Enhancing the ‘real world’ prediction of cardiovascular events and major bleeding with the CHA₂DS₂-VASc and HAS-BLED scores using multiple biomarkers

Abstract

Background: Atrial fibrillation (AF)-European guidelines suggest the use of biomarkers to stratify patients for stroke and bleeding risks. We investigated if a multibiomarker strategy improved the predictive performance of CHA₂DS₂-VASc and HAS-BLED in anticoagulated AF patients.

Methods: We included consecutive patients stabilized for six months on vitamin K antagonists (INRs 2.0–3.0). High sensitivity troponin T, NT-proBNP, interleukin-6, von Willebrand factor concentrations and glomerular filtration rate (eGFR; using MDRD-4 formula) were quantified at baseline. Time in therapeutic range (TTR) was recorded at six months after inclusion. Patients were follow-up during a median of 2375 (IQR 1564–2887) days and all adverse events were recorded.

Results: In 1361 patients, adding four blood biomarkers, TTR and MDRD-eGFR, the predictive value of CHA₂DS₂-VASc increased significantly by c-index (0.63 vs. 0.65; p = .030) and IDI (0.85%; p < .001), but not by NRI (−2.82%; p < .001). The predictive value of HAS-BLED increased up to 1.34% by IDI (p < .001). Nevertheless, the overall predictive value remains modest (c-indexes approximately 0.65) and decision curve analyses found lower net benefit compared with the originals scores.

Conclusions: Addition of biomarkers enhanced the predictive value of CHA₂DS₂-VASc and HAS-BLED, although the overall improvement was modest and the added predictive advantage over original scores was marginal.

Key Messages

• Recent atrial fibrillation (AF)-European guidelines for the first time suggest the use of biomarkers to stratify patients for stroke and bleeding risks, but their usefulness in real world for risk stratification is still questionable.

• In this cohort study involving 1361 AF patients optimally anticoagulated with vitamin K antagonists, adding high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, interleukin 6, von Willebrand factor, glomerular filtration rate (by the MDRD-4 formula) and time in therapeutic range, increased the predictive value of CHA₂DS₂-VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers.

• Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower.

Keywords:

• Atril fibrillation
• biomarkers
• haemorrhage
• risk assessment
• stroke

Disclosure statement

VR has received funding for consultancy and lecturing from Bristol-Myers-Squibb, Bayer and Boehringer-Ingelheim. FM has received funding for research, consultancy and lecturing from Abbott, Boston Scientifics, Bayer, Astra Zeneca, Daiichi-Sankyo, BMS/Pfizer and Boehringer-Ingelheim. GYHL has received funding for consultancy from Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife and Daiichi-Sankyo; and for lecturing from Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche and Daiichi-Sankyo. No fees are received personally.

None declared in relation to this manuscript for other authors.

Additional information

Funding

This work was supported by Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional (FEDER) (PI13/00513 and P14/00253), Fundación SÉNECA (grant number: 19245/PI/14), and Instituto Murciano de Investigación Biosanitaria (IMIB16/AP/01/06). José Miguel Rivera-Caravaca has received a grant from Sociedad Española de Trombosis y Hemostasia (Grant for short international training stays 2016).