Critical Care Management of Stroke NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NEURO LECTURE: Critical Care Management of Stroke Heustein Sy, MD

Review guidelines on the management of large hemispheric infarctions NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA OBJECTIVES: Review the evidence for the use of IV thrombolytics, and endovascular techniques in the treatment of stroke Review the evidence for decompressive craniectomy in the treatment of large hemispheric infarctions Review guidelines on the management of large hemispheric infarctions

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH NINDS 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH 1 2 3 4 5 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH 1 2 3 4 5 6

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH 1 2 3 4 5 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH 1 2 3 4 5 6

Ensure medical stability 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH GOALS: Ensure medical stability Quickly reverse any condition contributing to the symptoms Determine eligibility for thrombolytic therapy / thrombectomy Uncovering pathophysiologic basis of neurologic symptoms

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial METHODS: Acute ischemic stroke IV alteplase within 3 hours vs placebo 0.9mg/Kg up to 90mg 10% bolus then 60-minute infusion "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial METHODS: Acute ischemic stroke IV alteplase within 3 hours vs placebo 0.9mg/Kg up to 90mg 10% bolus then 60-minute infusion OUTCOMES: 3 month functional outcome Mortality Safety "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial METHODS: Acute ischemic stroke IV alteplase within 3 hours vs placebo 0.9mg/Kg up to 90mg 10% bolus then 60-minute infusion OUTCOMES: 3 month functional outcome Mortality Safety "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial METHODS: Acute ischemic stroke IV alteplase within 3 hours vs placebo 0.9mg/Kg up to 90mg 10% bolus then 60-minute infusion OUTCOMES: 3 month functional outcome Mortality Safety "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial METHODS: Acute ischemic stroke IV alteplase within 3 hours vs placebo 0.9mg/Kg up to 90mg 10% bolus then 60-minute infusion OUTCOMES: 3 month functional outcome Mortality Safety "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial RESULTS: 624 patients Functional Outcome (complete / near complete recovery) 38% vs 21% Outcome at 3 months *circles = favorable outcome *Benefit is sustained at 1 year f/u Outcome at Three Months in Part 2 of the Study, According to Treatment. Scores of <=1 on the NIHSS, 95 or 100 on the Barthel index, <=1 on the modified Rankin scale, and 1 on the Glasgow outcome scale were considered to indicate a favorable outcome. Values do not total 100 percent because of rounding "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial RESULTS: 624 patients 3 month mortality 17% vs 21% (not significant) The combined results of parts 1 and 2 are shown. There were 312 patients in each group, and no patient had missing data on mortality. Error bars represent the standard errors of the point estimates of survival at 30, 60, and 90 days. The number of patients surviving at each interval is shown. "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial RESULTS: 624 patients Rate of symptomatic ICH: 6.4% vs 0.6% Rate of severe systemic hemorrhage <1% "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

0-90 mins better outcome than 90-180 mins NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial RESULTS: 624 patients Functional Outcome (complete / near complete recover 38% vs 21% 0-90 mins better outcome than 90-180 mins "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 DEATH 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial CONCLUSION: NINDS (624) – IV tPA given within 0-3 hours statistically improved outcomes ECASS I (620) ECAS II (800) – Europe, supports NINDS ATLANTIS I (142) 0-6h ATLANTIS II (547) 3-5h 1996 – FDA approved IV tPA between 0-3h if selection criteria met TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h IV tPA 5 4 3 DEATH 6 "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial Inclusion criteria: Ischemic stroke with neurologic deficit Onset <3hours Age ≥18 years Exclusion criteria Historical Stroke / TBI past 3 months H/O ICH Intracranial neoplasm, AVM, aneurysm Recent intracranial or intraspinal surgery Arterial puncture (noncompressible site) past 7days Clinical SAH symptoms persistent HTN (≥185 / ≥110) Glu <50 mg/dL Active internal bleeding Acute bleeding diathesis Hematologic Platelet <100 AC use with INR >1.7 or PT >15s Heparin use within 48 hours + abN PTT DTI or Xa inhib use with lab evidence Head CT scan (+) hemorrhage (+) Extensive regions of hypodensity Relative exclusion criteria minor neurologic signs rapidly improving Major surgery / trauma x2wks GI or GU bleed x 3wks MI x 3mos Seizure at onset of stroke Pregnancy "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial Inclusion criteria: Ischemic stroke with neurologic deficit Onset <3hours Age ≥18 years Exclusion criteria Historical Stroke / TBI past 3 months H/O ICH Intracranial neoplasm, AVM, aneurysm Recent intracranial or intraspinal surgery Arterial puncture (noncompressible site) past 7days Clinical SAH symptoms persistent HTN (≥185 / ≥110) Glu <50 mg/dL Active internal bleeding Acute bleeding diathesis Hematologic Platelet <100 AC use with INR >1.7 or PT >15s Heparin use within 48 hours + abN PTT DTI or Xa inhib use with lab evidence Head CT scan (+) hemorrhage (+) Extensive regions of hypodensity Relative exclusion criteria minor neurologic signs rapidly improving Major surgery / trauma x2wks GI or GU bleed x 3wks MI x 3mos Seizure at onset of stroke Pregnancy "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial Inclusion criteria: Ischemic stroke with neurologic deficit Onset <3hours Age ≥18 years Exclusion criteria Historical Stroke / TBI past 3 months H/O ICH Intracranial neoplasm, AVM, aneurysm Recent intracranial or intraspinal surgery Arterial puncture (noncompressible site) past 7days Clinical SAH symptoms persistent HTN (≥185 / ≥110) Glu <50 mg/dL Active internal bleeding Acute bleeding diathesis Hematologic Platelet <100 AC use with INR >1.7 or PT >15s Heparin use within 48 hours + abN PTT DTI or Xa inhib use with lab evidence Head CT scan (+) hemorrhage (+) Extensive regions of hypodensity Relative exclusion criteria minor neurologic signs rapidly improving Major surgery / trauma x2wks GI or GU bleed x 3wks MI x 3mos Seizure at onset of stroke Pregnancy "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

? TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 6 DEATH NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA National Institute of Neurological Disorders and Stroke (NINDS) Trial TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 ? 6 DEATH "Tissue Plasminogen Activator For Acute Ischemic Stroke". New England Journal of Medicine 333.24 (1995): 1581-1588. Web.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III Methods: Randomized; alteplase vs placebo; within 3-4.5 hours 18-80y, AIS, Additional exclusions: >80y, NIHSS >25, h/o stroke + DM, on AC regardless of INR ITT=intention to treat. PP=per protocol. Includes *13 and †ten patients lost to follow-up, with imputation of worst possible outcome for the primary endpoint. Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

*Distribution of NIHSS scores at baseline NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III *Distribution of NIHSS scores at baseline Distribution of National Institutes of Health stroke scale (NIHSS) scores at baseline (A) and time from stroke onset to treatment initiation (B) In (B), patient numbers do not add up to the alteplase and placebo group totals of 418 and 403, respectively, because the exact time of treatment initiation was not available for 12 patients in the alteplase group and 15 in the placebo group. Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

*Time of stroke onset to initiation of treatment. NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III *Time of stroke onset to initiation of treatment. Distribution of National Institutes of Health stroke scale (NIHSS) scores at baseline (A) and time from stroke onset to treatment initiation (B) In (B), patient numbers do not add up to the alteplase and placebo group totals of 418 and 403, respectively, because the exact time of treatment initiation was not available for 12 patients in the alteplase group and 15 in the placebo group. Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

*mRS 30d for ITT (A) and per protocol (B) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III Primary outcome: disability at 3 months (0-1 vs 2-6) *mRS 30d for ITT (A) and per protocol (B) Figure 4: Distribution of scores on the modifi ed Rankin scale at day 30 for the intention-to-treat (A) and per-protocol (B) populations The stratifi ed analysis of the score distribution was compared by use of the Cochran–Mantel–Haenszel test, with adjustment for the baseline score on the National Institutes of Health stroke scale and for the time between the onset of stroke symptoms and initiation of treatment. Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA OUTCOME: primary outcome disability at 3months (mRS) 0-1 vs 2-6 RESULTS: 821 patients Favorable outcome 52% vs 45% OR 1.34 95%CI 1.02-1.76 NNT 14 Mortality no difference 7.7 vs 8.4% Symptomatic ICH 2.2% vs 0.25 // using NINDS definition 7.9% vs 3.5% CONLCUSION: IV alteplase at 3-4.5h leads to modest improvement in 3-month outcome with similar rate of symptomatic ICH as those treated within 3 hours NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III Favorable outcome 52% vs 45%, OR 1.34 (95% CI 1.02-1.76 p = 0.038) NNT 14 Adjusted analysis of favourable outcome (modifi ed Rankin scale 0–1) according to the fi nal and full models of adjustment Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

*Subgroup analysis of mortality PURPOSE: Methods: randomzied , 18-80y, AIS, alteplase vs placebo; in addition to standard exclusions added >80y, NIHSS >25, combi of stroke and DM, on anticoagulants regardless of INR); within 3-4.5 hrs OUTCOME: primary outcome disability at 3months (mRS) 0-1 vs 2-6 RESULTS: 821 patients Favorable outcome 52% vs 45% OR 1.34 95%CI 1.02-1.76 NNT 14 Mortality no difference 7.7 vs 8.4% Symptomatic ICH 2.2% vs 0.25 // using NINDS definition 7.9% vs 3.5% CONLCUSION: IV alteplase at 3-4.5h leads to modest improvement in 3-month outcome with similar rate of symptomatic ICH as those treated within 3 hours NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III Mortality: 7.7% vs 8.4% Symptomatic ICH: 2.2% vs 0.25%, using NINDS definition 7.9% vs 3.5% Figure 6: Subgroup analysis of mortality according to demographic characteristics, baseline clinical data, and past medical history Dashed vertical line represents the odds ratio for the whole intention-to-treat (ITT) population. Data are % (n/N), unless otherwise indicated. p values are for interaction based on logistic regression model with treatment, subgroup, and interaction term. NIHSS=National Institutes of Health stroke scale. Downloaded *Subgroup analysis of mortality Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 6 DEATH NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III CONLCUSION: IV alteplase at 3-4.5h leads to modest improvement in 3-month outcome with similar rate of symptomatic ICH AHA/ASA extended therapeutic window to 4.5h for subset with additional exclusion criteria TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 6 DEATH Additional relative exclusion criteria 1. Age >80 years 2. OAC use regardless of INR 3. Severe stroke (NIHSS >25) 4. Combination of old stroke + DM Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

? ? TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 6 DEATH NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA European Cooperative Acute Stroke Study III CONLCUSION: IV alteplase at 3-4.5h leads to modest improvement in 3-month outcome with similar rate of symptomatic ICH AHA/ASA extended therapeutic window to 4.5h for subset with additional exclusion criteria TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h 6h IV tPA 5 4 3 ? ? 6 DEATH Bluhmki, Erich et al. "Stroke Treatment With Alteplase Given 3·0–4·5 H After Onset Of Acute Ischaemic Stroke (ECASS III): Additional Outcomes And Subgroup Analysis Of A Randomised Controlled Trial". The Lancet Neurology 8.12 (2009): 1095-1102.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA The Third International Stroke Trial (IST 3) PURPOSE: determine efficacy of IV tPA if given within 6 hours PURPOSE METHODS: within 6 hours OUTCOME RESULTS: 3035 adults (attained only just over ½ of planned enrollment, underpowered to detect subgroup effects) 6 months nonsignificant trend for favorable outcome (alive and independent) 37% vs 35% adjusted OR 1.13 95% CI 0.95-1.35) Subgroup analysis 4.5-6h nonsignificant trend for favorable outcome (47% vs 43% adjusted OR 1.31 95% CI 0.89-1.93) "The Benefits And Harms Of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H Of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial". The Lancet 379.9834 (2012): 2352-2363.

*Outcome at 6 mos using OHS NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA The Third International Stroke Trial (IST 3) RESULTS: 3035 patients (underpowered to detect subgroup effects) 6 months functional outcome nonsignificant trend for favorable outcome: 37% vs 35% OR 1.13 95% CI 0.95-1.35 Subgroup analysis 4.5-6h: nonsignificant trend for favorable outcome: 47% vs 43% OR 1.31 95% CI 0.89-1.93 PURPOSE METHODS: within 6 hours OUTCOME RESULTS: 3035 adults (attained only just over ½ of planned enrollment, underpowered to detect subgroup effects) 6 months nonsignificant trend for favorable outcome (alive and independent) 37% vs 35% adjusted OR 1.13 95% CI 0.95-1.35) Subgroup analysis 4.5-6h nonsignificant trend for favorable outcome (47% vs 43% adjusted OR 1.31 95% CI 0.89-1.93) *Outcome at 6 mos using OHS Figure 2: Outcome at 6 months: Oxford Handicap Scale (OHS) by treatment group For the ordinal analysis, which was adjusted for age, National Institutes of Health Stroke Scale (NIHSS), delay (all linear), and and presence or absence of visible acute ischaemic change on baseline scan as judged by the expert reader, the statistical analysis plan prespecifi ed that OHS levels 4, 5, and 6 were grouped and 0, 1, 2, 3 remained discrete. In that analysis, the common odds ratio was 1·27 (95% CI 1·10–1·47; p=0·001). An ordinal analysis with OHS levels 0, 1, 2, 3, 4, 5, and 6 all discrete, adjusted in the same way, gave an odds ratio of 1·17 (95% CI 1·03–1·33; p=0·016). rt-PA=recombinant tissue plasminogen activator. "The Benefits And Harms Of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H Of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial". The Lancet 379.9834 (2012): 2352-2363.

X TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 DEATH 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA The Third International Stroke Trial (IST 3) CONCLUSION: Effectiveness of tPA from 4.5-6h equivocal TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h 6h IV tPA 5 4 3 X DEATH 6 "The Benefits And Harms Of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H Of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial". The Lancet 379.9834 (2012): 2352-2363.

X TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 DEATH 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA THE ISSUE OF CONSENT discussion of risk and benefits Neuro deficits of patient – can he participate? Time-dependent nature of benefits Alteplase  substantial evidence of safety and efficacy TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h 6h IV tPA 5 4 3 X DEATH 6 "The Benefits And Harms Of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H Of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial". The Lancet 379.9834 (2012): 2352-2363.

X TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 DEATH 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA THE ISSUE OF CONSENT THEREFORE: Consent is not required for tPA as emergent therapy if patient or surrogate consent is not possible. Need for informed consent outweighed by need for urgent intervention – treated under principle of presumption of consent TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h 6h IV tPA 5 4 3 X DEATH 6 "The Benefits And Harms Of Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator Within 6 H Of Acute Ischaemic Stroke (The Third International Stroke Trial [IST-3]): A Randomised Controlled Trial". The Lancet 379.9834 (2012): 2352-2363.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis Included 12 trials, 7012 patients 3035 of which were from IST-3 Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis 4 tables: #1 – Effects of tPA on early outcomes Eff ects of rt-PA on early outcomes (7 days) Data are numbers, unless otherwise indicated. Degrees of freedom is 1. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial. Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis 4 tables: #2 – Effects of tPA on final outcomes Figure 2: Eff ects of rt-PA on outcomes at fi nal follow-up Data are numbers, unless otherwise indicated. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial. mRS=modifi ed Rankin Scale. Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

*no subgroup analysis for4.5-6h NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis 4 tables: #3 – Effects of tPA on functional outcome (mRS 0-2) Subgroup between 3-6h nonsignificant trend toward favorable outcome (47% vs 46% OR 1.07 95% CI 0.96-1.20) *no subgroup analysis for4.5-6h Figure 3: Eff ects of rt-PA on alive and independent (mRS 0–2) and death by the end of follow-up and on symptomatic intracranial haemorrhage within the fi rst 7 days, by time to treatment Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis 4 tables: #4 – Effects of tPA on death and symptomatic ICH Figure 3: Eff ects of rt-PA on alive and independent (mRS 0–2) and death by the end of follow-up and on symptomatic intracranial haemorrhage within the fi rst 7 days, by time to treatment Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Wardlaw 2012 Meta-analysis 12 trials, 7012 patients, 3035 from IST3 IV alteplase within 6 hours led to significant increase in proportion of patients alive and independent 46% vs 42% OR 1.17 95% CI 1.06-1.29, but benefit driven by patients treated within 3 hours Subgroup 4971 between 3-6h – nonsignificant trend toward favorable outcome (47% vs 46% OR 1.07 95% CI 0.96-1.20), no subgroup analysis for4.5-6h IV alteplase within 6h led to significant increase in proportion of patients alive and independent 46% vs 42% OR 1.17 95% CI 1.06-1.29, but benefit driven by patients treated within 3 hours 4: Eff ect of rt-PA on alive and independent at the end of follow-up, subgrouped by age and time to treatment Data are numbers, unless otherwise indicated. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial Wardlaw, Joanna M et al. "Recombinant Tissue Plasminogen Activator For Acute Ischaemic Stroke: An Updated Systematic Review And Meta-Analysis". The Lancet 379.9834 (2012): 2364-2372.

TIMING NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Ingalsbe 2014 Meta-analysis 6756 patients (including >1700 >80y) 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Ingalsbe 2014 Meta-analysis 6756 patients (including >1700 >80y) 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 *Effect of alteplase on good outcome with different treatment delays based on age Eff ect of alteplase on a good stroke outcome (mRS 0−1) by age, with diff erent treatment delays Eff ect of age on the interaction between treatment delay and treatment eff ect p=0·08 (ie, not signifi cant but, if anything, in the direction of it lengthening, not shortening, the period during which alteplase is eff ective in older people). *All six estimates derived from a single stratifi ed logistic regression model that enables the odds ratio to be estimated separately for each group (also adjusted for baseline National Institutes of Health Stroke Scale score). mRS=modifi ed Rankin Scale. Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

*Effect of alteplase on fatal ICH within 7d NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Ingalsbe 2014 Meta-analysis *Effect of alteplase on fatal ICH within 7d 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 Eff ect of alteplase on fatal intracranial haemorrhage within 7 days by treatment delay, age, and stroke severity *For each of the three baseline characteristics, estimates were derived from a single logistic regression model stratifi ed by trial, which enables separate estimation of the OR for each subgroup after adjustment for the other two baseline characteristics (but not possible interactions with those characteristics). The overall eff ect in all patients is the trial-stratifi ed logistic regression estimate adjusted only for treatment allocation. NE=not estimable. Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Ingalsbe 2014 Meta-analysis 6756 patients (including >1700 >80y) 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 *graph shows linear relationship between the odds for good outcome plotted against treatment delaiy Figure 1: Eff ect of timing of alteplase treatment on good stroke outcome (mRS 0−1) The solid line is the best linear fi t between the log odds ratio for a good stroke outcome for patients given alteplase compared with those given control (vertical axis) and treatment delay (horizontal axis; pinteraction=0·016). Estimates are derived from a regression model in which alteplase, time to treatment, age, and stroke severity (handled in a quadratic manner) are included as main eff ects but the only treatment interaction included is with time to treatment. Only 198 patients (159 from IST−3) had a time from stroke onset to treatment of more than 6 h. The white box shows the point at which the estimated treatment eff ect crosses 1. The black box shows the point at which the lower 95% CI for the estimated treatment eff ect fi rst crosses 1·0. mRS=modifi ed Rankin Scale. Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

TAKE HOME: Benefit of thrombolysis decreases over time NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TAKE HOME: Benefit of thrombolysis decreases over time Each 15 min reduction in time to tPA associated with odds of walking at discharge (4%) odds of d/c to home (3%) odds of death before discharge (4%) odds of sxic hgic transformation (4%) THEREFORE: Give ASAP, do not delay until end of “time window” “We have time…” 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 Figure 1: Eff ect of timing of alteplase treatment on good stroke outcome (mRS 0−1) The solid line is the best linear fi t between the log odds ratio for a good stroke outcome for patients given alteplase compared with those given control (vertical axis) and treatment delay (horizontal axis; pinteraction=0·016). Estimates are derived from a regression model in which alteplase, time to treatment, age, and stroke severity (handled in a quadratic manner) are included as main eff ects but the only treatment interaction included is with time to treatment. Only 198 patients (159 from IST−3) had a time from stroke onset to treatment of more than 6 h. The white box shows the point at which the estimated treatment eff ect crosses 1. The black box shows the point at which the lower 95% CI for the estimated treatment eff ect fi rst crosses 1·0. mRS=modifi ed Rankin Scale. Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

