Challenges in cardiac device innovation: is neuroimaging an appropriate endpoint? Consensus from the 2013 Yale-UCL Cardiac Device Innovation Summit

Abstract

BackgroundNeurological events associated with transcatheter aortic valve implantation are major contributors to morbidity and mortality. Choosing an appropriate endpoint to determine neuroprotection device efficacy is a key difficulty inhibiting the translation of the innovation from the laboratory to the bedside. Cost and sample size limitations inhibit the feasibility of using the rate of clinical (such as stroke or other cerebral) events as the primary efficacy endpoint. This paper focuses on consensus opinions from the 2013 Yale-University College London (UCL) Device Innovation Summit.DiscussionNeuroimaging, specifically diffusion-weighted magnetic resonance imaging (DW MRI), may serve as a surrogate endpoint for clinical studies detecting cerebral events in which cost and sample-size limitations prohibit the use of clinical outcomes. A major limitation of using imaging to prove efficacy in cardiac device studies is that no standardized endpoint exists. Ongoing trials investigating cerebral protection devices for transcatheter aortic valve implantation are utilizing and reporting various qualitative and quantitative DW MRI values; however, single lesion volume, number of new lesions, and total lesion volume have been found to be the most reproducible and prognostically important imaging measures.SummaryDW MRI may be a useful surrogate endpoint for clinical studies detecting cerebral events to determine the device’s success in neurological protection. Consensus from the 2013 Yale-UCL Device Innovation Summit specifically recommends the reporting of mean single lesion volume, number of new lesions, and total volume, and encourages European Union (EU)-US regulatory consensus in the guidance of implementing this endpoint.

Selective Vulnerability of Cortical Border Zone to Microembolic Infarct

“…Even in the largest series, the majority of the lesions were asymptomatic, so that DWI was proposed as a surrogate marker to estimate neurological injury because of the rarity of neurological signs and symptoms. 39 Anyway, the consequences of accumulation of large lesion loads may be more relevant in the long term and possibly coresponsible for increased cognitive decline in patients with sources of microemboli. …”

Neurological Injury in Intermediate‐Risk Transcatheter Aortic Valve Implantation

“…However, clinically apparent stroke represents only the “tip of the iceberg” of neurological injury, with most events being subclinical . DWI is a highly sensitive and specific modality for the early detection of ischemic changes in acute stroke patients and has become a well‐established measure of cerebral embolization . A small number of studies have been published using this objective neurological endpoint.…”

“…The primary neurological endpoint was new DWI-positive lesions on the day 3AE1 MRI scan compared with baseline MRI, quantified by number and volume (in microliters, lL), in accordance with recommendations. 16,31 Secondary endpoints were new clinically apparent neurological injury, measured as stroke (major or minor), transient ischemic attack, postoperative cognitive dysfunction, and postoperative delirium at 3 days and 6 weeks, and 6MWD, 5MWT, EQ-5D, and KCCQ scores at 6 months compared with baseline measures. Summary statistics are presented as meanAEstandard deviation for approximately normally (or Gaussian) distributed data and medianAEinterquartile range for non-normally distributed data.…”

“…10 DWI is a highly sensitive and specific modality for the early detection of ischemic changes in acute stroke patients and has become a well-established measure of cerebral embolization. 16,31 A small number of studies have been published using this objective neurological endpoint. These studies have shown a very high (58-91%) incidence of new ischemic lesions after TAVI among high-risk and inoperable cohorts, [37][38][39][40][41][42][43] and the average incidence is considered to be 75%.…”

Neuron-Specific Enolase and Matrix Metalloproteinase 9 Signal Perioperative Silent Brain Infarction During or After Transcatheter Aortic Valve Implantation

“…3 Their frequent occurrence, objective measurement and clinical implications have increased interest in their routine detection and resulted in consensus statements recommending SBI as a surrogate for clinically apparent ischemic stroke. 4 However, imaging is expensive, time consuming, unsafe in acutely-ill patients, and not always available, rendering it unfeasible as a routine screening tool. For this purpose, a serum biomarker of cerebral infarction (equivalent to troponin for cardiac injury) would be the 'Holy Grail'.…”