Experts Find Link Between Cardiovascular Adverse Events and BRAF/MEK Inhibitor Therapy

Investigators behind a systematic review and meta-analysis have demonstrated a link between cardiovascular adverse events (CVAEs) and BRAF and MEK inhibitor therapy in patients with melanoma (JAMA Netw Open. 2019;2[8]:e198890).


“Cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized,” according to lead investigator Raluca I. Mincu, PhD, West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, Essen, Germany, and colleagues.


Seeking to determine the relationship between BRAF and MEK inhibitor therapy and CVAEs in patients with melanoma, Dr Mincu et al gathered data from 5 clinical trials of 2317 patients using PubMed, Cochrane, and Web of Science. They used keywords including vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib to sift through these databases from their respective dates of inception through November 30, 2018.


Studies were eligible for inclusion if they were randomized and reported on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors versus BRAF inhibitor monotherapy.


In addition to the main end points of pulmonary embolism, decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation, CVAEs of all grades and high-grade (≥3) were documented. Data were analyzed in accordance with PRISMA guidelines, and random- and fixed-effects analyses were used to determine pooled relative risks (RRs) and 95% CIs.


Ultimately, BRAF and MEK inhibitor therapy was tied to an increased risk for pulmonary embolism (RR, 4.36; 95% CI, 1.23-15.44; P = .02), decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94; P < .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = .005) versus BRAF inhibitor therapy alone. The RRs were deemed to be similar between both regimen cohorts with regard to myocardial infarction, atrial fibrillation, and QTc prolongation.


When Dr Mincu et al evaluated high-grade CVAEs, findings were consistent (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%). The RRs for high-grade pulmonary embolism were comparable for both cohorts.


Patients with a mean age <55 years had a higher associated risk for decrease in left ventricular ejection fraction (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for those with a mean follow-up time >15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02).


“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,” Dr Mincu and colleagues concluded.—Hina Porcelli

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