Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery

Abstract

Background: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy.

Methods: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery.

Results: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes.

Conclusions: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT03081052.

Keywords: cardiovascular surgical procedures; epoprostenol; heart transplantation; heart-assist devices; hypertension, pulmonary; nitric oxide.

Figure 1.. CONSORT diagram.

In all analyses, patients were analyzed according to their randomized group. Participants were excluded from the primary analysis if they were withdrawn, developed exclusion criteria after randomization, or remained on the transplant list but were not transplanted before the study completed enrollment. Study enrollment was completed once sample-size was achieved. None of the participants were lost to 90-day follow-up. *Eligible participants who were initially consented and randomized to INSPIRE-FLO, were awaiting LVAD surgery and found to be eligible for MOMENTUM-3 (NCT02224755, enrollment: September 2, 2014 - September 28, 2018, HeartMate III vs. HeartMate II LVAS for advance heart failure) or TVVAD (NCT03775759, start enrollment: August 22, 2018 and continued after October 2020, tricuspid valve repair vs no repair for moderate or severe tricuspid regurgitation) trials. As these LVAD recipients could potentially benefit from these surgical interventions, they were allowed to enroll in those other trials and were excluded from INSPIRE-FLO due to co-enrollment restrictions. iEPO, Inhaled epoprostenol; iNO, inhaled nitric oxide; ITT, Intention-to-treat.

Figure 2.. Risk Differences in RVF Development between iNO and iEPO Treatment Groups.

To determine the presence of clinical equivalence between iNO and iEPO, a lower and upper bounds of −15% and +15% was prespecified (red lines). *Risk difference is the absolute difference for equivalence and is determined by the two one-sided test procedure using two-sided α of 0.05. Setting α at .05 and testing the upper and lower bounds separately, equivalence is confirmed if both test results are significant. This procedure is then transformed into a single confidence interval, CI, by 1 − 2α (hence, 90% CI). A more conservative 95% CI (1 − α) was used for the unadjusted ITT (−8.3% to 13.3%), adjusted ITT (−7.0% to 15.4%), and per-protocol (−9.2% to 12.6%) analyses. †Relative risk, RR, is the risk of developing RVF if treated with iEPO compared with iNO ‡Multivariable logistic regression adjusted for operation (Left ventricular assist device implantation versus orthotopic heart transplantation) and preoperative platelet count. Risk difference and RR are derived from the multivariable logistic regression model. Differences between adjusted and unadjusted risk difference and RR were due to the difference in comparing two patients in the adjusted analysis with the same surgery type (LVAD or OHT) and preoperative platelet count. Number of events and their distribution between the unadjusted and adjusted analyses remained the same. §There were eight patients (four per treatment group) for whom the allocated treatment was not weaned per-protocol. Seven of these patients underwent orthotopic heart transplantation and one underwent LVAD implantation. ITT, Intention-to-treat; RVF, Right ventricular failure.

Figure 3.. Airway filter placement during mechanical ventilation for both iEPO and iNO delivery.

A. A transport ventilator is displayed, with inspiratory limb of circuit containing filters labeled with green checkmarks and the expiratory limb of the circuit returning to the ventilator containing a single filter labeled with an orange checkmark. This filter placement paradigm was applied to ventilators in the operating room, for transport, and in the intensive care unit. B. The intensive care unit ventilator is displayed, with inspiratory limb showing a filter placed between the inspiratory port and in-line iNO delivery device as well as one placed between the in-line iNO and iEPO delivery devices. C. Adopted from the iEPO delivery protocol (see Supplement 1), filters between the ventilator and the inspiratory and expiratory limbs of the ventilator circuit are displayed.