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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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 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 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.


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 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 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.


(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 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.


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.


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) 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 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.)


(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.)


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.


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 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.


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.


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.


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 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.


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.


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.


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.


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.


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.


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.


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%).


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.


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 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%).


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.


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.


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.


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 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.