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Corresponding author. Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, 473 W. 12th Avenue, Suite 200, Columbus, OH 43210, USA.
University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, GermanyDepartment of Medicine, Imperial College London, London, UKDepartment of Pneumology, Kerckhoff-Klinik, Bad Nauheim, Germany
Currently there is no validated risk assessment strategy for patients with CTEPH
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RRS 2.0, an updated version of REVEAL risk score, was applied to the CHEST study
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Riociguat improved RRS 2.0 and risk strata in CHEST
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RRS 2.0 was associated with survival and clinical worsening-free survival in CHEST
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RRS 2.0 may have utility in predicting outcomes in patients with CTEPH
Abstract
Background
Currently there are no risk assessment recommendations for chronic thromboembolic pulmonary hypertension (CTEPH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score (RRS), developed for risk assessment in patients with pulmonary arterial hypertension, has previously predicted outcomes in CTEPH. RRS 2.0 was developed to refine the RRS.
Methods
This post hoc analysis of the CHEST study (n = 237), which assessed riociguat in patients with inoperable and persistent/recurrent CTEPH, evaluated RRS 2.0 and its relationship with survival and clinical worsening-free survival (CWFS).
Results
At CHEST-1 Week 16, RRS 2.0 significantly improved and more patients moved into the low-risk stratum with riociguat versus placebo; these improvements were maintained at CHEST-2 Week 12. RRS 2.0 at CHEST-1 baseline and Week 16, and change in RRS 2.0 from CHEST-1 baseline to Week 16 were significant predictors of survival and CWFS in CHEST-2.
Conclusions
Our data suggest that RRS 2.0 may have utility in predicting outcomes and monitoring treatment response in patients with inoperable or persistent/recurrent CTEPH.
There are currently no recommendations regarding risk assessment in patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, risk assessment tools, including the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score (RRS) calculator, developed and validated for patients with pulmonary arterial hypertension (PAH), and the Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) risk score have been shown to discriminate prognosis for survival and clinical worsening-free survival (CWFS) or predict mortality in patients with inoperable or persistent/recurrent CTEPH [
]. An updated version of the RRS calculator with revised variables and cut points, RRS 2.0, was developed in order to refine risk prediction in PAH and optimize clinical relevance [
Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.
Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable CTEPH and persistent/recurrent CTEPH after pulmonary endarterectomy. In the 16-week, Phase III CHEST-1 study [
], riociguat had a favorable benefit–risk profile and demonstrated benefits in exercise and functional capacity in patients with CTEPH. An analysis of CHEST-1 data showed that riociguat significantly improved RRS compared with placebo in patients with CTEPH, and RRS was associated with survival and CWFS in the long-term extension CHEST-2 [
], except that risk strata were defined as low (RRS 2.0 ≤ 6), intermediate (RRS 2.0 7–9), and high (RRS 2.0 ≥ 10). The evaluable variables used to calculate RRS 2.0 are shown in Table S1. All-cause hospitalization was defined within the previous 30 days as 6-month data were not available. Pericardial effusion, diffusing capacity of the lung for carbon monoxide, and World Health Organization Group I subgroup information were also not available in the CHEST population. Clinical worsening was defined as death (all-cause mortality), heart/lung transplant, rescue pulmonary endarterectomy due to worsening pulmonary hypertension (PH), hospitalization due to worsening PH, start of new PH treatment, decrease of >15% from baseline or > 30% compared with the last study-related measurement in 6-min walking distance due to worsening PH, or worsening World Health Organization Functional Class due to worsening PH [
Overall, 237 patients with CTEPH (riociguat, n = 155; placebo, n = 82) completed CHEST-1 and entered CHEST-2. Baseline data used to calculate RRS 2.0 for CHEST-1 for all patients who entered CHEST-2 are shown in Table S1.
