COPD associated pulmonary hypertension: A post hoc analysis of the PERFECT study

Abstract

The PERFECT study, a randomized, controlled, double-blind study of inhaled treprostinil in patients with COPD and associated pulmonary hypertension (PH-COPD) was a negative trial that was terminated early. The reason(s) for the negative outcome remains uncertain. A post hoc analysis of data from the PERFECT study was undertaken to identify adverse responders and possibly potential responders. The goal was also to provide insight into phenotypes for possible inclusion and exclusion in future PH-COPD clinical trials. An adverse response on active treatment was seen in 36.4% (24/66) of the subjects compared to 27.6% (16/58) on placebo. There was no evidence to suggest that hyperinflation, bronchospasm, or occult heart failure played any role in the untoward outcomes of the study. The patients who died during the study all had baseline diffusing capacity for carbon monoxide ≤25% of predicted. Evidence of a potential response was seen in 10.6% (7/66) of the patients who received inhaled treprostinil. Patients who had evidence of a treatment response had a baseline mean pulmonary artery pressure of ≥40 mmHg and a forced expiratory volume in the first second of ≥40%. Change in N-terminal prohormone of brain natriuretic peptide did not predict clinical response. This post hoc analysis provides information that may potentially enable improved selection of patients for future therapeutic trials in PH-COPD. These analyses are post hoc, observational, and exploratory. The thresholds defining the spectrum of responders are preliminary and may require further refinement and validation in future studies.

Keywords: chronic obstructive; double‐blind method; hypertension; pulmonary; pulmonary disease; treprostinil.

Figure 1

Study design (reproduced with permission from the European Respiratory Journal). ITRE, inhaled treprostinil.

Figure 2

X−Y plots of RV/TLC% to mPAP (a) and PVR (b) based on treatment assignment, response, and mortality for both groups. FEV1, forced expiratory volume in 1 s; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; RV/TLC, residual volume to total lung capacity; WU, wood units.

Figure 3

X−Y plot of the PCWP to FEV1%, color‐coded by a 20% increase or decrease in NT‐proBNP at Week 6 for both groups. FEV1, forced expiratory volume in 1 s; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure. Reproduced and modified with permission from the European Respiratory Journal.

Figure 4

X−Y‐plot, color‐coded base on response, of (a) PCWP to mPAP; and (b) PCWP to PVR for both groups. The patients with PCWPs >15 mmHg had left ventricular diastolic pressure measurements ≤15 mmHg which qualified them for the study. mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance.

Figure 5

X−Y‐plots of DLCO% to mPAP, color‐coded by those who had a ≥3% drop in their FEV1/FVC for both groups. DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; mPAP, mean pulmonary arterial pressure; PP, percent predicted. Reproduced and modified with permission from the European Respiratory Journal.

Figure 6

X−Y‐plots, color‐coded based on response, of (a) DLCO% to mPAP; (b) DLCO% to PVR; (c) DLCO% to FEV1% for both groups. DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; mPAP, mean pulmonary arterial pressure; PP, percent predicted; PVR, pulmonary vascular resistance.