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Suppressor of Tumorigenicity 2 as a Biomarker in Pulmonary Arterial Hypertension and its Association with REVEAL Risk Score in Riociguat-Treated Patients in the RESPITE Study
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The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Table 1 Variable
Correlation P-value
Correlation R-squared
AUC, Ees/Ea <1.0
Resting thermodilution cardiac output (L/min) Exercise peak cardiac output (L/min) Pulmonary vascular compliance (mL/mmHg) Right arterial/pulmonary capillary wedge pressure Pulmonary artery pulsatility index Right ventricular stroke work index (g*m/m2) Tricuspid annular systolic plane excursion (mm) Right ventricular fractional area change (%) Stroke volume/End systolic volume (SV/ESV) Right ventricular ejection fraction (%) Change in End-systolic pressure, DESP (mm Hg) Change in End-systolic volume, DESV (mL) Change in End-diastolic volume, DEDV (mL) Exercise Change in ESV/ESP (mL/mm Hg)
0.001 0.050 0.002 0.210 0.164 0.512 0.136 0.712 0.023 0.025 0.158 0.009 0.008 0.002
0.273 0.117 0.259 − − − − − 0.146 0.143 − 0.188 0.194 0.257
0.76 0.69 0.75 − − − − − 0.64 0.65 − 0.78 0.78 0.80
213 Relationship between Race/Ethnicity and Survival in Patients with Pulmonary Arterial Hypertension (PAH) S. Medrek,1 S. Sahay,2 T. Kung,3 C. Zhao,3 and A.E. Frost.2 1Division of Pulmonary and Critical Care Medicine, University of New Mexico, Albuquerque, NM; 2Houston Methodist Hospital, Houston, TX; and the 3 Actelion, South San Francisco, CA. Purpose: Prior research suggests that PAH prevalence and subtype may vary by race/ethnicity. Although some data suggest that disease severity and clinical outcomes also differ by race/ethnicity, these data are limited and based on single-center analyses. The relationship between race/ethnicity and survival was evaluated in a US prospective multicenter registry of WHO group 1 PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Methods: Included patients were ≥18 years of age with pulmonary capillary wedge pressure ≤15 mmHg. Cox proportional hazard models were used to assess the association between race/ethnicity and survival, unadjusted or adjusted for prognostic factors of age, diagnostic status (i.e. newly or previously diagnosed), PAH etiology, and sex. The relationship between race/ethnicity and survival was also analyzed using a left-truncation which adjusts for time from diagnosis to study enrollment with covariates of age and PAH etiology. Results: This analysis included 3,046 patients: 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. A Kaplan-Meier estimate of survival by race/ethnicity indicated that white patients had the lowest survival rate. Results of an unadjusted Cox model were consistent with this, in that Asian or Pacific Islander (HR=0.46, 95% CI 0.28-0.76, p=0.002) or Hispanic (HR=0.74, 95% CI 0.56-0.97, p=0.029) patients had a lower risk of death than white patients; black patients had a similar risk as white patients. An evaluation of potentially prognostic factors by race/ethnicity revealed that white patients were older than patients of other races/ethnicities. When the Cox model was adjusted for age and other variables of potential prognostic impact that varied by race/ethnicity in this population, race/ethnicity was no longer significantly associated with survival (Asian or Pacific Islander vs. white HR=0.69, 95% CI 0.46-1.05, p=0.09; Hispanic vs. white HR=1.05, 95% CI 0.82-1.33, p=0.71; black vs white; HR=1.04, 95% CI 0.86-1.23; p=0.72). Survival analysis using left-truncation also showed no effect of race/ethnicity on survival. Conclusion: Contrary to earlier analyses and other diseases in which race/ ethnicity substantially impacts outcome, these data suggest that race/ethnicity is not a predictor of survival in patients with PAH. 214 Suppressor of Tumorigenicity 2 as a Biomarker in Pulmonary Arterial Hypertension and its Association with REVEAL Risk Score in RiociguatTreated Patients in the RESPITE Study R.L. Benza,1 J.R. Klinger,2 H.A. Ghofrani,3 P. Jansa,4 E. Gr€unig,5 D. Vizza,6 and M.M. Hoeper.7 1The Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA; 2Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of
