Optimizing clinical use of biomarkers in high‐risk acute heart failure patients

Abstract

AimThe clinical value of single biomarkers at single time-points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi-time-point analysis of biomarkers for the prediction of post-discharge clinical outcomes in high-risk AHF patients. Methods and resultsA set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30-day all-cause mortality, 30-day death or rehospitalization for renal/cardiovascular causes and 180-day all-cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time-dependent area under the curve (AUC) analysis. Forty-four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C-index < 0.70). However, multimarker models combining best-performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL)-6, cTnI, sST-2 and VEGFR-1 into a clinical model yielded a 11% increase in C-index to 0.84 and 0.78 for 30-day and 180-day all-cause mortality, respectively, and cNRI of 0.86 95% . Prognostic gain was modest for the 30-day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time-dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all-cause mortality over 180 days, with few exceptions including BUN and galectin-3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement.

Novel heart failure biomarkers: why do we fail to exploit their potential?

“…Nevertheless, because IL-6 has been shown to be involved in HF development, and because levels of this inflammatory marker are increased in HF and are able to predict HF outcome in various types of HF [5,[115][116][117][118][119], it could serve as an HF biomarker. The use of IL-6 in a multi-biomarker model has been suggested [120], but circulating IL-6 levels are also affected by factors like stress, physical exercise, gender and age [119]. Moreover, circulating levels are also increased in non-HF patients; for example, elevated IL-6 plasma levels were predictive for post-operative complications in patients post-abdominal surgery [121], and IL-6 levels were associated with outcome in acute stroke patients [122].…”

Endothelial Glycocalyx as Biomarker for Cardiovascular Diseases: Mechanistic and Clinical Implications

“…Longitudinal observational studies of patients with acute or chronic heart failure also suggest correlations to serum soluble sdc1 [45–47]. Neves et al studied 201 patients with acute decompensated heart failure [46].…”

“…Demissei et al also prospectively observed 2,033 patients with acute heart failure, after stabilization during hospital stay, of which 17.6% of patients died within 180 days of the study [45]. They evaluated the diagnostic accuracy of 44 biomarkers for heart failure, including sdc1.…”

“…They evaluated the diagnostic accuracy of 44 biomarkers for heart failure, including sdc1. Although differences in hazard ratios of sdc1 for 30-day and 180-day mortality were significant at 1.43 and 1.27 per 1 standard deviation, their C-statistics were not as high (0.767 for 30-day mortality and 0.706 for 180-day mortality), and continuous net reclassification improvements (cNRI) were only 0.38 and 0.24, when sdc1 was added to the conventional model [45]. …”

“…[45, 47] In addition, the interpretation of the tests requires special attention because the application of C-statistics often eliminates established risk factors from new models [60, 61], and net reclassification is often positive for even weak markers, leading to overestimation of the real risk. [62–64] Conversely, the clinical value of sdc1 as a prognosticator of cardiovascular events is still unestablished.…”