Pulmonary hypertension in COPD: results from the ASPIRE registry

Judith Hurdman, Robin Condliffe, Charlie A. Elliot, Andrew Swift, Smitha Rajaram, Christine Davies, Catherine Hill, Neil Hamilton, Iain J. Armstrong, Catherine Billings, Lauren Pollard, Jim M. Wild, Allan Lawrie, Rod Lawson, Ian Sabroe, David G. Kiely
European Respiratory Journal 2013 41: 1292-1301; DOI: 10.1183/09031936.00079512

Abstract

The phenotype and outcome of severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is described in small numbers, and predictors of survival are unknown. Data was retrieved for 101 consecutive, treatment-naïve cases of pulmonary hypertension in COPD.

Mean±sd follow-up was 2.3±1.9 years. 59 patients with COPD and severe pulmonary hypertension, defined by catheter mean pulmonary artery pressure ≥40 mmHg, had significantly lower carbon monoxide diffusion, less severe airflow obstruction but not significantly different emphysema scores on computed tomography compared to 42 patients with mild–moderate pulmonary hypertension. 1- and 3-year survival for severe pulmonary hypertension, at 70% and 33%, respectively, was inferior to 83% and 55%, respectively, for mild–moderate pulmonary hypertension. Mixed venous oxygen saturation, carbon monoxide diffusion, World Health Organization functional class and age, but not severity of airflow obstruction, were independent predictors of outcome. Compassionate treatment with targeted therapies in 43 patients with severe pulmonary hypertension was not associated with a survival benefit, although improvement in functional class and/or fall in pulmonary vascular resistance >20% following treatment identified patients with improved survival.

Standard prognostic markers in COPD have limited value in patients with pulmonary hypertension. This study identifies variables that predict outcome in this phenotype. Despite poor prognosis, our data suggest that further evaluation of targeted therapies is warranted.

The development of pulmonary hypertension (PH) in chronic lung diseases such as chronic obstructive pulmonary disease (COPD) has both functional and prognostic implications [1, 2]. PH in COPD (PH-COPD) is usually mild to moderate with preserved cardiac output, and evolves slowly alongside the progression of lung disease and hypoxaemia [3]. However, a minority of patients develop severe PH with elevations in pulmonary artery pressure that have been described as “out of proportion” to the underlying COPD [4, 5]. Hypotheses for the aetiology of this phenotype include greater susceptibility to alveolar hypoxia and/or tobacco smoke [6, 7], destruction of the capillary vascular bed [8], inflammatory factors initiating remodelling of the pulmonary vascular bed [9–11] or the coexistence of idiopathic pulmonary arterial hypertension (IPAH) in patients with lung disease [4].

Severe PH-COPD has been arbitrarily defined by a resting mean pulmonary artery pressure (PAP) ≥40 mmHg and occurs in ∼1% of patients with chronic respiratory failure related to COPD [4]. The high and increasing prevalence of COPD [12–14] and the substantial consequences of developing severe PH have generated increasing interest in PH-COPD; however in this group the employment of targeted pulmonary vascular therapy, while attractive, remains unproven [15].

The Sheffield Pulmonary Vascular Disease Unit delivers a supra-regional, adult UK PH service to a population with a COPD prevalence that is one of the highest in Europe [16]. The aim of this study was to compare the characteristics and outcomes of extensively phenotyped, consecutive patients with PH-COPD diagnosed at our specialist referral centre over a 9-year period.

METHODS

In the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry, 1737 consecutive, incident, treatment-naïve patients with suspected PH underwent diagnostic evaluation between February 2001 and February 2010 as previously detailed [17]. Diagnostic classification was by standard criteria following systematic, multidisciplinary assessment that included echocardiography, detailed blood testing, pulmonary function testing, overnight oximetry, isotope perfusion scanning, high-resolution computed tomography (HRCT), CT pulmonary angiography, right heart catheter (RHC) and, from 2004, cardiopulmonary magnetic resonance imaging (fig. 1). Following this detailed assessment, 101 patients were assigned the diagnosis PH-COPD (updated clinical classification of pulmonary classification (Dana Point, CA, USA; 2008) class 3.1) [18] and comprise the cohort examined in this study. All patients underwent RHC in a supine position and PH was defined as mean PAP ≥25 mmHg at rest [18], with mild–moderate PH-COPD defined as mean PAP ≥25 mmHg and <40 mmHg, and severe PH-COPD defined by mean PAP ≥40 mmHg [4].

