Single-center study finds similar risks for PGD-3 with both

In patients undergoing lung transplantation, risks for severe/grade 3 primary graft dysfunction (PGD-3) were similar whether patients were treated with inhaled epoprostenol (iEPO) or inhaled nitric oxide (iNO). Thus, researchers concluded, iEPO may be a viable option in the treatment of these patients.

They published their results in JAMA Surgery.

“Inhaled nitric oxide (iNO) is administered after lung transplant (LT) to promote lung-allograft function by improving oxygenation and lowering pulmonary vascular resistance. Consequently, iNO may help mitigate development of severe (grade 3) primary graft dysfunction (PGD-3), which is diagnosed within 72 hours after LT and is strongly associated with short- and long-term mortality. Although iNO is not approved by the U.S. Food and Drug Administration for this indication, international guidelines support its use after LT,” explained Kamrouz Ghadimi, MD, MHSc, of Duke University School of Medicine, Durham, North Carolina, and colleagues.

They added that iNO is roughly seven times more expensive than iEPO, and annual costs exceed millions of dollars nationwide, a disadvantage that has brought iEPO forward as a cost-saving alternative, despite a lack of robust evidence or comparisons with iNO.

In an interview with BreakingMED, Ghadimi explained the basis of their trial.

“The study started out as a quality initiative in 2014-2015 at Duke University Hospital. We were charged with the question of evaluating our bottom-line use in the cardiothoracic ICUs regarding inhaled pulmonary vasodilator usage as an adjunct for the medical management of patients undergoing cardiothoracic surgery. Importantly, the patient service line that uses these medications most commonly in our cardiothoracic ICU are those who undergo lung transplantation as well as those that undergo advanced heart failure operations such as left ventricular assist devices or heart transplantation,” he said.

“We wanted to better evaluate these patients, if indeed we could utilize an alternative medication to the solitary inhaled vasodilator nitric oxide; if we could do this safely; if we could develop protocols; if all the stakeholders would be on board, including respiratory therapy, clinicians, other staff physicians surrounding the care of these patients were in agreement; and how we could best implement and deliver the medication,” Ghadimi added.

In this independent analysis of patients from the Inhaled Selective Pulmonary Vasodilators for Advanced Heart Failure Therapies and Lung Transplantation Outcomes (INSPIRE-FLO) trial, Ghadimi and colleagues enrolled 201 patients (median age: 64 years; 64.2% men) with end-stage lung disease who underwent single (13.9%) or bilateral lung transplantation (86.1%). They grouped patients into five strata based on prognostic clinical features and then randomized patients per stratum to treatment with either iNO or iEPO at the time of lung transplantation.

The most common reason for lung transplantation was restrictive lung disease (62.7%), followed by obstructive disease (20.9%).

“These are very vulnerable patients. They entrust our program, our clinicians, and our staff and coordinators. We didn’t want to take this initiative lightly as we changed practice or implemented a new medication in this population,” noted Ghadimi.

The median duration of time from randomization to treatment was five days, and the treatment durations were similar between the two treatment groups (45.7 hours in the iNO group versus 46.6 hours in the iEPO group), as were allogeneic packed red blood cell transfusion and ECMO support. Delayed chest closure occurred in 15.3% and 6.8%, respectively (P=0.530).

Treatment with both agents was “initiated in the operating room before lung allograft reperfusion and administered continuously until cessation criteria met in the intensive care unit,” explained Ghadimi et al. In the intention-to-treat population, 103 patients were treated with iEPO and 98 with iNO.

The primary outcome—PGD-3 at 24, 48, or 72 hours after lung transplantation—occurred in 44.7% of patients treated with iEPO, compared with 39.8% of those treated with iNO (risk difference: 4.9%; TOST 90% CI: −6.4% to 16.2%: P=0.02 for equivalence). At 48 or 72 hours, these incidence rates were 28.2% and 26.5%, respectively (risk difference: 1.6%; 90% CI: −8.8% to 12.0% for equivalence); and at 72 hours, the rates were 16.3% versus 21.3% (risk difference: 5.0%; 90% CI: −4.5% to 14.6% for equivalence).

Researchers found no between-group differences in secondary outcomes, which included duration of mechanical ventilation, hospital and ICU length of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and mortality rates in hospital and at 30 and 90 days.

In their accompanying editorial, Ankit Bharat, MD, of Northwestern University Feinberg School of Medicine, Chicago, and fellow editorialists wrote: “The present study by Ghadimi et al lacks a control arm that did not receive any pulmonary vasodilators, allegedly owing to their institutional practices. Hence, it remains unclear whether either iNO or inhaled epoprostenol conferred any benefit and whether their use should be supported in routine prophylaxis against PGD. On the contrary, the seemingly higher rates of PGD might support that pulmonary vasodilators can paradoxically worsen allograft edema and increase PGD scores,” they wrote.

Ghadimi explained that at Duke University, they now use iEPO as an alternative to iNO based on these results, but he offered an important caveat.

“Other centers should consider the use of iEPO as an alternative to iNO based upon how they utilize the medications in their own centers. That’s important because how we utilize these medications might be different between centers,” he told BreakingMED. “At our center, we prophylactically put all patients on this medication. Other centers prefer to use the medication if it’s indicated, if there’s a reason to suspect that there is a problem with the lung graft, and that’s when they initiate it.”

“We use it in a certain way. I certainly encourage readers to look at our protocols (which are in the supplements) and take a deep dive and see how our approach fits in with theirs. I think there’s a lot of opportunity here for multicenter collaborations,” Ghadimi concluded.

Limitations of the study include its single-center design that was not placebo controlled, moderate size, and power, and short duration; the use of a prespecified equivalence margin based on an incidence range that may be too large; and the use of a stepwise, data-drive, model-building approach rather than a prespecified adjustment model due to the complexity of risk factors in these patients.

  1. In this single-center study, researchers found that rates of severe/grade 3 primary graft dysfunction (PGD-3) after lung transplantation were similar between patients treated with inhaled epoprostenol (iEPO) or inhaled nitric oxide (iNO).

  2. Be aware that this study investigated off-label use of both iEPO and iNO.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by the Duke University Health System.

Ghadimi reported receiving grant support from the National Institutes of Health, Duke Health, and the International Anesthesia Research Society–Mentored Research Training program.

Bharat reported no conflicts of interest.

Cat ID: 633

Topic ID: 630,633,570,633,730,192,195,925,159,312,492