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

Transcription

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 Subject enrollment by CTA and treatment group All Subjects n=656 Baseline CTA/MRA n=306 No Baseline CTA/MRA n= % 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)

4 IMS III: No Treatable Occlusion by CTA 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 Figure 3: Over 80 patients in IAT arm of IMS III had no treatable occlusion on angiography (Nearly 20%)

5 Endovascular therapy not administered n=89 Reason Frequenc y No treatable arterial occlusion (operator) 80* Inability to access 3 Recanalization after baseline angiogram Occlusion, but not responsible lesion 2 2 No reason 2 Figure 4: Over 20% of IAT cohort had no endovascular therapy administered

6 90-Day Modified Rankin Scale by Baseline NIHSS Strata and Treatment in IMS III NIHSS 8-19 NIHSS 20 All Endovascul ar MRS <=2 (%) 146 (48.3) IV tpa only Endovascul ar 74 (49.3) 31 (23.5) IV tpa only Endovascul ar 12 ( (40.8) IV tpa only 86 (38.7) Risk Difference (-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 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 Figure 6: Recent High Quality Trials Demonstrate: Endovascular is Efficacious (pre-specified analysis) Endovascular confers a statistically significant benefit across the spectrum of mrs 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 With CTA-confirmed occlusion at baseline, representative of current practice, IMS III has a statistically significant positive outcome for endovascular 7

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 IMS III Primary Safety End Points Endovascula r Therapy (n=434) Intravenous tpa Alone (n=222) p value Death at 90 days - no. (%) 83 (19.1%) 48 (21.6%) 0.52 Symptomatic ICH at 30 hours no. (%) 27 (6.2%) 13 (5.9%)

9 Figure 8: Recent High Quality Trials Demonstrate: Endovascular is Safe. SYNTHESIS Primary Safety End Points Endovascul ar Therapy (n=181) Intraveno us tpa Alone (n=181) p value Death at 7 days - no. (%) 14 (8%) 11 (6%) 0.53 Symptomatic ICH at 7 days no. (%) 10 (6%) 10 (6%) 0.99 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 9

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 Angiographic Reperfusion in IMS III N TICI 2-3 (%) TICI 2b-3 (%) Internal Carotid Artery M1 of Middle Cerebral Artery M2 if Middle Cerebral Artery Multiple M2s Basilar 4 NA NA 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 IMS III TICI Reperfusion Primary Target Occlusion Primary Target Vessel Frequency Percent with TICI 2-3 at completion of procedure Percent with TICI 2b-3 at completion of procedure All % 40% ICA extracranial occlusion 6 83% 33% ICA Intracranial 65 65% 38% ICA-T (41) (63%) (36%) Other Intracranial ICA (24) (67%) (42%) Figure M111: Low TICI 2b rates due 81% to first generation 44% endovascular technologies persisted in IMS III independent of LVO location. Half of reperfusion successes in IMS III were only TICI 2a results.

13 Study Outcomes Embolecto my, penumbral (n=34) Score on 90 day modified Rankin Score Standard Case, penumbral (n=34) Embolecto my, nonpenumb ral (n=30) Standard Case nonpenumb ral (n=20) Unadjusted 0.23 Mean Median % CI 3.3 to to to to 5.2 Adjusted 0.3 Mean Median % CI 3.2 to to to to 4.8 Good Outcome at 90 days # of patients (%) 7 (21) 9 (26) 5 (17) 2 (10) 0.48 Adjusted analysis (%) Death; number (%) 6 (18) 7 (21) 6 (20) 6 (30) 0.75 Hemorrhage; number (%) Symptomatic 3 (9) 3 (6) Asymptomatic 19 (56) 14 (41) 23 (77) 12 (60) 0.04 Final infarct Volume No. of patient p 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 Figure 13: Those MR RESCUE patients that DID achieve reperfusion enjoyed better clinical outcomes Outcome and Measure Patients with Reperfusion or Recvascularizatio n Pationes without reperfusion or Revascularization P value Reperfusion # of Patients Mean score on 90-day modified Rankin scale (95% CI) Mean absolute infarct growth (interquartile range - ml) 3.2 (2.6 to 3.8) 4.1 (3.7 to 4.5) (-13.7 to 50.3) 72.5 (5.6 to 120.7) <0.001 Partial or complete revascularization # of Patients Mean score on 90-day modified Rankin scale (95% CI) Mean absolute infarct growth (interquartile range - ml) 3.4 (3.1 to 3.9) 4.4 (4.0 to 4.8) (-8.8 to 89.2) 60.3 (19.9 to 93.3) 0.10

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. Fourtyfour minutes is far beyond reported standards with modern guide and distal access catheter technology.

17 IMS III Baseline Characteristics bcta No bcta Age, median (min-max) 70 (23-83) 68 (23-89) Male (%) 163 (53.3) 177 (50.6) Baseline NIHSS median (minmax) 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) (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)** 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 Trial NINDS ECASS III PROACT II Treatment Type IV t-pa vs. Placebo 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) Presentation NIHSS 14 vs vs vs. 17 Recanalization NR NR 66 vs. 18 Outcome (%) at 3 months mrs < 1 39 vs. 26 mrs < vs mrs < 2 40 vs. 25 SICH Rates (%) 6.4 vs vs 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) Time Window (hours) Presentation NIHSS Recanalization (%) Outcome (%) at 3 months mrs < (48 device alone) 68 (55 Merci alone) 81.6 (Device alone) SICH Rates (%)

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