OBJECTIVES: INTRODUCTION ADVANCES IN ACUTE STROKE CARE

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1 Brian A. Stettler, MD Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine Member, Greater Cincinnati/Northern Kentucky Stroke Team Cincinnati, Ohio OBJECTIVES: 1. Discuss the use of advanced diagnostic imaging in stroke. 2. Discuss the use of new therapies in ischemic stroke. 3. Discuss a novel medical treatment for hemorrhagic stroke. INTRODUCTION Recent years have brought many advances in both the diagnosis and treatment of acute stroke, with many technologies still undergoing testing in clinical trials. Unfortunately, despite this progress, stroke remains the third leading cause of death in the United States and the leading cause of disability. The narrow time windows from symptom onset to treatment, the relative lack of knowledge about stroke by the public, and a lack of variety of treatments for patients not considered eligible for recombinant tissue plasminogen activator (rt-pa) reduces the overall rate of treatment for acute stroke. This review will address some recent and emerging technologies for the diagnosis and treatment of acute stroke that may change the way this devastating disease is approached in the emergency department (ED). Stroke Diagnostics For the past twenty years, diagnostics in the setting of acute stroke have classically consisted of a fingerstick blood sugar and non-contrast computed tomography (CT) of the head. Both CT and magnetic resonance imaging (MRI) technology have advanced in recent years to not only be able to assess the cerebral tissue damaged from a stroke, but also include the ability to assess for arterial occlusion as well as estimate the amount of brain tissue at risk during stroke in order to confirm a diagnosis and guide potential therapy. One method of confirming the diagnosis of ischemic stroke and assessing the extent of the arterial blockage is through computed tomography angiography (CTA). For patients with ischemic stroke, CTA takes advantage of the widespread availability of CT scanners in EDs to allow a non-invasive look at the cerebral vasculature to assess for stenosis or occlusion. The technique uses standard spiral CT scanners with a 50 CC contrast bolus. The axial cuts, or source images, are then reformatted into a three-dimensional projection that allows visualization of the circle of Willis as well as proximal portions of the middle cerebral artery (MCA), anterior cerebral artery (ACA) and vertebrobasilar system. The entire process typically adds minutes to the standard non-contrasted CT imaging. The narrow time windows from symptom onset to treatment, the relative lack of knowledge about stroke by the public, and a lack of variety of treatments for patients not considered eligible for rt-pa, reduces the overall rate of treatment for acute stroke. 71

2 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies It is important to remember, however, that even in the absence of documented occlusion on CTA, a candidate for IV fibrinolysis should still be treated, as reversal of the neurologic deficit can still be achieved by opening a small-vessel occlusion not visualized on CTA. The advantages of CTA include its speed and availability as well as its ability to assess for occlusion of the cerebral vessels that could affect treatment algorithms. Lev et al 1 used CTA in 44 consecutive patients who presented within six hours of onset of symptoms to assess for occlusion of a cerebral vessel prior to angiographic correlation with diagnostic angiography. The study was designed to assess the feasibility that CTA could be used as a screening tool to decide when to proceed on to intraarterial (IA) fibrinolysis. Of 224 vessels studied with diagnostic angiography after CTA, the sensitivity of CTA for large-vessel occlusion was 98.4% with a specificity of 98.1% and overall accuracy of 98.2%. They concluded that CTA is highly accurate in the detection of large vessel occlusion and may be valuable for the triage of patients to intra-arterial thrombolysis. Another study performed by Verro et al 2 evaluated 54 consecutive patients presenting with symptoms of ischemia with non-contrasted CT followed by CTA of the circle of Willis. The study was used to select patients who did not meet standard National Institute of Neurological Disorders and Stroke (NINDS) IV fibrinolysis criteria for digital subtraction angiography (DSA) and potential IA fibrinolysis. The authors concluded that CTA provides an accurate assessment of occlusion in the acute setting and may be used to screen candidates for aggressive treatment who might otherwise not receive standard IV therapy due to exclusion. It is important to remember, however, that even in the absence of documented occlusion on CTA, a candidate for IV fibrinolysis should still be treated, as reversal of the neurologic deficit can still be achieved by opening a small-vessel occlusion not visualized on CTA. In fact, Verro et al suggested in a separate study that CTA did lead to more conservative management and lower rates of treatment compared to decisions made blinded to CTA results. 