Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry

Abstract

BackgroundThe United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension.Research QuestionWhat are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects?Study Design and MethodsThis study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019.ResultsMost patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001).InterpretationDifferences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery.Clinical Trial RegistrationClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov. The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov. FOR EDITORIAL COMMENT, SEE PAGE 1599Chronic thromboembolic pulmonary hypertension (CTEPH), an important diagnostic subgroup of pulmonary hypertension (PH), is characterized by the obstruction of pulmonary arteries with fibrotic, organized thrombus material and vascular remodeling resulting in PH and right ventricular failure.1Kim N.H. Delcroix M. Jais X. et al.Chronic thromboembolic pulmonary hypertension.Eur Respir J. 2019; 53: 1801915Crossref PubMed Scopus (267) Google Scholar Although CTEPH shares some clinical and pathologic characteristics with pulmonary arterial hypertension (PAH), the etiology, diagnosis, and treatment of CTEPH differ substantially from those of PAH. FOR EDITORIAL COMMENT, SEE PAGE 1599 Although many registries have focused on PAH,2Rich S. Dantzker D.R. Ayres S.M. et al.Primary pulmonary hypertension: a national prospective registry.Ann Int Med. 1987; 107: 216-223Crossref PubMed Scopus (1710) Google Scholar, 3Badesch D.B. Raskob G.E. Elliott C.G. et al.Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry.Chest. 2010; 137: 376-387Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar, 4Humbert M. Sitbon O. Chaouat A. et al.Pulmonary arterial hypertension in France: results from a national registry.Am J Respir Crit Care Med. 2006; 173: 1023-1030Crossref PubMed Scopus (1512) Google Scholar, 5Ling Y. Johnson M.K. Kiely D.G. et al.Changing demographics, epidemiology and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland.Am J Respir Crit Care Med. 2012; 186: 790-796Crossref PubMed Scopus (385) Google Scholar, 6McGoon M.D. Benza R.L. Escribano-Subias P. et al.Pulmonary arterial hypertension: epidemiology and registries.J Am Coll Cardiol. 2013; 62: D51-D59Crossref PubMed Scopus (351) Google Scholar there has not been a US multicenter registry focused on CTEPH. Investigators of the European CTEPH Registry described the epidemiology, risk factors, and outcomes of newly diagnosed European and Canadian patients with CTEPH.7Pepke-Zaba J. Delcroix M. Lang I. et al.Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.Circulation. 2011; 124: 1973-1981Crossref PubMed Scopus (661) Google Scholar,8Delcroix M. Lang M. Pepke-Zaba 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 (342) Google Scholar However, the evolution in medical and surgical approaches, including the availability of riociguat and balloon pulmonary angioplasty (BPA), as well as the differences in CTEPH management between the United States and Europe, provided the rationale to organize the first US CTEPH registry. The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) is a contemporary CTEPH registry involving 30 PH centers. The current report describes the demographic characteristics, medical history, symptoms, timeline to diagnosis, risk factors, diagnostic approach, disease management, and 1-year outcomes of 750 US patients newly diagnosed with CTEPH. The US-CTEPH-R is a multicenter, prospective, longitudinal registry of patients newly diagnosed with CTEPH. The University of California San Diego (UCSD) is the sponsor and coordinating institution for the study, approved by the UCSD Human Research Protection Program (Project #141379). Thirty US sites (e-Appendix 1), selected based on a feasibility survey and geographic distribution, participated in the registry. Following provision of written informed consent, each patient was assigned a unique numerical patient-identifier to maintain confidentiality as required by the Health Insurance Portability and Accountability Act. The first patient was enrolled in April 2015, and target enrollment of 750 patients was met in March 2018. All subjects were followed up biannually until the last subject completed 1 year of follow-up in March 2019. Consecutive patients diagnosed with CTEPH within 6 months of study consent and meeting the inclusion criteria were offered participation in the study. Time of diagnosis was defined as the date that the last of three hemodynamic and radiologic entry criteria for CTEPH (right heart catheterization, ventilation and perfusion lung scans, and pulmonary