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Figures for Draft Response to IMS III, MR RESCUE, and SYNTHSESIS Trials.

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Presentation on theme: "Figures for Draft Response to IMS III, MR RESCUE, and SYNTHSESIS Trials."— Presentation transcript:

1 Figures for Draft Response to IMS III, MR RESCUE, and SYNTHSESIS Trials

2 Figure 1: Lay Press Judgment May Belie a Deeper Examination of the Data. Truman ultimately defeated Dewey for the Presidency

3 All Subjects n=656 Baseline CTA/MRA n=306 No Baseline CTA/MRA n=350 47% 292 Baseline CTAs and 14 baseline MRAs Figure 2: Number of IMS III Patients who had pre-procedural imaging. This group represents the key subset analysis because of confirmed Large Vessel Occlusion (LVO) Subject enrollment by CTA and treatment group

4 80 Subjects: No treatable occlusion by operator - 41: M3 and/or M4 at Angiography by Core Lab - 15 CTA - 1 No Occlusion - 14 Occlusion - 1 ICA Terminus - 8 M1 - 4 M2 - 1 M3 IMS III: No Treatable Occlusion by CTA Figure 3: Over 80 patients in IAT arm of IMS III had no treatable occlusion on angiography (Nearly 20%)

5 ReasonFrequency No treatable arterial occlusion (operator) 80* Inability to access3 Recanalization after baseline angiogram 2 Occlusion, but not responsible lesion 2 No reason2 Figure 4: Over 20% of IAT cohort had no endovascular therapy administered Endovascular therapy not administered n=89

6 NIHSS 8-19NIHSS ≥ 20All Endovascular IV tPA onlyEndovascular IV tPA onlyEndovascular IV tPA only MRS <=2 (%)146 (48.3)74 (49.3)31 (23.5)12 (16.7177 (40.8)86 (38.7) Risk Difference-0.01 (-0.11, 0.09)0.07 (-0.04, 0.18)0.02 (-0.06, 0.09) CMH p-value 0.70 Breslow Day p-value 0.27 90-Day Modified Rankin Scale by Baseline NIHSS Strata and Treatment in IMS III Figure 5: Higher NIHSS corresponded with much greater endovascular treatment likely due to the increased incidence of LVO in subjects with NIHSS > 20 and greater opportunity to realize benefit

7 7 A. Demchuk, IMS III: Comparison of Outcomes between IV and IV/IA Treatment in Baseline CTA Confirmed ICA, M1, M2 and Basilar Occlusions, slide 20, Presented at ISC 2013, Honolulu Hawaii Endovascular confers a statistically significant benefit across the spectrum of mRS With CTA-confirmed occlusion at baseline, representative of current practice, IMS III has a statistically significant positive outcome for endovascular Figure 6: Recent High Quality Trials Demonstrate: Endovascular is Efficacious (pre-specified analysis)

8 Figure 7: Recent High Quality Trials Demonstrate: Endovascular is Safe. In IMS III, despite reduced dose IV tPA and being subjected to angiography (with 20% of pts without occlusion), endovascular therapy had NO increase in death or symptomatic ICH 8

9 Figure 8: Recent High Quality Trials Demonstrate: Endovascular is Safe. 9 SYNTHESIS conclusion: Subjecting ALL potential IV tPA patients to IA therapy, including those with minimal deficit (NIHSS of 2 included) and without confirmation of occlusion, demonstrated EQUAL efficacy to IV tPA with NO significant safety concerns

10 Figure 9: Percentage of Patients who achieved a functional outcome in IMS III based on reperfusion result (p=0.001) In IMS III, independent functional outcome (mRS 0-2) was strongly associated with TICI 2b- 3 revascularization. Though TICI 2b-3 is the modern endovascular standard, a low percentage of patients in IMS III achieved this technical result due to older, inferior technologies. TICI 2a was considered a good outcome in IMS III but clearly does not translate into good clinical outcomes

11 NTICI 2-3 (%)TICI 2b-3 (%) Internal Carotid Artery65 38 M1 of Middle Cerebral Artery1358144 M2 if Middle Cerebral Artery617044 Multiple M2s227723 Basilar4NA Angiographic Reperfusion in IMS III Figure 10: Few patients in IMS III met the clinically significant reperfusion standard due to use of first generation technologies. These TICI 2b and 3 rates fall well short of modern SWIFT and TREVO series

12 Primary Target VesselFrequency Percent with TICI 2-3 at completion of procedure Percent with TICI 2b-3 at completion of procedure All32874%40% ICA extracranial occlusion683%33% ICA Intracranial6565%38% ICA-T(41)(63%)(36%) Other Intracranial ICA(24)(67%)(42%) M113581%44% Figure 11: Low TICI 2b-3 rates due to first generation endovascular technologies persisted in IMS III independent of LVO location. Half of reperfusion successes in IMS III were only TICI 2a results. IMS III TICI Reperfusion Primary Target Occlusion

