Reply to Jin et al.: Inhaled Treprostinil after Initial Clinical Worsening: To Continue or Not to Continue, That’s the Question

From the Authors:

We thank the authors of the letter for their comments. Pulmonary veno-occlusive disease (PVOD) or PVOD-like areas have not only been reported in scleroderma but also in other forms of fibrotic lung disease, including idiopathic pulmonary fibrosis (1). We did not specifically look for PVOD or try to parse out patients who might have PVOD-like lesions in the context of this study. Indeed, this is a difficult diagnosis to confirm without a lung biopsy, which was not mandated in this study. Therefore, we cannot rule out that those who failed to respond to therapy or had clinical worsening on therapy might have had a component of PVOD. However, the fact that our study was positive, including in the subgroup of patients with connective tissue disease-related interstitial lung disease (ILD), suggests that the existence of any PVOD or PVOD-like lesions are of limited concern when starting patients on inhaled treprostinil (2, 3). We suspect that episodes of worsening seen in the context of the study were related to the severe underlying lung disease rather than necessarily being attributable to any PVOD.

Regarding targeted agents or other interventions that may have been used, the INCREASE clinical trial protocol did not allow patients to initiate antifibrotic medications or U.S. Food and Drug Administration-approved therapies for pulmonary arterial hypertension during the course of the 16-week study (2). Consequently, it is reasonable to conclude that the benefits in disease progression observed in the treatment arm are most likely attributable to inhaled treprostinil.

The authors state that additional studies of longer duration and specific subtypes should be undertaken. The INCREASE study is the largest study to date in group 3 pulmonary hypertension and was unequivocally positive, including the secondary endpoints, with no suggestion of harm in any subgroup. We, therefore, posit that doing longer studies of inhaled treprostinil is idealistic and not pragmatic. Furthermore, patients with a very poor prognosis are difficult to recruit and retain in long-duration clinical trials. Indeed, the enemy of good is better, or in this case, longer. Nonetheless, it is hoped that further supportive information might be gleaned from the open-label extension of the INCREASE study.

The authors highlight that some subgroups might not benefit from therapy, but therein lies the purpose of casting a broad net and including different forms of ILD since each group by itself might be too small to definitively demonstrate benefit. We should certainly not deny these patients with a morbid condition and few treatment options a viable, proven therapy based on theoretical concerns that they might not be of the right phenotype.

The authors accurately cite the incidence of adverse events of 93.3% in the active treatment arm of the INCREASE study but neglect to contextualize this against a very sick population with comorbidities and on concomitant medications, as evidenced by adverse events in 91.4% of the placebo patients. Similarly, as the authors point out, serious adverse events were reported in 23.3% of the active treatment arm, but once again, the 25.8% incidence of serious adverse events in the placebo arm is omitted. True, there was no survival benefit over 16 weeks, with 12 deaths in the placebo arm versus 10 in the treatment arm; but notably, all of the deaths in the placebo group occurred after a clinical-worsening event, which underscores the need to persist with therapy even in the face of disease progression. This surely then answers the author’s question of “to continue or not to continue.”