Cancer treatment today employs a combination of chemotherapy, radiotherapy, and surgery to prolong life and provide cure. However, many of these treatments can cause cardiovascular complications such as heart failure, myocardial ischemia/infarction, hypertension, thromboembolism, and arrhythmias 
. The risk of hypertension is increased three times with low dose and 7.5 times with high dose of bevacizumab 
. About 2–4% of patients (mostly pretreated with anthracyclines or irradiated to mediastinum) develop CHF, and 4–5%-arterial thromboembolic events. The use of bevacizumab is related to doubled risk of stroke, myocardial infarction, coronary disease and cardiac death 
. There have been postmarketing reports of adverse cardiac ischemic events associated with the use of bevacizumab 
. To improve the diagnosis and management of the cardiovascular side effects of anti-angiogenic drugs, the dialogue between oncologists and cardiologists should be strengthened 
. The association of ischemic heart disease with new agents presents a challenge for recognition because many RCTs may not be powered to reveal a significant relationship. Our meta-analysis of 7 RCTs has overcome this limitation of individual trials and demonstrated that bevacizumab may be associated with a significantly increased risk of ischemic heart disease (RR, 2.49; 95% CI 1.37–4.52) in patients with 3 kinds of tumors. This finding will help physicians and patients to recognize the risk of ischemic heart disease with the administration of bevacizumab.
The risk of bevacizumab-associated ischemic heart disease may be underestimated by previous studies, which showed no increased risk of ischemic heart disease with bevacizumab compared with a control 
. The failure to detect such an increase in ischemic heart disease risk is likely due to the limited number of trials included for the analysis. Because bevacizumab is increasingly used in the routine treatment of cancer patients and in the setting of clinical trials in combination with other agents 
, it is important for oncologists and primary care physicians to be aware of the increased incidence of ischemic heart disease associated with bevacizumab to monitor and treat it appropriately 
The mechanism behind bevacizumab increasing the risk of ischemic heart disease has been mostly linked to a pathologic perturbation at the level of the endothelial cell mediated by VEGF depletion. VEGF is also known to increase nitric oxide (NO) production by endothelial cells with resulting antiplatelet actions and inhibition of leukocyte adhesion 
. Inhibition of VEGF may increase the risk of cardiac ischemic events. The endothelial cell plays a critical role in vascular homeostasis and VEGF provides a vascular protective effect on the endothelial cell effect through anti-apoptosis, anti-inflammation and survival 
. Bevacizumab may increase expression of proinflammatory cytokines causing damage in ischemic heart. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure 
. Furthermore, a recent meta-analysis that including 3060 patients with colorectal cancer has showed that the addition of bevacizumab was related to increased rates of hypertension, proteinuria, bleeding and thromboembolic events, also leading to a slight increment on treatment interruptions. Other variables, such as hematologic toxicity and gastrointestinal perforation, were not statistically significant 
Our study showed that the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%–1.4%) and the RR was 2.49 (95% CI, 1.37–4.52) in patients with solid tumors who had been treated with bevacizumab. It is evident that risks of ischemic heart disease are all substantial among bevacizumab. Our results are consistent with those addressed in the review published in 2011 
. Many factors such as age, functional status, stage and histology of the malignant tumor, mobility, concurrent chemotherapy and prothrombotic states are known to contribute to the development of ischemic heart disease in cancer patients. We also explored risk factors for ischemic heart disease associated with bevacizumab. Our study demonstrated that the incidence of ischemic heart disease with bevacizumab varies significantly among patients with different types of tumors; higher risk was associated with colorectal cancer. But bevacizumab was not found to significantly increase the risk of cardiac ischemia in patients with renal cell carcinoma or liver cancer in comparison with controls. The difference in ischemic heart disease by cancer type also may reflect the extent of prior treatment and performance status in addition to its biology. The high risk of ischemic heart disease associated with colorectal cancer suggests a need for prophylaxis in these patients when treated with bevacizumab.
In addition to tumor type, another potential risk factor for ischemic heart disease may be the dose of bevacizumab. A high dose of bevacizumab (5 mg/kg per week) was found to be associated with a significantly increased risk of ischemic heart disease with an RR of 4.89 (95% CI, 1.04–23.04) in comparison with controls. However, for patients who were treated with a low dose of bevacizumab (2.5 mg/kg per week), their risk of ischemic heart disease also was significantly increased (RR, 2.14; 95% CI, 1.09–4.19). The interaction test did not showed significant differences in the cardiac risk between high dose and low dose subgroups (I2
0.34). Apparently, even low-dose bevacizumab is associated with the increased risk of ischemic heart disease. The data suggests that the so called low dose of bevacizumab may be already reaching the saturation level to induce cardiac ischemia.
Our study has the following limitations. First, the ability to detect ischemic heart disease may vary among institutions in which these trials were performed, and may cause bias of the reported incidence rates. A higher risk of adverse events was observed in patients with colorectal cancer - probably the statistical difference found on RR was related only to the sample size. Because in all groups of patients treated with bevacizumab the risk of ischemic heart disease was about 1%. As the number of patients included in this analysis was limited, the contribution of bevacizumab to ischemic heart disease in colorectal cancer patients remain poorly defined. There are two hypotheses to explain this result: firstly, the fact that trials being as divergent in their results as in their designs (number of patients, selection criteria, bevacizumab dose) could influence the data and consequently introduce bias. The second explanation is a possible interaction of bevacizumab. Second, the incidences of ischemic heart disease showed significant heterogeneity among the included studies. This may reflect differences in sample sizes, tumor type, concomitant chemotherapies, and many other factors among these studies. Despite these differences, the RRs reported by all of these studies showed remarkable nonheterogeneity. In addition, calculation using the random-effects model for incidence estimation may be able to minimize the problem. Third, the present study has the typical limitations of the meta-analytical methodology. Our findings and interpretations were limited by the quality and quantity of data that is available. An analysis of individual patient data would be more powerful to confirm our findings. The search covered a range of relevant sources. However, it was restricted only to English publications. Another concern is the possible existence of some unpublished studies, which could lead to potential publication bias, although we found no indication of such bias by using statistical methods designed to detect it. And we thought it was essential to evaluate the risk of cardiac events related to the combination of bevacizumab with different chemotherapy regimens. Our results indicated that bevacizumab was not found to significantly increase the risk of cardiac ischemia in 5-FU regimens patients in comparison with controls (OR, 1.92; 95% CI, 0.97–3.83). Future studies can focus on the separate comparison of ischemic heart disease associated with bevacizumab, according to cytotoxic elements involved and pattern of 5-FU administration. Finally, this is a meta analysis at the study level, and confounding factors at the patient level cannot be properly assessed and incorporated into the analysis.
In conclusion, our study has shown that the novel antiangiogenic agent bevacizumab is associated with a significantly increased risk of ischemic heart disease in colorectal cancer patients who receive concurrent chemotherapy or cytokine therapy. The risk is increased with both high and low doses of bevacizumab. The RR of ischemic heart disease may vary with tumor type. It is imperative for physicians and patients to recognize the risk. Our conclusions are limited by the available data. Bevacizumab may be continued if benefits of the drug outweigh the risk. Future studies are needed to investigate the prevention and management of ischemic heart disease associated with bevacizumab, especially in breast cancer, lung cancer, and ovarian cancer patients and its dose are important issues that need further evaluation by high-quality RCTs. Also, the need for detailed description of adverse events, especially in ischemic heart disease, in primary studies should be enhanced.