Biomarker‐guided management in acute heart failure: is there light at the end of the tunnel?

This article refers to ‘Improve Management of acute heart failure with ProcAlCiTonin in EUrope: results of the randomized clinical trial IMPACTEU Biomarkers in Cardiology (BIC) 18’, by M. Möckel et al., published in this issue on pages XXX. ‘Biomarkers will make bad doctors worse, and good doctors better’. Alan Maisel A biomarker is any laboratory measurement with the potential to increase precision in the detection and characterization of a disease. Biomarkers must be embedded in clinical algorithms to complement and not to replace clinical acumen, and they should be used only if their evaluation has consequences on clinical decision making. We must move beyond the observational report of the diagnostic and prognostic accuracy of biomarkers towards intervention studies conducted to prove outcome-relevant impacts on patient care.1 The hypothesis of biomarker-guided management arose almost 20 years ago by Richard Troughton and Mark Richards in a pilot study that used an objective measurement of natriuretic peptide (NP) in a small cohort of ambulatory heart failure (HF) patients.2 This initial study provided the nucleus for a multitude of prospective studies launched in subsequent years with conflicting results. The most recent GUIDE-IT trial, the largest and most ambitious NP-guided trial in ambulatory HF,3 was neutral for the biomarker-guided arm, thus putting the field of biomarker-guided management in ambulatory HF into the psychiatrist lounge. In the setting of acute HF (AHF), an area needing good news, the data follow a similar path. Two well-conducted NP-guided trials in AHF, PRIMA II4 and Carubelli et al.,5 have been disappointing. PRIMA II showed that, in stabilized patients hospitalized for AHF, N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided therapy using a pre-defined target (>30% reduction) did not reduce readmission or mortality at 180 days compared to conventional therapy.4 Carubelli et al.5 reported that, in patients hospitalized for AHF, enhanced therapy based on pre-discharge plasma levels of NT-proBNP was not associated with better long-term outcomes. Procalcitonin (PCT) has emerged recently as a very attractive companion biomarker in acute settings for antibiotic stewardship in infections of the respiratory tract and sepsis. Normal serum/plasma concentrations of PCT are <0.05 ng/mL, but PCT is produced in large quantities by many body tissues in systemic inflammation, particularly during bacterial infections.6-8 PCT levels parallel the severity of the inflammatory insult or infection, meaning that those with more severe disease have higher levels of PCT. In patients with acute dyspnoea, plasma PCT has been used to differentiate between AHF and superimposed pneumonia and been postulated as a promising biomarker for guiding antibiotic therapy in patients with AHF.9 In the current issue of the Journal, Möckel et al.10 provide the results of a randomized multicentre clinical trial, Improve Management of Acute Heart Failure with Procalcitonin in Europe (IMPACT EU). This study, which was terminated prematurely due to futility, aimed to evaluate whether PCT-guided initiation of antibiotics in patients with suspicion of AHF who present to the emergency department would improve clinical outcomes. Out of the 792 planned patients, 762 were enrolled when the safety and review committee recommended study discontinuation. Ultimately, only 742 patients could be analysed, with 90-day all-cause mortality of 10.3% in the PCT-guided group vs. 8.2% for standard care (P = 0.392). This prospective study originated from secondary analyses of the multicentre BACH study, in which investigators identified worse outcomes in patients treated with antibiotics and negative PCT.11 The well-designed and rigorously executed IMPACT EU trial provides a clear-cut answer to an attractive hypothesis, which can now rest in peace. We also await the results of IMPACT US, which has a similar design, and that will be reported soon. Nevertheless, as Einstein pointed some time ago, ‘If you want different results, do not do the same things.’ A number of well-acknowledged limitations apply to this trial, which may be summarized as follows: (i) the landscape of HF is changing quickly and AHF triage, diagnosis, and management has improved substantially recently; (ii) biomarker-guided trials are subject to physician and patient biases not present in the more conventional double-blind randomized controlled trials on drug efficacy. Is there any future for biomarker-guided management in AHF? The use of a biomarker of myocardial stress, e.g. NT-proBNP, or an infection surrogate, e.g. PCT, is currently discarded on the basis of the available data (Figure 1). As congestion is the landmark sign in patients with AHF, testing a biomarker of congestion seems to be the next logical step. Núñez and colleagues fostered such research using carbohydrate antigen 125 (CA125), which is widely available in all clinical laboratories, cheap, easy to measure, and reproducible, and has emerged as a valuable surrogate of fluid retention and inflammation in AHF. CA125 is synthesised by serous epithelial cells in response to congestion and/or inflammatory stimuli.12 Published data indicate that high levels of CA125, present in up to two-thirds of patients hospitalized for AHF,13 correlate well with the severity of AHF14 and are related to morbidity and mortality.15 The CHANCE-HF trial sought to evaluate the prognostic effect of CA125-guided therapy versus standard of care after hospitalization for AHF.16 This study showed that, after being discharged for AHF, CA125-guided therapy aiming to keep CA125 levels <35 U/mL is associated with a reduced risk of adverse 1-year outcomes. This effect was mainly driven by significant reduction of the rate of rehospitalization. More recently, the same team reported the results of the IMPROVE-HF (a randomized controlled trial of CA125-guided diuretic treatment vs. usual care in patients with AHF and renal dysfunction) trial.17 In patients with AHF and renal dysfunction at presentation, CA125-guided intravenous diuretic therapy resulted in better renal performance at 72 h and 30 days. This treatment strategy also improved the global visual analogue scale score and decreased the risk of adverse clinical endpoints at 30 days.17 Although further research is warranted to confirm the utility of CA125 for tailoring decongestive treatment in AHF, these two trials shed some end-of-the-tunnel light on biomarker-guided strategies in AHF (Figure 1). Other biomarkers such as high-sensitivity troponins18 and soluble ST2,19 both well-known predictors of ventricular remodelling and worse outcome in AHF, have not yet been tested in therapy guidance trials. Conflict of interest: none declared.