| アブストラクト | 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(R)) 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. |
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| 投稿者 | Dolladille, Charles; Font, Jonaz; Bejan-Angoulvant, Theodora; Zaman, Khalil; Sassier, Marion; Ezine, Emilien; Stefan, Andreea; Plane, Anne-Flore; Legallois, Damien; Milliez, Paul; Parienti, Jean-Jacques; Alexandre, Joachim |
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| 組織名 | 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.;Department of Pharmacology, CHU de Caen, 14000 Caen, France.;Medical Pharmacology Department, CHRU Tours, 37044 Tours, France.;Lausanne University Hospital (CHUV) and Swiss Group for Clinical Cancer Research;(SAKK), 1011 Lausanne, Switzerland.;Department of Dermatology, CHU de Caen, 14000 Caen, France.;Department of Cardiology, CHU de Caen, 14000 Caen, France.;Department of Cardiology, CHU de Caen, 14000 Caen, France; Medical School,;Universite Caen Normandie, UNICAEN, CHU de Caen, EA 4650 (Signalisation,;electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique),;14000 Caen, France.;Medical School, Universite Caen Normandie, UNICAEN, CHU de Caen, EA 4650;(Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion;myocardique), 14000 Caen, France.;Department of Biostatistics and Clinical Research, CHU de Caen, 14000 Caen,;France.;Cardiology, CHU de Caen, 14000 Caen, France; Department of Dermatology, CHU de;Caen, 14000 Caen, France. |
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