This May Be the Author's Version of a Work That Was Submitted/Accepted

This may be the author’s version of a work that was submitted/accepted for publication in the following source:

Fanning, Johnathon, Wesley, Allan, Platts, David, Walters, Darren, Ee- les, Eamonn, Seco, Michael, Tronstad, Oystein, Strugnell, Wendy, Barnett, Adrian, Clarke, Andrew, Bellapart, Judith, Vallely, Michael, Tesar, Peter, & Fraser, John (2014) The silent and apparent neurological injury in transcatheter aortic valve implantation study (SANITY): concept, design and rationale. BMC Cardiovascular Disorders, 14, Article number: 451-10.

This ﬁle was downloaded from: https://eprints.qut.edu.au/79721/

c Consult author(s) regarding copyright matters

This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other speciﬁed license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recog- nise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to [email protected]

License: Creative Commons: Attribution 4.0

Notice: Please note that this document may not be the Version of Record (i.e. published version) of the work. Author manuscript versions (as Sub- mitted for peer review or as Accepted for publication after peer review) can be identiﬁed by an absence of publisher branding and/or typeset appear- ance. If there is any doubt, please refer to the published source. https://doi.org/10.1186/1471-2261-14-45 Trial Designs

The Silent and Apparent Neurological Injury in Transcatheter Aortic Valve

Implantation (SANITY) Study : Concept, Design and rationale

Authors:

Dr. Jonathon P. Fanning BSc, MBBS*†δ

Dr. Allan J. Wesley MBChB, FRANZCR†

Mr. Michael Seco

Dr. Eamonn Eeles MBBS, MRCP, MSc†δ

Mr. Oystein Tronstad*†

Dr. David G. Platts B Med Sci, MBBS, MD, FRACP, FCCANZ, FESC, FASE*†δ

Associate Professor Darren L. Walters MBBS, M Phil, Grad. Cert Mang. (Health),

FRACP, FCSANZ, FSCAI†δ

Mrs. Wendy Strugnell BAppSc (MIT)†

Associate Professor Adrian G Barnett PhDϖ

Dr. Andrew Clarke MBBS, FRACS†

Dr. Judith Bellapart MD, ESICM, FCICM*δ

Associate Professor Michael Vallely

Professor John F. Fraser MB ChB, PhD, DA, MRCP (UK), FFARCSI, FRCA,

FCICM *†δ

* Critical Care Research Group (CCRG), The Prince Charles Hospital, Brisbane,

Queensland, AUSTRALIA

† The Prince Charles Hospital, Brisbane, Queensland, AUSTRALIA

δ School of Medicine, The University of Queensland, Brisbane, Queensland,

AUSTRALIA

ϖ Faculty of Health, School of Public Health and Social Work, Queensland

University of Technology, Brisbane, Queensland, AUSTRALIA

 The Royal Prince Alfred, Camperdown, NSW, AUSTRALIA

Address of Correspondence:

Dr. Jonathon P. Fanning

Critical Care Research Group (CCRG), University of Queensland

Level 2 Emergency Building, The Prince Charles Hospital

Rode Road, Chermside,

Brisbane, Queensland, 4032

AUSTRALIA

Ph: +61 410408777 e-mail: [email protected]

Word count: Total: 5,660 (Title page: 415 ; Abstract: 244 ; Body: 4,868 ;

Acknowledgements, Funding sources, Disclosures: 43; Appendices: 1,535 ; and

References: 2,085)

Keywords:

Aortic Stenosis; Transcatheter Aortic Valve Implantation; Transcatheter Aortic Valve

Replacement; Neurological injury; Stroke

Structured Abstract

Background

The incidence of clinically apparent stroke in transcatheter aortic valve implantation

(TAVI) exceeds that of any other procedure performed by interventional cardiologists and, in the index admission, occurs more than twice as frequently with TAVI than with surgical aortic valve replacement (SAVR). However, this represents only a hint of the vast burden of neurological injury that occurs during TAVI, with recent evidence suggesting that many strokes are clinically silent or only subtly apparent.

Additionally, such injury may present with subtle neurocognitive dysfunction rather than overt neurological deficits. The underlying insult behind all types of injury remains poorly characterized.

Methods

The Silent and Apparent Neurological Injury in TAVI (SANITY) Study is a prospective, multicenter, observational study comparing the incidence of neurological injury after TAVI versus SAVR. It introduces an intensive, standardized, formal neurologic and neurocognitive disease assessment for all aortic valve recipients, regardless of intervention (SAVR vs. TAVI), valve-type (bioprosthetic, Edwards

SAPIEN-XT or Medtronic CoreValve) or access route (sternotomy, transfemoral, transapical or transaortic). It also provides the most comprehensive monitoring of embolic insults than can be found in current literature, to more fully define the burden of neurological disease.

