(COR I; LOE B-NR) Blood glucose IV alteplase is recommended in otherwise eligible patients with initial glucose levels >50 mg/dL. (COR I; LOE A) CT IV alteplase administration is recommended in the setting of early ischemic changes on NCCT of mild to moderate extent (other than frank hypodensity). (COR I; LOE A) (Continued) Powers et al 2019 Guidelines for Management of AIS e367 Prior antiplatelet therapy IV alteplase is recommended for patients taking antiplatelet drug monotherapy before stroke on the basis of evidence that the benefit of alteplase outweighs a possible small increased risk of sICH. (COR I; LOE A) IV alteplase is recommended for patients taking antiplatelet drug combination therapy (eg, aspirin and clopidogrel) before stroke on the basis of evidence that the benefit of alteplase outweighs a probable increased risk of sICH. (COR I; LOE B-NR) End-stage renal disease In patients with end-stage renal disease on hemodialysis and normal aPTT, IV alteplase is recommended. (COR I; LOE C-LD) However, those with elevated aPTT may have elevated risk for hemorrhagic complications. Additional recommendations for treatment with IV alteplase for patients with AIS (COR IIa) And (COR IIb) 3 to 4.5 h Age For patients >80 y of age presenting in the 3- to 4.5-h window, IV alteplase is safe and can be as effective as in younger patients. (COR IIa; LOE B-NR) 3 to 4.5 h Diabetes mellitus and prior stroke In AIS patients with prior stroke and diabetes mellitus presenting in the 3- to 4.5- h window, IV alteplase may be as effective as treatment in the 0- to 3-h window and may be a reasonable option. (COR IIb; LOE B-NR) 3 to 4.5 h Severe stroke The benefit of IV alteplase between 3 and 4.5 h from symptom onset for patients with very severe stroke symptoms (NIHSS score >25) is uncertain. (COR IIb; LOE C-LD) 3 to 4.5 h Mild disabling stroke For otherwise eligible patients with mild disabling stroke, IV alteplase may be reasonable for patients who can be treated within 3 and 4.5 h of ischemic stroke symptom onset or patient last known well or at baseline state. (COR IIb; LOE B-NR) Wake-up and unknown time of onset IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) administered within 4.5 h of stroke symptom recognition can be beneficial in patients with AIS who awake with stroke symptoms or have unclear time of onset >4.5 h from last known well or at baseline state and who have a DW-MRI lesion smaller than one- third of the MCA territory and no visible signal change on FLAIR. (COR IIa; LOE B-R) Preexisting disability Preexisting disability does not seem to independently increase the risk of sICH after IV alteplase, but it may be associated with less neurological improvement and higher mortality. Therapy with IV alteplase for acute stroke patients with preexisting disability (mRS score 2) may be reasonable, but decisions should take into account relevant factors, including quality of life, social support, place of residence, need for a caregiver, patients and families preferences, and goals of care. (COR IIb; LOE B-NR) Patients with preexisting dementia may benefit from IV alteplase. Individual considerations such as life expectancy and premorbid level of function are important to determine whether alteplase may offer a clinically meaningful benefit. (COR IIb; LOE B-NR) Early improvement IV alteplase treatment is reasonable for patients who present with moderate to severe ischemic stroke and demonstrate early improvement but remain moderately impaired and potentially disabled in the judgment of the examiner. (COR IIa; LOE A) Seizure at onset IV alteplase is reasonable in patients with a seizure at the time of onset of acute stroke if evidence suggests that residual impairments are secondary to stroke and not a postictal phenomenon. (COR IIa; LOE C-LD) Blood glucose Treatment with IV alteplase in patients with AIS who present with initial glucose levels <50 or >400 mg/dL that are subsequently normalized and who are otherwise eligible may be reasonable. (Recommendation modified from 2015 IV Alteplase to conform to text of 2015 IV Alteplase. [COR IIb; LOE C-LD]) Coagulopathy IV alteplase may be reasonable in patients who have a history of warfarin use and an INR 1.7 or a PT <15 s. (COR IIb; LOE B-NR) The safety and efficacy of IV alteplase for acute stroke patients with a clinical history of potential bleeding diathesis or coagulopathy are unknown. IV alteplase may be considered on a case-by-case basis. (COR IIb; LOE C-EO) Dural puncture IV alteplase may be considered for patients who present with AIS, even in instances when they may have undergone a lumbar dural puncture in the preceding 7 d. (COR IIb; LOE C-EO) Arterial puncture The safety and efficacy of administering IV alteplase to acute stroke patients who have had an arterial puncture of a noncompressible blood vessel in the 7 d preceding stroke symptoms are uncertain. (COR IIb; LOE C-LD) Recent major trauma In AIS patients with recent major trauma (within 14 d) not involving the head, IV alteplase may be carefully considered, with the risks of bleeding from injuries related to the trauma weighed against the severity and potential disability from the ischemic stroke. (Recommendation modified from 2015 IV Alteplase to specify that it does not apply to head trauma. [COR IIb; LOE C-LD]) Recent major surgery Use of IV alteplase in carefully selected patients presenting with AIS who have undergone a major surgery in the preceding 14 d may be considered, but the potential increased risk of surgical-site hemorrhage should be weighed against the anticipated benefits of reduced stroke related neurological deficits. (COR IIb; LOE C-LD) GI and genitourinary bleeding Reported literature details a low bleeding risk with IV alteplase administration in the setting of past GI/genitourinary bleeding. Administration of IV alteplase in this patient population may be reasonable. (COR IIb; LOE C-LD (Note: Alteplase administration within 21 d of a GI bleeding event is not recommended; see Contraindications.) Table 8. Continued (Continued) Menstruation IV alteplase is probably indicated in women who are menstruating who present with AIS and do not have a history of menorrhagia. However, women should be warned that alteplase treatment could increase the degree of menstrual flow. (COR IIa; LOE C-EO) When there is a history of recent or active vaginal bleeding causing clinically significant anemia, then emergency consultation with a gynecologist is probably indicated before a decision about IV alteplase is made. (COR IIa; LOE C-EO) Because the potential benefits of IV alteplase probably outweigh the risks of serious bleeding in patients with recent or active history of menorrhagia without clinically significant anemia or hypotension, IV alteplase administration may be considered. (COR IIb; LOE C-LD) Extracranial cervical dissections IV alteplase in AIS known or suspected to be associated with extracranial cervical arterial dissection is reasonably safe within 4.5 h and probably recommended. (COR IIa; LOE C-LD) Intracranial arterial dissection IV alteplase usefulness and hemorrhagic risk in AIS known or suspected to be associated with intracranial arterial dissection remain unknown, uncertain and not well established. (COR IIb; LOE C-LD) Unruptured intracranial aneurysm For patients presenting with AIS who are known to harbor a small or moderate-sized (<10 mm) unruptured and unsecured intracranial aneurysm, administration of IV alteplase is reasonable and probably recommended. (COR IIa; LOE C-LD) Usefulness and risk of IV alteplase in patients with AIS who harbor a giant unruptured and unsecured intracranial aneurysm are not well established. (COR IIb; LOE C-LD) Intracranial vascular malformations For patients presenting with AIS who are known