Statin use is associated with lower risk of atrial fibrillation in women with coronary disease: the HERS trial.

OBJECTIVE: To determine the efficacy of statin treatment in atrial fibrillation (AF) prevention in women. DESIGN: Cohort study using data obtained in the Heart and Estrogen/Progestin Replacement Study (HERS). SETTING: Secondary analysis of a multicentre, randomised controlled clinical trial. PATIENTS: 2673 Postmenopausal women with coronary disease. MAIN OUTCOME MEASURES: AF prevalence at baseline and incident AF over a mean follow-up of 4.1 years. RESULTS: 88 Women with AF were identified: 29 at baseline and 59 during follow-up. Women with AF were significantly less likely to be taking a statin at study enrollment than those without AF (22% vs 37%, p = 0.003). Baseline statin use was associated with a 65% lower odds of having AF at baseline after controlling for age, race, history of myocardial infarction or revascularisation and history of heart failure (odds ratio 0.35, 95% confidence interval (CI) 0.13 to 0.93, p = 0.04). The risk of developing AF during the study among those free from AF at baseline, adjusted for the same covariates, was 55% less for those receiving statin treatment (hazard ratio 0.45, 95% CI 0.26 to 0.78, p = 0.004). CONCLUSIONS: Statin treatment is associated with a lower prevalence and incidence of AF after adjustment for potential confounders in postmenopausal women with coronary disease.

Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS).

BACKGROUND: Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. METHODS AND RESULTS: Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk. CONCLUSIONS: Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.

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] micromol/L) compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] micromol/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.

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics.

The Heart and Estrogen/progestin Replacement Study (HERS) is a randomized, double-blind, placebo-controlled trial designed to test the efficacy and safety of estrogen plus progestin therapy for prevention of recurrent coronary heart disease (CHD) events in women. The participants are postmenopausal women with a uterus and with CHD as evidenced by prior myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, or other mechanical revascularization or at least 50% occlusion of a major coronary artery. Between February 1993 and September 1994, 20 HERS centers recruited and randomized 2763 women. Participants ranged in age from 44 to 79 years, with a mean age of 66.7 (SD 6.7) years. Most participants were white (89%), married (57%), and had completed high school or some college (80%). As expected, the prevalence of coronary risk factors was high: 62% were past or current smokers, 59% had hypertension, 90% had serum LDL-cholesterol of 100 mg/dL or higher, and 23% had diabetes. Each woman was randomly assigned to receive one tablet containing 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily or an identical placebo. Participants will be evaluated every 4 months for an average of 4.2 years for the occurrence of CHD events (CHD death and nonfatal myocardial infarction). We will also assess other major CHD endpoints, including revascularization and hospitalization for unstable angina. The primary analysis will compare the rate of CHD events in women assigned to active treatment with the rate in those assigned to placebo. The trial was designed to have power greater than 90% to detect a 35% reduction in the incidence of CHD events, assuming a 50% lag in effect for 2 years and a 5% annual event rate in the placebo group. The design, analysis, and conduct of the study are controlled by the Steering Committee of Principal Investigators and coordinated at the University of California, San Francisco. HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events.

Ten-year trends in cigarette smoking among young adults, 1986-1996: the CARDIA study. Coronary Artery Risk Development In Young Adults.

PURPOSE: To calculate ten-year smoking trends in a longitudinal cohort of young adults, and to characterize trends by race, sex, education, and birth cohort. METHODS: Data on cigarette smoking have been collected for ten years (1986-1996) from 5115 black and white men and women, aged 18-30 years, participating in the Coronary Artery Risk Development In Young Adults (CARDIA) study. Regression analysis adjusting for intra-person correlation over time and weighting for factors affecting follow-up was used to estimate change in smoking rates. RESULTS: Overall, smoking rates declined in white women (-0.50%/year, p < 0.001) and white men (-0.24%/year, p = 0.03). Rates remained stable in black women and increased in black men (0.37%/year, p = 0.01). Declining rates were generally observed in white women of all educational levels and birth cohorts and in several subgroups of white men. Increasing rates among black men could be attributed primarily to increasing rates in the youngest birth cohort. Among black men and women, prevalence of smoking in 1986 was considerably lower in the youngest birth cohort compared to the oldest; however, the increasing rates of change in smoking rates observed among the youngest birth cohorts (and decreasing rates in the oldest) lessened the disparity in prevalence rates across birth cohorts by 1996. Smoking initiation rates were highest among black men; cessation rates were highest among white women. CONCLUSIONS: These findings confirm that declines in smoking prevalence are not occurring across all groups, and reveal populations in special need of targeted interventions, particularly young black men.