Conclusion

The SANITY study undertakes the most rigorous assessment of neurological injury reported in literature to date. It attempts to accurately characterize the insult and sustained injury associated with both TAVI and SAVR in an attempt to advance understanding of this complication and associations thus allowing for improved patient selection and procedural modification.

Background

Emerging data now supports TAVI as an acceptable strategy in the management of severe aortic stenosis (AS) amongst patients deemed ineligible or too high-risk for

SAVR. Despite the technique’s success, the risk of neurological insult and injury associated with TAVI has raised concerns. This injury may take the form of either cerebrovascular events (CVEs) - including major/disabling stroke, minor/non- disabling stroke, transient ischemic attacks (TIAs) or silent brain infarcts; or neurocognitive dysfunction - especially post-operative cognitive dysfunction (POCD) or post-operative delirium (POD). Such events may be overt, subtle, or clinically silent. While overt stroke rates have been reported in most safety and efficacy studies/registries, subtle and silent neurological injuries have been either unreliably recorded or, more often, largely ignored because of prevailing clinical approaches.

Additionally, although emboli are thought to be the major cause, especially of early neurological injury, the underlying insults behind both types of injury remain poorly characterized.

Clinically apparent Cerebrovascular Events

CVEs are more common post TAVI than after alternative management strategies, with rates amongst the highest reported for any cardiac procedure. CVEs post cardiovascular interventions vary in their presentation and timing, allowing for distinction of etiologies and risk factors (Table 1).

Thirty-day stroke rates of 3.3%, 2.4% and 1-2% have been reported for risk-matched populations undergoing TAVI, isolated AVR, and balloon valvuloplasty, respectively[1-3]. For all three interventions, this risk is highest within the first 24

hours, suggesting an early hazard phase immediately post-procedure[4]. It is this early hazard phase that is considered ‘procedurally-related’ and represents the period during which TAVI recipients are at increased risk. Improved understanding of events during this period therefore promises the greatest potential for optimization of TAVI and as such is the focus of the SANITY Study.

Silent Brain Infarction

In neuroimaging studies, clinically apparent strokes account for only a minority of

CVEs. Diffusion-weighted magnetic resonance imaging (DWI) studies have revealed the incidence of new ischemic lesions as approximately 75% post-TAVI, and as high as 93% [5, 6]. Comparatively, only 40-50% are evident in DWI studies following

SAVR, and 22% following retrograde catheterization of the aortic valve in AS[5, 7].

Understanding of these clinically silent CVEs is more limited than for clinically apparent strokes, with only a few published MRI-centered studies investigating their occurrence post-TAVI, amounting to fewer than 200 patients. The clinical relevance of this burden of infarct remains unknown, though has been suggested to correlate with increased risk of post-operative cognitive dysfunction (POCD) or post-operative delirium (POD)[8, 9].

Neurocognitive Impairment

Investigation into neurological injury post-TAVI has almost exclusively focused on

CVEs, with neurocognitive/neuropsychological disturbances disregarded. This reflects both the uncertain consequences of such neurological injury and the difficulty of detecting these events. Two entities of particular interest are post-operative delirium (POD) and post-operative cognitive dysfunction (POCD), which are defined

in Table 1. Though clinical experience suggests that these are common entities post- cardiovascular intervention and surgery, studies geared towards their detection are sparse and limited by insensitive screening tools.

Neurological Insult:

The underlying neurological insult resulting in injury is thought to be primarily an embolic phenomenon, though inter-related etiologic factors of hypoperfusion, thrombosis and hemorrhage are likely of importance. Transcranial Doppler (TCD) studies have demonstrated micro-emboli at all stages of the TAVI procedure, with cumulative embolic loads exceeding 700 high-intensity signals (HITS, a validated surrogate of emboli) reported, especially during stages of aortic valve manipulation/TAVI deployment. However, the TCD data used to quantify and characterize the embolic etiology is based on a limited number of small studies.

Importantly, no studies to date have compared the degree of neurological insult detected by TCD and MRI within the same cohort of patients.

Area of need

Clearly, across all forms of neurological injury, current understanding of the nature and character of both the injury and the underlying insult is incomplete. This is the consequence of studies not being specifically geared towards sensitive neurological insult/injury detection. The paucity of data reflects the relative ignorance of this complication in the face of the significant functional benefits to patients who are ineligible or at high-risk for SAVR. Refinement of TAVI continues with the expectation that complications can and should be minimized. Indeed, the greatest

barrier to TAVI extending into lower surgical risk and younger populations remain the risk of neurological injury.

