Benefits and harms associated with hormone replacement therapy: clinical decision analysis
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《英国医生杂志》
1 Centre for Biostatistics and Genetic Epidemiology, Department of Health Sciences, University of Leicester, Leicester LE1 6TP
Correspondence to: K R Abrams keith.abrams@le.ac.uk
Abstract
Although hormone replacement therapy (HRT) is mainly used to relieve menopausal symptoms, it has shown benefits in several chronic diseases such as osteoporosis, colorectal cancer, and depression; it may also have a protective role in dementia and cognitive decline in postmenopausal women.1-7 HRT is also associated with an increased risk of breast cancer, stroke, and venous thromboembolism.2 3 8 Ovarian and endometrial cancers have been associated with unopposed oestrogens and unopposed or sequential regimens, respectively, and continuous treatment with combined oestrogen and progestogen seems to protect against endometrial cancer.9-14 In contrast to observational studies, recent randomised controlled trials showed an increased risk of coronary heart disease associated with HRT.2 13 15 16 A modest increase in the risk of gallstones and possibly gallbladder cancer have been reported, but there is still a paucity of evidence.17-19
The prevention of chronic diseases, particularly osteoporosis, has been a strong consideration in the prescription of HRT, but potential risks need to be reviewed.13 14 16 20 Several decision analyses have assessed the risks and benefits of HRT, yet the only one that took into account recent evidence from randomised controlled trials, particularly the women's health initiative trial (16 600 women), was qualitative.13 21-28 The women's health initiative trial addressed this issue by defining a "global index," summarising the balance of risks and benefits of HRT. It could not recommend HRT for primary prevention of chronic diseases; in fact the trial was halted on the basis of an interim analysis. In balancing harms and benefits, the researchers did not consider menopausal symptoms, which could have been achieved by using quality of life (QoL). Therefore, although these results are important, they are not sufficient evidence on which to develop a strategy for HRT use. Given the potential harms of HRT, future large trials might be difficult to plan: based primarily on the women's health initiative trial, a large UK trial (22 000 women by the end of 2016) was halted.29
We performed a decision analysis on the benefits and harms of HRT based on the best currently available evidence. We considered combined HRT in women free of menopausal symptoms (when HRT might be given for primary prevention of chronic diseases) and in women with symptoms.
Methods
Our model showed a net harm associated with HRT use for five years in asymptomatic women, which increased with baseline risk of breast cancer (fig 2). The loss in QALYs associated with HRT use for five years was 0.2 months in perfect health (- 0.02 QALYs, 95% credibility interval - 0.04 to 0.00) for women at low risk (0.7%), 0.4 (- 0.03, - 0.05 to - 0.01) for women at average risk (1.2%), 2.4 (- 0.20, - 0.40 to - 0.03) for women at high risk (12%), and 9.7 (- 0.81, - 1.63 to - 0.09) for women at very high risk (50%).
Fig 2 Graphical presentation of net-benefit model, with 95% credibility intervals, after exclusion of menopausal symptoms (top) or inclusion of symptoms with QoL weight 0.75 (bottom)
Our main analysis showed HRT to be on average beneficial in women with menopausal symptoms, with the magnitude of benefit decreasing with increasing baseline risks of breast cancer. The results are, however, sensitive to the value assumed for the QoL associated with symptoms: figure 2 shows the results for a QoL value of 0.75 (95% confidence interval 0.66 to 0.83). For a baseline risk greater than 25% the probability of net harm was greater than 2.5%. In particular, the net benefit for women at low, average, high, and very high baseline risk was, respectively, 10.7 months in perfect health (QALYs 0.89, 95% credibility interval 0.56 to 1.26), 10.6 months (0.88, 0.55 to 1.25), 8.5 months (0.71, 0.33 to 1.12), and 1.2 months (0.10, - 0.78 to 0.89).
Results were robust when using multiway sensitivity analyses to assess the impact of different QoL values for all outcomes, except menopausal symptoms. In particular, when using extreme QoL values of 0.5 and 1 for each outcome, QALYs were 0.88 to 0.89 for women at low baseline risk of breast cancer, 0.87 to 0.89 for women at average risk, 0.65 to 0.73 for women at high risk, and - 0.13 to 0.17 for women at very high risk.
