Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II)

Context  The Heart and Estrogen/progestin Replacement Study (HERS) was a randomizedtrial of estrogen plus progestin therapy after menopause. Objective  To examine the effect of long-term postmenopausal hormone therapy oncommon noncardiovascular disease outcomes. Design and Setting  Randomized, blinded, placebo-controlled trial of 4.1 years' duration(HERS) and subsequent open-label observational follow-up for 2.7 years (HERSII), carried out between 1993 and 2000 in outpatient and community settingsat 20 US clinical centers. Participants  A total of 2763 postmenopausal women with coronary disease and averageage of 67 years at enrollment in HERS; 2321 women (93% of those surviving)consented to follow-up in HERS II. Intervention  Participants were randomly assigned to receive 0.625 mg/d of conjugatedestrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo(n = 1383) during HERS; open-label hormone therapy was prescribed at personalphysicians' discretion during HERS II. The proportions with at least 80% adherenceto hormones declined from 81% (year 1) to 45% (year 6) in the hormone groupand increased from 0% (year 1) to 8% (year 6) in the placebo group. Main Outcome Measures  Thromboembolic events, biliary tract surgery, cancer, fracture, andtotal mortality. Results  Comparing women assigned to hormone therapy with those assigned to placebo,the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolismdeclined from 2.66 (95% confidence interval [CI], 1.41-5.04) during HERS to1.40 (95% CI, 0.64-3.05) during HERS II (P for timetrend = .08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and3 of the 73 women with thromboembolism died within 30 days due to pulmonaryembolism. The overall RH for biliary tract surgery was 1.48 (95% CI, 1.12-1.95);for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture, 1.04 (95%CI, 0.87-1.25). There were 261 deaths among those assigned to hormone therapyand 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjustedand as-treated analyses did not alter our conclusions. Conclusions  Treatment for 6.8 years with estrogen plus progestin in older womenwith coronary disease increased the rates of venous thromboembolism and biliarytract surgery. Trends in other disease outcomes were not favorable and shouldbe assessed in larger trials and in broader populations.      

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women

Context.— Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. Objective.— To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. Design.— Randomized, blinded, placebo-controlled secondary prevention trial. Setting.— Outpatient and community settings at 20 US clinical centers. Participants.— A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. Intervention.— Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. Main Outcome Measures.— The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. Results.— Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). Conclusions.— During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.      

Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause

Context  The timing of initiation of hormone therapy may influence its effect on cardiovascular disease. Objective  To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began. Design, Setting, and Participants  Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10 739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16 608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998. Main Outcome Measures  Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials. Results  In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 379 cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was –6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was –2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and –1 per 10 000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06). Conclusions  Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms. Trial Registration  clinicaltrials.gov Identifier: NCT00000611      

Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause

Context  Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen has been found to lower Lp(a) levels in women. Objective  To determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women. Design and Setting  The Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled secondary prevention trial conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers. Participants  A total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years. Intervention  Participants were randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383). Main Outcome Measures  Lipoprotein(a) levels and CHD events (nonfatal myocardial infarction and CHD death). Results  Increased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (–5.8 [15] mg/dL) (-0.20 [0.53] µmol/L)compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] µmol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quartiles, respectively (P for interaction trend = .03). Conclusions  Our data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.      

Major and minor ECG abnormalities in asymptomatic women and risk of cardiovascular events and mortality

