NT-proBNP for Risk Assessment in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial

Study Questions:

What is the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and what is the treatment effect of apixaban according to NT-proBNP levels?


This was a prespecified substudy of the ARISTOTLE trial. In the double-blind, randomized ARISTOTLE trial, 18,201 patients with AF and at least one CHADS2 risk factor for stroke or systemic embolism were randomized to apixaban or warfarin. In the biomarker substudy, baseline blood samples were obtained from 14,892 patients. The relations between quartiles of NT-proBNP (Q1: ≤363 ng/L, Q2: 364-713 ng/L, Q3: 714-1250 ng/L, and Q4>1250 ng/L) and clinical outcomes were evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors.


Higher baseline NT-proBNP concentration was strongly associated with each of the major clinical outcomes except major bleeding. Higher levels were seen in patients with persistent/permanent AF, compared to paroxysmal AF. The annual rate of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile (adjusted hazard ratio [HR], Q4 vs. Q1, 2.35; 95% confidence interval [CI], 1.62-3.40; p < 0.0001). The adjusted HR (Q4 vs. Q1) for all-cause mortality was 2.25 (95% CI, 1.80-2.81; p < 0.0001), and for cardiac mortality, it was 2.50 (95% CI, 1.81-3.45; p < 0.0001). There was no significant interaction between baseline NT-proBNP levels and the effect of randomized treatment. The addition of NT-proBNP to the CHA2DS2VASc score improved prognostic discrimination, with an increase in the C-statistic from 0.620 (95% CI, 0.592-0.647) to 0.646 (95% CI, 0.619-0.673).


Levels of NT-proBNP are often elevated in persistent or permanent AF, independently associated with an increased risk for stroke and mortality, and associated with improved risk stratification beyond that offered by the CHA2DS2VASc score. There was no interaction between NT-proBNP and treatment, and apixaban was superior to warfarin across NT-proBNP quartiles.


In this prespecified ARISTOTLE biomarker substudy, the authors demonstrated that NT-proBNP levels are independently related to the risk of stroke or systemic embolism and all-cause and cardiac mortality. Of particular interest, the authors reported that ‘despite a CHA2DS2VASc score of 0-1, if NT-proBNP level was >1250 ng/L, the annual risk for stroke and systemic embolism equaled those with a score of ≥3 and levels ≤363 ng/L.’ Further research and studies should define the role of natriuretic peptides as a tool for selecting patients with AF for anticoagulation.

Clinical Topics: Anticoagulation Management

Keywords: Stroke, Proportional Hazards Models, Warfarin, Peptide Fragments, Risk Factors, Pyrazoles, Embolism, Risk Assessment, Pyridones, Natriuretic Peptide, Brain

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