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Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials

https://doi.org/10.1016/j.healun.2011.03.011Get rights and content

Background

Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil.

Methods

A retrospective review was conducted using data from a total of 811 patients with New York Heart Association Functional Class (NYHA FC) II to IV PAH, who were treated with subcutaneous treprostinil. Patient baseline disease and on-treatment parameters were analyzed by uni- and multivariate analyses for predictive value of 3-year survival with PAH.

Results

Among the baseline disease-related factors analyzed, there was a significantly higher risk of death (p < 0.001) associated with connective tissue disease–associated PAH relative to idiopathic PAH (hazard ratio for death [HR] 1.93), NYHA FC IV vs III (HR 2.31), pulmonary vascular resistance index (PVRI) >30 vs ≤16 mm Hg/liter/min/m2 (HR 2.44) and mixed venous oxygen saturation (SVO2) ≤55% vs >55%. The 6-minute walk distance (6MWD) of ≤295 m after 12 weeks of treprostinil treatment was associated with reduced survival at 3 years (58%). A ≥20-m increase from baseline in 6MWD was associated with greater survival (80%) vs smaller walk increments (69%; p = 0.039). Treprostinil dose of ≥40 ng/kg/min (p < 0.001) and every 10-ng/kg/min dose increase (p = 0.009) resulted in improved long-term survival. In a multivariate analysis, only SVO2, 6MWD and treprostinil dose were significant on-treatment predictors (p < 0.02) of survival.

Conclusions

Disease etiology, baseline factors (NYHA FC, PVRI and SVO2) and on-treatment factors (6MWD, SVO2 and treprostinil dose) were predictors of survival in this study and may be used to aid in treatment optimization.

Section snippets

Population description

This was a retrospective analysis of patients who were enrolled in 3 trials (P01: 04, 05, 06) of SC treprostinil treatment for PAH between June 25, 1998 and December 1, 2003.7, 21, 22 All non-chronic thromboembolic pulmonary hypertension (non-CTEPH) subjects enrolled in the open-label trial of SC treprostinil were included in the analysis, and all patients were on treprostinil therapy. Patients were followed for as long as they received treprostinil and were censored at the time of

Baseline characteristics

Of the 811 patients in this analysis, 628 (77%) were female, and the mean age was 45 (range 5 to 83) years. The most common diagnosis was IPAH (52%, n = 425). Patients in the database were NYHA FC II (16%, n = 126), NYHA FC III (76%, n = 614) and NYHA FC IV (9%, n = 71) at baseline. Twenty-three percent (186 of 811) of the patients were on concomitant PAH medications, including another prostanoid (8%, which includes patients transitioning to intravenous epoprostenol and patients on concomitant

Discussion

Because of the orphan disease status of PAH and ethical issues related to placebo treatment of patients with this debilitating disease, randomized, controlled trials are rarely adequately designed or powered to assess disease survival or prognostic factors of survival benefit.23 In the absence of well-controlled survival trials, there is a need to identify surrogate markers to accurately predict survival. Using a large database of patients with PAH receiving SC treprostinil, we sought to

Disclosure statement

United Therapeutics provided the authors with full access to the trial data and all statistical analyses, as directed by the authors. MedThink Communications provided editorial assistance and project management under the authors' direction, with financial support from United Therapeutics Corporation.

R.L.B. has served as a paid consultant to Pfizer and has received research funding from the sponsor (United Therapeutics Corp.), Lung Rx, Pfizer, Gilead Sciences and Actelion. He is a paid speaker

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