with imaging profile selection based upon the combination of a small-to-moderate-sized infarction and a visible intracranial occlusion in patients receiving IV-tPA. Reperfusion therapy may be futile in patients without proven vessel occlusion.

Acute Stroke Reperfusion Therapy Trends in the Expanded Treatment Window Era

The American Heart Association/American Stroke Association (AHA/ASA) recommended an expansion of the time window for acute ischemic stroke (AIS) reperfusion with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) from 3 to 4.5 hours after symptom onset. We examine rates of IV and intra-arterial (IA) reperfusion before and after the recommendations to track guideline adoption in community practice. Patients with AIS in the Paul Coverdell National Acute Stroke Registry spanning years 2007-2012 were identified. Trends in rates of IV rt-PA versus IA therapy were examined. Outcomes included symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, ability to ambulate at discharge, and discharge destination. From 2007 to 2012, there were 182,235 AIS patients (median age, 72 years; 51.5% women) in the database at the time of analysis. AIS patients receiving IV rt-PA increased significantly from 3.7% in 2007 to 5.1% in 2012 in the ≤3 hours time window and from .2% in 2007 to 1.3% in 2012 in the 3-4.5 hours time window (P < .001 for both). There was also a significant increase in the rate of IA therapy between 2007 and 2012 (P < .001). There was a significant decrease in the rate of sICH among patients who received any reperfusion between 2007 and 2012. There was a trend for increased utilization of IV rt-PA in the 0-3 hours and the 3-4.5 hours time windows, which began around the same time as the publication of AHA/ASA recommendations in 2009. This increase was associated with an increase in IA treatment rates along with a decrease in overall sICH rates for patients receiving any reperfusion.

Cost drivers for reperfusion therapy in acute stroke

Cost drivers for reperfusion therapy in acute stroke

Abstract 184: Drivers of Costs Associated With Reperfusion Therapy in Acute Stroke: The IMS III Trial

Importance: The annual costs of stroke to the nation have been estimated to be over $38 billion, with nearly $22 billion attributed to direct medical costs. Objective: To understand cost drivers during the initial hospitalization for acute ischemic stroke subjects in the IMS III Trial. Design, Setting and Participants: Prospective cost analysis of subjects from U.S. centers treated with IV t-PA alone or IV t-PA followed by endovascular therapy in the IMS III trial. Cost of initial hospital admission was estimated from the actual hospital charges on UB04 billing forms provided by the treating hospitals. Cost profiles of the IMS III treatment groups were compared to profiles of a sample of US patients from the HCUP National Inpatient Sample (NIS) for 2010. Interventions: IV t-PA alone as compared to IV t-PA followed by endovascular therapy. Main Outcome Measure: Costs of hospitalization for acute stroke subjects. Results: The adjusted cost of a stroke admission in the study was $35,130 for subjects treated with endovascular therapy following IV t-PA and $25,630 for subjects treated with IV t-PA alone (p&lt;0.0001). The higher cost in the endovascular therapy following IV t-PA treatment arm was largely explained by the costs of the devices. Significant factors related to costs included treatment group (higher costs with endovascular therapy), baseline NIH Stroke Scale (higher costs with higher severity), time from stroke onset to IV t-PA (lower costs with earlier treatment), age (higher costs with older age), stroke location (higher cost with right hemispheric location) and comorbid diabetes (higher costs with diabetes). The mean cost for subjects who had routine use of general anesthesia as part of endovascular therapy was $46,444 as compared to $30,350 for those who did not have general anesthesia. The costs of embolectomy for IMS III subjects and patients from the NIS cohort exceeded the Medicare DRG payment in more than 75% of hospitalized patients. Conclusions and Relevance: Changing the processes of acute stroke care, such as minimizing the time to start of IV t-PA and decreasing the use of routine general anesthesia, may improve the cost-effectiveness of medical and endovascular therapy for acute stroke.

Abstract 139: Acute Stroke Reperfusion Therapy Trends in the Expanded Treatment Window Era