Objectives

The SANITY study (ACTRN12613000083796) aims to provide the most comprehensive characterization to date of neurological insult and injury - both clinically apparent and silent - post TAVI and SAVR. Specific primary and secondary objectives are outlined in Table 2. These encompass pre-existing patient factors, and both intra- and post-operative factors thought to influence neurological insults and injury sustained during aortic valve interventions. It is hoped that improved understanding of these associations will permit detailed characterization of neurological injury during TAVI and allow for the identification of predictors of such injury.

Hypotheses

Based on the current concept of neurological injury and extrapolation of procedural risk factors for embolization, it is hypothesized that neurological insult is less pronounced with:

1. AVR than TAVI. This may be due to removal of the valvular source of

embolization, which in TAVI persists, pushed against the wall of the aorta and

potentially acting as a nidus for calcific emboli and altered rheology,

promoting thrombosis.

2. A transapical/transaortic than transfemoral approach. Transapical/ transaortic

routes avoid the risk of disrupting calcific plaques especially in the aortic arch,

an inherent risk with femoral access.

3. The Edwards SAPIEN versus Medtronic CoreValve. The CoreValve system is

associated with relatively slower stepwise release and repositioning, which is

postulated to ‘grate’ calcific debris off the stenotic valve.

Methods

Study Design

This is a prospective, multicenter, non-random observational study comparing the incidence of neurological injury associated with transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR).

Regularly held ‘Heart Team’ meetings - comprised of multiple disciplines including echocardiologists, interventional cardiologists, nurses and cardiothoracic surgeons – will assess high-risk patients with severe AS. Here, patients will be allocated to the intervention clinically indicated. Pending consent, such patients will be consecutively recruited into the SANITY study, resulting in cohort grouping as outlined in Figure 1.

Patient Population

Thorough pre-, intra- and post-procedural assessments allow for results to be adjusted for baseline status, thus permitting an inclusive approach to enrollment. As such, only patients unable to participate in aspects of assessment (Table 3) will be excluded.

Patients will then be grouped, as outlined above, for comparison.

Data Collection

The complete assessment regime and timing of each component can be found in

Figure 2. Where relevant, this regime was designed to be consistent with the

assessments recommended and satisfy the endpoints defined by the Valve Academic

Research Consortium updated standardized endpoints (VARC-2)[10]. A multi- disciplinary approach has been adopted to ensure that relevant experts address each assessment domain.

Medical/Medication History

Qualified medical or nursing personnel will administer a detailed, standardized questionnaire, either at the time of consent or, in cases of telephone consent, at first subsequent contact. This is aimed at identifying all pre-existing cerebrovascular and neurocognitive risk factors and assigning formal surgical-risk scores using the Society for Thoracic Surgeons (STS) scale and European System for Cardiac Operative Risk

Evaluation (EuroSCORE) I and II. At each contact specific questioning and chart review will target transient ischemic events that might otherwise be missed using the neurological assessment protocol outlined below.

Neurological and Cognitive Assessment

There are no standards or recommendations guiding neurocognitive assessment in the

TAVI population. It is clear that post-TAVI, the mini-mental state exam (MMSE) yields little information and is susceptible to a ‘learning effect’[6]. More recently, the

Montreal Cognitive Assessment (MoCA) has emerged as a useful cognitive screening test and generally is considered more sensitive for vascular cognitive impairment due to the inclusion of a thorough executive function assessment[11]. Additionally, the

Confusion Assessment Method (CAM) will be performed. This is the standard screening tool used in the detection of delirium in the postoperative period however, has not been validated in a post-cardiac intervention population against the ‘gold-

standard’ of a consultant psychiatrist/geriatrician clinical assessment[12]. These three tools (MoCA, CAM, consulting geriatrician’s assessment) will comprise the cognitive assessment for the SANITY study, providing clinically important information on the incidence and pattern of cognitive impairment in this population, and potentially validating the instruments themselves in the post-cardiac intervention/surgery population. Tests will be performed prior to the index procedure (to provide a baseline) and at days 1,4 and 7 and at 6 weeks and 3 months post-index procedure.

Clinical Neurological Assessment

The NIH Stroke Scale (NIHSS) is a widely validated tool, which facilitates the standardized objective quantification of impairment caused by stroke. Categorization of stroke severity (no stroke, minor stroke, moderate stroke, moderate to severe stroke and severe stroke) is permitted, based on the overall score. Where stroke is identified

(pre-existing or new), the modified Rankin Scale (mRS) will be applied to measure and monitor stroke-related disability. These assessments will be applied at the same time points as outlined for the cognitive assessment tools.

