Pulmonary Hypertension in Patients With COPD

BackgroundPulmonary hypertension (PH) in COPD is a poorly investigated clinical condition.Research QuestionWhich factors determine the outcome of PH in COPD?Study Design and MethodsWe analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH).ResultsThe population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes.InterpretationPatients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further.Trial RegistryClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Which factors determine the outcome of PH in COPD? We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov FOR EDITORIAL COMMENT, SEE PAGE 409Pulmonary hypertension (PH) is a frequent finding in advanced COPD; its prevalence in selected populations (candidates for lung transplantation or volume reduction surgery) is around 50%.1Vizza C.D. Lynch J.P. Ochoa L.L. Richardson G. Trulock E.P. Right and left ventricular dysfunction in patients with severe pulmonary disease.Chest. 1998; 113: 576-583Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 2Scharf S.M. Iqbal M. Keller C. Criner G. Lee S. Fessler H.E. Hemodynamic characterization of patients with severe emphysema.Am J Respir Crit Care Med. 2002; 166: 314-322Crossref PubMed Scopus (304) Google Scholar, 3Chaouat 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 (466) Google Scholar, 4Thabut 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 (348) Google Scholar In these patients, PH is usually mild to moderate, as defined by a mean pulmonary arterial pressure (mPAP) of 21 to 34 mm Hg, but about 6% to 8% of these patients demonstrate severe PH (mPAP ≥ 35 mm Hg or mPAP ≥ 25 mm Hg in the presence of low cardiac output).5Nathan 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 (185) Google Scholar The clinical importance of PH associated with COPD has been documented in several studies that demonstrated the independent prognostic role of PH in this population.3Chaouat 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 (466) Google Scholar,6Weitzenblum E. Hirth C. Ducolone A. Mirhom R. Rasaholinjanahary J. Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease.Thorax. 1981; 36: 752-758Crossref PubMed Scopus (67) Google Scholar, 7Cuttica 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 (122) Google Scholar, 8Andersen 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 (138) Google Scholar FOR EDITORIAL COMMENT, SEE PAGE 409 It is unclear whether patients with PH in COPD may benefit from treating the pulmonary vascular disease component. So far, only small randomized controlled studies have been performed using targeted therapies approved for pulmonary arterial hypertension (PAH) in PH in COPD, with heterogeneous results.9Stolz D. Rasch H. Linka A. et al.A randomised, controlled trial of bosentan in severe COPD.Eur Respir J. 2008; 32: 619-628Crossref PubMed Scopus (238) Google Scholar, 10Lederer D.J. Bartels M.N. Schluger N.W. et al.Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial.COPD. 2012; 9: 268-275Crossref PubMed Scopus (65) Google Scholar, 11Goudie A.R. Lipworth B.J. Hopkinson P.J. Wei L. Struthers A.D. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial.Lancet Respir Med. 2014; 2: 293-300Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 12Vitulo P. Stanziola A. Confalonieri M. et al.Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a randomized controlled multicenter clinical trial.J Heart Lung Transplant. 2017; 36: 166-174Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The main limitations of most of these studies include lack of power and poor selection of the populations studied (ie, patients with COPD and normal or mildly elevated pulmonary pressure). Although the role of PH therapy in patients with PH in COPD remains undefined, PAH therapies sometimes are used in these patients.13Gall H. Felix J.F. Schneck F.K. et al.The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups.J Heart Lung Transplant. 2017; 36: 957-967Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar To obtain more information on the population with PH in COPD, we analyzed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing, investigator-initiated, noninterventional, prospective European-based registry that enrolls patients with all forms of PH.14Hoeper M.M. Huscher D. Ghofrani H.A. et al.Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry.Int J Cardiol. 