TAKE HOME: Benefit of thrombolysis decreases over time NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TAKE HOME: Benefit of thrombolysis decreases over time Each 15 min reduction in time to tPA associated with odds of walking at discharge (4%) odds of d/c to home (3%) odds of death before discharge (4%) odds of sxic hgic transformation (4%) THEREFORE: Give ASAP, do not delay until end of “time window” “We have time…” 6756 patients (including >1700 subjects >80y) enrolled within 3-6h of AIS onset Primary outcome: proportion achieving good stroke outcome at 3-6mo (mRS 0-1) Within 3h – good outcome 33% vs 23% OR 1.75 95% CI 1.35-2.27) 3-4.5h 35% vs 30% OR 1.26 95% CI 1.05-1.51) 4.5-6h – 33 vs 31% OR 1.15 95% CI 0.95-1.40 Figure 1: Eff ect of timing of alteplase treatment on good stroke outcome (mRS 0−1) The solid line is the best linear fi t between the log odds ratio for a good stroke outcome for patients given alteplase compared with those given control (vertical axis) and treatment delay (horizontal axis; pinteraction=0·016). Estimates are derived from a regression model in which alteplase, time to treatment, age, and stroke severity (handled in a quadratic manner) are included as main eff ects but the only treatment interaction included is with time to treatment. Only 198 patients (159 from IST−3) had a time from stroke onset to treatment of more than 6 h. The white box shows the point at which the estimated treatment eff ect crosses 1. The black box shows the point at which the lower 95% CI for the estimated treatment eff ect fi rst crosses 1·0. mRS=modifi ed Rankin Scale. Ingalsbe, Graham. "Effect Of Treatment Delay, Age, And Stroke Severity On The Effects Of Intravenous Thrombolysis With Alteplase For Acute Ischaemic Stroke: A Meta-Analysis Of Individual Patient Data From Randomized Trials". The Journal of Emergency Medicine 48.5 (2015): 650.

X TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 DEATH 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: The sooner IV alteplase treatment is initiated, the more likely it is to be beneficial. Benefit extends to treatment started within 4.5 hours of stroke onset. Alteplase is beneficial regardless of age, stroke severity, or the associated increased risk of symptomatic or fatal ICH in the first days after alteplase treatment. Odds of a favorable three-month outcome decrease as the interval from stroke onset to start of alteplase treatment increases. Beyond 4.5 hours, harm may exceed benefit. TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h 6h IV tPA 5 4 3 X DEATH 6 TIME IS BRAIN: IV tPA must be given ASAP, and not be delayed until the end of the “time window.”

RECANALIZATION NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: RECANALIZATION = improved outcome + reduced mortality NINDS, etc did not monitor arterial occlusion or recanalization meta-analysis of 53 studies (2002) assessed recanalization in 2066 patients with acute ischemic stroke recanalization associated with good functional outcome at 3 months OR 4.43 95% CI 3.32-5.91 reduced mortality at 3 months OR 0.24 9% CI 0.16-0.35 SICH rates similar OR 1.11 95% CI 0.71-1.74 Rha, J. and Saver, J. (2007). The Impact of Recanalization on Ischemic Stroke Outcome: A Meta-Analysis. Stroke, 38(3), pp.967-973.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: RECANALIZATION = improved outcome + reduced mortality NINDS, etc did not monitor arterial occlusion or recanalization meta-analysis of 53 studies (2002) assessed recanalization in 2066 patients with acute ischemic stroke recanalization associated with good functional outcome at 3 months OR 4.43 95% CI 3.32-5.91 reduced mortality at 3 months OR 0.24 9% CI 0.16-0.35 SICH rates similar OR 1.11 95% CI 0.71-1.74 Varied according to intervention Spontaneous 24.1% IV thrombolysis 46.2% IA thrombolysis 63.2% Combined IV IA 67.5% Mechanical 83.6% Rha, J. and Saver, J. (2007). The Impact of Recanalization on Ischemic Stroke Outcome: A Meta-Analysis. Stroke, 38(3), pp.967-973.

Location of occlusion in the arterial tree proximal more resistant NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: FACTORS AFFECTING RECANALIZATION Location of occlusion in the arterial tree proximal more resistant cervical ICA clot  adjacent thrombosis, long thrombus unlikely to be lyzed Clot-specific factors: SIZE: Larger clots more resistant SOURCE: In situ thrombosis / atherosclerotic lesions more resistant than fibrin-rich cardiac emboli COMPOSITION: amount of RBC volume of emboli fibrin content density of clot calcified plaque / fat AGE: tPA  recent thromboemboli thrombectomy  older thromboemboli hyperacute thromboemboli platelet rich, less amenable to lysis Availability of collateral supply Elevated HCT – reduced reperfusion, larger infarct size Location of occlusion in the arterial tree More proximal occlusion more resistant to thrombolysis Clots in cervical ICA promotes adjacent thrombosys, long thrombus unlikely to be lyzed by IV tPA alone Clot-specific factors: size, composition, source SIZE: Larger clots more resistant to thrombolysis SOURCE: In situ thrombosis / atherosclerotic lesions more resistant than fibrin-rich cardiac emboli COMPOSITION: recanalization related to amount of RBC, inversely to volume of emboli, and fibrin content, and density of clot, tPA unlikely to disrupt calcified plaque / fat1 AGE: tPA more effective for recent thromboemboli; thrombectomy more effective for older thromboemboli; (fibrin / plasminogen content replaced) hyperacute thromboemboli may be platelet rich, less amenable to lysis Availability of collateral supply Elevated HCT – reduced reperfusion, larger infarct size *HCT determines whole blood viscosity, inversely related to cerebral blood flow LOCATION: EC ICA occlusion: IV tPA associated with partial or complete recanalization in 63%, often high-grade stenosis persists Carotid T occlusion: occlusion of ICA at bifurcation, IV tPA resulted in complete or partial recanalization in 40-67% within 24-36h MCA occlusion: complete recanalization in 39% by 2 hours, 9 % with tandem stenosis of ICA; prox MCA occlusion opened by IV tPA in ~20%, complete MCA recanalization at 24h in 53-68% Hyperdense artery sign / dense MCA sign: hyperdensity of the MCA on noncontrast CT Highly specific, poorly sensitive sign of MCA occlusion Associated with lower rates of favorable outcome at 90d Hypointense signal on MRI (GRE or T2W sequences) Denotes acute thrombosis / occlusion of MCA – AKA MCA susceptibility sign Often accompanied by ICA occlusion Associated with failed recanaliztion after tPA

SELECTION TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 5 4 3 6 DEATH NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: Selection of appropriate candidate – neuro exam, neuroimaging, eligibility inclusion/exclusion criteria Clot lysis / recanalization Limited efficacy for large vessel occlusions, especially large vessel clot burden >8mm 29% recanalization for M1 ELVO; 20.3% recanalization for combined M1 and distal ICA ELMVO, 6% recanalization for proximal ICA ELVO TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 6 DEATH

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS / ECASS / IST 3 / Meta analysis: Selection of appropriate candidate – neuro exam, neuroimaging, eligibility inclusion/exclusion criteria Clot lysis / recanalization Limited efficacy for large vessel occlusions, especially large vessel clot burden >8mm 29% recanalization for M1 ELVO; 20.3% recanalization for combined M1 and distal ICA ELMVO, 6% recanalization for proximal ICA ELVO TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 ? 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Until recently, only tPA has been shown to be efficacious by RTC IA therapy deemed “experimental” and supported only by small trials Positive earlier device trials  FDA approval for “clot retrieval” but not for “stroke treatment” 2013 IMS III trial stopped early due to no overall benefit of IA therapy 2014 positive trials with 2nd generation devices showed efficacy TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 ? 0h 6h DEATH 6 IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Until recently, only tPA has been shown to be efficacious by RTC IA therapy deemed “experimental” and supported only by small trials Positive earlier device trials  FDA approval for “clot retrieval” but not for “stroke treatment” 2013 IMS III trial stopped early due to no overall benefit of IA therapy 2014 positive trials with 2nd generation devices showed efficacy TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 GOAL is to deliver lower dose, but higher concentration of drug directly into clot to reduce systemic effects. 0h 6h DEATH 6 IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Early IA trials PROACT I – Prolyse for Acute Cerebral Thromboembolism PROACT II MELT - MCA Embolism Local Fibrinolytic Trial TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 GOAL is to deliver lower dose, but higher concentration of drug directly into clot to reduce systemic effects. 0h 6h DEATH 6 IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012) TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 GOAL is to remove clot from the occluded vessel 0h 6h DEATH 6 IA tPA 0h 8h Endovascular thrombectomy (ant)

Aspiration Device NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012) Aspiration Device

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012)

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012)

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012)

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Mechanical Clot Retrieval MERCI (2005) PENUMBRA (2008) SOLITAIRE (2012) TREVO (2012)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE Review of IA Trials with NEGATIVE results Documentation of ELVO not required 16% of had no thrombus or treatable thrombus in ICA to M2 Spread over several generation of stroke devices Stent retrievers used only in 1.5% TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE SUBGROUP ANALYSIS CTA demonstrating ELVO trended toward benefit ELVO and NIHSS>20 trended toward benefit Strong trend to benefit if tPA within 2 hours and IA <90 mins after TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA INTERVENTIONAL MANAGEMENT OF STROKE HOW TO OPTIMIZE FOR EFFICACY OF ENDOVASCULAR THERAPY? PICK THE RIGHT PATIENT ELVO High ASPECT Score Minimize time between onset to treatment Use 2nd generation stent retrievers Stroke systems of care to optimize door to groin stick TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 3h 4.5h IV tPA 5 4 3 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant)

Endovascular thrombectomy (ant) Endovascular thrombectomy (post) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 0h 3h 4.5h IV tPA 5 4 3 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant) 0h 24h Endovascular thrombectomy (post)

Endovascular thrombectomy (ant) Endovascular thrombectomy (post) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs MR CLEAN ESCAPE SWIFT PRIME EXTEND IA REVASCAT TIA ASA 1 2 Normal STROKE RIND REHAB RECOVERY 0h 0h 3h 4.5h IV tPA 5 4 3 0h 6h 6 DEATH IA tPA 0h 8h Endovascular thrombectomy (ant) 0h 24h Endovascular thrombectomy (post)

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone *all 4 trials stopped early after MR CLEAN results announced in late 2014 *4 trials enrolled overlapping but not identical populations, generally had similar results ESCAPE and EXTEND restricted eligibility functioning independently prior to stroke onset ESCAPE up to 12h, few patients enrolled >6h ESCAPE required small infarct core defined by ASPECTS 6-10 + evidence of mod to good collaterals EXTEND required evidence of salvageable brain tissue and ischemic core lesion volume <70ml on CTP

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone ASPECTS: Alberta Stroke Program Early CT Score Normal CT scan = ASPECTS of 10 points Diffuse ischemia of MCA territory = ASPECTS of Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670.

