The term pulmonary arterial hypertension (PAH) refers to a group of incurable disorders associated with a progressive increase in pulmonary vascular resistance (PVR), reduced exercise capacity and an end characterized by right ventricular failure and premature death.1 Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and possibly underdiagnosed disease, with probably similar behavior when pulmonary endarterectomy is not feasible. Two decades ago, it was observed that the mean survival in untreated PAH was 2.8 years after diagnosis.2 However, in the last 15 years and after extensive research with over 25 multicenter clinical trials and two meta-analyses, survival benefits have been demonstrated with new treatments.3,4 The primary objective in most of these trials was exercise capacity, while HRQL was included as a secondary endpoint in only a few.5–7 Since new treatments have led to CTEPH and PAH becoming “manageable chronic diseases”, improvements in HRQL are increasingly important for physicians and patients when evaluating their impact.6,8 Measuring the HRQL is also useful for evaluating the cost-benefit.9 Aside from some clinical trials, there are few studies on HRQL in PAH10,11 or CTEPH.12–14 It is known that, compared to healthy individuals, patients with PAH have reduced physical mobility, lower energy levels, increased pain and greater social isolation.12

The aim of this multicenter, non-interventional, descriptive study was to prospectively evaluate HRQL in a cohort of Spanish patients diagnosed with PAH or CTEPH in an unselected population from hospitals of different sizes and expertise. As a further objective, it was also proposed to determine which factors influence HRQL in these patients.

In this prospective study, we have tried to describe the evolution of HRQL in a national Spanish cohort of patients with PAH or CTEPH. Two generic questionnaires were chosen as measuring instruments, the SF-36 and EQ-5D, basically because these have been the most widely used in PAH clinical trials, and also due to lack of availability of specific questionnaires on these diseases in Spanish. Among the advantages of this choice is that it allows us to make comparisons with the normal population or other serious pathologies. The first major result was that HRQL in PAH and CTEPH was worse than in the normal Spanish population,15 and did not change in the survivors at 6 months of follow-up. An Australian study of a national cohort of patients with PAH also showed a deterioration in HRQL, although in that case the patient population included was one that had started a specific treatment.16 All PAH patients included were on specific treatment and, therefore, our study suggests that the impact of new PAH treatments on HRQL is not progressive but could possibly be sustained over time. This idea has already been previously explored. Thus, in a study of 177 PAH patients,17 HRQL improved modestly after bosentan treatment; this improvement remained stable for three months. This result contrasts with the HRQL results in clinical trials with PAH-specific drugs. Of a total of 26 published clinical trials, 12 included HRQL as a secondary endpoint.6,18,19 Of the latter, some measured HRQL using a specific questionnaire for cardiovascular disease, while only a few did so using a generic questionnaire. HRQL measurements did not vary in one third of these studies, although they improved moderately in the remainder.6,10,20 Therefore, the absence of significant variation in HRQL over the six months of the study is consistent with previous information. The best comparison of our results can be made with the SUPER study,10 where the same questionnaires were used in 278 patients; the SF-36 showed results very similar to ours, and distinct from the normal Spanish population.15

With respect to HRQL in CTEPH, this has been evaluated in very few studies,13,14 none of which were classed as clinical trials. A Japanese study compared 43 patients treated medically with 40 patients treated surgically.14 The SF-36 scores in the group treated medically were very similar to the results obtained in this study. Moreover, our results support the idea that patients with CTEPH attended by doctors specializing in this condition in Spain have a HRQL similar to patients with idiopathic PAH. When we analyzed potential differences at baseline between patients who worsened in the follow-up compared to those who did not, we did not find any differences in the baseline data, including HRQL. This result highlights the difficulties in establishing a prognosis in PAH or CTEPH patients.

In this respect, information from the HRQL is particularly relevant for helping to predict which patients will die or require a lung transplant in the following weeks or months.

In this study, this patient group presented an initial HRQL that was worse than the other patients, but with no differences in the 6MWT or FC. This information is relevant, and invites us to explore the design of new studies, as the value of HRQL as a potential prognostic predictor in PAH and CTEPH is not well established in the literature. The differences in HRQL observed between patients who died or required a lung transplant and the other subjects are not too far from the minimal important difference (MID), defined as the smallest change in the HRQL score that is considered significant for the patient. The largest study to attempt to define this MID was performed in the cohort of the SUPER study.21 The authors found that the MID for SF-36 physical functioning, role-physical, social functioning, and vitality scales and for 6MWD were 13, 25, 21, and 15 points, and 41 m, respectively. Although the study has numerous limitations recognized by the authors, including the fact that this was a post hoc analysis in a study with no statistical power for this objective, it is a first point of reference for establishing MID in HRQL in this pathology.

Various clinical determinants have been associated with the degree of impairment of HRQL in these patients, including the diagnosis and exercise capacity. We found that patients with PAH associated with a CTD, especially scleroderma, experienced poorer HRQL than patients with other disease forms (Table 2). Despite all the therapeutic measures available, these patients did not obtain the same level of benefits as the others, which is compatible with other studies.22–24 In our cohort, the physical component of the SF-36 and the score on the EQ-5D VAS correlated with the 6MWT; the scores worsened as the exercise capacity was reduced. This result is consistent with previously published data,22,25 and supports the importance of these clinical parameters in practice. Recently, an acceptable correlation has been observed between changes in the 6MWT and the physical component of the SF-36, which has served as a basis for setting the minimum clinically important difference in the 6MWT at 33 m.26 Patients diagnosed in the year prior to study inclusion had worse HRQL and 6MWT scores than patients who were diagnosed earlier. This has not been studied previously in the literature, but enables us to speculate about differences in survival between incident and prevalent patients. We also hypothesized that patients on complex parenteral treatment would have a poorer HRQL than those who were on simpler treatment. However, we did not find any differences in HRQL between patients who were receiving oral-inhaled medical treatment or another more invasive one. This result, although surprising, is consistent with published studies.12,23 Finally, it is a matter of speculation whether this reflects differences in the factors that determined the choice of therapy, or if these different treatments have the same impact on HRQL.

This study has the limitation of short follow-up, losses to follow-up and the use of only generic instruments to measure HRQL. Furthermore, we must bear in mind that the recruitment designed may represent a limitation in the external validity of the study and, in theory, may not be a good representation of the Spanish patient population. Finally, in future designs, it will be important to include specific questionnaires and longer follow-up to be able to see small changes in HRQL and their value for taking decisions in these patients.

In conclusion, our study systematically evaluated HRQL and its value in short-term follow-up in a national cohort of patients with PAH and CTEPH. We can confirm that there is serious impairment of HRQL in these patients, which varied little within six months. The most relevant result was the fact that HRQL measured using generic instruments was worse in patients who were near death. Future efforts and prospective studies will be required that include, as well as generic instruments, specific questionnaires to definitively establish the value of HRQL as a potential predictor of outcome in PAH and CTEPH.

AR has made substantial contributions to the conception, design, data collection, data analysis and interpretation, and drafting of the manuscript; JAB has made contributions to data collection and interpretation, and has provided a critical review of the manuscript; JSR has made contributions to data collection and interpretation, and has provided a critical review of the manuscript; RM has made contributions to the design, data collection, technical and logistic support, and data interpretation and provided a critical review of the manuscript; PE has made substantial contributions to the conception, design, data collection, data analysis and interpretation, and has provided a critical review of the manuscript.

This study is sponsored by Pfizer. Ms. Rocío Muñoz currently works in Laboratorios Pfizer, the company which sponsored this study. The other authors have no conflicts of interest and have ensured the impartiality of the article.