2013; 168: 871-880Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar The aim of the present study was to the clinical characteristics and outcomes of a population of patients with PH in COPD treated with targeted therapy to the outcomes of these patients with a population with idiopathic PAH to study the factors survival in patients with PH in COPD, to patients with moderate and severe PH in COPD on the from the 6th PH World and to the to COMPERA is a PH registry that was in and to patients PH from The and the with of the patients from is and and of PH to the N. M. et for the and of pulmonary hypertension: the for the and of Pulmonary Hypertension of the of and the for and for Heart and Lung Heart J. PubMed Scopus Google Scholar of the cardiac World Health Organization functional class (WHO 6-min walking distance pulmonary and selected of and information about for The all of patients on a are at the of and at in or the has a clinical lung in functional in PH or data or are during data of data had been in of The for the present was 1, at that patients had been enrolled the for the present were a of IPAH or PH in COPD, of ≥ and of data from at mPAP of mm Hg and mean pulmonary arterial pressure of mm Hg, for pulmonary vascular resistance of Patients were incident that the PH had been The of IPAH or PH in COPD was in in with the and of N. M. et for the and of pulmonary hypertension: the for the and of Pulmonary Hypertension of the of and the for and for Heart and Lung Heart J. PubMed Scopus Google Scholar and the 6th World Symposium on Pulmonary Hypertension G. D. et and clinical of pulmonary Respir J. 2019; 53: PubMed Scopus Google Scholar Patients with PH in COPD were included on the and a of of the to the 6th World Symposium on Pulmonary Hypertension 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 (185) Google Scholar the COPD population was in on hemodynamics at moderate PH in COPD, defined as mPAP of 25 to 34 mm Hg or mPAP of 21 to mm Hg with of ≥ and severe PH in COPD, defined as mPAP of 35 mm Hg or mPAP of ≥ 25 mm Hg with low cardiac The registry was approved by the of all and was from all patients of on and data are may at COMPERA is at To the impact of PH we the clinical from to the of was defined by an in 6MWD of ≥ 30 D. The in the for patients with pulmonary arterial J Respir Crit Care Med. 2012; PubMed Scopus Google Scholar or an in WHO data were as of patients and and were compared with the or data were as mean and were for data were with a a was The outcome was was compared using and the Patients with more than 5 years of were after was by to the that was to the patients, or was performed with patients at the of Patients to were at the of the To of death or were by on clinical and studies were sex, 6MWD, cardiac of the lung for and WHO a of left mPAP was only as a 35 mm Hg vs ≥ 35 mm of a high of and and were included in the with was to at and results of the data and results of the data are P were was for the and patients with patients with severe PH in COPD, and patients with moderate PH in COPD were for this the clinical and hemodynamic characteristics of the patients with PH in COPD predominantly were male and than patients with IPAH. with patients with patients with PH in COPD showed more severe and higher patients with PH in COPD, patients with severe PH in COPD, demonstrated worse 6MWD and more advanced functional Patients with severe PH in COPD showed hemodynamic similar to that of patients with patients with moderate PH in COPD and cardiac and of the Patients in the (n = (n = in (n = (n = mm mm mm mm mm are as mean or 6MWD = 6-min walking = = of the lung for IPAH = idiopathic pulmonary arterial mPAP = mean pulmonary arterial = of = pulmonary arterial PH = pulmonary = pulmonary vascular = = = lung WHO FC = World Health Organization functional in a are as mean or 6MWD = 6-min walking = = of the lung for IPAH = idiopathic pulmonary arterial mPAP = mean pulmonary arterial = of = pulmonary arterial PH = pulmonary = pulmonary vascular = = = lung WHO FC = World Health Organization functional the of PH at most of the patients with PH in COPD were treated with phosphodiesterase-5 in patients with was with a higher of patients at (n = in COPD (n = in (n = (n = COPD and COPD are as = IPAH = idiopathic pulmonary arterial = = phosphodiesterase-5 PH = pulmonary COPD and COPD in a are as = IPAH = idiopathic pulmonary arterial = = phosphodiesterase-5 PH = pulmonary were more frequent in the moderate PH in COPD group than in the IPAH group and the severe PH in COPD group In patients with of were the of lack of and were the of in patients with severe PH in COPD, lack of and for and of In patients with moderate PH in COPD, the were and was for patients with IPAH and patients with severe PH and with moderate with PH in COPD and lung in the IPAH group and and lung in the PH in COPD In the severe PH in COPD and lung In the moderate PH in COPD and lung survival at 1, 3, and 5 years in the IPAH group were 94%, and was better than the survival rates in the PH in COPD group 55%, and 38%; P The in survival for and = .004). patients who PH the results survival rates at 1, 3, and 5 years were 75%, and in the IPAH group and 86%, and in the PH in COPD the survival rates the PH in COPD patients with severe PH in COPD worse outcomes than patients with moderate PH in COPD, with survival at 1, 3, and 5 years of and compared with and = patients were at the of survival rates were 94%, and in the moderate PH in COPD group and and in the severe PH in COPD = In the associated with transplantation or death in with PH in COPD were higher low 6MWD, high high and high In the male sex, low 6MWD, and high associated with and were only in