Cognitive implications of subclinical leaflet thrombosis after transcatheter aortic valve implantation

This editorial refers to ‘Subclinical leaflet thrombosis after transcatheter aortic valve implantation is associated with silent brain injury on brain magnetic resonance imaging’, by A. Apor et al., https://doi.org/10.1093/ehjci/jeac191.

Transcatheter aortic valve implantation (TAVI) has evolved to become the standard of care for inoperable and high-risk patients with calcific aortic stenosis, with emerging evidence of safety and efficacy in lower risk individuals.¹ Hypoattenuated leaflet thickening (HALT) is the computed tomography (CT) correlate of bioprosthetic leaflet thrombosis and has been documented in at least 10% of TAVI recipients on four-dimensional, volume-rendered scans.^2,3 There remains uncertainty regarding HALT’s thromboembolic potential, its association with premature haemodynamic valve deterioration and mortality.² Whether HALT constitutes a risk for so-called ‘silent brain injury’, i.e. small embolic strokes which do not manifest with an acute neurologic deficit, and if such insults lead to cognitive decline, is unknown.

In the current issue of the journal, Aspor et al.⁴ investigated the implications of HALT for silent brain injury by analysing data from 153 TAVI recipients. Brain magnetic resonance imaging (MRI) was performed post-TAVI and at 6 months after implantation. Acute, silent brain injury was identified by the presence of cerebral ischaemic lesions on diffusion-weighted MRI, while chronic white matter hyperintensities were visualized with a fluid-attenuated inversion recovery sequence. HALT was associated with an increased burden of cerebral white matter hyperintensities at 6 months post-implant (seen in 66% of patients) but not with cognitive impairment. After 3 years of follow-up, neither HALT nor the burden of white matter hyperintensities led to a higher mortality.

The clinical importance of HALT is still debated, and data are inconsistent regarding its impact on mortality^2,5 and premature haemodynamic valve deterioration.² HALT has been linked to stroke, although this association was not confirmed in a large meta-analysis, which included >11 000 patients.³ Cerebral thromboembolic events, however, do not always present with clinical stroke but may manifest as so-called ‘silent brain injury’, which can be diagnosed on brain MRI and which has been associated with the development of subsequent cognitive decline, dementia and mood disorders.⁶ Silent brain injury on MRI has also been identified in patients with atrial fibrillation, carotid artery disease and various interventional procedures, supporting the embolic nature of this phenomenon.⁶ Since TAVI is an interventional procedure with the potential for cerebral thromboembolism, it is not surprising that silent brain injury has been reported post-procedure in the majority of TAVI recipients, while being associated with early cognitive decline.^6,7 TAVI per se, however, was not associated with cognitive decline in majority of recipients in a meta-analysis, which does not necessarily imply that silent brain injury may not cause cognitive impairment on an individual level.⁸ Aspor et al.⁴ were able to show that HALT does indeed lead to silent brain injury but does not translate into cognitive decline. This raises the intriguing possibility that silent brain injury-mediated cognitive decline post-TAVI is not related to HALT, but to alternative sources of emboli.

HALT is a contentious issue in TAVI: it can only be diagnosed in the majority of patients on CT, which is not recommended as a routine follow-up examination in most TAVI recipients. It will therefore generally not be diagnosed, except for the minority in whom hemodynamic valve deterioration or stroke are further investigated with CT. HALT is a dynamic process, which complicates its diagnosis, as well as the timing of the post-TAVI CT.^5,9 Even when diagnosed, the appropriate clinical response to HALT remains uncertain. In a sub-analysis of the Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy after Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes, it was shown that HALT can be prevented with oral anticoagulation, although mortality was increased in the orally anticoagulated arm.¹⁰ In the only dedicated HALT prevention study, The Anticoagulant Vs. Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement trial, TAVI recipients were randomized to edoxaban and dual antiplatelet therapy, with the occurrence of HALT as the primary outcome.¹¹ No difference in incident HALT was seen between the two treatment groups, and no difference was noted either in clinical cerebrovascular events, new lesions on brain MRI, or cognitive function.¹¹ Observational data suggest that HALT can be resolved with oral anticoagulation,⁵ but routine oral anticoagulation in all TAVI recipients is undesirable, since many individuals receiving TAVI are elderly and frail, and at high risk of bleeding complications. As yet, there is no clear evidence to support universal oral anticoagulation after TAVI in order to prevent HALT. The results from the current study are reassuring in terms of neurocognition: even though HALT was associated with silent brain injury, it remained subclinical, with no appreciable impact on cognition.⁴ While HALT has the potential to cause an increase in mortality, premature haemodynamic valve deterioration, and stroke, from the current analysis (which is the first and only study with such data available) silent brain injury and cognitive decline do not appear to figure prominently on the list of sequelae.⁴ Long-term outcome data from larger trials are required to accurately characterize HALT, clarify its clinical implications, and inform on effective prevention and treatment strategies.

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Author notes