Brown University, Providence, RI; 3University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; 4Clinicial Department of Cardiology and Angiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; 5Centre for Pulmonary Hypertension, Thorax Clinic at the University Hospital, Heidelberg, Germany; 6Pulmonary Hypertension Unit, Department of Cardiovascular and Respiratory Disease, La Sapienza University of Rome, Rome, Italy; and the 7Clinic for Respiratory Medicine, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany. Purpose: Suppressor of tumorigenicity 2 (ST-2) is a marker of cardiac remodeling and fibrosis that correlates with disease severity in patients with pulmonary arterial hypertension (PAH), and is thought to be a predictor of clinical worsening. We performed a post hoc analysis assessing ST-2 as a potential biomarker of likelihood of response in patients switching from phosphodiesterase type 5 inhibitors (PDE5i) to riociguat, and the association of ST-2 with REVEAL risk score (RRS) in the RESPITE study. Methods: RESPITE was a 24-week, open-label, uncontrolled, Phase IIIb study in PAH patients with an insufficient response to PDE5i. Patients underwent a PDE5i washout period before receiving riociguat individually adjusted up to 2.5 mg three times daily. Responder status at Week 24 was defined as freedom from clinical worsening, improvement of ≥30 m in 6-minute walking distance, and World Health Organization functional class I/II. Data were analyzed descriptively as mean§SD. Statistical significance was assessed using t tests. Results: At baseline, ST-2 was 21§15 ng/mL in the overall population (n=53), and responders (n=16) had lower ST-2 levels than non-responders (n=35) (17§8 vs 23§17 ng/mL). When patients were grouped according to RRS, ST-2 levels were lowest in low-risk patients (RRS 0-6; n=24) at baseline (15§7 ng/mL) and Week 24 (16§8 ng/mL) and highest in high-risk patients (RRS 9-13; n=17) at baseline (33§20 ng/ mL) and Week 24 (25§12 ng/mL). There was a significant positive correlation between ST-2 at baseline and RRS at baseline (r=0.71; p<0.0001) and at Week 24 (r=0.61; p<0.0001). There was no significant change in ST-2 from baseline to Week 24 in the overall population (p=0.10), responders (p=0.09), or non-responders (p=0.22). Interestingly, although minor increases in ST-2 levels were seen from baseline to Week 24 in the low- and intermediate-risk groups (+0.86 and +0.22 ng/mL, respectively), ST-2 had decreased by -10 ng/mL in the high-risk group at Week 24. Conclusion: ST-2 levels at baseline correlated with RRS at both baseline and Week 24 in RESPITE, and were lower in responders at baseline. Therefore, there may be potential for ST-2 as a biomarker to identify patients who may be at higher risk at treatment commencement. 215 Long-Term Outcomes in Pulmonary Arterial Hypertension by Functional Class: A Meta-Analysis of Randomized Controlled Trials and Observational Registries N.H. Kim,1 M. Fisher,2 D.S. Poch,1 C. Zhao,3 M. Shah,3 and S. Bartolome.4 1University of California, San Diego, La Jolla, CA; 2Emory School of Medicine, Atlanta, GA; 3Actelion, South San Francisco, CA; and the 4University of Texas, Southwestern Medical Center, Dallas, TX. Purpose: Patients with World Health Organization (WHO) functional class (FC) I/II pulmonary arterial hypertension (PAH) are often considered to be patients whose disease is controlled. However, little is known about their prognosis compared with patients with WHO FC III/IV disease. This meta-analysis evaluated survival outcomes in observational registries by FC, and compared treatment effects observed in randomized controlled trials (RCTs) by FC. Methods: We searched the PubMed and EMBASE databases for Englishonly articles, with our search supplemented by annual registry reports. Inclusion criteria for observational (minimal or no intervention) registries included patients with WHO group 1 pulmonary hypertension (PAH), N>30, and survival data. RCT inclusion criteria included patients with WHO group 1 pulmonary hypertension (PAH); morbidity, mortality, or time to worsening as primary or secondary endpoints; and a mean duration of exposure to study treatment >6 months. The primary outcome was
