It is found that CV disease and breast cancer have several overlapping risk factors, such as obesity and smoking, meanwhile cardiovascular events (CVEs) is considered as one of the major causes of death in breast cancer patients undergoing chemotherapy, and AIs may contribute to the development of CVEs [7, 50-52]. For older women, the CV disease may pose a greater mortality threat than breast cancer itself. Therefore, it is vital for clinicians and patients to realize the risk of CVEs related to cancer treatment, so as to optimize the treatment strategy and actively manage these adverse events. Aromatase inhibitors (AIs) are used as standard medication therapies for most breast cancer patients. However, its impact on the development of CVEs has not been sufficiently elucidated. Meanwhile, reliable data about the risk of CVEs in breast cancer patients treated with AIs is still scantly. Thus, we conducted this study to assess the risk and incidence of CVEs in breast cancer patients receiving AIs.
To our knowledge, this is the latest study to assess the CVEs risk of AIs treatment in breast cancer patients.Under the previous study，it was suggested that AIs were associated with a 19% (RR: 1.19, 95% CI: 1.07–1.34) increased risk of cardiovascular events compared with tamoxifen, and cardioprotective effects of the tamoxifen was considered to be accounted for the increased risk of cardiovascular events with AIs [54, 55]. However, it was indicated in our study that breast cancer treated with AIs do not have a significant risk of developing CVEs in comparison with the controls. However, the incidence of CVEs related to exemestane was higher than that of controls (OR=1.1564, 95% CI: 1.0656-1.2549, Figure 4) according to our sub-group analysis. Moreover, exemestane has a special role in the sequence of AIs during treatment of metastatic breast cancer as the drug may cause new responses following progression on non-steroidal AIs[56, 57]. Thus, it might be the other disadvantage to choose exemestane upfront based on very week data concerning the risk of CVEs. Furthermore, it was found that the the highest incidence of CVEs associated with AIs in breast cancer patients was 60.6%, and the lowest incidence of CVEs is 1.1%. The overall incidence of CVEs associated with AIs in breast cancer patients was 13.02%. In addition, the highest OR of developing CVEs with AIs versus controls in breast cancer patients was 1.1653, and the pooled OR of developing CVEs was 1.0760. More importantly, High-grade CVEs occurred in ten trials [34, 35, 38, 40-43, 45-47], and almost all of the high-grade CVEs occurred in patients treated with AIs.
Providing systemic education for breast cancer patients are important for proper management of AIs-induced CVEs. CVEs in breast cancer patients commonly including hypertension, ischemic cardiovascular disease, venous thrombosis, hypercholesterolaemia, arrhythmia, cardiac failure, peripheral arterial disease, embolism,myocardial infarction,atrial fibrillation[18-21] Usually, the incidence of CVEs is at the highest in the initial months of drug treatment and in the last stage of disease progression. On the contrary, the incidence is lower while patients responded to treatment. CVEs can lead to dose reduction and drug discontinuation in clinical treatment for breast cancer patients. Our findings clarified that the incidence of CVEs was higher in breast cancer patients receiving AIs compared to controls. In addition, the continued monitoring, effective and preventive management of CVEs are important for continued AI treatment in breast cancer patients. Thus, it is very important to educate both patients and physicians about the complication and prevention.
Development of an integrated disease evaluation system which is scientific, reasonable and practical for the prediction of CVEs in AI treated patients remains a key problem for clinicians. Immediate and accurate diagnosis is essential to reduce the incidence of AIs-related CVEs. However, some major cardiovascular events, such as myocardial infarction and stroke in individuals often appear without known pre-existing cardiovascular disease, and it increases the difficulty of health management in patients with breast cancer. The prevention of CVEs and the accurate risk assessment for breast cancer patients, remains to be serious public health challenges. The developed scoring equations which use cardiovascular risk factors to predict high risk population, tend to have limited accuracy. For example, the Framingham Risk Score (FRS) which is often considered the reference standard, tend to over-estimate risk in low risk populations and under-estimate risk in high risk populations. Thus, it is recommended to incorporate more risk markers or indications, such as metabolic syndrome, plasma C-reactive protein (C-RP), coronary artery calcium (CAC), carotid intima media thickness (IMT) and the ankle brachial index (ABI) are incorporated to improve the prediction of CVEs. All breast cancer patients with high risk factor for the development of AIs-induced CVEs should be carefully and cautiously cared by physicians, as well as the members of home care team.
The reasons for AIs-induced CVEs in patients with breast cancer is still confusing. The confounding factors of CVEs in breast cancer patients may from age-related condition, drug therapies or disease itself. AIs-related organ dysfunctions, such as digestive tract mucosa injury, lung and/ or renal injury also increase the incidence for CVEs[60, 61]. Older patients who suffer from physiological dysfunction and senile disease making them more susceptible to CV diseases, and physician should be aware of this while caring for these patient[62, 63]. It was shown that dietary supplements such as folic acid, vitamins B6 and vitamins B12, may reduce the rate of cardiovascular diseases, but it is uncertain if vitamin B supplementation reduces the risk of CVEs. Furthermore, recent studies with vascular diseases failed to prove the association between B-vitamin supplementation and cardiovascular diseases , and it needs further verification.Furthermore, limited drugs such as
Several limitations are presented in our study. Firstly, this is a meta-analysis based on previous studies and not on patient data.It is difficult to determine how the different event severity and timing of events might affect the current analyses. Moreover, there are a mix of advanced or metastatic and early breast cancer studies included in present study, and patients with metastatic breast cancer may have been exposed to a greater number of prior treatments that may also induced cardiotoxicity such as radiotherapy or anthracycline chemotherapy[65-69], which might affect cardiovascular outcomes.Thus, all of these above confounding variables including basic medication history and adjuvant therapy could not be considered in the analysis. Secondly, this meta-analysis is performed in patients with proper organ function, so the risk and sensitivity of CVEs may be higher in routine clinical practice. Thirdly, the studies were performed at various types of institutions by different researchers in this meta-analysis, and the evaluating and conclusion may be existed heterogeneous. In addition, the majority of studies have been conducted in Europe and America, which has limited the possibility to generalize the results. The limitations of the current study mean that high-quality RCTs with a large sample size are still needed to reliably evaluate the risk of AIs induced CVEs in patients with breast cancer.
Cancer-free survival rate has improved over the past 20 years for many individuals with breast cancer. However, chemotherapy associated CVEs compromised the improvement in cancer related survival. As a result, there is an emerging need to obtain valuable data to optimize medical scheme for chemotherapy in patients with breast cancer by reducing the risk of CVEs. Our study showed that the incidence of CVEs in AIs group was higher compared with the controls, meanwhile almost all of high-grade CVEs occurred in patients treated with AIs. Adverse events monitoring is particularly important in reducing CVEs for AIs treatment. Optimal management and accurate diagnosis of CVEs for breast cancer patients is critical for safe medication. Besides, there is an emerging need to develop accurate, cost-effective methods to identify those individuals treated for cancer at increased risk of CVEs.