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Ann Oncol. 2013 Dec;24(12):2943-52. doi: 10.1093/annonc/mdt292. Epub 2013 Aug 6.

Incidence and risk of hemorrhagic events with vascular endothelial growth factor receptor tyrosine-kinase inhibitors: an up-to-date meta-analysis of 27 randomized controlled trials.

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  • 1Medical Oncology Unit, Oncology Department, the Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.



We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine-kinase inhibitors (VEGFR-TKIs).


We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies.


The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8-12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19-2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86-1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all-grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high-grade hemorrhagic events.


While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events.


VEGFR-TKIs; cancer; hemorrhagic events; meta-analysis

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