to harbor an unruptured and untreated intracranial vascular malformation the usefulness and risks of administration of IV alteplase are not well established. (COR IIb; LOE C-LD) Because of the increased risk of ICH in this population of patients, IV alteplase may be considered in patients with stroke with severe neurological deficits and a high likelihood of morbidity and mortality to outweigh the anticipated risk of ICH. (COR IIb; LOE C-LD) CMBs In otherwise eligible patients who have previously had a small number (1 10) of CMBs demonstrated on MRI, administration of IV alteplase is reasonable. (COR IIa; Level B-NR) In otherwise eligible patients who have previously had a high burden of CMBs (>10) demonstrated on MRI, treatment with IV alteplase may be associated with an increased risk of sICH, and the benefits of treatment are uncertain. Treatment may be reasonable if there is the potential for substantial benefit. (COR IIb; Level B-NR) Concomitant tirofiban, epifibatide The efficacy of the IV glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide coadministered with IV alteplase is not well established. (COR IIb; Level B-NR) Extra-axial intracranial neoplasms IV alteplase treatment is probably recommended for patients with AIS who harbor an extra-axial intracranial neoplasm. (COR IIa; LOE C-EO) Acute MI For patients presenting with concurrent AIS and acute MI, treatment with IV alteplase at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated, is reasonable. (COR IIa; LOE C-EO) Recent MI For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase is reasonable if the recent MI was non-STEMI. (COR IIa; LOE C-LD) For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase is reasonable if the recent MI was a STEMI involving the right or inferior myocardium. (COR IIa; LOE C-LD) For patients presenting with AIS and a history of recent MI in the past 3 mo, treating the ischemic stroke with IV alteplase may be reasonable if the recent MI was a STEMI involving the left anterior myocardium. (COR IIb; LOE C-LD) Acute pericarditis For patients with major AIS likely to produce severe disability and acute pericarditis, treatment with IV alteplase may be reasonable (COR IIb; LOE C-EO) ; urgent consultation with a cardiologist is recommended in this situation. For patients presenting with moderate AIS likely to produce mild disability and acute pericarditis, treatment with IV alteplase is of uncertain net benefit. (COR IIb; LOE C-EO) Left atrial or ventricular thrombus For patients with major AIS likely to produce severe disability and known left atrial or ventricular thrombus, treatment with IV alteplase may be reasonable. (COR IIb; LOE C-LD) For patients presenting with moderate AIS likely to produce mild disability and known left atrial or ventricular thrombus, treatment with IV alteplase is of uncertain net benefit. (COR IIb; LOE C-LD) Other cardiac diseases For patients with major AIS likely to produce severe disability and cardiac myxoma, treatment with IV alteplase may be reasonable. (COR IIb; LOE C-LD) For patients presenting with major AIS likely to produce severe disability and papillary fibroelastoma, treatment with IV alteplase may be reasonable. (COR IIb; LOE C-LD) Procedural stroke IV alteplase is reasonable for the treatment of AIS complications of cardiac or cerebral angiographic procedures, depending on the usual eligibility criteria. (COR IIa; LOE A) Table 8. Continued (Continued) Powers et al 2019 Guidelines for Management of AIS e369 Table 8. Continued Systemic malignancy The safety and efficacy of IV alteplase in patients with current malignancy are not well established. (COR IIb; LOE C-LD) Patients with systemic malignancy and reasonable (>6 mo) life expectancy may benefit from IV alteplase if other contraindications such as coagulation abnormalities, recent surgery, or systemic bleeding do not coexist. Pregnancy IV alteplase administration may be considered in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. (COR IIb; LOE C-LD) The safety and efficacy of IV alteplase in the early postpartum period (<14 d after delivery) have not been well established. (COR IIb; LOE C-LD) Ophthalmological conditions Use of IV alteplase in patients presenting with AIS who have a history of diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions is reasonable to recommend, but the potential increased risk of visual loss should be weighed against the anticipated benefits of reduced stroke-related neurological deficits. (COR IIa; LOE B-NR) Sickle cell disease IV alteplase for adults presenting with an AIS with known sickle cell disease can be beneficial. (COR IIa; LOE B-NR) Hyperdense MCA sign In patients with a hyperdense MCA sign, IV alteplase can be beneficial. (COR IIa; LOE B-NR) Illicit drug use Treating clinicians should be aware that illicit drug use may be a contributing factor to incident stroke. IV alteplase is reasonable in instances of illicit drug use associated AIS in patients with no other exclusions. (COR IIa; LOE C-LD) Stroke mimics The risk of symptomatic intracranial hemorrhage in the stroke mimic population is quite low; thus, starting IV alteplase is probably recommended in preference over delaying treatment to pursue additional diagnostic studies. (COR IIa; LOE B-NR) Contraindications (COR III: No Benefit) And (COR III: Harm) nondisabling stroke For otherwise eligible patients with mild nondisabling stroke (NIHSS score 0 5), IV alteplase is not recommended for patients who could be treated within 3 h of ischemic stroke symptom onset or patient last known well or at baseline state. (COR III: No Benefit, LOE B-R) nondisabling stroke For otherwise eligible patients with mild nondisabling stroke (NIHSS score 0 5), IV alteplase is not recommended for patients who could be treated within 3 and 4.5 h of ischemic stroke symptom onset or patient last known well or at baseline state. (COR III: No Benefit, LOE C-LD) CT There remains insufficient evidence to identify a threshold of hypoattenuation severity or extent that affects treatment response to alteplase. However, administering IV alteplase to patients whose CT brain imaging exhibits extensive regions of clear hypoattenuation is not recommended. These patients have a poor prognosis despite IV alteplase, and severe hypoattenuation defined as obvious hypodensity represents irreversible injury. (COR III: No Benefit; LOE A) ICH IV alteplase should not be administered to a patient whose CT reveals an acute intracranial hemorrhage. (COR III: Harm; LOE C-EO) Ischemic stroke within 3 mo Use of IV alteplase in patients presenting with AIS who have had a prior ischemic stroke within 3 mo may be harmful. (COR III: Harm; LOE B-NR) Severe head trauma within 3 mo In AIS patients with recent severe head trauma (within 3 mo), IV alteplase is contraindicated. (COR III: Harm; LOE C-EO) Acute head trauma Given the possibility of bleeding complications from the underlying severe head trauma, IV alteplase should not be administered in posttraumatic infarction that occurs during the acute in-hospital phase. (COR III: Harm; LOE C-EO) (Recommendation wording modified to match COR III stratifications.) Intracranial/intraspinal surgery within 3 mo For patients with AIS and a history of intracranial/spinal surgery within the prior 3 mo, IV alteplase is potentially harmful. (COR III: Harm; LOE C-EO) History of intracranial hemorrhage IV alteplase administration in patients who have a history of intracranial hemorrhage is potentially harmful. (COR III: Harm; LOE C-EO) Subarachnoid hemorrhage IV alteplase is contraindicated in patients presenting with symptoms and signs most consistent with an SAH. (COR III: Harm; LOE C-EO) GI malignancy or GI bleed within Patients with a structural GI malignancy or recent bleeding