BACKGROUND: The American Heart Association/American Stroke Association (AHA/ASA) recommended an expansion of the time window for acute ischemic stroke (AIS) reperfusion with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) from 3 to 4.5 hours after symptom onset. We examined rates of IV and intra-arterial (IA) reperfusion before and after the recommendations to track guideline adoption in community practice. METHODS: Patients with AIS in the Paul Coverdell National Acute Stroke Registry spanning years 2007 to 2012 were identified. Trends in rates of IV rt-PA versus IA therapy were examined. Outcomes studied included symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, ability to ambulate at discharge, and discharge destination. RESULTS: From 2007 to 2012, there were 182,235 AIS patients (median age 72 years, 51.5% women) in the database. AIS patients receiving IV rt-PA increased significantly from 3.7% in 2007 to 5.1% in 2012 in the ≤ 3 hour time window and from 0.2% in 2007 to 1.3% in 2012 in the 3-4.5 hour time window (p&lt;0.001 for both). There was also a significant increase in rate of IA therapy between 2007 and 2012 from 0.5% to 1.9% (p&lt;0.001). There was a significant decrease in the rate of sICH among patients who received any reperfusion therapy between 2007 and 2012 (p=0.003). CONCLUSION: There was increased utilization of IV rt-PA in the 3-4.5 hour time window from 2007 to 2012, which is likely from guideline recommendations from the AHA/ASA. This increase was associated with an increase in IA treatment rate along with a decrease in overall sICH rates for patients receiving any reperfusion therapy.

Neurologist and emergency neuroendovascular revascularization -training programs for endovascular procedures-

Emergency neuroendovascular revascularization is a reperfusion therapy for acute stroke. The operator for this therapy has to obtain a license as a specialist in endovascular procedures. For neurologists wishing to acquire this license, there are two kinds of training programs: full-time training and concurrent training. Full-time training was chosen by the first author of this review, while concurrent training will be performed by staff in the author's department. The advantage of full-time training is the acquisition of a lot of experience of various diseases that are treated with endovascular procedures and managed in the periprocedural period. However, full-time training has the disadvantages of a requirement to discontinue medical care of neurological diseases except for stroke and employment at a remote institution. The advantages and disadvantages of concurrent training are the reverse of those of full-time training. Neither training system can succeed without cooperation from Departments of Neurology in neighboring universities and the institutional Department of Neurosurgery. It is particularly important for each neurologist to establish a goal of becoming an operator for recanalization therapy alone or for all fields of endovascular procedures because training will differ for attainment of each operator's goal.

Reply: ‘Central retinal artery occlusion and cerebral stroke’

Sir, We are grateful to Dr McLeod1 for the interest that he has shown in our paper.2 Rather, then there being a conspiracy to increase the confusion within central retinal artery occlusion (CRAO), our study demonstrates that the disease is incompletely understood. In particular, we disagree with Dr McLeod that the retinal penumbra lasts for more than 24 h. Retinal and cerebrovascular ischaemia share a number of common pathophysiological features and is reflected by the recent extended definition of stroke involving retinal as well as cerebral ischaemia.3 In vitro experiments show that when neuronal cells are deprived of oxygen, that within 5 s, there is evidence of neuronal dysfunction. Within 10 s, cell death occurs. The elegant experiment of Astrup et al4 demonstrated that the penumbra is a function of collateral perfusion and that if there was no resolution of the occlusion, then eventually the penumbra would fail, and infarction would be permanent. In cerebral stroke using perfusion imaging, various groups have demonstrated that the ischaemic penumbra may persist beyond 24 h. However, randomised controlled trials of reperfusion therapy in acute stroke have demonstrated on that in the majority of individuals, the ischaemic penumbra only extends out to 4.5 h and at maximum, 6 h.5, 6 The misperceptions that the retinal penumbra persists for 24 h, initially backed up by observational data, led to the design of two randomised controlled trials that recruited individual with central retinal artery occlusion of beyond 6 h. The EAGLE study recruited subjects up to 19 h of symptom onset,7 while our group conducted a randomised controlled trial of intravenous tPA given to individuals within 24 h of symptom onset.8 Both of these randomised controlled trials were negative studies, however, a signal was seen in individuals who receive tPA within 6 h of symptom onset.8 This mirrors the retinal tolerance time demonstrated in Hayreh's animal experiments of 4 h.9 Conversely, if the thrombus that initially caused a retinal artery occlusion resolves such that retinal perfusion is restored, then the symptoms will be invariably improved leading to a transient central retinal artery occlusion. Nevertheless, we agree with Dr McLeod that the classical clinical features of central retinal artery occlusion remain more or less the same, but that various findings may give a clue as to the time of the onset or alternatively the presence of partial occlusion. These are important points given that for randomised controlled trials on the treatment of CRAO are to succeed, then individuals need to be recruited within the shortest time possible.

