Joel A. Simon

Postmenopausal Hormone Therapy and Risk of Stroke

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...

Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease

OBJECTIVES This study sought to determine the independent association of renal insufficiency with cardiovascular risk among women with known coronary heart disease (CHD). BACKGROUND Although patients with end-stage renal disease and proteinuria are at high risk for cardiovascular events, little is known about the cardiovascular risk associated with moderate renal insufficiency. METHODS The Heart and Estrogen/progestin Replacement Study (HERS) was a clinical trial among 2,763 women with coronary disease who were randomized to conjugated estrogen plus progestins or identical placebo and followed for a mean of 4.1 years. Women were categorized as having normal renal function (creatinine < 1.2 mg/dl; n = 2,012), mild renal insufficiency (1.2 mg/dl to 1.4 mg/dl; n = 567) and moderate renal insufficiency (>1.4 mg/dl; n = 182). We examined the independent association of renal function with incident cardiovascular events including CHD death, nonfatal myocardial infarction, hospitalization for unstable angina, stroke and transient ischemic attacks. RESULTS Compared with women with normal renal function, those with mild and moderate renal insufficiency were older, more likely to be black, have a history of hypertension and diabetes and have higher serum levels of triglycerides and lipoprotein(a). After multivariate adjustment, both mild (relative hazards [RH] = 1.24; 95% confidence interval [CI]: 1.0 to 1.5) and moderate renal insufficiency (RH = 1.57; 95% CI: 1.2 to 2.1) were independently associated with increased risk for cardiovascular events compared with women with normal renal function. CONCLUSIONS Renal insufficiency is an independent risk factor for cardiovascular events in postmenopausal women with known coronary artery disease. Renal function may add helpful information to CHD risk stratification.

Factor V Leiden, Hormone Replacement Therapy, and Risk of Venous Thromboembolic Events in Women With Coronary Disease

Oral contraceptive use in women with factor V Leiden is associated with increased rates of venous thromboembolic events (VTEs). However, the effects of hormone replacement therapy (HRT) in postmenopausal women with factor V Leiden are not known. A nested case-control study was conducted among women with established coronary disease enrolled in 2 randomized clinical trials of HRT, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial. The Leiden mutation was present in 8 (16.7%) of 48 cases with VTE compared with only 7 (6.3%) of 112 controls (odds ratio [OR]Leiden 3.3, 95% CI 1.1 to 9.8;P =0.03). In women without the factor V Leiden mutation, risk associated with HRT use was significantly increased (ORHRT 3.7, 95% CI 1.4 to 9.4;P <0.01). On the other hand, in women with the factor V Leiden mutation, the estimated risk associated with HRT was increased nearly 6-fold, although the CIs were wide and included unity (ORHRT 5.7, 95% CI 0.6 to 53.9;P =0.13). The OR for women with the Leiden mutation who were also assigned to HRT compared with wild-type women assigned to placebo was 14.1 (95% CI 2.7 to 72.4, P =0.0015). In women with the factor V Leiden mutation who were treated with HRT, the estimated absolute incidence of VTE was 15.4 of 1000 per year compared with 2.0 of 1000 per year in women without the mutation who were taking a placebo (P =0.0015). On the basis of these data, in women with coronary disease, the estimated number needed to screen for factor V Leiden to avoid an HRT-associated VTE during 5 years of treatment is 376. If factor V Leiden genotyping becomes less expensive, it could be cost effective to screen for the presence of the mutation before instituting HRT in women with coronary disease.

Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment

Background— Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR, a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response. Methods and Results— Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C (P=0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (−1.23±0.04 mmol/L, n=209, versus −1.45±0.06 mmol/L, n=117; P=0.0008) and percent response (−36.9±1.0% versus −40.6±1.3%; P=0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (−28.2±4.9%, n=12 H2+H7 carriers, versus −41.5±0.5%, n=650 H2/H7 noncarriers; P=0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites. Conclusions— HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.

