Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study

Abstract End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test–retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen’s d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen’s d 0.81), whereas the effect size for the 6 min walk test (Cohen’s d 0.22) and log10NT-proBNP (Cohen’s d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials. Trial registration number NCT03841344.


INTRODUCTION
Pulmonary arterial hypertension (PAH) is progressive, leading to right ventricular (RV) failure and death. 1 Accurate measurement of RV function is important for assessment of disease severity and prognosis. [2][3][4] Despite new therapies and improvements in survival, 5 PAH remains a life-shortening condition. MRI is the gold standard for RV assessment, 6 has prognostic value 2 and predicts clinical worsening 7 in PAH. A trial end point that is highly repeatable, is sensitive to treatment and predicts outcomes would be highly desirable. 8 9 MRI has been proposed as a trial end point in PAH, 8 9 however, there is limited data on repeatability and treatment effect size.

METHODS Patients
Patients with PAH who were treatment-naïve commencing therapy, prevalent undergoing escalation of therapy and clinically stable requiring no escalation of therapy, were recruited. See online supplemental file S1.

Study investigations
Investigations performed at visit 1 included N-terminal pro-brain natriuretic peptide (NT-ProBNP), 6 min walk test (6MWT) and MRI. Follow-up visits 2 and 3 occurred approximately 6 months after study visit 1. Visits 2 and 3 occurred within 24 hours of each other (online supplemental figure S2).

MRI acquisition and analysis
All MRI examinations were performed on either a 1.5 T GE HDx (GE Healthcare, Milwaukee, USA) whole body scanner using an 8-channel cardiac coil or a 3 T Philips Ingenia (Best, The Netherlands) whole body scanner using a 32-channel dStream torso coil (online supplemental file S1). Analysis of MRI was undertaken blinded to the patient's data. RV parameters and pulmonary arterial flow were analysed on Qmass MEDIS suite (V.3.0.18.0, Medical Imaging Systems, The Netherlands) on short axis and phase contrast images, respectively. Regions of interest were drawn on the pulmonary artery and left atrium of the dynamic contrast-enhanced perfusion images to calculate first pass pulmonary transit time and full width at half maximum using in-house software (see online supplemental figure S3).

Six min walk test and NT-ProBNP
The 6MWT was performed by a respiratory physiologist. NT-ProBNP analysis was performed on patient plasma samples using the Luminex 100/200 multiplex analyser using the cardiovascular marker kit (HCVD-1MAG-67K Millipore) at the end of the study.

Statistical analysis
Repeatability was determined by the intraclass correlation coefficient (ICC) using a two-way mixed absolute agreement model with the average measure recorded. An ICC of ≥0.75 was considered excellent, 0.60-0.74 good, 0.40-0.59 fair and <0.40 poor. Mean difference and 95% CIs were presented where appropriate. Cohen's d (calculated with the averaged SD, d av ) was used to assess the standardised treatment effect size between visit 1 and visit 2. 10 A Cohen's d value of <0.20 was considered no change, 0.20-0.49 was considered fair change, 0.50-0.79 was considered a medium change and ≥0.80 was considered a large change. All analysis was performed on SPSS V.22 and GraphPad Prism V.16.

RESULTS Patients
Of 42 patients who completed the study, 16 were incident and treatment-naïve and initiated PAH therapy, 12 were prevalent and underwent an escalation of therapy and 14 were stable on therapy with no change in treatment occurring between the study visits.(online supplemental table S5).

Test-test repeatability (visits 2 and 3)
In patients with PAH, test-test repeatability was assessed between visits 2 and 3; 6MWT (ICC 0.987) and log 10 NT-ProBNP (ICC 0.772) had excellent repeatability. Of cardiac MRI metrics (table 1), all showed excellent repeatability. Data for MRI pulmonary flow and perfusion transit times are shown in table 1.

Treatment effect size (visits 1 and 2)
For all patients, initiating or escalating therapy (n=28), the only measurement with a large treatment effect size was RV ejection fraction

DISCUSSION
Investigations used to monitor disease severity in patients with PAH, namely 6MWT distance, NT-ProBNP level and MRI metrics, had excellent repeatability. In contrast, only MRI (RVEF) demonstrated a large treatment effect size in patients initiating or escalating therapies, whereas for the 6MWT and NT-ProBNP the treatment effect sizes were fair. As observed in previous clinical trials 1 and highlighted at the 6th World Symposium, 9 all metrics evaluated in patients with PAH escalating therapy had a lower treatment effect size compared with treatment-naïve patients initiating therapy. This represents a challenge when studying the effects of new therapies in PAH where the standard of care is combination treatment. 1 Importantly, MRI was still able to detect a medium treatment effect size in patients receiving background PAH therapy. Due to the large cost of conducting PAH therapy trials, strategies to reduce the size of studies and their duration using a surrogate end point that is repeatable and has a large treatment effect size would be highly desirable. 9 This study has a number of limitations including the small sample size and the lack of comparison with invasively measured pulmonary haemodynamics. Nonetheless, we have demonstrated in this exploratory study that MRI, the gold standard for RV function assessment, detects a larger treatment effect than the 6MWT or NT-proBNP. This may reflect the ceiling effect of the 6MWT and the effect of comorbidities (including chronic kidney disease) that may influence 6MWT distance and NT-proBNP levels. MRI metrics predict clinical worsening 7 and mortality 2-4 fulfilling many of the criteria of a surrogate end point. 9 Given that pulmonary haemodynamics are commonly used in early phase PAH studies, 1 a direct comparison of MRI metrics and pulmonary haemodynamics, to detect longitudinal change following PAH therapy, is now required if MRI imaging is to be considered a primary end-point for PAH therapy trials. 8 9 This study demonstrates the high repeatability of MRI metrics in PAH and the large treatment effect size support further evaluation of MRI as a non-invasive endpoint in PAH therapy trials.
Correction notice This article has been corrected since it was published Online First. Affiliations for FW and AC have been updated.