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone META ANALYSIS: 1287 subjects Functional independence (90d MRS 0-2) 46% vs 27% OR 2.35, 95% CI 1.85-2.98 Reduced disability / improvement of >=1 on 90d mRS OR 2.49 95% CI 1.76-3.53 Beneficial across wide range of patient subgroups Age>=80y High initial stroke severity Not treated with tPA No difference for rates of symptomatic ICH or 90d mortality

Demonstrate superiority to standard treatment with tPA alone SUMMARY: NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone SUMMARY: All 5 trials provide compelling evidence that quick, early thrombectomy with second-generation stent retriever devices is safe and effective for reducing disability when used to treat stroke caused by proximal large artery occlusions in the anterior circulation. NNT ranged from 3-7.5. MR CLEAN was the largest and with least restrictive eligibility criteria.

Demonstrate superiority to standard treatment with tPA alone NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 5 multicenter, open-label RCTs Demonstrate superiority to standard treatment with tPA alone SUMMARY: Who should undergo thrombectomy? Criteria modified from MR CLEAN trial: NIHSS >=2, ASPECTS >=6 on noncontrast CT ICH ruled out occlusion of distal ICA or M1 M2 or A1 A2 (CTA / MRA / DSA) Sufficient time to initiate thrombectomy within 6 hours of onset Informed consent >=18y Exclusion BP >185/110 mm Hg Glu <2.7 or >22.2 s/p tPA with dose >0.9mg/Kd or 90mg coagulopathy (Plt <40, INR >3)

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 DEATH 6 NINDS 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 DEATH 6 Alonso de Leciñana, M. et al. "Endovascular Treatment In Acute Ischaemic Stroke. A Stroke Care Plan For The Region Of Madrid". Neurología (English Edition) 28.7 (2013): 425-434.

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH NINDS 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 Stroke code activated 6 DEATH <4.5h >4.5h tPA Inclu/exclusion NO Thrombectomy Inclu/exclu NO YES YES GIVE tPA ICU monitoring THROMBECTOMY ICU monitoring STROKE UNIT Alonso de Leciñana, M. et al. "Endovascular Treatment In Acute Ischaemic Stroke. A Stroke Care Plan For The Region Of Madrid". Neurología (English Edition) 28.7 (2013): 425-434. (modified from)

1 2 TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 6 DEATH NINDS 1 2 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA TIA ASA Normal STROKE RECOVERY RIND REHAB 5 4 3 Stroke code activated 6 DEATH <4.5h >4.5h tPA Inclu/exclusion NO Thrombectomy Inclu/exclu NO YES YES GIVE tPA ICU monitoring THROMBECTOMY ICU monitoring STROKE UNIT Alonso de Leciñana, M. et al. "Endovascular Treatment In Acute Ischaemic Stroke. A Stroke Care Plan For The Region Of Madrid". Neurología (English Edition) 28.7 (2013): 425-434. (modified from)

Fin. Critical Care Management of Stroke NEURO LECTURE: NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA NEURO LECTURE: Critical Care Management of Stroke Heustein Sy, MD Fin.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS PURPOSE: determine efficacy of IA treatment of AIS from proximal occlusion in terms of functional outcome METHODS: randomized, IA treatment plus SOC vs SOC; eligible patients – prox occlusion in anterior circulation confirmed on vessel imaging that could be treated within 6 hours OUTCOME: primary outcome mRS at 90d "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS RESULTS 500 patients at 16 medical centers in Netherlands (233 IA vs 267 SOC) 445 (89%)patients treated with IV alteplase before randomization Retrievable stents used in 190 of 233 (81.5%) IA patients Primary and Secondary Outcomes and Treatment Effects.* * CT denotes computed tomography. † Values were adjusted for age; NIHSS score at baseline; time from stroke onset to randomization; status with respect to previous stroke, atrial fibrillation, and diabetes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs. no). ‡ The NIHSS score was determined for survivors only. The score was not available for 20 patients: 12 died before assessment was finished, and 8 had missing scores. § The NIHSS score was determined for survivors only. The score was not available for 74 patients: 56 died before assessment was finished, and 18 had missing scores. ¶ The Barthel index is an ordinal scale for measuring performance of activities of daily living. Scores ranges from 0 to 20, with 0 indicating severe disability and 19 or 20 indicating no disability that interferes with daily activities. ‖ The EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a standardized instrument for the measurement of health status. Scores range from −0.33 to 1.00, with higher scores indicating a better quality of life. ** Data for follow-up CT angiography were not available for 106 patients owing to imminent death or death (24 patients), decreased kidney function (13 patients), insufficient scan quality (5 patients), and other reasons (64 patients). †† Data for final infarct volume on noncontrast CT (performed at 3 to 9 days) were missing for 202 patients because of death (52 patients), hemicraniectomy (21 patients), technical errors with automated assessment (14 patients), or insufficient scan quality (5 patients) or because CT was not performed for reasons other than death (110 patients). "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS RESULTS Adjusted OR 1.67 (95%CI 1.21-2.30) Absolute difference of 13.5% points (95% CI 5.9-21.2) in rate of functional independence (mRS 0-2) (32.6 vs 19.1%) Primary and Secondary Outcomes and Treatment Effects.* * CT denotes computed tomography. † Values were adjusted for age; NIHSS score at baseline; time from stroke onset to randomization; status with respect to previous stroke, atrial fibrillation, and diabetes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs. no). ‡ The NIHSS score was determined for survivors only. The score was not available for 20 patients: 12 died before assessment was finished, and 8 had missing scores. § The NIHSS score was determined for survivors only. The score was not available for 74 patients: 56 died before assessment was finished, and 18 had missing scores. ¶ The Barthel index is an ordinal scale for measuring performance of activities of daily living. Scores ranges from 0 to 20, with 0 indicating severe disability and 19 or 20 indicating no disability that interferes with daily activities. ‖ The EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a standardized instrument for the measurement of health status. Scores range from −0.33 to 1.00, with higher scores indicating a better quality of life. ** Data for follow-up CT angiography were not available for 106 patients owing to imminent death or death (24 patients), decreased kidney function (13 patients), insufficient scan quality (5 patients), and other reasons (64 patients). †† Data for final infarct volume on noncontrast CT (performed at 3 to 9 days) were missing for 202 patients because of death (52 patients), hemicraniectomy (21 patients), technical errors with automated assessment (14 patients), or insufficient scan quality (5 patients) or because CT was not performed for reasons other than death (110 patients). "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS RESULTS In the shift analysis of mRS scores at 90 days, significant difference between the intervention group and the control group in the overall distribution of scores functional independence (mRS 0-2) (32.6 vs 19.1%) Figure 1. Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population. Shown is the distribution of scores on the modified Rankin scale. Scores range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability (patient is able to look after own affairs without assistance but is unable to carry out all previous activities), 3 moderate disability (patient requires some help but is able to walk unassisted), 4 moderately severe disability (patient is unable to attend to bodily needs without assistance and unable to walk unassisted), 5 severe disability (patient requires constant nursing care and attention), and 6 death. There was a significant difference between the intervention group and the control group in the overall distribution of scores in an analysis with univariable ordinal regression (common odds ratio, 1.66; 95% CI, 1.21 to 2.28), as well as after adjustment of the treatment effect for age; National Institutes of Health Stroke Scale score at baseline; time from stroke onset to randomization; status with respect to previous stroke, atrial fibrillation, and diabetes mellitus; and occlusion of the internal-carotid-artery terminus (yes vs. no) in an analysis with multivariable regression (adjusted common odds ratio, 1.67; 95% CI, 1.21 to 2.30). In the control group, only 1 patient (0.4%) had a modified Rankin score of 0. "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS RESULTS No significant difference in mortality or symptomatic ICH Safety Variables and Serious Adverse Events within 90 Days after Randomization. "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA MR CLEAN – MULTICENTER RCT OF EVT FOR AIS IN THE NETHERLANDS RESULTS No significant difference in mortality or symptomatic ICH CONCLUSION: IA treatment within 6h of stroke onset is effective and safe. Only first events of a type are listed. Patients having multiple events of one type were counted once. † For parenchymal hematoma, type 1 was defined by one or more blood clots in 30% or less of the infarcted area with a mild space-occupying effect, and type 2 was defined by blood clots in more than 30% of the infarcted area with a clinically significant space-occupying effect. ‡ For hemorrhagic infarction, type 1 was defined by small petechiae along the margins of the infarction, and type 2 was defined by more confluent petechiae within the infarction area. § P<0.001. "A Randomized Trial Of Intraarterial Treatment For Acute Ischemic Stroke". New England Journal of Medicine 372.4 (2015): 394-394.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA ESCAPE - Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke PURPOSE: Determine efficacy of endovascular treatment + SOC in AIS with a small infarct core, prox occlusion and mod-to-good collateral circulation METHODS: randomized, SOC vs SOC+endovascular treatment; prox occlusion in anterior circulation up to 12 hours after symptom onset; large core or poor collateral on CT and CTA excluded OUTCOMES: mRS at 90d, shift analysis Figure 1. Scores on the Modified Rankin Scale at 90 Days in the Intentionto- Treat Population. Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. Panel A shows the distribution of scores at 90 days in the intervention and control groups in the overall trial population. A significant difference between the intervention and control groups was noted in the overall distribution of scores (unadjusted common odds ratio, indicating the odds of improvement of 1 point on the modified Rankin scale, 2.6; 95% confidence interval, 1.7 to 3.8), favoring the intervention. Panel B shows the distribution of scores at 90 days in the intervention and control groups according to status with respect to intravenous (IV) alteplase treatment. In this analysis, there was no evidence of heterogeneity of effect (P = 0.89 for interaction by the Wald test). Goyal, Mayank et al. "Randomized Assessment Of Rapid Endovascular Treatment Of Ischemic Stroke".New England Journal of Medicine 372.11 (2015): 1019-1030.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA ESCAPE - Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke RESULTS: 22 centers worldwide, 316 patients (238 received IV alteplase, 120 vs 118 control) Median time from CT to first reperfusion 84 minutes Stopped early due to efficacy Figure 1. Scores on the Modified Rankin Scale at 90 Days in the Intentionto- Treat Population. Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. Panel A shows the distribution of scores at 90 days in the intervention and control groups in the overall trial population.. Panel B shows the distribution of scores at 90 days in the intervention and control groups according to status with respect to intravenous (IV) alteplase treatment. In this analysis, there was no evidence of heterogeneity of effect (P = 0.89 for interaction by the Wald test). *mRS at 90days showing significant difference between two groups, favoring intervention Goyal, Mayank et al. "Randomized Assessment Of Rapid Endovascular Treatment Of Ischemic Stroke".New England Journal of Medicine 372.11 (2015): 1019-1030.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA ESCAPE - Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke RESULTS: Rate of functional independence (90d mRS 0-2) 53% vs 29.3% p<0.001 Primary outcome favored intervention (common odds ratio 2.6 95% CI 1.7 to 3.8 p<0.001) * Differences (intervention group − control group) are shown as percentage points. † Adjusted estimates were calculated with the use of multiple regression analyses. Estimates were adjusted for age, sex, baseline NIHSS score, baseline ASPECTS, occlusion location, and status with respect to intravenous alteplase treatment, as prespecified in the protocol and statistical analysis plan. ‡ The primary analysis involved 164 participants in the intervention group and 147 participants in the control group. Scores on the modified Rankin scale of functional disability range from 0 (no symptoms) to 6 (death). The common odds ratio was estimated from an ordinal logistic- regression model and indicates the odds of improvement of 1 point on the modified Rankin scale, with a common odds ratio greater than 1 favoring the intervention. The proportional odds assumption was tested and found to be valid. § A modified Rankin score of 0 to 2 indicates functional independence. ¶ The Barthel Index is an ordinal scale for measuring performance of activities of daily living. Scores range from 0 to 100, with 0 indicating severe disability and 95 or 100 no disability that interferes with daily activities. ‖ A Thrombolysis in Cerebral Infarction (TICI) score of 2b or 3 indicates successful reperfusion (see Table S3 in the Supplementary Appendix). ** A modified Arterial Occlusive Lesion (AOL) score of 2 or 3 indicates partial or complete recanalization (see Table S3 in the Supplementary Appendix). †† Treatment effect was estimated with the use of simple linear regression. ‡‡ The EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale is a continuous scale measure of self-reported quality of life. Scores range from 0 to 100, with 0 indicating the worst possible quality of life and 100 the best possible quality of life. Goyal, Mayank et al. "Randomized Assessment Of Rapid Endovascular Treatment Of Ischemic Stroke".New England Journal of Medicine 372.11 (2015): 1019-1030.

