Charles Dolladille1, Jonaz Font2, Theodora Bejan-Angoulvant3, Khalil Zaman4, Marion Sassier2, Emilien Ezine5, Andreea Stefan5, Anne-Flore Plane6, Damien Legallois7, Paul Milliez8, Jean-Jacques Parienti9, Joachim Alexandre10. 1. Department of Pharmacology, CHU de Caen, 14000 Caen, France; Department of Cardiology, CHU de Caen, 14000 Caen, France. Electronic address: dolladille-c@chu-caen.fr. 2. Department of Pharmacology, CHU de Caen, 14000 Caen, France. 3. Medical Pharmacology Department, CHRU Tours, 37044 Tours, France. 4. Lausanne University Hospital (CHUV) and Swiss Group for Clinical Cancer Research (SAKK), 1011 Lausanne, Switzerland. 5. Department of Dermatology, CHU de Caen, 14000 Caen, France. 6. Department of Cardiology, CHU de Caen, 14000 Caen, France. 7. Department of Cardiology, CHU de Caen, 14000 Caen, France; Medical School, Université Caen Normandie, UNICAEN, CHU de Caen, EA 4650 (Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique), 14000 Caen, France. 8. Medical School, Université Caen Normandie, UNICAEN, CHU de Caen, EA 4650 (Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique), 14000 Caen, France. 9. Department of Biostatistics and Clinical Research, CHU de Caen, 14000 Caen, France. 10. Department of Pharmacology, CHU de Caen, 14000 Caen, France; Department of Cardiology, CHU de Caen, 14000 Caen, France; Department of Dermatology, CHU de Caen, 14000 Caen, France.
Abstract
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.
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 cancerpatients. 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.
Authors: Claire Glen; Yun Yi Tan; Ashita Waterston; Thomas R Jeffry Evans; Robert J Jones; Mark C Petrie; Ninian N Lang Journal: JACC CardioOncol Date: 2022-03-15