1. Neurological Events After TAVR FDA Perspective
Matthew G. Hillebrenner, M.S.E.
Acting Deputy Director
Division of Cardiovascular Devices
Office of Device Evaluation
FDA Town Hall I
CRT 2012

2. I have no real or apparent conflicts of interest to report.
Matthew G. Hillebrenner, MSE
I have no real or apparent conflicts of interest to report.

3. Knowing is Half the Battle
If we’re not looking, we probably won’t find it
Early OUS registry experience
PARTNER trial experience
Elevated stroke rate not anticipated based on existing data
No assessment of stroke disability
Now that we know, what are we going to do about it?
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4. Standardized Definitions
VARC
VARC II
Standardized Definitions for End Point Events in Cardiovascular Devices
Hicks et al.
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5. Stroke Definition and Classification
An acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction.
Classification
Ischemic stroke
Hemorrhagic stroke
Undetermined stroke
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6. Stroke Disability – Categorization
VARC Recommendations
Major: Modified Rankin score > 2 at 30 and 90 days
Minor: Modified Rankin score < 2 at 30 and 90 days
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7. Stroke Disability – Categorization
FDA Recommendations**
Disabling: Modified Rankin score > 2 at 90 days
Non-Disabling: Modified Rankin score < 2 at 90 days
** Based on input from FDA Stroke Team in effort to be consistent with neurological community
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8. Other Important Neurological Events
Transient ischemic attack (TIA)
Asymptomatic cerebral infarction
Encephalopathy
Intracranial hemorrhage (e.g., subdural hematoma)
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9. Current and Future FDA-Regulated Studies
Detailed neurological assessment on a subset (50%) of patients
Standard neurological assessment on patients not enrolled in sub-study
Standardized interview for the modified Rankin assessment
FDA has recommendations regarding questions
Stroke neurologists should be involved in trial planning (exec committee) and execution (CEC)
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10. Endpoint Considerations for TAVR Studies
Primary endpoint could be a composite of death and disabling stroke
Safety composites (e.g., MACCE) should include all stroke and TIA
A secondary safety composite should include all stroke, all TIA, and periprocedural encephalopathy
Patients and FDA interested in both physical and mental functioning, requiring careful assessment of both
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11. Other Considerations for TAVR Studies
Continue to work together to understand neurological event etiology
Use of adjunctive therapy (e.g., embolic protection devices) to prevent neurological complications
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12. Summary Neurological injury is a troubling complication of TAVR
All stakeholders must work together to better understand and evaluate these complications
Intensive neurological evaluation of patients required in TAVR studies
Contact FDA early to discuss recommendations for neurological assessment, which continue to evolve
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13. For copies of these slides email:
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14. Hillebrenner CRT 2012

15. Stroke Classification
Ischemic stroke: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke (ischemic stroke with hemorrhagic transformation)
Hemorrhagic stroke: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage.
Undetermined stroke: a stroke with insufficient information to allow categorization
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16. Other Important Neurological Events
Transient Ischemic Attack (TIA): A transient episode of focal neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.
Cerebral Infarction: Evidence of brain cell death from imaging studies or pathological examination. If there are clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic cerebral infarction.
Encephalopathy: Altered mental state (e.g., seizures, delirium, confusion, hallucinations, dementia, coma, psychiatric episode, etc.)
Intracranial Hemorrhage: Collection of blood between the brain and skull. Subcategorized as epidural, subdural, and subarachnoid bleeds.
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17. Detailed Neurological Assessment on a Subset of Patients
50% seems reasonable based on existing data
Consecutive patients at sites representing both high enrolling and low enrolling centers
Assessments at baseline, prior to discharge, 1 year, and after any neuro event (stroke, TIA, encephalopathy)
The neurological physical examination should be performed by a neurologist (neurology fellow is acceptable). Personnel performing other tests should be certified (external certification for NIHSS, either internal or external certification for MRS). The assessors should be independent from the study.
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18. Detailed Neurological Assessment on a Subset of Patients (cont)
Protocolized formal neurological examination which should include physical functioning as well as a basic neurocognitive evaluation to cover the major domains. This neurological examination should be performed by a stroke neurologist or a stroke neurology fellow. The Sponsor’s neurological consultants should propose the examination to be performed, each element of which should be captured on a case report form (CRF).
NIHSS performed by a non-neurologist may be used to supplement the neurologist-administered examination at the discretion of the Sponsor.
MRS or other stroke disability scale should be administered 90 days after a neurological event by certified personnel independent from the study. A uniform grading system using a structured interview, with the answers captured on a CRF, should be used. The choice of interview questions and scoring algorithm should be documented by the Sponsor. Recommend speaking with FDA regarding their recommendations (see later slide).
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19. Standard Neurological Assessment on Patients Not Enrolled in Sub-Study
All patients – NIHSS (performed by certified personnel) at baseline, prior to discharge, and at 1 year.
For patients diagnosed with a neurological event (stroke, TIA, encephalopathy):
consult by a neurologist;
NIHSS; and
Modified Rankin Score at 90 days post-event (administered by certified personnel and using a standardized interview).
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20. Standardized Interview for the Modified Rankin Assessment
The mRS is to be determined after the NIHSS and Barthel Index have been determined and graded and by the same rater.
The determination of the scale should be made from 5 to 0, i.e., the order presented.
The purpose of the mRS is to record whether the patient is dead, severely, moderately, or slightly disabled and if not dead or disabled, whether the patient is performing all usual activities without symptoms or not. Because subjects and family members may understate the severity of disability, it is important for the rating clinician to understand that the mRS is a clinical scale and not a patient-reported outcome. The rater may ask questions but must assess the disability whether or not in agreement with the subject or family.
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21. Standardized Interview Questions
5 – Severe disability: someone needs to be available at all times; care may be provided by either a trained or untrained caregiver
Does the person require constant care?
4 – Moderately severe disability: need for assistance with some basic activities of daily living (ADL), but not requiring constant care
Is assistance essential for eating, using the toilet, daily hygiene, or walking?
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22. Standardized Interview Questions continued
3 – Moderate disability: need for assistance with some instrumental ADL but not basic ADL
Is assistance essential for preparing a simple meal, doing household chores, looking after money, shopping, or travelling locally?
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23. Standardized Interview Questions continued
2 – Slight disability: limitations in participation in usual social roles, but independent for ADL
Has there been a change in the person’s ability to work or look after others if these were roles before stroke?
Has there been a change in the person’s ability to participate in previous social and leisure activities?
Has the person had problems with relationships or become isolated?
Do any of the following interfere with the subject’s ability to perform all usual activities: difficulty reading or writing, difficulty speaking or finding the right word, problems with balance or coordination, visual problems, numbness (face, arms, legs, hands, feet), loss of movement (face, arms, legs, hands, feet), difficulty with swallowing, or other symptom resulting from stroke?
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24. Standardized Interview Questions continued
1 – No significant disability: symptoms present but not other limitations
Does the subject have any symptoms that do not interfere with the performance of all usual activities?
0 – No symptoms at all: no limitations and no symptoms
NOTE: The above questions are a modification of the questions from Wilson et al., Stroke. 2002: 33:
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