At CHEST-1 baseline, mean (standard deviation) RRS 2.0 was 7.1 (2.7) with riociguat (n = 155) versus 6.9 (2.6) with placebo (n = 82). Across treatment groups, most patients were in the low-risk stratum (n = 100; 42%) or intermediate-risk stratum (n = 90; 38%) with 47 patients (20%) in the high-risk stratum (Fig. S1). In patients receiving riociguat, RRS 2.0 improved from CHEST-1 baseline to CHEST-1 Week 16 to 5.7 (3.1) (n = 155), with a least-squares mean difference versus placebo of −1.5 (95% confidence interval [95% CI] −2.0 to −1.0; p < 0.0001) (Table S2A).
At CHEST-1 Week 16, more patients receiving riociguat (70%) had improved RRS 2.0 from baseline versus placebo (39%) (Fig. S2). In addition, fewer patients receiving riociguat (12%) had worsened RRS 2.0 at CHEST-1 Week 16 from baseline versus placebo (34%) (Fig. S2). With riociguat, the proportion of patients in the low-risk stratum increased from 44% at CHEST-1 baseline to 62% at CHEST-1 Week 16 but remained stable at 39% with placebo (Fig. S1). These improvements with riociguat were maintained at CHEST-2 Week 12 (Fig. S1, Fig. S2, and Table S2B). In patients receiving placebo in CHEST-1 and riociguat in CHEST-2, RRS 2.0 and risk stratum improved at CHEST-2 Week 12 (Fig. S1, Fig. S2, and Table S2B).
Cox proportional-hazards models showed that RRS 2.0 at CHEST-1 baseline, CHEST-1 Week 16, and change from CHEST-1 baseline to CHEST-1 Week 16 were significant predictors of survival and clinical worsening in CHEST-2 (Table S3). A 1-point improvement in RRS 2.0 at CHEST-1 baseline was associated with a 26% and 24% reduction in the relative risk of death and clinical worsening, respectively, in CHEST-2 (Table S3). Similarly, a 1-point improvement in RRS 2.0 at CHEST-1 Week 16 was associated with a 27% and 25% reduction in the relative risk of death and clinical worsening, respectively, in CHEST-2 (Table S3). Harrell's C-indices indicated good predictive accuracy, with C-indices (standard error) for prediction of survival of 0.70 (0.05), 0.73 (0.05), and 0.73 (0.05) for RRS 2.0 at baseline, Week 16, and change from baseline to Week 16, respectively. Similarly, C-indices for prediction of clinical worsening were 0.69 (0.03), 0.72 (0.03), and 0.72 (0.03), respectively.
Risk stratum at CHEST-1 baseline and CHEST-1 Week 16 also showed significant differences in survival and CWFS curves (p < 0.0001 for all; Fig. 1). Estimated survival and CWFS rates based on Kaplan–Meier estimates at 1 and 2 years in CHEST-2 are shown in Table S4.
Fig. 1Kaplan–Meier analyses of survival by risk stratum at CHEST-1 baseline (A) and CHEST-1 Week 16 (B), and of clinical worsening-free survival at CHEST-1 baseline (C) and CHEST-1 Week 16 (D). Day 0 refers to the start of CHEST-2. Log-rank tests were used to determine differences between curves. Definitions of risk strata by RRS 2.0: low ≤6, intermediate 7–9, and high ≥10.
Riociguat significantly improved RRS 2.0 compared with placebo in patients with inoperable or persistent/recurrent CTEPH, in addition to improving RRS 2.0 risk stratum. This is consistent with prior analyses with the original RRS where the least-squares mean difference for change in RRS from baseline to CHEST-1 Week 16 with riociguat versus placebo was −0.97 (95% CI −1.38 to −0.57; p < 0.0001) [
]. Also similar to the original RRS, RRS 2.0 at CHEST-1 baseline, CHEST-1 Week 16, and change from CHEST-1 baseline to CHEST-1 Week 16 were all significantly associated with survival and CWFS. For both the original RRS and RRS 2.0, a 1-point reduction in RRS 2.0 at CHEST-1 Week 16 was associated with a 27–31% reduction in the relative risk of death in CHEST-2. Survival and CWFS were significantly different between RRS 2.0 risk strata at CHEST-1 baseline and CHEST-1 Week 16, similar to the results reported with the original RRS.
