Introduction:The combination of BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved survival in melanoma patients with BRAF V600 mutations. However, these agents can cause cardiovascular (CV) toxicity, compromising efficacy. This study evaluated the CV adverse events (cAEs) associated with BRAF/MEKi using the U.S. FDA Adverse Event Reporting System (FAERS) to identify new signals of disproportionate reporting (SDRs).Methods:Descriptive and disproportionality analyses were conducted on reports listing dabrafenib (D), vemurafenib (V), encorafenib (E), trametinib (T), cobimetinib (C), or binimetinib (B) as suspects in monotherapy or combination therapy (D + T, V + C, E + B), with melanoma as the indication and at least one cAE. Standardized MedDRA Queries (SMQs) related to cAEs, including bradyarrhythmias and tachyarrhythmias, cardiac failure, cardiomyopathy, thrombotic events, ischaemic heart disease, and myocarditis/pericarditis, were analyzed.Results:Of the 14,077,067 reports retrieved, 18,370 (0.1%) were linked to BRAF/MEKi, with 1591 (8.7%) reporting cAEs, primarily in combination therapy (n= 1268). Disproportionality analysis identified 64 clinically relevant SDRs, most of which were unexpected. Notable findings included bradyarrhythmias, such as QT prolongation with D + T (n= 59; Reporting Odds Ratio, ROR = 5.09, 95% Confidence Interval, CI = 3.94–6.58), cardiac failure with V + C (29; 3.76, 2.6–5.42), and tachyarrhythmias, particularly atrial fibrillation with D + T (99; 2.37, 1.94–2.89). Among embolic and thrombotic events, clinically significant SDRs were observed for disseminated intravascular coagulation with D + T (38; 10.22, 7.42–14.06) and pulmonary embolism with V + C (22; 2.79, 1.83–4.24).Conclusions:Our findings underscore the need for comprehensive CV monitoring in patients receiving BRAF/MEKi therapy to prevent or detect cAEs early and reduce treatment-related risks, particularly in high-risk populations.
引言：BRAF与MEK抑制剂（BRAF/MEKi）联合疗法显著改善了携带BRAF V600突变的黑色素瘤患者的生存率。然而，这些药物可能引发心血管（CV）毒性，从而影响疗效。本研究利用美国FDA不良事件报告系统（FAERS），评估了与BRAF/MEKi相关的心血管不良事件（cAEs），旨在识别新的报告失衡信号（SDRs）。 方法：对以达拉非尼（D）、维莫非尼（V）、恩考芬尼（E）、曲美替尼（T）、考比替尼（C）或比尼替尼（B）为可疑药物的单药或联合治疗（D+T、V+C、E+B）报告进行描述性分析和失衡性分析，适应症为黑色素瘤且至少包含一项cAE。分析了与cAEs相关的标准化MedDRA查询（SMQs），包括缓慢性心律失常与快速性心律失常、心力衰竭、心肌病、血栓事件、缺血性心脏病以及心肌炎/心包炎。 结果：在检索到的14,077,067份报告中，18,370份（0.1%）与BRAF/MEKi相关，其中1591份（8.7%）报告了cAEs，主要发生在联合治疗中（n=1268）。失衡性分析识别出64个具有临床相关性的SDRs，其中大多数是未预期的。值得注意的发现包括缓慢性心律失常，如D+T联合治疗引起的QT间期延长（n=59；报告比值比ROR=5.09，95%置信区间CI=3.94–6.58）；V+C联合治疗引起的心力衰竭（29；3.76，2.6–5.42）；以及快速性心律失常，特别是D+T联合治疗引起的心房颤动（99；2.37，1.94–2.89）。在栓塞和血栓事件中，观察到具有临床显著性的SDRs，包括D+T联合治疗引起的弥散性血管内凝血（38；10.22，7.42–14.06）和V+C联合治疗引起的肺栓塞（22；2.79，1.83–4.24）。 结论：我们的研究结果强调，在接受BRAF/MEKi治疗的患者中需要进行全面的心血管监测，以预防或早期发现cAEs，降低治疗相关风险，特别是在高危人群中。
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