Serological Assessments

Numerous serological markers of neurological injury that have been utilized previously in acute ischemic stroke (AIS) Most of these have not been studied to any great extent in patients undergoing cardiovascular interventions; thus, the ideal marker in this setting is unknown. Following careful consideration of strengths and weaknesses of each (Table 4), GFAP and S100B were selected for use in the SANITY study. The time points for testing will be pre-procedure and 24hrs, 48hrs, 72hrs and

96hrs post-procedure.

Imaging Assessments

Echocardiography:

Echocardiography either transoesophageal or transthoracic will be performed on all patients prior to and following the aortic valve procedure for the purposes of grading aortic stenosis. Additionally, evidence for intra-cardiac thrombi and spontaneous echo contrast will be sought. Increased presence of both of these parameters has been identified in TAVI patients, likely as a result of an acquired thrombophilic state [13].

Transcranial Doppler (TCD)

TCD uses Doppler ultrasonography transduced through established windows in the skull (areas of bone thinning) to detect and quantify emboli (high-intensity signals and micro-embolic signals) using defined criteria[14]. Additionally, cerebral blood flow can be measured and assessed with respect to changes in systemic pressure to determine cerebral autoregulation. These measures will be performed intra- operatively allowing for temporal analysis with relation to stage of procedure.

Carotid Duplex Ultrasound

The association between carotid stenosis and postoperative stroke following cardiovascular interventions remains controversial. It is feasible that CAS may play a role, albeit currently undefined, and may be a predictor of stroke in TAVI[15]. As such, carotid duplex ultrasound will be performed on all patients at baseline to identify CAS within the common, internal and external carotid arteries. Stenosis and plaque burden will be graded, taking into consideration all information from B-mode, pulsed-wave and color-flow Doppler.

CT Chest/Vascular Calcification Score

Arterial calcification correlates with atherosclerotic plaque burden[16]. The Agatston

Score Equivalent (ASE) is a widely used method of quantifying the calcified plaque burden in coronary arteries using non contrast CT[17]. Thus, a low dose, non contrast acquisition will form part of the standard CT angiographic assessment of the aorta and the iliofemoral access arteries as routinely performed for TAVI suitability assessment and planning. ASEs of the aorta can be calculated for each of the aortic vessel segments, including the aortic root and valve leaflets. The correlation between the vascular and aortic valve plaque burden and neurological insult can thus be determined.

Magnetic Resonance Imaging (MRI)

Recognized as the most sensitive technique for the detection of acute ischemic cerebral infarcts, DWI detects the restriction of water diffusion in cerebral tissue caused by hypoxic oedema within minutes of ischemia onset. Increased signal intensity on DWI is reliably detectable 4 hours post insult and persists for up to 10 days[18]. Lesions representing brain infarct can be quantified in number and size and volume using this modality.

Susceptibility Weighted Imaging (SWI) is a relatively new MRI sequence which is highly sensitive to the local magnetic field inhomogeneity caused by paramagnetic substances including the heme group in hemoglobin. SWI is commonly used as an adjunct to DWI in the assessment of cerebral ischaemia as it is extremely sensitive for detecting hemorrhagic transformation within regions of infarction; can demonstrate

acute thrombo-emboli sufficient to occlude arteries and can detect micro-hemorrhage, suspected to originate from diapedesis of red blood cells across overtly permeable capillaries. Peak incidence of hemorrhagic transformation occurs between 48 hrs and

5 days and can persist for years[18].

Patients will undergo a baseline MRI study one week prior to intervention. This more comprehensive study will include standard fast spin echo sequences, baseline DWI and SWI sequences and time of flight angiography of the circle of Willis to document pre-existing disease. At 4 days post intervention a limited study consisting of DWI,

SWI, T2 Flair and T1 imaging will be performed. The 4-day interval length allows for sufficient patient recovery post procedure to safely undergo an MRI examination and allows for establishment of the MRI detectable changes and maximum evolution of the ischemic change[19]. This limited acquisition is performed in 15 min for increased patient tolerance. A further limited examination after 6 weeks will include

DWI and SWI, demonstrating DWI resolution, infarct complications and finally accounting for all SWI lesions.

Monitoring

Cerebral Oxygen Saturation (rSO2):

Transcranial cerebral oximetry non-invasively monitors cerebral oxygen saturation in the frontal lobes of the brain and has been shown to correlate with cerebral venous oxygen saturation, which is traditionally considered the ‘gold-standard’ for determining oxygen delivery/consumption[20]. It has been used in a limited number of studies to monitor the cerebral oxygen delivery compromise associated with rapid ventricular pacing[21, 22]. This will be applied during the intra-operative period.