Limitations of this analysis include its post hoc nature, the high proportion of low-risk patients at baseline, and the potential for survivor bias in CHEST-2 long-term outcomes. While information for some RRS 2.0 variables was not available in the CHEST population, the RRS 2.0 is designed to retain utility when some data points or risk parameters are missing. It is also important to note that the variables and cut points of the RRS 2.0 were based on data showing a relationship between these variables and survival in patients with PAH. While this study suggests that the RRS 2.0 may have utility in predicting outcomes in patients with CTEPH, a risk calculator developed exclusively for patients with CTEPH may have led to different variables and cut points being included. Indeed, the relationship of RRS 2.0 and prognosis in patients with CTEPH should be further evaluated in larger clinical trials, in CTEPH registries, and using real-world data from clinical practice.
5. Conclusions
Currently there is no validated risk assessment strategy for patients with CTEPH and limited data are available for assessing established PAH risk assessment tools in CTEPH [
]. Our findings suggest that RRS 2.0 can discriminate outcomes in patients with inoperable or persistent/recurrent CTEPH and may therefore be a tool for predicting long-term outcomes in these patients, either in clinical practice or clinical studies, and for monitoring their response to treatment.
Funding
This study was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA). Bayer AG participated in the study design; in the collection, analysis, and interpretation of data; and in the decision to submit the article for publication.
CRediT authorship contribution statement
Raymond L. Benza: Conceptualization, Writing – review & editing. Harrison W. Farber: Writing – review & editing. Adaani E. Frost: Writing – review & editing. Hossein-Ardeschir Ghofrani: Writing – review & editing. Paul A. Corris: Writing – review & editing. Marc Lambelet: Formal analysis, Writing – review & editing. Sylvia Nikkho: Conceptualization, Writing – review & editing. Christian Meier: Conceptualization, Writing – review & editing. Marius M. Hoeper: Writing – review & editing, All authors have approved the final article.
Declaration of interests
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. R. L. Benza reports receiving grants from Actelion, Bayer AG, Bellerophon, and Eiger. H. W. Farber reports receiving grants from Actelion, Gilead, and United Therapeutics; and personal fees from Acceleron, Actelion, Altavant, Bayer AG, Bellerophon, Boehringer Ingelheim, Gilead, and United Therapeutics. A. E. Frost is on an endpoint adjudication committee for a study funded by United Therapeutics; is currently on the Independent Data Monitoring Committee (IDMC) for two studies funded by Actelion (UNISUS and MACITEPH); and is on the steering committee reimbursement for two studies funded by Phase Bio (COVID-19 TRIAL Data and Safety Monitoring Board member [now terminated] and PAH drug trial). H.-A. Ghofrani reports receiving grants from Actelion, Bayer AG, Ergonex, and Pfizer; personal fees from Actelion, Bayer AG, Ergonex, Gilead, GSK, Merck, Novartis, and Pfizer; and is currently on the IDMC for two studies funded by Actelion. P. A. Corris reports participation and remuneration in Clinical Trial Committees for Bayer and Johnson & Johnson. M. Lambelet is an external employee of Bayer AG. S. Nikkho is an employee of Bayer AG. C. Meier is an employee of Bayer AG. M. M. Hoeper reports receiving personal fees from Acceleron, Actelion, Bayer AG, GSK, Janssen, MSD, and Pfizer.
Acknowledgments
Medical writing services were provided by Rachael Powis, PhD, of Adelphi Communications Ltd, Macclesfield, UK funded by Bayer AG (Berlin, Germany) in accordance with Good Publications Practice (GPP3) guidelines.
The authors would like to thank Britta Brockmann, MSc, of Chrestos Concept GmbH & Co. KG (Essen, Germany) for her role and expertise in conducting the statistical analyses.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.
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