This article provides a practical overview regarding the emergent evaluation of a patient with acute ischemic stroke, including the decision to administer acute reperfusion therapy and other acute supportive care. It should be noted that “acute reperfusion therapy” refers to treatment aimed at emergently restoring blood flow in the acutely occluded cerebral artery, and may consist of IV thrombolysis and/or specific endovascular interventions such as intra-arterial thrombolysis or mechanical embolectomy.
This discussion is framed around the most recent American Heart Association/American Stroke Association guidelines, which serve as useful and comprehensive references to the reader.1
EMERGENT EVALUATION OF THE POTENTIAL ACUTE REPERFUSION CANDIDATE
Rapid evaluation and treatment is critical for the best outcomes. This has been shown both in the setting of IV thrombolysis (IV recombinant tissue-type plasminogen activator [rtPA]) and endovascular therapy. With IV rtPA, the number needed to treat to prevent one death or significant disability is 8 when treating within 3 hours of symptom onset, and 14 when treating from 3 to 4.5 hours.2,3 Figure 1-1 demonstrates the odds of good outcome with IV rtPA treatment among subjects pooled from major trials to date.4 It has also been demonstrated that every 30-minute delay in acute reperfusion leads to a 10% relative reduction in the likelihood of a good outcome.5
Figure 1-1. Odds of ...Image Tools
A patient should receive IV rtPA within 1 hour of arrival to an emergency department (and sooner is better) with the following goals.6
* Emergency department physician sees patient within 10 minutes of arrival
* Stroke consultant is notified within 15 minutes of arrival
* CT scan is completed within 25 minutes of arrival
* CT is interpreted within 45 minutes of arrival
Strategies likely to increase the speed of treatment include early stroke-team notification (preferably before or concurrent with CT scan performance); storage of rtPA in the emergency department; recognition that glucose level is the only necessary laboratory result if no clinical suspicion for bleeding diathesis is present; and mixing of IV rtPA (1:1 ratio with sterile water or normal saline) early.
DECISION TO ADMINISTER ACUTE REPERFUSION THERAPY
The following information is needed from the emergency department upon initial consultation to guide clinical decision making.
* Time that patient was last known to be well
* Any significant medical history
* A brief neurologic examination (ideally the NIH Stroke Scale [NIHSS])
* Glucose level (finger stick) and any other significant laboratory results
* Current blood pressure
* Results of acute brain imaging, typically CT scan, when available
Each of these points and their role in decision making are described in subsequent sections.
The patient’s “last known well” time determines potential treatment options. It is important to distinguish the time last known well from the time that the stroke deficits were first discovered, as demonstrated by Case 1-1.
IV thrombolysis, specifically using rtPA, should be considered for patients for whom it can be administered within 4.5 hours of onset. IV rtPA (at the dose of 0.9 mg/kg, maximum dose 90 mg, with 10% given as an initial bolus) has been shown to improve clinical outcomes for patients within 3 hours of onset by two randomized trials (jointly referred to as the National Institutes of Neurological Disorders and Stroke [NINDS] tPA Stroke Study),2 and within 3 to 4.5 hours by one randomized trial (European Cooperative Acute Stroke Study III).3 Specifically, within 3 hours of onset, despite a 6% increased risk of symptomatic intracranial hemorrhage, the overall absolute benefit of treatment is a 13% lower rate of significant disability (defined as a modified Rankin Scale of 0 or 1). This benefit is estimated to be as high as 33% for any improvement in the spectrum of independence to severe disability or death; Figure 1-27 illustrates potential treatment effects.8
Figure 1-2. Changes ...Image Tools
Several community cohorts,9 pooled analyses of other IV rtPA trials,4 and the 3-hour subgroup of the Third International Stroke Trial (IST-3) provide further supportive evidence.10 Of note, the US Food and Drug Administration has only approved the 3-hour time window for IV rtPA, whereas clinical guidelines recommend treatment up to 4.5 hours based on the current evidence.1 It should also be noted that no other lytic agent, such as reteplase or tenecteplase, has been demonstrated as an effective treatment for acute ischemic stroke.
Endovascular therapy for IV recombinant tissue-type plasminogen activator–ineligible patients. For patients ineligible for IV rtPA (because of, for example, time of onset, coagulopathy, or recent surgery) who have significant stroke deficits (typically, an NIHSS score of 8 or higher), endovascular therapy should be considered if treatment can be initiated within 6 hours (Case 1-2). Indirect evidence, including the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial of recombinant prourokinase and the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) of urokinase,11–13 suggests that intra-arterial rtPA initiated within 6 hours of onset will lead to better clinical outcomes than supportive care alone (ie, no reperfusion therapy). More recent evidence suggests that endovascular devices open major arterial occlusions more effectively, leading to their frequent clinical use in this setting; specifically, the most recent generation of mechanical embolectomy devices, including the Penumbra Aspiration System, the Solitaire Stent Retriever, and the TREVO2 Stent Retriever, report revascularization rates exceeding 80%.14–16 Comparable safety and efficacy between IV rtPA within 3 hours versus endovascular therapy within 6 hours in the SYNTHESIS trial also supports the approach for IV rtPA–ineligible patients who present early.17 Case series data also suggest reasonable safety for the use of intra-arterial thrombolysis in the nonneurosurgical postoperative setting.18 Devices available in the United States are shown in Figure 1-4.
Figure 1-4. Devices ...Image Tools
The role of imaging selection to identify patients beyond 6 hours from onset who will benefit from acute reperfusion therapies remains to be determined. A phase 2b study, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial, tested the penumbral hypothesis.19 A favorable CT-based or magnetic resonance–based penumbral selection pattern was defined as a predicted infarct core comprising 70% or more of “at-risk” tissue as identified by a complex voxel-by-voxel algorithm, and incorporating baseline NIHSS score for the CT-based cases as well. Patients for whom endovascular treatment could be initiated within 8 hours of symptom onset were randomized to mechanical embolectomy versus supportive care, and stratified by the presence of penumbra. The presence of penumbra did not discriminate between subjects who would differentially benefit from mechanical embolectomy, but did predict better clinical outcomes among those with penumbra regardless of treatment arm. Evidence for newer definitions of penumbra, and its use beyond 8 hours from onset, are limited to nonrandomized cohort studies of treated patients only.20,21 These single-arm trials are unable to discriminate between a predictor of treatment effect and a marker of better clinical outcome regardless of treatment. This is an active area of investigation, and several planned and ongoing randomized trials will likely inform this discussion in the future.22
An 78-year-old woman with a history of diabetes mellitus presented to the emergency department with acute left-sided weakness at 4:00 PM. Her husband had called 9–1–1 immediately upon identifying her symptoms at 3:30 PM. Emergency medical services (EMS) had promptly evaluated the patient and brought her to the stroke-ready emergency department. En route, EMS had prenotified the hospital, where a CT scan was performed upon the patient’s arrival. The CT scan showed minimal early ischemic changes and no intracranial hemorrhage. The patient’s finger-stick glucose level was 95 mg/dL, and her examination revealed left hemiplegia and anosognosia. Her husband reported that her only medication was metformin and she had no recent surgeries or prior history of intracranial hemorrhage. However, upon further discussion regarding the time of onset with the stroke clinician, it became clear that, while the patient’s symptoms were discovered at 3:30 PM, her husband had last seen her well before he left for work at 9:00 AM. The patient reported feeling fine until her husband came home. Her cell phone was checked, and she had not spoken to anyone that day. Her neighbor was called by the husband, and the patient had not been witnessed to be well by anyone else since 9:00 AM. Thus, it was 7 hours from last known well at this point, and IV recombinant tissue-type plasminogen activator (rtPA) was not administered.
Comment. In this case, if the patient had not had anosognosia, it may have been appropriate to identify the last known well time based on the patient’s own history. However, given her lack of appreciation for her deficit, her report could not be trusted. A normal CT scan has not been demonstrated to identify patients who might benefit from IV rtPA regardless of time from last known well. However, an active and promising area of investigation is to develop imaging markers that can identify patients who will benefit from IV rtPA treatment based on physiologic time. Had it not been for the unknown and potentially greater than4.5-hour time of onset, the patient in this case would have been eligible for IV rtPA.
A 65-year-old woman who was postoperative from coronary artery by pass graft surgery, was found to have right-sided weakness and confusion in the postoperative anesthesia care unit (PACU) upon regaining consciousness from general anesthesia at 3:00 PM. She was last known to be neurologically normal at 12:00 PM. The on-call neurologist, who was immediately activated by the PACU nurse, identified a left middle cerebral artery syndrome with global aphasia and right hemiparesis (NIH Stroke Scale score of 20). Given the recent surgery, she deemed the patient to be ineligible for IV recombinant tissue-type plasminogen activator (rtPA), and alerted the neurointerventional team regarding a potential endovascular case while transporting the patient to the CT scanner. The CT scan revealed no intracranial hemorrhage, no early ischemic changes, and a hyperdense left middle cerebral artery; the patient was briskly taken directly from the CT scanner to the neuroangiography suite. Groin stick was performed at 4 hours after her last time seen normal, and a left proximal middle cerebral artery thrombus was evacuated by mechanical embolectomy at 4.5 hours with complete angiographic reperfusion observed on final angiogram, as demonstrated in Figure 1-3. Upon reexamination after the procedure, the patient had regained strength on her right side and her aphasia (now primarily expressive) was improved. Follow-up CT scan showed a small branch middle cerebral artery infarct.
Figure 1-3. Example ...Image Tools
Comment. Given the recent surgery, IV rtPA could not be safely administered in this patient. In this case, emergent endovascular treatment was a consideration. Rapid time to angiographic reperfusion likely contributed to the improved clinical outcome seen after the procedure. Of note, despite the observation of complete angiographic reperfusion, some infarct burden remained. This may have been due to a distal embolus or brain tissue that was irreversibly infarcted by the time angiographic reperfusion was achieved.
In addition to eligibility based on time from onset, acute reperfusion treatment options are further determined by eliciting key medical history.
IV rtPA exclusion criteria and relative contraindications are listed in Box 1-1.1 A consensus definition of deficits that should typically be considered disabling (regardless of total NIHSS score) is shown in Table 1-1.
Table 1-1 Proposed O...Image Tools
Based on limited evidence, potential eligibility for endovascular therapy in IV rtPA–ineligible patients might include age younger than 85 years, NIHSS greater than or equal to 8, and treatment within 6 hours of onset.1,10,11
Box 1–1 IV rtPA Exclusion and Relative Contraindication Criteria
Key IV rtPA Exclusion Criteria
* Stroke or significant head trauma within 3 months
* Major surgery or serious trauma within 14 days
* Gastrointestinal or urinary hemorrhage within 21 days
* Arterial puncture at a noncompressible site within 7 days
* History of intracranial hemorrhage
* Intracranial neoplasm, arteriovenous malformation, or aneurysm
○ Some experts consider treating patients with remotely secured or unruptured aneurysms
* Symptoms of subarachnoid hemorrhage
* Active internal bleeding
* Pretreatment blood pressure with systolic >185 mm Hg or diastolic >110 mm Hg
* Clear and large hypodensity on CT scan
* Current bleeding diathesis including
○ International normalized ratio (INR) >1.7
○ Heparin within 48 hours resulting in abnormal partial thromboplastin time (PTT)
○ Platelets <100,000/mm3
○ Direct thrombin inhibitor (eg, dabigatran) or factor Xa inhibitor (eg, rivaroxaban, apixaban) use within 48 hours
▪ Optimal laboratory testing thresholds for safe IV recombinant tissue-type plasminogen activator (rtPA) use in this setting remain to be determined and are an area of active investigation.
* Serum glucose <50
○ If persistent symptoms after correction, or infarct is verified/supported by imaging, most experts would consider IV rtPA treatment.
Relative Contraindications for IV rtPA1
* Minor deficit
○ Rapidly improving deficits should not be considered a contraindication unless the remaining deficit is minor.23
○ A common definition of minor deficits is an NIH Stroke Scale (NIHSS) score ≤5 and not clearly disabling.
○ A consensus definition of deficits that should typically be considered disabling (regardless of total NIHSS score) is shown in Table 1-1.
* Myocardial infarction in the past 3 months
○ Some experienced centers treat this as a contraindication only if the myocardial infarction is subacute and transmural, or other signs suggest a high risk of hemopericardium, such as clinical or ECG evidence of pericarditis.
○ Concurrent acute myocardial infarction may benefit from IV rtPA as well and should be considered in consultation with a cardiologist; however, only lower stroke dosing of 0.9 mg/kg (not higher cardiac dosing of approximately 1.1 mg/kg) should be used in this setting.
* Seizure at presentation
○ If stroke is verified by imaging, IV rtPA treatment should be considered. However, the severity of concurrent stroke must be judged in the context of ictal/postictal presentation.
○ Must weigh risks and benefits in the individual circumstances.
Additional Exclusion Criteria for IV rtPA Within the 3- to 4.5-Hour Time Window1
* History of stroke AND diabetes mellitus
* NIHSS score >25
* Age >80 years old
* On warfarin (regardless of INR value)
Brief Examination and NIHSS
The examination helps the clinician determine that the patient is indeed having a stroke and gauge its severity. The NIHSS score, in particular, is a useful way to describe and follow the patient’s examination (Appendix A). All clinicians who care for stroke patients in the acute setting should be NIHSS certified (http://nihss-english.trainingcampus.net/uas/modules/trees/windex.aspx). However, emergency physicians are not always NIHSS trained, and a descriptive examination can be used to estimate the NIHSS score and thereby the severity of the stroke in that circumstance.
Treating a stroke mimic, such as a complicated migraine or seizure, with IV rtPA is inevitable sometimes. Fortunately, the risk of intracranial hemorrhage when treating a stroke mimic with IV rtPA inadvertently is extremely low (less than 1%) based on case series of tPA-treated stroke mimics and the cardiology literature.24 Therefore, time to treatment should not be lost with ancillary testing such as MRI or CT angiography if stroke seems likely but not definitive.
The role of adjunctive endovascular treatment for severe IV rtPA–treated ischemic strokes remains to be determined. The only randomized trial of the combined IV rtPA/endovascular approach to date, the Interventional Management of Stroke (IMS) III trial, did not demonstrate its superiority over IV rtPA alone among subjects of 18 to 83 years of age with severe strokes (NIHSS score of 8 or higher), although safety parameters were comparable.25 The trial results also suggested that the clinical benefit of successful flow restoration may be lost beyond 7 hours from stroke onset in the average patient. It has been hypothesized that subgroups of patients may benefit from endovascular therapy, such as those with the most severe deficits (eg, an NIHSS score greater than 20), patients with demonstrated large proximal arterial occlusions (such as internal carotid artery terminus occlusions or occlusions that are greater than 8 mm in length), and those whose occlusions are recanalized more rapidly or effectively. Several randomized trials of more selective patient subgroups are now underway.
Glucose and Other Laboratory Results
Testing for serum glucose level is necessary before the IV rtPA treatment decision.1 This should take minimal time when performed by finger stick and is often done by EMS en route. This test allows the clinician to exclude stroke mimics of hypoglycemia or hyperglycemia. If the hypoglycemic patient’s symptoms resolve after glucose administration, then IV rtPA may not be indicated. Hyperglycemia can present with choreiform movements that can be mistaken for stroke symptoms. Experts generally believe that neither hypoglycemia nor hyperglycemia should preclude IV rtPA treatment if the deficits are believed to be caused by concurrent ischemia.
Other laboratory results should be solicited if available, but they are not necessary. In particular, INR, PTT, and platelet count will help determine IV rtPA eligibility. However, IV rtPA administration should not be delayed for any laboratory result other than finger-stick glucose level unless a clinical suspicion for an abnormality exists. Fewer than three in 1000 patients will have unsuspected thrombocytopenia,26 and fewer than four in 1000 patients will have an unsuspected INR greater than 1.7.27
Blood pressure is generally maintained relatively high after acute ischemic stroke. In the setting of cerebral ischemia, a loss of cerebral autoregulation occurs such that systemic blood pressures directly affect cerebral perfusion pressure. In this setting, increased systemic blood pressure will improve blood flow to the cerebral infarct, often via collateral blood vessels, and thereby may reduce the extent of irreversible ischemia.
The upper limits of blood pressure control are dictated by the decision of whether to administer acute reperfusion therapy. The blood pressure must be less than 185 mm Hg systolic and 110 mm Hg diastolic for IV rtPA eligibility, and must be maintained below 180/105 mm Hg during and after IV rtPA administration. Gentle blood pressure reduction can usually be achieved with labetalol 10 mg IV. If this dose is not enough, then it might be doubled. If no response occurs, a nicardipine infusion (5 mg per hour IV, titrate up by 2.5 mg per hour every 5 to 15 minutes, maximum 15 mg per hour) may be needed and typically achieves the blood pressure goals. If nicardipine is not available, or contraindications exist for this or labetalol, another consideration is IV enalaprilat 3.25 mg to 6.5 mg.
Acute Brain Imaging
Imaging of the brain parenchyma serves the primary role of ruling out intracranial hemorrhage, including intracerebral, subarachnoid, and epidural/subdural locations. At most centers, a noncontrast CT scan is the most rapid modality available, although some centers may use limited MRI (specifically consisting of diffusion-weighted imaging [DWI], either susceptibility-weighted [SW] imaging or gradient echo [GRE] sequences, and fluid-attenuated inversion recovery [FLAIR] sequences) if rapidly available. Rarely, an acute CT scan will reveal a large and clear hypodensity that will lead to questioning the time of onset of the stroke and the possibility of an undiagnosed subacute stroke, both of which would contraindicate IV rtPA. Subtle changes may also be seen on CT scan, such as loss of gray-white differentiation or sulcal effacement, to support the diagnosis of ischemic stroke. While subtle ischemic changes on CT scan are not contraindications to acute reperfusion therapy, they do portend worse outcomes compared with those with lesser acute ischemic changes on CT scan.28
Advanced imaging, specifically head and neck vascular imaging with CT angiography or magnetic resonance angiography, can be valuable in planning the approach to endovascular therapy if indicated, determining the etiology of stroke for secondary prevention (eg, carotid endarterectomy), or obtaining supportive evidence for an ischemic stroke diagnosis. Using this as a first-line imaging approach for all “rule-out stroke patients” in an emergency department is likely to be inappropriate, given the additional radiation exposure to a diverse group of patients. In settings where an expert physician triages stroke patients, CT angiography or magnetic resonance angiography may be useful in selected cases (ie, IV rtPA–ineligible patients who arrive in the emergency department early) to identify symptomatic occlusions amenable to acute endovascular therapy while the neurointerventional team is being mobilized. In all cases, advanced neuroimaging should not delay the administration of IV rtPA.
To date, there is no known role for other forms of advanced imaging, such as perfusion studies with CT perfusion or magnetic resonance perfusion-weighted imaging, to select patients for acute reperfusion therapies. In particular, no data have supported the utility of identifying penumbra (ie, brain at risk for infarction without reperfusion) for IV rtPA decisions, as the majority of these patients will have penumbra within 4.5 hours, and the role of penumbral imaging for selecting patients for acute reperfusion treatment beyond 4.5 hours remains to be determined (as discussed earlier in this review).
POSTREPERFUSION THERAPY CARE
Standard post-tPA management for the first 24 hours includes the following:
* admission to a step-down or intensive care unit
* maintenance of nothing-by-mouth (NPO) status until dysphagia screening is performed to avoid aspiration pneumonia
* administration of isotonic IV fluids (not dextrose containing because of risk of hyperglycemia)
* blood pressure and neurologic monitoring every 15 minutes for 2 hours, then every 30 minutes for 6 hours, then every hour for 16 hours after treatment
* aggressive blood pressure treatment if systolic blood pressure is greater than 180 mm Hg or diastolic blood pressure is greater than 105 mm Hg
* emergent CT scan of the brain if neurologic decline, acute increase in blood pressure, nausea, vomiting, or new headache is present to rule out hemorrhagic transformation
* repeat brain imaging at 24 hours to assess for asymptomatic hemorrhage and to allow initiation of antiplatelet therapy
OTHER ACUTE ISCHEMIC STROKE MANAGEMENT CONSIDERATIONS
Blood Pressure in Patients With No Reperfusion Therapies
Data are very limited to dictate the optimal blood pressure in this setting. Experts generally recommend permissive hypertension if tolerated (up to 220/120 mm Hg) in the nonreperfusion therapy setting and consideration of lowering blood pressure by 15% over the first 24 hours.1
Less commonly, blood pressure may be low in the acute setting, and stroke deficits may improve with raising the pressure. Most experts will attempt IV fluid boluses to raise blood pressure in the setting of relative hypotension and see if stroke symptoms improve with this intervention. If the stroke deficits appear to be pressure dependent, more aggressive blood pressure support with pressors may be considered. Evidence for the role of pressors in the acute stroke setting is limited, however.
Glucose in the Acute Setting
Hyperglycemia (greater than 140 mg/dL) during the first 24 hours after stroke is a poor prognostic indicator. Whether acute correction will lead to better clinical outcomes after stroke is unknown. Current recommendations are to treat hyperglycemia to achieve a level lower than 180 mg/dL, and stricter glucose control is under study in a major randomized clinical trial.1
Antithrombotic Therapy in the Acute Setting
Aspirin should be initiated within 48 hours in all patients and is typically initiated in the emergency department if no acute reperfusion therapy is administered. If IV rtPA or acute endovascular therapy is administered, aspirin is initiated at approximately 24 hours and only after confirmation of no hemorrhagic transformation on the 24-hour CT scan. Early aspirin treatment leads to a 1% absolute reduction of stroke over the next 2 weeks.29,30 Recent evidence from a randomized trial in China of TIA and minor stroke patients who were not treated with IV tPA has suggested that short-term combined aspirin and clopidogrel administration may better prevent early stroke recurrence in minor strokes or TIAs, and further randomized study is currently underway in the United States.31
It is well established that acute anticoagulation (including unfractionated and low-molecular-weight heparin) does not improve clinical outcomes after acute ischemic stroke compared with antiplatelet therapy in unselected patients. There may be a role for acute anticoagulation in specific circumstances in which early stroke recurrence risk is high, but clinical data are lacking.
In summary, effective emergent evaluation of a stroke patient requires well-organized systems that maximize speed of assessment and administration of appropriate therapies. This article provides a practical overview of this process, and the reader is referred to the American Heart Association/American Stroke Association clinical guidelines for more detailed discussions. When these systems cannot appropriately be implemented at a given hospital, it is imperative that triage and bypass plans be implemented to maximize clinical outcomes after stroke.
* Rapid evaluation and treatment are critical for the best outcomes.
* A patient should receive IV recombinant tissue-type plasminogen activator within 1 hour of arrival to an emergency department (and sooner is better).
* IV thrombolysis, specifically using recombinant tissue-type plasminogen activator, should be considered for patients for whom it can be administered within 4.5 hours of onset of stroke deficits.
* For patients ineligible for IV recombinant tissue-type plasminogen activator who have significant stroke deficits (typically, an NIH Stroke Scale score of 8 or greater), endovascular therapy should be considered if treatment can be initiated within 6 hours.
* Rapidly improving deficits should not be considered a contraindication unless the remaining deficit is minor.
* Additional exclusion criteria for IV recombinant tissue-type plasminogen activator within the 3- to 4.5-hour time window include a history of stroke and diabetes mellitus, NIH Stroke Scale score greater than 25, age greater than 80 years, and warfarin use (regardless of international normalized ratio value).
* All clinicians who care for stroke patients in the acute setting should be NIH Stroke Scale certified.
* The risk of intracranial hemorrhage when treating a stroke mimic with IV recombinant tissue-type plasminogen activator inadvertently is extremely low (less than 1%).
* The combined IV/endovascular approach in all patients with an NIH Stroke Scale score of 8 or greater is not superior to IV recombinant tissue-type plasminogen activator alone despite comparable safety.
* One should not delay IV recombinant tissue-type plasminogen activator administration for any laboratory result other than finger-stick glucose level unless a clinical suspicion for an abnormality exists.
