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Quality of life

patients awaiting heart transplantation or lung volume reduction surgery. It has a prognostic relevance in PAH.7

It is more

objective than the 6MWT and it is recommended for use in the follow-up of PAH patients, providing a sensitive measure of the change in exercise capacity (peak oxygen uptake) and in the characteristics of the pulmonary circulation. Interestingly, the main thresholds regarding exercise capacity appear to be similar for patients evaluated for heart transplantation, awaiting lung surgery or suffering from PAH. A peak oxygen uptake above 15ml/min/kg is generally associated with a good prognosis, while values below 10ml/min/ kg are associated with a bad prognosis. This robust stratification may also be meaningful for the patients. Interestingly, as a study endpoint, CPET was not successful. This is mainly due to the fact that it is a technically challenging complex investigation and the experience of the healthcare worker plays an important role, which may be a drawback in multicentre trials.8


After the first drugs were approved for the therapy of PAH, the scenery of clinical trials changed. Due to ethical reasons, in most parts of the world, new study drugs were tested as add-on therapy on top of the existing baseline therapy. This allowed the planning of longer trials with clinically more relevant endpoints. An ultimate endpoint may be mortality; however, this is problematic, because it would be unethical to observe the deterioration of patients without taking action. The suggested alternative is to assess the time-to-clinical worsening (TTCW). TTCW is always a composite endpoint and it includes predefined and measurable events, such as all-cause mortality, non-elective hospital stay or disease progression usually characterised by the worsening of World Health Organization (WHO) functional class, right heart decompensation, the need for therapy escalation and the worsening of exercise capacity. In recent clinical trials, TTCW was included as a primary9 endpoint and it is the


recommended primary endpoint for future pivotal studies. TTCW is also meaningful for patients because it aims to represent everyday clinical situations in the best possible way.

To date, survival alone has not been set as primary endpoint in PAH studies and in the absence of statistical power, none of the individual studies revealed a

survival advantage for PAH therapies. Nevertheless, a meta-analysis of randomised, controlled trials was able to show a significant reduction in mortality of 43% in the patients treated with targeted PAH therapies.11


A number of questionnaires have been developed in order to assess QoL in patients. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)12

may be the best-known

specific PH questionnaire but also other tests have been used in PAH, such as the Minnesota Living with Heart Failure (MLwHF) questionnaire or the Short Form-36 (SF-36) questionnaire.13 Recently, a new health-related QoL measure, the emPHasis-10 questionnaire,14

was developed, which

showed excellent measurement properties and sensitivity to differences in clinical parameters. An actual ethnographic study

improvements in QoL (measured by the SF-36 questionnaire) and 6MWD. At all measured time-points, there was a close correlation between 6MWD and most QoL domains. In a 12-week, double-blind, placebo-controlled study with sildenafil and during the open-label extension of the study,18

sildenafil-treated patients,

compared with placebo-treated patients, exhibited significant improvement in exercise capacity and increases in all SF-36 domains at week 12 and these benefits were maintained for 24 weeks. A further study was conducted that aimed at determining whether functional and health-related QoL changes following treatment of PAH patients represent important benefits.5

In order to analyse

this, minimally important differences in exercise capacity, measured by the 6-minute walk distance and in health- related QoL, assessed by the SF-36 questionnaire, were defined. The minimally important difference in the

“Clinically meaningful endpoints representing patients’ daily QoL are now used as primary endpoints of clinical trials, allowing real-life conclusions to be drawn”

collected information on the QoL of 39 PH patients in an original way.15


were observed and filmed in their home for up to six hours, capturing the environment, interactions and activities of everyday life. This approach revealed major findings regarding the relation of patients to their disease that would not typically be uncovered using other techniques.

The question in terms of which clinical parameters most influence PAH patients’ QoL has been addressed in a recent prospective study.16

This study showed

that exercise capacity (six-minute walk distance and peak oxygen uptake) may reflect daily QoL (assessed by the SF-36 questionnaire) better than haemodynamic parameters and WHO functional class in patients with PAH and chronic thromboembolic PH. In addition, long-term oxygen therapy, right heart failure, age, anxiety and depression negatively affected different facets of QoL. The question of whether medical therapy improves QoL in PAH patients has also been addressed. In a retrospective analysis of 69 patients treated for six months with bosentan,17 the therapy was associated with

six-minute walk distance was in range with other similar studies (41 metres). Furthermore, this study provided the first estimated minimally important differences for major SF-36 domains. In addition, to associate clinically relevant parameters with QoL parameters, and in so doing connect them to the daily life of patients, there is evidence that QoL may be considered as a relevant clinical endpoint in itself. Maybe the best argument for this was delivered by a Swiss study that investigated the clinical relevance of the MLwHF questionnaire by prospectively studying 48 patients with either PAH or chronic thromboembolic PH.19

According to the

multivariate analysis in the study, QoL was the sole factor that predicted subsequent clinical outcomes, which suggests that QoL is a relevant prognostic marker. Remarkably, QoL was a stronger predictor for clinical outcome than established parameters, including WHO functional class, six-minute walk distance or right atrial pressure. Another study investigating the relevance of QoL parameters followed-up patients with PAH or chronic thromboembolic PH for an eight-year period and demonstrated


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