Figure 1–
Figure 1–

Diagnostic pathway. ASPIRE: Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre; PFT: pulmonary function testing; ISWT: incremental shuttle walking test; CXR: chest radiograph; CTPA: computed tomography pulmonary angiogram; HRCT: high-resolution computed tomography of the thorax; MRI: magnetic resonance imaging; PH: pulmonary hypertension; COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; PAP: pulmonary artery pressure. #: cardiopulmonary MRI was used routinely from 2004 onwards. : Other PH included: PH multiple diagnoses n=38, PH inclusion criteria not met n=85, PH lung with connective tissue disease n=102 and PH owing to heart disease and connective tissue disease n=33.

For the purposes of this study PH-COPD refers to patients with COPD as defined by post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio ≤0.7 where airflow obstruction was due to a combination of airway and parenchymal damage, as per National Institute for Health and Clinical Excellence (NICE) guidelines updated in 2010 [19] or significant emphysema. The degree of emphysema and any coexisting pulmonary fibrosis were assessed using HRCT scan independently evaluated by two chest radiologists blinded to clinical data and each other's findings. A visual scale based on previous studies [4, 20, 21] was used to score the degree of parenchymal abnormality in the upper, mid and lower zone of each lung (0= <5%, 1=5–25%, 2=26–50%, 3=51–75% and 4=76–100%) for both emphysema and fibrosis. In order to assess the distribution of parenchymal disease on HRCT for the purpose of this study, the sum of the right and left upper zone scores was compared to the sum of the right and left lower zone scores for emphysema and fibrosis, respectively. For computed tomography (CT) scan acquisition parameters please see the online supplementary material.

Date of diagnosis was taken as date of first RHC demonstrating PH. World Health Organization (WHO) functional class and pulmonary function tests (PFTs) [22, 23] obtained closest to the date of RHC were recorded as baseline measures. Exercise capacity was assessed using distance achieved during the incremental shuttle walking test (ISWD) [24].

The management of COPD was in accordance with contemporaneous guidelines [12, 19, 25, 26]. Pulmonary vascular therapy was used on a compassionate basis in severe PH-COPD with prior agreement from funding bodies, as per UK national commissioning policy [27, 28]. Endothelin receptor antagonists (ERA), phosphodiesterase-5-inhibitors (PDE-5I), and prostanoids were used as monotherapy or in combination, as clinically indicated.

The census point was date of death or August 1, 2011 in survivors. Mortality status was ascertained via the UK National Health Service enhanced reporting service death report. No patients were lost to follow-up. Ethical approval for analysis of routinely collected clinical data was granted by the North Sheffield Research Ethics Committee.

Statistical analysis

Continuous variables were described by mean±sd or, where non-parametric, median (interquartile range (IQR)). Comparisons between groups were performed using independent t-tests for parametric data and Mann–Whitney U-tests for nonparametric data. The Wilcoxon matched-pairs test was used to compare upper zone with lower zone emphysema and fibrosis scores on HRCT. Categorical data were compared using with the Chi-squared test. Survival from date of diagnosis was estimated using the Kaplan–Meier method, with comparison between groups performed by the log-rank test. Predictors of survival were assessed using forward stepwise Cox regression analysis. Variables with a p-value<0.05 at univariate analysis were considered for multivariate analysis. Due to colinearity only two pulmonary haemodynamic parameters (mean PAP and mixed venous oxygen saturation (SvO2)) were used in the multivariate model, and in view of less complete data, HRCT emphysema scores were not entered into the multivariate model. Receiver operating characteristics (ROC) curve analysis of survival at 2 years was used to derive threshold values for predictors of survival. The relationship between continuous variables was calculated using Pearson's correlation test. A p-value of <0.05 was deemed statistically significant throughout. Statistical analysis was performed using PASW Statistics v18 (SPSS, Chicago, IL, USA).

RESULTS

Demographics and baseline characteristics

The study cohort comprised 101 patients with PH-COPD. Mean age at diagnosis was 68.5±9.7 years with a male preponderance of 63%; 99% were Caucasian. The maximal duration of follow-up was 9 years with a mean follow-up of 2.3±1.9 years. During follow-up, 62 (61%) patients died and no patients underwent lung transplantation. Patients were assessed in clinical stability outside infective exacerbations; median C-reactive protein was 6.7 mg·L−1 (3.9–11.5 mg·L−1) and median neutrophil count was 6.0×109·L−1 (4.8–7.6×109·L−1). In 74 patients in whom HRCT scans were available for scoring, interobserver agreement was κ=0.74 (p<0.001). Maximum discrepancy between radiologists per zone was 1 point. This occurred in 13% of the zones scored and mean score was used for further analysis. In patients in whom scans could not be retrieved to allow formal scoring no significant fibrosis was noted on clinical reports.

In 42 patients, PH was mild to moderate (mean PAP 25–39 mmHg) and in 59 patients PH was severe (mean PAP ≥40 mmHg). In those with severe PH there was haemodynamic evidence of impaired cardiac function with elevated right atrial pressure, reduced cardiac index and mixed venous oxygen saturations (table 1). The phenotype of severe PH-COPD was also characterised by greater impairment of gas exchange, despite better preserved spirometry, but no statistically significant difference in the severity of emphysema on HRCT scan. Oxygen saturations at rest on room air were significantly lower in those with severe PH-COPD (p<0.001), but this hypoxaemia was adequately corrected, albeit requiring higher flows of long-term oxygen to achieve this. Eight patients with severe PH-COPD had pulmonary capillary wedge pressure (PCWP) >15 mmHg, but there was no difference in the prevalence of cardiac comorbidities when comparing the group with elevated PCWP to those with PCWP ≤15 mmHg. In addition, the mean left atrial size (maximum anterior–posterior diameter) on CT scan in patients with PCWP ≤15 mmHg at 3.6±0.9 cm was not significantly different to the 3.5±0.8 cm seen in patients with elevated wedge pressure (p=0.749).

View this table:
Table 1– Baseline characteristics

Overall on HRCT scan, 43 patients had no evidence of pulmonary fibrosis. Emphysematous change was more marked in the upper zones compared to the lower zones, whereas if a degree of fibrosis was noted this was more prominent in the lower zones (Wilcoxon matched pairs test, p both <0.001). Difference in overall HRCT scores for emphysema or fibrosis between those with mild–moderate versus severe PH-COPD did not reach statistical significance (table 1).

Noninvasive assessments

Estimated systolic PAP measured using echocardiogram correlated weakly with systolic PAP directly measured at RHC (r=0.54, p<0.01). In 61% of patients the estimated sysytolic PAP on echocardiogram differed from measured systolic PAP at RHC by >10 mmHg. There were weak correlations between mean PAP and the pulmonary artery and aortic diameter ratio, right ventricular and left ventricular diameter ratio measured on CT-scan and diffusing capacity of the lung for carbon monoxide (DLCO) (r=0.17, 0.29 and 0.39, respectively, p<0.05).

Survival and prognostic indicators

In those with severe PH-COPD, 1-year survival was 70% and 3-year survival was 33%, which is significantly worse than the 83% and 55%, respectively, seen in mild–moderate PH-COPD (fig. 2b) (p=0.011). ROC curve analysis confirmed mean PAP of 40 mmHg to be the optimal mean PAP threshold (sensitivity 68%, false-positive rate 45%) for determining survival (fig. 2a). At multivariate analysis, age, DLCO, SvO2 and WHO functional class (table 2) were independent predictors of survival. For these patients with PH-COPD, ROC curve analysis for age showed 73 years (sensitivity 58%, false-positive 26%); for DLCO 27% (sensitivity 69%, false-positive 32%); and for SvO2 65% (sensitivity 80%, false-positive 46%) to be the optimal thresholds for predicting survival (fig. 3a–c) (p≤0.001). 3-year survival in patients with PH-COPD in WHO functional class III at diagnosis was 47%, superior to 20% for patients presenting in WHO functional class IV (fig. 3d) (p=0.001).

