Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension

Rajeev Malhotra, Dean Hess, Gregory D Lewis, Kenneth D Bloch, Aaron B Waxman, Marc J Semigran, Rajeev Malhotra, Dean Hess, Gregory D Lewis, Kenneth D Bloch, Aaron B Waxman, Marc J Semigran

Abstract

Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O(2) for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years). Five-year survival was 56%. Baseline PVR (mean±SD 850±580 dyne-sec/cm(5)) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O(2) was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O(2) had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O(2) had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O(2) were independent predictors of survival. Reduction in PVR or mPAP during short-term administration of inhaled NO and O(2) predicts survival in PAH patients.

Conflict of interest statement

Conflict of Interest: None declared.

Figures

Figure 1
Figure 1
Changes in PVR with inhaled NO and O2 predict survival in PAH. Kaplan-Meier survival curves for PAH patients stratified by vasoreactivity, defined by at least a 30% decrease in PVR with vasodilator challenge. The Log-rank test shows reduced mortality in vasoreactive patients (P=0.039).
Figure 2
Figure 2
Changes in mPAP with inhaled NO predict and O2 survival in PAH. Kaplan-Meier survival curves for PAH patients stratified by vasoreactivity, defined by at least a 12% decrease in mPAP with vasodilator challenge. The Log-rank test demonstrates reduced mortality in vasoreactive patients (P=0.049).
Figure 3
Figure 3
Changes in PVR and mPAP with inhaled NO and O2 predict survival across multiple subpopulations of PAH. Forest plots of age-adjusted Cox proportional hazard ratios are depicted on a logarithmic scale, with ratios less than 1 indicating a favorable prognosis with vasoreactivity to inhaled NO and O2. In (A), vasoreactivity is defined as a≥30% decrease in PVR with vasodilator compared to baseline. In (B), vasoreactivity is defined as a≥12% decrease in mPAP with vasodilator compared to baseline. * indicates vasodilator non-responsiveness by current guidelines.[34] † indicates PAH associated with collagen vascular disease (CVD), portal hypertension, congenital heart disease, HIV, anorexigen use, or Gaucher's disease.
Figure 4a
Figure 4a
Acute pulmonary vasoreactivity with inhaled NO and O2 predicts survival in PAH patients not treated with calcium channel antagonists (CCA). Of the 66 PAH patients never treated with CCA, either a≥30% decrease in PVR (A) or a≥12% decrease in mPAP (B) with vasodilator at the time of diagnosis predicted improved Kaplan-Meier survival (P≤0.05 for both).
Figure 4b
Figure 4b
Acute pulmonary vasoreactivity with inhaled NO and O2 predicts survival in PAH patients not treated with calcium channel antagonists (CCA). Of the 66 PAH patients never treated with CCA, either a≥30% decrease in PVR (A) or a≥12% decrease in mPAP (B) with vasodilator at the time of diagnosis predicted improved Kaplan-Meier survival (P≤0.05 for both).

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