3 The goal in the use of rt-pa for fibrinolysis of an acute ischemic stroke is to salvage the maximum amount of neuronal tissue that has not yet infarcted. It has been shown that in acute arterial occlusion there is a central core of brain that infarcts within minutes due to complete loss of blood flow and a larger area of ischemic brain which remains alive but functions abnormally due to loss of normal oxygen supply, termed the ischemic penumbra. The presence or absence of an ischemic penumbra seems to correlate with the prognosis for recovery after fibrinolysis. 4,5 A lack of ischemic, but not yet infracted tissue reflects poorly on the chance of recovery after treatment. The gold standard for evaluation of the ischemic penumbra is investigation by MRI. Magnetic resonance imaging allows generation of images that show the area of decreased blood flow in the brain as well as the area of infarcted tissue, allowing a simple assessment of whether there still exists living tissue receiving inadequate blood flow that may benefit from fibrinolysis, also known as a diffusion-perfusion mismatch. Magnetic resonance angiography (MRA) functions in a fashion very similar to CTA, showing vessel anatomy, including cervical vessels and the circle of Willis. 72

3 Diffusion-weighted MRI involves a technique that displays a hyperintense, or white, signal which represents tissue which is largely unsalvageable and irreversibly damaged. While conventional MRI or non-contrasted CT takes up to six hours to demonstrate changes of ischemia, diffusion-weighted imaging (DWI) will document these changes within minutes from onset of ischemia. Perfusion-weighted MRI uses MRI to track a bolus of gadolinium through the brain. Both cerebral blood volume (CBV) and the time it takes for the gadolinium to pass through the brain can be assessed, allowing cerebral blood flow (CBF) to be indirectly imaged. A decrease in CBF reflects the area of tissue which is underperfused, encompassing both the infarct core and the penumbra. Comparison of the DWI to the PWI allows the clinician to subtract the DWI hyperintense signal from the abnormal signal on PWI to ascertain whether there is still tissue which is alive but underperfused. This is the target area of tissue for reperfusion. A matched area of DWI and PWI signal abnormality suggests little benefit to fibrinolysis, as the infarct is completed. Studies involving MRI in the hyperacute time period are small but encouraging. Parsons et al 4 performed a study utilizing DWI/PWI in acute stroke of less than 6 hours duration. The study involved 19 patients treated within 6 hours with IV rt-pa matched with 21 historical controls. All patients underwent DWI/ PWI, but they were given fibrinolysis based on standardized protocols and not by selection with MRI. The study showed that when patients were analyzed by group as either treated or not treated, there was a trend towards benefit with treatment, but no significant difference between the groups. However, when only patients with a DWI/PWI mismatch were analyzed, there was a significant improvement in both outcome National Institute of Health Stroke Scale (NIHSS ) (Mean 5.3 points, 95% CI points, p < 0.01) and functional independence by modified Rankin scale (mrs) (χ2 =4.6, p = 0.03) in the treated patients. Despite the small numbers in this study, it suggests that more benefit may be gained by treating patients with a DWI/ PWI mismatch on MRI. When assessing an acute stroke, typical MRI protocols in the hyperacute time period add only 20 minutes to overall treatment time. Cerebral perfusion CT also allows the differentiation of ischemic from infarcted tissue. In perfusion CT (PCT), a bolus of contrast is given IV and the attenuation of the brain parenchyma is then measured, with the thought that as the contrast passes through the parenchyma, the attenuation of the brain tissue will increase. Further, in the case of arterial occlusion, the increase in attenuation will be delayed or lost altogether in tissue that has decreased blood supply, allowing CT to identify tissue at risk of infarct or already infarcted. Tracking the contrast bolus in the parenchyma gives measures of CBF and CBV. Reduced perfusion with preserved or increased CBV is thought to represent areas of ischemia, while reduced perfusion coupled with reduced CBV is thought to represent already infarcted tissue. This allows the ultimate goal of determination of the ischemic penumbra by CT. The presence or absence of an ischemic penumbra seems to correlate with the prognosis for recovery after fibrinolysis. 73

4 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies The ideal patient for acute multimodal imaging is the patient who arrives with prolonged duration of symptoms in which advanced imaging may document salvageable brain or in the patient with an atypical presentation in which the diagnosis of stroke is in question. Studies of the diagnostic capability of CT perfusion have generally included small numbers of patients, but appear promising in comparison with MRI. Wintermark et al 6 evaluated 22 patients upon presentation to the ED with perfusion CT and then compared these images to delayed DWI MRI and found that the area of perfusion deficit on initial CT strongly correlated with the final DWI abnormality in patients without vessel recanalization (n= 8, correlation coefficient 0.958). The study further found that in those with arterial recanalization, the final infarct on the DWI was smaller than the area of total ischemia on initial CT, but larger than the area of initial infarct on CT, which they interpreted to show accurate CT depiction of the penumbra with some recovery after clot lysis (n=13). Ultimately, the authors concluded that PCT gives an accurate estimate of the area of ischemia and infarct, in comparison with MRI. Another study by Schramm et al 7 compared perfusion CT with perfusion-weighted MRI (PWI) and DWI to determine correlation between the two studies for area of perfusion and diffusion defects. In this study, 22 patients underwent both CT and MRI within six hours of onset of acute neurologic deficit. This study found no significant difference between perfusion CT lesion volume and PWI or CT perfusion evidence of infarction and DWI. This suggests good reproducibility between PCT and MRI for evaluation of the ischemic penumbra, although this will need to be confirmed with larger studies. The perfusion CT averaged approximately 10 minutes to complete and can be performed on most spiral CT scanners with the addition of imaging software, making it more accessible to most EDs in real-time. At this point, most centers still require a non-contrast CT as the gold standard to rule out hemorrhage prior to treatment with rt-pa, therefore the coupling of standard non-contrast CT imaging with advanced CT diagnostics makes practical sense. The ideal patient for acute multimodal imaging is the patient who arrives with prolonged duration of symptoms in which advanced imaging may document salvageable brain or in the patient with an atypical presentation in which the diagnosis of stroke is in question. In both of these instances, the advanced diagnostic imaging may help to guide therapy. Ongoing studies to evaluate the utility of DWI/PWI mismatch in patients with a prolonged time from symptom onset include DIAS II (Desmoteplase in Acute Ischemic Stroke II) which utilizes MRI to randomize patients to treatment with desmoteplase, a novel fibrinolytic, in the time frame from 3-9 hours from symptom onset. Only patients with a significant mismatch on imaging are entered, as they are thought to have salvageable brain. A preceding trial, DEDAS (Dose Escalation of Desmoteplase for Acute Ischemic Stroke) did show clinical benefit in the target population when treated with fibrinolytic at the prolonged time period. 8 A second study, EPITHET (Echoplanar Imaging Thrombolysis Evaluation Trial) also evaluates the use of MRI in the setting of prolonged time from symptom onset and is currently ongoing. This trial uses standard-dose rt-pa 3-6 hours from symptom onset in patients with significant DWI/PWI mismatch. Further studies are still needed, but in a patient with an 74

5 obvious proximal vessel occlusion and significant mismatch, a discussion of risks and benefits with the patient and family may favor treatment despite increased risk of hemorrhage beyond three hours. This patient may also be guided towards IA therapy if this is available at the treating institution or referral center. A final diagnostic tool that is still in the research stage is that of serum biomarkers. While a unique marker of cell death, such as troponin for the myocardium, has not yet been identified, there is ongoing work that suggests that a combination of serum markers may have sufficient sensitivity and specificity to be useful in the clinical arena. This biomarker panel would be ideal if it demonstrates a quick and accurate confirmatory test for cerebral ischemia while ruling out other causes of weakness. Acute Therapies in Ischemic Stroke There are many novel therapies for the treatment of ischemic stroke developed or advanced within the past few years, some of which are still undergoing evaluation in clinical research trials and some of which have entered clinical practice. These therapies include IA therapy with medications or mechanical devices for clot dissolution and removal, combined drug therapy, transcranial Doppler, novel fibrinolytic agents, and drugs designed to protect ischemic tissue from oxidative damage. A novel drug therapy for hemorrhagic stroke that may help decrease the size and resultant damage of intracerebral hemorrhage is also currently undergoing clinical testing. One of the therapies with the longest clinical track record that is still undergoing evaluation is IA therapy for acute ischemic stroke. The theoretical basis for this therapy is that a drug or a mechanical device delivered directly to the sight of an arterial occlusion may be better at achieving recanalization of the vessel and recovery of ischemic brain tissue. Therapy delivered IA has been around for more than a decade and has previously included pro-urokinase or rt-pa delivered directly or in close proximity to the thrombus by microcatheter. The treatment window for drug delivery typically extends out to six hours in this setting and sometimes beyond that time depending on the clinical picture and presence or absence of an ischemic penumbra. Two clinical trials already completed using drug delivery via the IA route of administration include the IMS (Interventional Management of Stroke) trial 9 using t-pa, and the PROACT II (Prolyse in Acute Cerebral Thromboembolism II) trial, which utilized pro-urokinase as a thrombolytic. 