Severe Pulmonary Hypertension in COPD

Abstract

BackgroundSevere pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization.Research QuestionCan noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease?Study Design and MethodsWe retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex.ResultsWe included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%–69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27–43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH).InterpretationIn patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable. Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization. Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease? We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex. We included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%–69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27–43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH). In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable. Take-home PointsStudy Question: Can noninvasive clinical tools predict severe pulmonary hypertension (PH) in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease?Results: The combination of echocardiographic systolic PAP of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and main pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values. Both airflow limitation and PH severity were associated independently with survival.Interpretation: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable. Study Question: Can noninvasive clinical tools predict severe pulmonary hypertension (PH) in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease? Results: The combination of echocardiographic systolic PAP of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and main pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values. Both airflow limitation and PH severity were associated independently with survival. Interpretation: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable. Pulmonary arterial pressure (PAP) often is increased moderately in patients with COPD.1Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease and hypoxia.Eur Respir J. 2019; 53: 1801914Crossref PubMed Scopus (237) Google Scholar Severe pulmonary hypertension (PH) is present in 1% to 4% of patients2Chaouat A. Bugnet A.S. Kadaoui N. et al.Severe pulmonary hypertension and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2005; 172: 189-194Crossref PubMed Scopus (486) Google Scholar, 3Thabut G. Dauriat G. Stern J.B. et al.Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation.Chest. 2005; 127: 1531-1536Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 4Scharf S.M. Iqbal M. Keller C. Criner G. Lee S. Fessler H.E. National Emphysema Treatment Trial (NETT) GroupHemodynamic characterization of patients with severe emphysema.Am J Respir Crit Care Med. 2002; 166: 314-322Crossref PubMed Scopus (312) Google Scholar, 5Andersen K.H. Iversen M. Kjaergaard J. et al.Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease.J Heart Lung Transplant. 2012; 31: 373-380Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 6Cuttica M.J. Kalhan R. Shlobin O.A. et al.Categorization and impact of pulmonary hypertension in patients with advanced COPD.Respir Med. 2010; 104: 1877-1882Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar and may represent a pulmonary vascular phenotype of COPD.7Kovacs G. Agusti A. Barbera J.A. et al.Pulmonary vascular involvement in COPD—is there a pulmonary vascular phenotype?.Am J Respir Crit Care Med. 2018; 198: 1000-1011Crossref PubMed Scopus (60) Google Scholar Such a phenotype may justify PAH therapy on an individual basis.1Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease and hypoxia.Eur Respir J. 2019; 53: 1801914Crossref PubMed Scopus (237) Google Scholar,8Galie N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1870) Google Scholar Given the high prevalence of COPD, probably many thousands of patients with COPD worldwide harbor severe PH, outnumbering patients with pulmonary arterial hypertension (PAH).7Kovacs G. Agusti A. Barbera J.A. et al.Pulmonary vascular involvement in COPD—is there a pulmonary vascular phenotype?.Am J Respir Crit Care Med. 2018; 198: 1000-1011Crossref PubMed Scopus (60) Google Scholar The 6th World Symposium on Pulmonary Hypertension (WSPH) proposed hemodynamic thresholds for the classification of COPD with no PH, mild to moderate PH, and severe PH.1Nathan S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease and hypoxia.Eur Respir J. 2019; 53: 1801914Crossref PubMed Scopus (237) Google Scholar However, little information is available regarding which clinical variables and noninvasive clinical tools predict the presence of severe PH in COPD, that is, which patients with COPD have a high risk of severe PH and should undergo diagnostic right heart catheterization (RHC). In little is the of the proposed and the severity of airflow limitation and pulmonary vascular disease to to which clinical variables and noninvasive diagnostic tools predict the presence of severe PH in COPD and the is of increasing airflow limitation and pulmonary vascular disease on all clinical thresholds that to the severity of pulmonary vascular disease the for severe and airflow limitation based on included patients the of pulmonary vascular disease hemodynamics to severe and airflow limitation mild to severe obstructive a analysis of all consecutive patients with COPD for suspected PH our clinic between 2005 and 2018. The diagnosis of COPD and the severity of airflow limitation were to the Global Initiative for Chronic Obstructive Lung Disease Initiative for Chronic Obstructive Lung the Global for the and of COPD. Global Initiative for Chronic Obstructive Lung Disease Scholar the PH the patients with COPD with no for PH were in the 3 PH in of pulmonary arterial pressure of mm Hg, the in PH in of on the the CT pulmonary or the in the chronic PH In the presence of for PH the in the PH In the in of mild airflow predicted) and no severe in the CT scan the in the PAH with COPD The the the of patients were The included a the Pulmonary Hypertension in COPD A of in in all patients G. R. et of pulmonary arterial pressure in vascular right heart 2010; Full Text Full Text PDF PubMed Scopus Google Scholar the were and The severity of PH to the of the 6th S.D. Barbera J.A. Gaine S.P. et al.Pulmonary hypertension in chronic lung disease and hypoxia.Eur Respir J. 2019; 53: 1801914Crossref PubMed Scopus (237) Google Scholar COPD with severe PH defined mean PAP of ≥ 35 mm Hg or of ≥ mm Hg with COPD with PH to moderate PH defined between and mm Hg or between and mm Hg with pulmonary vascular of ≥ 3 and COPD PH defined of mm Hg or of to mm Hg with pulmonary vascular of 3 of variables mean or median (interquartile range and Clinical potentially indicative of the presence of severe PH were analyzed using univariate logistic regression the of patients with severe PH with the severe PH with no PH or with mild to moderate PH). multivariate logistic regression analysis including all variables that showed a P of in the univariate the of severe PH in the the to the negative predictive and positive predictive for severe PH the with values and the defined thresholds were the of the to death or lung Clinical and potentially survival in the were analyzed using Cox regression were adjusted for age and sex. the the of hazard A stepwise multivariate Cox regression analysis including variables that showed a P of In a analysis in the of patients with severe patients with and severe PH and patients were and were PAH were using the or in of variables and using the or in of and survival or lung of patients were and were PAH using Cox regression A P of We included 142 patients with COPD in the clinical and hemodynamic in and were included in the and of patients showed mild to moderate airflow for severity of PH, patients no PH, moderate PH, and severe showed of ≥ 35 mm Hg and showed of to mm Hg with to our classification of the patients with PH, patients 3 PH, the patients were PH = mm Hg for FEV1 to stage of for mm analysis mm mm CT scan PA to Ao diameter PA hemodynamics mm mm vascular of pulmonary hypertension classification of PH 3 the patients were in the 3 PH showed in the lung a diagnosis of and 4 of in to Chronic PH and or median (interquartile = Ao = ascending = for = volume for = of lung for GOLD = Global Initiative for Chronic Obstructive Lung = mean pulmonary arterial NT-proBNP = N-terminal pro-brain natriuretic PA = pulmonary = pulmonary arterial PH = pulmonary = pulmonary vascular = systolic pulmonary arterial = systolic = lung = World = for the patients were in the 3 PH showed in the lung a diagnosis of and 4 of in to COPD. in a for COPD PH, PH, and Severe PH = PH = PH = Severe PH = mm Hg for FEV1 to predicted stage of for mm analysis mm mm CT scan PA to Ao diameter PA hemodynamics mm mm vascular 3 or median (interquartile Ao = ascending = for = volume for = of lung for GOLD = Global Initiative for Chronic Obstructive Lung = mean pulmonary arterial NT-proBNP = N-terminal pro-brain natriuretic PA = pulmonary = pulmonary arterial PH = pulmonary = pulmonary vascular = = systolic pulmonary arterial = systolic = lung = World = for in a or median (interquartile = Ao = ascending = for = volume for = of lung for GOLD = Global Initiative for Chronic Obstructive Lung = mean pulmonary arterial NT-proBNP = N-terminal pro-brain natriuretic PA = pulmonary = pulmonary arterial PH = pulmonary = pulmonary vascular = systolic pulmonary arterial = systolic = lung = World = or median (interquartile Ao = ascending = for = volume for = of lung for GOLD = Global Initiative for Chronic Obstructive Lung = mean pulmonary arterial NT-proBNP = N-terminal pro-brain natriuretic PA = pulmonary = pulmonary arterial PH = pulmonary = pulmonary vascular = = systolic pulmonary arterial = systolic = lung = World = In the univariate a of noninvasive clinical were associated with severe PH on multivariate included predictive variables our systolic PAP of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 and the main pulmonary artery (PA) to ascending aorta the diameter ratio on chest CT ≥ The positive predictive increased to the of positive criteria in a all criteria were of the and the positive predictive were and for severe PH, The presence of of the criteria of showed a sensitivity of of the criteria were present of the of severe PH In of negative and positive predictive sensitivity and multivariate model the ≥ Hg negative predictive positive predictive for the diagnosis of severe patients with severe PH, and a of the a model to predict the presence of severe PH in COPD with a of ≥ to the variables to with COPD in the in all criteria were = in the severe PH and no with COPD showed severe PH in of the criteria were = The of patients in may in (IQR, of patients and lung to The median to the combined of death or lung CI, In the for age and in the multivariate both airflow limitation (P = .002; GOLD stages 1-2 vs stage 3: HR, 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) were associated independently with survival. the combination of airflow limitation stages 1-2 vs stages and PH vs with (P = of GOLD stages or and nonsevere PH [95% CI, including GOLD stages 3 or 4 or severe PH (HR vs [95% CI, P = [95% CI, and with the combination of GOLD stages 3 or 4 and severe PH (HR vs 3.26 [95% CI, 1.62-6.57; P = [95% CI, survival the COPD is patients with GOLD stages or and severe PH patients with GOLD stages 3 or 4 and no or moderate PH 4 the of univariate and multivariate analysis for GOLD stage and PH severity of survival. the pulmonary and related to survival in the univariate analysis in patients with COPD with severe of were associated with of were with In the multivariate (P and vascular (P = remained of the for a were of and vascular of the our of patients were a PAH After the of patients of patients with severe PH vs of patients with moderate P a PAH or combination PAH treatment showed severe airflow severe hemodynamic and severe limitation of with the patients hemodynamics were in the vs survival between in the [95% CI, P = and in patients with severe PH [95% CI, P = In to for clinical variables and noninvasive diagnostic tools that may predict the presence of severe PH in COPD and to the of increasing airflow limitation and pulmonary vascular disease on We included all patients undergoing the criteria for COPD, of the for in many patients with COPD, is to on the for the between and 3 PH to We that patients with COPD, criteria for severe PH were based on of ≥ 35 mm Hg and on of to mm Hg in combination with of a noninvasive clinical using echocardiography, NT-proBNP level, and the PA to Ao diameter ratio chest CT scan predicts severe PH with high sensitivity and and is independently both the severity of airflow limitation and the severity of PH and that of the analyzed for the clinical of pulmonary vascular disease in COPD the the of Pulmonary Hypertension a in J. 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CT pulmonary artery to aorta ratio and for pulmonary hypertension in severe Full Text Full Text PDF PubMed Scopus Google Scholar In ratio a of COPD et Study arterial and of J Med. 2012; PubMed Scopus Google Scholar However, been for of severe PH in COPD. the clinical in our analysis severe PH in COPD and to and for clinical We that the severity of both airflow limitation and pulmonary vascular disease to increased mortality and the that and both and a of that G. Agusti A. Barbera J.A. et al.Pulmonary vascular involvement in COPD—is there a pulmonary vascular phenotype?.Am J Respir Crit Care Med. 2018; 198: 1000-1011Crossref PubMed Scopus (60) Google Scholar In patients with COPD and severe PH, a of variables were associated with survival in the univariate analysis with a predictive and pulmonary vascular with the predictive in patients with severe PH were which may for COPD or for 3 PH, lung for et in pulmonary hypertension to chronic lung of of the for Heart Lung Transplant. 