Figure 2–
Figure 2–

a) Receiver operating characteristics curve analysis of survival at 2 years for mean pulmonary arterial pressure (PAP) in pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD); b) cumulative survival from date of diagnosis in pulmonary hypertension associated with COPD by mean PAP. AUC: area under the curve.

View this table:
Table 2– Cox regression survival analysis to assess predictors of survival in pulmonary hypertension associated with chronic obstructive pulmonary disease
Figure 3–
Figure 3–

Cumulative survival from date of diagnosis in pulmonary hypertension associated with chronic obstructive pulmonary disease by receiver operating characteristic curve-derived thresholds of a) age; b) diffusing capacity of the lung for carbon monoxide (DLCO) and c) mixed venous oxygen saturation (SvO2); and by d) World Health Organization functional class (WHO-FC) at diagnosis.

Treatment in PH-COPD

43 patients with severe PH-COPD were treated compassionately with pulmonary vascular therapies; first-line treatment was with PDE-5I in 31 patients, ERA in 10 patients, s.c. treprostinil in one patient and nebulised iloprost in one patient (table 3). All patients received targeted pulmonary vascular therapy for at ≥3 months, unless death occurred before this time. In the group of patients with severe PH-COPD survival for the 43 treated patients was similar to the 16 untreated patients (fig. 4a), despite pulmonary haemodynamics being significantly worse in these patients who received therapy (table 4). For the purposes of this study, clinical improvement was defined as a reduction of >20% in pulmonary vascular resistance (PVR) or improvement in WHO functional class. At follow-up, RHC data was available for seven patients and showed >20% reduction in PVR in four patients. A further four patients experienced an improvement in WHO functional class after 4±2 months of treatment. The eight patients who demonstrated clinical improvement had superior survival when compared to the 35 patients receiving pulmonary vascular treatment without objective improvement (fig. 4b), even though there was no significant difference in demographics, haemodynamic severity, PFTs or HRCT scan scores between the two groups.

View this table:
Table 3– Therapy of patients with pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD)
Figure 4–
Figure 4–

a) Cumulative survival from date of diagnosis in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD) and mean pulmonary artery pressure (PAP) ≥40 mmHg by use of pulmonary vascular treatment; b) cumulative survival from diagnosis in patients with pulmonary hypertension associated with COPD and mean PAP ≥40 mmHg by features of response to pulmonary vascular treatment (improvement in World Health Organization functional class (WHO FC) or fall in pulmonary vascular resistance (PVR) >20%) compared to those without response.

View this table:
Table 4– Characteristics of patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD) and mean pulmonary artery pressure (PAP) ≥40 mmHg by treatment group

The effect of targeted pulmonary vascular therapy on oxygenation was assessed. For patients receiving PDE-5I, oxygen saturations at baseline and following the initial dose of PDE-5I were available for 21 patients. Median maximal desaturation within 4 h of acute dosing for this group was -1% (-0.5− -2%), with two patients desaturating ≥4% and one patient improving their oxygen saturations by ≥4%. Long-term follow-up data was analysed for patients receiving all forms of targeted pulmonary vascular therapy where oxygen saturations on air were available at baseline and follow-up. After a median 178 days of therapy, oxygen saturation on air increased by 1% (-2–7%) in 28 patients. There were no patients in whom there was a clinically significantly reduction in oxygen saturation with PDE-5I that resulted in discontinuation of therapy. In follow-up, exercise testing for patients receiving targeted pulmonary vascular therapy was variably performed and incomplete and did not allow for meaningful analysis.

DISCUSSION

This study describes several important observations regarding the largest cohort of patients with severe PH-COPD yet studied. First, we have confirmed a phenotype of markedly reduced gas transfer and greater hypoxaemia despite less pronounced airflow obstruction when compared to those with mild–moderate PH-COPD [4, 5]. In addition, we have demonstrated significantly worse WHO functional class and exercise capacity in severe PH-COPD, with a poor prognosis and a disease trajectory that is significantly worse than patients with mild–moderate PH-COPD [5, 29].

