Risk of ischaemic stroke associated with intravitreal bevacizumab – a hospital‐based case‐crossover study

Intravitreal use of bevacizumab might affect collateral circulation around atherosclerotic vessels and lead to ischaemic cerebrovascular adverse effects (Kamba & McDonald 2007). The present study aims to further evaluate the potential association between the development of cerebrovascular events and intravitreal use of bevacizumab. We conducted a retrospective case-crossover study of Taiwanese patients with ischaemic cerebrovascular events from 1 January 2007 to 30 June 2011 (according to ICD-9-CM codes in electronic chart database) who were aged ≥20 years. The index date was then defined as the date of hospitalization. The case period was defined as 1–30 days before the index date, and the control period, as 121–150 days before the index date. We doubled case period and control period into 1–60 and 91–150 days before the index date, respectively, as a sensitivity analysis. The main exposure of interest in this study was intravitreal bevacizumab use. We also identified any comorbid conditions and the use of other medication from the database. The definition of the case period is based on the pharmacokinetics of bevacizumab. The maximum serum concentration has been found to be achieved 8 days after intravitreal injection, and the elimination of bevacizumab in serum parallels the level found in the vitreous humour and has been found to fall below 1 mg/ml at 29 days after injection (Bakri et al. 2007). We compared bevacizumab use between the case and control periods and calculated the OR and 95% CI by conditional logistic regression. Statistical analyses were performed using SPSS version 16.0.1 (SPSS Inc, Chicago, IL, USA, 2007). We identified 1,856 patients who matched our criteria (62% male, mean age 71.2 years [SD = 13.9]). Among these cases, intravitreal bevacizumab was prescribed to 27 (1.4%) of the patients. In Table 1, it can be seen that there is no significant increase in the risk of ischaemic stroke associated with the use of intravitreal bevacizumab. The incidence of ischaemic stroke after intravitreal injection of bevacizumab is very low but seems to mostly occur during the first month after injection. Campbell et al. (2012) documented a time series analysis that showed that neither the trend nor the level of the stroke in the time series changed with the uptake of bevacizumab. Compared with ranibizumab, which is another anti-VEGF agent specifically designed to treat AMD, bevacizumab has been reported in the CATT as having a higher proportion of patients with serious systemic adverse events (CATT Research Group et al. 2011). Rate of myocardial infarction, which shares a similar thromboembolic mechanism to that of ischaemic stroke, was higher for an anti-VEGF group than a photodynamic therapy group and a community group in the study by Kemp and colleagues (Kemp et al. 2013); however, the author was not able to show that the results were related to anti-VEGF management and not the underlying diseases themselves. There were several limitations to this study. First, we did not have information on some risk factors, including blood pressure, glycemic control, body mass index, smoking and alcohol consumption. However, such personal lifestyle factors are unlikely to change substantially during short-term observation, and this would also be partially controlled by the case-crossover design. Second, we could not exclude unmeasured or residual confounders that have not been discussed in the study. In conclusion, intravitreal bevacizumab use for the treatment of AMD and diabetic macular oedema is not associated with a change in the rate of ischaemic stroke among patients attending Taipei City Hospital. Further randomized controlled trials are required to evaluate and validate these results.