event within 21 d of their stroke event should be considered high risk, and IV alteplase administration is potentially harmful. (COR III: Harm; LOE C-EO) Coagulopathy The safety and efficacy of IV alteplase for acute stroke patients with platelets <100000/mm3 , INR >1.7, aPTT >40 s, or PT >15 s are unknown, and IV alteplase should not be administered. (COR III: Harm; LOE C-EO) (In patients without history of thrombocytopenia, treatment with IV alteplase can be initiated before availability of platelet count but should be discontinued if platelet count is <100000/mm3 . In patients without recent use of OACs or heparin, treatment with IV alteplase can be initiated before availability of coagulation test results but should be discontinued if INR is >1.7 or PT is abnormally elevated by local laboratory standards.) (Recommendation wording modified to match COR III stratifications.) LMWH IV alteplase should not be administered to patients who have received a full treatment dose of LMWH within the previous 24 h. (COR III: Harm; LOE B-NR) (Recommendation wording modified to match COR III stratifications.) (Continued) Thrombin inhibitors or factor Xa inhibitors The use of IV alteplase in patients taking direct thrombin inhibitors or direct factor Xa inhibitors has not been firmly established but may be harmful. (COR III: Harm; LOE C-EO) IV alteplase should not be administered to patients taking direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a dose of these agents for >48 h (assuming normal renal metabolizing function). (Alteplase could be considered when appropriate laboratory tests such as aPTT, INR, ecarin clotting time, thrombin time, or direct factor Xa activity assays are normal or when the patient has not taken a dose of these ACs for >48 h and renal function is normal.) (Recommendation wording modified to match COR III stratifications.) Concomitant Abciximab Abciximab should not be administered concurrently with IV alteplase. (COR III: Harm; LOE B-R) Concomitant IV aspirin IV aspirin should not be administered within 90 min after the start of IV alteplase. (COR III: Harm; LOE B-R) Infective endocarditis For patients with AIS and symptoms consistent with infective endocarditis, treatment with IV alteplase should not be administered because of the increased risk of intracranial hemorrhage. (COR III: Harm; LOE C-LD) (Recommendation wording modified to match COR III stratifications.) Aortic arch dissection IV alteplase in AIS known or suspected to be associated with aortic arch dissection is potentially harmful and should not be administered. (COR III: Harm; LOE C-EO) (Recommendation wording modified to match COR III stratifications.) Intra-axial intracranial neoplasm IV alteplase treatment for patients with AIS who harbor an intra-axial intracranial neoplasm is potentially harmful. (COR III: Harm; LOE C-EO) Unless otherwise specified, these eligibility recommendations apply to patients who can be treated within 0 to 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Clinicians should also be informed of the indications and contraindications from local regulatory agencies (for current information from the US Food and Drug Administration refer to http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103172s5203lbl.pdf). For a detailed discussion of this topic and evidence supporting these recommendations, refer to the American Heart Association (AHA) scientific statement on the rationale for inclusion and exclusion criteria for IV alteplase in AIS.14 AC indicates anticoagulants; AIS, acute ischemic stroke; aPTT, activated partial thromboplastin time; BP, blood pressure; CMB, cerebral microbleed; COR, class of recommendation; CT, computed tomography; DW-MRI, diffusion-weighted magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; GI, gastrointestinal; ICH, intracerebral hemorrhage; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; LOE, level of evidence; MCA, middle cerebral artery; MI, myocardial infarction; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NCCT, noncontrast computed tomography; NIHSS, National Institutes of Health Stroke Scale; OAC, oral anticoagulant; PT, prothromboplastin time; sICH, symptomatic intracerebral hemorrhage; and STEMI, ST-segment elevation myocardial infarction. *When uncertain, the time of onset time should be considered the time when the patient was last known to be normal or at baseline neurological condition. Recommendation unchanged or reworded for clarity from 2015 IV Alteplase. See Table XCV in online Data Supplement 1 for original wording. See also the text of these guidelines for additional information on these recommendations. LOE amended to conform with American College of Cardiology/AHA 2015 Recommendation Classification System. COR amended to conform with American College of Cardiology/AHA 2015 Recommendation Classification System. Table 8. Continued Table 9. Treatment of AIS: IV Administration of Alteplase Infuse 0.9 mg/kg (maximum dose 90 mg) over 60 min, with 10% of the dose given as a bolus over 1 min. Admit the patient to an intensive care or stroke unit for monitoring. If the patient develops severe headache, acute hypertension, nausea, or vomiting or has a worsening neurological examination, discontinue the infusion (if IV alteplase is being administered) and obtain emergency head CT scan. Measure BP and perform neurological assessments every 15 min during and after IV alteplase infusion for 2 h, then every 30 min for 6 h, then hourly until 24 h after IV alteplase treatment. Increase the frequency of BP measurements if SBP is >180 mmHg or if DBP is >105 mmHg; administer antihypertensive medications to maintain BP at or below these levels (Table 5). Delay placement of nasogastric tubes, indwelling bladder catheters, or intra- arterial pressure catheters if the patient can be safely managed without them. Obtain a follow-up CT or MRI scan at 24 h after IV alteplase before starting anticoagulants or antiplatelet agents. AIS indicates acute ischemic stroke; BP, blood pressure; CT, computed tomography; DBP, diastolic blood pressure; IV, intravenous; MRI, magnetic resonance imaging; and SBP, systolic blood pressure. Reprinted from Jauch et al.1 Copyright 2013, American Heart Association, Inc. Powers et al 2019 Guidelines for Management of AIS e371 3.6. Other IV Fibrinolytics and Sonothrombolysis 3.6. Other IV Fibrinolytics and Sonothrombolysis COR LOE New, Revised, or Unchanged It may be reasonable to choose tenecteplase (single IV bolus of 0.25-mg/kg, maximum 25 mg) over IV alteplase in patients without contraindications for IV fibrinolysis who are also eligible to undergo mechanical thrombectomy. IIb B-R New recommendation. IV tenecteplase (0.25 mg/kg bolus, maximum 25 mg) was compared with IV alteplase (usual dose of 0.9 mg/kg over 60 minutes, maximum 90 mg) in the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke).178 This multicenter trial randomized 202 patients without previous severe disability and with documented occlusion of the internal carotid artery, proximal MCA (M1 or M2 segments), or basilar arteries presenting within 4.5 hours of symptom onset to receive 1 of these 2 fibrinolytic agents. Primary end point was reperfusion of >50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. The trial was designed to test for noninferiority and, if noninferiority proven, for superiority. Secondary outcomes included the mRS score at 90 days. Median NIHSS score was 17. The primary end point was achieved by 22% of patients treated with tenecteplase versus 10% of those treated with alteplase (P=0.002 for noninferiority and 0.03 for superiority). In an analysis of secondary end points, tenecteplase resulted in better functional outcomes at 90 days on the basis of the ordinal shift analysis of the mRS score (common OR [cOR], 1.7 [95% CI, 1.0 2.8]; P=0.04) but less robustly for the proportion who achieved an mRS score of 0 to 1 (P=0.23) or 0 to 2 (P=0.06). sICH rates were 1% in both groups. See Table XLIII in online Data Supplement 1. Tenecteplase administered as a 0.4-mg/kg single IV bolus has not been proven to be superior or noninferior to alteplase but might be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion. IIb B-R New recommendation. IV tenecteplase has been compared with IV alteplase up to 6 hours after stroke onset in 3 phase II and 1 phase III superiority trials; tenecteplase appears to be similarly safe, but it is unclear whether it is as effective as or more effective than alteplase.179 182 In the largest trial of 1100 subjects, tenecteplase at a dose of 0.4 mg/kg failed to demonstrate superiority and had a safety and efficacy profile similar to that of alteplase in a stroke population composed predominantly of patients with minor neurological impairment (median NIHSS score, 4) and no major intracranial occlusion.182 Tenecteplase is given as a single IV bolus as opposed to the 1-hour infusion of alteplase. See Table XLIII in online Data Supplement 1. The administration of IV defibrinogenating agents or IV fibrinolytic agents other than alteplase and tenecteplase is not recommended. III: No Benefit B-R Recommendation revised from 2013 AIS Guidelines. Randomized placebo-controlled trials have not shown benefit from the administration of IV streptokinase within 6 hours or desmoteplase within 3 to 9 hours after stroke onset in patients with ischemic penumbra, large intracranial artery occlusion, or severe stenosis.155,183 186 See Table XLIII in online Data Supplement 1. The use of sonothrombolysis as adjuvant therapy with IV fibrinolysis is not recommended. III: No Benefit A New recommendation. Since the publication of the 2013 AIS Guidelines, 2 RCTs of sonothrombolysis as adjuvant therapy for IV thrombolysis have shown no clinical benefit. NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) randomized 183 patients who had received either alteplase or tenecteplase for AIS within 4.5 hours of onset to either contrast-enhanced sonothrombolysis (93 patients) or sham (90 patients). Neurological improvement at 24 hours and functional outcome at 90 days were not statistically significantly different in the 2 groups, nor were the rates of sICH.187 CLOTBUST-ER (Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator [tPA] for Emergent Revascularization in Acute Ischemic Stroke) randomized 676 patients with AIS (NIHSS score 10) who received IV alteplase within 3 or 4.5 hours of symptom onset and randomly allocated to operator independent sonothrombolysis (335) or sham ultrasound (341).188 Compared with the control arm, the neurological improvement, death, and serious adverse events in the intervention arm were not statistically different. At this time, there are no RCT data to support additional clinical benefit of sonothrombolysis as adjuvant therapy for IV fibrinolysis. See Table XLIV in online Data Supplement 1. 3.7. Mechanical Thrombectomy 3.7.1. Concomitant With IV Alteplase COR LOE New, Revised, or Unchanged Patients eligible for IV alteplase should receive IV alteplase even if mechanical thrombectomy is being considered. I A Recommendation reworded for clarity from 2015 Endovascular. See Table XCV in online Data Supplement 1 for original wording. In patients under consideration for mechanical thrombectomy, observation after IV alteplase to assess for clinical response should not be performed. III: Harm B-R Recommendation revised from 2015 Endovascular. In pooled patient-level data from 5 trials (HERMES [Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials], which included the 5 trials MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-IA), the odds of better disability outcomes at 90 days (mRS score distribution) with the mechanical thrombectomy group declined with longer time from symptom onset to expected arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 3.00), ARD, 30.2%; and cOR at 8 hours, 1.57 (95% CI, 0.86 2.88), ARD, 15.7%, retaining statistical significance through 7 hours 18 Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 0.93]; ARD, The REVASCAT trial included a 30-minute period of observation before undertaking EVT. Available data do not directly address the question of whether patients should be observed after IV alteplase to assess for clinical response before pursuing mechanical thrombectomy. However, one can infer that because disability outcomes at 90 days were directly associated with time from symptom onset to arterial puncture, any cause for delay to mechanical thrombectomy, including observing for a clinical response after IV alteplase, should be avoided. Therefore, the recommendation is slightly modified from the 2015 Endovascular Update. See Tables XVII and XLV in online Data Supplement 1. 3.7.2. 0 to 6 Hours From Onset COR LOE New, Revised, or Unchanged Patients should receive mechanical thrombectomy with a stent retriever if they meet all the following criteria: (1) prestroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or MCA segment 1 (M1); (3) age 18 years; (4) NIHSS score of 6; (5) ASPECTS of 6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset. I A Recommendation revised from 2015 Endovascular. Results from 6 recent randomized trials of mechanical thrombectomy using predominantly stent retriever devices (MR CLEAN, SWIFT PRIME, EXTEND-IA, ESCAPE, REVASCAT, THRACE) support COR I, LOE A recommendations for a defined group of patients as described in the 2015 Guidelines.105 110 A pooled, patient-level analysis from 5 of these studies reported by the HERMES Collaboration showed treatment effect in the subgroup of 188 patients not treated with IV alteplase (cOR, 2.43 [95% CI, 1.30 4.55]); therefore, pretreatment with IV alteplase has been removed from the prior recommendation. The HERMES pooled patient-level data also showed that mechanical thrombectomy had a favorable effect over standard care in patients 80 years of age (cOR, 3.68 [95% CI, 1.95 6.92]).189 In patient-level data pooled from trials in which the Solitaire was the only or the predominant device used, a prespecified meta-analysis (SEER Collaboration [Safety and Efficacy of Solitaire Stent Thrombectomy Individual Patient Data Meta-Analysis of Randomized Trials]: SWIFT PRIME, ESCAPE, EXTEND-IA, REVASCAT) showed that mechanical thrombectomy had a favorable effect over standard care in patients 80 years of age (3.46 [95% CI, 1.58 7.60]).190 In a meta-analysis of 5 RCTs (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT), there was favorable effect with mechanical thrombectomy over standard care without heterogeneity of effect across patient age subgroups (for patients <70 and However, the number of patients in these trials who were 90 years of age was very small, and the benefit of mechanical thrombectomy over standard care in patients 90 years of age is not clear. As with any treatment decision in an elderly patient, consideration of comorbidities and risks should factor into the decision-making for mechanical thrombectomy. See Tables XVII and XLV in online Data Supplement 1. 3.7.1. Concomitant With IV Alteplase (Continued) COR LOE New, Revised, or Unchanged Powers et al 2019 Guidelines for Management of AIS e373 Direct aspiration thrombectomy as first-pass mechanical thrombectomy is recommended as noninferior to stent retriever for patients who meet all the following criteria: (1) prestroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or M1; (3) age 18 years; (4) NIHSS score of 6; (5) ASPECTS 6; and (6) treatment initiation (groin puncture) within 6 hours of symptom onset. I B-R Recommendation revised from 2015 Endovascular. Comparative available randomized data has assessed patients primarily in the therapeutic window within 6 hours of onset. The COMPASS (Comparison of Direct Aspiration Versus Stent Retriever as a First Approach) trial randomized patients with (1) prestroke mRS score of 0 to 1; (2) causative occlusion of the internal carotid artery or M1; (3) age 18 years; (4) NIHSS score of 5; (5) ASPECTS 6; and (6) treatment can be initiated (groin puncture) within 6 hours of symptom onset to aspiration thrombectomy or stentriever thrombectomy as first-line technique. Primary outcome was noninferiority of mRS score at 90 days. An mRS score of 0 to 2 was achieved in 69 of 134 (52%) of patients in the aspiration group and 67 of 136 (50%) in the stentriever group, demonstrating noninferiority of aspiration thrombectomy compared with stentriever thrombectomy (Pnoninferiority =0.0014). No difference in recanalization rates or intracranial hemorrhage was found.192 The ASTER trial (Contact Aspiration vs Stent Retriever for Successful Revascularization) compared the contact aspiration technique and the standard stent retriever technique as first-line mechanical thrombectomy for successful revascularization within 6 hours among patients with acute anterior circulation ischemic stroke and LVO. Eligibility criteria were different from COMPASS, lacking specification of NIHSS or ASPECTS. Primary outcome was successful revascularization. The proportion of patients with successful revascularization at the end of all interventions was 85.4% (n=164) in the contact aspiration group versus 83.1% (n=157) in the stent retriever group (OR, 1.20 [95% CI, 0.68 2.10]; P=0.53; difference, 2.4% [95% CI, 5.4 to 9.7]). The secondary clinical end point of mRS score of 0 to 2 at 90 days was achieved by 82 of 181 (45.3%) in the contact aspiration group versus 91 of 182 (50.0%) in the stent retriever group (OR, 0.83 [95% CI, 0.54 1.26]; P=0.38). Given its superiority design to detect a 15% difference in the primary end point, this trial was not designed to establish noninferiority.193 The Penumbra Separator 3D Trial compared a 3-D stent retriever combined with aspiration to aspiration alone as first-line intracranial mechanical thrombectomy for successful revascularization within 8 hours among patients with AIS (NIHSS score of at least 8) and LVO refractory to or ineligible for IV alteplase in a 1:1 randomized, noninferiority trial with a 15% noninferiority margin. The primary end point of mTICI grade 2 to 3 occurred in 87.2% of the combination group versus 82.3% in the aspiration alone group, meeting the noninferiority criterion of lower 90% confidence bound less than 15%. A 90-day mRS score of aspiration alone group.194 The trial demonstrated noninferiority of 3-D stent retriever with aspiration versus aspiration alone, using older-generation aspiration technology. The trial was not powered to demonstrate noninferiority in the secondary outcome of 90-day functional independence. See Table XVII in online Data Supplement 1. Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the MCA segment 2 (M2) or MCA segment 3 (M3) portion of the MCAs. IIb B-R Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE revised. See Table XCV in online Data Supplement 1 for original wording. In pooled patient-level data from 5 trials (HERMES, which included the 5 trials MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-IA), the direction of treatment effect for mechanical thrombectomy over standard care was favorable in M2 occlusions, but the adjusted cOR was not significant (1.28 [95% CI, 0.51 3.21]).189 In patient- level data pooled from trials in which the Solitaire was the only or the predominant device used, a prespecified meta-analysis (SEER Collaboration: SWIFT PRIME, ESCAPE, EXTEND-IA, and REVASCAT) showed that the direction of treatment effect was favorable for mechanical thrombectomy over standard care in M2 occlusions, but the OR and 95% CI were not significant.190 In an analysis of pooled data from SWIFT (Solitaire With the Intention for Thrombectomy), STAR (Solitaire Flow Restoration Thrombectomy for Acute Revascularization), DEFUSE 2, and IMS III, among patients with M2 occlusions, reperfusion was associated with excellent functional outcomes (mRS score 0 1; Therefore, the recommendation for mechanical thrombectomy for M2/M3 occlusions does not change substantively from the 2015 AHA/ASA focused update. See Tables XVII and XLV in online Data Supplement 1. Although its benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have prestroke mRS score >1, ASPECTS <6, or NIHSS score <6, and causative occlusion of the internal carotid artery (ICA) or proximal MCA (M1). IIb B-R Recommendation unchanged from 2015 Endovascular. Although the benefits are uncertain, the use of mechanical thrombectomy with stent retrievers may be reasonable for carefully selected patients with AIS in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset and who have causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries. IIb C-LD Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. 3.7.2. 0 to 6 Hours From Onset (Continued) COR LOE New, Revised, or Unchanged 3.7.3. 6 to 24 Hours From Onset COR LOE New, Revised, or Unchanged In selected patients with AIS within 6 to 16 hours of last known normal who have LVO in the anterior circulation and meet other DAWN or DEFUSE 3 eligibility criteria, mechanical thrombectomy is recommended. I A New recommendation. In selected patients with AIS within 16 to 24 hours of last known normal who have LVO in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy is reasonable. IIa B-R New recommendation. The DAWN trial used clinical-core mismatch (a combination of NIHSS score and imaging findings on CTP or DW-MRI) as eligibility criteria to select patients with large anterior circulation vessel occlusion for treatment with mechanical thrombectomy between 6 and 24 hours from last known normal. This trial demonstrated an overall benefit in function outcome at 90 days in the treatment group (mRS score 0 2, 49% versus 13%; adjusted difference, 33% [95% CI, 21 44]; posterior probability of superiority >0.999).51 In DAWN, there were few strokes with witnessed onset (12%). The DEFUSE 3 trial used perfusion-core mismatch and maximum core size as imaging criteria to select patients with large anterior circulation occlusion 6 to 16 hours from last seen well for mechanical thrombectomy. This trial showed a benefit in functional outcome at 90 days in the treated group (mRS score 0 2, 44.6% versus 16.7%; RR, 2.67 Benefit was independently demonstrated for the subgroup of patients who met DAWN eligibility criteria and for the subgroup who did not. DAWN and DEFUSE 3 are the only RCTs showing benefit of mechanical thrombectomy >6 hours from onset. Therefore, only the eligibility criteria from one or the other of these trials should be used for patient selection. Although future RCTs may demonstrate that additional eligibility criteria can be used to select patients who benefit from mechanical thrombectomy, at this time, the DAWN or DEFUSE 3 eligibility should be strictly adhered to in clinical practice.51,52 See Table XVII in online Data Supplement 1. 3.7.4. Technique COR LOE New, Revised, or Unchanged Use of stent retrievers is indicated in preference to the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) device. I A Recommendation unchanged from 2015 Endovascular. The technical goal of the thrombectomy procedure should be reperfusion to a modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b/3 angiographic result to maximize the probability of a good functional clinical outcome. I A Recommendation reworded for clarity from 2015 Endovascular. See Table XCV in online Data Supplement 1 for original wording. Mechanical thrombectomy aims to achieve reperfusion, not simply recanalization. A variety of reperfusion scores exist, but the mTICI score is the current assessment tool of choice, with proven value in predicting clinical outcomes.196,197 All recent endovascular trials used the mTICI grade 2b/3 threshold for adequate reperfusion, with high rates achieved. In HERMES, 402 of 570 patients (71%) were successfully reperfused to mTICI grade 2b/3.189 Earlier trials with less efficient devices showed lower recanalization rates, a factor in their inability to demonstrate benefit from the procedure (IMS III, 41%; MR RESCUE, 25%). The additional benefit of pursuing mTICI of grade 3 rather than grade 2b deserves further investigation. To ensure benefit, reperfusion to mTICI grade 2b/3 should be achieved as early as possible within the therapeutic window. I A Recommendation revised from 2015 Endovascular. In the 6- to 24-hour thombectomy window evaluation and treatment should proceed as rapidly as possible to ensure access to treatment for the greatest proportion of patients. I B-R New recommendation. In pooled patient-level data from 5 trials (HERMES, which included the 5 trials MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-IA), the odds of better disability outcomes at 90 days (mRS scale distribution) with the mechanical thrombectomy group declined with longer time from symptom onset to expected arterial puncture: cOR at 3 hours, 30.2%; cOR at 8 hours, 1.57 (95% CI, 0.86 2.88), and ARD, 15.7%, retaining statistical significance through 7 hours Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 0.93]; ARD, The 6- to 16- and 6- to 24-hour treatment windows trials, which utilized advanced imaging to identify a relatively uniform patient group, showed limited variability of treatment effect with time in these highly selected patients.51,52 The absence of detailed screening logs in these trials limits estimations of the true impact of time in this population. To ensure the highest proportion of eligible patients presenting in the 6- to 24-hour window have access to mechanical thrombectomy, evaluation and treatment should be as rapid as possible. A variety of reperfusion scores exist, but the mTICI score is the current assessment tool of choice, with proven value in predicting clinical outcomes.128,129 All recent endovascular trials used the mTICI 2b/3 threshold for adequate reperfusion, with high rates achieved. In HERMES, 402 of 570 patients (71%) were successfully reperfused to TICI 2b/3.189 Earlier trials with less efficient devices showed lower recanalization rates, 1 factor in their inability to demonstrate benefit from the procedure (IMS III, 41%; MR RESCUE, 25%). See Tables XVII and XLV in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e375 It is reasonable to select an anesthetic technique during EVT for AIS on the basis of individualized assessment of patient risk factors, technical performance of the procedure, and other clinical characteristics. IIa B-R Recommendation revised from 2015 Endovascular. Conscious sedation (CS) was the anesthetic modality widely used during endovascular procedures for acute stroke in the recent endovascular trials (90.9% of ESCAPE, 63% of SWIFT PRIME) with no clear positive or negative impact on outcome. In MR CLEAN, post hoc analysis showed a 51% (95% CI, 31 86) decrease in treatment effect with general anesthesia (GA) compared with CS.198 In THRACE, 51 of 67 patients receiving GA and 43 of 69 patients receiving CS during acute stroke endovascular procedures achieved mTICI grade 2b/3 (P=0.059) with no impact on functional outcomes (35 of 67 patients with GA and 36 of 74 with CS had an mRS score of 0 2 at 90 days).109 Thirty-five of 67 patients with GA and 36 of 74 with CS during acute stroke endovascular procedures had mRS scores of 0 to 2 at 90 Although several retrospective studies suggest that GA for acute stroke endovascular procedures produces worsening of functional outcomes, the limited available prospective randomized data do not support this. Three small ( 150 participants each) single-center RCTs have compared GA with CS during acute stroke endovascular procedures. All failed to show superiority of GA for the primary end point (2 clinical, 1 DW-MRI infarct growth), whereas 2 of the 3 showed better outcomes for GA for some of the many secondary clinical end points.199 201 Until further data are available, either method of procedural sedation for acute stroke endovascular procedures is reasonable. See Tables XLVI and XLVII in online Data Supplement 1. The use of a proximal balloon guide catheter or a large-bore distal-access catheter, rather than a cervical guide catheter alone, in conjunction with stent retrievers may be beneficial. IIa C-LD Recommendation and COR unchanged from 2015 Endovascular. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Treatment of tandem occlusions (both extracranial and intracranial occlusions) when performing mechanical thrombectomy may be reasonable. IIb B-R Recommendation revised from 2015 Endovascular. Tandem occlusions were included in recent endovascular trials that showed benefit of mechanical thrombectomy over medical management alone. In the HERMES meta-analysis, 122 of 1254 tandem occlusions (RR, 1.81 [95% CI, 0.96 3.4]) and 1132 of 1254 nontandem occlusions (RR, 1.71 [95% CI, 1.40 2.09]) were reported compared with medical occlusions (RR, 1.34 [95% CI, 0.87 2.07]) were treated compared with IV alteplase alone.109 In HERMES, there is heterogeneity of treatment methods directed to the proximal extracranial carotid occlusion (no revascularization of the proximal lesion versus angioplasty versus stenting). A retrospective analysis of pooled data from 18 centers examined 395 patients with AIS caused by tandem lesion of the anterior circulation who underwent mechanical thrombectomy (TITAN [Thrombectomy in Tandem Lesions]). mTICI grade 2b/3 was achieved in 76.7% of patients. At 90 days, 52.2% achieved an mRS score of 0 to 2, 13.8% had parenchymal hematoma, and 13.2% were dead.202 Multiple retrospective reports detail the technical success of mechanical thrombectomy for tandem occlusions but do not provide specifics on comparative approaches. No conclusions about the optimum treatment approach for patients with tandem occlusions are therefore possible. See Tables XVII and XLV in online Data Supplement 1. The safety and efficacy of IV glycoprotein IIb/IIIa inhibitors administered during endovascular stroke treatment are uncertain. IIb C-LD New recommendation. Uncertainty remains about the safety and efficacy of IV glycoprotein IIb/IIIa inhibitors, including abciximab, administered in the setting of endovascular stroke treatment. The published literature is limited primarily to case series and retrospective reviews of single-center databases and focuses largely on administration of IV glycoprotein IIb/IIIa inhibitors to prevent thrombus formation during emergent carotid and vertebrobasilar artery stenting and Further research is needed comprising multicenter analyses of endovascular stroke therapy necessitating adjunctive antiplatelet therapy for emergent angioplasty and stenting. See Table XXXIX in online Data Supplement 1. Use of salvage technical adjuncts, including intra-arterial fibrinolysis, may be reasonable to achieve mTICI grade 2b/3 angiographic results. IIb C-LD Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Intra-arterial fibrinolytic therapy played a limited role in the recent endovascular trials but was used as rescue therapy, not initial treatment. In MR CLEAN, the EVT method was at the discretion of operator, with 40 of 233 treated with alternative stent retrievers to Trevo and Solitaire or intra-arterial alteplase. Details are not available, but no patients were treated with intra-arterial alteplase alone. Twenty-four of 233 (10.3%) had treatment with a second modality. Treatment method had no impact on outcomes in this trial.206 In THRACE, an intra-arterial lytic was used to a maximum dose of 0.3 mg/kg and allowed to establish goal reperfusion, only after mechanical thrombectomy was attempted. A mean dose of 8.8 mg was administered in 15 of 141 patients receiving mechanical thrombectomy (11%). There was no effect on outcomes compared with mechanical thrombectomy alone. 3.7.4. Technique (Continued) COR LOE New, Revised, or Unchanged 3.7.5. Blood Pressure Management COR LOE New, Revised, or Unchanged In patients who undergo mechanical thrombectomy, it is reasonable to maintain the BP at 180/105 mmHg during and for 24 hours after the procedure. IIa B-NR New recommendation. In patients who undergo mechanical thrombectomy with successful reperfusion, it might be reasonable to maintain BP at a level <180/105 mmHg. IIb B-NR New recommendation. There are very limited data to guide BP management during and after the procedure in patients who undergo mechanical thrombectomy. RCT data on optimal BP management approaches in this setting are not available. The vast majority of patients enrolled in <6-hour RCTs received IV alteplase, and the trial protocols stipulated management according to local guidelines with BP 180/105 during and for 24 hours after the procedure for these participants. Two trial protocols provided additional recommendations. The ESCAPE protocol states that SBP 150 mmHg is probably useful in promoting and keeping collateral flow adequate while the artery remains occluded and that controlling BP once reperfusion has been achieved and aiming for a normal BP for that individual is sensible. Labetalol or an IV -blocker such as metoprolol in low doses is recommended.105 The DAWN protocol recommends maintaining SBP <140 mmHg in the first 24 hours in subjects who are reperfused after mechanical thrombectomy (defined as achieving more than two-thirds MCA territory reperfusion).51 Further studies are needed to determine the optimal BP target during and after mechanical thrombectomy. See Table XVII in online Data Supplement 1. 3.8. Other Endovascular Therapies 3.8. Other EVTs COR LOE New, Revised, or Unchanged Mechanical thrombectomy with stent retrievers is recommended over intra- arterial fibrinolysis as first-line therapy. I C-EO Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with the ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Intra-arterial fibrinolysis initiated within 6 hours of stroke onset in carefully selected patients who have contraindications to the use of IV alteplase might be considered, but the consequences are unknown. IIb C-EO Recommendation reworded for clarity from 2015 Endovascular. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. 3.9. Antiplatelet Treatment 3.9. Antiplatelet Treatment COR LOE New, Revised, or Unchanged Administration of aspirin is recommended in patients with AIS within 24 to 48 hours after onset. For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial benefit or withholding such treatment is known to cause substantial risk. I A Recommendation revised from 2013 AIS Guidelines. The safety and benefit of aspirin in the treatment of patients with AIS were established by 2 large clinical trials This has recently been confirmed by a large Cochrane review of aspirin trials.209 In patients unsafe or unable to swallow, rectal or nasogastric administration is appropriate. Limited data exist on the use of alternative antiplatelet agents in the treatment of AIS. However, in patients with a contraindication to aspirin, administering alternative antiplatelet agents may be reasonable. A retrospective analysis of consecutive ischemic stroke patients admitted to a single center in Seoul, South Korea, found no increased risk of hemorrhage with early initiation of antiplatelet or anticoagulant therapy (<24 hours) after IV alteplase or EVT compared with initiation >24 hours.177 However, this study may have been subject to selection bias, and the timing of initiation of antiplatelet therapy or anticoagulation should be made on an individual level, balancing risk and benefit. The recommendation was modified from the previous guideline to remove the specific dosing recommendation initial dose is 325 mg because previous clinical trials supporting its use for AIS included doses of 160 to 300 mg. See Tables XLII and XLVIII in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e377 In patients presenting with minor noncardioembolic ischemic stroke (NIHSS score 3) who did not receive IV alteplase, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset. I A New recommendation. Two independent multicenter, randomized, double-blind, placebo-controlled trials have established the efficacy of short-term dual antiplatelet therapy to prevent recurrent ischemic stroke in patients with minor stroke or high-risk TIA. The CHANCE trial (Clopidogrel in High Risk Patients With Acute Nondisabling Cerebrovascular Events; N=5170) conducted in China studied the efficacy of short-term dual antiplatelet therapy begun within 24 hours in patients with minor stroke (NIHSS score 3) or high-risk TIA (ABCD2 [Age, Blood Pressure, Clinical Features, Duration, Diabetes] score 4). The dosing regimen was clopidogrel at an initial dose of 300 mg followed by 75 mg/d for 90 days plus aspirin at a dose of 75 mg/d for the first 21 days or placebo plus aspirin (75 mg/d for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome of recurrent stroke at 90 days (ischemic or hemorrhagic) favored dual antiplatelet therapy over aspirin alone: hazard Post hoc analysis found a small but measurable reduction in poor functional outcome (mRS score 2 6) on dual antiplatelet therapy compared with aspirin alone (absolute RR, 1.7% However, a post hoc time-course analysis showed that the benefit in reducing recurrent ischemic stroke compared with the risk of bleeding on dual antiplatelet therapy dissipated after 10 days A subsequent report of 1-year outcomes found a durable treatment effect, but the HR for secondary stroke prevention was only significantly beneficial in the first 90 days.213 In addition, subgroup analyses found no benefit of clopidogrel plus aspirin in carriers of a CYP2C19 loss-of-function allele214 or those with a single acute infarction or no infarction compared with those with multiple acute infarctions,215 although these subgroup analyses were likely underpowered. The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; N=4881) was conducted in North America, Europe, Australia, and New Zealand, with the majority (83%) enrolled in the United States (75% white, 20% Similar to CHANCE, the target enrollment population included minor stroke (NIHSS score 3) or high-risk TIA (ABCD2 score 4) within 12 hours of symptom onset. Patients were randomized to either clopidogrel plus aspirin (600-mg loading dose of clopidogrel followed by 75 mg/d from day 2 90) plus open-label aspirin (50 325 mg/d) versus aspirin alone (50 325 mg/d) for 90 days. The primary outcome was a composite of ischemic stroke, myocardial infarction (MI), or death resulting from an ischemic vascular event up to 90 days, with a secondary safety end point of major hemorrhage during the same time period. Compared with aspirin alone, aspirin plus clopidogrel resulted in fewer 0.4%; HR, 2.32 [95% CI, 1.10 4.87]; P=0.02). Overall, the beneficial effect of aspirin plus clopidogrel was driven by a reduction in ischemic stroke (HR, 0.72 [95% CI, 0.56 0.92]; P=0.01) and greatest in the first 30 days of treatment from symptom onset (HR, 0.73 [95% CI, 0.56 0.95]; P=0.02). However, the risk of major hemorrhage was greatest after the first 7 days of treatment (HR, 2.69 [95% CI, 1.05 6.86]; P=0.04). There was no significant added benefit of aspirin plus clopidogrel after 30 days of treatment. In addition, in a prespecified analysis of functional outcomes determined by 90- day mRS score 2 for new disability, there was no difference between groups (HR, 0.97 [95% CI, 0.82 1.14]; P=0.71). See Table XLVIII in online Data Supplement 1. The efficacy of the IV glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in the treatment of AIS is not well established. IIb B-R Recommendation revised from 2013 AIS Guidelines. Prospective, randomized, open-label phase II trials of tirofiban217 have suggested safety for treatment in patients with AIS. Single-arm studies of eptifibatide as adjunctive therapy to IV alteplase support ongoing RCTs to establish safety and efficacy.173,174 Further trials are necessary to clarify the safety and efficacy of this intervention. See Tables XXXIX and XLVIII in online Data Supplement 1. Ticagrelor is not recommended over aspirin for treatment of patients with minor acute stroke. III: No Benefit B-R New recommendation. The recently completed SOCRATES trial (Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was a randomized, double-blind, placebo-controlled trial of ticagrelor versus aspirin begun within 24 hours in patients with minor stroke (NIHSS score 5) or TIA (ABCD2 score 4). With a primary outcome of time to the composite end point of stroke, MI, or death up to 90 days, ticagrelor was not found to be superior to aspirin However, because there were no significant safety differences in the 2 groups, ticagrelor may be a reasonable alternative in stroke patients who have a contraindication to aspirin. See Table XLVIII in online Data Supplement 1. The administration of the IV glycoprotein IIb/IIIa inhibitor abciximab as medical treatment for AIS is potentially harmful and should not be performed. III: Harm B-R Recommendation revised from 2013 AIS Guidelines. A recent Cochrane review of IV glycoprotein IIb/IIIa receptor antagonists in the treatment of AIS found that these agents are associated with a significant risk of ICH without a measurable improvement in death or disability.220 The majority of trial data apply to abciximab, which was studied in the AbESTT trial (A Study of Effectiveness and Safety of Abciximab in Patients With Acute Ischemic Stroke). The phase III trial was terminated early because of an unfavorable risk-benefit analysis.221 See Table XLVIII in online Data Supplement 1. Aspirin is not recommended as a substitute for acute stroke treatment in patients who are otherwise eligible for IV alteplase or mechanical thrombectomy. III: Harm B-R Recommendation revised from 2013 AIS Guidelines. Recommendation was modified to eliminate wording about acute interventions, which are broadly defined, and to specify that aspirin is a less effective substitute for the treatment of AIS in patients who are otherwise eligible for IV alteplase or mechanical thrombectomy. 3.9. Antiplatelet Treatment (Continued) COR LOE New, Revised, or Unchanged 3.10. Anticoagulants COR LOE New, Revised, or Unchanged The usefulness of urgent anticoagulation in patients with severe stenosis of an internal carotid artery ipsilateral to an ischemic stroke is not well established. IIb B-NR Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. The safety and usefulness of short-term anticoagulation for nonocclusive, extracranial intraluminal thrombus in the setting of AIS are not well established. IIb C-LD New recommendation. The optimal medical management of patients with AIS and radiologic evidence of nonocclusive, intraluminal thrombus (eg, cervical carotid, vertebrobasilar arteries) remains uncertain. Several small observational studies have suggested the safety of short-term IV heparin or LMWH in this setting,222,223 but further research is required to establish safety and efficacy. See Table XLIX in online Data Supplement 1. At present, the usefulness of argatroban, dabigatran, or other thrombin inhibitors for the treatment of patients with AIS is not well established. IIb B-R Recommendation revised from 2013 AIS Guidelines. Several observational studies have demonstrated the safety and feasibility of treating AIS with thrombin inhibitors as either a single or an adjunct therapy to alteplase. The oral direct thrombin inhibitor dabigatran was studied in 53 patients with TIA or minor stroke (NIHSS score 3) with no occurrences of sICH up to 30 days.224 ARTSS (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)-1 was an open-label, pilot safety study of argatroban infusion plus IV alteplase in 65 patients with complete or partially occlusive thrombus diagnosed by transcranial In the ARTSS-2 phase II study, patients with AIS treated with alteplase (N=90) were randomized to receive placebo or argatroban (100- g/kg bolus), followed by infusion of either 1 (low dose) or 3 (high dose) g/kg per minute for 48 hours. Rates of sICH were similar among the control, low-dose, and high-dose arms: 3 of 29 (10%), 4 of 30 (13%), Further trials are necessary to clarify the safety and efficacy of this intervention. See Tables XLIX and L in online Data Supplement 1. The safety and usefulness of oral factor Xa inhibitors in the treatment of AIS are not well established. IIb C-LD New recommendation. Limited data exist on the use of factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) for treatment of patients with AIS.227 Several prospective observational studies and early-phase trials are ongoing (NCT02279940, NCT02042534, NCT02283294). Further clinical trials are needed. See Table LI in online Data Supplement 1. Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after AIS, is not recommended for treatment of patients with AIS. III: No Benefit A Recommendation and LOE unchanged from 2013 AIS Guidelines. COR amended to conform with ACC/AHA 2015 Recommendation Classification System. Further support for this unchanged recommendation from the 2013 AIS Guidelines is provided by 2 updated meta- analyses that confirm the lack of benefit of urgent anticoagulation.228,229 An additional study, not included in these meta-analyses, investigated the efficacy of LMWH compared with aspirin in preventing early neurological deterioration in an unblinded RCT. Although there was a statistically significant difference in early neurological deterioration at 10 days after admission (LMWH, 27 [3.95%] versus aspirin, 81 [11.82%]; P<0.001), there was no difference in 6-month See Table L in online Data Supplement 1. 3.11. Volume Expansion/Hemodilution, Vasodilators, and Hemodynamic Augmentation 3.11. Volume Expansion/Hemodilution, Vasodilators, and Hemodynamic Augmentation COR LOE New, Revised, or Unchanged Hemodilution by volume expansion is not recommended for treatment of patients with AIS. III: No Benefit A Recommendation and LOE unchanged from 2013 AIS Guidelines. COR amended to conform with ACC/AHA 2015 Recommendation Classification System. A recent Cochrane review of 4174 participants from multiple RCTs confirmed the previous guideline recommendation that hemodilution therapy, including varying methods of volume expansion with or without venesection, demonstrates no significant benefit in patients with AIS.231 See Table LII in online Data Supplement 1. The administration of high-dose albumin is not recommended for the treatment of patients with AIS. III: No Benefit A Recommendation revised from 2013 AIS Guidelines. The ALIAS (Albumin in Acute Ischemic Stroke) part II trial of high-dose albumin infusion versus placebo in patients with AIS was terminated early for futility.232 Combined analysis of the ALIAS parts I and II trials demonstrated no difference between groups in 90-day disability.233 See Table LII in online Data Supplement 1. 