10 Both of these trials used extended time windows of seven and eight hours from symptom onset, respectively, for the completion of the IA procedure. The IMS protocol called for a novel approach, instituting a reduced dose of IV rt- PA in patients with an NIHSS >10 presenting within three hours of symptom onset. All patients in IMS then went to angiography and also received IA rt-pa if they were found to have a large-vessel occlusion. This protocol allowed early initiation of therapy in the ED, but still takes advantage of directed fibrinolytic via the IA route. There was no randomization and all patients were treated, with the NINDS trial used as historical controls for comparison. The 80 subjects treated in IMS had a better clinical outcome by all endpoints than the placebo-treated patients in the NINDS trial 11 and a similar outcome to the IV rt-pa treated historical controls from NINDS. Symptomatic hemorrhage rates were also similar to IV rt-pa at 6.3%. The subjects in PROACT II were randomized to IA pro-urokinase plus heparin during angiography or a 4-hour infusion of heparin alone. The 121 subjects treated with IA pro-urokinase were more likely to have a mrs of 2 or less at 90 days than the 59 controls (p= 0.04) despite an increased risk of symptomatic intracerebral hemorrhage (10% vs 2% for controls, p=0.06). There was no difference in overall mortality in PROACT II between treated patients (25%) and controls (27%) despite the increased incidence of hemorrhage. 75

6 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies it remains to be proven whether IV/IA or IV therapy alone is superior within three hours of symptom onset. From these data, many questions remain unanswered. As IMS used combined intravenous rt-pa initiated within three hours and IA rt-pa, but had similar outcomes to the treated patients in the NINDS trial, it remains to be proven whether IV/IA or IV therapy alone is superior within three hours of symptom onset. This question is currently being studied in the ongoing IMS III trial, which randomizes patients to either IV rt-pa therapy or combined IV/IA within three hours of symptom onset. Another IA therapy currently under study is the use of mechanical devices. The MR RESCUE (MR and Recanalization of Stroke Clots Using Embolectomy) trial randomizes patients based on the presence of a DWI/PWI difference to either best medical treatment or IA therapy with the MERCI retriever, a mechanical device designed to remove thrombus from proximal cerebral vessels without chemical agents. Study patients can be treated out to eight hours from symptom onset and are still eligible for treatment even if systemically anticoagulated with heparin or coumadin, as opposed to traditional treatment with IV rt-pa. Initial experience with this device has been fairly positive, as reported in the MERCI trial. 12 The device did show a statistically significant ability to achieve recanalization at 46 % vs 18% of historical controls (p < ), although the long-term clinical benefit is more debatable. Only 28% of patients treated with the device achieved a mrs of 2 or less and the mortality was 44% at 90 days in treated patients. While both of these outcomes are substantially worse than previous benchmarks, the strokes treated in MERCI were more severe, as measured by the NIHSS, than previous trials. Further, many of the treated patients were ineligible for other therapies, such as fibrinolytic, and the mechanical device offered the only possibility of therapy for their severe deficit. The addition of advanced diagnostic imaging in MR RESCUE may help define which group of patients will benefit from this novel therapy. Another recent advance in acute stroke care comes with the testing of combined therapy in the early stages of acute ischemic stroke. There are several ongoing clinical trials that are testing the combination of a fibrinolytic agent with the addition of a glycoprotein IIb/IIIa inhibitor. The combination of these agents in previous cardiac trials has shown decreased rates of post-infarction complications, such as reinfarction and death. 13,14 This is most likely due to increased recanalization and maintenance of vessel patency by attacking both the fibrin meshwork of the clot and disassociating the platelets from the thrombus as well. One trial that is currently ongoing, the CLEAR trial (Combined Approach to Lysis Utilizing Eptifibatide and rt-pa in Acute Ischemic Stroke) randomizes patients to treatment with standard rt-pa or low-dose rt-pa and eptifibatide within three hours of symptom onset. Goals of this trial are to assess both the efficacy of the combined approach to see if there is increased rate of recovery from stroke, but also to see if combined therapy at lower doses is safer than standard rt-pa, with lower rates of symptomatic intracranial hemorrhage (sich). 76

