Reducing the time interval from ED presentation to initial brain imaging can help to reduce the time to treatment initiation. Studies have shown that median or mean door-to-imaging times of 20 minutes can be achieved in a variety of different hospital settings.79 81 See Tables XVI and XVII in online Data Supplement 1. Noncontrast CT (NCCT) is effective to exclude ICH before IV alteplase administration. I A Recommendation revised from 2013 AIS Guidelines. Magnetic resonance (MR) imaging (MRI) is effective to exclude ICH before IV alteplase administration. I B-NR Recommendation revised from 2013 AIS Guidelines. CTA with CTP or MR angiography (MRA) with diffusion-weighted magnetic resonance imaging (DW-MRI) with or without MR perfusion is recommended for certain patients. I A New recommendation. In many patients, the diagnosis of ischemic stroke can be made accurately on the basis of the clinical presentation and either a negative NCCT or one showing early ischemic changes, which can be detected in the majority of patients with careful attention.82,83 NCCT scanning of patients with acute stroke is effective for the rapid detection of acute ICH. NCCT was the only neuroimaging modality used in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (Recombinant Tissue-Type Plasminogen Activator) trials and in ECASS (European Cooperative Acute Stroke Study) III and is therefore sufficient neuroimaging for decisions about IV alteplase in most patients.48,49 Immediate CT scanning provides high value for patients with acute stroke.84,85 MRI was as accurate as NCCT in detecting hyperacute intraparenchymal hemorrhage in patients presenting with stroke symptoms within 6 hours of onset when gradient echo sequences were used.86,87 In patients who awake with stroke or have unclear time of onset >4.5 hours from baseline or last known well, MRI to identify diffusion-positive fluid-attenuated inversion recovery (FLAIR) negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom CTA with CTP or MRA with DW-MRI with or without MR perfusion is useful for selecting candidates for mechanical thrombectomy between 6 and 24 hours after last known well.51,52 See specific recommendations below. See Tables XVII through XX in online Data Supplement 1. 2.2.2. IV Alteplase Eligibility COR LOE New, Revised, or Unchanged Administration of IV alteplase in eligible patients without first obtaining MRI to exclude cerebral microbleeds (CMBs) is recommended. I B-NR New recommendation. CMBs are common in patients receiving IV alteplase, occurring in 15% to 27%.89 94 Such patients were undoubtedly included in the pivotal NINDS and ECASS III trials that established the benefits of IV alteplase treatment.48,49 Two meta- analyses of the association of baseline CMBs and the risk of sICH after IV alteplase reported that sICH is more common in patients with baseline CMBs, whereas 2 other meta-analyses and 1 multicenter study did not.89 93 In 2 studies using ECASS II sICH criteria, the rates in patients with CMBs were 5.8% and 6.5% compared with 5.3% in ECASS III.49,90,91 One study analyzing the risk of sICH in patients with CMBs detected after IV alteplase treatment reported sICH of 5% using the NINDS criteria compared with 6.4% in the NINDS tPA trials.48,94 The risk of sICH in patients with >10 CMBs (30% 47%) is consistently reported as significantly greater than in those with no CMBs (1% 4.4%). However, these data are based on <50 patients, constituting <2% of these series.90,91,93,94 No RCTs of IV alteplase in AIS with baseline MRI to identify CMBs have been conducted, so no determination of the effect of baseline CMB on the treatment effect of alteplase with CMB is available. In the absence of direct evidence that IV alteplase provides no benefit or produces harm in eligible patients with CMBs, withholding treatment on the basis of the presence of CMBs could lead to the exclusion of patients who would benefit from treatment. See Table XXI in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e357 In patients eligible for IV alteplase, because benefit of therapy is time dependent, treatment should be initiated as quickly as possible and not delayed for additional multimodal neuroimaging, such as CT and MRI perfusion imaging. I B-NR New recommendation. NCCT was the only neuroimaging modality used in the NINDS rt-PA trial and in ECASS III and is therefore sufficient neuroimaging for decisions about IV alteplase in most patients.48,49 Multimodal CT and MRI, including diffusion and perfusion imaging, are not necessary when the diagnosis of ischemic stroke is very likely, and their performance may delay time-sensitive administration of IV alteplase. In some cases, particularly when there is substantial diagnostic uncertainty, advanced imaging may be beneficial. See Table XX in online Data Supplement 1. In patients with AIS who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well or at baseline state, MRI to identify diffusion-positive FLAIR-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition. IIa B-R New recommendation. The WAKE-UP trial (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke) randomized 503 patients with AIS who awoke with stroke or had unclear time of onset >4.5 hours from last known well and could be treated with IV alteplase within 4.5 hours of stroke symptom recognition. Eligibility required MRI mismatch between abnormal signal on DW-MRI and no visible signal change on FLAIR. DW-MRI lesions larger than one-third of the territory of the middle cerebral artery (MCA), NIHSS score >25, contraindication to treatment with alteplase, or planned thrombectomy were all exclusions. The trial was terminated early for lack of funding before the designated 800 patients were randomized. Ninety-four percent were wake-up strokes. Median NIHSS score was 6. Median time from last known well was slightly over 10 hours. At baseline, one-third of the patients had vessel occlusion on time-of-flight MRA, and three-quarters of the FLAIR lesions were <9 mL. The end point of an mRS score of 0 to 1 at 90 days was achieved in 53.3% of the IV alteplase group and in 41.8% of the placebo group (P=0.02).88 See Table XIX in online Data Supplement 2.2.3. Mechanical Thrombectomy Eligibility Vessel Imaging COR LOE New, Revised, or Unchanged For patients who otherwise meet criteria for mechanical thrombectomy, noninvasive vessel imaging of the intracranial arteries is recommended during the initial imaging evaluation. I A Recommendation reworded for clarity from 2015 Endovascular. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. For patients with suspected LVO who have not had noninvasive vessel imaging as part of their initial imaging assessment for stroke, noninvasive vessel imaging should then be obtained as quickly as possible (eg, during alteplase infusion if feasible). I A Recommendation revised from 2015 Endovascular. COR and LOE unchanged. A recent systematic review evaluated the accuracy of prediction instruments for diagnosing LVO.4 In the setting where confirmed ischemic stroke patients would be assessed by a neurologist or emergency physician in the ED, the authors suggested that the NIHSS score is the best of the LVO prediction instruments. According to their meta-analysis, a threshold of 10 would provide the optimal balance between sensitivity (73%) and specificity (74%). To maximize sensitivity (at the cost of lower specificity), a threshold of 6 would have 87% sensitivity and 52% specificity. However, even this low threshold misses some cases with LVO, whereas the low specificity indicates that false- positives will be common. The sensitivity of CTA and MRA compared with the gold standard of catheter angiography ranges from 87% to 100%, with CTA having greater accuracy than MRA.95,96 Pivotal trials of mechanical thrombectomy all required noninvasive CTA or MRA diagnosis of LVO as an inclusion criterion. See Tables XVII and XXII in online Data Supplement 1. In patients with suspected intracranial LVO and no history of renal impairment, who otherwise meet criteria for mechanical thrombectomy, it is reasonable to proceed with CTA if indicated before obtaining a serum creatinine concentration. IIa B-NR New recommendation. Analyses from a number of observational studies suggest that the risk of contrast-induced nephropathy secondary to CTA imaging is relatively low, particularly in patients without a history of renal impairment. Moreover, waiting for these laboratory results may lead to delays in mechanical thrombectomy.97 102 See Table XXIII in online Data Supplement 1. In patients who are potential candidates for mechanical thrombectomy, imaging of the extracranial carotid and vertebral arteries, in addition to the intracranial circulation, may be reasonable to provide useful information on patient eligibility and endovascular procedural planning. IIb C-EO New recommendation. Knowledge of vessel anatomy and presence of extracranial vessel dissections, stenoses, and occlusions may assist in planning endovascular procedures or identifying patients ineligible for treatment because of vessel tortuosity or inability to access the intracranial vasculature. 2.2.2. IV Alteplase Eligibility (Continued) COR LOE New, Revised, or Unchanged It may be reasonable to incorporate collateral flow status into clinical decision-making in some candidates to determine eligibility for mechanical thrombectomy. IIb C-LD Recommendation revised from 2015 Endovascular. Several studies, including secondary analyses from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for AIS in the Netherlands) and IMS (Interventional Management of Stroke) III, provide data supporting the role of collateral assessments in identifying patients likely or unlikely to benefit from mechanical thrombectomy.103,104 The ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times), using multiphase CTA to select patients with moderate to good collateral circulation for mechanical thrombectomy up to 12 hours from onset, was stopped early for efficacy.105 Acquisition of advanced imaging should not delay door to groin puncture times. See Tables XXIV and XXV in online Data Supplement 1. 2.2.4. Mechanical Thrombectomy Eligibility Multimodal Imaging COR LOE New, Revised, or Unchanged When selecting patients with AIS within 6 to 24 hours of last known normal who have LVO in the anterior circulation, obtaining CTP or DW-MRI, with or without MRI perfusion, is recommended to aid in patient selection for mechanical thrombectomy, but only when patients meet other eligibility criteria from one of the RCTs that showed benefit from mechanical thrombectomy in this extended time window. I A New recommendation. The DAWN trial (Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) used clinical-core mismatch (a combination of age-adjusted NIHSS score and age-adjusted core infarct size on CTP or DW-MRI) as an eligibility criterion to select patients with large anterior circulation vessel occlusion for mechanical thrombectomy between 6 and 24 hours from last known normal. This trial demonstrated an overall benefit in functional 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 The DEFUSE 3 trial (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) 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, 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. When evaluating patients with AIS within 6 hours of last known normal with LVO and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 6, selection for mechanical thrombectomy based on CT and CTA or MRI and MRA is recommended in preference to performance of additional imaging such as perfusion studies. I B-NR New recommendation. Of the 6 RCTs that independently demonstrated clinical benefit of mechanical thrombectomy with stent retrievers when performed <6 hours from stroke onset, 4 trials (REVASCAT [Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset], SWIFT PRIME [Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits Intra-Arterial], and ESCAPE)105 108 used some form of advanced imaging to determine eligibility, whereas 2 (THRACE [Trial and Cost Effectiveness Evaluation of Intra-Arterial Thrombectomy in Acute Ischemic Stroke] and MR CLEAN)109,110 required only NCCT and demonstration of LVO. Because the last 2 studies independently demonstrated benefit in the treated group, the role of additional imaging-based eligibility criteria is not well established and could lead to the exclusion of patients who would benefit from treatment and are therefore not indicated at this time. Further RCTs may be helpful to determine whether advanced imaging paradigms using CTP, CTA, and MRI perfusion and diffusion imaging, including measures of infarct core and penumbra, are beneficial for selecting patients for reperfusion therapy who are within 6 hours of symptom onset and have an ASPECTS <6. See Table XVII in online Data Supplement 1. 2.2.3. Mechanical Thrombectomy Eligibility Vessel Imaging (Continued) COR LOE New, Revised, or Unchanged Powers et al 2019 Guidelines for Management of AIS e359 2.3. Other Diagnostic Tests 2.3. Other Diagnostic Tests COR LOE New, Revised, or Unchanged Only the assessment of blood glucose must precede the initiation of IV alteplase in all patients. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Recommendation was modified to clarify that it is only blood glucose that must be measured in all patients. Other tests, for example, international normalized ratio, activated partial thromboplastin time, and platelet count, may be necessary in some circumstances if there is suspicion of coagulopathy. Given the extremely low risk of unsuspected abnormal platelet counts or coagulation studies in a population, IV alteplase treatment should not be delayed while waiting for hematologic or coagulation testing if there is no reason to suspect an abnormal test. Baseline electrocardiographic assessment is recommended in patients presenting with AIS but should not delay initiation of IV alteplase. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Baseline troponin assessment is recommended in patients presenting with AIS but should not delay initiation of IV alteplase or mechanical thrombectomy. I C-LD Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Usefulness of chest radiographs in the hyperacute stroke setting in the absence of evidence of acute pulmonary, cardiac, or pulmonary vascular disease is unclear. If obtained, they should not unnecessarily delay administration of IV alteplase. IIb B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Additional support for this reworded recommendation from the 2013 AIS Guidelines comes from a cohort study of 615 patients, 243 of whom had chest x-ray done before IV alteplase. Cardiopulmonary adverse events in the first 24 hours of admission, endotracheal intubation in the first 7 hours, and in-hospital mortality were not different between the 2 groups. Patients with chest x-ray done before treatment had longer mean DTN times than those who did not (75.8 minutes versus 58.3 minutes; P=0.0001).111 See Table XXVI in online Data Supplement 1. 3. General Supportive Care and Emergency Treatment 3.1. Airway, Breathing, and Oxygenation 3.1. Airway, Breathing, and Oxygenation COR LOE New, Revised, or Unchanged Airway support and ventilatory assistance are recommended for the treatment of patients with acute stroke who have decreased consciousness or who have bulbar dysfunction that causes compromise of the airway. I C-EO Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Supplemental oxygen should be provided to maintain oxygen saturation >94%. I C-LD Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. 3. Supplemental oxygen is not recommended in nonhypoxic patients with AIS. III: No Benefit B-R Recommendation unchanged from 2013 AIS Guidelines. COR and LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Additional support for this unchanged recommendation from the 2013 AIS Guidelines is provided by an RCT of 8003 participants randomized within 24 hours of admission. There was no benefit on functional outcome at 90 days of oxygen by nasal cannula at 2 L/min (baseline O2 continuously for 72 hours or nocturnally for 3 nights.112 See Table XXVII in online Data Supplement 1. Hyperbaric oxygen (HBO) is not recommended for patients with AIS except when caused by air embolization. III: No Benefit B-NR Recommendation revised from 2013 AIS Guidelines. The limited data available on the utility of HBO therapy for AIS (not related to cerebral air embolism) show no HBO therapy is associated with claustrophobia and middle ear barotrauma,114 as well as an increased risk of seizures.115 Given the confines of HBO chambers, the ability to closely/adequately monitor patients may also be compromised. HBO thus should be offered only in the context of a clinical trial or to individuals with cerebral air embolism. See Table XXVIII in online Data Supplement 1. 