Effect of Hormone Replacement Therapy on Cardiovascular Outcomes: A Meta-Analysis of Randomized Controlled Trials

Blogger's Note: Table 3 included: 1) vascular risk factors; 2) health women or hysterectomy 

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Background

Hormone replacement therapy (HRT) is widely used to controlling menopausal symptoms and prevent adverse cardiovascular events. However, the benefit and risk of HRT on cardiovascular outcomes remains controversial.......

Table 3. Subgroup analysis for the effect of hormone replacement therapy on coronary events, and stroke.

Discussion

Recently, evidence from large-scale randomized controlled trials [17]–[19] has shown that HRT is not significantly more effective than placebo in reducing the rate of coronary events. In addition, the risk of life-threatening stroke events has been shown to increase with HRT. This comprehensive systematic review included 38908 individuals in 10 trials with a broad range of baseline characteristics. The results of our study suggest that HRT does not effect on the incidence of coronary events, myocardial infarction, cardiac death, total mortality, or revascularization. In addition, estrogen therapy alone significantly increased the risk of stroke events when compared with placebo.
The relationship between HRT and coronary heart disease were described initially by observational studies [3], [26], however, the effect of HRT in reducing the risk of coronary events has not been confirmed by randomized controlled trials. The reason for this could be as follows: observational studies and randomized controlled trials may be at least partially attributable to differences in the clinical characteristics of the study populations, including differences in age, years since menopause; furthermore, the possibility that these associations mere reflect the effects of the diet or lifestyle on cardiovascular disease rates cannot be ruled out, which led us may overestimate the effect of this relationship. Therefore, we carried out a systematic review and meta-analysis based on randomized controlled trials to explain the possible effect of HRT on coronary events, and any possible drug-related adverse events.

Our main findings are in contrast with the findings of previous study [6], and also support the conclusions that HRT does not effect on the risk of coronary events, myocardial infarction, cardiac death, total mortality, or revascularization. The reason for these could be that although estrogen therapy reduces plasma levels of LDL cholesterol and increases levels of HDL cholesterol, could improves endothelial vascular function, however, it also has adverse physiological effects, including increasing the plasma levels of triglycerides, small dense LDL particles, C-reactive protein, and so on [27]–[30]. Therefore, although HRT may have direct beneficial effects on cardiovascular outcomes, these effects may be reduced or balanced by the adverse physiological effects.
HRT play an important role on the risk of incident stroke when compared with placebo. The small but persistent increase in systolic blood pressure in women receiving hormore replacement therapy is one possible contributor to this effect because relatively small differences in systolic blood pressure have been positively associated with differences in stroke and cardiovascular disease rates [31]–[32].
There was no significant differences between HRT and placebo in the relative risk for total mortality, the reason for this could be that the use of HRT resulted in a higher rate of nonfatal stroke and a suggestion of more severe functional deficits, which may have contributed to a high mortality rate. Hence, the effect of HRT on total mortality may be reduced or balanced by drug-related adverse events.
No significant differences in the relative risk of coronary events, myocardial infarction, cardiac death, and revascularization. The reason for the absence of an effect of HRT could be that HRT has proinflammatory effects that offset its beneficial effects. Previous epidemiologic studies [3] and clinical trials [5] concluded that women reveived HRT always with higher levels of C-reactive protein. A important meta-analysis [33] already suggested that elevated levels of C-reactive protein, and the underlying inflammation were associated with the risk of cardiovascular events in women.
Previous meta-analysis [6], [34] has illustrated that the risk of coronary events is not significantly reduced using HRT when compared with placebo, moreover, the risk of stroke was significantly increased by HRT compared with placebo, these conclusions were similar to our current study. Our subgroup analysis studied important factors which could affect the interpretation of our data, these conclusions were similar to previous meta-analysis. The results of this meta-analysis are promising because we updata the results and resolve the uncertain efficacy of HRT in postmenopausal women. Furthermore, we also conducted subgroup analysis to evaluate the potential effect of HRT on cardiovascular outcomes in some specific subsets.
The limitations of our study are as follows: (1) Inherent assumptions made for all meta-analysis, because the analysis uses pooled data either from published papers or provided by individual study authors, individual data and original data were not available, which prevented us doing more detailed relevant analysis and obtaining more comprehensive results. (2) Different follow-up times could have affected our conclusions about the association between HRT and coronary outcomes. Therefore, we just gave a relative result by comparing HRT with placebo and provided a synthetic and comprehensive review.
Despite the limitations of our study, the results suggest that HRT should not be recommeded for cardiovascular disease prevention in postmenopausal women. Therefore, in future study, it is important to focus on healthy individuals for primary prevention of cardiovascular disease, and to combined other drugs to provide an optimal therapy that minimizes adverse events in postmenopausal women. We suggest that the ongoing trials be improved in the following ways: (1) the adverse events in clinical trials should be recorded and reported normatively, so that the side-effects of any treatment can be evaluated in future trials. (2) the role of treatment duration and dosage should be investigated in more detail to explore optimal dose and duration of treatment.