{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:50:20Z","timestamp":1790337020594,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,7,17]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (\u03946MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in \u03946MWD against the probability of a clinical event in pulmonary arterial hypertension trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      First, to determine whether \u03946MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the \u03946MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug\/dose-level combinations. \u03946MWD accounted for 22.1% (95% confidence interval, 12.1%\u2013 31.1%) of the treatment effect (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001). The meta-analysis showed an average difference in \u03946MWD of 22.4 m (95% confidence interval, 17.4\u201327.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33\u20130.57). The meta-regression revealed a significant threshold effect of 41.8 m.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Our results suggest that \u03946MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.112.105890","type":"journal-article","created":{"date-parts":[[2012,6,13]],"date-time":"2012-06-13T23:30:01Z","timestamp":1339630201000},"page":"349-356","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":226,"title":["Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials"],"prefix":"10.1161","volume":"126","author":[{"given":"Nicole B.","family":"Gabler","sequence":"first","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"French","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Strom","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold I.","family":"Palevsky","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren B.","family":"Taichman","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Kawut","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Halpern","sequence":"additional","affiliation":[{"name":"From the Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology (N.B.G., B.F., B.L.S., S.M.K., S.D.H.); Leonard Davis Institute of Health Economics (B.F., B.L.S., S.D.H.); Pulmonary, Allergy, and Critical Care Division (H.I.P., D.B.T., S.M.K., S.D.H.); and Pulmonary Vascular Disease Program of the Penn Cardiovascular Institute (H.I.P., D.B.T., S.M.K., S.D.H.), Perelman 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