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Table 1 Variable
Correlation P-value
Correlation R-squared
AUC, Ees/Ea <1.0
Resting thermodilution cardiac output (L/min) Exercise peak cardiac output (L/min) Pulmonary vascular compliance (mL/mmHg) Right arterial/pulmonary capillary wedge pressure Pulmonary artery pulsatility index Right ventricular stroke work index (g*m/m2) Tricuspid annular systolic plane excursion (mm) Right ventricular fractional area change (%) Stroke volume/End systolic volume (SV/ESV) Right ventricular ejection fraction (%) Change in End-systolic pressure, DESP (mm Hg) Change in End-systolic volume, DESV (mL) Change in End-diastolic volume, DEDV (mL) Exercise Change in ESV/ESP (mL/mm Hg)
0.001 0.050 0.002 0.210 0.164 0.512 0.136 0.712 0.023 0.025 0.158 0.009 0.008 0.002
0.273 0.117 0.259 − − − − − 0.146 0.143 − 0.188 0.194 0.257
0.76 0.69 0.75 − − − − − 0.64 0.65 − 0.78 0.78 0.80
213 Relationship between Race/Ethnicity and Survival in Patients with Pulmonary Arterial Hypertension (PAH) S. Medrek,1 S. Sahay,2 T. Kung,3 C. Zhao,3 and A.E. Frost.2 1Division of Pulmonary and Critical Care Medicine, University of New Mexico, Albuquerque, NM; 2Houston Methodist Hospital, Houston, TX; and the 3 Actelion, South San Francisco, CA. Purpose: Prior research suggests that PAH prevalence and subtype may vary by race/ethnicity. Although some data suggest that disease severity and clinical outcomes also differ by race/ethnicity, these data are limited and based on single-center analyses. The relationship between race/ethnicity and survival was evaluated in a US prospective multicenter registry of WHO group 1 PAH, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL). Methods: Included patients were ≥18 years of age with pulmonary capillary wedge pressure ≤15 mmHg. Cox proportional hazard models were used to assess the association between race/ethnicity and survival, unadjusted or adjusted for prognostic factors of age, diagnostic status (i.e. newly or previously diagnosed), PAH etiology, and sex. The relationship between race/ethnicity and survival was also analyzed using a left-truncation which adjusts for time from diagnosis to study enrollment with covariates of age and PAH etiology. Results: This analysis included 3,046 patients: 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. A Kaplan-Meier estimate of survival by race/ethnicity indicated that white patients had the lowest survival rate. Results of an unadjusted Cox model were consistent with this, in that Asian or Pacific Islander (HR=0.46, 95% CI 0.28-0.76, p=0.002) or Hispanic (HR=0.74, 95% CI 0.56-0.97, p=0.029) patients had a lower risk of death than white patients; black patients had a similar risk as white patients. An evaluation of potentially prognostic factors by race/ethnicity revealed that white patients were older than patients of other races/ethnicities. When the Cox model was adjusted for age and other variables of potential prognostic impact that varied by race/ethnicity in this population, race/ethnicity was no longer significantly associated with survival (Asian or Pacific Islander vs. white HR=0.69, 95% CI 0.46-1.05, p=0.09; Hispanic vs. white HR=1.05, 95% CI 0.82-1.33, p=0.71; black vs white; HR=1.04, 95% CI 0.86-1.23; p=0.72). Survival analysis using left-truncation also showed no effect of race/ethnicity on survival. Conclusion: Contrary to earlier analyses and other diseases in which race/ ethnicity substantially impacts outcome, these data suggest that race/ethnicity is not a predictor of survival in patients with PAH. 214 Suppressor of Tumorigenicity 2 as a Biomarker in Pulmonary Arterial Hypertension and its Association with REVEAL Risk Score in RiociguatTreated Patients in the RESPITE Study R.L. Benza,1 J.R. Klinger,2 H.A. Ghofrani,3 P. Jansa,4 E. Gr€unig,5 D. Vizza,6 and M.M. Hoeper.7 1The Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA; 2Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of
