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Quality of life

introduced as an endpoint in PAH studies. CPET is widely used in medicine and plays an important role in the evaluation of patients awaiting heart transplantation or lung volume reduction surgery. It has a prognostic relevance in PAH.7

It is more objective than the

6MWD 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

Mortality and time to clinical worsening 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. 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.9 The suggested alternative for the use


of survival as primary endpoint 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. The first large pivotal trial using time to clinical worsening as primary end-point was the SERAPHINE study.10 In this study, the novel dual endothelin- receptor antagonist, macitentan, was investigated and the primary endpoint was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH. Within the study, worsening of PAH was by far the most frequent event, which was a priori defined as the decrease in the 6MWD of at least 15% from baseline (confirmed by a second test within two weeks), and the

therapy has been upgraded in the actual guidelines.13

A further large clinical trial choosing a composite primary end point of time to clinical worsening was the GRIPHON study,14

successfully assessing the

efficacy of the IP receptor agonist selexipag.


A number of questionnaires have been developed in order to assess QoL in patients. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)15

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.16 Recently, a new health-related QoL measure, the emPHasis-10 questionnaire,17

was developed, which showed excellent measurement

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

worsening of PAH symptoms (worsening WHO class or appearance or worsening of signs of right heart failure not responding to oral diuretic therapy), and the need for additional PAH treatment. The primary end point was reached and use of this complex but clinically relevant composite end point reflecting patients’ daily quality of life was appreciated by the scientific community. Sponsors of clinical trials were encouraged to use similar endpoints in upcoming trials.11 Another large clinical study using a similar composite end point was the AMBITION study,12

investigating the

effectivity of an upfront combination therapy with ambrisentan plus tadalafil versus the monotherapy with one of these compounds. In this event-driven study, the primary endpoint was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalisation for worsening PAH, disease progression, or unsatisfactory long-term clinical response, these latter ones characterised by the decrease in the 6-minute walk distance (6MWD) and advanced WHO stage. Based on the success of this trial, the strategy of upfront combination

properties and sensitivity to differences in clinical parameters. An actual ethnographic study collected information on the QoL of 39 PH patients in an original way.18

Patients 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.19

This study

showed that exercise capacity (6MWD 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.

A recent study20 investigated the inter-relationship of dyspn0ea,

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