Abstract TP247: Real-time Videomonitoring Markedly Shortens Time Delays For Reperfusion In Acute Stroke

Introduction: Shortening door-to-needle time is one of the major goals of reperfusion therapy for acute stroke. Real-time videomonitoring provides 24/7 expert support and may potentially accelerate actions taken and improve the decision-making in candidates for reperfusion. We aimed to evaluate the impact of real-time videomonitoring on shortening in-hospital time delays for reperfusion therapy and on the quality of care in acute stroke patients. Methods: We evaluated consecutive patients, candidates for reperfusion who underwent stroke code activation. All were admitted to the ER and emergently evaluated by a Stroke Neurologist either in a designated stroke box with videomonitoring (VM) or in a conventional box without VM (NonVM). In all patients, time delays were prospectively collected in specific worksheets. Real-time VM was conducted by experienced stroke researchers who interacted and encouraged speediness of the evaluation process as well as timed and stored images at pre-specified time-points. Results: A total of 100 patients were evaluated. 50 on each arm. There were no significant differences between groups in baseline characteristics: Age (VM 70.7 ±16 vs. 71.1±12 in NonVM patients), gender (52% and 50% of men), median time from symptoms onset to admission (76 vs. 73min) and baseline stroke severity NIHSS score (6 vs. 7). In the VM group the median time for blood sampling was 5minutes, and duration of TCD exam 7minutes. Overall median time in box was significantly shorter in VM 13±9min compared to NonVM 20±12 min, p=0.045. VM significantly reduces the time to fist neurological evaluation &lt;5min (VM 98% vs. NonVM 88%), p=0.038. Door-to-CT time was &lt;25minutes in VM (50%) compared to NonVM (42%), p=0,052. 48% of VM and 44% of NonVM patients received reperfusion therapy. The goal of door-to-needle &lt;40min was achieved in 77.8% of VM compared to only 52% of NonVM patients (p=0.034). Conclusion: Real-time VM markedly reduces in-hospital delays for reperfusion therapy by shortening time to neurological evaluation, time to CT, and door-to-needle times. Larger studies are needed to evaluate the yield and impact of real-time VM on stroke outcome.

Advanced imaging to extend the therapeutic time window of acute ischemic stroke

Reperfusion therapy for acute stroke has evolved from the initial use of intravenous tissue plasminogen activator (tPA) within 3 hours of symptom onset to more recent guideline-recommended use up to 4.5 hours. In addition, endovascular therapy is increasingly utilized for stroke treatment and is typically initiated up to 8 hours after onset. Recent studies demonstrate that imaging of the ischemic penumbra with diffusion/perfusion magnetic resonance imaging (MRI) can identify subgroups of patients who are likely to improve following successful reperfusion (Target Mismatch profile) and others who are at increased risk for hemorrhage and poor clinical outcomes (Malignant profile). New data indicate that stent retriever devices provide better recanalization efficacy and clinical outcomes than the previously available mechanical thrombectomy devices. Going forward, we believe that the use of penumbral imaging with validated MRI techniques, as well as the currently less well-validated computed tomography (CT) perfusion approach, will maximize benefit and reduce the risk of adverse events and poor outcomes when used both early after stroke onset and at later time points. New trials that feature diffusion/perfusion MRI or CT perfusion-based patient selection for treatment with intravenous tPA and or endovascular therapies versus nonreperfused control groups are planned or in progress. We predict that these trials will confirm the hypothesis that penumbral imaging can enhance patient selection and extend the therapeutic time window for acute ischemic stroke.

Reperfusion Therapy for Acute Stroke Improves Outcome by Decreasing Neuroinflammation

Inflammation is a major step in the ischemic cascade, and proinflammatory cytokines, adhesion molecules and chemokines have been related to brain injury after stroke. To investigate if tissue plasminogen activator (tPA) treatment decreases the deleterious neuroinflammatory response that follows ischemic stroke. Our target population was 80 patients with ischemic stroke involving the middle cerebral artery (MCA) territory. Among them, 41 received tPA within 3h of symptom onset according to National Institute of Neurological Disorders and Stroke recommendations and the remaining 39 were assessed prior to local approval of tPA. In all patients, blood samples were obtained at 12 and 24h after symptom onset. Serum determinations of interleukin (IL)-6, inter-cellular adhesion molecule 1 (ICAM-1), IL-8 and tumor necrosis factor-alpha (TNF-α) were obtained by ELISA. National Institutes of Health Stroke Scale (NIHSS) and transcranial Doppler recordings (proximal/distal occlusion, p.o/d.o) were obtained at baseline and follow-up. No differences were found between the two groups in baseline NIHSS scores (tPA = 17 and control = 17; p = 0.38) or MCA status (tPA: p.o = 65.8%, control: p.o = 55.3%; p = 0.41). We found a lower level of mean IL-6 and IL-8 in the tPA treatment group: IL-6 (14.06 vs. 37.88pg/ml, p = 0.001) and IL-8 (70.98 vs. 465pg/ml, p < 0.001). No significant changes appeared for ICAM-1 and TNF-α. This biological response was accompanied by a neurological improvement (24h NIHSS: tPA = 11 and control = 15; p = 0.024) and a mortality reduction (tPA = 9.75% vs. controls = 28.2%; p = 0.038). Patients who improved and those who recanalised had the lowest IL-6 levels (p < 0.005). tPA treatment reduces the severity of the inflammatory phenomena that follows stroke. These results may partially explain the efficacy of reperfusion therapy on stroke outcome.

