Background

The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized.

Aim

To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting.

Methods

We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data.

Results

MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58–7.07), peripheral oedema (OR 2.87 95% CI 1.93–4.27) and syncope (OR 6.71, 95% CI 3.00–14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03–10.09), peripheral oedema (arOR 1.39, 95% CI 1.17–1.66), syncope (arOR 1.56, 95% CI 1.22–1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04–7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21–1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach.

Conclusions

In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.

中文翻译：

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快速加速的纤维肉瘤B型和/或丝裂原激活的细胞外信号调节激酶抑制剂的心血管安全性：荟萃分析和药物警戒失调分析相结合的混合方法。

背景

不能充分表征快速加速的纤维肉瘤B型（BRAF）和有丝分裂原激活的细胞外信号调节激酶（MEK）抑制剂引起的心血管不良事件的风险。

目标

为了评估在随机安慰剂对照的临床试验中以及在现实生活中与BRAF和/或MEK抑制剂有关的心血管不良事件的风险。

方法

我们使用了两种方法。首先，我们对随机安慰剂对照的临床试验进行了系统的回顾和荟萃分析，报告了BRAF和/或MEK抑制剂在癌症患者中心血管不良事件的发生率。其次，我们使用年龄和性别调整后的报告比值比（arOR）及其来自世界卫生组织抗癌药物相关报告的药物警戒数据库（VigiBase®）的95％置信区间（CI）进行了不成比例分析，以进行调查真实数据。

结果

MEK抑制剂增加射血分数降低的风险（比值比[OR] 3.35，95％CI 1.58–7.07），周围水肿（OR 2.87 95％CI 1.93–4.27）和晕厥（OR 6.71，95％CI 3.00–14.99）在安慰剂对照的随机临床试验中与安慰剂比较。BRAF和MEK抑制剂联合治疗进一步增加了射血分数降低的风险。在不成比例的分析中，我们发现射血分数降低的过度报告（arOR 8.42，95％CI 7.03–10.09），外周水肿（arOR 1.39，95％CI 1.17-1.66），晕厥（arOR 1.56，95％CI 1.22– 1.99），BRAF和MEK抑制剂的扭转尖端/ QT延长（arOR 6.13，95％CI 5.04–7.47）和室上性心律失常（arOR 1.50，95％CI 1.21–1.85）。在两种方法中，BRAF和MEK抑制剂均与高血压无关。

结论

总之，在随机安慰剂对照的临床试验中，MEK抑制剂增加了射血分数降低，外周水肿和晕厥的风险。现实生活中的数据证实了这些发现，并提示使用BRAF / MEK抑制剂可引起扭转尖端/ QT延长和室上性心律失常的其他风险。