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Meta-Analysis
. 2015 Jan 20;112(2):296-305.
doi: 10.1038/bjc.2014.564. Epub 2014 Nov 6.

QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors

P Ghatalia  1 , Y Je  2 , M D Kaymakcalan  3 , G Sonpavde  4 , T K Choueiri  3
Affiliations
Meta-Analysis

QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors

P Ghatalia et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
Selection process for trials included in the meta-analysis.
Figure 2
Figure 2
VEGFR TKIs were associated with a significantly higher risk for all-grade QTc interval prolongation compared with no TKIs (RR=8.75, P<0.001, 95% CI 4.97–15.4). There was no evidence of heterogeneity (Q=10.55, P=0.879, I2=0.0%). The size of the squares indicates the weight of the study, and the diamond indicates the summary RR.
Figure 3
Figure 3
Relative risk of all grades of QTc interval prolongation associated with doses of vandetanib (100 and 300 mg). The size of the squares indicates the weight of the study, and the diamond indicates the summary RR.
See this image and copyright information in PMC

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