Long-term Survival and Quality of Life: Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) causes significant morbidity and mortality, but long-term outcomes from contemporary multicenter studies are lacking.Research QuestionHow are survival and health-related quality of life characterized in patients with CTEPH who are classified as inoperable, who are operable but have not undergone surgery, and who have undergone surgery including pulmonary thromboendarterectomy?Study Design and MethodsPatients with CTEPH recruited from 30 US sites from 2015 through 2018 completed the 36-item Short Form Health Survey (SF-36) and EmPHasis-10 survey at baseline and 6-month intervals. Mixed model repeated measures analysis was used to compare between-group differences in score up to 2 years vs baseline. Multivariable Cox proportional hazards models were used to analyze survival by CTEPH group.ResultsSeven hundred fifty patients with a median age of 59 years were enrolled; 566 patients, 88 patients, and 96 patients were in the operated, operable but no surgery, and inoperable groups, respectively. Survival at 1, 2, and 3 years was 93%, 91%, and 87%, respectively. Patients in the inoperable and the operable but no surgery groups showed higher mortality rates relative to the operated group (hazard ratios, 2.10 [95% CI, 1.17-3.77] and 2.19 [95% CI, 1.20-3.99], respectively). The EmPHasis-10 and both SF-36 scores improved during follow-up, with larger increases for the operated group (P < .05, unadjusted and adjusted vs inoperable and operable but no surgery groups at all time points up to 2 years for the SF-36 physical component score and EmPHasis-10 and at some time points for the SF-36 mental component score).InterpretationBetter survival and quality-of-life outcomes were observed in patients undergoing pulmonary thromboendarterectomy. Chronic thromboembolic pulmonary hypertension (CTEPH) causes significant morbidity and mortality, but long-term outcomes from contemporary multicenter studies are lacking. How are survival and health-related quality of life characterized in patients with CTEPH who are classified as inoperable, who are operable but have not undergone surgery, and who have undergone surgery including pulmonary thromboendarterectomy? Patients with CTEPH recruited from 30 US sites from 2015 through 2018 completed the 36-item Short Form Health Survey (SF-36) and EmPHasis-10 survey at baseline and 6-month intervals. Mixed model repeated measures analysis was used to compare between-group differences in score up to 2 years vs baseline. Multivariable Cox proportional hazards models were used to analyze survival by CTEPH group. Seven hundred fifty patients with a median age of 59 years were enrolled; 566 patients, 88 patients, and 96 patients were in the operated, operable but no surgery, and inoperable groups, respectively. Survival at 1, 2, and 3 years was 93%, 91%, and 87%, respectively. Patients in the inoperable and the operable but no surgery groups showed higher mortality rates relative to the operated group (hazard ratios, 2.10 [95% CI, 1.17-3.77] and 2.19 [95% CI, 1.20-3.99], respectively). The EmPHasis-10 and both SF-36 scores improved during follow-up, with larger increases for the operated group (P < .05, unadjusted and adjusted vs inoperable and operable but no surgery groups at all time points up to 2 years for the SF-36 physical component score and EmPHasis-10 and at some time points for the SF-36 mental component score). Better survival and quality-of-life outcomes were observed in patients undergoing pulmonary thromboendarterectomy. Take-home PointStudy Question: Do differences exist in long-term outcomes, including survival and quality of life, for patients with chronic thromboembolic pulmonary hypertension (CTEPH) classified as inoperable, operable but no surgery, and operated and underwent pulmonary thromboendarterectomy (PTE)?Results: Scores for the EmPHasis-10 and both 36-item Short Form Health Survey scores improved during follow-up, with larger increases for patients with CTEPH in the operated group vs the inoperable and operable but no surgery groups, whereas survival at up to 4 years of follow-up also was highest in patients with CTEPH undergoing PTE surgery.Interpretation: Better survival and quality-of-life outcomes were observed in patients undergoing PTE surgery relative to both patients classified as operable who did not undergo surgery and to those classified as inoperable. Study Question: Do differences exist in long-term outcomes, including survival and quality of life, for patients with chronic thromboembolic pulmonary hypertension (CTEPH) classified as inoperable, operable but no surgery, and operated and underwent pulmonary thromboendarterectomy (PTE)? Results: Scores for the EmPHasis-10 and both 36-item Short Form Health Survey scores improved during follow-up, with larger increases for patients with CTEPH in the operated group vs the inoperable and operable but no surgery groups, whereas survival at up to 4 years of follow-up also was highest in patients with CTEPH undergoing PTE surgery. Interpretation: Better survival and quality-of-life outcomes were observed in patients undergoing PTE surgery relative to both patients classified as operable who did not undergo surgery and to those classified as inoperable. Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when organized thromboemboli obstruct the pulmonary vascular bed, leading to dyspnea and fatigue and potentially to right heart failure and death. Current treatment of CTEPH includes pulmonary thromboendarterectomy (PTE), generally preferred when clot location and patient characteristics are favorable1Quadery S.R. Swift A.J. Billings C.G. et al.The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension.Eur Respir J. 2018; 52Crossref PubMed Scopus (60) Google Scholar, 2Delcroix M. Lang I. Pepke-Zaba J. et al.Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.Circulation. 2016; 133: 859-871Crossref PubMed Scopus (424) Google Scholar, 3Hobohm L. Keller K. Munzel T. Konstantinides S.V. Lankeit M. Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.Pulm Circ. 2021; 1120458940211008069Crossref Scopus (5) Google Scholar, 4Condliffe R. Kiely D.G. Gibbs J.S. et al.Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension.Am J Respir Crit Care Med. 2008; 177: 1122-1127Crossref PubMed Scopus (339) Google Scholar; balloon pulmonary angioplasty (BPA)5Mahmud E. Patel M.P. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.Circ Cardiovasc Interv. 2018; 11e007462Crossref Scopus (0) Google Scholar; medical therapies6Ghofrani H.A. D’Armini A.M. Grimminger F. et al.Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.N Engl J Med. 2013; 369: 319-329Crossref PubMed Scopus (985) Google Scholar; and long-term anticoagulation. Although improvements in outcomes of patients with CTEPH after PTE have been documented,3Hobohm L. Keller K. Munzel T. Konstantinides S.V. Lankeit M. Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.Pulm Circ. 2021; 1120458940211008069Crossref Scopus (5) Google Scholar,7Madani M.M. Auger W.R. Pretorius V. et al.Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients.Ann Thorac Surg. 2012; 94 (discussion 103): 97-103Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar,8Kerr K.M. Elliott C.G. Chin K. et al.Results from the United States Chronic Thromboembolic Pulmonary Hypertension Registry: enrollment characteristics and 1-year follow-up.Chest. 2021; 160: 1822-1831Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar contemporary multicenter outcome data from studies in the United States are not available. In addition, serial assessment of patient-reported symptoms and health-related quality of life is very limited, despite the importance of these end points as outcome measures of medical and surgical interventions for CTEPH.9McGoon M.D. Ferrari P. Armstrong I. et al.The importance of patient perspectives in pulmonary hypertension.Eur Respir J. 2019; 53Crossref Scopus (73) Google Scholar The United States Chronic Thromboembolic Pulmonary Hypertension Registry was organized to provide contemporary outcomes data for patients with CTEPH who received a diagnosis and were treated at 30 US pulmonary hypertension (PH) centers. The objective of the current analyses was to evaluate and compare long-term outcomes for symptoms, health-related quality of life, hospitalizations, and survival across three subgroups of patients with CTEPH: those who underwent PTE surgery during the study period (operated group), those were eligible for but had not undergone surgery (operable but no surgery group), and those who were not eligible for surgery (inoperable group). The United States Chronic Thromboembolic Pulmonary Hypertension Registry is a multicenter, prospective, longitudinal cohort study of patients with newly diagnosed CTEPH. The University of California, San Diego, is the sponsor and coordinating institution for the study, approved by the University of California, San Diego, Human Research Protection Program (Project no. 141379). Thirty US sites participated. Enrollment was from April 2015 through March 2018, with follow-up until March 2019. Consecutive patients with a diagnosis of CTEPH received within 6 months of consent and meeting the inclusion criteria were offered participation in the study. Patients had precapillary PH diagnosed by right heart catheterization (mean pulmonary arterial pressure [mPAP] of ≥ 25 mm Hg, pulmonary arterial wedge pressure of ≤ 15 mm Hg or > 15 mm Hg if justified by the investigator) and showed evidence of CTEPH on imaging that was reviewed for eligibility by an adjudication team. Patients were classified by the enrolling center as having operable or inoperable CTEPH, and if inoperable, the reasons for this classification. Details have been published previously.8Kerr K.M. Elliott C.G. Chin K. et al.Results from the United States Chronic Thromboembolic Pulmonary Hypertension Registry: enrollment characteristics and 1-year follow-up.Chest. 