While SvO2 has prognostic value in unselected patients with COPD [30], independent prognostic markers in patients with PH in COPD have not previously been described. We have identified age, DLCO, SvO2 and WHO functional class as independent predictors of survival in PH-COPD. Although a mean PAP ≥40 mmHg is traditionally used to define those with severe PH-COPD, SvO2 ≤65% and DL,CO ≤27% are perhaps better thresholds to define poor outcome in PH-COPD. It is interesting to note, however, that a mean PAP of 40 mmHg, the traditionally used threshold for describing severe PH-COPD, was in fact the optimal mean PAP value derived by ROC curve analysis of subsequent survival. These important parameters have utility in counselling patients regarding prognosis. In addition, while in mild–moderate PH-COPD exercise capacity is limited by exhaustion of ventilatory reserve [31], mean PAP ≥40 mmHg has recently been shown to characterise patients with PH-COPD who have an exhausted circulatory reserve on exercise [32].

Patients with severe PH-COPD were more hypoxaemic on room air and more hypocarbic; the latter presumably reflecting hyperventilation to improve oxygenation. Interestingly, although hypoxaemia was adequately corrected by long term oxygen therapy, severe PH persisted. These observations support the hypothesis that hypoxia is not the sole driver of severe PH-COPD [2, 33]. There is little data supporting the use of pulmonary vasodilators used in PAH in patients with PH-COPD [34–37]. However, there is growing interest in considering randomised controlled trials (RCTs) in this population, given the pulmonary haemodynamic characteristics of these patients. In the present study, patients with severe PH-COPD who received compassionate treatment with targeted pulmonary vasodilator therapy had a very poor outcome with a 1-year survival of 72%, which was not significantly different to those who did not receive targeted therapy (63%, p=0.672), although the treated group had more severe pulmonary haemodynamics. The lack of a demonstrated survival benefit, however, does not necessarily confirm a lack of efficacy, but does suggest that with current targeted therapies the outcome for the group as a whole remains poor. Mechanisms suggested to contribute to the severe haemodynamic change seen in patients with severe PH-COPD include destruction of the capillary vascular bed or the development of a vasculopathy [4, 5]. Interestingly, the 19% of patients with severe PH-COPD identified arbitrarily as having an objective response to therapy based on improvements in WHO functional class or a >20% fall in PVR had a superior survival compared to nonresponders and may represent a phenotype in which there is a greater degree of potentially treatment-responsive vasculopathy compared to emphysematous obliteration of the pulmonary microvascular bed. Although these observations are based on small numbers they do raise the possibility that a proportion of patients with PH-COPD may derive benefit from targeted therapies and support further investigation in the context of RCTs. A previous study raised concerns regarding acute worsening of oxygen saturation in patients with modest PH-COPD but more severe airflow obstruction who receive a dose of sildenafil [34]. In the current study no clinically significant worsening of oxygen saturations was observed acutely in patients receiving sildenafil, although these results should be treated with caution as this study was not primarily designed to assess this effect. Importantly, we have identified markers of disease severity in PH-COPD that may be helpful in defining patient groups for further study, and given the extremely high observed mortality, survival may be an appropriate end-point in such studies. Whether exercise testing is an appropriate end-point for studies in PH-COPD cannot be ascertained by this study.

We have recently also shown the importance of accurate phenotyping of patients with PH using multi-modality assessment, including imaging and RHC, and that classification predicts outcome [17]. A significant number of patients with severe PH-COPD had spirometric values which would have allowed entry into RCTs of therapies for IPAH and would have met registry criteria for IPAH [38], despite their having severe emphysema. This observation emphasises the importance of HRCT assessment of lung parenchyma in those with RHC parameters suggestive of IPAH. In the ASPIRE registry patients who clearly had combined fibrosis-emphysema syndrome were classified as having PH-lung secondary to mixed obstructive and restrictive defects, and were not enrolled in the current study. On further detailed quantitative radiological evaluation for the purposes of this study (not available at the time of initial classification), two patients with a diagnosis of PH-COPD did have more significant elevation of fibrosis scores. However, emphysema scores for both of these patients were greater than their fibrosis scores. The vast majority of patients otherwise had no or minimal fibrosis and when present its extent was not significantly different between the mild–moderate PH-COPD and severe PH-COPD groups.

