1/19/2018. Endovascular Therapy for Stroke

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1 Endovascular Therapy for Stroke 1

2 PROACT II (1999, IA urokinase)first to demonstrate benefit of EST Newer trials (including MERCI in 2005) demonstrated vessel recanalization but no clinical benefit 2

3 Based on the DOE (Disease Oriented Endpoint) of recanalization, FDA approved devices under 510(K) clearance (doesn t require evidence of clinical benefit) Other studies started, but many places started doing the procedures right away 3

4 IMS-III, SYNTHESIS and MR RESUCE published in NEJM all different, but all negative 4

5 Pro-EST crowd had lots of criticisms of these studies o Most used non-con CTs rather than CTA/MRA o Time windows were too long o Used wrong equipment (MERCI, rather than newer/shinier devices) MERCI recanalized vessels about 2/3 of the time, newer devices around 80% of the time how big a difference is that? No RCT to this point showed improvement in any POE (Patient Oriented Endpoint), only the DOE of vessel recanalization 5

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7 MR CLEAN published New Year s Day 2015 a big deal First RCT to show significant improvement in clinical outcomes with EST (NNT: 7) PROBE design (Prospective Randomized Open Label Blinded Endpoint) Highly selected pt population o o Large anterior circ stroke w/large vessel occlusion of ACA, MCA or distal ICA demonstrated by CTA or MRA Intervention w/in 6 hours of symptom onset Pts ineligible for one treatment eligible for the others o 89% received IV tpa No difference in mortality or sich, BUT 5.6% developed new stroke in new distribution (embolizataion?) vs 0.4% of control group (NNH: 19) 7

8 6 other RCTs were underway when MR CLEAN s results were released at ISC in November 2014 All 6 did interim analyses, stopped early, and sprinted to publish their results EXTEND-IA Tiny numbers, great outcomes (NNT 2-5) ESCAPE 12 hours NNT 5 8

9 EXTEND-IA o Only 70 pts, strange outcome measures (3 days, plus another perfusion DOE; 90d mrs was secondary outcome) o Intervention begun within 6 hours, completed within 8 o NNT 2-5 depending on outcome ESCAPE o 12-hour window o Used ASPECT scores rather than CTA/MRA o Only study to show SS mortality benefit (NNT 11) o NNT for 90d mrs 0-2: 5 SWIFT PRIME NNT: 4 REVASCAT 8 hours NNT 6.5 9

10 SWIFT PRIME o Required no large ischemic core on perfusion imaging o Changed imaging criteria half-way through o 90d mrs 0-2: NNT 4 REVASCAT o Site selection: had to be doing 60 procedures/year Intrinsic bias towards doing procedures why would you be when there was no evidence at this point? o 8-hour window, no large infarct o Pts had to be either ineligible for IV tpa or have CTA-proven lack of recanalization within 30 minutes of tpa o 90d mrs 0-2: NNT 6.5 THERAPY Stopped early No SS benefit THRACE in 2016 NNT: 9 No SS difference in mrs w/ordinal analysis 10

11 THERAPY o Stopped after only 108 of planned 692 pts enrolled o Trend towards positive but not SS THRACE o 2 nd largest enrollment o 90d mrs 0-2: NNT 9 (ordinal analysis of mrs showed no benefit) One small/underpowered failed trial and one trial with benefit that is smaller and questionable first trials not published in NEJM, no fanfare DAWN 6-24 hours NNT: 3 11

12 Extended window (6-24h) includes wake up strokes Stopped early d/t benefit Co-primary endpoints o Novel, complicated endpoint positive (?) o 90d mrs 0-2: NNT 3 12

13 DEFUSE 3: Stopped early d/t benefit (6-16 hrs; not yet published) CRISP: trying to ID pts >6 hrs who will benefit o perfusion target mismatch profile on CTA POSITIVE: 6-12 hrs 13

14 STATS/METHODS 14

15 Statistical/Methodological Concerns All trials after MR CLEAN stopped early (tends to magnify benefit) o 2 of the 3 trials closest to completion (also 2 with largest enrollments) had the smallest benefit of all of the trials Ordinal analysis used in many of the studies (controversial) Intrinsic bias many of the researchers have been involved in these projects for decades; REVASCAT site selection All either fully or partially funded by device manufacturers All were open label mrs has poor inter-rater reliability o Problem with using a subjective measure with poor inter-rater reliability in an open-label trial when you know whether or not you got the special treatment All compared to tpa alone (no placebo) STUDY PTS/CENTER/YEAR IMS-III 2.0 SYNTHESIS 3.6 MR RESCUE 0.8 MR CLEAN 9.4 EXTEND-IA 3.1 ESCAPE 8.2 (17.3?) SWIFT PRIME 2.5 REVASCAT 12.2 THERAPY 1.1 THRACE 3.4 DAWN

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17 Only EXTEND-IA told us how many they screened o Almost 7800 strokes to enroll 70 (0.9% of strokes eligible; 1/110) If you need to treat 7 for one to get benefit (MR CLEAN), that s 1/770 strokes that will benefit from this therapy Would require massive overhaul of EMS and hospital systems, massive costs o Every stroke pt would require CTA (~$ dye/radiation) o Diverting all stroke pts to centers w CTA/MRA available 17

18 What are the chances hospitals will make this kind of investment (devices, staff, training, on-call interventionalists 24/7) and be happy with one procedure every 2 months? o o Already was happening at sites chosen for the REVASCAT trial, likely many others Remember negative results of IMS-III, SYNTHESIS, MR RESUCE in pt populations that weren t highly selected SUMMARY 7 RCTs have demonstrated benefit (NNT: 2-12) of ETS if: o Anterior stroke o Clot in a large proximal vessel by CTA/MRA ETS benefits only 1/~770 stroke patients Areas for future study o ID middle ground group that could benefit o ETS without IV tpa? o Extending the window Indication creep a huge concern 18

19 References/Additional Reading A TRIAL OF IMAGING SELECTION AND ENDOVASCULAR TREATMENT FOR ISCHEMIC STROKE Kidwell, C.S., et al, N Engl J Med 368(10):914, March 7, 2013 (MR RESCUE) ENDOVASCULAR TREATMENT FOR ACUTE ISCHEMIC STROKE Ciccone, A., et al, N Engl J Med 368(10):904, March 7, 2013 (SYNTHESIS) ENDOVASCULAR THERAPY AFTER INTRAVENOUS T-PA VERSUS T-PA ALONE FOR STROKE Broderick, J.P., et al, N Engl J Med 368(10):893, March 2013 (IMS-III) A RANDOMIZED TRIAL OF INTRAARTERIAL TREATMENT FOR ACUTE ISCHEMIC STROKE. Berkhemer OA, et al. N Engl J Med. 2015;372:(1) (MR CLEAN) RANDOMIZED ASSESSMENT OF RAPID ENDOVASCULAR TREATMENT OF ISCHEMIC STROKE Goyal, M., et al, N Engl J Med 372(11):1019, March 12, 2015 (ESCAPE) ENDOVASCULAR THERAPY FOR ISCHEMIC STROKE WITH PERFUSION-IMAGING SELECTION Campbell, B.C.V., et al, N Engl J Med 372(11):1009, March 12, 2015 (EXTEND-IA) STENT-RETRIEVER THROMBECTOMY AFTER INTRAVENOUS T-PA VS. T-PA ALONE IN STROKE. Saver JL, et al. N Engl J Med (SWIFT PRIME) THROMBECTOMY WITHIN 8 HOURS AFTER SYMPTOM ONSET IN ISCHEMIC STROKE. Jovin TG et al. N Engl J Med (REVASCAT) MECHANICAL THROMBECTOMY AFTER INTRAVENOUS ALTEPLASE VERSUS ALTEPLASE ALONE AFTER STROKE (THRACE): A RANDOMIZED CONTROLLED TRIAL. Bracard, S, et al, Lancet Neurol. 2016;15(11): (THRACE) ASPIRATION THROMBECTOMY AFTER INTRAVENOUS ALTEPLASE VERSUS INTRAVENOUS ALTEPLASE ALONE Mocco, J, et al. Stroke. 2016;47(9): (THERAPY) THROMBECTOMY 6 TO 24 HOURS AFTER STROKE WITH A MISMATCH BETWEEN DEFICIT AND INFARCT, Nogueira, AP, et al. N Engl J Med DOI: /NEJMoa JOURNAL JAM 10 PART 2: ENDOVASCULAR THERAPY FOR STROKE, Helman, A, et al. SGEM#137: A FOGGY DAY ENDOVASCULAR TREATMENT FOR ACUTE ISCHEMIC STROKE Spiegel, R. The Skeptics Guide to EM. THE ADVENTURE OF THE CARDBOARD BOX REVISITED, Spiegel, R. THE CASE OF THE ERRATIC PENDULUM, Spiegel, R. 19

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21 DING DONG, THE DROUGHT IS DEAD!!! 21

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