Serum Fatty Acids and the Risk of Stroke

BACKGROUND AND PURPOSE To examine the relationship between serum fatty acids, which reflect dietary intake, and stroke, we conducted a nested case-control study of 96 men with incident stroke and 96 control subjects matched by age, clinical center, treatment group, and date of randomization who were enrolled in the Multiple Risk Factor Intervention Trial. METHODS After confirming the stability of the stored serum samples, we measured serum cholesterol ester and phospholipid fatty acid levels as the percentage of total fatty acids by gas-liquid chromatography and examined their association with incident stroke. Using stepwise conditional logistic regression that controlled for risk factors for stroke, we determined which fatty acids were independent correlates of stroke. RESULTS In univariate models, a standard deviation (SD) increase (1.37%) in phospholipid stearic acid (18:0) was associated with a 37% increase in the risk of stroke, whereas an SD increase (0.06%) in phospholipid omega-3 alpha-linolenic acid (18:3) was associated with a 28% decrease in the risk of stroke (all P < .05). Only alpha-linolenic acid in the cholesterol ester fraction was associated with the risk of stroke in multivariate models: an SD increase (0.13%) in the serum level of alpha-linolenic acid was associated with a 37% decrease in the risk of stroke (P < .05). Systolic blood pressure and cigarette smoking were also independently associated with stroke risk. CONCLUSIONS Our findings suggest that higher serum levels of the essential fatty acid alpha-linolenic acid are independently associated with a lower risk of stroke in middle-aged men at high risk for cardiovascular disease.

The relation of α-linolenic acid to the risk of prostate cancer: a systematic review and meta-analysis

BACKGROUND alpha-Linolenic acid (ALA; 18:3n-3) has been associated inconsistently with an increased risk of prostate cancer. Additional studies have become available since the publication of 2 previous meta-analyses. OBJECTIVE The objective was to review the published data on the relation between ALA and prostate cancer. DESIGN We conducted a systematic review to identify studies that included data on ALA and risk of prostate cancer. Data were pooled from studies that compared the highest ALA quantile with the lowest ALA quantile, and risk estimates were combined by using a random-effects model. RESULTS The relation between ALA and prostate cancer is inconsistent across studies. We pooled data from 8 case-control and 8 prospective studies. The summary estimate revealed that high ALA dietary intakes or tissue concentrations are weakly associated with prostate cancer risk (relative risk [RR]: 1.20; 95% CI: 1.01, 1.43). When examined by study type (ie, retrospective compared with prospective or dietary ALA compared with tissue concentration) or by decade of publication, only the 6 studies examining blood or tissue ALA concentrations revealed a statistically significant association. With the exception of these studies, there was significant heterogeneity and evidence of publication bias. After adjustment for publication bias, there was no association between ALA and prostate cancer (RR: 0.96; 95% CI: 0.79, 1.17). CONCLUSIONS Studies examining the relation between ALA and prostate cancer have produced inconsistent findings. High ALA intakes or high blood and adipose tissue concentrations of ALA may be associated with a small increased risk of prostate cancer. However, these conclusions are qualified because of the heterogeneity across studies and the likelihood of publication bias.

Intensive smoking cessation counseling versus minimal counseling among hospitalized smokers treated with transdermal nicotine replacement: a randomized trial

PURPOSE To determine whether an intensive cognitive-behavioral intervention begun during hospitalization when combined with transdermal nicotine replacement therapy is more effective than a minimal counseling intervention combined with transdermal nicotine replacement therapy in helping inpatients to quit smoking. METHODS A total of 223 patients who smoked were enrolled in a hospital-based randomized smoking cessation trial at the San Francisco Veterans Affairs Medical Center. One hundred and seven participants (48%) received intensive counseling and outpatient telephone follow-up; 116 participants (52%) received minimal counseling. All study participants received 2 months of transdermal nicotine replacement therapy. We determined 6-month quit rates by self-report and measured saliva cotinine levels or obtained proxy reports to confirm self-reported smoking cessation at 12 months. Analyses adjusted for baseline differences in the distribution of coronary disease. RESULTS At 6 months, 35% (36/103) of the intensive intervention group reported quitting, compared with 21% (23/109) of the comparison group (relative risk [RR] = 1.7; 95% confidence interval [CI]: 1.1 to 2.7). At 12 months, the self-reported quit rate was 33% (33/99) in the intensive intervention group versus 20% (21/103) in the comparison group (RR = 1.7; 95% CI: 1.1 to 2.7). Based on biochemical or proxy confirmation, 29% (30/102) in the intensive intervention group versus 20% (21/107) in the comparison group quit smoking at 12 months (RR = 1.6; 95% CI: 0.96 to 2.5). CONCLUSION Hospital-initiated smoking cessation interventions that include transdermal nicotine replacement therapy can improve long-term quit rates.