2021; 160: 1822-1831Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Patients were subdivided further into three groups: operated (patients undergoing PTE surgery during the study period), operable but no surgery (patients classified as operable who did not undergo surgery), and inoperable. Patients completed the Rand version of the 36-item Short-Form Health Survey (SF-36) and EmPHasis-10 at baseline and at 6-month intervals after enrolment. The SF-36 is a 36-item patient-reported survey of general health that has had good reliability and validity across many patient populations and settings.10Frendl D.M. Ware Jr., J.E. Patient-reported functional health and well-being outcomes with drug therapy: a systematic review of randomized trials using the SF-36 health survey.Med Care. 2014; 52: 439-445Crossref PubMed Scopus (78) Google Scholar, 11Mathai S.C. Suber T. Khair R.M. Kolb T.M. Damico R.L. Hassoun P.M. Health-related quality of life and survival in pulmonary arterial hypertension.Ann Am Thorac Soc. 2016; 13: 31-39Crossref PubMed Scopus (53) Google Scholar, 12Sanders J. Bowden T. Woolfe-Loftus N. Sekhon M. Aitken L.M. Predictors of health-related quality of life after cardiac surgery: a systematic review.Health Qual Life Outcomes. 2022; 20: 79Crossref Scopus (5) Google Scholar The EmPHasis-10 is a 10-item disease-specific questionnaire developed to assess symptoms of PH; it has good internal and test-test reliability and was developed and validated in patients with pulmonary arterial hypertension and CTEPH.13Yorke J. Corris P. Gaine S. et al.emPHasis-10: development of a health-related quality of life measure in pulmonary hypertension.Eur Respir J. 2013; Google Scholar Scores for the SF-36 physical component score (PCS) and mental component score (MCS) were calculated using standard methodology with a potential range from 0 to 100; the general population mean ± SD is 50 ± 10 for both, with higher scores corresponding to better health-related quality of life. Scores for the EmPHasis-10 range from 0 to 50, with lower scores corresponding to fewer symptoms. A descriptive analysis was performed for demographic characteristics. Medians and interquartile ranges were reported for continuous variables and a frequency table was reported for categorical variables. For comparisons among the three groups, a Kruskal-Wallis test was performed for continuous variables and a Fisher exact test for categorical variables. When the overall group comparisons were significantly different (P < .05), a Wilcoxon rank-sum test and Fisher exact test were performed for the between-group (pairwise) comparisons. To account for multiple testing, Bonferroni correction was applied for pairwise comparisons using a critical P value for pairwise comparisons of .017. Hospitalizations were calculated as an incident rate, hospitalizations per 100 person-years, excluding scheduled hospitalizations for PTE surgery or BPA procedures. Survival analysis outcome was assessed using Kaplan-Meier methods from the date of consent up to 48 months of follow-up for the group overall and after stratification by median age and by sex, respectively, with log-rank tests performed for the analysis. Stratification by median age and sex were chosen because prior studies have shown differences in outcomes by sex and in older age groups, older than approximately 60 years.14Benza R.L. Gomberg-Maitland M. Elliott C.G. et al.Predicting survival in patients with pulmonary arterial hypertension: the REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies.Chest. 2019; Abstract Full Text Full Text PDF Scopus (329) Google Scholar Patients were censored for early discontinuation or at study exit for those completing the planned 48 months of follow-up. Cox proportional hazards models were performed with a significant critical level of 0.05. Variables included in the univariable analyses were age, sex (female as the reference), race (Black as the reference vs White), World Health Organization functional classes III and IV (World Health Organization classes I and II combined as reference), COPD, atrial fibrillation (AF), coronary artery disease, sleep-disordered breathing, stroke or transient ischemic attack, any cancer, splenectomy, BMI (BMI ≤ 30 kg/m2 as reference vs > 30 kg/m2), right