Brown University, Providence, RI; 3University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; 4Clinicial Department of Cardiology and Angiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; 5Centre for Pulmonary Hypertension, Thorax Clinic at the University Hospital, Heidelberg, Germany; 6Pulmonary Hypertension Unit, Department of Cardiovascular and Respiratory Disease, La Sapienza University of Rome, Rome, Italy; and the 7Clinic for Respiratory Medicine, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany. Purpose: Suppressor of tumorigenicity 2 (ST-2) is a marker of cardiac remodeling and fibrosis that correlates with disease severity in patients with pulmonary arterial hypertension (PAH), and is thought to be a predictor of clinical worsening. We performed a post hoc analysis assessing ST-2 as a potential biomarker of likelihood of response in patients switching from phosphodiesterase type 5 inhibitors (PDE5i) to riociguat, and the association of ST-2 with REVEAL risk score (RRS) in the RESPITE study. Methods: RESPITE was a 24-week, open-label, uncontrolled, Phase IIIb study in PAH patients with an insufficient response to PDE5i. Patients underwent a PDE5i washout period before receiving riociguat individually adjusted up to 2.5 mg three times daily. Responder status at Week 24 was defined as freedom from clinical worsening, improvement of ≥30 m in 6-minute walking distance, and World Health Organization functional class I/II. Data were analyzed descriptively as mean§SD. Statistical significance was assessed using t tests. Results: At baseline, ST-2 was 21§15 ng/mL in the overall population (n=53), and responders (n=16) had lower ST-2 levels than non-responders (n=35) (17§8 vs 23§17 ng/mL). When patients were grouped according to RRS, ST-2 levels were lowest in low-risk patients (RRS 0-6; n=24) at baseline (15§7 ng/mL) and Week 24 (16§8 ng/mL) and highest in high-risk patients (RRS 9-13; n=17) at baseline (33§20 ng/ mL) and Week 24 (25§12 ng/mL). There was a significant positive correlation between ST-2 at baseline and RRS at baseline (r=0.71; p<0.0001) and at Week 24 (r=0.61; p<0.0001). There was no significant change in ST-2 from baseline to Week 24 in the overall population (p=0.10), responders (p=0.09), or non-responders (p=0.22). Interestingly, although minor increases in ST-2 levels were seen from baseline to Week 24 in the low- and intermediate-risk groups (+0.86 and +0.22 ng/mL, respectively), ST-2 had decreased by -10 ng/mL in the high-risk group at Week 24. Conclusion: ST-2 levels at baseline correlated with RRS at both baseline and Week 24 in RESPITE, and were lower in responders at baseline. Therefore, there may be potential for ST-2 as a biomarker to identify patients who may be at higher risk at treatment commencement. 215 Long-Term Outcomes in Pulmonary Arterial Hypertension by Functional Class: A Meta-Analysis of Randomized Controlled Trials and Observational Registries N.H. Kim,1 M. Fisher,2 D.S. Poch,1 C. Zhao,3 M. Shah,3 and S. Bartolome.4 1University of California, San Diego, La Jolla, CA; 2Emory School of Medicine, Atlanta, GA; 3Actelion, South San Francisco, CA; and the 4University of Texas, Southwestern Medical Center, Dallas, TX. Purpose: Patients with World Health Organization (WHO) functional class (FC) I/II pulmonary arterial hypertension (PAH) are often considered to be patients whose disease is controlled. However, little is known about their prognosis compared with patients with WHO FC III/IV disease. This meta-analysis evaluated survival outcomes in observational registries by FC, and compared treatment effects observed in randomized controlled trials (RCTs) by FC. Methods: We searched the PubMed and EMBASE databases for Englishonly articles, with our search supplemented by annual registry reports. Inclusion criteria for observational (minimal or no intervention) registries included patients with WHO group 1 pulmonary hypertension (PAH), N>30, and survival data. RCT inclusion criteria included patients with WHO group 1 pulmonary hypertension (PAH); morbidity, mortality, or time to worsening as primary or secondary endpoints; and a mean duration of exposure to study treatment >6 months. The primary outcome was