The correlation between ADT and cardiovascular toxicity is a debatable topic in PCa treatment. Multiple researches explored this relationship with different outcomes.
Our results indicated that ADT was associated with a significant increase in risk of AMI, CHD, and HF, but not found to be associated with SCD; the individual administration of each type of ADT was associated with AMI and CHD, except for AA; AA alone was only significantly associated with the increased risk of AMI, but not CHD. In addition, using ADT more than 5 years would not lead to an increased risk of AMI compared with less than 5 years. Three previous researches are diverged with our results due to their small number of endpoints. Furthermore, multiple former studies illustrated that orchiectomy was not associated with CHD events [25, 26]. This may attribute to their enrollment setting, men chose orchiectomy were older, suffered from more advanced stage of PCa and accompanied by more comorbidities, which in turn may affect the risk of CVD endpoints [27]. The distinction in inclusion criteria and duration of ADT may also lead to variation. Furthermore, three studies [5, 28, 29] failed to detect a significant association between ADT and cardiovascular related death, due to the fact that the previous or later ADT users were not ruled out in control group.
ADT is the primary systemic therapy for prostate cancer and nearly half of patients received ADT during their disease course [30]. However, patients initiating ADT suffered from adverse effects including weight gain, insulin resistance, decreased libido, obesity, sarcopenia; as well as cerebrovascular events and metabolic syndrome (MetS) all of which could possibly be induced by deficiency of testosterone [31, 32]. MetS is a major public health challenge due to its effect on the progression of CVD, cardiac mortality and its high prevalence in general population [33]. Clinical features of MetS caused by ADT are different from classically-defined MetS in terms of high-density lipoprotein-C (HDL-C) response and fat accumulation, all of which could elevate triglycerides, blood pressure and glucose levels [34-36]. Such components would also accelerate atherosclerosis [37].
It has been suggested that maximal androgen blockade (MAB), in which surgical (orchiectomy) or medical castration (GnRH agonists) is combined with AA therapy, could improve clinical efficacy [38]. Based on our study, we found although the combined utilization of GnRH agonists and AA could increase the risk of cardiac adverse effects significantly, no significant difference was detected when compared GnRH agonists plus AA with the individual GnRH agonists in the risk of AMI and CHD, but GnRH agonists plus AA was more likely to increase the risk of CHD compared with surgical castration or AA. Therefore, we could draw a conclusion that GnRH agonists, rather than AA, may play a role in increasing risk of cardiac events in MAB therapy. A number of analyses have suggested that CVD was associated with GnRH agonists though its potential mechanism remained unclear. Several risk factors may contribute to the greater risk of CVD during GnRH agonists therapy such as hyperglycemia, dyslipidemia and obesity [39]. Furthermore, it has been proved that human heart tissue expresses the GnRH agonists receptor, and a basic study on rat heart tissue demonstrated that stimulating these receptors with GnRH agonists could cause progression in the contractility of the cardiomyocyte [40]. The promoting effect of GnRH agonists on atherosclerotic through boosting the development of metabolic complications seems to offer another plausible mechanism that could distinguish different forms of ADT in terms of associated CVD risk and hence is worthy of further exploration [30]. Our results revealed the combined application of AA and GnRH agonists had a similar risk of AMI and CHD compared with monotherapy ADT method, therefore, the combined application of AA and GnRH agonists is in prior position in terms of overall survival as the current EAU-ESTRO-SIOG guidelines [41, 42] recommended based on a large Cochrane review which compared different types of ADT and different dosages in subgroup analysis [43],
Multiple earlier studies have proved that GnRH agonists were associated with a higher risk of CVD compared with orchiectomy [44], whereas our study indicated orchiectomy monotherapy could also lead to cardiac events. Orchiectomy can lead to a low level of testosterone though it remains unclear how low testosterone levels causes major cardiovascular events. Callou de Sá et al. [44] indicated that men with CHD had higher oestradiol and free oestrogen index (FEI) levels. As a matter of fact, high level estrogen can increase heart attack risk by accelerating coagulation and platelet aggregation in coronary arteries [45]. A nationwide, population-based study, provided exclusive evidence to show that closed risk of fatal CVD was observed for men treated by GnRH agonists compared with orchiectomy[25]. Further, larger population-based trial is needed to determine whether interventions like orchiectomy that raise estrogen levels might promote the progression of CHD, so that clinical doctors could be conscious of the serious potential risks of orchiectomy and ensure medical safety when deciding the type of ADT for patients.
