Utilisation of the simple and inexpensive 6-minute walk test provides valuable information about a patient's functional status and reflects activities of daily living1. As such, the change from baseline in 6-minute walk distance (6MWD) has been used as a primary endpoint in pulmonary arterial hypertension (PAH), allowing differences (e.g. improvements) in exercise capacity to be detected between the placebo and study drug arms of clinical studies. Until recently, change in 6MWD has served as the primary endpoint in all placebo-controlled pivotal trials of currently available PAH treatments, playing an important role in their regulatory approval2.
A clinical endpoint should directly measure how a patient feels, functions or survives3 and primary endpoints in PAH trials must be clinically relevant, sensitive to treatment effect, measurable and interpretable4. Although change in 6MWD has been accepted by regulatory authorities as a primary endpoint that reflects function4, it is not established as a surrogate endpoint for outcome in PAH; in fact, the validity of the improvement in 6MWD as a potential surrogate for long-term outcomes (morbidity and mortality) in PAH patients has never been thoroughly tested5. The scientific community is now asking the question ‘Is the change in 6MWD predictive of long-term outcomes in PAH?' This question is highly relevant today, given the growing recognition of the need to employ clinically meaningful primary endpoints that directly reflect disease progression3.
A number of recently published articles and editorials have examined the relationship between 6MWD and outcomes in PAH (see slide 1). Although evidence suggests that both baseline and absolute 6MWD during therapy are correlated with outcome in PAH5-9, it has become clear that a change in 6MWD with treatment is neither a reliable nor an accurate surrogate for outcome in PAH5,7,10-12 (see slide 2).
The results of a meta-analysis of 22 short-term randomised trials in PAH, involving 3112 patients, showed that there was no relationship between change in 6MWD and death, hospitalisation for PAH, initiation of PAH rescue therapy or a composite time to clinical worsening (TTCW) outcome combining these individual components11 (see slide 3). Similarly, a pooled analysis of 10 randomised controlled trials (RCTs) of PAH-specific therapies revealed that a change in 6MWD did not explain a large proportion of the treatment effect on clinical worsening10. In fact, the change in 6MWD explained only 22% of the treatment effect10 and is, therefore, not sensitive to the entire effect of treatment intervention. As such, the authors concluded that a change in 6MWD has only modest validity as a surrogate endpoint10. In support of these findings, analysis of the data from the ARIES extension study revealed that the change in 6MWD from baseline to week 12 was not predictive of 2-year survival7.
Experts at the 5th World Symposium on PH in Nice recently proposed a 4-level hierarchy for endpoints in RCTs, according to the strength in which they reflect true clinical benefit to patients13. Since 6MWD is not considered a validated surrogate in PAH, it may be included at either level 3 (non-validated surrogate) or 4 (correlate; slide 4)13. All-cause death and morbidity and mortality endpoints for PAH, however, were included in level 1, as they are considered to be true clinical efficacy measures13. As such, drugs evaluated using a morbidity and mortality primary endpoint have been highlighted in the updated treatment algorithm13. Experts at the 4th World Symposium on PH in Dana Point recommended the use of a composite clinical outcome endpoint (morbidity and mortality) as the primary endpoint for pivotal phase III PAH trials4 (see slide 5). Experts in Nice suggested that this endpoint may be enhanced with the addition of ‘worsening of PAH symptoms’14. Change in 6MWD should be used as a secondary endpoint to provide information on the effect of the tested drug on exercise capacity2,4.
The SERAPHIN study employed a composite morbidity and mortality primary endpoint15, demonstrating that it is feasible to conduct such a study and directly assess the effect of a therapy on long-term clinical outcomes.
In the phase III SERAPHIN trial, the primary endpoint was met; macitentan significantly reduced the risk of morbidity-mortality events, as measured by the composite endpoint, up to end of treatment versus placebo by 45% in the 10 mg group (97.5% CI: 24-61%; p < 0.001)15.
The effect of macitentan on 6MWD and the association between the change in 6MWD and the composite endpoint of PAH-related death or hospitalisation were explored in the SERAPHIN trial. Change in 6MWD from baseline to month 6 is not significantly associated with the risk of PAH-related death or hospitalisation (see slide 6). As such, results from the first RCT assessing long-term outcomes in PAH suggest that there is no association between changes in 6MWD and long-term clinical outcome16.