Health-related quality of life in patients with pulmonary arterial hypertension
© Taichman et al. 2005
Received: 21 June 2005
Accepted: 10 August 2005
Published: 10 August 2005
Improved outcomes with expanding treatment options for patients with pulmonary arterial hypertension present the opportunity to consider additional end-points in approaching therapy, including factors that influence health-related quality of life. However, comparatively little is known about health-related quality of life and its determinants in patients with pulmonary arterial hypertension.
Health-related quality of life was evaluated in a cross sectional study of 155 outpatients with pulmonary arterial hypertension using generic and respiratory-disease specific measurement tools. Most patients had either World Health Organization functional Class II or III symptoms. Demographic, hemodynamic and treatment variables were assessed for association with health-related quality of life scores.
Patients with pulmonary arterial hypertension suffered severe impairments in both physical and emotional domains of health-related quality of life. Patients with idiopathic ("primary") pulmonary arterial hypertension had the best, and those with systemic sclerosis the worst health-related quality of life. Greater six-minute walk distance correlated with better health-related quality of life scores, as did functional Class II versus Class III symptoms. Hemodynamic measurements, however, did not correlate with health-related quality of life scores. No differences in health-related quality of life were found between patients who were being treated with calcium channel antagonists, bosentan or continuously infused epoprostenol at the time of quality of life assessment.
Health-related quality of life is severely impaired in patients with pulmonary arterial hypertension and is associated with measures of functional status. Specific associations with impaired health-related quality of life suggest potential areas for targeted intervention.
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by progressive dyspnea and exercise limitation. If not effectively controlled, PAH often progresses to right heart failure and premature death [1–3]. Fortunately, recent dramatic advances in pharmacological treatment have brought about significant improvements in physical functioning and survival, and new therapeutic options are emerging at a rapid pace . Improved outcomes with expanding treatment options present the opportunity to consider additional end-points in choosing approaches to therapy, including factors influencing health-related quality of life.
Presently, little is known about the determinants of health-related quality of life (HRQOL) in patients with PAH. An improved understanding of these determinants will be essential as HRQOL becomes an important outcome in research on therapeutics for PAH [5, 6].We studied health-related quality of life in a large population of PAH patients and performed an initial assessment of the clinical factors associated with better (or worse) HRQOL.
Study Design and Patients
We conducted a cross sectional survey of HRQOL in patients cared for in the Pulmonary Vascular Disease Program at the University of Pennsylvania Health System. Previously established as well as newly referred patients with PAH were asked to complete HRQOL questionnaires over one year (October, 2002 – September, 2003). PAH was defined according to standard criteria, including a mean pulmonary artery pressure >25 mmHg at rest or 30 mmHg with exertion, and the absence of significant left heart dysfunction [7, 8]. Patients completed questionnaires without assistance at regularly scheduled appointments prior to the physician evaluation. Physicians and nurses were not aware of HRQOL survey responses.
Patient demographics, symptoms, medications, and physical exam findings on the day of HRQOL evaluations were obtained by chart review, as were demographic values. Test results within three months of HRQOL assessment were recorded (e.g. hemodynamic values from cardiac catheterization in 103 patients and six-minute walk distance in 33 patients).
Health-Related Quality of Life Measurements
We administered a generic and a respiratory disease-specific quality of life questionnaire. The Medical Outcome Study 36 Item Short Form health survey (SF-36, standard form, version 2; Quality Metric, Lincoln, RI) yields scaled scores in 8 physical and mental health areas affected by health and disease conditions, in addition to physical component and mental component summary scores . The St. George's Respiratory Questionnaire (SGRQ) is a well validated respiratory disease specific HRQOL measure, yielding scores related to symptoms (concerning the frequency and severity of respiratory symptoms), activity (the degree to which activities are limited by breathlessness), and impact (aspects of social and psychological function affected by respiratory disease). In addition, a total score summarizes disease impact on overall health status .
Scores for the 8 domains and 2 summary measures of the SF-36, and the 4 scores of the SGRQ were calculated electronically according to published guidelines, including imputation for missing responses . Higher SF-36 scores indicate better quality of life, whereas higher SGRQ scores indicate poorer HRQOL. SF-36 scores are normalized to a mean of 50 and standard deviation of 10, based on the normal US population. Mean raw scores on the SGRQ were compared with established normal population scores .
