Pre-treatment lysis time of plasma-derived fibrin clots and bleeding in patients on oral anticoagulants for atrial fibrillation in the ARISTOTLE trial

Clinical Snapshot

Key Findings

• P Value: P = 0.001 (unadjusted), P = 0.016 (adjusted)

• Effect Size: HR 2.99 (shortest vs longest lysis time quartile)

• Primary Outcome: Major and clinically relevant non-major bleeding: 6.3%/year (Q1) vs 2.1%/year (Q4)

• Nnt Or Sensitivity: Number needed to harm approximately 24 patients per year (based on 4.2% absolute risk difference)

• Confidence Interval: 95% CI 1.75-5.12

Clinical Application

Fibrin clot lysis time testing requires specialised laboratory facilities and is not routinely available in clinical practice Could complement existing bleeding risk tools like HAS-BLED in Australian AF management, but would require TGA approval for diagnostic use and PBS consideration for funding Patients with atrial fibrillation requiring oral anticoagulation, particularly those at uncertain bleeding risk

Abstract

BACKGROUND AND AIMS: Oral anticoagulation reduces stroke risk in patients with atrial fibrillation (AF) but increases bleeding. Longer fibrin clot lysis time has been shown to predict adverse cardiovascular outcomes in acute coronary syndromes. This study explored relationships between fibrin clot lysis time at randomization and clinical outcomes in patients with AF enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. METHODS: Plasma samples were obtained from anticoagulation-naïve participants, before initiation of study medication (n = 1841). Fibrin clot turbidimetry was performed, and lysis time determined. Associations between lysis time and characteristics, biomarkers, and on-treatment bleeding and cardiovascular events were assessed by lysis time quartile (Q1-4, shortest to longest). RESULTS: A shorter lysis time was associated with being older, male, permanent AF, lower body mass index, estimated glomerular filtration rate and C-reactive protein, and higher N-terminal pro-B-type natriuretic peptide. Major and clinically relevant non-major bleeding was significantly more frequent in lysis time Q1 vs. Q4 [6.3%/yr vs. 2.1%/yr; HR, 2.99 (95% CI, 1.75-5.12); P = .001], including after multifactorial adjustment [HR, 2.61 (1.45-4.69); P = .016]. Those in Q2 and Q3 had intermediate bleeding risk vs. Q4 [HR, 2.21 (1.27-3.87); 2.08 (1.18-3.66) respectively], suggesting a graduated effect. Treatment allocation to apixaban vs. warfarin did not affect the relationship between lysis time and bleeding (interaction-P = .80). There was no significant association between lysis time and a composite of cardiovascular death, stroke, systemic embolism or myocardial infarction. CONCLUSIONS: Shorter pre-treatment fibrin clot lysis time independently predicted higher bleeding risk in patients receiving oral anticoagulation for AF.

References

1. 1.Granger, C. B., Alexander, J. H., McMurray, J. J., Lopes, R. D., Hylek, E. M., Hanna, M., Al-Khalidi, H. R., Ansell, J., Atar, D., Avezum, A., Bahit, M. C., Diaz, R., Easton, J. D., Ezekowitz, J. A., Flaker, G., Garcia, D., Geraldes, M., Gersh, B. J., Golitsyn, S., ... Wallentin, L. (2011). Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 365(11), 981-992. https://doi.org/10.1056/NEJMoa1107039