angiography) was met. Hemodynamic criteria included a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg measured by right heart catheterization and pulmonary capillary wedge pressure ≤ 15 mm Hg, or > 15 mm Hg if justified by the investigator. Radiologic criteria included mismatched perfusion defects on ventilation and perfusion scanning and findings compatible with chronic thromboembolic disease on digital subtraction (DSA), CT angiography, or magnetic resonance angiography. A physician adjudication team (e-Appendix 2) reviewed imaging, with two adjudicators agreeing independently that imaging met the predefined criteria for CTEPH. Subjects meeting enrollment criteria were followed up longitudinally. Patients who had previously undergone pulmonary thromboendarterectomy (PTE) or BPA were excluded. All evaluations and procedures performed were at the discretion of the treating clinician. Data collected at enrollment are given in the text and tables. Longitudinal data were collected biannually during patient clinic visits or by patient telephone call and/or chart abstraction. Descriptive analysis provided the median and first/third quartiles for continuous variables and a frequency table reported for categorical variables. For comparisons among the three groups, a Kruskal-Wallis test was performed for continuous variables and Fisher exact test for categorical variables. The Wilcoxon rank sum test and Fisher exact test were used for between-group (pairwise) comparisons when the overall group comparisons differed significantly (P < .05). To account for multiple testing, Bonferroni’s correction was applied, in which the critical P value for each pairwise between-group comparison was defined as P < .0167. Subgroup analysis of Operated and Operable/No Surgery patients comparing covariates of age, sex, race, and co-morbidities identified by the Fisher exact test to be significantly different between the groups was performed by using univariate logistic regression analysis. R 3.5.2 statistical software (www.rproject.org; R Foundation for Statistical Computing) was used for analysis. Between April 2015 and March 2018, a total of 803 patients consented to participate in the US-CTEPH-R. Fifty subjects (6.2%) failed radiologic adjudication. The most common reasons included: acute rather than chronic pulmonary embolism (PE; n = 18), no chronic PE (n = 16), or advanced parenchymal lung disease (n = 12). Three other subjects were excluded, resulting in 750 subjects in the final analysis with subjects from US (e-Appendix All were for were Operable and UCSD was the (n = of the subjects from Subjects enrolled at UCSD were more Operated compared with the centers. Inoperable patients included those with disease co-morbidities advanced and hemodynamic patients multiple to surgery. the operable did not undergo surgery. The most common included subject or surgery risk most to and patient well with multiple reasons for not undergoing including advanced for The patients of the total underwent PTE at US of which were US-CTEPH-R logistic regression analysis identified advanced (P < (P = the of COPD (P = ventricular (P = or (P = a history of (P = and a history of (P = or (P = as covariates with operable patients not undergoing surgery at enrollment was subjects of the total cohort Inoperable and Operable/No Surgery subjects were older than Operated subjects P < .001). The median was and Inoperable subjects had a Most subjects were functional class at enrollment was no in functional class or among the three = (n = (n = Surgery (n = and median among three groups, P < P < Surgery P < among three groups, P < Surgery P < median among three groups, P < P < median n = n = n = n = functional class from to of among three groups, P < P < Surgery P < = CTEPH = chronic thromboembolic pulmonary PTE = pulmonary = first/third = World Health among three groups, P < P < Surgery P < table in a = CTEPH = chronic thromboembolic pulmonary PTE = pulmonary = first/third = World Health The of patients with CTEPH (87.9%) reported a history of acute PE with or DVT treated with or of the total CTEPH cohort reported of PE The patients reported no history of acute PE or DVT or a history of DVT PE DVT was of in an was reported in of patients. included and/or at reported included and/or Patients and/or less The median from of until clinical of CTEPH was months months) for the total study Although of subjects reported treatment of the median from PE to of CTEPH in group with was months were to other than CTEPH in included PE (n (n = COPD (n = (n = (n = and heart (n = included hypertension surgery COPD and artery disease 3 and was more common in Operable COPD more with CTEPH in