Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial

Abstract

Objective: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE.

Methods: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%.

Results: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test).

Conclusions: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography.

Clinical trial registration: NCT01939301.

Keywords: Brain natriuretic peptide; Echocardiography; Heart failure; Nitric oxide; Pulmonary embolism; Pulmonary hypertension; Randomized trial; Troponin.

Conflict of interest statement

Conflicts of interest: No other authors have a conflict to report

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Flow diagram showing the numbers of patients screened, consented, enrolled and treated per protocol

Figure 2.

Dot plot showing plasma concentration of troponin T at enrollment, and then again after 24 hours of treatment for patients each treated with either placebo (n=38, squares), or 50 parts per million of inhaled nitric oxide (n=38, circles). The bottom panels show the median and interquartile ranges. The cutoff for abnormal was 14 pg/mL

Figure 3.

Dot plot showing plasma concentration of brain natriuretic peptide at enrollment, and then again after 24 hours of treatment for patients each treated with either placebo (n=38, squares), or 50 parts per million of inhaled nitric oxide (n=38, circles). The bottom panels show the median and interquartile ranges. The cutoff for abnormal was 90 pg/mL.

Figure 4.

Dot plot showing plasma concentration of nitrates at enrollment, and then again after 24 hours of treatment for patients each treated with either placebo (n=38, squares), or 50 parts per million of inhaled nitric oxide (n=38, circles). The bottom panels show the median and interquartile ranges.