7 A second ongoing clinical trial using combined therapy incorporates many of the aspects already discussed. ROSIE (Reperfusion of stroke Safety study Imaging Evaluation) uses MRI to document a DWI/PWI mismatch and then randomizes those patients with a mismatch who present within 24 hours of stroke symptom onset to a combination of reteplase (rt-pa) plus abciximab or abciximab alone. Both of these trials are using lower doses of the fibrinolytic agent than the typical cardiac dose and are following patients for evidence of hemorrhage and clinical outcome. While the tissue of the heart and the brain are not similar, it is hoped that the combined therapies will show better, safer recanalization of cerebral vessels compared to the standard therapy of rt-pa. A final therapy to be discussed for acute ischemic stroke treatment is that of transcranial Doppler ultrasound (TCD). Transcranial Doppler ultrasound uses high energy ultrasound to penetrate the skull for monitoring of vasospasm or occlusion of the large cerebral vessels such as the MCA or basilar artery. It was postulated that the energy of TCD, in the presence of a thrombus treated with rt-pa, may also speed recanalization of the target vessel. Alexandrov et al reported on TCD therapy in combination with rt-pa in 126 patients, 63 randomized to TCD therapy plus rt-pa and 63 treated with IV rt-pa only. TCD did show effectiveness in arterial recanalization of the MCA, although the effects on clinical outcome were minimal. 15 All patients presented within three hours of symptom onset, received rt-pa at standard dosing, and had a middle cerebral artery occlusion as documented by TCD and clinical symptoms. Complete recanalization of the target vessel that was sustained at two hours occurred in the TCD-treated group in 24 of 63 patients and in 8 of 63 controls (p = 0.002) There was no difference in sich or death in the groups, but the clinical improvement in the TCDtreated group was not significantly better than the control group. While these data are encouraging, more work is required to determine if there is a select group of patients upon which this therapy should be instituted. Further, the therapy is technically difficult to achieve in the ED, as most hospitals do not have anyone trained in the use of TCD available on call and there is no standardized device for delivering this therapy which is very operator-dependent. One of the therapies long sought in the realm of acute stroke care is that of a neuroprotectant. It is thought that part of the damage to the brain in the setting of ischemic stroke occurs due to the formation of free radicals within the brain tissue after arterial occlusion and subsequent reperfusion. The hope for this elusive neuroprotectant drug is that it would have few side effects and be easily administered to salvage ischemic brain from damage by these free radicals, both before and after fibrinolytic therapy, as well as in patients otherwise ineligible for treatment. There have been many examples of successful agents in laboratory animals and bench research, but until recently there have been no reported successes in human clinical trials. The SAINT trial (Stroke-Acute Ischemic NXY Treatment Trial) reported While the tissue of the heart and the brain are not similar, it is hoped that the combined therapies will show better, safer recanalization of cerebral vessels compared to the standard therapy of rt-pa. 77

8 ADVANCING THE STANDARD OF CARE: Cardiovascular and Neurovascular Emergencies There was a significant improvement in all clinical outcomes, including mrs, Barthel index, and Glascow outcome scale in patients treated with rfviia as opposed to placebo. on the use of an agent labeled NXY-059 in 1722 patients with acute ischemic stroke that presented within six hours of symptom onset. 16 Patients were randomized to an infusion of NXY-059 over a 72 hour period versus placebo. NXY-059 did show a very modest clinical benefit in the modified Rankin scale at 90 days as compared to placebo. This effect was lost, however, in looking at NIHSS and Barthel index, as there was no difference at 90 days in these outcome scales between study patients and controls. Interestingly, in a post-hoc analysis, it was found that in patients treated with rt-pa in the trial, there was a significantly lower rate of sich in patients treated with NXY-059 versus placebo (2.5% vs 6.4% respectively, p = 0.036). While this is yet unconfirmed, this suggests that there may be some protective effect against hemorrhagic transformation in patients treated with fibrinolytic agents, raising the possibility of using these agents in combination with NXY-059 in the future. The SAINT II