Reveal Lite 2 Risk Assessment in Patients With Pulmonary Arterial Hypertension From the Griphon Study: A Post-Hoc Analysis Demonstrates Association of Risk Status With Long-Term Outcomes

Abstract

Risk assessment is key for optimal management of patients (pts) with pulmonary arterial hypertension (PAH). REVEAL Lite 2 (RL2) is a non-invasive risk assessment tool for PAH. In this post-hoc analysis of the GRIPHON study (NCT01106014), RL2 was applied to assess its prognostic and predictive value in PAH pts randomized to selexipag, a selective IP prostacyclin receptor agonist, or placebo.METHODS: RL2 was used to calculate risk score and pts were categorized into low, intermediate and high-risk strata at baseline (randomization) and post-baseline timepoints. Analyses were performed to examine associations between risk category and change in risk category with long-term outcome (time to first morbidity/mortality event; MM) and the treatment effect of selexipag on long-term outcome by risk category. Hazard ratios (HR) and concordance index (C-index) were calculated using Cox proportional hazard model. Change in risk category from baseline was compared between treatment arms by proportional odds model. RESULTS:At baseline: overall 41% pts were low, 26% intermediate and 33% high risk; proportions were similar between treatment arms. Risk category at baseline was predictive of time to first MM: with selexipag, HR were 2.09 for intermediate vs low and 5.38 for high vs low risk; with placebo, HR were 2.41 for intermediate vs low and 3.50 for high vs low risk. C-index values at baseline, 4, 6 and 12 months, respectively were 0.68, 0.74, 0.76 and 0.73 for selexipag and 0.65, 0.67, 0.66 and 0.70 for placebo. Change in risk category correlated with change in MM rate: improvement in risk category correlated with a reduction in MM rate (HR vs no change in risk 0.43, 0.39, 0.42 at 4, 6, and 12 months, respectively); while worsened risk category correlated with an increase in MM rate (HR vs no change in risk 2.82, 3.05, 3.77 at 4, 6 and 12 months, respectively). Selexipag was approximately twice as likely to improve pts' risk profile than placebo (odds ratio of improvement for selexipag/placebo: 2.0, 1.8, 1.9 at 4, 6, and 12 months, respectively; p<0.001 for all comparisons). Selexipag reduced the MM rate across all baseline risk categories: HR 0.57 (p¼0.0178) for low, 0.42 (p¼0.0001) for intermediate, and 0.71 (p¼0.0326) for high-risk pts, respectively compared with placebo.CONCLUSIONS: RL2 risk category and change in risk category are prognostic for long-term outcome. Selexipag treatment improved risk profile and long-term outcome compared with placebo; selexipag treatment effect on long-term outcome was strongest for pts at low and intermediate risk at baseline. CLINICAL IMPLICATIONS: RL2 risk assessment is prognostic of long-term outcome in pts with PAH and can detect response to treatment. Simple risk assessment tools may have utility for treatment monitoring and as an endpoint in PAH clinical trials.

Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension

“…Studies that applied risk scores to clinical trials as post hoc analyses or exploratory endpoints have previously suggested that risk scores distinguish between treatment arms in clinical trials 15,18,20–22 ; however, an individual patient data meta‐analysis of the SERAPHIN, GRIPHON, and AMBITON clinical trials did not find that risk scores were predictive of long‐term outcomes 23 . REVEAL 2.0 and REVEAL Lite 2.0 have been shown to predict prognosis in individual patients on treatment and have excellent concordance indices (> 0.7), 24–27 demonstrating that they may have the potential to be used in clinical practice. Risk scores can be seen as more clinically meaningful than single endpoints, with a dynamic relationship between changes in score and changes in outcome, a key requirement for surrogate endpoints 28 ; however, further refinement of risk scores may be necessary to infer surrogacy.…”