Cerebral embolization during transcatheter aortic valve implantation (TAVI) can lead to a spectrum of clinically relevant manifestations, ranging from overt stroke to mild neurologic or cognitive deficits and subclinical cerebral infarcts. This study sought to determine the frequency of neurologic injury, cerebral ischemic lesions, and cognitive dysfunction in subjects undergoing contemporary commercial TAVI in the United States. Neuro-TAVR is the first prospective, multicenter study to use serial systematic neurologic and cognitive assessments and diffusion-weighted magnetic resonance imaging (at 4 ± 2 days after procedure) to investigate the incidence and severity of neurologic injury after contemporary unprotected TAVI in the United States.
A total of 44 consecutive patients underwent TAVI at 5 US sites. Diffusion-weighted magnetic resonance imaging lesions were detected in 94%, with a mean of 10.4 ± 15.3 lesions per subject and a median total lesion volume of 295 mm 3 (interquartile range 71.6 to 799.6 mm 3 ). New neurologic impairment (worsening in National Institutes of Health Stroke Scale score from baseline with new cerebral lesions) occurred in 22.6% (7 of 31) of subjects at discharge and 14.8% (4 of 27) at 30 days. In addition, cognitive decrements from baseline were identified by the Montreal Cognitive Assessment in 33% (12 of 36) of subjects at discharge and 41% (13 of 32) at 30 days. In conclusion, this contemporary cohort of US patients confirms that TAVI results in cerebral infarction in most patients and that 1 in 5 patients have measurable neurologic impairment and 1 in 3 patients have decrease in cognitive measures by Montreal Cognitive Assessment score after TAVI, reinforcing the need for methods to mitigate the risk of brain injury during TAVI.
Stroke is among the most feared complications of cardiac interventions due to its extreme morbidity and mortality burden. With increased operator experience and lower profile next-generation transcatheter aortic valve implantation (TAVI) devices, recent clinical trials report improving stroke rates (in the range of 1.5% to 6%) and disabling stroke rates below 2% at 30 days. There is, however, growing evidence that neurologic events are substantially underreported after TAVI and surgical aortic valve replacement (SAVR). Messe et al found a disturbing 17% early stroke rate after SAVR when neurologists performed systematic evaluations. Likewise, systematic neurologic and neuroimaging follow-up in TAVI populations has revealed clinically apparent postprocedure neurologic deficits accompanied by cerebral ischemia in 15% to 28% of patients. Furthermore, post-TAVI cerebral infarction detected by diffusion-weighted magnetic resonance imaging (DW-MRI) occurs in 68% to 100% of subjects with TAVI in non-US series. Although not always clinically apparent, these ischemic brain lesions have been linked to cognitive decrease, a greater than twofold risk of subsequent dementia, and a greater than threefold risk of future stroke. The Neuro-TAVI study is the first contemporary prospective, multicenter observational study since commercialization of TAVI in the United States to systematically evaluate the frequency of brain infarction based on DW-MRI, coupled with systematic neurologic and cognitive evaluation to detect the full spectrum of symptomatic brain injury after TAVI.
Methods
The Neuro-TAVR trial ( NCT02073864 ) was a prospective, multicenter, observational study designed to evaluate neurologic injury, cerebral ischemic lesions, and cognitive change in subjects undergoing contemporary commercial TAVI without cerebral protection in the United States. Eligible subjects presented with severe symptomatic aortic stenosis referred for TAVI due to high or extreme surgical risk. Exclusion criteria included recent (<72 hours) acute myocardial infarction, recent (<6 months) stroke or transient ischemic attack, cardiogenic shock, impaired renal function (glomerular filtration rate <30 mg/dl), past or pending organ transplant, active peptic ulcer or recent (<6 months) gastrointestinal bleeding, and a history of bleeding diathesis or coagulopathy or contraindications to antiplatelet or anticoagulant therapy. Potential subjects were excluded if they were undergoing TAVI through the subclavian or direct aortic route, had severe peripheral artery disease that precluded vascular access, had known hypersensitivity to contrast that could not be adequately premedicated, had contraindications to cerebral MRI, or if another intervention was planned during or within 2 weeks before TAVI, or treatment with any other investigational device or procedure that was planned at any time during the study period. The institutional review board at each center approved the study protocol, all subjects provided written informed consent, and the study was conducted in accordance with the principles of the Declaration of Helsinki.
TAVI was performed with commercially approved transcatheter valve systems (SAPIEN/XT transcatheter heart valve [Edwards Lifesciences, Irvine, California] or CoreValve transcatheter aortic valve replacement platform [Medtronic, Inc., Minneapolis, Minnesota]) according to standard institutional procedures under local or general anesthesia. Standard dual antiplatelet therapy with aspirin (300-325 mg loading dose and 75-325 mg daily maintenance dose indefinitely) and clopidogrel (≥300 mg loading dose >6 hours before the procedure or 600 mg periprocedure, and 75 mg daily maintenance dose for ≥6 months) was recommended.