Context  Data are sparse regarding the prevalence, incidence, and independent prognostic value of minor and/or major electrocardiographic (ECG) abnormalities in asymptomatic postmenopausal women. There is no information on the effect, if any, of hormonal treatment on the prognostic value of the ECG. Objective  To examine association of minor and major baseline and incident ECG abnormalities with long-term cardiovascular morbidity and mortality. Design, Setting, and Participants  Post-hoc analysis of the estrogen plus progestin component of the Women's Health Initiative study, a randomized controlled primary prevention trial of 14 749 postmenopausal asymptomatic women with intact uterus who received 1 daily tablet containing 0.625 mg of oral conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate or a matching placebo. Participants were enrolled from 1993 to 1998, and the estrogen plus progestin trial was stopped on July 7, 2002. Main Outcome Measures  The Novacode criteria were used to define minor, major, and incident ECG abnormalities. Cardiovascular end points included incident coronary heart disease (CHD) and cardiovascular disease (CVD) events. Results  Among women with absent (n = 9744), minor (n = 4095), and major (n = 910) ECG abnormalities, there were 118, 91, and 37 incident CHD events, respectively. The incident annual CHD event rates per 10 000 women with absent, minor, or major ECG abnormalities were 21 (95% confidence interval [CI], 18-26), 40 (95% CI, 32-49), and 75 (95% CI, 54-104), respectively. After 3 years of follow-up, 5% of women who had normal ECG at baseline developed new ECG abnormalities with an annual CHD event rate of 85 (95% CI, 44-164) per 10 000 women. The adjusted hazard ratios for CHD events were 1.55 (95% CI, 1.14-2.11) for minor baseline, 3.01 (95% CI, 2.03-4.46) for major baseline, and 2.60 (95% CI, 1.08-6.27) for incident ECG abnormalities. There were no significant interactions between hormone treatment assignment and ECG abnormalities for risk prediction of cardiovascular end points. For prediction of CHD events, the addition of ECG findings to the Framingham risk score increased from 0.69 to 0.74 the area under the receiver operating characteristic curve. Similar findings were found for incident CVD events. Conclusions  Among asymptomatic postmenopausal women, clinically relevant baseline and incident ECG abnormalities are independently associated with increased risk of cardiovascular events and mortality, and the information is incremental to the established method of risk stratification. Trial Registration  clinicaltrials.gov Identifier: NCT00000611      

Long-term Intake of Dietary Fiber and Decreased Risk of Coronary Heart Disease Among Women

Context  Epidemiological studies of men suggest that dietary fiber intake protects against coronary heart disease (CHD), but data on this association in women are sparse. Objective  To examine the association between long-term intake of total dietary fiber as well as fiber from different sources and risk of CHD in women. Design and Setting  The Nurses' Health Study, a large, prospective cohort study of US women followed up for 10 years from 1984. Dietary data were collected in 1984, 1986, and 1990, using a validated semiquantitative food frequency questionnaire. Participants  A total of 68,782 women aged 37 to 64 years without previously diagnosed angina, myocardial infarction (MI), stroke, cancer, hypercholesterolemia, or diabetes at baseline. Main Outcome Measure  Incidence of acute MI or death due to CHD by amount of fiber intake. Results  Response rate averaged 80% to 90% during the 10-year follow-up. We documented 591 major CHD events (429 nonfatal MIs and 162 CHD deaths). The age-adjusted relative risk (RR) for major CHD events was 0.53 (95% confidence interval [CI], 0.40-0.69) for women in the highest quintile of total dietary fiber intake (median, 22.9 g/d) compared with women in the lowest quintile (median, 11.5 g/d). After controlling for age, cardiovascular risk factors, dietary factors, and multivitamin supplement use, the RR was 0.77 (95% CI, 0.57-1.04). For a 10-g/d increase in total fiber intake (the difference between the lowest and highest quintiles), the multivariate RR of total CHD events was 0.81 (95% CI, 0.66-0.99). Among different sources of dietary fiber (eg, cereal, vegetables, fruit), only cereal fiber was strongly associated with a reduced risk of CHD (multivariate RR, 0.63; 95% CI, 0.49-0.81 for each 5-g/d increase in cereal fiber). Conclusions  Our findings in women support the hypothesis that higher fiber intake, particularly from cereal sources, reduces the risk of CHD.      

Major risk factors as antecedents of fatal and nonfatal coronary heart disease events

