Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial

Abstract

Importance: Inhaled nitric oxide (iNO) is commonly administered for selectively inhaled pulmonary vasodilation and prevention of oxidative injury after lung transplant (LT). Inhaled epoprostenol (iEPO) has been introduced worldwide as a cost-saving alternative to iNO without high-grade evidence for this indication.

Objective: To investigate whether the use of iEPO will lead to similar rates of severe/grade 3 primary graft dysfunction (PGD-3) after adult LT when compared with use of iNO.

Design, setting, and participants: This health system-funded, randomized, blinded (to participants, clinicians, data managers, and the statistician), parallel-designed, equivalence clinical trial included 201 adult patients who underwent single or bilateral LT between May 30, 2017, and March 21, 2020. Patients were grouped into 5 strata according to key prognostic clinical features and randomized per stratum to receive either iNO or iEPO at the time of LT via 1:1 treatment allocation.

Interventions: Treatment with iNO or iEPO initiated in the operating room before lung allograft reperfusion and administered continously until cessation criteria met in the intensive care unit (ICU).

Main outcomes and measures: The primary outcome was PGD-3 development at 24, 48, or 72 hours after LT. The primary analysis was for equivalence using a two one-sided test (TOST) procedure (90% CI) with a margin of 19% for between-group PGD-3 risk difference. Secondary outcomes included duration of mechanical ventilation, hospital and ICU lengths of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and in-hospital, 30-day, and 90-day mortality rates. An intention-to-treat analysis was performed for the primary and secondary outcomes, supplemented by per-protocol analysis for the primary outcome.

Results: A total of 201 randomized patients met eligibility criteria at the time of LT (129 men [64.2%]). In the intention-to-treat population, 103 patients received iEPO and 98 received iNO. The primary outcome occurred in 46 of 103 patients (44.7%) in the iEPO group and 39 of 98 (39.8%) in the iNO group, leading to a risk difference of 4.9% (TOST 90% CI, -6.4% to 16.2%; P = .02 for equivalence). There were no significant between-group differences for secondary outcomes.

Conclusions and relevance: Among patients undergoing LT, use of iEPO was associated with similar risks for PGD-3 development and other postoperative outcomes compared with the use of iNO.

Trial registration: ClinicalTrials.gov identifier: NCT03081052.

Figure 1.. Flow of Participants in a Study of Inhaled Pulmonary Vasodilators for Adult Lung Transplant (LT)

In all analyses, patients were analyzed according to their randomized group (inhaled nitric oxide [iNO] and inhaled epoprostenol [iEPO]). Participants were excluded from the intention-to-treat (ITT) analysis if they were withdrawn, developed exclusion criteria after randomization, or remained on the LT list and did not receive a transplant. Those who received the allocated treatment at the time of LT were included in an ITT analysis. Study enrollment was completed once the calculated sample size was achieved. None of the participants were lost to 90-day follow-up. CLAD indicates chronic lung allograft dysfunction; ECMO, extracorporeal membrane oxygenation. ^aIncluded 1 patient for lung-kidney and 4 patients for lung-liver transplants. ^bPatient with diagnosis that did not fit 1 of the 5 randomization strata. ^cIneligibility for enrollment noted after consent and randomization but before LT.

Figure 2.. Risk Differences and Relative Risks of Severe Primary Graft Dysfunction (PGD-3) Development Between Treatment Groups

To determine the presence of clinical equivalence between inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO), lower and upper bounds of −19% and 19% were prespecified. Risk difference and relative risk (RR) are derived from the multivariable logistic regression model. Differences between adjusted and unadjusted risk difference and RR are owing to the difference in comparing 2 patients in the adjusted analysis with the same-sex mismatch and chest closure status. However, number of events and their distribution between the unadjusted and adjusted analyses remain the same. ^aIndicates the risk of developing PGD-3 if treated with iNO compared with iEPO. ^bIndicates the absolute difference between grade 3 primary graft dysfunction (PGD-3) rates between groups and is determined by the two one-sided test (TOST) procedure. Setting α at .05 and testing the upper and lower bounds separately, equivalence is concluded only if both test results are significant. To transform this procedure into a single CI, 1 − 2α (90%) is used and the TOST CI becomes the intersection of the TOST CIs. A more conservative 95% CI (1 − α) was determined and also demonstrated exclusion of the lower and upper bounds of the margin in support of equivalence for the unadjusted intention to treat (ITT) (−8.6% to 18.3%), adjusted ITT (−9.5% to 18.8%), and per-protocol (−8.2% to 18.8%) analyses. ^cMultivariable logistic regression adjusted for delayed chest closure and donor-recipient sex mismatch from the selected model (eTable 1 in Supplement 2).