the Inoperable cohort and the Operable/No Surgery cohort than in the Operated cohort patients with CTEPH who underwent PTE were less likely to report a history of cancer. therapy at enrollment included and was the most common followed by and no was reported in At of subjects were Inoperable patients were more likely than those Operable to PH therapy P < .001) was most followed by therapies were used to of at = (n = (n = Surgery (n = and PH among three groups, P < P < 1 on of are as n = total of subjects in cohort on pulmonary hypertension therapy of subjects in cohort on = = = among three groups, P < P < table in a Data on of are as n = total of subjects in cohort on pulmonary hypertension therapy of subjects in cohort on = = = perfusion defects in of the patients. defects were larger than in of patients and or in Inoperable and Operable/No Surgery subjects had perfusion defects compared with Operated patients. defects to lung were more in Operable/No Surgery subjects compared with the Operated and Inoperable patients = (n = (n = Surgery (n = and imaging among three groups, P < group Surgery P < among three groups, P < group Surgery P < group P < of among three groups, P < group Surgery P < group P < of among three groups, P < group Surgery P < group P < among three groups, P < group Surgery P < group P < = CT disease = of most on or = digital subtraction = perfusion or in lung on ventilation and perfusion = perfusion defects to among three groups, P < Between group Surgery P < Between group P < table in a = CT disease = of most on or = digital subtraction = perfusion or in lung on ventilation and perfusion = perfusion defects to to CT the most of was in the or pulmonary the most in the or pulmonary artery defined as the most in or more or pulmonary was more in the Inoperable and Operable/No Surgery groups compared with the Operated catheterization PH with a median of 44 mm Hg and a pulmonary vascular resistance of Wood units were among the three that was in the Operated Operable/No Surgery group and was in the Operated Inoperable = (n = (n = Surgery (n = and mm mm among three groups, P < group Surgery P < mm among three groups, P < group P < are as median of are used for and are = mean pulmonary artery = pulmonary capillary wedge = pulmonary vascular = right = Wood among three groups, P < Between group Surgery P < Between group P < table in a Data are as median of are used for and are = mean pulmonary artery = pulmonary capillary wedge = pulmonary vascular = right = Wood A was identified in of the subjects with identified in and/or of or was in and in of group (n = that was more common in Operated and Operable/No Surgery patients compared with Inoperable patients P = of the registry cohort had undergone 3.9% had a history of and had PTE was performed on US-CTEPH-R patients. chronic thromboembolic disease or pulmonary was in most with of the right lung more than the lung surgical was performed at the of PTE in of a or (n = was the most common followed by artery (n = or (n = in hemodynamic compared with baseline from 44 to mm Hg, from to and total pulmonary resistance from to Wood in-hospital was 3.9% (n = with of to right ventricular (n = pulmonary (n = pulmonary (n = other surgical (n = (n = or other (n = subjects underwent including who were 6 who were operable did not undergo and who underwent PTE and at 1 year in Operated subjects n = to follow-up, n = n = n = 1), Inoperable patients n = to follow-up, n = n = 1), and 15 Operable/No Surgery patients n = to follow-up, n = n = Although functional class was in the three groups at at 1-year follow-up, the Operated group had a functional class compared with the Inoperable and Surgery (P < .001) of the Operated group were functional class or at 1 year (82.9%) compared with the Inoperable (48.2%) or Operable/No Surgery (56%) (P < .001). However, three functional class at 1 Operated subjects were on oxygen, diuretics, or therapy compared with the Inoperable group at 1 year (P < .001). The of therapy from baseline in the Operated group and at 1 year in the Inoperable and Surgery groups differed for the three Operable/No and P = Most in the Operated group were with three to of the 10 in the Inoperable group were to heart and of the in the Operable/No Surgery group were to heart with to The US-CTEPH-R is the first prospective, multicenter, observational registry of US patients newly diagnosed with CTEPH. The US-CTEPH-R a contemporary of US patients with including and clinical results of diagnostic medical characteristics of patients selected for PTE and those and outcomes 1 year from the registry was that the diagnosis of CTEPH be study sites PH patients diagnosed with CTEPH (6.2%) failed the of acute PE from chronic thromboembolic disease the most common for adjudication has been reported J. Delcroix M. Lang I. et al.Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.Circulation. 2011; 124: 1973-1981Crossref PubMed Scopus (661) Google S. et of diagnostic in chronic thromboembolic pulmonary hypertension: results from the European CTEPH Respir J. PubMed Scopus Google Scholar diagnostic delays were with a median of 10 months and a of months an acute PE to CTEPH the of of patients to as or The of was that patients were diagnosed at an advanced of At most subjects were functional class and > of subjects had a > mm Hg with pulmonary vascular resistance and than of the patients required diuretics, and were treated with therapy and/or Most registry patients reported a history of acute with no Patients described of an acute and of the subjects reported a history of PE an that a of chronic PE have been at the of an as has been reported by et of chronic thromboembolic pulmonary hypertension acute pulmonary PubMed Scopus Google Scholar with CTEPH described in other cohort et of chronic thromboembolic pulmonary hypertension acute pulmonary PubMed Scopus Google S. et for chronic thromboembolic pulmonary hypertension.Eur Respir J. PubMed Scopus Google Pepke-Zaba et with diagnosis and of chronic thromboembolic pulmonary a 2013; PubMed Scopus Google Scholar were in including a history of non-type O blood group, and of patients with CTEPH were Inoperable patients were older than Operated and less likely to be have a history of non-type O blood group, or and more likely to have COPD and/or a history of cancer. with the Inoperable Operable/No Surgery patients were older and more likely to have ventricular and/or a history of than the Operated patients with CTEPH. functional and were not different between the Operable/No Surgery and Operated However, as with the Inoperable diagnostic was in the Operable/No Surgery group compared with the Operated group, to more with the to advanced and Operable/No Surgery patients had perfusion defects and disease on than the Operated group, the that less disease and of surgical the not to with surgery. therapy was more common in Inoperable subjects compared with Operated Although there are no data to of the Operated subjects therapy to surgery. the registry data that PTE most patients with operable CTEPH. At the 1-year follow-up, an was in functional class in three However, the Operated group in functional of medical and survival compared with the other two with the median in the European CTEPH J. Delcroix M. Lang I. et al.Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.Circulation. 2011; 124: 1973-1981Crossref PubMed Scopus (661) Google Scholar the median of the US-CTEPH-R subjects was and functional class were A is in the of the with the European CTEPH Registry subjects and the US-CTEPH-R and The US registry a of and Patients in the US-CTEPH-R more reported a history of acute PE and PE a of DVT registries that Inoperable subjects were less likely to have a history of DVT compared with Operable US-CTEPH-R patients were more likely to report a history of and and the percentage of subjects with disease on imaging were between the US-CTEPH-R and the European CTEPH of the subjects were operable underwent in to the reported operable underwent in the European CTEPH reasons for the the adjudication of subjects in the differences in the of and a of surgical in the US-CTEPH-R. For at of the enrolled subjects were a to a surgical study have been This analysis was an at a of the of patients with CTEPH in the United are differences between in as well as co-morbidities that surgical This resulted in some between the Inoperable and Operable/No Surgery US-CTEPH-R sites are PH more advanced and CTEPH the enrolled by registry likely not the CTEPH for in the to a PH of the sites were surgical which the percentage of Operable patients in the US-CTEPH-R. 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S. of the The sponsor had no in the of the study, the and analysis of the or the of the The and at the registry sites in are for the and provided by and at and The and be in the of the with Data the United States Chronic Thromboembolic Pulmonary Hypertension Pulmonary thromboembolic pulmonary hypertension is a pulmonary vascular disease that from or pulmonary embolism. treatment of CTEPH has been pulmonary which is the of pulmonary artery with advanced surgical of as balloon pulmonary angioplasty designed for those who are not as surgical and medical with have been in of clinical right ventricular and survival of patients with CTEPH. PDF

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