Context  A frequently cited concept is that individual major risk factors for coronary heart disease (CHD) are absent in many patients (perhaps >50%) with CHD. However, prior studies have not systematically evaluated the extent to which CHD patients have previous exposure to at least 1 risk factor, including diabetes, cigarette smoking, or clinically elevated levels of cholesterol or blood pressure. Objective  To determine the frequency of exposure to major CHD risk factors. Design, Setting, and Participants  Three prospective cohort studies were included: the Chicago Heart Association Detection Project in Industry, with a population sample of 35 642 employed men and women aged 18 to 59 years; screenees for the Multiple Risk Factor Intervention Trial, including 347 978 men aged 35 to 57 years; and a population-based sample of 3295 men and women aged 34 to 59 years from the Framingham Heart Study (FHS). Follow-up lasted 21 to 30 years across the studies. Main Outcome Measures  Fatal CHD in all cohorts and nonfatal myocardial infarction (MI) in the FHS, compared by exposure to major CHD risk factors, defined as total cholesterol of at least 240 mg/dL (=" BORDER="0">6.22 mmol/L), systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, cigarette smoking, and diabetes. Participants were stratified by sex and age (18-39 vs 40-59 years). Results  For fatal CHD (n = 20 995), exposure to at least 1 clinically elevated major risk factor ranged from 87% to 100%. Among those aged 40 to 59 years at baseline with fatal CHD (n = 19 263), exposure to at least 1 major risk factor ranged from 87% to 94%. For nonfatal MI, prior exposure was documented in 92% (95% CI, 87%-96%) (n = 167) of men aged 40 to 59 years at baseline and in 87% (95% CI, 80%-94%) (n = 94) of women in this age group. Conclusions  Antecedent major CHD risk factor exposures were very common among those who developed CHD, emphasizing the importance of considering all major risk factors in determining CHD risk estimation and in attempting to prevent clinical CHD. These results challenge claims that CHD events commonly occur in persons without exposure to at least 1 major CHD risk factor.      

Drug treatment of hyperlipidemia in women

Context  Several clinical trials have evaluated the effects of lipid-lowering medications on coronary heart disease (CHD). Many of the trials have not included enough women to allow sex-specific analyses or have not reported results in women separately. Objectives  To assess and synthesize the evidence regarding drug treatment of hyperlipidemia for the prevention of CHD events in women and to conduct a meta-analysis of the effect of drug treatment on mortality. Data Sources  We searched MEDLINE, the Cochrane Database, and the Database of Abstracts of Reviews of Effectiveness for articles published from 1966 through December 2003. We reviewed reference lists of articles and consulted content experts. Study Selection and Data Extraction  Studies of outpatients that had a treatment duration of at least 1 year, assessed the impact of lipid lowering on clinical outcomes, and reported results by sex were included. Outcomes evaluated were total mortality, CHD mortality, nonfatal myocardial infarction, revascularization, and total CHD events. Summary estimates of the relative risks (RRs) with therapy were calculated using a random-effects model for patients with and without a previous history of cardiovascular disease. Data Synthesis  Thirteen studies were included. Six trials included a total of 11 435 women without cardiovascular disease and assessed the effects of lipid-lowering medications. Lipid lowering did not reduce total mortality (RR, 0.95; 95% confidence interval [CI], 0.62-1.46), CHD mortality (RR, 1.07; 95% CI, 0.47-2.40), nonfatal myocardial infarction (RR, 0.61; 95% CI, 0.22-1.68), revascularization (RR, 0.87; 95% CI, 0.33-2.31), or CHD events (RR, 0.87; 95% CI, 0.69-1.09). However, some analyses were limited by too few CHD events in the available trials. Eight trials included 8272 women with cardiovascular disease and assessed the effects of lipid-lowering medications. Lipid lowering did not reduce total mortality in women with cardiovascular disease (RR, 1.00; 95% CI, 0.77-1.29). However, lipid lowering reduced CHD mortality (RR, 0.74; 95% CI, 0.55-1.00), nonfatal myocardial infarction (RR, 0.71; 95% CI, 0.58-0.87), revascularization (RR, 0.70; 95% CI, 0.55-0.89), and total CHD events (RR, 0.80; CI, 0.71-0.91). Conclusions  For women without cardiovascular disease, lipid lowering does not affect total or CHD mortality. Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively. For women with known cardiovascular disease, treatment of hyperlipidemia is effective in reducing CHD events, CHD mortality, nonfatal myocardial infarction, and revascularization, but it does not affect total mortality.      

Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study

Context  Microvascular processes have been hypothesized to play a greater role in the development of coronary heart disease (CHD) in women than in men; however, prospective clinical data are limited. Objective  To examine the association between retinal arteriolar narrowing, a marker of microvascular damage from hypertension and inflammation, and incident CHD in healthy middle-aged women and men. Design, Setting, and Participants  The Atherosclerosis Risk in Communities Study, an ongoing prospective, population-based cohort study in 4 US communities initiated in 1987-1989. Retinal photographs were taken in 9648 women and men aged 51 to 72 years without CHD at the third examination (1993-1995). To quantify retinal arteriolar narrowing, the photographs were digitized, individual arteriolar and venular diameters were measured, and a summary arteriole-to-venule ratio (AVR) was calculated. Main Outcome Measure  Risk of CHD associated with retinal arteriolar narrowing. Results  During an average 3.5 years of follow-up, 84 women and 187 men experienced incident CHD events. In women, after controlling for mean arterial blood pressure averaged over the previous 6 years, diabetes, cigarette smoking, plasma lipid levels, and other risk factors, each SD decrease in the AVR was associated with an increased risk of any incident CHD (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.72) and of acute myocardial infarction (RR, 1.50; 95% CI, 1.10-2.04). In contrast, AVR was unrelated to any incident CHD in men (RR, 1.00; 95% CI, 0.84-1.18) or to acute myocardial infarction (RR, 1.08; 95% CI, 0.85-1.38). Conclusion  Retinal arteriolar narrowing is related to risk of CHD in women but not in men, supporting a more prominent microvascular role in the development of CHD in women than in men. Future work is needed to confirm these findings.      

Fish and omega-3 fatty acid intake and risk of coronary heart disease in women

Context  Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women. Objective  To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women. Design, Setting, and Participants  Dietary consumption and follow-up data from 84 688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994. Main Outcome Measures  Incident nonfatal myocardial infarction and CHD deaths. Results  During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend = .001). Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction. Conclusion  Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths.      

Marital stress worsens prognosis in women with coronary heart disease: The Stockholm Female Coronary Risk Study

Context  Psychosocial stress has been associated with incidence of coronary heart disease (CHD) in men, but the prognostic impact of such stress rarely has been studied in women. Objective  To investigate the prognostic impact of psychosocial work stress and marital stress among women with CHD. Design and Setting  Population-based, prospective follow-up study conducted in the city of Stockholm, Sweden. Participants  A total of 292 consecutive female patients aged 30 to 65 years (n = 279 working or cohabiting with a male partner) who were hospitalized for acute myocardial infarction or unstable angina pectoris between February 1991 and February 1994. Patients were followed up from the date of clinical examination until August 1997 (median, 4.8 years). Main Outcome Measures  Recurrent coronary events, including cardiac death, acute myocardial infarction, and revascularization procedures, by marital stress (assessed using the Stockholm Marital Stress Scale, a structured interview) and by work stress (assessed using the ratio of work demand to work control). Results  Among women who were married or cohabiting with a male partner (n = 187), marital stress was associated with a 2.9-fold (95% confidence interval [CI], 1.3-6.5) increased risk of recurrent events after adjustment for age, estrogen status, education level, smoking, diagnosis at index event, diabetes mellitus, systolic blood pressure, smoking, triglyceride level, high-density lipoprotein cholesterol level, and left ventricular dysfunction. Among working women (n = 200), work stress did not significantly predict recurrent coronary events (hazard ratio, 1.6; 95% CI, 0.8-3.3). Conclusions  Our results indicate that marital stress but not work stress predicts poor prognosis in women aged 30 to 65 years with CHD. These findings differ from previous findings in men and suggest that specific preventive measures be tailored to the needs of women with CHD.      

Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial

Context  In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective  To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants  Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention  Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcome Measures  All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results  Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction = .54). Conclusions  This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.      

Job strain and risk of acute recurrent coronary heart disease events

Context  There is evidence that job strain increases the risk of a first coronary heart disease (CHD) event. However, little is known about its association with the risk of recurrent CHD events after a first myocardial infarction (MI). Objective  To determine whether job strain increases the risk of recurrent CHD events. Design, Setting, and Patients  Prospective cohort study of 972 men and women aged 35 to 59 years who returned to work after a first MI and were then followed up between February 10, 1996, and June 22, 2005. Patients were interviewed at baseline (on average, 6 weeks after their return to work), then after 2 and 6 years subsequently. Job strain, a combination of high psychological demands and low decision latitude, was evaluated in 4 quadrants: high strain (high demands and low latitude), active (high demands and high latitude), passive (low demands and low latitude), and low strain. A chronic job strain variable was constructed based on the first 2 interviews, and patients were divided into those exposed to high strain at both interviews and those unexposed to high strain at 1 or both interviews. The survival analyses were presented separately for 2 periods: before 2.2 years and at 2.2 years and beyond. Main Outcome Measure  The outcome was a composite of fatal CHD, nonfatal MI, and unstable angina. Results  The outcome was documented in 206 patients. In the unadjusted analysis, chronic job strain was associated with recurrent CHD in the second period after 2.2 years of follow-up (hazard ratio [HR], 2.20; 95% CI, 1.32-3.66; respective event rates for patients exposed and unexposed to chronic job strain, 6.18 and 2.81 per 100 person-years). Chronic job strain remained an independent predictor of recurrent CHD in a multivariate model adjusted for 26 potentially confounding factors (HR, 2.00; 95% CI, 1.08-3.72). Conclusion  Chronic job strain after a first MI was associated with an increased risk of recurrent CHD.      

Migraine and risk of cardiovascular disease in women

Context  Migraine with aura has been associated with an adverse cardiovascular risk profile and prothrombotic factors that, along with migraine-specific physiology, may increase the risk of vascular events. Although migraine with aura has been associated with increased risk of ischemic stroke, an association with cardiovascular disease (CVD) and, specifically, coronary events remains unclear. Objective  To evaluate the association between migraine with and without aura and subsequent risk of overall and specific CVD. Design, Setting, and Participants  Prospective cohort study of 27 840 US women aged 45 years or older who were participating in the Women's Health Study, were free of CVD and angina at study entry (1992-1995), and who had information on self-reported migraine and aura status, and lipid measurements. This report is based on follow-up data through March 31, 2004. Main Outcome Measures  The primary outcome measure was the combined end point of major CVD (first instance of nonfatal ischemic stroke, nonfatal myocardial infarction, or death due to ischemic CVD); other measures were first ischemic stroke, myocardial infarction, coronary revascularization, angina, and death due to ischemic CVD. Results  At baseline, 5125 women (18.4%) reported any history of migraine; of the 3610 with active migraine (migraine in the prior year), 1434 (39.7%) indicated aura symptoms. During a mean of 10 years of follow-up, 580 major CVD events occurred. Compared with women with no migraine history, women who reported active migraine with aura had multivariable-adjusted hazard ratios of 2.15 (95% confidence interval [CI], 1.58-2.92; P<.001) for major CVD, 1.91 (95% CI, 1.17-3.10; P = .01) for ischemic stroke, 2.08 (95% CI, 1.30-3.31; P = .002) for myocardial infarction, 1.74 (95% CI, 1.23-2.46; P = .002) for coronary revascularization, 1.71 (95% CI, 1.16-2.53; P = .007) for angina, and 2.33 (95% CI, 1.21-4.51; P = .01) for ischemic CVD death. After adjusting for age, there were 18 additional major CVD events attributable to migraine with aura per 10 000 women per year. Women who reported active migraine without aura did not have increased risk of any vascular events or angina. Conclusions  In this large, prospective cohort of women, active migraine with aura was associated with increased risk of major CVD, myocardial infarction, ischemic stroke, and death due to ischemic CVD, as well as with coronary revascularization and angina. Active migraine without aura was not associated with increased risk of any CVD event.      

Major outcomes in moderately hypercholesterolemic,hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)

Context  Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups. Objective  To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least 1 additional CHD risk factor. Design and Setting  Multicenter (513 primarily community-based North American clinical centers), randomized, nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Participants  Ambulatory persons (n = 10 355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes. Intervention  Pravastatin, 40 mg/d, vs usual care. Main Outcome Measures  The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included nonfatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer. Results  Mean follow-up was 4.8 years. During the trial, 32% of usual care participants with and 29% without CHD started taking lipid-lowering drugs. At year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care; among the random sample who had LDL-C levels assessed, levels were reduced by 28% with pravastatin vs 11% with usual care. All-cause mortality was similar for the 2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P = .88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual care. CHD event rates were not significantly different between the groups (RR, 0.91; 95% CI, 0.79-1.04; P = .16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual care. Conclusions  Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.      

Estrogen plus progestin and risk of venous thrombosis

Context  Postmenopausal hormone therapy increases the risk of venous thrombosis. It is not known whether other factors influencing thrombosis add to this risk. Objective  To report final data on incidence of venous thrombosis in the Women’s Health Initiative Estrogen Plus Progestin clinical trial and the association of hormone therapy with venous thrombosis in the setting of other thrombosis risk factors. Design, Setting, and Participants  Double-blind randomized controlled trial of 16 608 postmenopausal women between the ages of 50 and 79 years, who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control study. Baseline gene variants related to thrombosis risk were measured in the first 147 women who developed thrombosis and in 513 controls. Intervention  Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate, or placebo. Main Outcome Measures  Centrally validated deep vein thrombosis and pulmonary embolus. Results  Venous thrombosis occurred in 167 women taking estrogen plus progestin (3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years); hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared with women between the ages of 50 and 59 years who were taking placebo, the risk associated with hormone therapy was higher with age: HR of 4.28 (95% CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38) for women aged 70 to 79 years. Compared with women who were of normal weight and taking placebo, the risk associated with taking estrogen plus progestin was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94) and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the hormone-associated risk of thrombosis with a 6.69-fold increased risk compared with women in the placebo group without the mutation (95% CI, 3.09-14.49). Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify the association of hormone therapy with venous thrombosis. Conclusions  Estrogen plus progestin was associated with doubling the risk of venous thrombosis. Estrogen plus progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.      

Abdominal Adiposity and Coronary Heart Disease in Women

Context.— Obesity is a well-established risk factor for coronary heart disease (CHD), but whether regional fat distribution contributes independently to risk remains unclear. Objective.— To compare waist-hip ratio (WHR) and waist circumference in determining risk of CHD in women. Design and Setting.— Prospective cohort study among US female registered nurses participating in the Nurses' Health Study conducted between 1986, when the nurses completed a questionnaire, and follow-up in June 1994. Participants.— A total of 44,702 women aged 40 to 65 years who provided waist and hip circumferences and were free of prior CHD, stroke, or cancer in 1986. Main Outcome Measures.— Incidence of CHD (nonfatal myocardial infarction or CHD death). Results.— During 8 years of follow-up 320 CHD events (251 myocardial infarctions and 69 CHD deaths) were documented. Higher WHR and greater waist circumference were independently associated with a significantly increased age-adjusted risk of CHD. After adjusting for body mass index (BMI) (defined as weight in kilograms divided by the square of height in meters) and other cardiac risk factors, women with a WHR of 0.88 or higher had a relative risk (RR) of 3.25 (95% confidence interval [CI], 1.78-5.95) for CHD compared with women with a WHR of less than 0.72. A waist circumference of 96.5 cm (38 in) or more was associated with an RR of 3.06 (95% CI, 1.54-6.10). The WHR and waist circumference were independently strongly associated with increased risk of CHD also among women with a BMI of 25 kg/m² or less. After adjustment for reported hypertension, diabetes, and high cholesterol level, a WHR of 0.76 or higher or waist circumference of 76.2 cm (30 in) or more was associated with more than a 2-fold higher risk of CHD. Conclusions.— The WHR and waist circumference are independently associated with risk of CHD in women.      

Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality

Context  For women, impact of cardiovascular risk factors measured in young adulthood, particularly favorable (low-risk) profile, on mortality has been difficult to assess due to low short-term death rates. Objective  To assess the relationship of baseline coronary risk factor status to mortality from coronary heart disease (CHD), cardiovascular diseases (CVDs), and all causes in young women. Design  Prospective cohort study. Setting and Participants  A total of 7302 women aged 18 to 39 years without prior CHD or major electrocardiographic abnormalities screened between 1967 and 1973 for the Chicago Heart Association Detection Project in Industry. Risk groups were defined using national guidelines for values of systolic and diastolic blood pressure, serum cholesterol level, body mass index, presence of diabetes, and smoking status. Participants were divided into 4 groups: low risk, 0 risk factors high but 1 or more unfavorable, 1 only risk factor high, and 2 or more risk factors high. Main Outcome Measures  All-cause mortality, CHD mortality, and CVD mortality; hazard ratio of outcome measures comparing low-risk group with other groups. Results  Only 20% met low-risk criteria; 59% had high levels of 1 or more risk factors. During an average follow-up of 31 years, there were 47 CHD deaths, 94 CVD deaths, and 469 deaths from all causes. The age-adjusted CVD death rate per 10 000 person-years was lowest for low-risk women and increased with the number of risk factors, ie, 1.5, 1.7, 5.0, and 9.1 for low-risk; 0, 1, and 2 or more risk factors high, respectively. Multivariate-adjusted CVD mortality hazard ratio for low-risk women was 0.19 (95% confidence interval, 0.08-0.45) compared with women with 2 or more risk factors high. Similar patterns were observed for CHD and all-cause mortality and for both blacks and whites. Conclusion  For women with favorable levels for all 5 major risk factors at younger ages, CHD and CVD are rare; long-term and all-cause mortality are much lower compared with others.      

Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial

Context  Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown. Objective  To determine the effect of raloxifene on cardiovascular events in osteoporotic postmenopausal women. Design  Secondary analysis of data from the Multiple Outcomes of Raloxifene Evaluation trial, a randomized, double-blind, placebo-controlled trial conducted between November 1994 and September 1999. Setting  Outpatient and community settings at 180 sites in 25 countries. Participants  A total of 7705 osteoporotic postmenopausal women (mean age, 67 years). Intervention  Patients were randomly assigned to receive raloxifene, 60 mg/d (n = 2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years. Main Outcome Measures  Cardiovascular events, including coronary events (myocardial infarction, unstable angina, or coronary ischemia) and cerebrovascular events (stroke or transient ischemic attack), collected as safety end points and subsequently adjudicated by a cardiologist blinded to therapy. Cardiovascular risk at study entry was determined by the presence of multiple cardiovascular risk factors or prior coronary events or revascularization procedure. Results  In the overall cohort, there were no significant differences between treatment groups in the number of combined coronary and cerebrovascular events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene, and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were 0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30) for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results were obtained when coronary and cerebrovascular events were analyzed separately. Among the subset of 1035 women with increased cardiovascular risk at baseline, those assigned to raloxifene had a significantly lower risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI, 0.38-0.95 for both raloxifene groups). The number of cardiovascular events during the first year was not significantly different across groups in the overall cohort (P = .94), or among women at increased cardiovascular risk (P = .86) or with evidence of established coronary heart disease (P = .60). Conclusions  Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. Before raloxifene is used for prevention of cardiovascular events, these findings require confirmation in trials with evaluation of cardiovascular outcomes as the primary objective.      

Prevalence of conventional risk factors in patients with coronary heart disease

Context  It is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension). This claim implies that other factors play a significant role in CHD and has led to considerable interest in nontraditional risk factors and genetic causes of CHD. Objective  To determine the prevalence of the 4 conventional risk factors among patients with CHD. Design, Setting, and Patients  In 2002-2003, we analyzed data for 122 458 patients enrolled in 14 international randomized clinical trials of CHD conducted during the prior decade. Patients included 76 716 with ST-elevation myocardial infarction, 35 527 with unstable angina/non–ST-elevation myocardial infarction, and 10 215 undergoing percutaneous coronary intervention. Main Outcome Measures  Prevalence of each conventional risk factor and number of conventional risk factors present among patients with CHD, compared between men and women and by age at trial entry. Results  Among patients with CHD, at least 1 of the 4 conventional risk factors was present in 84.6% of women and 80.6% of men. In younger patients (men 55 years and women 65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD was related to cigarette smoking in men and cigarette smoking and diabetes in women. Smoking decreased the age at the time of CHD event (at trial entry) by nearly 1 decade in all risk factor combinations. Conclusions  In direct contrast with conventional thinking, 80% to 90% of patients with CHD have conventional risk factors. Although research on nontraditional risk factors and genetic causes of heart disease is important, clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 conventional risk factors and the lifestyle behaviors causing them to reduce the epidemic of CHD.