Association Between Growth Differentiation Factor-15 and Outcomes Among Patients With Heart Failure: A Systematic Literature Review

Background: Growth differentiation factor-15 (GDF-15) is upregulated during myocardial injury and stress, and is an emerging biomarker of adverse outcomes in patients with heart failure (HF). Although systematic literature reviews (SLRs) of GDF-15 and HF have been conducted, few assessed outcomes other than mortality. Aim: This SLR examined the association of GDF-15 levels with a broad range of outcomes in patients with HF. Methods: Following PRISMA guidelines, Embase and Medline were searched to identify articles published 1/1/2014–8/23/2022 reporting outcomes associated with GDF-15 in adults with HF. Both cross-sectional (assessed at the same time as GDF-15) and longitudinal outcomes were included. Results: Sixty-three publications met eligibility criteria: 45 were observational studies and 18 post hoc analyses of randomized controlled trials. A total of 19 outcomes were identified. The most frequently reported longitudinal outcomes were mortality (n=32), composite endpoints (e.g., death ± hospitalization; n=28) and hospitalization (n=11). The most common cross-sectional outcome was biomarkers of kidney function (n=22). Of 27 studies assessing all-cause mortality, 24 conducted multivariable analyses (MVA), of which 22 (91.7%) reported a significant, independent association between higher baseline GDF-15 and all-cause death. Among the 26 studies reporting association between baseline GDF-15 and composite endpoints, 19 used MVA and 13/19 (68.4%) reported at least one significant association. Among 10 studies assessing hospitalization and baseline GDF-15, 8/10 (80%) reported outcomes using MVA, of which 50% found a significant association. Twenty studies assessed the cross-sectional association between baseline GDF-15 levels and measures of kidney function. Of these, 7 used MVA and reported statistically significant associations. Conclusions: The results of the SLR suggest that GDF-15 is an independent predictor of mortality and other adverse, nonfatal outcomes in patients with HF. Better understanding of the potential prognostic role of GDF-15 in HF could improve clinical risk prediction and identify patients with HF who may warrant additional treatment optimization/intensification.