the in the the on of patients of Predictors for or Lung in the PH in COPD for the and the (n = was the at 5 FC mm ≥ 35 mm are as 6MWD = 6-min walking = of the lung for mPAP = mean pulmonary arterial = of = pulmonary vascular = WHO FC = World Health Organization functional was the in a PH of Predictors for or Lung in the PH in COPD for the and the (n = (n = of at 5 FC mm ≥ 35 mm = 6-min walking mPAP = mean pulmonary arterial PH = pulmonary = pulmonary vascular = WHO FC = World Health Organization functional of in a are as 6MWD = 6-min walking = of the lung for mPAP = mean pulmonary arterial = of = pulmonary vascular = WHO FC = World Health Organization functional 6MWD = 6-min walking mPAP = mean pulmonary arterial PH = pulmonary = pulmonary vascular = WHO FC = World Health Organization functional 6MWD was in for patients with IPAH and patients with PH in COPD WHO FC was for patients with IPAH and for patients with PH in COPD The of 6MWD of ≥ 30 m from was similar in the PH in COPD group compared with the IPAH group vs P = with the severe PH in COPD group and the moderate PH in COPD group vs P = WHO FC by ≥ class in of patients with IPAH and in of patients with PH in COPD = with on in severe PH in COPD compared with moderate PH in COPD vs P = with a to therapy in the PH in COPD group were a low 6MWD and a high WHO FC at pulmonary and hemodynamics and In the IPAH higher higher and higher WHO FC were associated with to therapy the patients with PH in COPD on clinical at we that patients who the of a clinical a better survival than patients who this was to patients with severe PH in COPD The present study the characteristics and outcome of patients with PH in COPD treated with approved for Our results that patients with PH in COPD achieved a worse clinical and a survival than patients with similar hemodynamic The of transplantation or death in patients with PH in COPD was related to the of but to male sex, low 6MWD, and high PVR. Patients with severe PH in COPD achieved worse outcomes than patients with moderate PH in COPD, that the moderate and severe PH in COPD, as during the PH has clinical 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 (185) Google Scholar In data raise the that some patients with severe PH in COPD may benefit from with PAH The COPD population in the present mainly of patients with severe The hemodynamic of these patients was similar to that of patients with IPAH. the presence of a severe pulmonary J. S. Iversen M. D. C. Pulmonary arterial in after transplantation with of pulmonary hypertension in chronic obstructive pulmonary disease.J Heart Lung Transplant. 2013; 32: Full Text Full Text PDF PubMed Scopus Google Scholar Despite similar hemodynamic impairment, patients with severe PH in COPD showed a worse and worse than patients with for and The was around in patients with severe PH in COPD, that about the in the IPAH are in with H. Felix J.F. Schneck F.K. et al.The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups.J Heart Lung Transplant. 2017; 36: 957-967Abstract Full Text Full Text PDF PubMed Scopus (127) Google J. R. et al.Pulmonary hypertension in COPD: results from the Respir J. 2013; PubMed Scopus Google A. is an independent of outcomes in pulmonary hypertension associated with Full Text Full Text PDF PubMed Scopus Google Scholar It remains unclear whether the survival these from in the or the for better in patients with PH in approved for the of PAH have been in patients with PH in COPD, but with and an only to but a in and functional in patients with advanced COPD and mild D. Rasch H. Linka A. et al.A randomised, controlled trial of bosentan in severe COPD.Eur Respir J. 2008; 32: 619-628Crossref PubMed Scopus (238) Google Scholar In a similar a showed on and of A.R. Lipworth B.J. Hopkinson P.J. Wei L. Struthers A.D. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial.Lancet Respir Med. 2014; 2: 293-300Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar In a study the hemodynamic of and E. et and of in patients with chronic obstructive pulmonary disease and pulmonary J Respir Crit Care Med. 2010; PubMed Scopus Google Scholar showed a reduction in mPAP at and during with an of at but during In studies in patients with COPD with or mild to demonstrate an in D.J. Bartels M.N. Schluger N.W. et al.Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial.COPD. 2012; 9: 268-275Crossref PubMed Scopus (65) Google H. S. et al.Sildenafil in COPD volume or Respir J. 2008; 31: PubMed Scopus Google S. J. et al.Sildenafil to outcomes in COPD: a controlled Respir J. 2013; PubMed Scopus Google Scholar main of these studies is that most of the enrolled patients had mild or moderate may that therapy in in hemodynamics or In in a study that included only patients with severe PH in COPD, demonstrated improvements in hemodynamics and and in COPD in compared with P. Stanziola A. Confalonieri M. et al.Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a randomized controlled multicenter clinical trial.J Heart Lung Transplant. 