Aim

To summarize the validity of the following outcome measures:

• Clinical worsening
• Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
• World Health Organization (WHO) functional class (FC)
• Six-minute walk distance (6MWD).

Findings

Clinical Worsening

The composite outcome of clinical worsening — combining the events of death, heart or lung transplantation, atrial septostomy, initiation of new pulmonary hypertension (PH) medications, hospitalization, persistent decrease of > 15 % from baseline or > 30% compared with the last measurement in 6MWD due to worsening PH, and persistent worsening of WHO FC due to deterioration of PH as a single outcome — may improve precision (increased statistical power would make it easier to detect a therapeutic benefit) and offer a more global assessment of the patient and his/her clinical state by including nonfatal but important morbid events in the course of disease.³⁴ Therefore, it is likely a clinically relevant outcome. However, there are limitations using composite outcomes in PH studies:³⁴

• Confounding may occur if a component outcome occurs at a different rate versus others in the composite outcome, especially during a trial of short duration
• Including outcomes such as hospitalization in a composite outcome may be a problem because they may, at least partially, be driven by social or nonmedical factors, which may disproportionately influence a composite also containing more direct measures of disease progression (death)
• A composite outcome driven by individual outcomes with centre-specific availability (lung transplantation and atrial septostomy) may pose difficulty in multicenter trials
• In a composite outcome, each of the components has equal clinical implications
• There is no standardized definition for clinical worsening and the component end points vary across pulmonary arterial hypertension (PAH) trials.

A recent assessment of survival in an observational study suggested that clinical worsening was highly predictive of subsequent mortality and was meaningful as a primary end point in clinical trials of PAH.³⁵

Clinical worsening is recommended as a key outcome for use in PAH studies by the European Medicines Agency, the World Symposium on Pulmonary Hypertension 2008 Dana Point, and 2013 Nice clinical trial design task forces.^43-45

Cambridge Pulmonary Hypertension Outcome Review

CAMPHOR is a self-administered, disease-specific instrument designed to assess symptoms, activity limitations, and quality of life in patients with PH.³⁶ It includes a 25-item overall symptom scale based on three subscales (energy [10 items], breathlessness [eight items] and mood [seven items]), a 15-item function scale, and a 25-item quality of life scale.³⁶ The questions for the symptom and quality of life scales have dichotomous (true or false) response options, whereas the functioning scale has a three-point response option (able to do on own without difficulty, able to do on own with difficulty, unable to do on own). The scoring of the scales range from 0 to 25 for symptoms, 0 to 30 for functioning, and 0 for 24 for quality of life, with higher scores indicating more severe symptoms or functional impairment, and worse quality of life.³⁶

The CAMPHOR symptom, functioning, and quality of life scales showed good construct validity, test–retest reliability, and internal consistency in UK,³⁶ US,⁴⁶ and Australian and New Zealand^47,48 PAH patients. Known group validity was also demonstrated.^36,46-48 No information was found on the responsiveness or minimal clinically important difference (MCID) of the symptom, functioning, or quality-of-life scales of the CAMPHOR questionnaire.

A preference-based utility index (score 1 = perfect health; 0 = death) was developed based on the health state determined by six items from the CAMPHOR quality-of-life scale.⁴⁹ The index showed good test–retest reliability, construct validity, and known group validity.^37,49 Using anchor and distribution-based methods, estimates of the utility index MCID ranged from 0.05 to 0.13, with 0.09 selected as the most reasonable estimate of the within-group MCID.³⁷

World Health Organization Functional Classification

The WHO FC system for PH was adapted from the New York Heart Association (NYHA) functional classification system for heart failure.¹ The WHO functional class system is used widely in clinical practice and as an outcome in clinical trials. One study reported clinicians’ assessment of FC varied widely in PAH, especially when classifying patients as FC II or III.³⁸ The intra-class correlation coefficient was low (approximately 0.6). In one instance, 53% of clinicians classified a patient as FC II and 47% classified the patient as FC III. Thus, despite wide use of the WHO classification system, inter-rater agreement may be poor. FC may also be less responsive to changes perceived by patients as clinically important, than other measures, such as the CAMPHOR functional scale or utility index.³⁷

Six-Minute Walk Distance

The 6MWD measures the distance a patient can walk in six minutes. Change in 6MWD is the most widely used test to assess exercise capacity in PAH and is used in most PAH trials as a primary outcome.^50-54 6MWD is also used in clinical practice and is widely accepted by regulatory agencies.⁵⁵ The main advantage of the 6MWD is its ease of administration; it is a submaximal exercise test that can be performed by a patient who is unable to tolerate maximal cardiopulmonary exercise testing.⁵³ Baseline 6MWD in PAH treatment studies has been shown to correlate with long-term outcomes such as morbidity and mortality, as has the absolute 6MWD during treatment for PAH.^40,56 The change in 6MWD is a surrogate outcome and has demonstrated moderate to poor correlation with key clinical outcomes in PAH.^39-41,56,57 However, some studies have shown that a decline in 6MWD may be more strongly associated with prognosis than stable or increased 6MWD.^56,57 Performance on the 6MWD may be influenced by patient age, sex, height, weight, lung function, and ethnicity, and it may be susceptible to motivational factors and a training effect.^58-60 Furthermore, in multi-centre trials, experience and technical skills may vary between sites, and the correlations between the 6MWD and cardiopulmonary exercise testing might improve over time with increasing experience.⁶¹ There is also evidence of a ceiling effect on the 6MWD, whereby the effect of the treatment on the test is diminished due to the inclusion of patients with milder disease (NYHA/WHO FC II, baseline 6MWD > 450 m) who demonstrate a smaller improvement with treatment given the relatively higher baseline 6MWD value versus patients with more severe PAH.⁶² Despite these limitations, improvement in function, as reflected by 6MWD, remains clinically valuable in PAH. Mathai et al., using distributional and anchor-based methods of estimating an MCID, reported a change of 33.0 m (range 25.1 to 38.6 m) for patients with PAH compared with placebo.⁴²

Conclusion

Of the four reviewed outcome measures — 6MWD, CAMPHOR, WHO FC, clinical worsening — used in the GRIPHON trial, only the 6MWD and CAMPHOR have been validated in PAH. In patients with PAH, an MCID of 33.0 m (range: 25.1 m to 38.6 m) has been reported for the 6MWD, and 0.09 for the CAMPHOR utility index. Clinical worsening is recommended as a key outcome for use in PAH studies.