Invasive Blood Pressure

Hemodynamic instability leading to systemic hypotension may impair cerebral perfusion pressure beyond auto-regulatory capacity, resulting in hypoperfusion[23].

While itself a cause of ischaemia, low cerebral flow magnifies the effects of microemboli by impairing their clearance and permitting small emboli to lodge[24].

Telemetry:

Intra- and post-operative telemetry will be employed to measure the duration of rapid ventricular pacing and detect new onset atrial fibrillation (NOAF). NOAF complicates

14–32% of TAVI procedures and episodes as brief as 30 seconds have been associated with up to a three-fold increased risk of CVE’s [25]. Patients will be monitored on telemetry during and for a minimum of 3 days following the index procedure.

Quality of Life

Quality of life (QoL) assessment during post-procedural follow-up is crucial to determining the clinical benefit of TAVI and consequences of neurological and cognitive insult and injury. Recommendations of the VARC-2 necessitate both a health-specific measure and generalized measure of QoL [26]. As such, the heart failure specific Kansas City Cardiomyopathy Questionnaire (KCCQ) [27], and the generic European Quality of Life instrument-5D (EQ-5D) [28] have been selected.

These will be performed prior to and 3 months following index procedure.

Frailty and Functional Outcome Measures:

Functional capacity will be measured objectively by the six-minute walk test

(6MWT), conducted according to American Thoracic Society guidelines [29]. This simple, practical and inexpensive sub-maximal exercise test assesses functional capacity [30], is closely linked to activities of daily living and has been proposed as both a functional status indicator and an outcome measure [31]. Similarly, gait speed is an important indicator of frailty [32], with slow gait a strong predictor of adverse outcomes, including disability, high healthcare utilization and mortality [33].

Frailty can be described as a vulnerability to adverse events that is associated with, but separate from chronological age[34]. Implicitly, all patients requiring TAVI as opposed to open aortic valve surgery must have frailty as a barrier to standard treatment. Frailty is therefore an important contributor to the choice of TAVI and a potential confounder regarding outcomes, including delirium. Deficit accumulation provides a robust measure of frailty[35]. This measure improves understanding of what is happening to the frailest frail and those unable to complete performance-based tests.

Endpoint Definitions

The endpoints for the SANITY study are outlined in Figure 3. Primary endpoints focus on the characterization and quantification of the neurological insult, with specific reference to the embolic load, as detected by transcranial Doppler and new ischemic lesions on MRI. Secondary end points focus on the clinically apparent neurological injury sustained and markers of insult / injury.

Statistical Analysis

An estimated 100 patients will be recruited into this study, fifty in each of the two treatment arms (SAVR and TAVI). Fifty patients per group yields 90% power to detect a difference in mean HITS of 500 in one group and 518 in another, assuming a standard deviation of 30 and a two-sided statistical significance of 5%. This is based upon estimates drawn from previous data on the quantification of embolic load during

TAVI/AVR. Fifty patients per group also provides 90% power to detect differences in the incidence of new DWI lesions with two-sided statistical significance of 5%, assuming overall incidence estimates of 76% and 45% with TAVI and AVR, respectively, as previously reported.

Multiple regression models will be used to adjust for potential confounders identified based upon clinical importance and statistical selection The key output will be the estimated treatment difference and 95% confidence intervals for the primary group from the multiple regression model. Additionally, longitudinal analysis will be used to examine all outcomes with repeated data again with application of multiple regression model. Treatment failure and withdrawal will be considered on an intention-to-treat basis, providing a more realistic estimate of the difference between groups in actual clinical practice.

Limitations

Across all TAVI literature the identification of a risk-matched control group has proven difficult. The validity of high-risk SAVR patients as a ‘control group’ has previously been questioned, given that level of health risk is a factor determining which procedure will be used. Comparison between these two groups however is more clinically relevant as AVR is the current ‘gold-standard’ for eligible patients

with AS. Additionally, by pooling data from the two treatment groups for multivariate analysis, it will be possible to assess whether pre-procedural general health is a significant predictor of insult / injury.

This study will be non-randomized and non-blinded. Though multiple regression analysis will be used to minimize confounding, this is not a substitute for blinding or randomization, and unmeasured confounders may produce hidden bias.

Finally, a clinical follow-up duration of three months limits conclusions regarding delayed and late neurological injury. Such a timeframe can be justified, however, given that DWI findings resolve within this timeframe (usually quoted as occurring by 30 days even in overt stroke) and reversible neurocognitive deficits generally resolve by 3 months[9]. Consequently, the financial costs and patient burdens of prolonging follow-up cannot be ethically justified.