Estrogen replacement therapy and mortality among older women. The study of osteoporotic fractures.

BACKGROUND: Most previous studies of estrogen replacement therapy (ERT) and mortality have focused on younger women. Recently, it has been suggested that the effect of ERT on mortality may represent a "healthy-user" effect, ie, those with healthier lifestyles having a greater likelihood of receiving ERT. METHODS: Nine thousand seven hundred four women, 65 years or older, participated; 1258 (14.1%) reported current use of ERT for at least 1 year at entry. During an average follow-up of 6.0 years, 1054 women (11.8%) died. RESULTS: After adjusting for multiple variables, mortality rate was lower among current (relative risk [RR], 0.69; 95% confidence interval [CI], 0.54-0.87) and past users (RR, 0.79; 95% CI, 0.66-0.95), mainly due to reductions in deaths due to cardiovascular disease. The protective effect of ERT was greatest among women younger than 75 years (RR, 0.55; 95% CI, 0.40-0.76) compared with women from 75 to 84 years of age (RR, 0.93; 95% CI, 0.62-1.41) and 85 years or older (RR, 1.33; 95% CI, 0.43-4.12). The RR for overall mortality was 0.95 (95% CI, 0.68-1.32) among short-term users (1-9 years) compared with 0.55 (95% CI, 0.40-0.75) among long-term users (> or = 10 years). Deaths considered unrelated to ERT tended also to be reduced in current users younger than 75 years (RR, 0.72; 95% CI, 0.49-1.06) and current long-term users (RR, 0.75; 95% CI, 0.51-1.10). CONCLUSIONS: Estrogen replacement therapy is associated with lower overall mortality rates and reduced deaths due to cardiovascular disease. Women using ERT had healthier lifestyles, and the risk for death thought to be unrelated to ERT also tended to be lower in ERT users, suggesting in part a healthy-user effect.

Changes in HIV-related behaviors among heterosexual alcoholics following addiction treatment.

In order to measure changes in HIV-related behaviors among heterosexual alcoholics following treatment, we conducted a prospective cohort study of 700 self-identified alcoholics recruited from five public alcohol treatment centers, all of which included HIV risk-reduction counseling. Respondents underwent an HIV antibody test and interviewer-administered questionnaire at entry to alcohol treatment and after a mean of 13 months later. Compared to baseline, at follow-up there was an overall 26% reduction in having sex with an injection-drug-using partner (23% versus 32%, P < .001) and a 58% reduction in the use of injection drugs (15% versus 37%, P < .001), along with smaller improvements in other behaviors. Respondents also showed a 77% improvement in consistent condom use with multiple sexual partners (35% versus 20%, P < .01) and a 23% improvement in partner screening (71% versus 57%, P < .001). Respondents who remained abstinent showed substantially greater improvement than those who continued to drink.

Seven-year trends in plasma low-density-lipoprotein-cholesterol in young adults: the CARDIA Study.

To identify determinants of recent secular trends in lipids and characterize their influence on age-related increases in LDL-cholesterol, we examined a cohort of black and white men and women aged 18-30 in 1985-1986. Secular trends were determined by comparing participants aged 25-30 at baseline with those aged 25-30 at year 7 (2788 and 1395 participants, respectively). LDL-cholesterol was lower among those 25-30 at year 7 (5.9 to 10.2 mg/dL, depending on race-sex group; P < 0.001); weight was higher (8.3 to 12.5 lb; P < 0.001); Keys score was lower (-4.2 to -7.3 units; P < 0.001); and use of oral contraceptives was greater (white women only, P < 0.01). Among 4086 participants followed for 7 years, LDL-cholesterol changed little or decreased, despite substantial weight increases in all groups (11.6 to 19.0 lb; P < 0.001). Keys scores decreased by 6.1 to 8.0 units, and use of oral contraceptives decreased (P < 0.001). Declining secular trends in LDL-cholesterol occurred despite upward trends in weight; the decline was associated with lower dietary fat and cholesterol and offset expected age-related increases in LDL-cholesterol.