2019; Full Text Full Text PDF PubMed Scopus Google A. is an of in pulmonary hypertension associated with Full Text Full Text PDF PubMed Scopus Google Scholar or pulmonary artery et Study arterial and of J Med. 2012; PubMed Scopus Google J.B. S.P. Pulmonary artery is associated with severe of Full Text Full Text PDF PubMed Scopus Google Scholar, N. et al.Pulmonary artery to aorta ratio and risk of mortality in the the Respir J. PubMed Scopus Google Scholar, S. et al.Pulmonary artery a of pulmonary hypertension and in patients with chronic obstructive pulmonary Med. Full Text Full Text PDF PubMed Scopus Google Scholar The that the of a high pulmonary vascular an of in the multivariate analysis that may represent an in which In patients with COPD and severe PH pulmonary arterial pressure with patients with no PH or nonsevere PH, that heart disease heart with may a relevant in a of the pulmonary in patients with COPD and severe PH and A. Dauriat G. et al.Pulmonary arterial in patients with COPD with severe pulmonary 2019; Full Text Full Text PDF PubMed Scopus Google Scholar with J. S. Iversen M. C. Pulmonary arterial in with severity of pulmonary hypertension in chronic obstructive pulmonary disease.J Heart Lung Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar PAH therapy is for 3 N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1870) Google Scholar and may in severe PH on an individual or in of an increased risk of should in N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1870) Google Scholar of the of PAH have been in that patients with severe A. M. et in severe pulmonary hypertension associated with chronic obstructive pulmonary a clinical Heart Lung Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. M. of patients with severe PH to lung disease with and PubMed Scopus Google Scholar, S. et of therapy in pulmonary hypertension to a PubMed Scopus Google Scholar, G. A. of pulmonary hypertension in chronic obstructive pulmonary Respir 3: PubMed Scopus Google Scholar, S. in chronic obstructive pulmonary a J 53: Google Scholar, G. M. A. A. R. Pulmonary arterial therapy in COPD patients with severe pulmonary hypertension and airflow PubMed Scopus Google Scholar, A. S. C. et al.Severe pulmonary hypertension associated with hemodynamic with 2015; PubMed Scopus Google Scholar In the present therapy in patients with severe PH with patients with moderate PH vs impaired in of pulmonary hemodynamics and patients treatment showed a survival no a may the that a of patients with COPD and severe PH The of PAH treatment in patients with COPD and severe PH in our is the COPD with the of mortality in which all patients clinical and clinical and were a and a of the the included patients the of pulmonary vascular involvement and airflow our may to for patients with COPD with a of pulmonary vascular and our of hemodynamic severity predicts survival in COPD. However, to an increased of the and of in patients with severe PH for may We of our a and and the the and of our in our of patients with COPD is patients with severe PH, of a in a PH in a COPD in which severe PH may present in 1% to 4% of A. Bugnet A.S. Kadaoui N. et al.Severe pulmonary hypertension and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2005; 172: 189-194Crossref PubMed Scopus (486) Google Scholar, 3Thabut G. Dauriat G. Stern J.B. et al.Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation.Chest. 2005; 127: 1531-1536Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 4Scharf S.M. Iqbal M. Keller C. Criner G. Lee S. Fessler H.E. National Emphysema Treatment Trial (NETT) GroupHemodynamic characterization of patients with severe emphysema.Am J Respir Crit Care Med. 2002; 166: 314-322Crossref PubMed Scopus (312) Google O.A. Fessler et and of pulmonary hypertension in severe Med. Full Text Full Text PDF PubMed Scopus Google Scholar may the of our for analysis of the pulmonary vascular which the main of the based on the of the with severe and may have been in the and the of a FEV1 to ratio of of to have obstructive disease in our to for variables in COPD, to mortality risk in patients with COPD with increasing severity of airflow limitation and pulmonary vascular in COPD, the were included in our survival The severity of both airflow limitation and pulmonary vascular disease and independently may to impaired survival in patients with COPD. Severe PH is predicted the combination of echocardiography, NT-proBNP and chest CT PA to Ao diameter to A. and G. to analysis and of the N. A. M. and A. to analysis and G. and to all of the in the and for the of the and the of the to the and of the and the The have to that no for The have to the G. and and the and and and and the and and and and the and and and and and the A. and and and the and and and and the G. N. A. J. M. 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