= prox occlusion + small core + mod to good collaterals + NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA ESCAPE - Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke RESULTS: Rate of functional independence (90d mRS 0-2) 53% vs 29.3% p<0.001 Primary outcome favored intervention (common odds ratio 2.6 95% CI 1.7 to 3.8 p<0.001) Intervention associated with reduced mortality (10.4% vs 19.0% in control p=0.04) * Differences (intervention group − control group) are shown as percentage points. † Adjusted estimates were calculated with the use of multiple regression analyses. Estimates were adjusted for age, sex, baseline NIHSS score, baseline ASPECTS, occlusion location, and status with respect to intravenous alteplase treatment, as prespecified in the protocol and statistical analysis plan. ‡ Two hemicraniectomy procedures were performed. The indications for hemicraniectomy were malignant middle-cerebral-artery ischemic stroke (one patient in the control group) and symptomatic intracerebral hemorrhage (one patient in the intervention group). § Symptomatic intracerebral hemorrhage was clinically determined at the study site. ¶ Hematoma occurred in two participants at the site of groin puncture. Neck hematoma occurred in the single participant in whom direct carotid access was used, after femoral access was unsuccessful. prox occlusion + small core + mod to good collaterals + rapid endovascular treatment = improved functional outcomes + reduced mortality Goyal, Mayank et al. "Randomized Assessment Of Rapid Endovascular Treatment Of Ischemic Stroke".New England Journal of Medicine 372.11 (2015): 1019-1030.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA SWIFT PRIME - Solitaire with Intention for Thrombectomy as Primary Endovascular Treatment PURPOSE: determine long term functional outcome with thrombectomy (stent retriever), in addition to tPA METHOD: randomized, patients with stroke + IV rTPA to tPA alone vs endovascular thrombectomy with stent retriever, within 6 hours; confirmed occlusions in prox anterior circulation and absence of large ischemic-core lesions OUTCOMES: severity of global disability at 90d by mRS Functional Outcomes at 90 Days, According to the Score on the Modified Rankin Scale. Shown are the 90-day scores on the modified Rankin scale for the patients in the two treatment groups. Scores range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability (able to carry out all usual activities, despite some symptoms), 2 slight disability (able to look after own affairs without assistance but unable to carry out all previous activities), 3 moderate disability (requires some help but able to walk unassisted), 4 moderately severe disability (unable to attend to bodily needs without assistance and unable to walk unassisted), 5 severe disability (requires constant nursing care and attention, bedridden, and incontinent), and 6 death. Persons with a score of 0, 1, or 2 are considered to be independent in daily function. Neurovascular thrombectomy with the use of a stent retriever was associated with a significant shift in the distribution of scores toward lesser disability (P<0.001 by the Cochran–Mantel–Haenszel test), including an absolute increase of 25 percentage points in the proportion of patients who were functionally independent at 90 days (P<0.001). The term t-PA denotes tissue plasminogen activator. Saver, Jeffrey L. et al. "Stent-Retriever Thrombectomy After Intravenous T-PA Vs. T-PA Alone In Stroke". New England Journal of Medicine 372.24 (2015): 2285-2295.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA SWIFT PRIME - Solitaire with Intention for Thrombectomy as Primary Endovascular Treatment RESULTS: 39 centers, 196 patients (98 each) Reperfusion 88% Stopped early due to efficacy *thrombectomy with stent retriever associated with shift in the distribution of scores toward lesser disability (P<0.001), including an absolute increase of 25% in the proportion who were functionally independent at 90 days (P<0.001) Functional Outcomes at 90 Days, According to the Score on the Modified Rankin Scale. Shown are the 90-day scores on the modified Rankin scale for the patients in the two treatment groups. Scores range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability (able to carry out all usual activities, despite some symptoms), 2 slight disability (able to look after own affairs without assistance but unable to carry out all previous activities), 3 moderate disability (requires some help but able to walk unassisted), 4 moderately severe disability (unable to attend to bodily needs without assistance and unable to walk unassisted), 5 severe disability (requires constant nursing care and attention, bedridden, and incontinent), and 6 death. Persons with a score of 0, 1, or 2 are considered to be independent in daily function. Neurovascular thrombectomy with the use of a stent retriever was associated with a significant shift in the distribution of scores toward lesser disability (P<0.001 by the Cochran–Mantel–Haenszel test), including an absolute increase of 25 percentage points in the proportion of patients who were functionally independent at 90 days (P<0.001). The term t-PA denotes tissue plasminogen activator. Saver, Jeffrey L. et al. "Stent-Retriever Thrombectomy After Intravenous T-PA Vs. T-PA Alone In Stroke". New England Journal of Medicine 372.24 (2015): 2285-2295.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA SWIFT PRIME - Solitaire with Intention for Thrombectomy as Primary Endovascular Treatment RESULTS: Thrombectomy reduced disability at 90d over entire range of scores on the mRS (p<0.001) Rate of functiona independence (mRS 0-2) higher (60% vs 35% p<0.001) No significant differences in 90d mortality (9% vs 12% p=.5) or symptomatic ICH (0% vs 3% (p=0.12) * Plus–minus values are means ±SD. CI denotes confidence interval, and NA not applicable. † Shown are the results of the prespecified Cochran–Mantel–Haenszel test for the shift in disability score. Similar results were found in the analysis of the common odds ratio (odds ratio, 2.63; 95% CI, 1.57 to 4.40; P<0.001). ‡ Functional independence was defined as a score of 0, 1, or 2 on the modified Rankin scale. § One patient in the group that received intravenous t-PA alone requested the deletion of all data, including vital status. ¶ Substantial reperfusion was defined as reperfusion of at least 50% and a modified Thrombolysis in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion). Successful reperfusion was defined as reperfusion of at least 90%, as assessed with the use of perfusion CT or MRI. Data on successful reperfusion were not obtained for all the patients after the adoption of the protocol amendment making penumbral imaging optional. Saver, Jeffrey L. et al. "Stent-Retriever Thrombectomy After Intravenous T-PA Vs. T-PA Alone In Stroke". New England Journal of Medicine 372.24 (2015): 2285-2295.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA SWIFT PRIME - Solitaire with Intention for Thrombectomy as Primary Endovascular Treatment RESULTS: Thrombectomy reduced disability at 90d over entire range of scores on the mRS (p<0.001) Rate of functiona independence (mRS 0-2) higher (60% vs 35% p<0.001) No significant differences in 90d mortality (9% vs 12% p=.5) or symptomatic ICH (0% vs 3% (p=0.12) * Plus–minus values are means ±SD. CI denotes confidence interval, and NA not applicable. † Shown are the results of the prespecified Cochran–Mantel–Haenszel test for the shift in disability score. Similar results were found in the analysis of the common odds ratio (odds ratio, 2.63; 95% CI, 1.57 to 4.40; P<0.001). ‡ Functional independence was defined as a score of 0, 1, or 2 on the modified Rankin scale. § One patient in the group that received intravenous t-PA alone requested the deletion of all data, including vital status. ¶ Substantial reperfusion was defined as reperfusion of at least 50% and a modified Thrombolysis in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion). Successful reperfusion was defined as reperfusion of at least 90%, as assessed with the use of perfusion CT or MRI. Data on successful reperfusion were not obtained for all the patients after the adoption of the protocol amendment making penumbral imaging optional. Saver, Jeffrey L. et al. "Stent-Retriever Thrombectomy After Intravenous T-PA Vs. T-PA Alone In Stroke". New England Journal of Medicine 372.24 (2015): 2285-2295.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA SWIFT PRIME - Solitaire with Intention for Thrombectomy as Primary Endovascular Treatment CONCLUSIONS: In patients receiving IV tPA for occlusion of prox anterior circulation, thrombectomy with stent retriever within 6h after onset improved functional outcomes at 90d. * Plus–minus values are means ±SD. CI denotes confidence interval, and NA not applicable. † Shown are the results of the prespecified Cochran–Mantel–Haenszel test for the shift in disability score. Similar results were found in the analysis of the common odds ratio (odds ratio, 2.63; 95% CI, 1.57 to 4.40; P<0.001). ‡ Functional independence was defined as a score of 0, 1, or 2 on the modified Rankin scale. § One patient in the group that received intravenous t-PA alone requested the deletion of all data, including vital status. ¶ Substantial reperfusion was defined as reperfusion of at least 50% and a modified Thrombolysis in Cerebral Infarction score of 2b (50 to 99% reperfusion) or 3 (complete reperfusion). Successful reperfusion was defined as reperfusion of at least 90%, as assessed with the use of perfusion CT or MRI. Data on successful reperfusion were not obtained for all the patients after the adoption of the protocol amendment making penumbral imaging optional. Saver, Jeffrey L. et al. "Stent-Retriever Thrombectomy After Intravenous T-PA Vs. T-PA Alone In Stroke". New England Journal of Medicine 372.24 (2015): 2285-2295.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA EXTEND IA - Extending the Time for Thrombolysis in Emergency Neuro Deficits — Intra-Arterial PURPOSE: Can more advanced imaging selection, recently developed devices and earlier intervention improve outcome? METHODS: randomized; patients who received IV tPA within 4.5h to undergo thrombectomy with Solitaire FR stent retriever vs tPA alone; occlusion of ICA or MCA, evidence of salvageable brain tissue and ischemic core <70ml on CT perfusion imaging OUTCOMES: coprimary outcomes – reperfusion at 24h and early neuro improvement (>=8pt reduction in NIHSS or score of 0 or 1at day 3; secondary outcomes functional score on mRS at 90d Campbell, Bruce C.V. et al. "Endovascular Therapy For Ischemic Stroke With Perfusion-Imaging Selection". New England Journal of Medicine 372.11 (2015): 1009-1018.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA EXTEND IA - Extending the Time for Thrombolysis in Emergency Neuro Deficits — Intra-Arterial Campbell, Bruce C.V. et al. "Endovascular Therapy For Ischemic Stroke With Perfusion-Imaging Selection". New England Journal of Medicine 372.11 (2015): 1009-1018.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA EXTEND IA - Extending the Time for Thrombolysis in Emergency Neuro Deficits — Intra-Arterial RESULTS: Stopped early due to efficacy after 70patients randomized (35 each group) %ischemic territory reperfused at 24h greater in endovascular group (100% vs 37% (p<0.001) Endovascular therapy (median 210 minutes after onset) increased early neuro improvement at 3 days (80% vs 37% p=0.002) and improved functional outcome at 90d with more patients achieving functional independence (mRS 0-2) 71% vs 40% p=0.01 * NA denotes not applicable. † Values are odds ratios unless otherwise indicated. Odds ratios or median differences are for the endovascular-therapy group as compared with the alteplase-only group. ‡ Reperfusion was defined as the percentage reduction in the perfusion-lesion volume between initial imaging and 24-hour imaging. This value can be negative if hypoperfusion becomes more severe over time. This analysis was adjusted for the site of vessel occlusion at baseline. The effect size in this category is the Wilcoxon–Mann–Whitney generalized odds ratio. § Early neurologic improvement was defined as a reduction of 8 points or more on the National Institutes of Health Stroke Scale (NIHSS) or a score of 0 or 1 at 3 days. This analysis was adjusted for the NIHSS score and age at baseline. ¶ The initial analysis of the modified Rankin scale was an ordinal analysis that used the full range of the scale from 0 (normal function) to 6 (death) and is expressed as a Wilcoxon–Mann–Whitney generalized odds ratio. The analysis was adjusted for the baseline NIHSS score (≤15 vs. >15) and age (≤70 years vs. >70 years) with the use of a permutation method to accommodate small stratum size. This method does not produce confidence intervals. In addition, scores on the modified Rankin scale were analyzed for an outcome with functional independence (score of 0 to 2) or an excellent outcome (score of 0 or 1), adjusted for the full range of ages and baseline score on the NIHSS. ‖ Symptomatic intracerebral hemorrhage was defined as a large parenchymal hematoma (blood clot occupying >30% of infarct volume with mass effect) and an increase of 4 points or more in the NIHSS score. ** The effect size in this category is a risk difference, as measured in percentage points for symptomatic intracerebral hemorrhage and parenchymal hematoma. †† A more detailed list of tertiary outcomes is provided in Table S3 in the Supplementary Appendix. ‡‡ Recanalization was defined as a Thrombolysis in Myocardial Infarction score of 2 or 3 (partial or complete restoration of flow at the site of arterial occlusion).21 This analysis was adjusted for the site of vessel occlusion at baseline. §§ Infarct growth was defined as the increase in the ischemic core volume from baseline to 24 hours and was adjusted for the ischemic core volume at baseline. ¶¶ Home time (the number of days spent at home during the first 90 days after the diagnosis of stroke) was adjusted for the NIHSS score and age at baseline. ‖‖ The effect size in this category is the median difference in infarct growth (as measured in milliliters and transformed by an exponent of 0.2 owing to a non-normal distribution) and the median difference in days for home time, as calculated by median regression. Campbell, Bruce C.V. et al. "Endovascular Therapy For Ischemic Stroke With Perfusion-Imaging Selection". New England Journal of Medicine 372.11 (2015): 1009-1018.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA EXTEND IA - Extending the Time for Thrombolysis in Emergency Neuro Deficits — Intra-Arterial RESULTS: Early and sustained reduction in NIHSS scores *box plots for the changes in the distribution of scores on the NIHSS from baseline to 24 hours, 3 days, and 90 days; early and sustained reduction in NIHSS scores in the endovascular-therapy group Reperfusion and Functional Scores. Panel A shows box plots for the rate of reperfusion at 24 hours (the coprimary end point) among patients receiving intravenous alteplase plus endovascular therapy (endovascular-therapy group) and those receiving alteplase only (100% vs. 37%, P<0.001). The horizontal line within the box plot for the alteplase-only group represents the median, the top and bottom of each box indicate the interquartile range, I bars indicate 1.5 times the interquartile range, and the circles indicate outliers. For the endovascular-therapy group, the median was 100%, with six outliers. Panel B shows box plots for the changes in the distribution of scores on the National Institutes of Health Stroke Scale (NIHSS) from baseline to 24 hours, 3 days, and 90 days. NIHSS is a standardized neurologic examination and ranges from 0 (normal) to 42 (death), with lower scores indicating less severe stroke. There was an early and sustained reduction in NIHSS scores in the endovascular-therapy group, as compared with the alteplase-only group. Campbell, Bruce C.V. et al. "Endovascular Therapy For Ischemic Stroke With Perfusion-Imaging Selection". New England Journal of Medicine 372.11 (2015): 1009-1018.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA EXTEND IA - Extending the Time for Thrombolysis in Emergency Neuro Deficits — Intra-Arterial RESULTS: mRS scores at 90 days – in endovascular group, no patient had a score of 5 Figure 2. Scores on the Modified Rankin Scale at 90 Days in the Intentionto- Treat Population. Shown are the percentages of patients in the endovascular-therapy group and the alteplase-only group with scores from 0 to 6 on the modified Rankin scale as follows: 0, no symptoms; 1, no clinically significant disability; 2, slight disability (able to handle own affairs without assistance but unable to carry out all previous activities); 3, moderate disability requiring some help (e.g., with shopping, cleaning, and finances but able to walk unassisted); 4, moderately severe disability (unable to attend to bodily needs without assistance and unable to walk unassisted); 5, severe disability (requiring constant nursing care and attention); and 6, death. In the endovascular group, no patients had a score of 5. CONCLUSIONS: in patients with prox occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with Solitaire FR stent retriever, compared to tPA alone improved reperfusion, early neuro recovery and functional outcome Campbell, Bruce C.V. et al. "Endovascular Therapy For Ischemic Stroke With Perfusion-Imaging Selection". New England Journal of Medicine 372.11 (2015): 1009-1018.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset PURPOSE: assess safety and efficacy of thrombectomy for treatment of stroke METHODS: randomized, 4 centers in Catalonia, Spain; within 8 hours from onset, medical therapy (including IV tPA when eligible) and endovascular therapy with Solitaire stent retriever vs medical therapy alone, confirmed prox anterior occlusion and absence of large infarct on neuroimaging; all patients tPA did not achieve revascularization or was contraindicated OUTCOMES: primary outome severity of global disability at 90d (mRS) * CT denotes computed tomography, and MRI magnetic resonance imaging. † The modified Rankin scale of functional disability ranges from 0 (no symptoms) to 6 (death). ‡ Dramatic neurologic improvement was defined as a reduction of at least 8 points on the NIHSS or a score of 0 to 2 at 24 hours. NIHSS scores at 24 hours were not available for 3 patients in each group because of early death or intubation. § Scores on the Barthel Index range from 0 to 100, with higher values indicating good performance of daily living activities. A score between 95 and 100 indicates no disability that interferes with daily activities. Included are patients who were alive at 90 days. ¶ Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) range from −0.33 to 1, with higher scores indicating a better quality of life. ‖ The P value was calculated by means of the Wilcoxon rank-sum test. Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset RESULTS: 206 patients enrolled max planned 690pts but halted early due to loss of equipoise from other similar trials * CT denotes computed tomography, and MRI magnetic resonance imaging. † The modified Rankin scale of functional disability ranges from 0 (no symptoms) to 6 (death). ‡ Dramatic neurologic improvement was defined as a reduction of at least 8 points on the NIHSS or a score of 0 to 2 at 24 hours. NIHSS scores at 24 hours were not available for 3 patients in each group because of early death or intubation. § Scores on the Barthel Index range from 0 to 100, with higher values indicating good performance of daily living activities. A score between 95 and 100 indicates no disability that interferes with daily activities. Included are patients who were alive at 90 days. ¶ Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) range from −0.33 to 1, with higher scores indicating a better quality of life. ‖ The P value was calculated by means of the Wilcoxon rank-sum test. Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset RESULTS: Decreased severity of disability over range of MRS (adjusted OR for improvement of 1 point 1.7 95% CI 1.05 to 2.8 Increased rates of functional independence (mRS 0-2) at 90d (43.7% vs 28.2% adjusted OR 2.1 95% CI 1.1 to 4.0) * CT denotes computed tomography, and MRI magnetic resonance imaging. † The modified Rankin scale of functional disability ranges from 0 (no symptoms) to 6 (death). ‡ Dramatic neurologic improvement was defined as a reduction of at least 8 points on the NIHSS or a score of 0 to 2 at 24 hours. NIHSS scores at 24 hours were not available for 3 patients in each group because of early death or intubation. § Scores on the Barthel Index range from 0 to 100, with higher values indicating good performance of daily living activities. A score between 95 and 100 indicates no disability that interferes with daily activities. Included are patients who were alive at 90 days. ¶ Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) range from −0.33 to 1, with higher scores indicating a better quality of life. ‖ The P value was calculated by means of the Wilcoxon rank-sum test. Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset RESULTS: Decreased severity of disability over range of MRS (adjusted OR for improvement of 1 point 1.7 95% CI 1.05 to 2.8 Increased rates of functional independence (mRS 0-2) at 90d (43.7% vs 28.2% adjusted OR 2.1 95% CI 1.1 to 4.0) Figure 1. Distribution of Functional Scores at 90 Days (Intention-to-Treat Population). Shown are scores on the modified Rankin scale for patients in the thrombectomy group and the control group who were evaluated by means of video recording (in 106 patients) and by local investigators (in 65 patients). Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms; 1, no clinically significant disability; 2, slight disability (able to handle own affairs without assistance but unable to carry out all previous activities); 3, moderate disability requiring some help, but able to walk unassisted; 4, moderately severe disability (unable to attend body needs and unable to walk); 5, severe disability (requiring constant nursing care and attention); and 6, death. Scores of 5 and 6 were combined for the analysis. A significant difference between the thrombectomy group and the control group was noted in the overall distribution of scores (adjusted common odds ratio for improvement of 1 point on the modified Rankin scale, 1.7; 95% confidence interval, 1.05 to 2.8). *distribution of functional scores at 90 days - significant difference noted in overall distribution of scores Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset RESULTS: Rate of symptomatic ICH 1.9% in both groups Moratlity rate 18.4% and 15.5% (p=0.60) * Negative values for the between-group difference favor the control group. The risk ratio is for the thrombectomy group as compared with the control group. A complete list of adverse events is provided in Tables S6 and S7 in the Supplementary Appendix. † The adjusted risk ratio for death at 90 days was 1.1 (95% CI, 0.8 to 1.4). ‡ Symptomatic intracranial hemorrhage was defined as parenchymal hemorrhage type 2 on follow-up imaging and neurologic deterioration of at least 4 points on the NIHSS, according to the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) criteria, or any symptomatic intracranial hemorrhage and neurologic worsening of at least 4 points on the NIHSS, according to the second European–Australasian Acute Stroke Study (ECASS II) criteria. § Asymptomatic intracranial hemorrhage was defined as any parenchymal hematoma with no neurologic worsening, as adjudicated by local investigators. ¶ Parenchymal hematomas were graded according to the neuroimaging core laboratory classification. ‖ Neurologic worsening was defined as an increase of at least 4 points on the NIHSS within 5 days after stroke onset that was not attributed to intracranial hemorrhage or malignant cerebral edema. ** Malignant cerebral edema was treated with decompressive hemicraniectomy in 3 patients in the thrombectomy group and in 6 patients in the control group. †† All procedure-related complications were reported by the clinical events committee. ‡‡ Vasospasm events were reported by local investigators and the angiography core laboratory. Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA REVASCAT- Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset CONCLUSIONS: anterior occlusion treated within 8 h, stent retriever thrombectomy reduced severity of disability and increased rate of functional independence * Negative values for the between-group difference favor the control group. The risk ratio is for the thrombectomy group as compared with the control group. A complete list of adverse events is provided in Tables S6 and S7 in the Supplementary Appendix. † The adjusted risk ratio for death at 90 days was 1.1 (95% CI, 0.8 to 1.4). ‡ Symptomatic intracranial hemorrhage was defined as parenchymal hemorrhage type 2 on follow-up imaging and neurologic deterioration of at least 4 points on the NIHSS, according to the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) criteria, or any symptomatic intracranial hemorrhage and neurologic worsening of at least 4 points on the NIHSS, according to the second European–Australasian Acute Stroke Study (ECASS II) criteria. § Asymptomatic intracranial hemorrhage was defined as any parenchymal hematoma with no neurologic worsening, as adjudicated by local investigators. ¶ Parenchymal hematomas were graded according to the neuroimaging core laboratory classification. ‖ Neurologic worsening was defined as an increase of at least 4 points on the NIHSS within 5 days after stroke onset that was not attributed to intracranial hemorrhage or malignant cerebral edema. ** Malignant cerebral edema was treated with decompressive hemicraniectomy in 3 patients in the thrombectomy group and in 6 patients in the control group. †† All procedure-related complications were reported by the clinical events committee. ‡‡ Vasospasm events were reported by local investigators and the angiography core laboratory. Jovin, Tudor G. et al. "Thrombectomy Within 8 Hours After Symptom Onset In Ischemic Stroke". New England Journal of Medicine 372.24 (2015): 2296-2306.

