Medical and Clinical Pharmacology Unit, University Hospital Centre Toulouse, Toulouse, France.
Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, Toulouse University Hospital, Faculty of Medicine, Toulouse, France.
Br J Clin Pharmacol. 2023 Apr;89(4):1338-1348. doi: 10.1111/bcp.15576. Epub 2022 Nov 13.
Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF.
Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias.
Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis.
The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.
近年来，已经检测到与蛋白激酶抑制剂（PKI）暴露相关的心力衰竭（HF）的药物警戒信号。我们的目的是确定与 HF 发展最相关的 PKI。
使用法国国家医疗保健数据库，对 2011 年 1 月至 2014 年 6 月期间新暴露于 PKI 的所有患者进行了 18 个月的随访。使用特定的住院诊断和长期 HF 相关疾病代码来识别 HF 患者。测量 HF 发生率比（IRR），并使用 Cox 模型估计调整后的危险比（aHR）。进行敏感性分析以限制潜在的适应症和竞争风险偏倚。
研究了 13 种 PKI。在研究期间登记的 49714 名新 PKI 使用者中，HF 的平均 IRR 为每 100 人年 3.38，中位发病时间为 155 天。我们发现六种药物的 HF 发病率显著增加：帕唑帕尼（aHR=2.42，95%置信区间[CI]1.67-3.52）、达沙替尼（aHR=2.22，95%CI1.42-3.44）、鲁索利替尼（aHR=2.11，95%CI1.69-2.64）、克唑替尼（aHR=1.71，95%CI1.07-2.72）、依维莫司（aHR=1.45，95%CI1.26-1.67）和维莫非尼（aHR=1.37，95%CI1.01-1.86）。敏感性分析与我们的主要分析一致。
本研究提供了与 PKI 暴露后 HF 相关的知识。进一步的研究可以证实达沙替尼、依维莫司、帕唑帕尼和鲁索利替尼的结果，特别是在我们的敏感性分析中，对于结果略高于显著性阈值的两种药物，即克唑替尼和维莫非尼，也可以证实这些结果。