3.2. Blood Pressure 3.2. Blood Pressure COR LOE New, Revised, or Unchanged Hypotension and hypovolemia should be corrected to maintain systemic perfusion levels necessary to support organ function. I C-EO New recommendation. The blood pressure (BP) level that should be maintained in patients with AIS to ensure the best outcome is not known. Some observational studies show an association between worse outcomes and lower BPs, whereas others have No studies have addressed the treatment of low BP in patients with stroke. In a systematic analysis of 12 studies comparing the use of IV colloids and crystalloids, the odds of death or dependence were similar. Clinically important benefits or harms could not be excluded. There are no data to guide volume and duration of parenteral fluid No studies have compared different isotonic fluids. See Table XXIX in online Data Supplement 1. Patients who have elevated BP and are otherwise eligible for treatment with IV alteplase should have their BP carefully lowered so that their SBP is <185 mmHg and their diastolic BP is <110 mmHg before IV fibrinolytic therapy is initiated. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. The RCTs of IV alteplase required the BP to be <185 mmHg systolic and <110 mmHg diastolic before treatment and <180/105 mmHg for the first 24 hours after treatment. Options to treat arterial hypertension in patients with AIS who are candidates for immediate reperfusion therapy are given in Table 5. Some observational studies suggest that the risk of hemorrhage after administration of alteplase is greater in patients with higher BPs125 131 and in patients with more BP variability.132 The exact BP at which the risk of hemorrhage after IV alteplase increases is unknown. It is thus reasonable to target the BPs used in the RCTs of IV alteplase. See Tables XX and XXX in online Data Supplement 1. In patients for whom mechanical thrombectomy is planned and who have not received IV fibrinolytic therapy, it is reasonable to maintain BP 185/110 mmHg before the procedure. IIa B-NR Recommendation revised from 2013 AIS Guidelines. Of the 6 RCTs that each independently demonstrated clinical benefit of mechanical thrombectomy with stent retrievers when performed <6 hours from stroke onset, 5 (REVASCAT, SWIFT PRIME, EXTEND-IA, THRACE, and MR CLEAN)106 110 had eligibility exclusions for BP >185/110 mmHg. The sixth, ESCAPE,105 had no BP eligibility exclusion. DAWN also used an exclusion for BP >185/110 mmHg.51 RCT data for optimal BP management approaches in this setting are not available. Because the vast majority of patients enrolled in these RCTs had preprocedural BP managed below 185/110 mmHg, it is reasonable to use this level as a guideline until additional data become available. See Table XVII in online Data Supplement 1. The usefulness of drug-induced hypertension in patients with AIS is not well established. IIb B-R Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. 3.1. Airway, Breathing, and Oxygenation (Continued) COR LOE New, Revised, or Unchanged Powers et al 2019 Guidelines for Management of AIS e361 3.3. Temperature COR LOE New, Revised, or Unchanged Sources of hyperthermia (temperature >38 C) should be identified and treated, and antipyretic medications should be administered to lower temperature in hyperthermic patients with stroke. I C-LD Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Additional support for this recommendation unchanged from the 2013 AIS Guidelines is provided by a large retrospective cohort study conducted from 2005 to 2013 of patients admitted to intensive care units in Australia, New Zealand, and the United Kingdom. Peak temperature in the first 24 hours <37 C and >39 C was associated with an increased risk of in-hospital death compared with normothermia in 9366 patients with AIS.133 See Tables XXXI and XXXII in online Data Supplement 1. In patients with AIS, the benefit of treatment with induced hypothermia is uncertain. IIb B-R Recommendation revised from 2013 AIS Guidelines. To date, studies of hypothermia in AIS show no benefit in functional outcome and suggest that induction of hypothermia increases the risk of infection, including pneumonia.134 137 These studies use a variety of methods to induce hypothermia and are small/underpowered, meaning that a benefit for hypothermia in AIS cannot be definitively excluded. A large phase III trial of hypothermia in AIS is ongoing. See Tables XXXIII and XXXIV in online Data Supplement 1. 3.4. Blood Glucose 3.4. Blood Glucose COR LOE New, Revised, or Unchanged Hypoglycemia (blood glucose <60 mg/dL) should be treated in patients with AIS. I C-LD Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Evidence indicates that persistent in-hospital hyperglycemia during the first 24 hours after AIS is associated with worse outcomes than normoglycemia, and thus, it is reasonable to treat hyperglycemia to achieve blood glucose levels in a range of 140 to 180 mg/dL and to closely monitor to prevent hypoglycemia in patients with AIS. IIa C-LD Recommendation and COR unchanged from 2013 AIS Guidelines. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Table 5. Options to Treat Arterial Hypertension in Patients With AIS Who Are Candidates for Emergency Reperfusion Therapy* COR IIb LOE C-EO Patient otherwise eligible for emergency reperfusion therapy except that BP is >185/110 mmHg: Labetalol 10 20 mg IV over 1 2 min, may repeat 1 time; or Nicardipine 5 mg/h IV, titrate up by 2.5 mg/h every 5 15 min, maximum 15 mg/h; when desired BP reached, adjust to maintain proper BP limits; or Clevidipine 1 2 mg/h IV, titrate by doubling the dose every 2 5 min until desired BP reached; maximum 21 mg/h Other agents (eg, hydralazine, enalaprilat) may also be considered If BP is not maintained 185/110 mmHg, do not administer alteplase Management of BP during and after alteplase or other emergency reperfusion therapy to maintain BP 180/105 mmHg: Monitor BP every 15 min