Endovascular thrombectomy (ant) NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 1 2 TIA ASA Normal STROKE RECOVERY 3 RIND REHAB 6 5 4 0h 3h 4.5h IV tPA 0h 6h DEATH IA tPA 0h 8h Endovascular thrombectomy (ant)

? 1 2 LARGE HEMISPHERIC INFARCTS TIA ASA Normal RECOVERY 3 RIND REHAB NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 1 2 LARGE HEMISPHERIC INFARCTS TIA ASA Normal RECOVERY 3 RIND REHAB 6 5 4 ? DEATH

Between 2001 and 2004, 4 other studies were initiated: NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA The Hemicraniecomy And Durotomy On Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) randomized 26 patients between 2000 and 2003. Between 2001 and 2004, 4 other studies were initiated: Hemicraniectomy For Malignant Middle Cerebral Artery Infarcts (HeMMI) Philippines 3 European trials HAMLET (Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial) in the Netherlands DECIMAL (Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarcts) in France DESTINY (Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery) in Germany.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DECIMAL - Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarcts Purpose: Assess efficacy of decompressive craniectomy in malignant MCA infarction Methods: France, multicenter, randomized trial; single-blind, 18-55y, malignant MCA Outcomes: functional outcome (mRS <=3 at 6 months) Vahedi, K. et al. "Sequential-Design, Multicenter, Randomized, Controlled Trial Of Early Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarction (DECIMAL Trial)".Stroke 38.9 (2007): 2506-2517.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DECIMAL - Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarcts RESULTS: 38 patients, stopped by data safety monitoring committee (slow recruitment and pooled analysis with 2 other European trials) mRS <=3 at 6 months and 1 year 25% and 50% vs 5.6% and 22.2% (control) (p=0.18, p=0.10) *mRS score distribution in the 2 therapeutic groups at the 6-month and 1-year follow-up Figure 4. mRS score distribution in the 2 therapeutic groups at the 6-month and 1-year follow-up. (Numbers of patients are shown in parentheses.) Vahedi, K. et al. "Sequential-Design, Multicenter, Randomized, Controlled Trial Of Early Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarction (DECIMAL Trial)".Stroke 38.9 (2007): 2506-2517.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DECIMAL - Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarcts RESULTS: absolute reduction of death 52.8% (p<0.0001) Figure 5. Kaplan–Meier survival curves for the 2 treatment groups. Conclusion: early decompressive craniectomy increased >2x number of patients with moderate disability and significantly reduced (>half) mortality rate. Vahedi, K. et al. "Sequential-Design, Multicenter, Randomized, Controlled Trial Of Early Decompressive Craniectomy In Malignant Middle Cerebral Artery Infarction (DECIMAL Trial)".Stroke 38.9 (2007): 2506-2517.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA Purpose: determine 30-day mortality and 6- and 12-month functional outcomes Methods: prospective, multicenter, randomized, controlled, clinical trial; sequential design Outcome: mRS dichotomized to 0-3 vs 4-6 Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA Purpose: determine 30-day mortality and 6- and 12-month functional outcomes Methods: prospective, multicenter, randomized, controlled, clinical trial; sequential design Outcome: mRS dichotomized to 0-3 vs 4-6 Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA Purpose: determine 30-day mortality and 6- and 12-month functional outcomes Methods: prospective, multicenter, randomized, controlled, clinical trial; sequential design Outcome: mRS dichotomized to 0-3 vs 4-6 Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA RESULTS: 32 patients significant reduction in mortality achieved 15 of 17 (88%) in DHC vs 7 of 15 (47%) of conservative therapy survived after 30 days (p=0.02) Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA RESULTS: 47% vs 27% had mRS 0-3 after 6 and 12 months (p=0.23) Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA RESULTS: 47% vs 27% had mRS 0-3 after 6 and 12 months (p=0.23) Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA RESULTS: 47% vs 27% had mRS 0-3 after 6 and 12 months (p=0.23) Figure 1. Functional outcome according to the mRS after 6 (a) and 12 (b) months (ITT analysis). Lines indicate the differences between both treatment arms: mRS score 0 to 3 versus 4 to 6 (primary end point) and 0 to 4 versus 5 to 6 (secondary end point). Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DESTINY - Decompressive Surgery for the Treatment of Malignant Infarction of the MCA CONCLUSIONS: DHC reduces mortality in LHI Failed to demonstrate superiority of DHC Projected size 188 patients Terminated in light of joint analysis of the 3 other European trials Figure 1. Functional outcome according to the mRS after 6 (a) and 12 (b) months (ITT analysis). Lines indicate the differences between both treatment arms: mRS score 0 to 3 versus 4 to 6 (primary end point) and 0 to 4 versus 5 to 6 (secondary end point). Juttler, E. et al. "Decompressive Surgery For The Treatment Of Malignant Infarction Of The Middle Cerebral Artery (DESTINY): A Randomized, Controlled Trial". Stroke 38.9 (2007): 2518-2525.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial PURPOSE: determine effect of DHC after longer interval (within 4 days of onset of symptoms) Methods: patients with space-occupying hemispheric infarction, randomized within 4 days of stroke onset to surgical decompression vs best medical treatment. Outcome: primary outcome mRS at 1 year (dichotomized 0-3 vs 4-6); dichotomy of mRS between 4 and 5; case fatality, QOL, symptoms of depression ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial RESULTS: 64 patients, 32 in DHC, 32 to best medical treatment ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