Our subgroup analysis for the duration of ADT indicated that long-term ADT was not associated with an excess risk of AMI when regarding 5 year as threshold. In an observational study, Efstathiou et al. [23] indicated that long-term ADT administration could not increase the risk of cardiovascular mortality compared with short-term in men with locally advanced PCa. In another study, patients from control group received short-term androgen suppression while patients who received 2-5 years of further treatment were recruited as experiment group, the result demonstrated that no significant difference was observed in overall mortality between short-term group and long-term group [22]. On the other hand, evidence from another more resent study suggested the cardiovascular risk factors such as hyperglycemia, frank diabetes, and MetS are more likely to occur in patients with long-term ADT over 12 months, while with short-term ADT, (3–6 months) users are only affected by temporary insulin resistance [31]. Therefore, the optimum duration of ADT application should be adapted to comorbidities conditions and risk factors of individual patients.
Based on our results, the administration of ADT was not associated with SCD, but led to an increased risk of HF. Several former analyses have investigated this relationship between SCD and ADT, and came up with very different results. Several studies showed that ADT could significantly improve prostate cancer–specific survival and overall survival [5, 46, 47]. On the other hand, Gandaglia et al. [14] indicated the usage of GnRH agonists was related to significantly increased risk of SCD in patients with non-metastatic PCa. This distinction could be accounted for the enrollment setting. Clinical trials usually enroll patients younger and healthier with lower risk level of cardiac morbidity and mortality. Further studies with more rational enrollment settings are needed to evaluate the benefits and risks of ADT. Although our results suggested that ADT was not related to an increased risk of cardiovascular mortality, many previous studies have suggested that patients treated by ADT have higher rates of non-cancer death compared with the general population because of diabetes or other adverse effects. Meng et al. [48] demonstrated in a recent meta-analysis that GnRH agonists alone, GnRH agonists plus AA and orchiectomy were significantly related to stroke in patients treated by ADT. This effect is noteworthy because it may reverse the survival benefit of ADT in men affected by PCa.
The previous literature also showed conflicting evidence evaluating the link between ADT and HF. Multiple previous studies revealed men treated with ADT were associated with significantly increased of fatal and nonfatal HF in all patients especially for those with pre-existing CVD which met our results [32]; whereas only one propensity-score matching cohort study from Canada demonstrated that incidence of HF was not higher among ADT users with HR= 0.95; 95%CI, 0.90-1.00. Research which explored the impact of ADT on cardiomyocyte contractility at molecular level, and the results of testosterone therapy for HF at clinical level is needed to specify the possible relationship between HF and ADT.
This study has limitations. First, although we have strictly followed the PRISMA guidance, tried our best to apply the most extensive keywords and conducted the selection as impartial as possible, we know that some potential studies may still be neglected in our search, which would compromise our results. Second, the heterogeneity of our study was high, probably due to included studies used different criteria for patient recruitment, different defination of CHD, AMI, SCD, HF among studies and different treatment method for PCa, and because they included disease of variable severity. We could not explore the source of the heterogeneity through subgroup analyses because of the limited quantity of included studies. However, the ‘‘remove-one’’ sensitivity analysis suggested that our findings are convincible. The funnel plot also indicated that there is no publication bias. Future studies should aim to recruit consecutive cases under ADT treatment with more detailed subgroup analysis and assess cardiac risk using standarlized instruments that have cross-centre validity. Third, our analysis pooled together both RCT and observational studies, and subgroup analyses based on study design were not performed in the AMI and CHD subgroup, because all the included studies are designed observationally for AMI and CHD subgroup. Fourth, some included studies do not provide direct data for analysis, so we have to calculate and extract the data we needed by ourselves, this may have an impact on the overall result to some extent.