Erik Oltmann, PGY-1 August 20, 2015 LSU Journal Club “Stent-Retriever Thrombectomy after Intravenous t-PA vs t-PA Alone in Stroke” NEJM June 11, 2015; 372:2285-2295; DOI: 10.1056/NEJMoa1415061 SWIFT PRIME Investigators, et al. Erik Oltmann, PGY-1 August 20, 2015

Background 795,000 patients experience an Ischemic Stroke each year t-PA only effective when given within 4.5 hours of onset Effective in <30% of patients with a Large Occlusion of Major Vessels (13-50% in M1 of MCA and Intracranial ICA) Stent-Retrieval devices Entrap the Thrombus between the stent and the vessel wall to restore Anterograde Blood Flow Struts on the stent allows thrombotic material to be Retrieved by the Catheter tPA at 4.5 hours: - Age <80 | NO DM2 + stroke | NO Coumadin/warfarin | NIHSS <25

Research Question Is the addition of Stent-Retriever Thrombectomy to IV t-PA for Acute Ischemic Stroke involving the Proximal Anterior Intracranial Circulation a Safe and Efficacious treatment? establish the efficacy and safety of rapid neurovascular thrombectomy with the stent retriever in conjunction with intravenous t-PA versus intravenous t-PA alone in patients with acute ischemic stroke.

Study Design December 2012 through November 2014, 196 patients enrolled in SWIFT PRIME Trial Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment International, Multicenter, Prospective, Randomized, Clinical Trial 39 centers in the US and Europe

Study Design: INCLUSION CRITERIA 18-80 Years of Age Acute Ischemic Stroke with a NIHSS Score of 8-29 (Mod-Sev deficit) and Baseline Modified Rankin Score <1 Imaging-confirmed occlusion of the Intracranial Internal Carotid Artery, the First Segment of Middle Cerebral Artery, or Both Receiving or had received IV t-PA within 4.5 hrs, and able to undergo initiation of Endovascular Treatment within 6 hrs of Onset Modified Rankin: 0-6 1 = no significant disability 2 = slight; able to perform ADLs 3 = mod; able to walk unassisted; some help 4 = mod-sev; unable to walk w/o assist; unable to independent perform ADLs 5 = sev; bedridden, incontinent 6 = death

Study Design: EXCLUSION CRITERIA t-PA Contraindicated Rapid Improvement of Neuro Symptoms Contrast and Metal Allergies Hereditary or Acquired Bleeding Diathesis Creatinine >2.0 | GFR <30 | ESRD on Dialysis Presentation suggestive of Aortic Dissection or SAH Comorbidities that would confound Neuro and Functional Evaluation Contraindications for t-PA: evidence of hemorrhage on CT; clinical suspicion of SAH; multi-lobar ischemia; hx of hemorrhage; BP >185/>110; PLT <100,000; Heparin w/i 48 or current Hep/Warf use; elevated PTT Relative Contraindications: NIHSS>22 or<4 or rapidly improving; 14d post op or post trauma; recent GI/GU hemorrhage (21d); recent AMI (3 mos); pericarditis; Glucose<50 OR >400; Age>80; hx of ischemic stroke AND diabetes These questions help you to identify if the study is valid (internal validity) and whether the results are generalizable to the sort of patients you are likely to see. (external validity)

Study Design Patients balanced with respect to 4 factors: Investigational Site Baseline Severity: NIHSS score ≤17 vs. >17 Age: <70 yoa vs. ≥70 yoa Occlusion Location: Middle Cerebral vs. Internal Carotid Randomly assigned to one of two treatment groups: Intervention Group (98): IV t-PA plus Stent Retriever Control Group (98): IV t-PA alone Patients Evaluated at 27 hrs  7-10 days  30 days  90 days **10 patients in interventional group lost to follow up or did not receive thrombectomy

Demographic and Clinical Characteristics Saver JL et al. N Engl J Med 2015;372:2285-2295.

Demographic and Clinical Characteristics Saver JL et al. N Engl J Med 2015;372:2285-2295.

Results INTERVENTION GROUP: median time from onset to groin puncture was 224 min 88% of patients regained Substantial Reperfusion Reduced disability at 90 days over the Entire Range of scores on the Modified Rankin scale (P<0.001) The rate of functional independence (mRS score 0 to 2) was higher in Intervention group than Control group 60% vs. 35%, P<0.001 NO Significant Differences between groups in 90-day Mortality (9% vs. 12%, P = 0.50) or Symptomatic Intracranial Hemorrhage (0% vs. 3%, P = 0.12) Less Disabled: NNT = 2.6 Functionally Independent: NNT = 4 | RR = 1.7

Saver JL et al. N Engl J Med 2015;372:2285-2295. Primary and Secondary Outcomes Saver JL et al. N Engl J Med 2015;372:2285-2295. Figure 2. Analysis of Functional Independence at 90 Days in Pre-specified Subgroups.  Functional independence was defined as a score on the modified Rankin scale of 0, 1, or 2. P values were based on the Breslow–Day test for homogeneous odds ratios across subgroups. Squares indicate point estimates for treatment effects, and the size of the square is proportional to the precision of the estimate. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. The threshold of 17 was the threshold used in stratifying randomization. The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core; a score of 6 or 7 indicates moderate infarct core, and a score of 8 or higher small infarct core. For the time from stroke onset to randomization, the median value was prespecified as the cutoff point for analysis and was found to be 189 minutes. M1 denotes first segment of the middle cerebral artery, and M2 second segment of middle cerebral artery.

Saver JL et al. N Engl J Med 2015;372:2285-2295. Primary and Secondary Outcomes Saver JL et al. N Engl J Med 2015;372:2285-2295. Figure 2. Analysis of Functional Independence at 90 Days in Pre-specified Subgroups.  Functional independence was defined as a score on the modified Rankin scale of 0, 1, or 2. P values were based on the Breslow–Day test for homogeneous odds ratios across subgroups. Squares indicate point estimates for treatment effects, and the size of the square is proportional to the precision of the estimate. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. The threshold of 17 was the threshold used in stratifying randomization. The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core; a score of 6 or 7 indicates moderate infarct core, and a score of 8 or higher small infarct core. For the time from stroke onset to randomization, the median value was prespecified as the cutoff point for analysis and was found to be 189 minutes.

Saver JL et al. N Engl J Med 2015;372:2285-2295. Functional Independence at 90 Days Saver JL et al. N Engl J Med 2015;372:2285-2295. Figure 2. Analysis of Functional Independence at 90 Days in Pre-specified Subgroups.  Functional independence was defined as a score on the modified Rankin scale of 0, 1, or 2. P values were based on the Breslow–Day test for homogeneous odds ratios across subgroups. Squares indicate point estimates for treatment effects, and the size of the square is proportional to the precision of the estimate. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. The threshold of 17 was the threshold used in stratifying randomization. The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core; a score of 6 or 7 indicates moderate infarct core, and a score of 8 or higher small infarct core. For the time from stroke onset to randomization, the median value was prespecified as the cutoff point for analysis and was found to be 189 minutes. M1 denotes first segment of the middle cerebral artery, and M2 second segment of middle cerebral artery.

Saver JL et al. N Engl J Med 2015;372:2285-2295. Functional Independence at 90 Days Saver JL et al. N Engl J Med 2015;372:2285-2295. ASPECTS Scores Figure 2. Analysis of Functional Independence at 90 Days in Pre-specified Subgroups.  Functional independence was defined as a score on the modified Rankin scale of 0, 1, or 2. P values were based on the Breslow–Day test for homogeneous odds ratios across subgroups. Squares indicate point estimates for treatment effects, and the size of the square is proportional to the precision of the estimate. Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits. The threshold of 17 was the threshold used in stratifying randomization. The Alberta Stroke Program Early CT Score (ASPECTS) ranges from 0 to 10, with higher scores indicating a smaller infarct core; a score of 6 or 7 indicates moderate infarct core, and a score of 8 or higher small infarct core. For the time from stroke onset to randomization, the median value was prespecified as the cutoff point for analysis and was found to be 189 minutes. M1 denotes first segment of the middle cerebral artery, and M2 second segment of middle cerebral artery.

Saver JL et al. N Engl J Med 2015;372:2285-2295. Functional Independence at 90 Days Saver JL et al. N Engl J Med 2015;372:2285-2295.

Safety Outcomes

Safety Outcomes

Safety Outcomes

Conclusions Improved 90 day Functional independence Modified Rankin Score <2 Better outcomes across ALL scores of Rankin More successful reperfusion at 27hrs 83% vs 40% No significant difference in rates of ALL intracranial hemorrhage Numerically more SAH with Thrombectomy These questions help you to identify if the study is valid (internal validity) and whether the results are generalizable to the sort of patients you are likely to see. (external validity)

Limitations Small, Homogenous patient population Need to expand the demographics Only studied in the M1 Segment of MCA and Intracranial ICA Further studies in more Distal Vessels Sites were Tertiary Care Centers with established Stroke-Intervention programs and skilled Interventionalists Safety in Non-tertiary Centers? No significant difference in relative benefit on pts sent on transfer from OSH

Authors Jeffrey L. Saver, M.D., Mayank Goyal, M.D., Alain Bonafe, M.D., Hans-Christoph Diener, M.D., Ph.D., Elad I. Levy, M.D., Vitor M. Pereira, M.D., Gregory W. Albers, M.D., Christophe Cognard, M.D., David J. Cohen, M.D., Werner Hacke, M.D., Ph.D., Olav Jansen, M.D., Ph.D., Tudor G. Jovin, M.D., Heinrich P. Mattle, M.D., Raul G. Nogueira, M.D., Adnan H. Siddiqui, M.D., Ph.D., Dileep R. Yavagal, M.D., Blaise W. Baxter, M.D., Thomas G. Devlin, M.D., Ph.D., Demetrius K. Lopes, M.D., Vivek K. Reddy, M.D., Richard du Mesnil de Rochemont, M.D., Oliver C. Singer, M.D., and Reza Jahan, M.D., for the SWIFT PRIME Investigators*

References http://www.medscape.com/viewarticle/772506_3 http://www.nejm.org/doi/full/10.1056/NEJMoa1415061 http://www.nejm.org/doi/full/10.1056/NEJM199512143332401 http://www.icahn.org/files/Stroke_Library_/Tools/stroke_inclusion_exclusion_stroke_.pdf http://www.strokecarenow.com/wp-content/uploads/IV-tPA-Screening-Checklist-with-ED-signature.pdf http://radiopaedia.org/articles/alberta-stroke-program-early-ct-score-1 http://www.ischemaview.com/what-is-rapid