Data were entered into a Microsoft Access 5.1 database (Microsoft Corporation) and statistical analysis performed with SAS 8.2 software (SAS Institute, Cary, NC). Data were analyzed for differences using an independent t-test for binary predictors, ANOVA for categorical predictors, and correlation coefficients for continuous measures. Comparisons between patient groups were limited to the physical and mental component summary scores of the SF-36, and significant associations defined as those having a p ≤ 0.05.
Normalized physical and mental component summary scores were calculated from published studies of populations with various chronic diseases using reported individual SF-36 domain scores and an on-line scoring program http://www.sf-36.org/nbscalc/index.shtml.
This study was approved by the Institutional Review Board of the University of Pennsylvania.
Age, years (mean ± SD)
53 ± 13
Female, n (%)
Anorectic Agent Use
Other (i.e., HIV, PVOD)
WHO I, %
WHO II, %
WHO III, %
WHO IV, %
Mean RA pressure (mmHg)
8.7 ± 2.6
Mean PA pressure (mmHg)
47 ± 17
Cardiac output (liters/min)
4.9 ± 1.8
630 ± 425
Calcium Channel Blocker
Oxygen, as needed
Health-Related Quality of Life Scores
Factors Associated with Impaired Quality of Life
Certain symptoms were associated with worsened HRQOL. Chest pain and pre-syncope were each associated with poorer physical component scores (p ≤ 0.02 for each), generalized fatigue with lower physical and mental component scores (p ≤ 0.03, each). Common side effects of epoprostenol therapy (diarrhea, jaw pain) were not related to further impairment in HRQOL. Patients who reported abdominal discomfort had significantly worse physical and mental component summary scores, and the presence of abdominal tenderness on physical exam was associated with worsened MCS scores (p ≤ for each). The only additional finding on physical examination associated with poorer HRQOL was the presence of peripheral edema, with which lower physical component summary scores (p ≤ 0.0001) and mental component scores (p = 0.02) were seen.
Changes in health-related quality of life have been reported in trials of medications for pulmonary arterial hypertension. Improvements over pre-treatment scores have been seen in association with increased exercise capacity resulting from various therapies [12–16]. Focused assessments of health-related quality of life itself, however, are lacking and a systematic evaluation of the factors influencing it has not been previously reported in this patient population. A recent cross-sectional study of 53 patients with PAH reported moderate to severe impairments in multiple domains of HRQOL, both physical and emotional .
In the present study we have assessed a large population of patients with PAH and have identified demographic, symptom and treatment factors associated with better or poorer health-related QOL. Significantly impaired HRQOL was found in each of the eight domains of the SF-36, representing those physical, social and emotional characteristics generally accepted as most directly affected by health and disease [18, 19]. Similarly, impaired HRQOL was observed on all scales of a respiratory-specific assessment tool (the Saint George's Respiratory Questionnaire). We found HRQOL to be best for patients with idiopathic PAH and worst for those with systemic sclerosis, unrelated to the type of vasodilator therapy used, and to be correlated with functional but not hemodynamic assessments.
Several important clinical parameters were associated with the degree of impairment in quality of life we observed, including diagnosis and exercise capacity. In addition to their poorer overall prognosis [27, 28], we found that patients with PAH associated with systemic sclerosis experience worse health-related QOL than patients with other forms of the disease. Despite clear improvements in hemodynamics and exercise capacity as compared to untreated patients, those with systemic sclerosis do not benefit to the same degree as patients with IPAH in response to PAH-specific therapies [29, 30]. Further investigations are required to determine whether these patients derive less benefit in HRQOL in response to these therapies, or whether other specific interventions can result in improvements.
The results of a six-minute walk test have been shown to correlate with each the WHO functional Class and patient survival . In our sample, the distance walked in six minutes correlated with health-related quality of life. Scores worsened as exercise capacity declined. Our data similarly indicated worse scores in patients with WHO Class III symptoms as compared with Class II. The low number of patients with WHO Class I or IV symptoms in our population, however, limits further comparisons. By contrast, it is interesting that our data did not indicate a correlation with hemodynamic values. This suggests that a patient's overall functional status is of greater importance than actual hemodynamic values in determining HRQOL. Such findings, if confirmed, emphasize the importance of such functional endpoints in clinical trials, and may help direct choices of therapy so as to bring about the greatest improvement in a patient's sense of well-being. These findings, however, require confirmation with larger data sets that allow for HRQOL assessments both before and after cardiac catheterization, the results of which frequently change in response to therapy.
