Clinical Research Study
CA125-Guided Diuretic Treatment Versus Usual Care in Patients With Acute Heart Failure and Renal Dysfunction

https://doi.org/10.1016/j.amjmed.2019.07.041Get rights and content

Abstract

Background

The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation.

Methods

This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively.

Results

The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m2. Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m2) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391).

Conclusion

A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction.

Introduction

Clinical Significance

  • At 72 hours, the CA125-guided strategy group had a higher dose of loop diuretics and higher urine volume than in usual-care protocols.

  • At 72 hours, the CA125-guided strategy group showed more improved renal function than patients in usual-care protocols.

  • The CA125-guided strategy derived in significant reductions in clinical events at 30 days.

  • Our data support CA125 to adjust diuretics dose in acute heart failure with renal dysfunction.

The optimal diuretic strategy in patients with acute heart failure remains unclear,1,2 particularly when renal dysfunction coexists at presentation.2,3 Overwhelming evidence indicates that the coexistence of these 2 conditions is associated to longer hospital stays and higher risk of adverse clinical outcomes.4

Recent studies indicated that the prognostic implications of worsening renal function are strongly related to clinical response, volume status, magnitude of changes in renal function, and degree of baseline renal impairment.3, 4, 5, 6 Recent studies have highlighted the potential contribution of renal venous congestion to renal impairment3,7 beside the putative effect of renal hypoperfusion. Unfortunately, traditional methods of evaluation have limited accuracy in terms of assessing the severity and organ distribution of fluid overload. Indeed, no clinical tool in the routine patient management can identify whether renal hypoperfusion or renal venous congestion play a major role in the pathogenesis of renal dysfunction in acute heart failure.8

Carbohydrate antigen 125 (CA125) has emerged as a reliable marker of congestion in patients with acute heart failure.9 Indeed, a recent clinical trial showed that, compared to usual care, CA125-guided therapy was associated with a marked reduction in the composite endpoint of 1-year death or acute heart failure-related readmission in acute heart failure. The improvement in prognosis was mainly the effect of individualizing patients’ decongestive therapy.10 However, CHANCE-HF design did not address the role of worsening renal function in the outcomes tested. Preliminary observational data suggest that plasma levels of CA125 may play a role for tailoring the intensity of diuretic treatment in patients with acute heart failure and renal dysfunction on admission by identifying the congestive renal failure phenotype.11 Specifically, in patients with acute heart failure, we found that higher doses of diuretics translated into lower adverse events and short-term improvement in renal function in those with higher values of CA125 and renal dysfunction on admission. At the opposite, in those with low CA125 and renal dysfunction on admission, higher diuretic doses were associated with higher risk of adverse clinical events and further worsening renal function.11

In this trial, we hypothesize CA125 diuretic-guided treatment compared with standard of care will improve short-term renal and clinical outcomes in patients with acute heart failure and renal dysfunction at presentation, a subset of patients known to be at higher risk of adverse events and in which the intensity of depletive treatment is even more uncertain.1,2

Section snippets

Study Design

This investigator-initiated, multicenter, open-label, parallel study, randomized patients with acute heart failure and renal dysfunction at presentation in 2 groups (1:1). One group received usual care (ie, regular loop diuretics with dosage based on clinical evaluation and no knowledge of CA125 values). The other group received loop diuretics with dosage based on plasma levels of CA125 (CA125 guided).12 Due to the study design, physicians were not blinded to patient allocation. All other

Discussion

In acute heart failure, renal dysfunction at presentation is highly prevalent and associated with adverse outcomes.3,4 The use of intravenous loop diuretics remains the cornerstone of treatment for acute heart failure syndromes; however, its dose titration is still determined empirically by a trial-and-error process.1 The uncertainty about the optimal dose of diuretics is even more important when there is concomitant renal dysfunction at presentation.1,3 This unmet need prompted us to compare a

Conclusion

In patients with acute heart failure and renal dysfunction at presentation, CA125-guided intravenous diuretic therapy had no effect on eGFR at 24 hours but resulted in better renal performance at 72 hours and 30 days. In addition, with this strategy a borderline reduction of adverse clinical endpoints was also noted at 30 days. This preliminary evidence requires additional and better-powered studies confirming the utility of CA125 for tailoring decongestive treatment in scenarios of acute heart

Acknowledgments

We gratefully acknowledge the assistance of Amparo Villaescusa, Paula Lizandra, Antonio Gabarrón, Marta Peiró, Loli Iglesias, and Bernat Navarro.

References (28)

Cited by (56)

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    Citation Excerpt :

    Traditionally a marker for ovarian cancer, CA-125 is produced by pleural and pericardial mesothelial cells during hemodynamic and inflammatory stress. CA-125 is a strong predictor of acute HF among outpatients, and biomarker-guided therapy has already been shown to improve renal function parameters and outcomes in acute decompensated HF.19-22 IL1RL1 (sST2), FGF-21, GDF-15, and FABP4 were among other significant up-regulated biomarkers, previously shown to be involved in inflammation, lipid metabolism, oxidative stress, cardiac remodeling, and worse outcomes.23-26

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Funding: This work was supported by: Project PI13/01519 in collaboration with “Plataforma de Unidades de Investigación Clínica y Ensayos Clínicos” (SCReN) (PT13/0002/0031). Co-funded by “Fondos FEDER”; unrestricted grants from “Proyectos de Investigación de Insuficiencia Cardiaca de la Sección de Insuficiencia Cardiaca 2015” and “Beca Mutual Médica 2014”; PIE15/00013, and CIBER CV 16/11/00420 and 16/11/00403. The funder has no role in the study design, data collection, analysis and modeling, interpretation of the results, and in writing the manuscript.

Conflicts of Interest: JN received board speaker fees and travel expenses from Novartis, Roche Diagnostics, Abbott, Rovi, Vifor Pharma, and AstraZeneca. LF received speaker fees and travel expenses from Novartis. VB-G received speaker fees and travel expenses from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Pfizer, LivaNova, Sanofi, Ferrer, Medtronic, and St Jude Medical. JS received speaker fees from Astra-Zeneca, Abbott, and Edwards Lifesciences. JLG received board membership fees, speaker fees, and consulting fees from Astra Zeneca and Vifor Fresenius Medical Care Renal Pharma. AAV received consultancy fees and/or research grants from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, GlaxoSmithKline, Novartis, Roche Diagnostics, and Servier. AB-G received board membership fees and travel expenses from Novartis, Roche Diagnostics, and Critical Diagnostics. PL, SG-B, CB, SV, JMN, RS, RE, JMV, AC, MR, CC, VB, EV, ES, MCM, GM, AC, ER, AM, PP, MJB, JL JN, FJC eport none.

Authorship: All the authors had access to the data and a role in writing this manuscript.

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