Chin Melanie P, Wrolstad Danielle, Bakris George L, Chertow Glenn M, de Zeeuw Dick, Goldsberry Angie, Linde Peter G, McCullough Peter A, McMurray John J, Wittes Janet, Meyer Colin J
Reata Pharmaceuticals, Irving, Texas.
Statistics Collaborative, Washington, DC.
J Card Fail. 2014 Dec;20(12):953-8. doi: 10.1016/j.cardfail.2014.10.001. Epub 2014 Oct 13.
A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2-related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention.
We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to <30 mL min(-1) 1.73 m(-2)) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events.
Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.
一项3期随机临床试验旨在测试巴多昔芬甲基（一种核因子红细胞2相关因子2（Nrf2）激活剂）是否能减缓4期慢性肾病和2型糖尿病患者进展至终末期肾病。该试验因巴多昔芬甲基组心力衰竭增加而终止；许多事件在临床上与液体潴留有关。
我们将2185例2型糖尿病（T2DM）和4期慢性肾病（CKD）（估计肾小球滤过率为15至<30 mL·min⁻¹·1.73 m⁻²）患者随机分为每日一次的巴多昔芬甲基（20 mg）组或安慰剂组。我们使用分类和回归树分析来确定预测心力衰竭或液体超负荷事件的基线因素。基线B型利钠肽升高和既往因心力衰竭住院被确定为心力衰竭事件的预测因素；在有这些危险因素的患者中，巴多昔芬甲基使心力衰竭风险增加60%。对于没有这些基线特征的患者，巴多昔芬甲基治疗组和安慰剂治疗组的心力衰竭事件风险相似（2%）。相同的危险因素也被确定为液体超负荷的预测因素，并且似乎与其他严重不良事件有关。
在基线时心力衰竭风险增加的易感患者亚组中，巴多昔芬甲基导致了与心力衰竭和/或液体超负荷相关的事件。在未来任何巴多昔芬甲基试验中，都需要仔细选择参与者并密切监测研究药物，以降低心力衰竭和其他严重不良事件的风险。
