Levels of Alkaline Phosphatase and Bilirubin Are Surrogate End Points of Outcomes of Patients With Primary Biliary Cirrhosis: An International Follow-up Study
Levels of Alkaline Phosphatase and Bilirubin Are Surrogate End Points of Outcomes of Patients With Primary Biliary Cirrhosis: An International Follow-up Study
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DOI：
10.1053/j.gastro.2014.08.029
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发表时间：
2014-12-01
期刊：
影响因子：
29.4
通讯作者：
Hansen, Bettina E.
中科院分区：
文献类型：
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作者：
Lammers, Willem J.;van Buuren, Henk R.;Hansen, Bettina E.
背景与目的：需要原发性胆汁性肝硬化（PBC）患者长期结局的无创替代终点来监测疾病进展并评估潜在的治疗方法。我们对队列研究中的个体患者数据进行了荟萃分析，以评估患者的碱性磷酸酶和胆红素水平是否与其结果相关并可用作替代终点。方法：我们对 15 项北美和欧洲长期随访队列研究中的 4845 名患者的数据进行了荟萃分析。在相对于临床终点（肝移植或死亡）的不同时间点，分析不同环境和亚人群的碱性磷酸酶和胆红素水平。结果：4845 名患者中，1118 名达到临床终点。中位随访时间为 7.3 年； 77% 的人在入学后存活了 10 年。研究入组时（基线）和每年测量的碱性磷酸酶和胆红素水平（持续 5 年）与临床结果密切相关（较低水平与较长的无移植生存期相关）。研究入组后 1 年，碱性磷酸酶水平为正常上限 (ULN) 2.0 倍最能预测患者结果（C 统计量，0.71），但并不明显优于其他阈值。患者的碱性磷酸酶水平为 ULN 的 2.0 倍 (P < .0001)。研究入组后一年的碱性磷酸酶绝对水平比水平百分比变化更好地预测患者结果。研究入组一年后，胆红素水平为 ULN 的 1.0 倍最能预测患者的无移植生存期（C 统计量，0.79）。患者的胆红素水平为 ULN 的 1.0 倍 (P < .0001)。结合碱性磷酸酶和胆红素的水平可以提高预测患者生存时间的能力。我们证实了多个亚组（例如未接受熊去氧胆酸治疗的患者）以及研究入组后不同时间点的碱性磷酸酶和胆红素水平的预测价值。结论：碱性磷酸酶和胆红素水平可以预测 PBC 患者的结局（肝移植或死亡），并可用作治疗试验的替代终点。
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 sub-populations 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 (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 (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.