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

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.

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? Hillebrenner CRT 2012

Standardized Definitions VARC VARC II Standardized Definitions for End Point Events in Cardiovascular Devices Hicks et al. Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

Other Important Neurological Events Transient ischemic attack (TIA) Asymptomatic cerebral infarction Encephalopathy Intracranial hemorrhage (e.g., subdural hematoma) Hillebrenner CRT 2012

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) Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

For copies of these slides email: Matthew.Hillebrenner@fda.hhs.gov Hillebrenner CRT 2012

Hillebrenner CRT 2012

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 Hillebrenner CRT 2012

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. Hillebrenner CRT 2012

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. Hillebrenner CRT 2012

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). Hillebrenner CRT 2012

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). Hillebrenner CRT 2012

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. Hillebrenner CRT 2012

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? Hillebrenner CRT 2012

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? Hillebrenner CRT 2012

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? Hillebrenner CRT 2012

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: 33:2243-2246. Hillebrenner CRT 2012