An alternative approach for dealing with the uncertainty in QoL values is to consider the implication for an individual woman according to her baseline risk of breast cancer and the utility she ascribes to her own menopausal symptoms. The contour plot in figure 3 provides a graphical representation of the probability of net harm associated with use of combined HRT for five years for different combinations of utilities and baseline risks. For example, a 50 year old woman with a baseline risk of breast cancer over five years of 5.4% (calculated using the Gail predictive model44) and who attributes a utility of 0.90 to her menopausal symptoms (she would rather live four and a half years without symptoms than five years with symptoms), would have a probability of overall harm between 0 and 1%. The data on QoL for menopausal symptoms in this plot were modelled without uncertainty, since the utility is assumed to be obtained directly from the woman rather than being an estimate for an average woman. The probabilities of net harm shown in the plot represent the most plausible point estimates derived from our model.(Cosetta Minelli, research)
Correspondence to: K R Abrams keith.abrams@le.ac.uk
Abstract
Although hormone replacement therapy (HRT) is mainly used to relieve menopausal symptoms, it has shown benefits in several chronic diseases such as osteoporosis, colorectal cancer, and depression; it may also have a protective role in dementia and cognitive decline in postmenopausal women.1-7 HRT is also associated with an increased risk of breast cancer, stroke, and venous thromboembolism.2 3 8 Ovarian and endometrial cancers have been associated with unopposed oestrogens and unopposed or sequential regimens, respectively, and continuous treatment with combined oestrogen and progestogen seems to protect against endometrial cancer.9-14 In contrast to observational studies, recent randomised controlled trials showed an increased risk of coronary heart disease associated with HRT.2 13 15 16 A modest increase in the risk of gallstones and possibly gallbladder cancer have been reported, but there is still a paucity of evidence.17-19
The prevention of chronic diseases, particularly osteoporosis, has been a strong consideration in the prescription of HRT, but potential risks need to be reviewed.13 14 16 20 Several decision analyses have assessed the risks and benefits of HRT, yet the only one that took into account recent evidence from randomised controlled trials, particularly the women's health initiative trial (16 600 women), was qualitative.13 21-28 The women's health initiative trial addressed this issue by defining a "global index," summarising the balance of risks and benefits of HRT. It could not recommend HRT for primary prevention of chronic diseases; in fact the trial was halted on the basis of an interim analysis. In balancing harms and benefits, the researchers did not consider menopausal symptoms, which could have been achieved by using quality of life (QoL). Therefore, although these results are important, they are not sufficient evidence on which to develop a strategy for HRT use. Given the potential harms of HRT, future large trials might be difficult to plan: based primarily on the women's health initiative trial, a large UK trial (22 000 women by the end of 2016) was halted.29
We performed a decision analysis on the benefits and harms of HRT based on the best currently available evidence. We considered combined HRT in women free of menopausal symptoms (when HRT might be given for primary prevention of chronic diseases) and in women with symptoms.
Methods
Our model showed a net harm associated with HRT use for five years in asymptomatic women, which increased with baseline risk of breast cancer (fig 2). The loss in QALYs associated with HRT use for five years was 0.2 months in perfect health (- 0.02 QALYs, 95% credibility interval - 0.04 to 0.00) for women at low risk (0.7%), 0.4 (- 0.03, - 0.05 to - 0.01) for women at average risk (1.2%), 2.4 (- 0.20, - 0.40 to - 0.03) for women at high risk (12%), and 9.7 (- 0.81, - 1.63 to - 0.09) for women at very high risk (50%).
Fig 2 Graphical presentation of net-benefit model, with 95% credibility intervals, after exclusion of menopausal symptoms (top) or inclusion of symptoms with QoL weight 0.75 (bottom)
Our main analysis showed HRT to be on average beneficial in women with menopausal symptoms, with the magnitude of benefit decreasing with increasing baseline risks of breast cancer. The results are, however, sensitive to the value assumed for the QoL associated with symptoms: figure 2 shows the results for a QoL value of 0.75 (95% confidence interval 0.66 to 0.83). For a baseline risk greater than 25% the probability of net harm was greater than 2.5%. In particular, the net benefit for women at low, average, high, and very high baseline risk was, respectively, 10.7 months in perfect health (QALYs 0.89, 95% credibility interval 0.56 to 1.26), 10.6 months (0.88, 0.55 to 1.25), 8.5 months (0.71, 0.33 to 1.12), and 1.2 months (0.10, - 0.78 to 0.89).
Results were robust when using multiway sensitivity analyses to assess the impact of different QoL values for all outcomes, except menopausal symptoms. In particular, when using extreme QoL values of 0.5 and 1 for each outcome, QALYs were 0.88 to 0.89 for women at low baseline risk of breast cancer, 0.87 to 0.89 for women at average risk, 0.65 to 0.73 for women at high risk, and - 0.13 to 0.17 for women at very high risk.
An alternative approach for dealing with the uncertainty in QoL values is to consider the implication for an individual woman according to her baseline risk of breast cancer and the utility she ascribes to her own menopausal symptoms. The contour plot in figure 3 provides a graphical representation of the probability of net harm associated with use of combined HRT for five years for different combinations of utilities and baseline risks. For example, a 50 year old woman with a baseline risk of breast cancer over five years of 5.4% (calculated using the Gail predictive model44) and who attributes a utility of 0.90 to her menopausal symptoms (she would rather live four and a half years without symptoms than five years with symptoms), would have a probability of overall harm between 0 and 1%. The data on QoL for menopausal symptoms in this plot were modelled without uncertainty, since the utility is assumed to be obtained directly from the woman rather than being an estimate for an average woman. The probabilities of net harm shown in the plot represent the most plausible point estimates derived from our model.(Cosetta Minelli, research)