Six-minute walk distance

The 6MWD test measures the distance a patient can walk in six minutes. Change in 6MWD is the most widely used test to assess exercise capacity in pulmonary arterial hypertension (PAH) and is used in most PAH trials as a primary outcome.^35–39 6MWD is also used in clinical practice and is widely accepted by regulatory agencies. The main advantage of 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 (CPET).³⁸ 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.⁷ However, change in 6MWD is a surrogate outcome and has demonstrated moderate to poor correlation with key clinical outcomes in PAH.^7–9 Performance on 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.^40–42 Furthermore, in multi-centre trials, experience and technical skills may vary between sites, and the correlations between 6MWD and CPET might improve over time with increasing experience.⁴³ There is also evidence of a ceiling effect on 6MWD, whereby the effect of the treatment on the test is diminished due to the inclusion of patients with milder disease (New York Heart Association [NYHA]/WHO functional class 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.⁴⁴ 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 m to 38.6 m) compared with placebo for patients with PAH.²⁹

Modified Borg Dyspnea Scale and Borg CR10

The Borg CR10 and the Modified Borg Dyspnea scales are patient self-reported measures of one’s difficulty in breathing upon exertion. The instruments provide a standard method for patients to select ratings of dyspnea on a scale based on descriptors that correspond to specific numbers (which are not linearly spaced). The CR10 is a categorical scale with a score from 0 to 10, where 0 represents normal breathing and 10 represents maximum dyspnea.⁴⁵ However, patients may report a score greater than 10 to describe their own sensation of dyspnea with greater precision than a 10-point score would allow, thus making this an open scale. The modified Borg dyspnea score is a version of the CR10;⁴⁵ it uses a scale from 0 to 10, where 0 represents no dyspnea and 10 represents maximal dyspnea. Scores are obtained at the end of the 6MWD test and reflect the maximum degree of dyspnea at any time during the walk test. Although it is a subjective assessment scale for assessing the intensity of breathlessness, the modified Borg dyspnea scale has been shown to be reliable for quantifying dyspnea in trial patients with chronic obstructive pulmonary disease (COPD) who have undergone a six-minute treadmill walk test.^46–48 No published studies have clearly addressed the MCID of the Borg dyspnea scores in PAH. Distribution-based analyses of data from trials in patients with COPD and heart failure suggest the MCID is 1 point.^30,31 A recent study (abstract) indicated that the MCID in patients with PAH may be < 1, with distribution-based estimates ranging from 0.70 to 1.24 points and an anchor-based estimate of 0.36 points.³² The authors suggested their MCID estimates are smaller than for COPD or heart failure because of differences in the perception of dyspnea between diseases.

World Health Organization functional classification for pulmonary hypertension

The WHO functional class system for pulmonary hypertension (PH) was adapted from the 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 functional class varied widely in PAH, especially when classifying patients as functional class II or III.²⁸ The intra-class correlation coefficient was low (approximately 0.6). In one instance, 53% of clinicians classified a patient as functional class II and 47% classified the patient as functional class III. Thus, despite wide use of the WHO classification system, inter-rater agreement may be poor.

Clinical worsening

The composite outcome of clinical worsening — combining the events of death, heart or lung transplantation, atrial septostomy, initiation of new 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 functional class 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.⁴⁹ Therefore, it is likely a clinically relevant outcome. However, there are limitations using composite outcomes in PH studies:⁴⁹

• 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.
• The inclusion of outcomes such as hospitalization in a composite outcomes 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 multi-centre 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 PAH trials.

In a recent assessment of survival in an observational study, Frost et al. suggested that clinical worsening was highly predictive of subsequent mortality and was meaningful as a primary end point in clinical trials of PAH.⁵⁰

EuroQol 5-Dimensions questionnaire

EQ-5D^51,52 is a generic quality of life instrument that may be applied to a wide range of health conditions and treatments. The first of two parts of the EQ-5D is a descriptive system that classifies respondents (aged ≥ 12 years) into one of 243 distinct health states. The descriptive system consists of the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three possible levels (1, 2, or 3) representing “no problems”, “some problems”, and “extreme problems”, respectively. Respondents are asked to choose the level that reflects their health state for each of the five dimensions. A scoring function can be used to assign a value (EQ-5D index score) to self-reported health states from a set of population-based preference weights.^51,52 The second part is a 20 cm visual analogue scale (EQ-VAS) that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state”. Respondents are asked to rate their health by drawing a line from an anchor box to the point on the EQ-VAS that best represents their health on that day.

Hence, the EQ-5D produces three types of data for each respondent:

• A profile indicating the extent of problems on each of the five dimensions represented by a five-digit descriptor, such as 11121, 33211, etc.
• A population preference-weighted health index score based on the descriptive system.
• A self-reported assessment of health status based on the EQ-VAS.

The EQ-5D index score is generated by applying a multi-attribute utility function to the descriptive system. Different utility functions are available that reflect the preferences of specific populations (e.g., US or UK). The lowest possible overall score (corresponding to severe problems on all five attributes) varies depending on the utility function that is applied to the descriptive system (e.g., −0.59 for the UK algorithm and −0.109 for the US algorithm). Scores less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1.00 are assigned to the health states “dead” and “perfect health”, respectively. The EQ-5D demonstrated convergent validity with the Medical Research Council (MRC) Dyspnoea Scale in both primary and specialist care settings within the UK and US and across five EU countries.⁵³ The MCID for the EQ-5D in general use ranges from 0.033 to 0.074.³³

Living with Pulmonary Hypertension questionnaire

The LPH questionnaire was derived from the Minnesota Living with Heart Failure Questionnaire for use in PH populations. The instrument comprises 21 items, responded to on a 6-point Likert scale ranging from 0 (“No”) to 5 (“Very much”). The responses to all 21 questions are summed for a total score ranging from 0 to 105. A physical dimension score (range 0 to 40, eight items) and an emotional dimension score (range 0 to 25, five items) can also be calculated. A higher score on all LPH scores indicates that patients are more affected by their PH.⁵⁴ In terms of clinical validity, the LPH physical and total scores were able to differentiate between patients of different severity levels, based on WHO functional class or 6MWD. The LPH emotional score did not demonstrate the same differentiation. There was high correlation between the Borg scores and the LPH physical score. A change of 3 points for the sub-scales (range: 1.48 to 4.71) and 7 points (range: 4.41 to 11.02) for the total score were indicated as the MCID values for PAH.

Conclusion

Of the six reviewed outcome measures — 6MWD, modified Borg Dyspnea Scale/CR10, WHO functional class, clinical worsening, EQ-5D, and LPH — used in the PATENT-1 trial, only 6MWD and LPH have been validated in PAH. An MCID of 33.0 m (range: 25.1 m to 38.6 m) has been reported for 6MWD in patients with PAH. The MCID for the change in LPH total score has been reported to be 7 points. Clinical worsening is recommended as a key outcome for use in PAH studies.