Inhaled Treprostinil Reduces PH-ILD Hospitalizations, but Safety Concerns Emerge

Two posters presented at the CHEST 2024 annual meeting in Boston, Massachusetts, found that although using inhaled treprostinil (iTRE) resulted in fewer hospitalizations related to pulmonary hypertension due to interstitial lung disease (PH-ILD), its safety profile needs to be reevaluated due to a postmarketing increase in serious adverse events (AEs).

Although inhaled treprostinil reduces hospitalizations in patients with pulmonary hypertension due to interstitial lung disease, real-world data suggest a higher rate of serious adverse events than previously reported in clinical trials. | Image Credit: catinsyrup - stock.adobe.com

iTRE is a vasodilator that relaxes blood vessels and improves blood flow, reducing pulmonary artery pressure and improving oxygenation.¹ The FDA approved it in May 2022 to treat pulmonary arterial hypertension and PH-ILD; however, real-world evidence on utilization and impact on outcomes is needed.

Impact of iTRE on PH-ILD Hospitalizations

The first poster analyzed iTRE use among those in the Clinformatics Data Mart Database.² After identifying iTRE initiators, the researchers matched them with up to 4 controls based on various factors that included sex, race, and having any hospitalizations in the 6 months before their index visit. Patients who used iTRE were indexed on the date of initiation, while controls were indexed on the date of the first-observed PH diagnosis between March 31, 2021, and June 30, 2023.

Also, patients in both cohorts needed to be at least 18 years old on the index date, continuously enrolled for 6 months before the index dat, and have 1 inpatient or 2 outpatient medical claims for ILD separated by at least 30 days in the 6 months before the index date; iTRE initiators also needed to have medical claims with a PH diagnosis in the 6-month preindex period.

Their outcomes of interest were all-cause per-person per-month (PPPM) hospitalizations and intensive care unit (ICU) hospitalizations. After adjusting for baseline comorbidities, they used a repeated measures analysis of variance (ANOVA) to generate adjusted mean values in PPPM hospitalizations.

Through their selection process, the researchers identified 153 patients who initiated iTRE and 380 control patients with PH-ILD. Among the iTRE and control groups, the mean (SD) ages at index were 72.4 (9.1) and 72.9 (9.4) years (P = .57), and the mean follow-up times were as 8.0 (6.0) vs 8.7 (7.0) months (P = .24), respectively.

Looking at the pre- vs postindex periods, the mean all-cause PPPM hospitalizations remained the same for patients who initiated iTRE (0.10 [0.13] vs 0.10 [0.18) but significantly increased for the control group (0.15 [0.20] vs 0.36 [0.33]). The severity of hospitalizations as determined by PPPM ICU utilization in the pre- vs postindex periods demonstrated a similar pattern among those who initiated iTRE (mean, 0.06 [0.11] vs 0.07 [0.16]) compared with the control group (0.07 [0.14] vs 0.22 [0.29]).

Additionally, the repeated measures ANOVA controlling for baseline comorbidities found that patients who initiated iTRE experienced significantly fewer PPPM hospitalizations in the postindex period than those in the control group (0.14 vs 0.37; P < .01).

Lastly, when controlling for baseline comorbidities, patients who initiated iTRE had a 35% decreased risk of experiencing any hospitalization in the postindex period compared with the control group (relative risk [RR], 0.65; 95% CI, 0.51-0.83; P < .01).

"Overall, hospitalizations significantly increased in patients with PH-ILD if they remained untreated vs those who received treatment," presenter Steven Cassady, MD, assistant professor at the University of Maryland School of Medicine, said during a rapid fire session. "Using this real-world claims database, utilizing iTRE was associated with fewer all-cause hospitalizations and ICU-related use compared with those who remained untreated."

Postmarketing Safety Concerns of iTRE

Despite the previoys findings, the second poster showed that the adverse effect (AE) profile of iTRE needs to be better accessed.³ iTRE was approved by the FDA based on findings from the INCREASE trial (NCT02630316), but given the increased usage of this treatment, the researchers performed a comprehensive postmarketing safety profile of the medication among the general population.

To do so, they used the FDA Adverse Event Reporting System (FAERS) database. From this database, the researchers discovered 3042 AEs reported in adult patients from 2022 to December 31, 2023; of these, 419 (13.8%) were reported by health care professionals (HCPs). They further analyzed the AEs by gender (female vs male) and by age group (18-64, 65-85, > 85 years).

Of the reported AEs, 60% were serious and included conditions like heart failure, arrhythmias, and chest pain. Other reported AEs included dyspnea (26.5%), cough (26.5%), headache (17.7%), respiratory failure (13.6%), death (9.8%), and cardiac arrest (2.1%).

Therefore, the researchers noted that their mild to moderate AE findings, like cough, headache, and dyspnea, were similar to the INCREASE trial. However, unlike the INCREASE trial, which showed about 23% serious AEs, the researchers found that 60% of reported AEs in the FAERS database were serious.

Consequently, the researchers noted the need for further investigation into the iTRE AE profile. Lastly, because of the associated AEs, they urged clinicians to have increased vigilance when prescribing this medication.

"We are very excited about this medication [iTRE], but we also have to think about possible side effects that have not been considered before approval of the medication," Sharad Oli, MD, pulmonary and critical care fellow at Wayne State University, told The American Journal of Managed Care^® (AJMC^®). "These [the AEs] were all reported after the approval of the medication."

Although iTRE shows promise in reducing hospitalizations and ICU utilization for patients with PH-ILD, this significant postmarketing increase in serious AEs warrants a safety profile reevaluation.

References

1. Treprostinil oral inhalation. Medline Plus. Updated on April 15, 2023. Accessed October 2, 2024. https://medlineplus.gov/druginfo/meds/a622039.html#:~:text=Treprostinil%20oral%20inhalation%20is%20used,lungs%2C%20and%20improving%20blood%20flow.

2. Cassady SJ, Ramani GV, Wu B, et al. Real-world hospitalization differences in patients with pulmonary hypertension due to interstitial lung disease: initiating inhaled treprostinil vs those who remain untreated. Poster presented at: CHEST Annual Meeting 2024; October 6-9, 2024; Boston, MA. doi:10.1016/j.chest.2024.06.3557

3. Oli S, Oli S, Niraula S, Khanal R. Exploring the increased serious adverse events associated with inhaled treprostinil: an FDA Adverse Event Reporting System database analysis. Poster presented at: CHEST Annual Meeting 2024; October 6-9, 2024; Boston, MA. doi:10.1016/j.chest.2024.06.2104