Reperfusion Therapy in Acute Stroke: State-of-the-Art and Future Directions

Reperfusion therapy with IV rt-PA and recanalization produces good outcomes in patients with acute stroke, but challenges remain. It is estimated that 85% of all ischemic strokes are not treated with thrombolysis; thus, improved and early access to treatment is needed. It is suggested that the 3 to 6-hour time window for treatment may be extended by better patient selection criteria using transcranial Doppler markers of the diffusion-perfusion mismatch method [Restrepo L et al. J Neuroimaging 2006] and combination therapies, such as reduced-dose rt-PA plus eptifibatide [Pancioli AM et al. Stroke 2008] or rt-PA plus GPIIb/IIIa antagonists.

The Physiologic Time Window in Acute Stroke

The most important treatment variable for a successful functional outcome following ischemic stroke is time to thrombolysis treatment. Recent evidence suggests that although earlier treatment leads to a better outcome, the treatment opportunity window is not fixed. This article discusses recent clinical trials that defined the optimal time window to maximize the effectiveness of reperfusion therapy in acute stroke.

Catheter‐based therapy for acute ischemic stroke: A national unmet need

Early reperfusion therapy for acute stroke, similar to acute myocardial infarction, has the best opportunity to reduce morbidity and mortality. Treatment options include intravenous (IV) thrombolysis therapy and/or catheter-based therapy (CBT). Catheter-based therapies include local intra-arterial thrombolysis, mechanical thrombectomy, and angioplasty techniques. Intravenous thrombolysis is limited to the first three hours after symptom onset, which excludes many patients with disabling stroke deficits. Catheter-based therapy is effective up to seven hours after onset, but availability is limited by the lack of neurointerventionalists available around the clock to provide this care. To increase the number of providers for acute stroke reperfusion therapy, we have formed a multidisciplinary team to take advantage of cardiologists' carotid stent placement experience to provide continuous coverage for emergency reperfusion therapy. We present two cases of acute stroke treated with CBT by interventional cardiologists.

Ultrasound-Enhanced Thrombolysis

See related article, pages 1470–1475. Intravenous tissue plasminogen activator (tPA) infusion is the fastest and easiest way to initiate reperfusion therapy in acute stroke. However, poor recovery can still be expected in up to 50% of patients, likely as a result of the initial severity of ischemic insult and slow and incomplete thrombolysis.1,2 Clinical improvement and functional independence after stroke usually occur after arterial recanalization.3–6 A recent meta-analysis showed that recanalization is associated with a 4- to 5-fold increase in the odds of a good final functional outcome and a 4- to 5-fold reduction in the odds of death.7 These results lend strong support to the hypothesis that recanalization is the mechanism of how systemic tPA increases the likelihood of recovery from stroke and the use of recanalization as a surrogate end point in phase II trials of reperfusion agents in acute ischemic stroke. Over the past 30 years, in vitro and animal studies have provided evidence that thrombolysis with tPA can be enhanced with ultrasound. Although the mechanisms are still not fully understood, it is known that ultrasound accelerates enzymatic fibrinolysis primarily through nonthermal mechanisms by increasing transport of drug molecules into the clot.8,9 Mechanical effects of ultrasound radiation forces have the ability to influence drug transport. In addition, ultrasound can promote the motion of fluid through and around the …

Differences in Response to Reperfusion Therapies in Acute Stroke Between Men and Women: Mediated by Sex or by Chance?

To the Editor: Drs Sandercock and Lewis remind us of some of the very real hazards of subgroup analysis. Performing multiple “one-variable-at-time” subgroup analyses will inevitably yield spurious results.1,2 This problem of spurious false-positive results, however, is not one that is directly addressed by increased sample size or statistical power, as they imply. Further, they seem to argue that the proper response to the risk of spurious false-positive results is to cease all analyses on variation in the effect of thrombolysis in stroke until the IST-3 Trial is completed. We respectfully disagree. Although multiple “one-variable-at a-time” subgroup analyses may sometimes yield misleading results, for treatments with both risks and benefits such as recombinant tissue plasminogen activator for stroke, reporting only the summary result is also likely to be misleading, because the …