Rheumatology Advance Access originally published online on August 18, 2006
Rheumatology 2006 45(12):1455-1457; doi:10.1093/rheumatology/kel273
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EDITORIALS |
Need for improved outcome measures in pulmonary arterial hypertension related to systemic sclerosis
Department of Rheumatology, University Hospital Zurich, Switzerland, 1Division of Rheumatology/ZAFES, J.W. Goethe University Frankfurt, 2German Rheumatism Research Centre, Berlin, 3Pediatric Rheumology Clinic, General Hospital Eilbek, Germany, 4Rheumatology Research Unit, 6th Avenue Specialist Centre Cotton Tree 4558, Sunshine Coast, Queensland, Australia, 5Centre for Rheumatology, Royal Free and University College, Medical School, London, UK, 6Service de Pneumologie et Reanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, Hopital Antoine-Beclere, Universite Paris-Sud, Clamart, France, 7Universita Degli Studie Terapia Medica I, Florence, Italy, 8University of Michigan Scleroderma Program, Ann Arbor, Michigan, 9Division of Pulmonary and Critical Care Medicine, University of California, San Diego School of Medicine, La Jolla and 10Division of Rheumatology, Department of Medicine, David Geffen School at UCLA, Los Angeles, CA, USA
Correspondence to: O. Dister, Department of Rheumatology, University Hospital Zurich, Switzerland. E-mail: Oliver.Distler{at}usz.ch
SSc-pulmonary disease is a devastating condition
Pulmonary disease is a frequent complication of systemic sclerosis (SSc) and is at the same time challenging for the treating physician. Besides lung fibrosis, pulmonary arterial hypertension (PAH)—defined as a mean pulmonary artery pressure above 25 mmHg at rest or above 30 mmHg during exercise by right heart catheterization—can occur both in the limited and diffuse subset of SSc and leads to right cardiac overload with exercise intolerance, dyspnea and arrhythmia [1]. The natural history of PAH associated with SSc (APAH/SSc) is devastating. While 1-, 3- and 5-yr survival rates after diagnosis in the idiopathic form (IPAH) are 68, 48 and 34% (median life expectancy 2.8 yrs) in untreated patients, several studies have shown that the prognosis in APAH/SSc is even worse. Median survival in untreated patients is only 12 months, and the risk of death is nearly tripled [2, 3].
Recently some effective therapies for PAH have become available
In the last few years, a number of new agents became available for the treatment of PAH. They have been tested in a series of open as well as randomized controlled trials, and included about 20% APAH/SSc patients. Examples are the prostaglandin-derivates (epoprostenol [4], treprostinil [5], beraprost [6, 7] and iloprost [8]), the endothelin receptor antagonists (bosentan [9, 10], sitaxsentan [11] and ambrisentan [12]) and the PDE-5-inhibitor sildenafil [13]. Well-designed controlled trials are of great importance in this context because the value of these expensive treatments must be shown to patients and physicians, as well as to health insurance agencies and regulatory authorities.
Measures of response for PAH remain limited
One of the major challenges for the design of these studies is the decision regarding appropriate primary endpoints. Endpoints most often used are exercise capacity measured by 6-min walk distance, pulmonary haemodynamics, clinical events and peak VO2 [14]. However, none of these endpoints is optimal or undisputed. In a workshop on endpoints in PAH trials from the Third World Symposium on Pulmonary Hypertension in 2003 [15], experts concluded the following:
- Standard haemodynamic measurements in patients with PAH correlate with clinical state, functional class, exercise capacity and prognosis, but these correlations are not high. Mean pulmonary artery pressures (including right heart catheterization) often fail to reach statistically significant correlation with outcome in PAH treatment trials;
- The well-known NYHA/WHO functional classification may be too crude to be used as a single endpoint in clinical trials;
- The 6-min walk test, even though it is the most widely used primary endpoint and the only measure of exercise capacity accepted by the FDA, is not validated for PAH patients with less severe disease such as NYHA/WHO functional class I/II [15].
In APAH/SSc, the validation of possible study endpoints is even less convincing than in PAH in general. In a systematic review of endpoints during the OMERACT-6 workshop on Outcome Measure Development for Clinical Trials in SSc, each outcome measure was assessed as to whether it meets the standards of the ‘OMERACT Filter’ of truth (face, content, construct and criterion validity), discrimination (reliability/reproducibility and sensitivity to change) and feasibility [16, 17]. As a result of this systematic review, only invasive haemodynamics (right heart catheterization) passed the OMERACT filter and was rated to be ‘ready for use in clinical trials in SSc patients’ [18]. All other typically used endpoints such as exercise tests, dyspnea indices or non-invasive haemodynamics (2-D echocardiography), were not validated in one or more filter categories, and therefore not recommended for trials. This situation has not changed much since this evaluation. As an example, the 6-min walk test has good face validity (credibility) and trials on PAH that included SSc patients showed that it is feasible in APAH/SSc. However, the construct validity (biological sense) and discrimination validity (sensitivity to change) has been only partially demonstrated in patients recruited to trials of PAH, since these trials were greatly underpowered for the subset of APAH/SSc patients. Content validity (comprehensiveness) and reliability of the 6-min walk test have not been established in SSc.
