Surrogate endpoints in pulmonary arterial hypertension trials

Why don't you just look at the pulmonary artery pressure? This question is frequently asked when we discuss endpoints in pulmonary arterial hypertension (PAH) trials with colleagues from other disease areas. Trials of antihypertensive drugs simply look at blood pressure changes, whereas pivotal trials in PAH use change in 6-min walk distance or time to clinical worsening as primary outcome measures. Why the difference? It is not just the invasiveness of right heart catheterisation but much more a question of validated surrogate endpoints. The US Food and Drug Administration (FDA) and other regulatory agencies approve drugs when they improve how patients feel, function, or survive. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In systemic hypertension, lowering blood pressure predicts reductions in major adverse cardiovascular events including stroke, myocardial infarction, and cardiovascular death, and so authorities accept blood pressure reduction as a surrogate endpoint—ie, a substitute for a clinically meaningful endpoint that is expected to predict the effect of a therapy. 1 Temple R Are surrogate markers adequate to assess cardiovascular disease drugs?. JAMA. 1999; 282: 790-795 Crossref PubMed Scopus (298) Google Scholar In PAH, there is no convincing evidence that reductions in pulmonary artery pressure or pulmonary vascular resistance are directly linked to improved exercise capacity or better survival. Hence, change in 6-min walk distance is being frequently used as a primary endpoint assessing the function part of the FDA paradigm. Time to clinical worsening has been applied as well, a composite endpoint based on death, PAH-related worsening, and prespecified reductions in exercise capacity. However, these endpoints have limitations. Improvement in 6-min walk distance reflects better exercise capacity but is no surrogate of better outcomes. 2 Gabler NB French B Strom BL et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012; 126: 349-356 Crossref PubMed Scopus (185) Google Scholar Time to clinical worsening does not capture clinical improvement, and reducing clinical worsening events does not necessarily lead to better survival. 3 Sitbon O Channick R Chin KM et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015; 373: 2522-2533 Crossref PubMed Scopus (607) Google Scholar , 4 Galiè N Barberà JA Frost AE et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015; 373: 834-844 Crossref PubMed Scopus (750) Google Scholar , 5 Pulido T Adzerikho I Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369: 809-818 Crossref PubMed Scopus (981) Google Scholar In addition, studies designed to show improvement in time to clinical worsening require large sample sizes, a challenge in a rare disease like PAH. Hence, there is an ongoing search for surrogate endpoints. Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trialsMulticomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Full-Text PDF