Pharmacometrics, Bayer AG - Pharmaceuticals, Wuppertal, Germany.
Quantitative Pharmacology, Bayer AG - Pharmaceuticals, Wuppertal, Germany.
Clin Pharmacol Ther. 2021 Aug;110(2):498-507. doi: 10.1002/cpt.2222. Epub 2021 Mar 27.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT-proBNP/mortality relationship in real-world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT-proBNP / clinical event end-point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT-proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT-proBNP and clinical outcome is well described by an E model. The NT-proBNP independent baseline risk (R , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7-4.9%)) is very low compared with the potential NT-proBNP-associated maximum risk (R : 55.2%/79.4% (61.5-89.0%)). The NT-proBNP concentration associated with the half-maximal risk is comparable in RWD and across clinical studies (EC : 3,880/2,414 pg/mL (1,460-4,355 pg/mL)). Model-based predictions of phase III outcomes, relying on short-term NT-proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT-proBNP as a surrogate for clinical outcome in HF trials. NT-proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT-proBNP measurement can therefore enable shorter and smaller but still reliable HF trials.
N 端脑利钠肽前体（NT-proBNP）是心力衰竭（HF）中一种成熟的生物标志物，但在 HF 试验中作为潜在替代终点标志物存在争议。我们分析了 IBM Watson Health Explorys 数据库中 108330 例 HF 患者的真实世界数据（RWD）中的 NT-proBNP/死亡率关系，并将其与 20 项临床 HF 研究中的 NT-proBNP/临床事件终点关系进行了比较。使用分层统计模型，我们量化了功能关系和研究间变异性。为了独立验证模型，我们仅根据各自研究早期测量的 NT-proBNP，预测了五项 III 期 HF 研究的结局风险比。在 RWD 和临床研究中，NT-proBNP 与临床结局的关系很好地用 E 模型描述。与潜在的 NT-proBNP 相关的最大风险（R：55.2%/79.4%（61.5-89.0%））相比，NT-proBNP 独立的基线风险（R，RWD/研究中位数（研究间四分位距）：5.5%/3.0%（1.7-4.9%））非常低。RWD 和临床研究中，与风险减半相关的 NT-proBNP 浓度相似（EC：3880/2414pg/ml（1460-4355pg/ml））。仅基于短期 NT-proBNP 数据的 III 期结局模型预测结果与最终试验结果一致，置信区间相似。我们的分析将 NT-proBNP 作为 HF 试验中临床结局的替代标志物。治疗持续时间不到 10 周的短期 NT-proBNP 治疗后，定量预测风险比的置信水平与最终试验结果相当。因此，早期 NT-proBNP 测量可以使 HF 试验更短、更小但仍然可靠。
