Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients with Atrial Fibrillation: Insights from the ARISTOTLE Trial.

Wallentin L, Hijazi Z, Andersson U, on behalf of the ARISTOTLE Investigators.
Circulation. 2014 Oct 7. pii: CIRCULATIONAHA.114.011204. [Epub ahead of print]

Background

The risk of stroke in atrial fibrillation (AF) can be reduced by oral anticoagulation. This treatment is, however, associated with a risk of major bleeding. Thus, reduction of stroke and risk of bleeding need to be balanced when considering anticoagulation for stroke prevention in AF. Risk scores exist to assess both the risk of stroke (CHA₂DS₂-VASc) and the risk of bleeding (HAS-BLED). Unfortunately, the risk factors for stroke and major bleeding overlap to a large extent. Thus, a need exists for new and independent risk indicators for stroke, bleeding and mortality in patients with AF.
Several biomarkers have been identified to predict risk of stroke, mortality and bleeding in patients with AF, including markers of myocardial damage (troponin) [1-3] or cardiac dysfunction (NT-proBNP) [3,4], as well as markers of renal dysfunction [5-7].  
Growth differentiation factor 15 (GDF-15), a marker of oxidative stress and inflammation [8-10] provided independent prognostic information on CV events beyond CV risk factors and other biomarkers in different patient categories. This is a predefined biomarker substudy within the ARTISTOTLE trial that assesses the associations between GDF-15 levels at baseline and clinical outcomes while adjusting for established CV risk factors and other biomarkers in almost 15000 AF patients [11]. Furthermore, prognostic information of GDF-15 levels were compared with the currently used risk assessment scores.

Main results

• GDF-15 level distribution was skewed in the total population, without differences between the randomised treatment groups. 60.4% of patients had GDF-15 above 1200 ng/L, which is the 90^th percentile of healthy subjects of similar age. Over 32% had levels above 1800 ng/L, which is considered the highest risk group among patients with coronary artery disease.
• Annual rates of stroke increased with rising GDF-15 levels. In unadjusted analysis an annual rate of 2.03% was seen in patients with GDF-15 in the highest quartile (>2052 ng/L), while patients in the lowest quartile (<977 ng/L) showed an annual rate of 0.9%.
• GDF-15 level and the CHA₂DS₂-VASc score provided statistically significant independent prognostic information on the risk of stroke. Both c-indexes were hardly changed when the other factor was added.
• Analysis suggests that there is a consistent increase in hazard of the primary endpoint from 1000 to 3500 ng/L when GDF-15 is modelled as a continuous variable.
• Higher GDF-15 levels were strongly associated with total and cardiac mortality, with 4-5 times higher rates in the highest vs. the lowest GDF-15 quartile in unadjusted analyses. Both GDF-15 and CHA₂DS₂-VASc score provided statistically significant independent prognostic information on mortality. Adding GDF-15 gave a net reclassification improvement of 26% as compared to CHA₂DS₂-VASc and biomarkers.
• Higher GDF-15 levels were significantly associated with higher rate of major bleeding (3.5 times higher in the highest compared to the lowest quartile in unadjusted analyses). The GDF-15 level and the HAS-BLED score provided significant independent prognostic information on major bleeding. Adding GDF-15 to the HAS-BLED score and other biomarkers gave a net reclassification improvement of 33%.

Conclusion

This substudy of ARISTOTLE shows that GDF-15 levels in AF are associated to a higher risk of all CV outcomes. After adjusting for baseline characteristics, co-morbidities and biomarkers, the GDF-15 level remained an independent risk indicator for major bleeding and death. Thus, GDF-15 appears to improve risk stratification for bleeding and mortality beyond clinical risk factors in anticoagulated patients with AF, and may be added to clinical risk stratification models.
Since GDF-15 partly reflects the same process as the biomarkers NT-proBNP and cardiac troponin, GDF-15 was not an independent risk indicator for stroke in the presence of both other biomarkers.

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