*mRS after 1 year NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial RESULTS: No effect on primary outcome (ARR 0%, 95% CI -21 to 21) *mRS after 1 year Figure 2: Distribution of scores on the modifi ed Rankin scale after 1 year ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial RESULTS: No effect on primary outcome (ARR 0%, 95% CI -21 to 21) Reduced case fatality (ARR 38%, 15-60) Primary and secondary outcomes after 1 year ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA HAMLET - Hemicraniectomy After MCA Infarction With Life-Threatening Edema Trial Conclusions: Surgical decompression reduces case fatality and poor outcome in patients with space-occupying infarctions treated within 48 hours of onset Does not improve functional outcome when delayed for up to 96h after stroke onset. Primary and secondary outcomes after 1 year ReferencesHofmeijer, Jeannette et al. "Surgical Decompression For Space-Occupying Cerebral Infarction (The Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial". The Lancet Neurology 8.4 (2009): 326-333.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) Methods: Lit search for RCTs on effects of DHC in mMCAI Outcomes: mortality and major disability (mRS 4-5), secondary outcomes of death or major disability (mRS>3) and death or severe disability (mRS >4) Fig. 3 e Comparison of DHC versus medical treatment for primary outcomes: (A) Death at 12-month. (B) Major disability (mRS score: 4e5) among survivors at 12-month. Yang, Ming-Hao et al. "Decompressive Hemicraniectomy In Patients With Malignant Middle Cerebral Artery Infarction: A Systematic Review And Meta-Analysis". The Surgeon 13.4 (2015): 230-240.

Death at 12 month NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) RESULTS: Included 6 studies, 314 patients DHS significantly decreased mortality risk. Fig. 3 e Comparison of DHC versus medical treatment for primary outcomes: (A) Death at 12-month. (B) Major disability (mRS score: 4e5) among survivors at 12-month. Death at 12 month Yang, Ming-Hao et al. "Decompressive Hemicraniectomy In Patients With Malignant Middle Cerebral Artery Infarction: A Systematic Review And Meta-Analysis". The Surgeon 13.4 (2015): 230-240.

mRS 4-5 at 12 month NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) RESULTS: Higher portion of major disability (mRS 4-5) among survivors Fig. 3 e Comparison of DHC versus medical treatment for primary outcomes: (A) Death at 12-month. (B) Major disability (mRS score: 4e5) among survivors at 12-month. mRS 4-5 at 12 month Yang, Ming-Hao et al. "Decompressive Hemicraniectomy In Patients With Malignant Middle Cerebral Artery Infarction: A Systematic Review And Meta-Analysis". The Surgeon 13.4 (2015): 230-240.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) CONCLUSION: DHC significantly decreased mortality with nonsignificant increase in proportion of survivors with major disability Fig. 3 e Comparison of DHC versus medical treatment for primary outcomes: (A) Death at 12-month. (B) Major disability (mRS score: 4e5) among survivors at 12-month. Yang, Ming-Hao et al. "Decompressive Hemicraniectomy In Patients With Malignant Middle Cerebral Artery Infarction: A Systematic Review And Meta-Analysis". The Surgeon 13.4 (2015): 230-240.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY II HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) PURPOSE: Determine benefit of DHC in older patients Methods: 112 patients 61 years or older with malignant MCA infarction to conservative treatment vs hemicraniectomy. Assigned within 48 hours Outcomes: Primary end point – survival without severe disability (mRS 0-4) * There were 27 known survivors in the surgery group and 15 known survivors in the control group. † Both the mental-component and physical-component summary scores of the Medical Outcomes Study 36-Item Short- Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating greater well-being. In this study, no patients had a mental-component summary score higher than 75 and no patients had a physical-component summary score higher than 50. ‡ Scores on the Hamilton Depression Rating Scale range from 0 to 52, with higher scores indicating greater severity of symptoms and scores higher than 19 indicating severe depression. § Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale range from 0 (worst quality of life) to 100 (best quality of life). Jüttler, Eric et al. "Hemicraniectomy In Older Patients With Extensive Middle-Cerebral-Artery Stroke".New England Journal of Medicine 370.12 (2014): 1091-1100.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY II HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) RESULTS: Survival without severe disability 38% vs 18% (OR 2.91, 95% CI 1.6 to 7.49 (p=0.04) mRS 3 = 7% vs 3% mRS 4 = 32% vs 15% mRS 5 = 28% vs 13% * There were 27 known survivors in the surgery group and 15 known survivors in the control group. † Both the mental-component and physical-component summary scores of the Medical Outcomes Study 36-Item Short- Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating greater well-being. In this study, no patients had a mental-component summary score higher than 75 and no patients had a physical-component summary score higher than 50. ‡ Scores on the Hamilton Depression Rating Scale range from 0 to 52, with higher scores indicating greater severity of symptoms and scores higher than 19 indicating severe depression. § Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale range from 0 (worst quality of life) to 100 (best quality of life). Jüttler, Eric et al. "Hemicraniectomy In Older Patients With Extensive Middle-Cerebral-Artery Stroke".New England Journal of Medicine 370.12 (2014): 1091-1100.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY II HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) PURPOSE: Determine benefit of DHC in older patients Methods: 112 patients 61 years or older with malignant MCA infarction to conservative treatment vs hemicraniectomy. Assigned within 48 hours Outcomes: Primary end point – survival without severe disability (mRS 0-4) * There were 27 known survivors in the surgery group and 15 known survivors in the control group. † Both the mental-component and physical-component summary scores of the Medical Outcomes Study 36-Item Short- Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating greater well-being. In this study, no patients had a mental-component summary score higher than 75 and no patients had a physical-component summary score higher than 50. ‡ Scores on the Hamilton Depression Rating Scale range from 0 to 52, with higher scores indicating greater severity of symptoms and scores higher than 19 indicating severe depression. § Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale range from 0 (worst quality of life) to 100 (best quality of life). Jüttler, Eric et al. "Hemicraniectomy In Older Patients With Extensive Middle-Cerebral-Artery Stroke".New England Journal of Medicine 370.12 (2014): 1091-1100.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY II HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) RESULTS Lower mortality in surgery group 33% vs 70% Figure 2. Kaplan–Meier Estimates of Survival in the Hemicraniectomy and Control Groups. The effect of hemicraniectomy in reducing mortality was clearly due to increased survival rates in the early phase, but it remained stable throughout the whole observation period. Jüttler, Eric et al. "Hemicraniectomy In Older Patients With Extensive Middle-Cerebral-Artery Stroke".New England Journal of Medicine 370.12 (2014): 1091-1100.

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY II HAMLET DHC MA DHC Systematic Review and Meta-Analysis (2015) CONCLUSION: DHC increased survival without severe disability among patients 61y or older with malignant MCA infarction. Majority of survivors required assistance with most bodily needs * There were 27 known survivors in the surgery group and 15 known survivors in the control group. † Both the mental-component and physical-component summary scores of the Medical Outcomes Study 36-Item Short- Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating greater well-being. In this study, no patients had a mental-component summary score higher than 75 and no patients had a physical-component summary score higher than 50. ‡ Scores on the Hamilton Depression Rating Scale range from 0 to 52, with higher scores indicating greater severity of symptoms and scores higher than 19 indicating severe depression. § Scores on the EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale range from 0 (worst quality of life) to 100 (best quality of life). Jüttler, Eric et al. "Hemicraniectomy In Older Patients With Extensive Middle-Cerebral-Artery Stroke".New England Journal of Medicine 370.12 (2014): 1091-1100.

1 2 LARGE HEMISPHERIC INFARCTS TIA ASA Normal RECOVERY 3 RIND REHAB 6 NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA 1 2 LARGE HEMISPHERIC INFARCTS TIA ASA Normal RECOVERY 3 RIND REHAB 6 5 4 DEATH Decompressive Hemicraniectomy

1 2 TIA ASA Normal STROKE RECOVERY 3 RIND REHAB 6 5 4 NINDS 1 2 TIA ASA NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA Normal STROKE RECOVERY 3 RIND REHAB 6 5 4 Alonso de Leciñana, M. et al. "Endovascular Treatment In Acute Ischaemic Stroke. A Stroke Care Plan For The Region Of Madrid". Neurología (English Edition) 28.7 (2013): 425-434.

Endovascular thrombectomy (ant) Endovascular thrombectomy (post) 1 2 TIA ASA Normal STROKE RECOVERY 3 RIND REHAB 6 5 4 0h 3h 4.5h IV tPA 0h 6h DEATH IA tPA 0h 8h Endovascular thrombectomy (ant) 0h 24h Endovascular thrombectomy (post)

NINDS ECASS I / II ATLANTIS I / II ECASS III IST 3 2012 MA 2014 MA PROACT I / II MELT MERCI / MULTI PENUMBRA-PIVOT SWIFT TREVO I / II IMS I-III SYNTHESIS MR RESCUE MR CLEAN ESCAPE SWIFT-PRIME EXTEND IA REVASCAT DECIMAL DESTINY HAMLET DHC MA