PDF(Pubmed)
Abstract：
Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate.
This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world.
This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS).
The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens.
We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%.
By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.
This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world.
This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS).
The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens.
We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%.
By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.
摘要：
■肝损伤是内皮素受体拮抗剂（ERA）的标志性不良反应。自从第一种药物以来，波生坦已广泛应用于临床,肝毒性一直伴随着ERA的历史。新的ERA已被证明具有较低的肝脏风险，但目前的研究结果是不一致的。基于ERA的靶向药物组合通常用于治疗肺动脉高压，肝损伤的风险难以估计。
■本研究旨在比较现实世界中ERA和不同ERA组合方案与肝损伤的相关性。
■这是一项回顾性研究，使用不良事件报告系统（食品和药物管理局AERS，FAERS）。
■该研究使用比例失衡和贝叶斯分析来挖掘2004年1月至2022年12月的FAERS数据，以确定三个ERA与肝损伤的关联，并进一步挖掘由于ERA与其他靶向药物的组合而导致的肝损伤风险。此外,我们分析了发病时间，死亡率,不同ERA联合方案引起肝损伤的住院率。
■我们筛选出3581例ERA相关肝损伤事件，其中波生坦(59.82%)病例最多。肝损伤患者以女性为主(60.63%),年龄集中在61至75岁之间（26.75％）。根据不同的信号挖掘方法,报告优势比(ROR；3.38，95%置信区间=3.23-3.53)，比例报告比(PRR；3.22，χ2=37.84)，贝叶斯置信传播神经网络(BCPNN;1.68,95%置信区间=1.61),多项目伽玛泊松收缩器(MGPS；3.21，95%置信区间=3.09)，与ambrisentan和Macitentan相比，波生坦与肝损伤的相关性最强。此外，波生坦+西地那非[ROR（2.52，95%置信区间=2.23-2.84），PRR（2.44，χ2=15.92），BCPNN(1.29，95%置信区间=1.14)，MGPS(2.44，95%置信区间=2.21)]，波生坦+依前列醇[ROR（5.39，95%置信区间=4.29-6.77），PRR（4.94，χ2=65.18），BCPNN(2.30，95%置信区间=1.83)，MGPS(4.94，95%置信区间=4.08)]，波生坦+伊洛前列素[ROR（2.70，95%置信区间=2.11-3.45），PRR（2.61，χ2=31.03），BCPNN(1.38，95%置信区间=1.08)，MGPS（2.61，95％置信区间=2.12）]具有由三个ERA组合方案引起的肝损伤的较高风险。与所有ERA组合方案相关的肝毒性发作的中位时间为259天(四分位距:58-716.5天)。最后,ERA联合治疗方案出现肝毒性的患者的住院率为47.86%,死亡率为12.67%.
■通过挖掘FAERS，我们分析并比较了不同ERA和ERA联合治疗方案相关的肝损伤风险，以及所有ERA联合方案的起效时间和不良反应结局。根据研究结果,波生坦的肝损伤风险最高，波生坦+西地那非联合治疗方案，波生坦+依前列醇,波生坦+伊洛前列素有更高的肝损伤风险。从治疗的早期阶段开始，我们需要定期监测患者的肝功能，尤其是女性和老年人，并在肝损伤发生后立即停止可疑药物。
■本研究旨在比较现实世界中ERA和不同ERA组合方案与肝损伤的相关性。
■这是一项回顾性研究，使用不良事件报告系统（食品和药物管理局AERS，FAERS）。
■该研究使用比例失衡和贝叶斯分析来挖掘2004年1月至2022年12月的FAERS数据，以确定三个ERA与肝损伤的关联，并进一步挖掘由于ERA与其他靶向药物的组合而导致的肝损伤风险。此外,我们分析了发病时间，死亡率,不同ERA联合方案引起肝损伤的住院率。
■我们筛选出3581例ERA相关肝损伤事件，其中波生坦(59.82%)病例最多。肝损伤患者以女性为主(60.63%),年龄集中在61至75岁之间（26.75％）。根据不同的信号挖掘方法,报告优势比(ROR；3.38，95%置信区间=3.23-3.53)，比例报告比(PRR；3.22，χ2=37.84)，贝叶斯置信传播神经网络(BCPNN;1.68,95%置信区间=1.61),多项目伽玛泊松收缩器(MGPS；3.21，95%置信区间=3.09)，与ambrisentan和Macitentan相比，波生坦与肝损伤的相关性最强。此外，波生坦+西地那非[ROR（2.52，95%置信区间=2.23-2.84），PRR（2.44，χ2=15.92），BCPNN(1.29，95%置信区间=1.14)，MGPS(2.44，95%置信区间=2.21)]，波生坦+依前列醇[ROR（5.39，95%置信区间=4.29-6.77），PRR（4.94，χ2=65.18），BCPNN(2.30，95%置信区间=1.83)，MGPS(4.94，95%置信区间=4.08)]，波生坦+伊洛前列素[ROR（2.70，95%置信区间=2.11-3.45），PRR（2.61，χ2=31.03），BCPNN(1.38，95%置信区间=1.08)，MGPS（2.61，95％置信区间=2.12）]具有由三个ERA组合方案引起的肝损伤的较高风险。与所有ERA组合方案相关的肝毒性发作的中位时间为259天(四分位距:58-716.5天)。最后,ERA联合治疗方案出现肝毒性的患者的住院率为47.86%,死亡率为12.67%.
■通过挖掘FAERS，我们分析并比较了不同ERA和ERA联合治疗方案相关的肝损伤风险，以及所有ERA联合方案的起效时间和不良反应结局。根据研究结果,波生坦的肝损伤风险最高，波生坦+西地那非联合治疗方案，波生坦+依前列醇,波生坦+伊洛前列素有更高的肝损伤风险。从治疗的早期阶段开始，我们需要定期监测患者的肝功能，尤其是女性和老年人，并在肝损伤发生后立即停止可疑药物。
