A systematic review and meta-regression analysis to examine the ‘timing hypothesis’ of hormone replacement therapy on mortality, coronary heart disease, and stroke

Abstract

BackgroundThe ‘Timing Hypothesis’ states that the benefits and harms of hormone replacement therapy (HRT) are related to the proximity with which it is begun following the onset of menopause. The primary aim of this analysis was to test for heterogeneity of treatment effect for HRT using Chi2 and I2 tests for younger versus older initiators of HRT. The secondary aim was to perform a meta-regression with mean age at trial baseline as the covariate for various outcomes.MethodsYounger initiation trials were defined as those with mean age of participants <60 years and older initiation trials were those with mean age >60 years. The primary endpoints included all-cause mortality, cardiac mortality, coronary heart disease (CHD) events (a composite of cardiac mortality and nonfatal myocardial (MI)), and a composite of stroke, transient ischemic attack (TIA) and systemic embolism.ResultsThirty-one RCTs were identified comparing HRT users to nonusers (n = 40,521). There was significant heterogeneity of treatment effect between younger versus older HRT initiators for all-cause mortality (Chi2 = 9.74, p = 0.002, I2 = 89.7%), cardiac mortality (Chi2 = 4.04, p = 0.04, I2 = 75.2%), and CHD events (Chi2 = 3.06, p = 0.08, I2 = 67.3%). Both groups experienced an increase in stroke, TIA and systemic embolism (1112/18,774 in the HRT group versus 734/18,070 in the control group; OR = 1.52; 95% confidence interval (CI) = 1.38–1.67). When performing the meta-regression, as age increased the treatment effect of HRT was increased for stroke, TIA and systemic embolism (point estimate 0.006 with a standard error of 0.002) (p = 0.0003).ConclusionYounger initiation of HRT may be effective in reducing death and cardiac events. However, younger HRT initiators remained at an increased risk of stroke, TIA and systemic embolism and this risk increased as average age increased. Younger menopausal women using HRT to treat vasomotor symptoms do not appear to be at an increased risk of dying or experiencing CHD events.

A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases

“…Subgroup analyses of observational studies were conducted by route of administration (oral and non-oral), study design (cohort, nested case-control, and case-control), recency of MHT (past and current), and study quality (good/fair and poor). We defined the timing of initiation of MHT based on the criteria of the timing hypothesis presented in a previous RCT meta-analysis conducted by Boardman et al 16 and Nudy et al 17 . Subgroup analyses were performed when the number of studies was adequate.…”

“…We considered multivariable adjusted-estimates as a priority for the meta-analysis, thus potentially attenuating the effects of confounding factors. Nudy et al conducted another RCT-based meta-analysis to assess the assumption of the timing hypothesis 17 . They reported that younger MHT users had a decreased risk of all-cause death and cardiac events (a composite of cardiac mortality and non-fatal MI), whereas the risk of a composite of stroke, transient ischemic attack (TIA), and systemic embolism increased as age increased.…”

“…Two previous RCT-based meta-analyses 16,17 did not assess the effects by confounding factors owing to insufficient information, but a more recent systematic review 18 reported the effects of the timing of initiation, route of administration, duration, and dose on CVD risk. They reported that a low dose of oral MHT and transdermal MHT may have beneficial effects on CVD, including stroke and VTE.…”

Hormone therapy for first-line management of menopausal symptoms: Practical recommendations

“…Although evidence does not support use of HT solely for primary prevention of chronic diseases, 8,12 symptomatic women who begin HT in early menopause may gain protection from certain chronic conditions. 13,16…”

HRT and breast cancer risk

“…The Lancet study did not address mortality, only incidence of breast cancer, so findings must be weighed against a recent systematic review that showed that starting HRT close to the menopause may also reduce all-cause mortality and cardiac death, with no evidence of an increase in breast cancer mortality 5. Also, the most recent paper from the Women’s Health Initiative randomised trials showed that women who started treatment with oestrogen alone between the ages of 50 and 59 had a lower mortality than placebo controls when followed for 18 years 6…”