for 2 h from the start of alteplase therapy, then every 30 min for 6 h, and then every hour for 16 h If systolic BP >180 230 mmHg or diastolic BP >105 120 mmHg: Labetalol 10 mg IV followed by continuous IV infusion 2 8 mg/min; or Nicardipine 5 mg/h IV, titrate up to desired effect by 2.5 mg/h every 5 15 min, maximum 15 mg/h; or Clevidipine 1 2 mg/h IV, titrate by doubling the dose every 2 5 min until desired BP reached; maximum 21 mg/h If BP not controlled or diastolic BP >140 mmHg, consider IV sodium nitroprusside AIS indicates acute ischemic stroke; BP, blood pressure; COR, class of recommendation; IV, intravenous; and LOE, Level of Evidence. *Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from rapid reductions in BP such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Data derived from Jauch et al.1 3.5. IV Alteplase 3.5.1. General Principles COR LOE New, Revised, or Unchanged In patients eligible for IV alteplase, benefit of therapy is time dependent, and treatment should be initiated as quickly as possible. I A Recommendation reworded for clarity from 2013 AIS Guidelines. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. In patients undergoing fibrinolytic therapy, physicians should be prepared to treat potential emergent adverse effects, including bleeding complications and angioedema that may cause partial airway obstruction. I B-NR Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. See Table 6 for options for management of symptomatic intracranial bleeding occurring within 24 hours after administration of IV alteplase for treatment of AIS and Table 7 for options for management of orolingual angioedema associated with IV alteplase administration for AIS. The potential risks should be discussed during IV alteplase eligibility deliberation and weighed against the anticipated benefits during decision- making. I C-EO Recommendation and COR unchanged from 2015 IV Alteplase. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. Treating clinicians should be aware that hypoglycemia and hyperglycemia may mimic acute stroke presentations and determine blood glucose levels before IV alteplase initiation. IV alteplase is not indicated for nonvascular conditions. III: No Benefit B-NR Recommendation reworded for clarity from 2015 IV Alteplase. COR and LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Because time from onset of symptoms to treatment has such a powerful impact on outcomes, treatment with IV alteplase should not be delayed to monitor for further improvement. III: Harm C-EO Recommendation wording modified from 2015 IV Alteplase to match COR III stratifications and reworded for clarity. COR and LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. 3.5.2. Time Windows COR LOE New, Revised, or Unchanged IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is recommended for selected patients who can be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in Table 8 to determine patient eligibility. I A Recommendation reworded for clarity from 2013 AIS Guidelines. COR and LOE unchanged. See Table XCV in online Data Supplement 1 for original wording. The safety and efficacy of this treatment when administered within the first 3 hours after stroke onset are solidly supported by combined data from multiple RCTs155 157 and confirmed by extensive community experience in many The eligibility criteria for IV alteplase have evolved over time as its usefulness and true risks have become clearer. A recent AHA statement provides a detailed discussion of this topic.14 Eligibility recommendations for IV alteplase in patients with AIS are summarized in Table 8. The benefit of IV alteplase is well established for adult patients with disabling stroke symptoms regardless of age and stroke severity.78,159 Because of this proven benefit and the need to expedite treatment, when a patient cannot provide consent (eg, aphasia, confusion) and a legally authorized representative is not immediately available to provide proxy consent, it is justified to proceed with IV alteplase in an otherwise eligible adult patient with a disabling AIS. In a recent trial, a lower dose of IV alteplase (0.6 mg/kg) was not shown to be noninferior to standard-dose IV alteplase for the reduction of death and disability at 90 See Table XX in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e363 IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) is also recommended for selected patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in Table 8 to determine patient eligibility. I B-R Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. One trial (ECASS III) specifically evaluating the efficacy of IV alteplase within 3 and 4.5 hours after symptom onset49 and pooled analysis of multiple trials testing IV alteplase within various time windows155 157 support the efficacy of IV alteplase up to 4.5 hours after symptom onset. ECASS III excluded octogenarians, patients taking warfarin regardless of international normalized ratio, patients with combined history of diabetes mellitus and previous ischemic stroke, and patients with very severe strokes (NIHSS score >25) because of a perceived excessive risk of intracranial hemorrhage in those cases. However, careful analysis of available published data summarized in an AHA/American Stroke Association (ASA) scientific statement indicates that these exclusion criteria from the trial may not be justified in practice (Table 8).14 See Table XX in online Data Supplement 1. IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 minutes with initial 10% of dose given as bolus over 1 minute) administered within 4.5 hours of stroke symptom recognition can be beneficial in patients with AIS who awake with stroke symptoms or have unclear time of onset >4.5 hours 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. IIa B-R New recommendation. The WAKE-UP RCT randomized 503 patients with AIS who awoke with stroke or had unclear time of onset and could be treated with IV alteplase within 4.5 hours of stroke symptom recognition. Eligibility required MRI mismatch between abnormal signal on DW-MRI and no visible signal change on FLAIR. DW-MRI lesions larger than one-third of the territory of the MCA, NIHSS score >25, contraindication to treatment with alteplase, or planned thrombectomy were all exclusions. Ninety-four percent were wake-up strokes. Median NIHSS score was 6. Median time from last known well to symptom recognition was 7 hours and to alteplase administration slightly over 10 hours. The primary end point of an mRS score 0 to 1 at 90 days was achieved in 53.3% of the alteplase group and in 41.8% of the placebo group (P=0.02). Only 20% had LVO of the intracranial internal carotid or proximal middle cerebral arteries.88 See Table XIX in online Data Supplement 1. 3.5.3. Mild Stroke COR LOE New, Revised, or Unchanged For otherwise eligible patients with mild but disabling stroke symptoms, IV alteplase is recommended for patients who can be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. I B-R Recommendation revised from 2015 IV Alteplase. COR and LOE added to conform with ACC/AHA 2015 Recommendation Classification System. For otherwise eligible patients with mild disabling stroke symptoms, IV alteplase may be reasonable for patients who can be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state. IIb B-NR New recommendation. For otherwise eligible patients with mild nondisabling stroke symptoms (NIHSS score 0 5), IV alteplase is not recommended for patients who could be treated within 3 hours of ischemic stroke symptom onset or patient last known well or at baseline state. III: No Benefit B-R New recommendation. For otherwise eligible patients with mild non-disabling stroke symptoms (NIHSS 0 5), IV alteplase is not recommended for patients who could be treated within 3 and 4.5 hours of ischemic stroke symptom onset or patient last known well or at baseline state. III: No Benefit C-LD New recommendation. Subgroup analyses of the NINDS rt-PA Trial and IST (International Stroke Trial)-3 with mild stroke defined in various ways have inconsistently shown a benefit for IV alteplase.161 163 A meta-analysis of 9 trials of IV alteplase in AIS including subjects from the NINDS rt-PA trial and IST-3 showed benefit for patients with mild stroke defined as NIHSS In ECASS III, there was no significant interaction of benefit (mRS score 0 1 at 90 days) or safety (sICH or death) with stroke severity when patients were categorized by baseline NIHSS score of 0 to 9, 10 to 19, and In SITS-ISTR (Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Registry), good functional outcomes (mRS score 0 1 at 90 days) and risk of sICH were similar or the same in mild stroke treated in Similarly, in the AHA GWTG registry, good functional outcomes, mortality, and risk of sICH were the same in mild stroke treated in 0 to 3 and 3 to 4.5 hours.167 These patients were not further categorized by whether their acute neurological deficits were disabling. The PRISMS RCT (A Study of the Safety and Efficacy of Activase [Alteplase] in Patients With Mild Stroke) evaluated IV alteplase in patients with mild (NIHSS score 0 5) AIS whose acute neurological deficits were judged to not interfere with activities of daily living or prevent return to work. There was no benefit of treatment within 3 hours of onset.168 See Tables XXXV and XXXVI in online Data Supplement 1. 3.5.2. Time Windows (Continued) COR LOE New, Revised, or Unchanged 3.5.4. Other Specific Circumstances COR LOE New, Revised, or Unchanged IV alteplase for adults presenting with an AIS with known sickle cell disease can be beneficial. IIa B-NR New recommendation. A case-control analysis using the population from the AHA GWTG-Stroke registry, including 832 cases with sickle cell disease (all adults) and 3328 age-, sex-, and race-matched controls without sickle cell disease with similar severity of neurological deficits at presentation, showed that sickle cell disease did not have a significant impact on the safety or the outcome at discharge of treatment with IV alteplase.169 See Table XXXVII in online Data Supplement 1. 2. In patients with a hyperdense MCA sign, IV alteplase can be beneficial. IIa B-NR New recommendation. Analyses of data from RCTs of IV alteplase for AIS have shown no statistically significant deleterious interaction on clinical outcomes between alteplase treatment and the hyperdense MCA sign on baseline CT. In the NINDS rt-PA trial, there was no interaction between hyperdense MCA sign and treatment for outcomes at 3 months measured by any of the 4 clinical scales (mRS score 0 1, NIHSS score 0 1, Barthel Index score 95, Glasgow Outcome Scale score 0 1) or for death.170 In IST-3, no significant interaction of the hyperdense MCA sign with benefit of alteplase measured by the Oxford Handicap Score at 6 months was observed.171,172 See Table XXXVIII in online Data Supplement 1. 3.5.5. Bleeding Risk COR LOE New, Revised, or Unchanged Given the extremely low risk of unsuspected abnormal platelet counts or coagulation studies in a population, it is reasonable that urgent IV alteplase treatment not be delayed while waiting for hematologic or coagulation testing if there is no reason to suspect an abnormal test. IIa B-NR Recommendation and COR unchanged from 2015 IV Alteplase. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. In otherwise eligible patients who have previously had a small number (1 10) of CMBs demonstrated on MRI, administration of IV alteplase is reasonable. IIa B-NR New recommendation. 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. IIb B-NR New recommendation. CMBs are common in patients receiving IV alteplase, occurring in 15% to 27%.89 94 No RCTs of IV alteplase in AIS with baseline MRI to identify CMBs have been conducted, so no determination of the effect of baseline CMB on the treatment effect of alteplase with CMB is available. Two meta-analyses of the association of baseline CMBs on the risk of sICH after IV alteplase reported that sICH is more common in patients with baseline CMBs, whereas 2 other meta-analyses and 1 multicenter study did not.89 93 In 2 studies using ECASS II sICH criteria, the rates in patients with CMBs were 5.8% and One study analyzing the risk of sICH in patients with CMBs detected after IV alteplase treatment reported sICH of 5% using the NINDS criteria compared with 6.4% in the NINDS rt-PA trials.48,94 The risk of sICH in patients with >10 CMBs (30% 47%) is consistently reported as significantly greater than in those with no CMBs (1% 4.4%). However, these data are based on <50 patients, constituting < 2% of these series.90,91,93,94 Meta-analysis of 4 studies that provide information on 3- to 6-month functional outcomes showed that the presence of CMBs was associated with worse outcomes after IV alteplase compared with patients without CMBs (OR, 1.58 [95% CI, 1.18 2.14]; P=0.002).89 Thus, the presence of CMBs increases the risk of ICH and the chances of poor outcomes after IV alteplase, but it is unclear whether these negative effects fully negate the benefit of IV alteplase. It is also unknown whether the location and number of CMBs may differentially influence outcomes. These questions deserve further investigation. See Table XXI in online Data Supplement 1. The efficacy of the IV glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide coadministered with IV alteplase is not well established. IIb B-R Recommendation revised from 2013 AIS Guidelines. Single-arm studies of eptifibatide as adjunctive therapy to IV alteplase support ongoing RCTs to establish safety and Further clinical trials are needed. See Table XXXIX in online Data Supplement 1. 5. Abciximab should not be administered concurrently with IV alteplase. III: Harm B-R Recommendation reworded for clarity from 2015 IV Alteplase. COR and LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. IV aspirin should not be administered within 90 minutes after the start of IV alteplase. III: Harm B-R New recommendation. The ARTIS trial (Antiplatelet Therapy in Combination with rt-PA Thrombolysis in Ischemic Stroke) compared the effects of very early addition (within 90 minutes) of 300 mg IV aspirin to alteplase with standard treatment with alteplase without IV aspirin.175 The trial was terminated after 642 of the 800 targeted patients had been enrolled because IV aspirin was associated with an increased risk of symptomatic intracranial hemorrhage (4.3% versus 1.6% in the standard treatment group; RR, 2.78 [95% CI, 1.01 7.63]; P=0.04) and no difference in the rate of favorable functional outcome (mRS score 0 2) at 3 months (54.0% of patients in the aspirin group versus 57.2% of patients in the standard treatment group; RR, 0.94 [95% CI, 0.82 1.09]; P=0.42). See Table XL in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e365 IV alteplase should not be administered to patients who have received a full treatment dose of low-molecular-weight heparin (LMWH) within the previous 24 hours. III: Harm B-NR Recommendation reworded for clarity from 2015 IV Alteplase. COR and LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. The recommendation refers to full treatment doses and not to prophylactic doses. The 2015 Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke stated, Intravenous alteplase in patients who have received a dose of LMWH within the previous 24 hours is not recommended. This applies to both prophylactic doses and treatment doses (COR III; Level of Evidence B). 14 This statement was updated in a subsequently published erratum to specify that the contraindication does not apply to prophylactic doses. 3.5.6. Post-alteplase Treatment COR LOE New, Revised, or Unchanged BP should be maintained at <180/105 mmHg for at least the first 24 hours after IV alteplase treatment. I B-R Recommendation reworded for clarity from 2013 AIS Guidelines. COR unchanged. LOE amended to conform with ACC/AHA 2015 Recommendation Classification System. See Table XCV in online Data Supplement 1 for original wording. Main elements of postthrombolysis care are listed in Table 9. ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) randomized 2196 alteplase-eligible patients with AIS and systolic BP (SBP) 150 mmHg to receive intensive target SBP of 130 to 140 mmHg within 1 hour versus guideline target SBP <180 mmHg; 1081 were in the intensive group, and 1115 were in the guideline group.176 Median time from stroke onset to randomization was 3.3 hours. Mean SBP in the intensive group was 144.3 mmHg, and mean SBP in the guideline group was 149.8 mmHg. Primary outcome mRS score at 90 days did not differ between the 2 groups. Although fewer patients in the intensive group had ICH, the number of patients with serious adverse events did not differ between the 2 groups. Although intensive BP lowering was observed to be safe, the observed reduction in ICH did not lead to improved clinical outcome compared with guideline treatment. See Table XLI in online Data Supplement 1. The risk of antithrombotic therapy (other than IV aspirin) within the first 24 hours after treatment with IV alteplase (with or without mechanical thrombectomy) is uncertain. Use 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. IIb B-NR New recommendation. 