That abdominal complaints were associated with impaired HRQOL may be an important finding among patients with PAH. While abdominal discomfort might be caused by impaired splanchnic perfusion due to poor cardiac performance, it can also (perhaps more commonly) result from any of a number of processes common in non-PAH patients (e.g. gastroesophageal reflux and peptic ulcer disease). Even if not the result of PAH's effect on circulatory function itself, the significant association of abdominal discomfort with HRQOL noted here warrants further investigation. Similarly, while swelling and edema are a common symptom and finding among patients with advanced PAH and cor pulmonale, the additional impairment in HRQOL associated with diuretic use emphasizes the need to be mindful of appropriate titration to the degree required to prevent significant fluid collection.
No difference was found in HRQOL between patients who were receiving calcium channel antagonists, bosentan or epoprostenol therapies at the time HRQOL assessments were made. We cannot determine from the present study whether this reflects differences in the factors that determined the choice of therapy, or if these treatments do indeed result in equivalent HRQOL. While it might be expected that the need for continuous intravenous therapy would be associated with worse HRQOL, the inconveniences of such treatment might be off-set by the resultant substantial and sustained improvements in exercise capacity. Further, HRQOL reflects an individual's satisfaction with his or her life as it is affected by health. As such, HRQOL will be affected differently on the basis of individual desires, perceptions and expectations . Epoprostenol therapy requires a motivated patient willing and able to provide a high degree of self-care. Such therapy may thereby select for individuals whose HRQOL is influenced to a greater degree by a sense of control over one's disease and its treatments. Additional prospective studies will be required to further evaluate these possibilities, and to determine whether choice of therapy can be expected to influence a patient's HRQOL.
There are several limitations of this study. Retrospective collection of patient symptoms and diagnoses may have resulted in misclassification bias and thereby influenced the observed effects of various factors on HRQOL. Missing items on HRQOL questionnaires may not be equally distributed among patients, and could therefore serve as an additional source of bias. Multi-centered studies will be required to be sure that the associations with reported symptoms and treatments found here do not overly reflect the practice styles of the physicians at this single specialized center. Larger prospective studies are required to better assess potential differences in HRQOL resulting from different treatments.
There is no currently available instrument designed specifically for the assessment of health-related quality of life in patients with pulmonary arterial hypertension . We have used the SF-36, a non-disease specific instrument and the most widely used worldwide in studies of many individual disease populations . While we have used the SGRQ (an instrument aimed a patients with respiratory disease) as a means to compare and provide some validation of the results seen with the SF-36, this too is limited in its ability to evaluate many items contributing to HRQOL in patients with pulmonary arterial hypertension. The SGRQ was developed to assess patients with COPD. As such, many of its questions address symptoms not typical of pulmonary arterial hypertension (e.g. wheezing and productive cough). Further, other symptoms attributable to cor pulmonale and commonly faced by patients with pulmonary arterial hypertension are not addressed in the SGRQ. While several HRQOL instruments have been developed for patients with left heart failure, these too have significant limitations in application to other populations and have not been validated for use in patients with cor pulmonale. Indeed, pulmonary arterial hypertension represents a hybrid of respiratory and cardiac symptoms, signs and treatments. Pepke-Zaba and colleagues have recently reported on the development of a PAH-specific HRQOL questionnaire . The availability of such an instrument specifically developed for evaluation of patients with pulmonary arterial hypertension will be an important contribution to future studies aimed at better understanding and improving HRQOL .
Our study provides an initial systematic evaluation of health-related quality of life in a large population of patients with pulmonary arterial hypertension. We found profound impairment in all domains of HRQOL measured by both generic and respiratory-disease specific measures, and associations with assessments of functional status as well as specific demographic, symptom and treatment factors. As therapeutic options expand, the factors associated with impaired HRQOL identified here may suggest areas for further study and targeted intervention in efforts to improve outcomes for patients with pulmonary arterial hypertension.
List of Abbreviations Used
Pulmonary Arterial Hypertension
Health-Related Quality Of Life
Medical Outcomes Study 36 Short Form
St. George's Respiratory Questionnaire
Physical Component Summary
Mental Component Summary
Idiopathic Pulmonary Arterial Hypertension
World Health Organization.
We thank Ms. Peggy Hegarty for expert assistance in the preparation of this manuscript. JS was supported by a medical student fellowship from FOCUS on Health & Leadership for Women at the University of Pennsylvania. DBT received support from a Development Partners' Junior Faculty Award from GSK Pharmaceuticals and from a Stephan A. Hansel Award from the Foundation for Pulmonary Hypertension.
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