Summary

The SANITY Study offers the most comprehensive neurological/neurocognitive assessment of the high-risk TAVI and AVR patient population to date. Well- established and recommended assessments are complemented by those that are novel and unique, thereby offering the potential of improved understanding of the interventions in question, correlation of risk factors and prognostic markers, and validation of assessment tools. Such knowledge is vital to establishing both suitable assessment batteries and guidelines in this unique, high-risk group of patients, and to advancing strategies for neurological injury reduction.

Acknowledgements

Disclosures

Fanning, J.P. supported by:

University of Queensland Research Scholarship

The Prince Charles Hospital Foundation (TPCHF)

Fraser, J.F. supported by:

Office of Health and Medical Research (OHMR) fellowship

Walters, D.W. Consultant to Medtronic and Edwards Past proctor for Edwards Investigator in Edwards, Medtronic and Boston Scientific clinical studies.

Appendices

Table 1: Definitions used for the trial

A. Cerebrovascular Event definitions[10]

Diagnostic Criteria:

Acute episode of a focal or global neurological deficit with at least one of

the following: change in the level of consciousness, hemiplegia,

hemiparesis, numbness, or sensory loss affecting one side of the body,

dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological

signs or symptoms consistent with stroke.

A. Stroke

Duration of a focal or global neurological deficit ≥ 24 hours; OR <24 hours

if available neuroimaging documents a new hemorrhage or infarct; OR the

neurological deficit results in death.

Aetiology:

i. Ischemic: an acute episode of focal cerebral, spinal or retinal

dysfunction caused by infarction of the central nervous system

tissue.

ii. Hemorrhagic: an acute episode of focal or global cerebral or

spinal dysfunction caused by intraparenchymal, intraventricular, or

subarachnoid hemorrhage.

iii. Undetermined: insufficient information to allow categorization as

ischemic or hemorrhagic.

Severity:

i. Disabling stroke (Major): an mRS of 2 or more at 90 days and an

increase in at least one mRS category from an individuals pre-

stroke baseline.

ii. Non-disabling stroke (Minor): an mRS score of <2 at 90 days or

one that does not result in an increase in at least one mRS category

from an individual’s pre-stroke baseline.

B. TIA:

Duration of a focal or global neurological deficit <24 hours, any available

neuroimaging does not demonstrate a new hemorrhage or infarct.

Qualifiers:

 Exclusion of non-stroke causes for clinical presentation

o e.g. brain tumour, trauma, infection, hypoglycemia, peripheral lesion,

pharmacological influences etc.

 Determined by or in conjunction with the designated internal medicine

specialist or neurologist.

 Diagnosis confirmed by at least one of the following:

 Neuroimaging procedure (CT scan or MRI brain) and/or

 Neurologist or neurosurgical specialist

B. Neurocognitive Impairment

A. Post-operative Cognitive Dysfunction (POCD)

Definition: Deterioration of intellectual function presenting as impaired

memory or concentration presenting with temporal association to surgery.

B. Post-operative Delirium (POD)

Definition: An acute disturbance of consciousness and a change in cognition

with tendency to fluctuate during the course of the day and occurring in

patients without some other identifiable aetiology and following normal

emergence from anaesthesia.

Qualifiers:

 Determined by specialist geriatrician assessment

 In conjunction with CAM and MoCA assessment tools

Table 2: Objectives of the SANITY Study

Primary Objectives:

Characterize neurological insult (Transcranial Doppler evidence of microemboli) and neurological injury (MRI evidence of new ischemic lesions) during the TAVI procedure compared with AVR

Define the association between incidence of neurological insult and injury with:

- Aortic Valve Intervention (TAVI, AVR)

Secondary Objectives:

Define the association between incidence of neurological insult and injury with:

- TAVI access (transfemoral, transapical, transaortic)

- TAVI prosthesis (Edwards SAPIEN, Medtronic CoreValve)

Define the association between incidence of neurological insult and:

- Clinically apparent neurological injury

- New Onset Atrial Fibrillation

- Neurocognitive dysfunction

- Degree of vascular / aortic valve calcification

- Rapid ventricular pacing and cerebral desaturation

- Serological markers of neurological injury (S100B and GFAP)

- Cerebrovascular reserve

- Effect on cerebral blood flow

Validate:

- GFAP as a serological marker of neurological injury in cardiovascular

intervention

- Neurocognitive screening tools in cardiothoracic intervention

Table 3: Eligibility Criteria

Inclusion Criteria Exclusion Criteria

Informed consent for participation Lacks capacity to consent for him or

herself

Severe Aortic Stenosis Pre-existing neurological impairment

- AVA <0.8cm2 - Modified Rankin score ≥ 3 (i.e.

