Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial

Abstract

Rationale The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives This post hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group ( P = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%; P = 0.005). Conclusions Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice.

Inhaled Treprostinil in Pulmonary Hypertension in the Context of Interstitial Lung Disease: A Success, Finally

“…Because FVC decline and exacerbation accounted for almost 50% of all worsening events, this is a potential weakness of this analysis. Despite acknowledging these limitations, the current analysis provides a very consistent picture of the positive effects of continued inhaled treprostinil in PH-ILD and clearly further supports the primary analysis ( 9 , 11 ). After a long and sometimes painful journey of negative and inconclusive clinical trials, inhaled treprostinil therapy is a success for the treatment of PH-ILD, finally.…”

“…Most importantly, the two subgroup cohorts of patients with >1 worsening event can no longer be regarded as a randomized subset, as the selection of these groups occurred not in a randomized fashion but following clinical events. Although the baseline characteristics show good matching, we do not know whether the functional status of the patients was still comparable at the time when the first event occurred ( 11 ). Moreover, two of the worsening categories, ⩾10% decline in FVC and exacerbation of the pulmonary disease, were captured as safety variables and might therefore be less well standardized as variables that are captured for endpoint assessments.…”

“…198–207 ) set out to answer exactly these important questions in a post hoc analysis of the INCREASE data set focusing on ILD subgroups and consecutive clinical worsening events ( 11 ). The subgroup analysis revealed a very consistent favorable trend for all subgroups and for all the event categories investigated, which, however, reached statistical significance only for the overall number of events in the largest group of idiopathic interstitial pneumonias ( 11 ). This is not to blame, as statistical power was adjusted to the total study population and not to the subgroups.…”

“…The clinical worsening events included a ⩾15% decline in 6MWD, cardiopulmonary hospitalization, lung transplantation, or death during the study and a ⩾10% decline in the FVC and exacerbations of underlying lung disease; the latter two criteria were collected as safety endpoints and were not included as part of the prespecified composite of clinical worsening. This elegant analysis demonstrated a huge imbalance of worsening events in favor of treprostinil therapy: in the inhaled treprostinil group, 11/163 patients had >1 event versus 26/163 patients in the placebo group; this also included a clearly lower mortality rate with inhaled treprostinil, suggesting that continuing treatment is the way to go ( 11 ). However, there are limitations that apply to this study and to post hoc analyses in general.…”

Real‐world use of inhaled treprostinil for lung disease‐pulmonary hypertension: A protocol for patient evaluation and prescribing

“…The effect of inhaled treprostinil on 6MWD also drove a reduction in clinical worsening risk by 39% (95% CI: 0.40-0.92; p = 0.04) compared to placebo-treated patients. Post-hoc analyses suggest treatment benefit for disease progression 4 and, unexpectedly, forced vital capacity. 5 Collectively, these results have perpetuated enthusiasm for the use of inhaled treprostinil in clinical practice.…”