The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

Abstract Background PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a ‘ceiling effect’ masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW > 450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW > 450 m, groups often excluded from previous trials. Methods We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW ≤ 450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. Pt. Group SITAX BL 6MW mean ± SE ( n ) PBO BL 6MW mean ± SE ( n ) Treatment effect P value = Traditional Pts. 311 ± 14 (47) 348 ± 17 (23) 65 ± 17 0.0002 All Pts. 390 ± 10 (118) 413 ± 14 (60) 34 ± 10 0.0005 Conclusion Existence of a ‘ceiling effect’ is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.