Effect of a short course of parenteral treprostinil therapy on right heart structure and function in pulmonary arterial hypertension

Abstract

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, leading to increased afterload and right-sided heart failure. It is important to routinely assess disease progression and treatment response, with echocardiography an increasingly recognized important component of risk assessment. Parenteral prostacyclin therapy has been shown to be associated with improvements in right-sided cardiac structure and function, which are prognostic in PAH. Purpose To describe changes in right-sided cardiac structural and functional parameters after a short course of parenteral treprostinil. Methods The EXPEDITE trial (NCT03497689) was a 16-week open-label study of WHO Functional Class (FC) II or III patients with PAH designed to assess short-term (expedited) induction therapy with parenteral treprostinil over 2-8 weeks, to facilitate transition to comparable doses of oral treprostinil. The subset of patients in the per-protocol population that had clinical and/or echocardiographic data available at both baseline (prior to initiation of parenteral treprostinil) and end of induction (2-8 weeks) were included for analysis. Changes in each parameter were analyzed using the non-parametric Wilcoxon signed-rank test. Results In the per-protocol population of EXPEDITE (n=29), the median age was 56 years, 62% were female, and 79% were white. At baseline, 52% were classified as WHO FC II and 48% WHO FC III. Patients were on either no (n=6, 21%), 1 (n=11, 38%), or 2 (n=12, 41%) background PAH therapies. The end of the parenteral treprostinil induction period occurred at Week 2 (n=1), Week 4 (n=5), or Week 8 (n=23); the median (interquartile range) parenteral treprostinil dose achieved was 23.8 (20, 39.3) ng/kg/min. Median changes from baseline to the end of the parenteral treprostinil induction period for this analysis are shown in Table 1. There were directional changes for most measures of right-sided cardiac structure and function that reflected overall improvement; two key markers of cardiac function, cardiac output and NT-proBNP significantly improved. Conclusions In this trial of expedited parenteral treprostinil induction, we saw favorable directional trends in changes in right heart structure and function that were achieved in 8 weeks or less, including some statistically-significant parameters known to have prognostic value in PAH. The relatively rapid improvements we observed in this small cohort may signal important changes in risk status, and support treatment guidelines emphasizing importance of early improvement in the first 3-6 months following treatment. Furthermore, changes in cardiac structure and function often occur before other clinically-evident indicators of disease progression, and early response to treatment has been shown to impact long-term outcomes in patients with PAH. Larger studies with short-term serial right heart imaging assessment to confirm findings are warranted.Table 1