Television viewing and cardiovascular risk factors in young adults: the CARDIA study.

Cross-sectional associations between self-reported hours of television (TV) viewing per day and cardiovascular risk factors were assessed in a biracial (black and white) study population of 4280 men and women, ages 23 to 35 years, undergoing the year-5 follow-up examination for the Cardiovascular Risk Development in Young Adults (CARDIA) study in 1990 to 1991. Number of hours of TV viewing per day was higher in blacks than in whites and was inversely associated with education and income. Relative to "light" TV viewers (0 to 1 h/d), "heavy" TV viewers (> or = 4 h/d) had a higher prevalence (P < 0.05) of obesity, smoking, and high hostility score in all race/gender groups, and of physical inactivity in all groups except black men. Among whites, "heavy" TV viewers had higher depression scores, and among blacks, reported more alcohol use. TV viewing was not associated with hypertension and lipid abnormalities. Heavy TV viewing is a modifiable behavior that is associated with increased prevalence of several cardiovascular risk factors.

Cholesterol screening in asymptomatic adults, revisited. Part 2.

OBJECTIVE: To assess the role of serum lipid levels as screening tests in adults. DESIGN: Pooled analysis of clinical trials, supplemented by analysis of data from the Framingham Heart Study, to estimate the effect of cholesterol reduction in patient groups stratified by cardiac risk. STUDY SELECTION: Published randomized controlled trials of cholesterol reduction, meta-analyses of such trials, prospective cohort studies of the association between cholesterol levels and morbidity and death related to coronary heart disease, and cost-effectiveness analyses of cholesterol reduction. DATA ANALYSIS: Two-stage logistic regression on cardiac risk factors and outcomes in the Framingham Heart Study. The first stage predicted the risk for death from coronary heart disease using standard risk factors but not cholesterol; the second stage predicted the risk for death from coronary heart disease and all causes as functions of age and cholesterol level, stratified by the risk predicted from the first stage. RESULTS: Randomized clinical trials show that cholesterol reduction confers survival benefits in patients with symptomatic coronary disease. In asymptomatic middle-aged men, who are at lower risk for death from coronary disease, cholesterol reduction prevents coronary disease but has not been shown to prolong life. The risk model based on analysis of the data from the Framingham Heart Study is consistent with the randomized trial data and shows that in the demographic groups excluded from trials, the hypothetical benefits of cholesterol reduction are greatest when the underlying risk for coronary disease is greatest. CONCLUSIONS: Screening with total cholesterol levels is most likely to be useful when done in populations at high short-term risk for dying of coronary heart disease, such as survivors of myocardial infarction and middle-aged men with multiple cardiac risk factors. In these populations, cholesterol reduction appears to be both effective and cost-effective. In other populations, the benefits of reduction are much smaller or are uncertain.

Carcinogenicity of lipid-lowering drugs.

OBJECTIVE: To review the findings and implications of studies of rodent carcinogenicity of lipid-lowering drugs. DATA SOURCES: Summaries of carcinogenicity studies published in the 1992 and 1994 Physicians' Desk Reference (PDR), additional information obtained from the US Food and Drug Administration, and published articles identified by computer searching, bibliographies, and consultation with experts. STUDY SAMPLE: We tabulated rodent carcinogenicity data from the 1994 PDR for all drugs listed as "hypolipidemics." For comparison, we selected a stratified random sample of antihypertensive drugs. We also reviewed methods and interpretation of carcinogenicity studies in rodents and results of clinical trials in humans. DATA SYNTHESIS: All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents, in some cases at levels of animal exposure close to those prescribed to humans. In contrast, few of the antihypertensive drugs have been found to be carcinogenic in rodents. Evidence of carcinogenicity of lipid-lowering drugs from clinical trials in humans is inconclusive because of inconsistent results and insufficient duration of follow-up. CONCLUSIONS: Extrapolation of this evidence of carcinogenesis from rodents to humans is an uncertain process. Longer-term clinical trials and careful postmarketing surveillance during the next several decades are needed to determine whether cholesterol-lowering drugs cause cancer in humans. In the meantime, the results of experiments in animals and humans suggest that lipid-lowering drug treatment, especially with the fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease.