Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross-sectional and longitudinal analysis using two large national registries

Avirup Guha, Prantesh Jain, Michael G. Fradley, Daniel Lenihan, Jahir M. Gutierrez, Chhavi Jain, Marcos de Lima, Jill S. Barnholtz-Sloan, Guilherme H. Oliveira, Afshin Dowlati, Sadeer Al-Kindi

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background: Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood. Methods: 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. Results: 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). Conclusions and Relevance: In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Original languageEnglish (US)
Pages (from-to)3862-3872
Number of pages11
JournalCancer Medicine
Volume10
Issue number12
DOIs
StatePublished - Jun 2021
Externally publishedYes

Keywords

  • BRAF inhibitors
  • BRAF/MEK inhibitors
  • cardiotoxicity
  • cardiovascular adverse events
  • FAERS
  • Marketscan
  • pharmacoepidemiology

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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