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.

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.