Harrington Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.
Division of Hematology and Medical Oncology, University Hospitals Cleveland Medical Center, Seidman Cancer Center at Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Cancer Med. 2021 Jun;10(12):3862-3872. doi: 10.1002/cam4.3938. Epub 2021 May 13.
Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.
This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.
In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).
In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.
单独使用 BRAF 抑制剂与联合使用 BRAF/MEK 抑制剂相关的心血管不良事件（CVAEs）尚未完全了解。
本研究纳入了所有接受 BRAF 抑制剂（vemurafenib、dabrafenib、encorafenib）或联合 BRAF/MEK 抑制剂（vemurafenib/cobimetinib；dabrafenib/trametinib；encorafenib/binimetinib）治疗的成年患者。我们利用了 2011 年至 2018 年期间 FDA 的不良事件报告系统（FAERS）和纵向 Truven Health Analytics/IBM MarketScan 数据库进行研究。使用调整后的回归技术研究了各种 CVAEs，包括动脉高血压、心力衰竭（HF）和静脉血栓栓塞（VTE）。
在 FAERS 中，报告了 7752 例 AE（40%为 BRAF，60%为 BRAF/MEK）。中位年龄为 60 岁（IQR 49-69），女性占 45%，97%为黑色素瘤患者。其中，567 例（7.4%）为心血管不良事件（死亡率为 19%）。与单药治疗相比，联合治疗与 HF（报告比值比[ROR] = 1.62（CI = 1.14-2.30）；p = 0.007）、动脉高血压（ROR = 1.75（CI = 1.12-2.89）；p = 0.02）和 VTE（ROR = 1.80（CI = 1.12-2.89）；p = 0.02）风险增加相关。Marketscan 有 657 名中位年龄为 53 岁（IQR 46-60）的患者，女性占 39.3%，88.7%为黑色素瘤患者。在开始用药后的 6 个月内，接受联合治疗的患者中有 26.2%（CI：14.8%-36%）发生 CVAEs，而接受单药治疗的患者中有 16.7%（CI：13.1%-20.2%）发生 CVAEs。与单药治疗相比，联合治疗与 CVAEs 相关（调整后的 HR：1.56（CI：1.01-2.42）；p = 0.045）。
在两个独立的真实世界队列中，与单药治疗相比，联合使用 BRAF/MEK 抑制剂会导致 CVAEs 增加，尤其是 HF 和高血压。