trial is currently ongoing to further investigate the clinical efficacy of NXY-059 as a neuroprotectant and confirm or dispute previous results. Given the cost associated with the agent, it would be difficult for the health care system to support the drug in all ischemic strokes unless a more brisk clinical effect is seen in follow-up trials. Regardless, the search for an effective and well-tolerated neuroprotectant agent continues. Acute Therapies in Hemorrhagic Stroke There have been few effective therapies in the setting of hemorrhagic stroke, and particularly intra-cerebral hemorrhage (ICH), and this disease process is associated with a very high morbidity and mortality. While work continues on the issues surrounding optimal blood pressure and glucose management after ICH, one therapy for ICH has shown some promise in a recent trial. Previous work has shown that 26% of patients with ICH will have growth of the size of the hemorrhage within the first few hours and that this is significantly associated with clinical worsening. 17 A recent trial by Mayer et al reported on the use of recombinant Factor VIIa (rfviia) in the setting of ICH. 18 In this trial, 399 patients were randomized to placebo or escalating doses of rfviia given by IV bolus. Subjects presented to the ED within 3 hours of symptom onset and IV treatment had to be complete by four hours. Clinical outcomes were assessed at 90 days. There was a significant improvement in all clinical outcomes, including mrs, Barthel index, and Glascow outcome scale in patients treated with rfviia as opposed to placebo. There was a small increase in non-fatal thromboembolic events in the treated patients, but overall mortality was significantly reduced by the study drug (29% vs 18% placebo, p = 0.02). The FAST (Recombinant Factor VIIa in Acute Intracerebral Haemorrhage) trial is currently ongoing to confirm the results of this dose-finding trial. If the results are confirmed, this will represent the first proven drug therapy for ICH in the hyperacute time period. 78

9 SUMMARY In conclusion, a great many advances have occurred in the treatment of acute stroke in recent years. Both diagnostics and therapeutics have improved, with many encouraging trials ongoing to answer questions that remain about combined therapies, as well as extending the time window to treatment. The future will see the evolution of many of these therapies into clinical practice to advance the options available for care of the patient who presents to the ED with acute stroke. REFERENCES 1. Lev MH, Farkas J, Rodriguez VR, et al. CT Angiography in the rapid triage of patients with hyperacute stroke to intraarterial thrombolysis: Accuracy in the detection of large vessel thrombus. J Comput Assist Tomogr 2001;25(4): Verro P, Tanenbaum LN, Borden NM, Sen S, Eshkar N. CT Angiography in acute ischemic stroke: Preliminary results. Stroke 2002;33(1): Verro P, Tanenbaum LN, Borden N, Eshkar N, Sen S. Clinical application of CT angiography in acute ischemic stroke. Clinical Neurology and Neurosurgery; In Press. 4. Parsons MW, Barber PA, Chalk J, et al. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol 2002;51(1): Singer OC, du Mesnil de Rochemont R, Foerch C, et al. Early functional recovery and the fate of the diffusion/perfusion mismatch in patients with proximal middle cerebral artery occlusion. Cerebrovasc Dis 2004;17(1): Wintermark M RM, Thiran JP, Maeder P, Chalaron M, Schnyder P, Bogousslavsky J, Meuli R. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol 2002;51(4): Schramm P, Schellinger PD, Klotz E, et al. Comparison of perfusion computed tomography and computed tomography angiography source images with perfusion-weighted imaging and diffusion-weighted imaging in patients with acute stroke of less than 6 hours duration. Stroke 2004;35(7): Furlan AJ, Eyding D, Albers GW, et al. Dose escalation of desmoteplase for acute ischemic stroke (dedas): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37(5): The IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the interventional management of stroke study. Stroke 2004;35(4): Furlan A, Higashida R, Wechsler L, et al. Intraarterial pro-urokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. JAMA 1999;282(21): The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333(24): Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005;36(7): Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis : results of the thrombolysis in myocardial infarction (TIMI) 14 trial. Circulation 1999;99(21): The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339(7): Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351(21): Lees KR, Zivin JA, Ashwood T, et al. NXY- 059 for acute ischemic stroke. N Engl J Med 2006;354(6): Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997;28(1): Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352(8): Both diagnostics and therapeutics have improved, with many encouraging trials ongoing to answer questions that remain about combined therapies, as well as extending the time window to treatment. Copyright EMCREG-International,