ENRICH ICH Trial Results - Implement MIPS for Stroke

Agenda
• The MIPS approach used in ENRICH
• ENRICH unique features and results as published in the New England Journal of Medicine
• Code ICH: A Call to Action (STROKE)
• AHA/ASA Guidelines related to potential MIS candidates
• Next steps

1. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
The ENRICH Trial
Evidence for Early ICH Intervention

2. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Agenda
•The MIPS approach used in ENRICH
•ENRICH unique features and results as published in NEJM
•Code ICH: A Call to Action (STROKE)
•AHA/ASA Guidelines related to potential MIS candidates
•Next steps

3. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Minimally Invasive Parafascicular Surgery (MIPS)
Standardized Procedure Required for ENRICH
Overview

4. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS Standardized Approach
Requiredfor ENRICH Surgical Patients
•At its core, MIPS is built on preservationof white matter tracts
•Access with BrainPathis based on minimizing disruption of healthy tissue via a trans-sulcalroute
•Trajectories are designed on the concept of being parafascicular
•Running parallel to WMTs may lessen shear forces on surrounding healthy tissue
•Allows maximal clot evacuation with the Myriad multifunctional device for suction and cutting, plus
enhanced visualization with Myriad NOVUS
Prior to the trial, all neurosurgeons were trained on the principles of minimally invasive,
trans-sulcal, parafascicular surgery which included hands-on technical instruction

5. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS Standard Tools
BrainPath
Minimally-Invasive Navigable Port-based
Access to the ICH
–Minimally disruptive access –
–Avoid cannulation injuries –
Myriad
Automated, Multi-Functional Instrument
Designed Specifically for MIS Corridors
–Effectively removes liquefied or crosslinked clots
through cutting, suction, and blunt dissection –

6. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS: The Way You Access an ICH Matters
*Enlarged for viewing

7. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Overview
In this trial of minimally invasive cerebral hematoma removal within 24 hours after onset of
hemorrhage, functional outcomes were better with surgery than with medical treatment,
particularly among patients with lobar hemorrhages.
N EnglJ Med Volume 390(14):1277-1289. April 11, 2024

8. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: Study Leadership
Scientific Leadership –Multidisciplinary Team led by Emory University
•Daniel Barrow, MD (Neurosurgery)
•Gustavo Pradilla, MD (Neurosurgery)
•Jonathan Ratcliff, MD (Neurocritical Care)
•Jason Allen, MD (Neuroradiology)
•David Wright, MD (Emergency Medicine)
•Michael Frankel, MD (Neurology)
•Alex Hall, DSc, MS, RN (Clinical Research Scientist)
Healthcare Economists –University of Pittsburgh
•Janel Hanmer, MD (Med. Dir. Patient Reported Outcomes Center)
•Kenneth Smith, MD (Prof. Med., Clinical & Translational Science)
Data Safety Monitoring Board & Medical Monitor
•Mark Hadley, MD (DSMB Chair) –University of Alabama
•Greg Campbell, PhD (Biostatistician) –GCStatConsulting, LLC
•Opeolu Adeoye, MD (Medical Monitor) –Barnes Jewish, Washington University
Sponsor
Statistics
CRO

9. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: 37 Contributing Clinical Sites

10. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: Trial Design
1.Primary endpoint (UW-mRS) at 180 days
•Patient-centered scale better reflects societal and patient values of a particular outcome
•Increased statistical power relative to binary responder endpoint (e.g., mRS 0-3 vs 4-6)
2.Bayesian primary analysis tests for differences in mean UW-mRS
•Posterior probability of superiority
•Mean UW-mRS improved in MIPS vs MM patients
•Statistical significance threshold ≥ 0.975 in favor of treatment
3.Adaptive sample size
•150 to 300 patients –find the sample size that’s “just right” (Goldilocks)
4.Population enrichment based on hematoma location
•Lobar and ABG
Ratcliff , et al. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH): Study protocol for a multi-centered two-arm randomized adaptive trial.Front Neurol. 2023;14:1126958. Published 2023
Mar 16. doi:10.3389/fneur.2023.1126958

11. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: Key Inclusion/Exclusion Criteria
Inclusion Criteria
•Aged 18 to 80 years
•CT: acute, spontaneous, primary ICH
•ICH volume 30-80 mL
•Intervention can be initiated within 24
hrsof symptoms (≤8 hours preferred)
•GCS 5-14
•Historical mRS 0 or 1
Exclusion Criteria
•Recurrent ICH or other vascular
abnormality
•NIHSS ≤5
•IVH >50% of the lateral ventricles
•Uncorrected coagulopathy or known
clotting disorder
•Anticoagulants not rapidly reversible
•No reasonable expectation of recovery,
DNR/comfort measures, or life
expectancy <6 months
Ratcliff , et al. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH): Study protocol for a multi-centered two-arm randomized adaptive trial.Front Neurol. 2023;14:1126958. Published 2023
Mar 16. doi:10.3389/fneur.2023.1126958

12. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: Interim Analyses & Enrichment
25 25 20 30 25 25
0 50 100 150 200 250 300
C
a
t
e
g
o
r
y
1
Number of Patients Enrolled
Enrich for lobar
Stop ABGenrollment
150 175 200220 250
*Interim analysis performed early due to COVID-19
275 300
Final analysis

13. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH: CONSORT Diagram
Assessed for Eligibility (n=11,603*)
Randomized (n=300)
MIPS (n=150)
102 Had lobar ICH
48 Had ABG ICH
Medical Management (n=150)
106 Had lobar ICH
44 Had ABG ICH
Excluded(n=11,303)
10,611 Did not meet entry criteria
692 ABG hemorrhage after
enrollment adaptation
Allocation
Follow-up
Analysis
1 Lost to follow-up
2 Withdrew consent
7 Lost to follow-up
4 Withdrew consent
150 analyzed in ITT analysis
147 observed mRSat 6 months
150 analyzed in ITT analysis
139 observed mRSat 6 months
*Screening abnormally high due to site variation

14. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Primary Objectives
Efficacy
•Demonstrate that surgery improves functional outcome by improvement in
the utility-weighted modified Rankin Scale (UW-mRS) score at 180 days
Safety
•Surgery does not result in increased mortalitywhen compared to medically
treated subjects at 30 days
•Surgery does not result in an increase in hemorrhage volumebetween index
CT and 24h follow-up CT as compared to medical management
Economic
•Quantify the cost per quality-adjusted life-years (QALY) gained through
surgery at 90, 120, and 180days

15. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Utility-Weighted Modified Rankin Score
(UW-mRS) at 180 Days
mRS Utility Weight
0(no symptoms) 1.0
1(no significant disability)0.91
2(slight disability) 0.76
3(moderate disability) 0.65
4(moderate-severe disability)0.33
5(severe disability) 0
6(dead) 0
•Enrolled 300 patients within 24 hrsfrom LKN
•Discharge and Day 180 assessments performed in
person
•Otherwise by structured telephone interview
during COVID and post-COVID (as required)
•Primary ITT analysis evaluated if mean UW-mRS
score at 180 days in MIPS group was superior to
MM group
*UW = expresses the desirability of a specific
outcome to a patient/society

16. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Secondary Endpoints
•ICU length of stay
•Hospital length of stay
•mRS at discharge or 7 days, 30 days, 90 days, and 180 days
•Proportion of patients with mRS of 0-3 at 180 days
•Impact of % ICH reduction with MIPS on mRS at 180 days
•Impact of EOT volume with MIPS on mRS at 180 days

17. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Economic Endpoints
Primary cost-effectiveness endpoint: cost per quality-adjusted life year (QALY) gained
through MIPS compared to best MM
•Results of the CEA will have implications for both the Hospital and Healthcare regardless of
favorable/unfavorable results
Key Secondary cost-effectiveness endpoints:
•Cost per 30-day readmission and per infection avoided through MIPS
•Cost of healthcare utilization pathways
•Cost per death avoided
•Cost per gain in UW-mRS and ordinal mRS
•And the estimated global budget impact per patient
Comprehensive Cost-Effectiveness Analysis (CEA) evaluates MIPS intervention compared to best
MM from both the hospital and healthcare perspectives; reports resulting impact on QALY

18. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
ENRICH Results

19. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS
(N=150)
Medical Management
(N=150)
Median age (IQR) –years 64 (56 –72) 62 (51 –73)
Female sex 48% 52%
Race
White 71% 69%
Black / African American 24% 27%
Other 6% 5%
Hispanic/Latino ethnicity 6% 7%
Medical History
Cardiovascular disease 82% 78%
Central nervous system disease 30% 28%
Endocrine or renal disorder 28% 26%
Current/former cigarette smoking 45% 40%
Daily alcohol use 26% 32%
Demographic and Medical Characteristics

20. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Clinical Presentation
MIPS
(N=150)
Medical Management
(N=150)
Median score on NIHSS (IQR) 26 (11–22) 18 (13–22)
Score on GCS at randomization
4–8 17% 19%
9–14 83% 81%
Median hematoma volume (IQR) –mL 54 (37–72) 55 (40–73)
Intraventricular hemorrhage present 43% 39%
ICH Location
Anterior basal ganglia 32% 29%
Lobar 68% 71%
Left hemisphere 49% 53%
Median ICH score (IQR) 2 (1–2) 2 (1–2)
Median FUNC score (IQR) 8 (6–8) 8 (6–8)
Median APACHE II score (IQR) 12 (10–14) 12 (11–14)
Score on mRSof 1 before ICH occurred 19% 11%

21. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Timing of ICH and Intervention
MIPS
(N=150)
Medical Management
(N=150)
Time from LKN to randomization
≤8 hours 28% 25%
≤12 hours 49% 46%
Median (IQR) 12.8 (7.8–18.7) 12.9 (7.5–17.7)
Median time from LKN to surgery (IQR) 16.75 (10.70–21.25) NA
Median time from randomization to surgery (IQR)1.48 (0.97–2.43) NA
LKN: last known normal

22. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS Superior to Medical Management
2
4
9
21
15
22
31
27
31
30
16
13
35
30
0 102030405060708090100
Medical
Management
(N=139)
MIPS
(N=147)
0123456
mRSat 180 Days
MIPS
(N=147)
Medical
Management
(N=139)
Percent of Patients
Mean UW-mRS at 180 Days
0.458
0.374
Difference 0.084
(95% CrI: 0.005 –0.163)
98.1% posterior
probability of superiority
Significance Threshold:
Probability >97.5%

23. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Posterior Distribution of Treatment Effect
Location Estimate (95% CrI)
Probability of
Superiority
ABG -0.013 (-0.147, 0.116)43.0%
Lobar 0.127 (0.035, 0.219)99.7%
Combined0.084 (0.005, 0.163)98.1%

24. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Secondary Endpoints
•All results in NEJM reported using Bayesian analyses at the Journal’s request
•Pre-specified p-values from ENRICH Statistical Analysis Plan (SAP) also provided in
this presentation

25. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Significantly Shorter Lengths of ICU & Hospital Stay
14.9
18.1
0
5
10
15
20
25
MIPS Medical Management
Difference: -3.2 days
95% CrI: -5.9 to -0.4
p = 0.021
6.9
9.7
0
5
10
15
20
25
MIPS Medical Management
Difference: -2.8 days
95% CrI: -4.5 to -1.1
p < 0.001
Mean In-Hospital Length of StayMean ICU Length of Stay

26. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS Benefits on mRS Observed Early &
Remained Significant Through Follow-up
Time Point
Ordinal Logistic Regression Analysis
(odds of higher mRSwith MIPS vs MM)
Odds Ratio (95% CrI)P-value
Discharge 0.376 (0.230 to 0.577)<0.001
30 days 0.504 (0.326 to 0.741)<0.001
90 days 0.665 (0.437 to 0.970)0.029
180 days 0.658 (0.433 to 0.957)0.032
0.1 1 10
Favors Medical ManagementFavors MIPS

27. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Better ICH Evacuation Associated with Better
Clinical Outcomes with MIPS
Endpoint Mean in MIPS Group Odds Ratio (95% CrI) P-value
Hematoma reduction after MIPS –%-73.2% ±37.8 reduction0.871 (0.792 to 0.951)*0.005
Hematoma volume after MIPS –mL 14.9 ±21.7 mL 0.725 (0.604 to 0.845)†<0.001
* Every additional 10% reduction in hematoma volume with MIPS associated with 12.9%
decreasein the odds of a worse mRS score
† Every additional 10 mL reduction in hematoma volume with MIPS associated with 27.5%
decreasein the odds of a worse mRS score

28. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Patients with mRS 0-3 at 180 Days
50.3%
41.0%
0
20
40
60
80
100
MIPS Medical Management
Difference: 9.2 percentage points
95% CrI: -2.0 to 20.3
p = 0.11
Patients with
mRSof 0-3 at
180 Days
(%)

29. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Significantly Fewer Ventilator Days with MIPS
5.3
8.8
0
2
4
6
8
10
12
14
MIPS Medical Management
Difference: -3.5 days
95% CrI: -5.7 to -1.5
p < 0.001
58.7%
52.0%
0
20
40
60
80
100
MIPS Medical Management
Difference: 6.7 percentage points
95% CrI: -4.6 to 17.8
p = 0.30
Mean No. Days with Mechanical VentilationPatients with Mechanical Ventilation in ICU

30. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Decompressive Hemicraniectomy Rate
Lower with MIPS
3.3%
20.0%
0
5
10
15
20
25
30
MIPS Medical Management
Difference: -16.6 points
95% CrI: -23.9 to -9.9
p < 0.001
Patients with Decompressive Hemicraniectomy

31. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Post-MIPS Hematoma Volumes
Parameter
MIPS
(N=150)
Mean hematoma volume after MIPS (±SD) 14.9 ±21.7 mL
Median hematoma volume after MIPS (IQR)7.17 (1.95–17.34)
Volume after MIPS ≤15 mL 72.7%
Median hematoma reduction (IQR) 87.7% (65.15–96.61)

32. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Lower In-Hospital and 30-day Mortality
with MIPS
9.3%
18.0%
0
5
10
15
20
25
30
MIPS Medical Management
4.7%
12.7%
0
5
10
15
20
25
30
MIPS Medical Management
Difference: -8.0 percentage points
95% CrI: -14.5 to -1.8
Posterior probability of superiority: 99.4%
Death by 30 daysDeath in Hospital after Randomization
Difference: -8.7 percentage points
95% CrI: -16.4 to -1.0
Posterior probability of superiority: 98.7%

33. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Study Limitations
•Generalizability
•Excluded thalamic hemorrhages, extensive IVH
•Excluded ICH < 30 or > 80 mL
•Hematoma volume calculation
•ABC/2 is crude
•Centrally adjudicated by neuroradiologists
•UW-mRS
•Used in ischemic trials, ENR is first RCT for ICH
•Bayesian analyses
•Potential for over-influence by prespecified prior distributions
•Sensitivity analyses completed

34. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Conclusions
•ENRICH is the first MC-RCT to demonstrate functional benefit of surgical ICHevacuationin
patientswith supratentorial ICH presenting within 24 hours of LKN
•MIPS is safe, resulted in substantial clot evacuation, and improved the UW-mRSat 6
months relative to standard medical management
•The overall benefit of MIPS appears to be from the strong positive effect observed for
participants with lobar ICH
•Basal Ganglia –Neutral
•Lobar –Positive
•Combined –Positive

35. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Implementing the Evidence
Based Approach
•Patient and Pathway
•Physician Education/Training
•Technology Needs

36. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Code ICH: A Call to Action
•Code ICH: A Call to Action –AHA/ASA Consensus Group
statement
•Calls for evidence-based, rapid, standardized ICH
protocol
•Hematoma expansion (HE) is the primary target in the
emergency setting
•BP control, hemostatic therapy, AC reversal
•MIS evacuation is a promising approach to ICH treatment
•Screening for surgical intervention should be performed in
the emergency setting
•There should be pathways for rapid surgical evaluation
•Transfer to neurosurgery-capable centers should be
considered
•Early evacuation of larger lobar ICH is one of the most
attractive targets for improving outcomes
Li Q, YakhkindA, Alexandrov AW, et al. Code ICH: A Call to Action. Stroke. 2024;55(2):494-505.
doi:10.1161/STROKEAHA.123.043033

37. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
2022 AHA/ASA ICH MIS Guidelines
Minimally Invasive Surgery:
•Can be useful to reduce mortality compared with
medical management alone
•May be reasonable to select over conventional
craniotomy to improve functional outcomes
Patient Inclusion Criteria:
•Supratentorial
•ICH volume > 20-30 mL
•GCS score 5-12
Patients to
evaluate for MIPS
Greenberg SM, ZiaiWC, CordonnierC, et al. Stroke. 2022;53(7).
doi:10.1161/str.0000000000000407

38. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Pathway Development
•Points of discussion
•Modification of existing protocols (i.e. ischemic stroke, etc)
•Patient pathways from ED admission vs transfer from outside hospitals
•Efficient care coordination (ex: Viz.ai, RapidAI, etc)
•Identification of primary service and appropriate consult services
•Trained MIPS neurosurgeons call schedules
•OR staff and scheduling
•Emergent/trauma designation of qualifying ICH patients
•Staff education of patient acuity (urgent vs emergent)

39. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Non-contrast CT shows
intracerebral hemorrhage
ED Referral to Neurology,
Neurosurgery, ICU
Admit to ICU,
Repeat HCT with CT
Angiography at 6 hours
CTA Positive: Per Vascular
Neurosurgeon on Call
CTA Negative
Medical Stroke
Management per
Neurology/ICU
Contraindication to
surgical evacuation?
Yes: (surgery contraindicated)
•Age >80
•Uncorrectable Coagulopathy
•Minimally symptomatic or deeply
comatose (GCS 15 w/o weakness
or GCS <5)
•Medically unable to tolerate
surgery
•Hematoma <20 or >80mL
•IVH >50% of lateral ventricle(s)
•>24 hours since symptom onset
•Brainstem hemorrhage
NoCerebellar?
Yes: Per
Neurosurgeonon
call
No
Concern for
secondary
hemorrhage?
Yes: MRI brain w/
and w/o
Underlying
Lesion?
Yes: Per
Neurosurgeonon
call
No
Contact Parafascicular
Neurosurgeonfor evaluation
(Dr. Pradilla) and pre-op for
possible intervention
Stroke Rehab
*Example provided by Emory University
AI ICH identification and
notification of
appropriate personnel
Stroke Alert ICH Protocol –Example*

40. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
MIPS ICH Patient Criteria –Example*
Inclusion Criteria
•Acute, spontaneous, primary ICH
•Age < 80 years old
•Lobar ICH
•30-80 mL
•Anterior BG ICH
•20-50 mL
•Preservation of tracts
•Spot sign
•Target spot
•IVH
•Reversible anticoagulation
Exclusion Criteria
•Vascular malformation
•Thalamic ICH
•Massive IVH
•ESRD
•Coagulopathy or anticoagulants not
rapidly treatable
•Poor premorbid mRS
•Age > 80 years
*Post-ENRICH Patient Selection Criteria implemented
by highest enrolling investigator

41. © 2024. Early Minimally Invasive Removal of Intracerebral Hemorrhage (ENRICH).
Thank You