DW-MRI of the brain was performed at 4 ± 2 days after procedure according to a standardized image acquisition protocol. Baseline brain MRI was not performed due to the known low frequency of preprocedural brain lesions (<1%) and the resulting drop out of the postprocedural imaging study. DW-MRI data were analyzed at an independent core laboratory (Global Institute for Research, Richmond, Virginia) by 2 independent physicians using validated qualitative and quantitative methods (Vitrea Version 6.3.2, Toshiba America Medical Systems, Tustin, California); details have been reported previously.
All subjects underwent clinical and detailed neurologic and cognitive assessment at baseline, after procedure, and at 30 days. Neurologic assessments included standard clinical scales (the National Institutes of Health Stroke Scale [NIHSS] and the modified Rankin Scale [mRS]); cognitive assessments included the Montreal Cognitive Assessment (MoCA), the Digit Symbol Substitution Test, Trail Making Tests Part A and B, and tests of letter and category fluency. Dedicated staff were identified at each center to perform the neurological and cognitive assessments; these subjects were NIHSS certified, trained in administration of the mRS and cognitive tests, and blinded to DW-MRI findings.
Primary end points were the presence, number, and volume of new postprocedure DW-MRI lesions and the degree of cognitive change defined by mean change and any worsening in score from baseline to each follow-up. Secondary end points were standard safety outcomes predischarge and at 30 days, including all-cause and cardiovascular mortality, neurological events, life-threatening (or disabling) bleeding, acute kidney injury, myocardial infarction, and major and minor vascular complications, all defined according to Valve Academic Research Consortium-2 (VARC-2) recommendations. All adverse events were adjudicated by an independent Clinical Events Committee (Yale Cardiovascular Research Group, New Haven, Connecticut), which included a cardiac surgeon, an interventional cardiologist, and a vascular neurologist. Independent site monitoring was performed on 100% of clinical fields and clinical events.
The Neuro-TAVR study was an exploratory study and no formal hypothesis testing was planned; therefore, all results should be considered hypothesis-generating. All analyses were conducted in the Intention-to-Treat population without imputation for missing data and reported using appropriate descriptive statistics. Continuous variables are presented as mean ± SD when the data are approximately normally distributed; skewed data, such as those obtained through MRI, are presented as median and interquartile range. Binary variables are described as frequencies and percentages.
Results
From October 2014 to May 2015, a total of 44 subjects were enrolled at 5 US centers. Patient flow and follow-up rates are detailed in Figure 1 . The study population is representative of patients meeting current high and extreme risk indications for TAVI ( Table 1 ), with a mean age of 83.2 ± 6.8 years, severe functional limitations (81.4% New York Heart Association class III/IV), heart team–determined frailty in 87.5%, and frequent comorbidities (diabetes, hypertension, and hyperlipidemia); 29.5% of subjects had atrial fibrillation on admission.
| Baseline Characteristic | Total (N = 44) | Procedural Variable | Total (N = 44) |
|---|---|---|---|
| Age (years, mean±SD) | 83.2 ± 6.8 | General anesthesia | 65.9% |
| Men | 65.9% | Balloon pre-dilatation | 90.9% |
| Diabetes mellitus | 43.2% | TEE guidance | 95.5% |
| Hypertension requiring medications | 81.8% | TAVI implants | 100% |
| Hyperlipidemia requiring medications | 77.3% | Medtronic CoreValve | 34.1% |
| Atrial fibrillation | 29.5% | Edwards SAPIEN (all) | 65.9% |
| Prior myocardial infarction | 25% | SAPIEN | 20.9% |
| Prior coronary artery bypass grafting | 36.4% | SAPIEN XT | 44.2% |
| Prior percutaneous coronary intervention | 45.5% | Other valve prosthesis | 3.5% |
| NYHA Class III/IV | 81.4% | Valve–in-valve implant | 7.3% |
| Peripheral vascular disease | 18.2% | Total contrast (ml) | 146± 60 |
| Prior stroke/TIA | 15.9% | Total fluoroscopy time (min) | 17.9± 9.1 |
| Chronic obstructive pulmonary disease | 31.8% | Conversion to surgery | 2.3% |
| Home oxygen therapy | 4.9% | Mechanical assist device | 0% |
| Chronic kidney disease | 18.2% | Adjunct pharmacology | |
| Porcelain aorta | 5.0% | Aspirin + clopidogrel | 61.4% |
| Frailty | 87.5% | Aspirin only | 36.4% |
| EuroScore II (mean±SD) | 7.2±4.3 | Clopidogrel only | 0% |
| STS Score (mean±SD) | 10±6.0 | Warfarin | 22.7% |
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