Novel Biomarkers of Heart Failure: Do They Have Incremental Clinical Utility?

Clinicians often struggle to reliably determine the clinical stability of patients with chronic heart failure (HF). The availability of diagnostic and prognostic biomarkers over the past decade has enabled much needed objective assessments in an otherwise highly subjective management process. In this issue of the Journal, 2 experienced biomarker research teams provide contrasting insights into the contribution of novel and clinically available HF biomarkers—soluble ST2 (sST2) and galectin-3 (Gal-3)—to risk stratification of ambulatory patients with HF. Such discordance creates a very divisive debate over how to best determine the usefulness of biomarkers in the clinical management of patients with HF. This is true even for the most widely-studied and clinicallyadopted HF biomarker to date—natriuretic peptides. In a meticulously conducted serial biomarker study at the Mayo Clinic, Miller et al assert that sST2 (and to a lesser extent Gal-3) may serve as an independent predictor of adverse events, and that serial measures of sST2 (but not Gal-3) may identify the highest-risk ambulatory patients with HF. It should be noted that relevant confounding clinical factors of adverse longitudinal outcomes consistently identified in earlier heart failure studies were not incorporated (age, sodium, and blood urea nitrogen, to name a few) in their models. The exclusion of clinical variables in the head-to-head analysis comparing relative prognostic values of biomarkers, although appropriate owing to the limited number of events, can be easily overlooked in their optimistic conclusions. Nevertheless, an insightful aspect of the Mayo Clinic report comes from the description of the patterns of change in biomarkers over time. With the use of the arbitrary cutoff values, more than one-third of patients had Gal-3 values change from “low” to “high,” and more than one-fourth of patients showed similar change for sST2 values. The authors attempted to model survival time with sST2 and other biomarkers (as dichotomous variables with the “best-fit” cutoff values) by taking different values at different times during the study. In so doing, they incorporated variables measured sequentially as “timevarying covariates” to eliminate time bias. The value of sST2 changes as survival time changes. Putting it simply, these findings suggest that “high” sST2 portends a poor prognosis whenever it is measured (whether at baseline or at followup). In fact, it would be surprising (and counterintuitive) for a biomarker measured at one time point to have different prognostic significance when measured at a different time point. Furthermore, a change would be meaningful only if the followup value of a biomarker reaches a lower stratum of risk rather than the actual degree by which it is reduced. The Penn Heart Failure Study, which previously demonstrated the incremental prognostic value of sST2 with the use of a threshold method similar to that used in the Mayo Clinic study, provides a somewhat contrasting viewpoint in a new analysis of their single-draw multicenter cohort study. In the new analysis, baseline Gal-3 levels demonstrated superb riskdiscrimination over other standard biomarkers in assessing long-term risk of adverse events—particularly in patients with HF and preserved left ventricular ejection fraction (LVEF). The relatively large cohort provided only several minor threats to validity. First, the authors did not adjust for New York Heart Association (NYHA) functional class or LVEF in their analysis, because they thought that these covariates would be on the causal pathway. Indeed, both biomarkers may track with clinical severity but can be likely be affected by a variety of mechanisms and are likely important confounders but not mediators (ie, on the causal pathway) of the Gal-3–risk relationship. From a more pragmatic perspective, both NYHA functional class and LVEF are routinely (and easily) assessed in clinical practice. Understanding their impact on the Gal-3–risk relationship would be a very useful message to clinicians attempting to interpret the value of this novel biomarker. Perhaps one of the more interesting results from the Penn Heart Failure Study was the finding that Gal-3 levels had a relatively higher outcome discriminatory ability in HF From the Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio. Reprint requests: W. H. Wilson Tang, MD, 9500 Euclid Ave, Desk J3-4, Cleveland, OH 44195. Tel: +1-216-444-2121; Fax: +1-216-445-6165. E-mail: tangw@ccf.org Manuscript received February 8, 2016; revised manuscript accepted February 18, 2016. See page 264 for disclosure information. 1071-9164/$ see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2016.02.006