In this study patients were catheterised in clinical stability without exacerbations, which are associated with significant rises in mean PAP [39]. Noninvasive measures in these patients did not correlate reliably with mean PAP at RHC, as described elsewhere [40]. This compounds the difficulty in distinguishing patients with severe PH-COPD from patients with severe COPD without PH and emphasises the importance of cardiac catheterisation where knowledge of the patient's pulmonary vascular status is important. The presence of features of the phenotype of severe PH described here and elsewhere [4], such as a very low DLCO or severe hypoxaemia in the setting of relatively well preserved spirometry can raise suspicion, although thorough investigation is required to characterise these patients and to exclude other causes of PH and is best performed at specialist centres, through which RCTs of therapies may be coordinated [33].

COPD is a systemic disease and the BODE (body mass index (BMI), airflow obstruction, dyspnoea, exercise capacity) index recognises BMI in addition to markers of reduced respiratory reserve, namely FEV1, Medical Research Council dyspnoea score and exercise capacity as important prognostic markers [41]. In the current study, functional class, as well as age at diagnosis and measures of gas transfer and cardiac function, was shown to independently predict survival, but importantly FEV1, BMI and exercise capacity did not. This implies that conventional COPD prognostic models may not apply in patients with PH-COPD. This is noteworthy in view of the increasing interest in the accurate phenotyping of distinct subgroups of patients with COPD.

This study has certain limitations. The population studied represents a highly selected cohort of patients referred to a supra-regional PH referral centre in whom the elevation in PAP was thought to be out of proportion to the severity of underlying respiratory disease. Therefore no estimate of the incidence or prevalence of PH-COPD in the COPD population can be drawn from this study. Also, despite the routine use of HRCT scan in diagnostic evaluation, HRCT films were unavailable for scoring for 27 patients. However, pulmonary function did not significantly differ in the group with and the group without CT films available for scoring (data not shown). Furthermore, the clinical reports of HRCT were consulted as part of data collection to confirm that patients did not have significant pulmonary fibrosis. A small number of patients in whom COPD was the clear cause for PH, but who had elevations in PCWP without increased prevalence of cardiovascular morbidity, were included in the cohort. In these patients, left heart disease was not thought to be the cause of pulmonary hypertension and, indeed, the left atrium size was usually normal in these patients.

Conclusion

Patients referred to a specialist centre with PH-COPD have a poor prognosis that can be best predicted by age, functional status and markers of gas exchange and transport, but not by FEV1. Despite this poor prognosis, our data suggests that a subgroup of patients may exhibit a clinical response to pulmonary vascular therapies used in PAH. Given the high mortality of this condition, studies of specific treatment for PH-COPD are needed.

Footnotes

  • For editorial comments see page 1241.

  • This article has supplementary material available from www.erj.ersjournals.com

  • Support Statement

    This work was supported by an unrestricted educational grant from Actelion pharmaceuticals (J. Hurdman); Medical Research Council Career Development Award [grant number G0800318] (A. Lawrie); the National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit (R. Condliffe, C.A. Elliot, A. Swift, J.M. Wild, I. Sabroe, D.G. Kiely).

  • Statement of Interest

    Conflict of interest information can be found alongside the online version of this article at www.erj.ersjournals.com

  • Received May 18, 2012.
  • Accepted August 23, 2012.

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Pulmonary hypertension in COPD: results from the ASPIRE registry
Judith Hurdman, Robin Condliffe, Charlie A. Elliot, Andrew Swift, Smitha Rajaram, Christine Davies, Catherine Hill, Neil Hamilton, Iain J. Armstrong, Catherine Billings, Lauren Pollard, Jim M. Wild, Allan Lawrie, Rod Lawson, Ian Sabroe, David G. Kiely
European Respiratory Journal Jun 2013, 41 (6) 1292-1301; DOI: 10.1183/09031936.00079512
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