13 Study Outcomes Embolectomy, penumbral (n=34) Standard Case, penumbral (n=34) Embolectomy, nonpenumbral (n=30) Standard Case nonpenumbral (n=20) p Score on 90 day modified Rankin Score Unadjusted0.23 Mean3.93.444.4 Median4344 95% CI3.3 to 4.42.8 to 4.03.4 to 4.63.6 to 5.2 Adjusted0.3 Mean3.33.444.2 Median4344 95% CI3.2 to 4.42.9 to 3.93.8 to 4.71.7 to 4.8 Good Outcome at 90 days # of patients (%)7 (21)9 (26)5 (17)2 (10)0.48 Adjusted analysis (%)14239100.39 Death; number (%)6 (18)7 (21)6 (20)6 (30)0.75 Hemorrhage; number (%) Symptomatic3 (9)3 (6)000.24 Asymptomatic19 (56)14 (41)23 (77)12 (60)0.04 Final infarct Volume No. of patient evacuated32 3019 Median (interquartile range) - mL 58.1 (34.5 to 138.2) 37.3 (24.9 to 78.3) 172.6 (84.6 to 273.8) 217.1 (144.3 to 282.8) <0.001 Absolute infarct growth No of patients evacuated 32 1019 Median - mL27.16.755.183.80.009 Figure 12: Due to poor technical performan ce of first generation devices, IAT patients in MR RESCUE did NOT achieve greater reperfusio n than Standard Medical Care Patients

14 Outcome and Measure Patients with Reperfusion or Recvascularization Pationes without reperfusion or Revascularization P value Reperfusion # of Patients43 Mean score on 90-day modified Rankin scale (95% CI) 3.2 (2.6 to 3.8)4.1 (3.7 to 4.5)0.04 Mean absolute infarct growth (interquartile range - mL) 9.0 (-13.7 to 50.3)72.5 (5.6 to 120.7)<0.001 Partial or complete revascularization # of Patients7922 Mean score on 90-day modified Rankin scale (95% CI) 3.4 (3.1 to 3.9)4.4 (4.0 to 4.8)0.04 Mean absolute infarct growth (interquartile range - mL) 17.7 (-8.8 to 89.2)60.3 (19.9 to 93.3)0.10 Figure 13: Those MR RESCUE patients that DID achieve reperfusion enjoyed better clinical outcomes

15 Figure 14: In IMS III, time from IV to IAT initiation was greater than 2 hours and greatly exceeds IMS I and II. Though likely secondary to decentralization of care secondary to development of PMSC’s, this diminishes the clinical benefit with endovascular therapy in the trial.

16 Figure 15: IMS III patients further suffered a significant lag between groin access and initiation of IAT at the lesion. Fourty- four minutes is far beyond reported standards with modern guide and distal access catheter technology.

17 bCTANo bCTA Age, median (min-max)70 (23-83)68 (23-89) Male (%)163 (53.3)177 (50.6) Baseline NIHSS median (min-max)17 (7-40)17 (9-40) ASPECTS 8-10 (%)177 (57.8)201 (57.4) Onset to iv tPA initiation, minutes; mean (SD)123 (33.4)123.1 (34) IV tPA to Groin Puncture, minutes: mean (SD)80.7 (26.3)*90.1 (35.5)* Groin puncture to IA Therapy, minutes: mean (SD)40.1 (22)**49.9 (24.2)** IMS III Baseline Characteristics Figure 16: Time from puncture to START of IAT was 50 minutes for non cta centers; Centers that did baseline cta's were 20 min faster to IA intervention in IMS III

18 FIGURE 17 RCT for AIS Revascularization: Control arms of PROACT II and NINDS give some indication of LVO natural history TrialNINDS ECASS III PROACT II Treatment Type IV t-PA vs. Placebo IA pUK + Hep vs. Hep Patients 333 (168 vs. 165) 821 (418 vs. 403) 180 (121 vs. 59) Time Window (hours) 0-33-4.50-6 Presentation NIHSS 14 vs. 15 10.7 vs. 11.6 17 vs. 17 RecanalizationNRNR 66 vs. 18 Outcome (%) at 3 months mRS < 1 39 vs. 26 mRS < 1 52.4 vs. 45.2 mRS < 2 40 vs. 25 SICH Rates (%) 6.4 vs. 0.6 2.4 vs. 0.2 10 vs. 2

19 FIGURE 18 Prospective Intervention Trials: Inferior Outcomes with First Generation Devices Trial IMS- II MERCI Multi- MERCI Penumbra Treatment Type IV t-PA + IA t-PA + EKOS + low dose hep IA Merci + IAT IA Merci + IAT + IVT IA Penumbra + IAT Patients 81 (IAT-55) 141164125 Time Window (hours) 0-30-80-80-8 Presentation NIHSS 19201917 Recanalization (%) 58 60.3 (48 device alone) 68 (55 Merci alone) 81.6 (Device alone) Outcome (%) at 3 months mRS < 2 46363625 SICH Rates (%)

20 FIGURE 19: Outcomes at 3 months better with Reperfusion Study mRS < 2 (%) Mortality (%) MERCI 46 vs. 10.4 (P<0.0001) 31.8 vs. 54.2 (P=0.001) Muti-MERCI 49.1 vs. 9.6 (P<0.001) 24.8 vs. 51.9 (P<0.001) IMS I & II Pooled Analysis 45.6 vs. 6.9 (P=0.004) 10.9 vs. 34.5 (P=0.01)

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