Need for improved outcome measures in APAH/SSc
Taken together, there is, on the one hand, the rapid development of new therapeutic options for patients with PAH and the need to show the efficacy of these expensive treatments to patients, physicians, health insurance agencies and regulatory authorities in well-designed clinical trials. On the other hand, outcome measures required for the design of these trials are only poorly defined and validated in APAH/SSc. This clearly shows the urgent need for a structured approach to define clinical endpoints for APAH/SSc that take into account the methodological problems associated with possible SSc-specific confounding factors (e.g. musculoskeletal problems, joint contractures, fatigue and deconditioning, that may affect cardiopulmonary testing). As a next step, these clinical endpoints must be validated according to the OMERACT filter.
An approach to improving measures of response
To address the necessary definition of outcome measures in APAH/SSc, an interdisciplinary working group adhering to OMERACT principles (EPOSS= Expert Panel on Outcomes measures in PAH related to Systemic Sclerosis) has started a staged process to develop consensus—a Delphi exercise [19]. The Delphi exercise (named after the Greek oracle) was developed by social science researchers in the 1950s. It uses a series of questionnaires to aggregate the knowledge, judgments and opinions of experts in order to reach consensus on complex questions [20, 21]. In the current application, the Delphi technique will enable a large group of geographically dispersed experts from different specialities to identify and define outcome measures in APAH/SSc.
The steps of the Delphi approach are summarized in Figure 1. After definition of the project scope, a small steering committee (e.g. EPOSS steering committee) designs a questionnaire in which participants are asked for their opinion on the specific problem (e.g. possible outcome measures in APAH/SSc). This questionnaire is then sent to a larger respondent group consisting of experts in the field representing various specializations (e.g. rheumatologists, cardiologists and pulmonologists experienced in both PAH and SSc). After the questionnaire is returned, the steering committee summarizes the results (e.g. collection of all suggested outcome measures in APAH/SSc), and develops another questionnaire, in which the respondent group is informed about the results of the first round and asked to rate the answers in terms of the relative usefulness or importance of the measures (e.g. rating of outcome measures mentioned by all participants). In the third Delphi round, participants are informed on the median ratings of the whole group and are provided at least one opportunity to re-evaluate their original answers against the background of the answers of the other participants (e.g. re-evaluation of their rating of APAH/SSc outcome measures) [19]. At the end of the ongoing Delphi study in APAH/SSc, expert consensus will be reached, as to which outcome measures or composite outcome measures are of most importance in APAH/SSc. This conclusion/consensus will of course require data-based validation.
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Key elements of the Delphi technique are the structured flow of information, feedback to the participants, and anonymity for the participants during the exercise itself (thus not inhibiting their input). These characteristics offer distinct advantages over conventional face-to-face conferences and other communication tools and many of the problems of group dynamics are bypassed. An important issue and potential bias in a Delphi process is recruiting the ‘correct’ respondent group. Although it has been shown that doctors who are willing to participate in expert panels are representative of their colleagues, the exact composition of the panel can affect the results obtained [22]. Thus, to account for the interdisciplinary approach that is commonly used in the clinical care of APAH/SSc patients, members of the respondent group in this Delphi approach were selected from rheumatology, pulmonology and cardiology subspecialities. It has to be emphasized that the Delphi technique was successfully used in the past in rheumatology, e.g. to develop a consensus-based set of core domains for outcome studies in psoriatic arthritis and evidence-based recommendations for the management of ankylosing spondylitis [23, 24].
Summary
The rapid development of new therapies for patients with PAH requires the confirmation of their treatment efficacy in well-designed, randomized controlled trials. Unfortunately, beyond right heart catheterization, outcome measures for APAH/SSc, which are necessary for the design of such studies are poorly defined and those available are at best only partially validated. To overcome these shortcomings, a Delphi exercise is being performed (currently in Round 2) to obtain an expert consensus opinion, on the most appropriate and comprehensive, non-invasive combination of measures to use for APAH/SSc. The validation of this combination of outcome measures could then be undertaken in prospective clinical trials or available databases.
Acknowledgements
The EPOSS group is supported by an unrestricted educational grant from Actelion Pharmaceuticals, Allschwil, Switzerland.
C.P.D. has received research funding from or acted as a consultant to Actelion, Encyrive, Genzyme and Asprova Pharmaceuticals. I.F. received a speakers fee for the participation on the Actelion winter school 2006. M.H. received honoraria and research support from Actelion. D.F. was a consultant on study, design and related matters with unrestricted honorarium; grant/research—Actelion. J.S. has received honoraria, consultancy income and funded research from Actelion. P.N. has lectured on behalf of Actelion Pharmaceuticals. O.D. received speakers fee for scientific lectures from Actelion.
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