Diuretic resistance and the efficacy of natriuresis-guided diuretic therapy in acute heart failure: a post-hoc analysis of the PUSH-AHF trial

Background Diuretic resistance is common in acute decompensated heart failure (ADHF) patients and associated with residual congestion as well as high rehospitalization rates. Recently the BAN-ADHF score has been suggested as an easily available tool to predict diuretic resistance. It is currently unknown whether natriuresis-guided diuretic therapy might be more effective in patients at risk of diuretic resistance. Purpose To investigate the interaction between diuretic resistance, as assessed by the BAN-ADHF score, with regard to the effect of natriuresis-guided therapy compared to standard of care in patients with ADHF on natriuresis and the combined endpoint of 180-day all-cause mortality and adjudicated HF rehospitalization. Methods This study is a post-hoc analysis of the PUSH-AHF trial. Diuretic resistance was defined as a BAN-ADHF score ≥ 12. The primary outcome was the interaction between randomized treatment allocation, BAN-ADHF score and the dual primary outcomes of the PUSH-AHF trial. Results The BAN-ADHF score was available in 306 patients, with 65 (21%) patients classified as diuretic resistant at baseline. Patients with diuretic resistance had a longer history of HF, more comorbidities, lower kidney function and higher NT-proBNP levels (all p<0.001). Patients with diuretic resistance had a significantly lower mean 24-h natriuresis (294 versus 398 mmol, p<0.001, 48-h natriuresis (514 versus 641 mmol, p=0.001), and 24-h diuresis (3338 versus 3680 mL, p=0.033) compared to patients without diuretic resistance. There was a significant treatment interaction for the effect of natriuresis-guided therapy and diuretic resistance on decongestive response, where natriuresis-guided therapy was more effective in increasing 48-h, and 72-h natriuresis in diuretic resistant patients (p-int=0.038 and 0.068). Patients with diuretic resistance were at increased risk of all-cause mortality or HF rehospitalization at 180 days compared those without diuretic resistance (HR 3.5 (95% CI: 2.3-5.3); p<0.001), regardless of treatment allocation (P-int=0.39). Patients with diuretic resistance at baseline had a significantly longer length of hospital stay compared to those without diuretic resistance (median of 9 versus 6 days, p<0.001). However, there was a significant interaction between treatment allocation and diuretic resistance (p-int<0.001), where a trend to a 2 day shorter length of stay in patients with diuretic resistance randomized to natriuresis guided therapy was observed (p=0.068). Conclusion Natriuresis-guided therapy in patients with ADHF increased 24-h natriuresis irrespective of diuretic resistance at baseline. However, our data suggest that natriuresis guided therapy might be more effective in diuretic resistant patient compared to non-diuretic resistant patients in improving decongestive response and reducing length of stay.