atrial pressure, mPAP, cardiac index, and pulmonary vascular resistance. An unadjusted Cox proportional hazards model with group in the model (operated group as the reference group) was completed along with three multivariable models: (1) limited model adjusted for age, sex, and race; (2) prespecified model adjusted for age, sex, race, BMI, COPD, AF, history of cancer, right atrial pressure, and cardiac index, chosen based on prevalence in the population plus association with survival in similar populations, with diabetes and coronary arterial disease excluded because of correlation with other variables; and (3) inclusion of all covariates that were statistically significant (P < .05) in the univariable analysis. For the SF-36 PCS, SF-36 MCS, and EmPHasis-10 outcomes, descriptive analysis was performed for the scores and change scores from baseline at each study visit. Profile plots (mean with 95% CI) were provided for scores and change scores from baseline by group and visit, and in an exploratory analysis, plots were created after stratification by median age. A responder analysis was performed evaluating the proportion of patients with an improvement in scores equal to or more than the reported minimally important difference for these scales, using a change in score of ≥ 5 for the SF-36 MCS and SF-36 PCS and ≤ –6 for the EmPHasis-10.15Mathai S.C. Puhan M.A. Lam D. Wise R.A. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension.Am J Respir Crit Care Med. 2012; 186: 428-433Crossref PubMed Scopus (191) Google Scholar,16Borgese M. Badesch D. Bull T. et al.EmPHasis-10 as a measure of health-related quality of life in pulmonary arterial hypertension: data from PHAR.Eur Respir J. 2021; 57Crossref Scopus (15) Google Scholar ORs, 95% CIs, and P values were calculated (P values from the Fisher exact test). Mixed model repeated measures (MMRM) analyses were performed for the SF-36 PCS, SF-36 MCS, and EmPHasis-10 outcomes. The population for MMRM model includes the patients who had baseline outcome values and at least one follow-up value. Dependent variables included in the MMRM model were the change scores of the outcomes from baseline at months 6, 12, 18, and 24. Fixed effects in the MMRM model were group, visit, group-by-visit interaction, baseline outcome score, and covariates of interest. Visit was considered as a categorical variable. To account for multiple testing for pairwise comparisons, Bonferroni correction was applied, in which the critical P value was < .017. The predefined covariates of interest that were adjusted for in the MMRM models were the same variables included in the prespecified survival model, as listed above. Patient-reported outcome (PRO) scores also were evaluated after stratification by median age. Analyses of the effects of PH medical therapies and BPA on PRO results were not analyzed because of the varied timing of initiation relative to survey administration. Statistical analyses were performed using R version 3.6.1 software (R Foundation for Statistical Computing). A total of 750 patients with CTEPH were enrolled from 30 PH centers in the United States. Median age was 59 years, and the cohort was 51% male (Table 1). Enrolled patients were classified as operated (ie, underwent PTE; n = 566 [75%]), inoperable (n = 96 [13%]), and operable but no surgery (n = 88 [12%]) (Fig 1). Operated patients were significantly younger and had lower rates of COPD or a history of cancer vs patients in the inoperable and operable but no surgery groups, and the operated group included slightly more male patients, although the sex difference was not statistically significant across the three groups. BMI was lowest in the inoperable group. For patients undergoing PTE surgery, surgery was performed a median of 0.26 months (interquartile range, 0.16-1.8 months) from screening. BPA was performed in 40 patients from 12 centers and included 27 patients from the inoperable group, six patients from the operable but no surgery group, and seven patients from the operated group. PH medical therapy at baseline was reported in 39%, 65%, and 50% of patients in the operated, inoperable, and operable but no surgery groups, respectively; these percentages increased at 1 year for the inoperable and operable but no surgery groups, but decreased in the operated group (e-Table 1).Table 1DemographicsTotal Cohort (N = 750)Operated (n = 566)Inoperable (n = 96)Operable But No Surgery (n = 88)P ValueAge, y59 (46-69)57 (44-67)67 (56-74)66 (52-73)< .001aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.,bBetween-group operable no surgery vs operated pairwise comparisons, P < .017 was statistically significant.Sex, % male50.852.740.649.4.094Race or ethnicity. . .. . .. . .. . .. . . Non-Hispanic White492 (65.6)373 (65.8)65 (67.7)55 (61.8).026bBetween-group operable no surgery vs operated pairwise comparisons, P < .017 was statistically significant. Non-Hispanic Black168 (22.4)120 (21.2)19 (19.8)29 (32.6). . . Hispanic44 (5.9)40 (7.1)4 (4.2)0 (0). . . Other46 (6.1)33 (5.8)8 (8.3)5 (5.6). . .BMI, kg/m229.7 (25.8-35.9)30.4 (26.1-36.3)27.3 (23.8-34.1)30.4 (26.5-35.3).006aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.6MWD, m329 (235-400), n = 374334 (235-406) n = 253321 (244-376) n = 64310 (228-388) n = 58.390WHO FC, %. . .. . .. . .. . ..058 I2136. . . II22212327. . . III63655658. . . IV1312189. . .Obesity, BMI > 30 kg/m2369 (49)289 (51)35 (36.5)45 (51.1).027aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.Extreme obesity, BMI > 40 kg/m2108 (14.4)90 (15.8)5 (5.2)13 (14.8).013aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.COPD114 (15.2)70 (12.4)23 (24)21 (23.9)< .001aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.,bBetween-group operable no surgery vs operated pairwise comparisons, P < .017 was statistically significant.Systemic hypertension271 (36.1)202 (35.7)35 (36.5)34 (38.6).857Coronary artery disease82 (10.9)54 (9.5)13 (13.5)15 (17.1).069Atrial fibrillation53 (7.1)40 (7.1)5 (5.2)8 (9.1).581History of stroke or TIA41 (5.5)29 (5.1)7 (7.3)5 (5.7).634Sleep-disordered breathing209 (27.9)164 (29.0)21 (21.9)24 (27.3).362Asthma92 (12.3)76 (13.4)8 (8.3)8 (9.0).269Diabetes113 (15.1)77 (13.6)17 (17.7)19 (21.4).10Splenectomy (any)46 (6.0)29 (5.1)10 (10.4)7 (8.0).094History of any cancer2Delcroix M. Lang I. Pepke-Zaba J. et al.Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.Circulation. 2016; 133: 859-871Crossref PubMed Scopus (424) Google Scholar69 (9.2)42 (7.4)14 (14.6)13 (14.8).013RAP (mmHg)9 (6-13), n = 7029(6-13), n = 5339 (5-14), n = 889 (6-13), n = 81).801mPAP, mm Hg44 (36-53), n = 75044 (36-52), n = 56645 (34-50), n = 9640 (32-49), n = 88.024aBetween-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.PCWP, mm Hg12 (8-15), n = 73112 (8-15), n = 55111(9-14), n = 9312 (9-14), n = 87.643Cardiac output, L/mincThermodilution values used for reporting cardiac output and cardiac index whenever available; otherwise Fick value reported.4.59 (3.63-5.55), n = 7374.57(3.6-5.57), n = 5564.68 (4.07-5.63), n = 944.40 (3.6-5.42), n = 87.419Cardiac index, L/min/m2c2.23(1.84-2.7), n = 7172.2 (1.8-2.68), n = 5422.49 (2.1-2.88), n = 912.2 (1.83-2.67), n = 84.003bBetween-group operable no surgery vs operated pairwise comparisons, P < .017 was statistically significant.PVR, WU6.86 (4.55-10.1), n = 7226.90 (4.74-10.29), n = 5456.33 (4.46-9.11), n = 916.53 (3.67-10.09), n = 86.248Data are presented as No. (%) or median (interquartile range), unless otherwise indicated. FC = functional class; mPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; 6MWD = 6-min walk distance; TIA = transient ischemic attack; WHO = World Health Organization.a Between-group inoperable vs operated pairwise comparisons, P < .017 was statistically significant.b Between-group operable no surgery vs operated pairwise comparisons, P < .017 was statistically significant.c Thermodilution values used for reporting cardiac output and cardiac index whenever available; otherwise Fick value reported. Open table in a new tab Data are presented as No. (%) or median (interquartile range), unless otherwise indicated. FC = functional class; mPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; 6MWD = 6-min walk distance; TIA = transient ischemic attack; WHO = World Health Organization. Over a median of 25 months of follow-up, 319 hospitalizations involving 188 patients occurred, excluding scheduled hospitalizations related to PTE surgery or BPA procedures (e-Table 2). Common reasons for hospitalization included PH (39%), reported as either new cardiopulmonary symptoms or right heart failure, thromboembolism (8%), or hemorrhage (6%). The hospitalization rate per 100 person-years was lower in the PTE group at 25.0 per 100 person-years (95% CI, 22.2-28.1 per 100 person-years) vs 32.9 per 100 person-years (95% CI, 24.7-43.1 per 100 person-years) and 37.9 per 100 person-years (95% CI, 29.7-47.7 per 100 person-years) in the inoperable and operable but no surgery groups, respectively. In the cohort overall, 75 deaths occurred, and survival at 1, 2, and 3 years was 93%, 91%, and 87%, respectively; this includes 22 perioperative deaths in the operated group (3.9%). Variables associated with lower survival included older age, World Health Organization functional classes III and IV, and comorbidities including COPD, AF, coronary arterial disease, OSA, and more severe hemodynamics including higher right atrial pressure, mPAP, and pulmonary vascular resistance (Table 2).Table 2Univariable Analysis of Time to DeathVariableHazard RatioP ValueWHO