- Mean Aortic Valve Gradient Moderate disability; requiring

>40mmHg some help, but able to walk

- Peak jet velocity >4m/s without assistance)

Planned TAVI or AVR Contraindication to MRI (including

incompatible metallic prosthesis/foreign

body, inability to lie flat, claustrophobia

requiring sedation)

EuroScore >20 or STS-PROM >10 Non or poor English-speaking due to

nature of and unknown validity in such

populations cognitive testing

Previous Aortic Valve Repair /

replacement

Coronary artery disease requiring revascularisation (including patients undergoing combined AVR and CABG)

Table 4: A comparison of Serological Markers of Neurological Injury Used in SANITY Test Function/Rational for Use Strengths & Weaknesses Study CK-BB Involved in energy metabolism Levels do not correlate with stroke severity NO of neural cells

Neuron-specfic enolase A glycolytic enzyme involved in Levels increase after acute brain injury NO (NSE) anaerobic metabolism of glucose Non-specific; levels increase after ANY injury After acute stroke, levels do not correlate with function

Neurofilaments Proteins integrated into neuronal Relationship to infarct size & functional outcome unclear NO (NfH) & axonal cytoskeleton

Tau Microtubule-associated protein Poor sensitivity for stroke; only high in 27-48% of patients NO stabilizes axonal cytoskeleton & transport of vesicles to synapse

S100 proteins Calcium-binding proteins involved Best established marker of acute brain ischemia YES various cellular processes Levels correlate with infarct size, clinical severity & functional outcome Presence in non-neural tissues like adipocytes, chondrocytes & melanocytes reduce specificity

GFAP Intermediate filament in astroglial Levels correlate with infarct size, clinical severity & YES cytoskeleton; involved in repair of functional outcome neural tissue after injury Subtypes exist specific to different tissues, which enhances

SANITY Study Investigational Protocol V3.0 26

specificity However, not yet validated in cardiac intervention patients

SANITY Study Investigational Protocol V3.0 27

Figure 1: SANITY Study Design

SANITY Study Investigational Protocol V3.0 28

Figure 2: Overview of SANITY Assessments

SANITY Study Investigational Protocol V3.0 29

Figure 3: Overview of SANITY Variables and Endpoints

SANITY Study Investigational Protocol V3.0 30

References: 1. Eggebrecht, H., et al., Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. Eurointervention, 2012. 8(1): p. 129-38. 2. Vasques, F., et al., Immediate and late outcome of patients aged 80 years and older undergoing isolated aortic valve replacement: A systematic review and meta-analysis of 48 studies. American Heart Journal, 2012. 163(3): p. 477-485. 3. O'Brien, S.M., et al., The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Part 2‚ÄîIsolated Valve Surgery. The Annals of Thoracic Surgery, 2009. 88(1, Supplement): p. S23-S42. 4. Tay, E.L.W., et al., A High-Risk Period for Cerebrovascular Events Exists After Transcatheter Aortic Valve Implantation. JACC: Cardiovascular Interventions, 2011. 4(12): p. 1290-1297. 5. Astarci, P., et al., Magnetic resonance imaging evaluation of cerebral embolization during percutaneous aortic valve implantation: comparison of transfemoral and trans-apical approaches using Edwards Sapiens valve. European Journal of Cardio-Thoracic Surgery, 2011. 40(2): p. 475-479. 6. Kahlert, P.M.D., et al., Cerebral Embolization During Transcatheter Aortic Valve Implantation: A Transcranial Doppler Study. Circulation, 2012. 126(10): p. 1245-1255. 7. Omran, H., et al., Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. The Lancet, 2003. 361(9365): p. 1241-1246. 8. Rudolph, J.L., et al., Measurement of post-operative cognitive dysfunction after cardiac surgery: a systematic review. Acta Anaesthesiologica Scandinavica, 2010. 54(6): p. 663-677. 9. Saczynski, J.S., et al., Cognitive Trajectories after Postoperative Delirium. New England Journal of Medicine, 2012. 367(1): p. 30-39. 10. Kappetein, A.P., et al., Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. European Heart Journal, 2012. 33(19): p. 2403-2418. 11. Godefroy, O., et al., Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination to Detect Poststroke Cognitive Impairment?: A Study With Neuropsychological Evaluation. Stroke, 2011. 42(6): p. 1712-1716. 12. Inouye, S.K., et al., Clarifying Confusion: The Confusion Assessment Method. Annals of Internal Medicine, 1990. 113(12): p. 941. 13. Lenders, G.D., et al., Poster session 492: Transoesophageal echocardiography for the assessment of cardiac thromboembolic risk in transcatheter aortic valve implantation. European Heart Journal ‚Äì Cardiovascular Imaging, 2012. 13(suppl 1): p. i76-i99. 14. American Heart Association. Heart disease and stroke statistics: 2005 update. Dallas, Texas: American Heart Association, 2004.

