Aims Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of cardiovascular mediators. Its administration has been shown to be associated with impaired cardiac contraction and kidney haemodynamics while its inhibition restored cardiac contraction in a pre‐clinical model of severe heart failure in mice. Circulating DPP3 (cDPP3) was found to be elevated in shock. The present study aims to assess the association between cDPP3 and worsening haemodynamics, namely refractory shock, in a cohort of cardiogenic shock (CS). Methods and results This is an ancillary study of OptimaCC, a prospective, double‐blind, multicentre, randomized study assessing efficacy and safety of catecholamines in 57 patients with CS after acute myocardial infarction. cDPP3 was measured in plasma at inclusion, 24 h, 48 h, and 72 h, and haemodynamic and biological parameters were recorded at inclusion. cDPP3 values were higher in refractory CS than non‐refractory CS at inclusion (median [interquartile range]; 76.1 [37.9–238.7] ng/mL vs. 32.8 [23.9–47.6] ng/mL, P = 0.014), at 24 h (P < 0.001) and up to 48 h (P = 0.027). Furthermore, cDPP3 at inclusion discriminated CS patients who did develop refractory shock vs. non‐refractory with an area under the curve of 0.73 (95% confidence interval [CI] 0.55–0.92). The high cDPP3 group (cDPP3 ≥59.1 ng/mL) at inclusion had a higher Simplified Acute Physiology Score II (SAPS II), lower cardiac index and lower estimated glomerular filtration rate. More importantly, in CS patients with high cDPP3 at inclusion, those who rapidly decreased cDPP3 at 24 h exhibited a striking reduction in the occurrence of refractory shock and death. Conclusion In CS patients, cDPP3 gives an early prediction of outcome, including development of refractory status and/or survival. Clinical Trial Registration: http://clinicaltrials.gov Identifier NCT01367743

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