functional classaReference for WHO functional class is classes I and II combined.. . .. . . III2.625.011 IV4.175.001COPD2.851< .001Atrial fibrillation2.673.001CAD2.286.003Sleep-disordered breathing2.0.003Stroke/TIA1.82.13Any cancer1.546.2Race1.375.28Sex1.112.65Splenectomy1.11.82Age1.024.005BMI0.681.10RAP1.047.011mPAP1.042< .001Cardiac index0.916.64PVR1.113< .001CAD = coronary arterial disease; mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; TIA = transient ischemic attack; WHO = World Health Organization.a Reference for WHO functional class is classes I and II combined. Open table in a new tab CAD = coronary arterial disease; mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; TIA = transient ischemic attack; WHO = World Health Organization. Survival by CTEPH group is shown in Figure 2 (Kaplan-Meier curve) and e-Table 3, which shows the survival and characteristics of this cohort vs other multicenter cohorts with CTEPH. One-, 2-, and 3-year survival was 95%, 93%, and 90% (operated group); 88%, 84%, and 80% (inoperable group); and 91%, 85%, and 74% (operable but no surgery group), respectively. Patients in the inoperable and the operable but no surgery groups showed significantly higher mortality relative to the operable group based on univariable Cox proportional hazards models (hazard ratios, 2.1 [95% CI, 1.17-3.77] and 2.19 [95% CI, 1.2-3.99], respectively). Results were similar in multivariable models, with hazard ratios that approached or met statistical significance (Table 3).Table 3Multivariable Analyses of Time to DeathVariableGroupHR (95% CI)P ValueUnadjusted modelOperatedReference. . .Inoperable2.10 (1.17-3.77).0126Operable but no surgery2.19 (1.20-3.99).0104Adjusted for age, sex, and raceOperatedReference. . .Inoperable1.84 (1.00-3.39).0499Operable but no surgery1.96 (1.06-3.66).032Adjusted for age, sex, race, and prespecified variablesOperatedReference. . .Inoperable1.71 (0.89-3.28).108Operable but no surgery1.96 (1.05-3.68).035Adjusted for variables significant in the univariable analysisOperatedReference. . .Inoperable2.24 (1.16-4.35).0166Operable but no surgery2.03 (1.07-3.86).0299Prespecified variables included BMI, COPD, history of any cancer, right atrial pressure, and cardiac index. Variables significant in the univariable analysis were age, functional class, COPD, coronary artery disease, atrial fibrillation, OSA, right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance. HR = hazard ratio. Open table in a new tab Prespecified variables included BMI, COPD, history of any cancer, right atrial pressure, and cardiac index. Variables significant in the univariable analysis were age, functional class, COPD, coronary artery disease, atrial fibrillation, OSA, right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance. HR = hazard ratio. Survival curves stratified by median age and sex are shown in e-Figure 1. Formal statistical analyses were not performed for these subgroups given the small sample sizes, but qualitatively, outcomes seemed generally similar for male vs female patients, whereas perioperative mortality seemed modestly higher for patients older than the median age compared with those younger than the median age. Baseline and follow-up scores for the EmPHasis-10 and SF-36 are shown in Figure 3. In the cohort overall, the SF-36 PCS was lower than the SF-36 MCS at baseline, with a mean of 34.6 (SD, 8.3) on the SF-36 PCS and 44.5 (SD, 12.1) on the SF-36 MCS. The baseline EmPHasis-10 mean score was 30.4 (SD, 11.5). Follow-up scores, assessed every 6 months, improved across all three groups vs baseline (operated, inoperable, and operable but no surgery). Improvement vs baseline was larger in the operated group, with similar results after stratification by median age (e-Figs 2, 3). In a responder analysis assessing the proportion of patients meeting or exceeding the minimally important difference for each scale at 6 and 12 months, a larger proportion of patients reached this level in the operated group vs the inoperable and operable but no surgery groups (Fig 4, e-Table 4). In the MMRM models including both unadjusted results and results adjusted for demographics, comorbidities, and hemodynamics, the change score from baseline score also was significantly greater for the operated group relative to both the operable but no surgery and inoperable groups at most time points (e-Tables 5-16 for scores by visit, change from baseline scores by visit, and unadjusted and adjusted MMRM model results summary). The US CTEPH Registry was designed to provide demographics and outcomes of a large cohort of patients with CTEPH and included 750 patients with CTEPH from 30 centers in the United States. Baseline characteristics were reported previously8Kerr K.M. Elliott C.G. Ch