2017; 36: 166-174Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar In the present most of the patients in the PH in COPD were treated with of the patients showed in 6MWD of ≥ 30 and showed an in WHO FC showed improvements in compared with the present IPAH and are with the data from and P. Stanziola A. Confalonieri M. et al.Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: a randomized controlled multicenter clinical trial.J Heart Lung Transplant. 2017; 36: 166-174Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar finding of the present study is the of a clinical to PH therapy and survival in patients with severe PH in Our results that patients with severe PH in COPD with a clinical to therapy as an in 6MWD of ≥ 30 m or in WHO achieved a better survival compared with patients who this this was to the of patients with severe PH in In patients with moderate PH in COPD showed a higher of PH compared with patients with severe PH in COPD or IPAH. may of in this Our are in with by and J. R. et al.Pulmonary hypertension in COPD: results from the Respir J. 2013; PubMed Scopus Google Scholar in a of patients with severe PH in In that a in of or in WHO FC after initiation of PH patients with a better survival compared with patients who these that some patients with severe PH in COPD may benefit from therapy PH and the for randomized controlled in this The main limitations of the present study are related to the of a registry and include lack of of the lung for some and lack of of hemodynamics and during a of data were in the and data on were we the that some patients were In of the patients with PH in COPD received medical therapy the study had group and selection In of of medical registry data have to as hypothesis data that PH are in patients with PH in COPD, and are to to these the of clinical In the present patients with PH in COPD had a poorer than patients with IPAH. The of death in patients with PH in COPD was by male sex, a low 6MWD, and high PVR. Our data that therapy in patients with COPD and severe PH may and WHO FC in a of patients and that patients with COPD and PH who to therapy may have a better than patients who clinical to in randomized controlled clinical Which are the clinical characteristics of PH in COPD patients and are on with patients with patients with PH in COPD have similar hemodynamic but worse and Risk factors for death in PH in COPD are male sex, high low 6MWD, and high PVR. In patients with severe PH in COPD (mPAP ≥ 35 mm improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy are associated with better Patients with PH in COPD have a poorer than patients with IPAH. Predictors of death in patients with PH in COPD are related to sex, and pulmonary vascular patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Which are the clinical characteristics of PH in COPD patients and are on with patients with patients with PH in COPD have similar hemodynamic but worse and Risk factors for death in PH in COPD are male sex, high low 6MWD, and high PVR. In patients with severe PH in COPD (mPAP ≥ 35 mm improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy are associated with better Patients with PH in COPD have a poorer than patients with IPAH. Predictors of death in patients with PH in COPD are related to sex, and pulmonary vascular patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. C. D. M. M. and E. G. are the of the of the the data and C. D. M. E. D. and D. H. to the of the had to all of the data in the and for the of the data and the of the data and N. M. H. A. M. H. S. D. R. M. M. A. D. R. J. S. R. M. A. G. S. C. H. and D. to the study data and to the of the have and the and to for all of the in that related to the or of of the are investigated and The have to the C. D. has received for as a and an from the and M. M. H. has received or for from and D. H. has received from and D. P. has received for from and N. received from and M. has received from and H. A. G. has received for at or from and is of for and has received from the of and the for and M. has received and for from and H. has received and for from and and from J. L. has received for and from and S. R. has received for or from and D. D. for or from and in clinical for and and to from R. has received from and M. C. has received for from and from and M. has received for from and A. from and on the of and and on for and D. S. received for or a to from and R. E. has received and for from and J. S. R. G. has received and for from and M. D. has received or from and from and and from and is of the for Pulmonary Hypertension and of the for and in pulmonary vascular at the of J. C. has received for and from and as as and from C. has received and for from and H. has received for or from and D. has or had has received or from and in the of of and its In has a for the of E. G. has received for at or from and of The had role in the of the the or of the or the of the H. J. H. A. of Giessen and Lung of the for Lung H. R. of S. for and Care H. C. L. C. of L. of E. of of of Pulmonary and of and of Heart of The and in the of the with