@article{0828670e19bb4b358e934070c8a143e1,
title = "Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: An international follow-up study",
abstract = "BACKGROUND & AIMS: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points.METHODS: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death).RESULTS: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P <.0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P <.0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment.CONCLUSIONS: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.",
keywords = "Autoimmune Liver Disease, Biomarker, New Therapies, Response To Treatment",
author = "{Global PBC Study Group} and Lammers, {Willem J.} and {Van Buuren}, {Henk R.} and Hirschfield, {Gideon M.} and Janssen, {Harry L A} and Pietro Invernizzi and Mason, {Andrew L.} and Ponsioen, {Cyriel Y.} and Annarosa Floreani and Christophe Corpechot and Mayo, {Marlyn J.} and Battezzati, {Pier M.} and Albert Par{\'e}s and Frederik Nevens and Burroughs, {Andrew K.} and Kowdley, {Kris V.} and Trivedi, {Palak J.} and Teru Kumagi and Angela Cheung and Ana Lleo and Imam, {Mohamad H.} and Kirsten Boonstra and Nora Cazzagon and Irene Franceschet and Raoul Poupon and Lloren{\c c} Caballeria and Giulia Pieri and Kanwar, {Pushpjeet S.} and Lindor, {Keith D.} and Hansen, {Bettina E.}",
note = "Funding Information: Funding This investigator-initiated study was supported by unrestricted grants from Intercept Pharmaceuticals and Zambon Nederland BV and was funded by the Foundation for Liver and Gastrointestinal Research (a not-for-profit foundation) in Rotterdam, The Netherlands. The supporting parties had no influence on the study design, data collection and analyses, writing of the manuscript, or the decision to submit the manuscript for publication. Funding Information: Conflicts of interest The authors disclose the following: H.R.V. has received unrestricted grants from Intercept Pharmaceuticals and Zambon Nederland BV. G.M.H. is a study investigator for Intercept Pharmaceuticals, Dr Falk Pharma, Gilead Sciences, Lumena Pharmaceuticals, FFP Pharma, and Janssen and is an unpaid consultant for Intercept, Lumena Pharmaceuticals, and FFP Pharma. H.L.A.J. has received grants from and is a consultant for Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics, Abbott, Santaris, Medtronic, and Tibotec. P.I. is a consultant for Menarini Diagnostics, Instrumentation Laboratories, and Medigene. A.L.M. has received funding from the Canadian Institutes for Health Research, Canadian Liver Foundation, Alberta Heritage Foundation for Medical Research, and Alberta Cancer Foundation, and Abbvie and Gilead Sciences have provided medications for ongoing clinical trials. C.Y.P. has received unrestricted grants from Abbvie, Dr Falk Pharma, and Takeda; consultancy fees from Abbvie, GlaxoSmithKline, and Takeda; and speaker{\textquoteright}s fees from Abbvie, MSD, Takeda, and Ferring Pharmaceuticals. M.J.M. has received grant support in the form of conducting sponsor-initiated clinical trials from Intercept Pharmaceuticals, Gilead Sciences, Salix, Lumena Pharmaceuticals, and NGM. A.P. is a consultant for Lumena Pharmaceuticals, Inc. K.V.K. has received grants and research support from AbbVie, Beckman, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Ikaria, Intercept Pharmaceuticals, Janssen, Merck, Mochida, and Vertex; received consultancy fees from Novartis and Tekmira Pharmaceuticals (honorarium payable to institution); and served as an advisory board member for AbbVie, Boehringer Ingelheim, Gilead Sciences, Ikaria, Janssen, Merck, and Trio Health (honorarium payable to institution). P.J.T. is the recipient of a Wellcome Trust Clinical Research Fellowship. T.K. has received fellowship support from an unrestricted grant from Axcan Pharma. K.D.L. is a member of the American Association for the Study of Liver Diseases Governing Board and primary author of guidelines on primary sclerosis cholangitis (to be completed this year) and is an unpaid advisor for Intercept Pharmaceuticals and Lumena Pharmaceuticals. The remaining authors disclose no conflicts. Publisher Copyright: {\textcopyright} 2014 AGA Institute.",
year = "2014",
month = dec,
day = "1",
doi = "10.1053/j.gastro.2014.08.029",
language = "English (US)",
volume = "147",
pages = "1338--1349.e5",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",
}