* Subtle ischemic changes on CT scan are not contraindications to acute reperfusion therapy.
* Standard post–tissue plasminogen activator management for the first 24 hours includes aggressive blood pressure treatment if systolic blood pressure is greater than 180 mm Hg or diastolic blood pressure is greater than 105 mm Hg.
* Experts generally recommend permissive hypertension if tolerated (up to 220/120 mm Hg) in the nonreperfusion therapy setting.
* Current recommendations are to treat hyperglycemia to a level lower than 180 mg/dL.
* Early aspirin treatment leads to a 1% absolute reduction of stroke over the next 2 weeks.
* Short-term combined aspirin and clopidogrel administration may better prevent early stroke recurrence in minor strokes or TIAs.
1. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44 (3): 870–947.
2. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333 (24): 1581–1587.
3. Hacke W, Donnan G, Fieschi C; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363 (9411): 768–774.
4. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375 (9727): 1695–1703.
5. Khatri P, Abruzzo T, Yeatts SD, et al. Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Neurology 2009; 73 (13): 1066–1072.
6. Marler JR, Jones PW, Emr W. Proceedings of a national symposium on rapid identification and treatment of acute stroke. Bethesda, MD: The National Institute of Neurologic Disorders and Stroke (NINDS), National Institutes of Health, 1997; 97: 4239.
7. Saver JL. Thrombolytic therapy in stroke. Medscape. emedicine.medscape.com/article/1160840-overview. Updated September 18, 2012. Accessed February 6, 2014.
8. Gadhia J, Starkman S, Ovbiagele B, et al. Assessment and improvement of figures to visually convey benefit and risk of stroke thrombolysis. Stroke 2010; 41 (2): 300–306.
9. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke 2003; 34 (12): 2847–2850.
10. The IST3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379 (9834): 2352–2363.
11. 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 (21): 2003–2011.
12. Ogawa A, Mori E, Minematsu K, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007; 38 (10): 2633–2639.
13. Fields JD, Khatri P, Nesbit GM, et al. Meta-analysis of randomized intra-arterial thrombolytic trials for the treatment of acute stroke due to middle cerebral artery occlusion. J Neurointerv Surg 2011; 3 (2): 151–155.
14. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012; 380 (9849): 1231–1240.
15. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012; 380 (9849): 1241–1249.
16. Bose A, Henkes H, Alfke K, et al. The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol 2008; 29 (7): 1409–1413.
17. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368 (10): 904–913.
18. Chalela JA, Katzan I, Liebeskind DS, et al. Safety of intra-arterial thrombolysis in the postoperative period. Stroke 2001; 32 (6), 1365–1369.
19. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368 (10): 914–923.
20. Lansberg MG, Straka M, Kemp S, et al. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol 2012; 11 (10): 860–867.
21. Jovin TG, Liebeskind DS, Gupta R, et al. Imaging-based endovascular therapy for acute ischemic stroke due to proximal intracranial anterior circulation occlusion treated beyond 8 hours from time last seen well: retrospective multicenter analysis of 237 consecutive patients. Stroke 2011; 42 (8): 2206–2211.
22. Parsons MW, Albers GW. MR RESCUE: is the glass half-full or half-empty? Stroke 2013; 44 (7): 2055–2057.
23. The Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force; Levine SR, Khatri P, Broderick JP, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria part 1: rapidly improving stroke symptoms. Stroke 2013; 44 (7): 2055–2057.
24. Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series. Stroke 2011; 42 (6): 1771–1774.
25. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013; 368 (10): 893–903.
26. Cucchiara BL, Jackson B, Weiner M, Messe SR. Usefulness of checking platelet count before thrombolysis in acute ischemic stroke. Stroke 2007; 38 (5): 1639–1640.
27. Rost NS, Masrur S, Pervez MA, et al. Unsuspected coagulopathy rarely prevents IV thrombolysis in acute ischemic stroke. Neurology 2009; 73 (23): 1957–1962.
28. Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDS rtPA Stroke Study. Stroke 2005; 36 (10): 2110–2115.
29. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349 (9066): 1641–1649.
30. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349 (9065): 1569–1581.
31. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369 (1): 11–19.