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Inhaled nitric oxide after left ventricular assist device implantation: A prospective, randomized, double-blind, multicenter, placebo-controlled trial

https://doi.org/10.1016/j.healun.2011.03.005Get rights and content

Background

Used frequently for right ventricular dysfunction (RVD), the clinical benefit of inhaled nitric oxide (iNO) is still unclear. We conducted a randomized, double-blind, controlled trial to determine the effect of iNO on post-operative outcomes in the setting of left ventricular assist device (LVAD) placement.

Methods

Included were 150 patients undergoing LVAD placement with pulmonary vascular resistance ≥200 dyne/sec/cm–5. Patients received iNO (40 ppm) or placebo (an equivalent concentration of nitrogen) until 48 hours after separation from cardiopulmonary bypass, extubation, or upon meeting study-defined RVD. For ethical reasons, crossover to open-label iNO was allowed during the 48-hour treatment period if RVD criteria were met.

Results

RVD criteria were met by 7 of 73 patients (9.6%; 95% confidence interval, 2.8–16.3) in the iNO group compared with 12 of 77 (15.6%; 95% confidence interval, 7.5–23.7) who received placebo (p = 0.330). Time on mechanical ventilation decreased in the iNO group (median days, 2.0 vs 3.0; p = 0.077), and fewer patients in the iNO group required an RVAD (5.6% vs 10%; p = 0.468); however, these trends did not meet statistical boundaries of significance. Hospital stay, intensive care unit stay, and 28-day mortality rates were similar between groups, as were adverse events. Thirty-five patients crossed over to open-label iNO (iNO, n = 15; placebo, n = 20). Eighteen patients (iNO, n = 9; placebo, n = 9) crossed over before RVD criteria were met.

Conclusions

Use of iNO at 40 ppm in the perioperative phase of LVAD implantation did not achieve significance for the primary end point of reduction in RVD. Similarly, secondary end points of time on mechanical ventilation, hospital or intensive care unit stay, and the need for RVAD support after LVAD placement were not significantly improved.

Section snippets

Methods

This study was conducted at 8 centers in the United States and Germany between September 2003 and March 2008. Each country's national health authority and local Investigational Review Board/Ethics Committees approved the study. Consent of participating patients was obtained according to local requirements. The study was designed and monitored by a Steering Committee (Appendix 1). An independent Data and Safety Monitoring Committee reviewed unblinded safety data. Investigators are listed in

Results

The study included 150 patients, with 73 randomized to the iNO group and 77 to the placebo groups. The study therapy was not administered to 13 patients (4 iNO, 9 placebo), resulting in 137 patients for the safety and per-protocol populations, comprising 69 in the iNO group and 68 in the placebo group (Figure 1).

In the ITT population, the iNO group had a higher mean age compared with placebo; both groups were otherwise well matched in demographics and baseline characteristics (Table 2),

Discussion

Right heart dysfunction is still a major complication of LVAD placement.5, 7 Elevated PVR is a pre-operative risk factor for morbidities,12, 14 and the absence of pulmonary vasoreactivity confers a worse prognosis.23 Inhaled NO selectively reduces PVR in patients undergoing cardiac surgical procedures.12 Reduction in PVR decreases RV afterload, which in turn may prevent RVD. Numerous strategies have been used to avoid RVD after LVAD placement, including optimizing device placement timing by

Disclosure statement

This study was sponsored by and statistical analysis of the data was conducted by Ikaria Inc, Clinton, New Jersey. General editorial support (eg, format, style) for this article was provided by Peloton Advantage LLC and funded by INO Therapeutics LLC, a subsidiary of Ikaria Inc.

All authors were responsible for data analysis and interpretation, as well as the development and final approval of the paper. Conception and design of the study were conducted by the Steering Committee members listed in

References (25)

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