Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors
Authors: Raluca I. Mincu, Amir A. Mahabadi, Lars Michel, Simone M. Mrotzek, Dirk Schadendorf, Tienush Rassaf, Matthias Totzeck
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized. <h3>Objective</h3> To determine the association of BRAF and MEK inhibitor treatment with CVAEs in patients with melanoma compared with BRAF inhibitor monotherapy. <h3>Data Sources</h3> PubMed, Cochrane, and Web of Science were systematically searched for keywords<i>vemurafenib</i>,<i>dabrafenib</i>,<i>encorafenib</i>,<i>trametinib</i>,<i>binimetinib</i>, and<i>cobinimetinib</i>from database inception through November 30, 2018. <h3>Study Selection</h3> Randomized clinical trials reporting on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors compared with patients with melanoma being treated with BRAF inhibitor monotherapy were selected. <h3>Data Extraction and Synthesis</h3> Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Pooled relative risks (RRs) and 95% CIs were determined using random-effects and fixed-effects analyses. Subgroup analyses were conducted to assess study-level characteristics associated with CVAEs. <h3>Main Outcomes and Measures</h3> The selected end points were pulmonary embolism, a decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation. All-grade and high-grade (≥3) CVAEs were recorded. <h3>Results</h3> Overall, 5 randomized clinical trials including 2317 patients with melanoma were selected. Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (RR, 4.36; 95% CI, 1.23-15.44;<i>P</i> = .02), a decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94;<i>P</i> &lt; .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97;<i>P</i> = .005) compared with BRAF inhibitor monotherapy. The RRs for myocardial infarction, atrial fibrillation, and QTc prolongation were similar between the groups. These results were consistent when assessing high-grade CVAEs (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73;<i>P</i> = .005;<i>I</i><sup>2</sup> = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08;<i>P</i> = .005;<i>I</i><sup>2</sup> = 0%), but RRs for high-grade pulmonary embolism were similar between groups. A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10;<i>P</i> = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12;<i>P</i> = .02). <h3>Conclusions and Relevance</h3> Therapy with BRAF and MEK inhibitors was associated with a higher risk of CVAEs compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.