Health-related quality of life in patients with pulmonary arterial hypertension

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 [4]. 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.

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 [17].

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.

While we are not surprised to find reduced health-related quality of life in patients with PAH, the severity of impairment is remarkable. Impaired HRQOL – both physical and emotional – is associated with many chronic and physically debilitating conditions. The impairments observed in our population of PAH patients are as severe (and in many respects more so) than those reported in studies of patients with other severely debilitating and life-threatening conditions such as spinal cord injury, interstitial lung disease or cancer unresponsive to therapy (Figure 7) [20‐26]. Indeed, Shafazand et al. found their patients with PAH unhappy enough with their condition as to be willing to accept a significant risk of death in exchange for a potential cure [17].

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 [31]. 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 [17]. 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 [5]. We have used the SF-36, a non-disease specific instrument and the most widely used worldwide in studies of many individual disease populations [9]. 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 [32]. 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 [5].

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.