title: QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors.
abstract: BACKGROUND
  Multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are known to cause cardiac toxicity, but the relative risk (RR) of QTc interval prolongation and serious arrhythmias associated with them are not reported.
  
  
  METHODS
  We conducted a trial-level meta-analysis of randomised phase II and III trials comparing arms with and without a US Food and Drug Administration-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib and regorafenib). A total of 6548 patients from 18 trials were selected. Statistical analyses were conducted to calculate the summary incidence, RR and 95% CIs.
  
  
  RESULTS
  The RR for all-grade and high-grade QTc prolongation for the TKI vs no TKI arms was 8.66 (95% CI 4.92-15.2, P<0.001) and 2.69 (95% CI 1.33-5.44, P=0.006), respectively, with most of the events being asymptomatic QTc prolongation. Respectively, 4.4% and 0.83% of patients exposed to VEGFR TKI had all-grade and high-grade QTc prolongation. On subgroup analysis, only sunitinib and vandetanib were associated with a statistically significant risk of QTc prolongation, with higher doses of vandetanib associated with a greater risk. The rate of serious arrhythmias including torsades de pointes did not seem to be higher with high-grade QTc prolongation. The risk of QTc prolongation was independent of the duration of therapy.
  
  
  CONCLUSIONS
  In the largest study to date, we show that VEGFR TKI can be associated with QTc prolongation. Although most cases were of low clinical significance, it is unclear whether the same applies to patients treated off clinical trials.
authors.affiliation: Department of Internal Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ghatalia
authors.affiliation: Department of Food and Nutrition, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Je
authors.affiliation: Dana Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue (DANA 1230), Boston, MA, 02215-5415 USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Kaymakcalan
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, UAB Medical CenterBirmingham, AL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: Dana Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue (DANA 1230), Boston, MA, 02215-5415 USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009200:Myocardial Contraction / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012306:Risk
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor