We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
There was no strong evidence of effect on risk of stroke in this group .
Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
This is an up date d version of a Cochrane review published in 2013 .
OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .
Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women
Coronary artery disease is the leading cause of death among women in the United States , accounting for 23 % of all deaths [ 1 , 2 ] . The incidence of coronary artery disease in women aged 35 to 44 years is 1 per 1000 , increasing to 4 per 1000 in women aged 45 to 54 years [ 3 , 4 ] . Among women in their fifth decade , the incidence of coronary artery disease is one half that of men . By the sixth decade , however , women and men have the same incidence of coronary disease [ 2 , 5 , 6 ] . This disparity between premenopausal women and men of similar age suggests that endogenous sex hormones such as estrogen may have a significant cardioprotective influence . In postmenopausal women , estrogen replacement therapy independently decreases the risk for cardiovascular events and mortality [ 6 , 7 ] . Estrogen therapy limited the uptake of cholesterol ester into the arterial wall and attenuated the development of dietary-induced atherosclerosis in monkeys and baboons that had ovariectomy [ 8 - 10 ] . Angiographic studies have consistently found less coronary artery disease in women who receive estrogen replacement therapy  [ 7 , 11 , 12 ] . Beneficial effects of estrogen replacement therapy include its ability to reduce low-density lipoprotein ( LDL ) cholesterol levels and increase high-density lipoprotein ( HDL ) cholesterol levels [ 13 ] . Nonetheless , multiple regression analyses suggest that only 25 % to 50 % of the reduction in cardiovascular events is attributable to the lipid-lowering effects of estrogen replacement therapy [ 14 ] , suggesting that other mechanisms contribute to its cardioprotective potential . One such mechanism may involve the effect of estrogen on vascular function . Specifically , estrogen may directly enhance the activity of the endothelium-derived relaxing factor nitric oxide [ 10 , 15 - 17 ] and thereby lessen the potential for coronary vasoconstriction and thrombosis [ 18 - 21 ] . When administered to rabbits that had ovariectomy  , long-term estrogen replacement improved endothelium-dependent relaxation in vitro [ 15 , 16 ] . In addition , both short-term and long-term estrogen administration improves in vivo the endothelium-dependent vasodilation in coronary arteries of atherosclerotic cynomolgus monkeys that had ovariectomy [ 10 , 17 ] . Several recent studies have suggested that short-term estrogen administration improves endothelium-dependent vasodilation of the coronary arteries of postmenopausal women [ 22 , 23 ] . We hypothesized that long-term estrogen administration would improve vasomotor function in postmenopausal women . Accordingly , we conducted a double-blind , r and omized , crossover , placebo-controlled trial to assess the effect of estrogen replacement therapy on endothelium-dependent vasodilation in postmenopausal women . We used high-resolution ultrasonography to serially assess vasomotor function in a peripheral conduit vessel , the brachial artery . Methods Patients The patients enrolled in this study were recruited from a larger cohort that was participating in a clinical research trial investigating the effect of estrogen replacement therapy on lipoprotein metabolism . Thirteen postmenopausal women aged 44 to 69 years ( average age , 55 7 years ) participated in this study . Women were eligible if menopause had occurred at least 1 year previously . Menopause was confirmed by measuring serum follicle-stimulating hormone levels . No patient had received hormone replacement therapy for at least 2 months before the study began . A history and physical examination were done to exclude persons with clinical evidence of coronary or peripheral atherosclerosis . Initial evaluation included a Papanicolaou smear ( if not done in past year ) , complete blood count , routine chemistry panel , and lipid profile .  Inclusion criteria included mild hypercholesterolemia , defined as a serum cholesterol level of 5.17 mmol/L to 6.20 mmol/L and an LDL cholesterol level of 3.36 mmol/L to 4.13 mmol/L. Exclusion criteria included hypertension , diabetes mellitus , tobacco use , obesity ( body weight > 135 % of ideal weight ) , history of breast or uterine cancer , thromboembolism , and liver or renal disease . Eligible patients were placed on a  low-cholesterol diet  ( American Heart Association phase I ) for 6 weeks before r and omization . Patients were r and omly assigned to one of three treatment groups : placebo , oral 17 -estradiol ( Estrace , Mead Johnson , Evansville , Indiana . ) at a dose of 1 mg/d , or oral 17 -estradiol at a dose of 2 mg/d . At the conclusion of each 9-week treatment period , the patients were given progesterone ( Provera , Upjohn , Kalamazoo , Michigan ) at 10 mg/d for 10 days . Hormone replacement therapy was discontinued for 3 weeks before patients crossed over to the next treatment regimen . All patients received placebo and the two doses of estrogen in r and om order . Vascular function studies ( described below ) were done during the eighth or ninth week of each treatment period . Experimental Protocol Studies were done in a temperature-controlled vascular research laboratory . All patients were placed in the supine position . We studied vascular reactivity in a conduit vessel , the brachial artery , as previously described . An imaging study of the brachial artery was done using a high-resolution ultrasound machine ( Toshiba , Model SSA-270 , Otawara-shir , Tochigi-Ken , Japan ) that was equipped with a 7.5 MHz linear-array transducer . Baseline images of the brachial artery were obtained proximal to the antecubital fossa . Imaging of the artery was done longitudinally , allowing clear visualization of the posterior wall intima-lumen interface and the anterior wall media-adventitial interface . We assessed endothelium-dependent vasodilation by measuring the change in the caliber of the brachial artery during reactive hyperemia , a maneuver that increases flow through the conduit segment being studied ( flow-mediated vasodilation ) . To create this stimulus , a cuff placed on the upper arm was inflated to suprasystolic pressure for 5 minutes , thereby occluding flow to the forearm . This results in dilatation of downstream forearm resistance vessels . After cuff deflation , reactive hyperemia occurs , as brachial artery blood flow increases to accommo date the dilated resistance vessels . Imaging of the brachial artery was continually done for the 5-minute period after cuff deflation until basal conditions were re-established . Thereafter , sublingual nitroglycerin ( at a dose of 0.4 mg ) was administered to assess endothelium-independent vasodilation . The artery was studied for an additional 5 minutes . Blood pressure and heart rate were monitored continuously throughout the procedure . All images were recorded on Super VHS videotape for subsequent analysis . Image analysis was done on a personal computer that was equipped with a video frame grabber . Images recorded on videotape were analyzed by an investigator blinded to treatment assignment . Previous studies have shown that the peak diameter change during reactive hyperemia occurs approximately 1 minute after cuff deflation and 3 minutes after nitroglycerin administration [ 41 ] . We used these time points in our study . Images corresponding to the end of the T wave on a simultaneous electrocardiograph were selected and digitized . Image analysis was then done using a proprietary analysis software that search ed for the shortest distance between the points on the arterial wall , creating 10 to 20 paired measurements along a 10-mm length . We measured arterial diameter from the intima-lumen interface on the posterior wall to the media-adventitial interface on the anterior wall . We calculated brachial artery diameter by averaging these paired lumen measurements and reported them in millimeters using calibration factors derived from real-time ultrasonography . We used an average of three separate measurements for each condition . In our laboratory , this technique has a variability of only 0.0 0.1 mm [ 24 ] . To assure that the blood flow stimulus during reactive hyperemia was similar during each treatment phase , forearm blood flow was measured by venous occlusion strain gauge plethysmography using calibrated mercury-in-silastic strain gauges as previously described [ 25 ] . Statistical Analysis The variables compared during the placebo period and during therapy with each dose of estrogen included blood pressure , heart rate , forearm blood flow , basal brachial artery diameter , and the percentage increase in diameter during reactive hyperemia and after patients received sublingual nitroglycerin . Values are expressed as the mean SE . For statistical analysis , we used repeated-measure analysis of variance and the Scheffe-F post hoc test [ 26 ] . Significance was accepted at P 0.05 . Results Baseline Hemodynamic Measurements The effect of estrogen treatment on blood pressure , heart rate , forearm blood flow and forearm vascular resistance is presented in Table 1 . Estrogen therapy did not affect blood pressure or heart rate . Basal forearm blood flow tended to be higher during both estrogen treatment phases ( P = 0.08 ) . Basal forearm vascular resistance was similar during all three treatment phases . The peak forearm blood flow during reactive hyperemia was similar during placebo receipt and each estrogen treatment period . However , peak forearm blood flow was greater when patients received the 1-mg dose of estradiol than when they received the 2-mg dose ( P = 0.05 ) . Table 1 . Effect of Estrogen Replacement on Hemodynamic Measurements Flow-Mediated Endothelium-Dependent Vasodilation We obtained technically adequate ultrasound images during reactive hyperemia for 12 of the 13 patients . The brachial artery diameter , under basal conditions , measured 3.5 mm , 3.4 mm , and 3.3 mm while patients received placebo , estradiol at 1 mg/d , and estradiol at 2 mg/d , respectively ( P > 0.2 ) . The percentage increase in brachial artery diameter during reactive hyperemia for each treatment period is shown in Figure 1 . The change in brachial artery diameter was greater when patients received estradiol treatment ( 13.5 % and
We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
There was no strong evidence of effect on risk of stroke in this group .
Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
This is an up date d version of a Cochrane review published in 2013 .
OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .