Phenotype and outcome correlates of high dose loop diuretics in type 1 pulmonary hypertension

Abstract Background Use of higher dose of loop diuretics has been associated with worse survival in acute and chronic heart failure. The use of loop diuretics in type 1 pulmonary hypertension (PAH) is generally less frequent compared to heart failure and required doses may be lower. the clinical and prognostic characteristics of patients requiring high dose of loop diuretics in PAH remain unexplored. Purpose We studied the characteristics of patients requiring different doses of loop diuretic and their association with survival in PAH. Methods Patients with a diagnosis of PAH according to 2015 European guidelines criteria enrolled from 2001 and 2021 at seven European centers for the management of PAH and with available information on loop diuretic use were retrospectively included in the study. High dose diuretic use was defined according to the median dose of furosemide in the overall cohort and patients were then divided into two subgroups: no/low dose and high dose diuretic use. Primary outcome was 5-year survival. Predictors of high dose diuretic use were assessed by multivariable logistic regression analysis. Multivariable Cox regression analysis was performed to test the association between high dose diuretic use and 5-year survival. Results Among the 402 patients included (median age 61 years, IQR 49-74; 67% females), 231 (57%) were treated with loop diuretics. Median furosemide dose was 25 mg (IQR 0-40 mg) and accordingly patients were divided in no/low dose (n. 260, 65%, median dose 0 mg, IQR 0-20) vs high dose (n. 142, 35%, median dose 40, 50-100) diuretic ones. Patients in the high dose group were older, had more comorbidities, including impaired renal function (Figure 1) and the characteristics of a more severe disease (41% vs 27% at intermediate-high risk and 42% vs 22% at high risk based on COMPERA 2.0 classification, p<0.001). Predictors of high dose loop diuretic use were obesity (OR 2.04, 95%CI 1.06-3.91, p=0.032), COMPERA 2.0 risk class (OR 1.66, 95%CI 1.19-2.31, p=0.003) and right atrial pressure risk class (OR 2.23, 95%CI 1.42-3.51, p=0.001). Rates of monotherapy, dual and triple combination therapy were similar in patients at no/low vs high dose. Crude 5-year survival was significantly lower in patients in the high dose group (log-rank p=0.002). However, after adjustment for age, sex and main risk factors (i.e. COMPERA 2.0 score, TAPSE/PASP, right atrial pressure and cardiac index), high loop diuretic dose was not significantly associated with higher 5-year mortality risk. Conclusions Use of high dose of loop diuretics in PAH characterizes patients with higher burden of comorbidities, more severe disease and worse survival. However, in PAH the need of high loop diuretic dose represents a marker of disease severity rather than an independent prognostic factor.Figure 1Figure 2.