SANITY Study Investigational Protocol V3.0 31

15. Aono, Y., et al., Plasma fibrinogen, ambulatory blood pressure, and silent cerebrovascular lesions: the Ohasama study. Arterioscler Thromb Vasc Biol., 2007. 27: p. 963-968. 16. Allison, M.A., M. Criqui, and C.M. Wright, Patterns and Risk Factors for Systemic Calcified Atherosclerosis. Ateriosclerosis Thrombosis and Vascular Biology, 2004. 24: p. 331-336. 17. Agaston, A.S., et al., Quantification of Coronary Artery Calcium Using Ultrafast Computed Tomography. Journal of the American College of Cardiology, 1990. 14(4): p. 827-32. 18. Allen, L.M., et al., Sequence-specific MR Imaging Findings that are useful in Dating Ischemic Stroke. RadioGraphics, 2012. 32: p. 1285- 1297. 19. Schlaug, G., et al., Time course of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology, 1997. 49(1): p. 113- 119. 20. Paarmann, H., et al., Non-invasive cerebral oxygenation reflects mixed venous oxygen saturation during the varying haemodynamic conditions in patients undergoing transapical transcatheter aortic valve implantation. Interactive Cardiovascular & Thoracic Surgery, 2012. 14(3): p. 268-72. 21. Bila, R.H., et al., Cerebral oximetry monitoring during transcatheter aortic valve implantation (TAVI) [Conference Abstract]. Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 2012. Conference: 15th Annual Meeting of the International Society for Minimally Invasive Cardiothoracic Surgery, ISMICS 2012 Los Angeles, CA United States. Conference Start: 20120530 Conference End: 20120602. Conference Publication: (var.pagings). 7 (2): p. 134. 22. Brodt, J. and E. Maratea. Cerebral Oxygenation During Transcatheter Aortic Valve Implantation. in Anesthesiology 2012. 2012. Washington, D.C., USA. 23. Kapadia, S. Three-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in "inoperable" Patients with severe Aortic Stenosis : The PARTNER Trial. in Transcatheter Cardiovascular Therapies (TCT) 2012. 2012. Miami, FL, USA. 24. Caplan Lr, H.M., IMpaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Archives of Neurology, 1998. 55(11): p. 1475-1482. 25. Amat-Santos, I.J., et al., Incidence, Predictive Factors, and Prognostic Value of New-Onset Atrial Fibrillation Following Transcatheter Aortic Valve Implantation. Journal of the American College of Cardiology, 2012. 59(2): p. 178-188. 26. Chou, C.C., et al., Adults with late stage 3 chronic kidney disease are at high risk for prevalent silent brain infarction: a population-based study. Stroke, 2011. 42(8): p. 2120-2125. 27. Green, C.P., et al., Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. 2000. 35(5): p. 1245-1255. 28. Group, T.E., EuroQol - a new facility for the measurement of health- related quality of life. Health Policy, 1990. 16(3): p. 199-208.

SANITY Study Investigational Protocol V3.0 32

29. Eguchi, K., et al., Smoking is associated with silent cerebrovascular disease in a high-risk Japanese community-dwelling population. Hypertens Res., 2004. 27(10): p. 747-754. 30. Eguchi, K., K. Kario, and K. Shimada, Greater impact of coexistence of hypertension and diabetes on silent cerebral infarcts. Stroke, 2003. 34(10): p. 2471-2474. 31. Feiwell, R.J., et al., Detection of clinically silent infarcts after carotid endarterectomy by use of diffusion-weighted imaging. AJNR Am J Neuroradiol., 2001. 22(4): p. 646-649. 32. Fujishima, M., et al., Deep white matter lesions on MRI, and not silent brain infarcts are related to headache and dizziness of non-specific cause in non-stroke Japanese subjects. Intern Med., 2000. 39(9): p. 727-731. 33. Gerriets, T., et al., Evaluation of methods to predict early long-term neurobehavioral outcome after coronary artery bypass grafting. Am J Cardiol., 2010. 105(8): p. 1095-1101. 34. McMillan, G.J. and R.E. Hubbard, Frailty in older inpatients: what physicians need to know. QJM, 2012. 105(11): p. 1059-1065. 35. Rockwood, K. and A. Mitnitski, Frailty in Relation to the Accumulation of Deficits. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2007. 62(7): p. 722-727.

SANITY Study Investigational Protocol V3.0 33