Willem J Lammers1, Henk R van Buuren1, Gideon M Hirschfield2, Harry L A Janssen3, Pietro Invernizzi4, Andrew L Mason5, Cyriel Y Ponsioen6, Annarosa Floreani7, Christophe Corpechot8, Marlyn J Mayo9, Pier M Battezzati10, Albert Parés11, Frederik Nevens12, Andrew K Burroughs13, Kris V Kowdley14, Palak J Trivedi2, Teru Kumagi15, Angela Cheung3, Ana Lleo4, Mohamad H Imam16, Kirsten Boonstra6, Nora Cazzagon7, Irene Franceschet7, Raoul Poupon8, Llorenç Caballeria11, Giulia Pieri13, Pushpjeet S Kanwar14, Keith D Lindor17, Bettina E Hansen18. 1. Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands. 2. NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, England. 3. Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada. 4. Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy. 5. Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada. 6. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. 7. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. 8. Centre de Référence des Maladies Inflammatoires des VoiesBiliaires, Hôpital Saint-Antoine, APHP, Paris, France. 9. Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas. 10. Department of Health Sciences, Università degli Studi di Milano, Milan, Italy. 11. Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain. 12. Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 13. The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, England. 14. Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington. 15. Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan. 16. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 17. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; College of Health Solutions, Arizona State University, Phoenix, Arizona. 18. Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands. Electronic address: b.hansen@erasmusmc.nl.
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.
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.
Authors: Jessica K Dyson; Gideon M Hirschfield; David H Adams; Ulrich Beuers; Derek A Mann; Keith D Lindor; David E J Jones Journal: Nat Rev Gastroenterol Hepatol Date: 2015-02-03 Impact factor: 46.802