Outcomes of Patients Across the Spectrum of Pulmonary Hypertension Groups Prescribed Inhaled Treprostinil

Abstract

Pulmonary hypertension (PH) frequently complicates cardiopulmonary conditions and associates with worse outcomes. Treatment of PH disproportionate to concomitant heart and lung disease remains controversial, although inhaled treprostinil (iTRE) was recently approved for use in group 3 PH due to interstitial lung disease. We evaluated the impact of iTRE treatment on rates of disease progression in patients who fell into a spectrum of World Symposium PH groups. METHODS:We performed a retrospective cohort study in patients with PH who were treated with iTRE at Duke University between 2009 and 2017. All patients had PH (mean pulmonary artery pressure (mPAP) $ 25mmHg) due to groups 1, 4 or 5, and a subset had mixed disease with group 1 PH and components of groups 2 or 3 (a pulmonary vascular resistance [PVR] > 3 WU and pulmonary capillary wedge pressure > 15mmHg or with significant lung disease, respectively). We compared time to disease worsening, a composite measure of death, lung transplant or transition to IV prostacyclin, among patients who discontinued iTRE within 3 months versus patients remaining on iTRE > 3 months. We used multivariable cox proportional hazards models to adjust for age, sex and REVEAL Lite 2 Score. We also compared time to disease worsening among different PH groups, and evaluated if PH group mediated the relationship between iTRE duration and disease worsening. RESULTS:Our cohort included 270 patients with PH classified as follows: 30.6% group 1, 10% mixed group 1 and 2, 32.2% mixed group 1 and 3, 11.1% mixed group 1,2 and 3, and 15.9% with either group 4 or 5. The cohort had a median mPAP of 50.0 mmHg (44.0, 57.0) and median PVR of 9.1 mm Hg/l•min (7.1, 11.6). Clinical and demographic characteristics were similar among the 203 (75.2%) subjects who continued iTRE for at least 3 months compared to the 67 (24.8%) who discontinued iTRE prior to 3 months. In a multivariable model, patients who discontinued iTRE prior to 3 months had a higher risk of disease worsening compared to patients who tolerated iTRE for > 3 months (HR 1.82 [95% CI 1.47, 2.16], p < 0.009). Patients with mixed groups 1,2, and 3 PH had the highest risk of disease worsening (p¼0.02) in a univariable model, but in a multivariable model time to disease worsening did not significantly differ by PH group (p = 0.26). PH group also did not mediate the relationship between iTRE duration and disease worsening (p = 0.156).CONCLUSIONS: Irrespective of disease severity, discontinuation of iTRE before 3 months was associated with a higher risk of disease worsening. PH group was not associated with risk of disease worsening among PH patients started on iTRE.CLINICAL IMPLICATIONS: Treatment with iTRE in patients with PH groups 1&2 or 1&3 resulted in similar outcomes as in patients with group 1 disease. Prospective, randomized studies are necessary to confirm this finding.