Neurofilament Light Chain and Risk of Stroke in Patients With Atrial Fibrillation.

Background: Biomarkers reflecting brain injury are not routinely used in risk assessment of stroke in atrial fibrillation (AF). Neurofilament light chain (NFL) is a novel biomarker released into blood after cerebral insults. We investigated the association between plasma concentrations of NFL, other biomarkers, and risk of stroke and death in patients with AF not receiving oral anticoagulation.
Methods: For this observational study, baseline plasma samples were available from 3077 patients with AF randomized to aspirin in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; 2003 to 2008) and AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; 2007 to 2009). Median follow-up was 1.5 years. NFL was analyzed with a Single Molecule Array (Simoa). Associations with outcomes (total stroke or systemic embolism, ischemic stroke, cardiovascular death, and all-cause death) were explored with Cox regression models.
Results: In the combined cohort, the median NFL level was 16.9 ng/L (interquartile range, 11.1-26.5 ng/L), the median age was 71 years, 58% were men, and 13% had a history of previous stroke. NFL was associated with older age, higher creatinine, lower body mass index, previous stroke, female sex, and diabetes but not cardiac rhythm. Higher NFL was associated with a higher risk of stroke or systemic embolism (n=206) independently of clinical characteristics (hazard ratio, 1.27 [95% CI, 1.10-1.46] per doubling of NFL) and other biomarkers (hazard ratio, 1.18 [95% CI, 1.01-1.37]) and including in patients without previous stroke (hazard ratio, 1.23 [95% CI, 1.02-1.48]). NFL was also independently associated with cardiovascular (n=219) and all-cause (n=311) death. The C index for stroke using only NFL was 0.642, on par with the currently used clinical risk scores. Addition of information on NFL improved discrimination in a model also including clinical information, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and high-sensitivity cardiac troponin T, yielding a C index of 0.727.
Conclusions: NFL reflects overt and covert episodes of cerebral ischemia and improves risk assessment of stroke and death in patients with AF without oral anticoagulation, including in patients without previous stroke. The combination of NFL with information on age, history of stroke, and other biomarkers should be explored as a future avenue for stroke risk assessments in patients with AF.
Competing Interests: Dr Aulin receives research support from The Bissen Brainwalk Foundation, Hjärt-Lungfonden (The Swedish Heart Lung Foundation), and Uppsala University Hospital, Sweden. Dr Sjölin reports no conflicts. J. Lindbäck reports institutional research grant from Bristol-Myers Squibb/Pfizer. Dr Benz reports consulting or honoraria payments from AstraZeneca and Bristol-Myers Squibb and participation in an educational program supported by Boston Scientific (Fellowship Herzrhythmus). Dr Eikelboom reports institutional research grants and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Eli Lilly, Glaxo Smith Kline, Janssen, and Sanofi. Dr Hijazi reports lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Roche Diagnostics; consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Meda, Merck Sharp & Dohme, Pfizer, and Roche Diagnostics; and research grants from the Swedish Society for Medical Research (S17-0133) and the Swedish Heart-Lung Foundation (20170718). Dr Kultima reports no conflicts. Dr Oldgren reports fees to his institution from Amgen, AstraZeneca, Bayer, Novartis, and Roche Diagnostics. Dr Wallentin reports institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim, as well as institutional research grants from Merck & Co and Roche. Dr Burman reports institutional research grants and research support from the Selander Foundation.