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. However, this study may have been subject to selection bias, and the timing of the initiation of antiplatelet therapy or anticoagulation should be based on an individual level, balancing risk and benefit.177 See Table XLII in online Data Supplement 1. 3.5.5. Bleeding Risk (Continued) COR LOE New, Revised, or Unchanged Table 6. Management of Symptomatic Intracranial Bleeding Occurring Within 24 Hours After Administration of IV Alteplase for Treatment of AIS COR IIb LOE C-EO Stop alteplase infusion CBC, PT (INR), aPTT, fibrinogen level, and type and cross-match Emergent nonenhanced head CT Cryoprecipitate (includes factor VIII): 10 U infused over 10 30 min (onset in 1 h, peaks in 12 h); administer additional dose for fibrinogen level of <150 mg/dL Tranexamic acid 1000 mg IV infused over 10 min OR -aminocaproic acid 4 5 g over 1 h, followed by 1 g IV until bleeding is controlled (peak onset in 3 h) (Potential for benefit in all patients, but particularly when blood products are contraindicated or declined by patient/family or if cryoprecipitate is not available in a timely manner.) Hematology and neurosurgery consultations Supportive therapy, including BP management, ICP, CPP, MAP, temperature, and glucose control AIS indicates acute ischemic stroke; aPTT, activated partial thromboplastin time; BP, blood pressure; CBC, complete blood count; COR, class of recommendation; CPP, cerebral perfusion pressure; CT, computed tomography; ICP, intracranial pressure; INR, international normalized ratio; IV, intravenous; LOE, Level of Evidence; MAP, mean arterial pressure; and PT, prothrombin time. Sources: Sloan et al,138 Mahaffey et al,139 Goldstein et al,140 French et al,141 Yaghi et al,142 144 Stone et al,145 and Frontera et al.146 Table 7. Management of Orolingual Angioedema Associated With IV Alteplase Administration for AIS COR IIb LOE C-EO Maintain airway Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. Edema involving larynx, palate, floor of mouth, or oropharynx with rapid progression (within 30 min) poses higher risk of requiring intubation. Awake fiberoptic intubation is optimal. Nasal-tracheal intubation may be required but poses risk of epistaxis after IV alteplase. Cricothyroidotomy is rarely needed and also problematic after IV alteplase. Discontinue IV alteplase infusion and hold ACE inhibitors Administer IV methylprednisolone 125 mg Administer IV diphenhydramine 50 mg Administer ranitidine 50 mg IV or famotidine 20 mg IV If there is further increase in angioedema, administer epinephrine (0.1%) 0.3 mL subcutaneously or by nebulizer 0.5 mL Icatibant, a selective bradykinin B2 receptor antagonist, 3 mL (30 mg) subcutaneously in abdominal area; additional injection of 30 mg may be administered at intervals of 6 h not to exceed a total of 3 injections in 24 h; and plasma-derived C1 esterase inhibitor (20 IU/kg) has been successfully used in hereditary angioedema and ACE inhibitor-related angioedema Supportive care ACE indicates angiotensin-converting enzyme; AIS, acute ischemic stroke; COR, class of recommendation; IV, intravenous; and LOE, Level of Evidence. Sources: Foster-Goldman and McCarthy,147 Gorski and Schmidt,148 Lin et al,150 Correia et al,151 O Carroll and Aguilar,152 Myslimi et al,153 and Pahs Table 8. Eligibility Recommendations for IV Alteplase in Patients With AIS Indications (COR I) Within 3 h* IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) is recommended for selected patients who may be treated within 3 h of ischemic stroke symptom onset or patient last known well or at baseline state. Physicians should review the criteria outlined in this table to determine patient eligibility. (COR I; LOE A) Within 3 h Age For otherwise medically eligible patients 18 y of age, IV alteplase administration within 3 h is equally recommended for patients 80 and >80 y of age. (COR I; LOE A) Within 3 h Severe stroke For severe stroke, IV alteplase is indicated within 3 h from symptom onset of ischemic stroke. Despite increased risk of hemorrhagic transformation, there is still proven clinical benefit for patients with severe stroke symptoms. (COR I; LOE A) Within 3 h Mild disabling stroke For otherwise eligible patients with mild but disabling stroke symptoms, IV alteplase is recommended for patients who can be treated within 3 h of ischemic stroke symptom onset or patient last known well or at baseline state (COR I; LOE B-R) 3 4.5 h* IV alteplase (0.9 mg/kg, maximum dose 90 mg over 60 min with initial 10% of dose given as bolus over 1 min) is also recommended for selected patients who can be treated within 3 and 4.5 h of ischemic stroke symptom onset or patient last known well. Physicians should review the criteria outlined in this table to determine patient eligibility. (COR I; LOE B-R) 3 4.5 h Age IV alteplase treatment in the 3- to 4.5-h time window is recommended for those patients 80 y of age, without a history of both diabetes mellitus and prior stroke, NIHSS score 25, not taking any OACs, and without imaging evidence of ischemic injury involving more than one-third of the MCA territory. (COR I; LOE B-R) Urgency Treatment should be initiated as quickly as possible within the above-listed time frames because time to treatment is strongly associated with outcomes. (COR I; LOE A) BP IV alteplase is recommended in patients with BP <185/110 mmHg and in those patients whose BP can be lowered safely to this level with antihypertensive agents, with the physician assessing the stability of the BP before starting IV alteplase. (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. 