Peripheral Arterial Disease in Randomized Trial of Estrogen With Progestin in Women With Coronary Heart Disease The Heart and Estrogen/Progestin Replacement Study

BackgroundPostmenopausal estrogen use has been associated with reduced carotid atherosclerosis in observational studies, but this relationship has not been confirmed in a clinical trial. The impact of estrogen on atherosclerotic disease in other peripheral arteries is unknown. Methods and ResultsPostmenopausal women with coronary heart disease (CHD) and an intact uterus (n=2763) were randomly assigned to conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) daily or to placebo in a secondary CHD prevention trial. This analysis focuses on incident peripheral arterial procedures and deaths in the 2 treatment groups; peripheral vascular disease was a predefined secondary outcome. During a mean of 4.1 years of follow-up, 311 peripheral arterial events were reported in 213 women, an annual incidence of 2.9%. The number of women who had peripheral arterial events was 99 among those assigned to active estrogen/progestin and 114 among those assigned to placebo, a nonsignificant difference (relative hazard 0.87, 95% CI 0.66 to 1.14). In the placebo group, hypertension and diabetes mellitus were independently associated with higher rates of peripheral arterial events, and plasma HDL cholesterol and body mass index were associated with lower rates of peripheral arterial events. In the estrogen/progestin group, current smoking and diabetes were independent predictors of peripheral arterial events. Incident peripheral arterial disease was not a significant predictor of coronary, cardiovascular, or total mortality. ConclusionsTreatment with oral conjugated estrogen plus medroxyprogesterone acetate was not associated with a significant reduction in incident peripheral arterial events in postmenopausal women with preexisting CHD.

Relation of serum ascorbic acid to mortality among US adults.

Purpose: To examine the relation between serum ascorbic acid (SAA), a marker of dietary intake (including supplements), and cause-specific mortality. Subjects and Methods: We analyzed data from a probability sample of 8,453 Americans age ≥30 years at baseline enrolled in the Second National Health and Nutrition Examination Survey (NHANES II), who were followed for mortality endpoints. We calculated relative hazard ratios as measures of disease association comparing the mortality rates in three biologically relevant SAA categories. Results: Participants with normal to high SAA levels had a marginally significant 21% to 25% decreased risk of fatal cardiovascular disease (CVD) (p for trend = 0.09) and a 25% to 29% decreased risk of all-cause mortality (p for trend <0.001) compared to participants with low levels. Because we determined that gender modified the association between SAA levels and cancer death, we analyzed these associations stratified by gender. Among men, normal to high SAA levels were associated with an approximately 30% decreased risk of cancer deaths, whereas such SAA levels were associated with an approximately two-fold increased risk of cancer deaths among women. This association among women persisted even after adjustment for baseline prevalent cancer and exclusion for early cancer death or exclusion for prevalent cancer. Conclusions: Low SAA levels were marginally associated with an increased risk of fatal CVD and significantly associated with an increased risk for all-cause mortality. Low SAA levels were also a risk factor for cancer death in men, but unexpectedly were associated with a decreased risk of cancer death in women. If the association between low SAA levels and all-cause mortality is causal, increasing the consumption of ascorbic acid, and thereby SAA levels, could decrease the risk of death among Americans with low ascorbic acid intakes.

Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study

Data from the Third National Health and Nutrition Examination Survey (1) indicate that 11% of U.S. women have a history of clinical gallbladder diseasethat is, either previous cholecystectomy or self-reported history of gallstones. Factors associated with gallbladder disease, at least in some studies, include older age, female sex, white ethnicity/race, obesity, rapid weight loss, and, among women, greater parity, use of oral estrogencontaining contraceptives, and postmenopausal estrogen therapy (2). These associations, in general, have been based on observational data and may partly reflect the effects of ascertainment and recall bias, as well as confounding. While some observational studies suggest that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold (3), such an association has not been reported consistently (2, 3). The effect of combined estrogen plus progestin therapy has been less well studied, and no recent clinical trial data exist on the relation of such therapy to the risk for biliary tract surgery among postmenopausal women. To determine whether estrogen plus progestin therapy is associated with the risk for biliary tract surgery among postmenopausal women, we analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), the first large randomized, double-blind trial of estrogen plus progestin therapy for the secondary prevention of coronary heart disease (4). Gallbladder disease events, including biliary tract surgery, were among several prespecified secondary outcomes of interest. Methods Participants Between 1 February 1993 and 1 October 1994, 2763 postmenopausal women with coronary artery disease were recruited from 20 clinical centers across the United States for participation in HERS, a randomized, double-blind study of the effect of combined, continuous estrogenprogestin therapy (conjugated equine estrogens, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d) on recurrent coronary heart disease events. Baseline data, which were collected at the visits for initial screening and random allocation, included demographic characteristics, medical history, risk factors for coronary heart disease, physical examination, and laboratory data. Women were not eligible to enroll in HERS if they had used any estrogen or female hormones within the previous 3 months, including pills, suppositories, injections, vaginal creams, or transdermal patches. We excluded 510 women from these analyses who reported at enrollment a history of surgical gallbladder removal. We did include, however, 123 women with a self-reported history of gallstones who had not undergone cholecystectomy. After these exclusions, data from 2253 participants were available for analysis. Measurements Baseline data included participant age, years of education, number of pregnancies, ethnicity/race (white, African American, or other), past use of postmenopausal estrogen therapy, history of cigarette smoking, history of alcohol consumption, and diabetes mellitus. Data were also obtained on use of lipid-lowering medications and antihypertensive medications, including thiazide diuretics. Participants who stated that they had smoked at least 100 cigarettes in their life were considered to have a history of smoking. Participants were asked, Has a doctor told you that you had diabetes, sugar diabetes, or high blood sugar? Those who answered yes were classified as having a history of diabetes. Women with a history of gestational diabetes only were classified as not having diabetes mellitus. Participants were weighed without shoes or outdoor clothing on a standard balance-beam scale to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm by using the height rod of a standard beam scale or, where available, a wall-mounted stadiometer. We calculated the body mass index as weight (kg)/height (m2). At baseline, year 1, and the end of the study, serum lipid and lipoprotein levels were obtained from all participants and were measured at the Johns Hopkins Lipoprotein Analytical Laboratory, Baltimore, Maryland, which is certified by the U.S. Centers for Disease Control and Prevention for the measurement of serum lipids and lipoproteins. Ascertainment of End Points Participants were determined to have incident gallbladder disease by physician adjudicators who were blinded to the randomization status [active hormone treatment or placebo]. Symptomatic nonsurgical biliary tract disease was defined as a hospital admission for acute cholecystitis, choledocholithiasis, or gallstone pancreatitis and was established on the basis of 1) reported symptoms in combination with elevated levels on liver function testing and gallstones with dilated biliary ducts on abdominal ultrasonography or 2) nuclear medicine scan diagnostic of acute gallbladder disease. Incident biliary tract surgery, which included cholecystectomy, sphincterotomy, or bile duct exploration, was established by review of operative reports and discharge summaries. All biliary tract surgeries were cholecystectomies with the exception of 12 sphincterotomies and 2 stent insertions. Nonsurgical and surgical gallbladder disease events were considered separate end points and are mutually exclusive. The main HERS results, reported in 1998 (4), were based on the near-final data available at that time. We present the updated and final results for incident biliary tract events (5). Statistical Analysis We used unpaired two-tailed t-tests to compare the age, level of education, number of pregnancies, body mass index, alcohol consumption, serum lipid level, and lipoprotein levels of the women randomly assigned to receive postmenopausal hormone therapy or placebo. Using chi-square tests, we compared the hormone therapy and placebo groups according to ethnicity/race, history of lipid-lowering medication use, prestudy postmenopausal estrogen use, thiazide diuretic use, cigarette smoking, ascorbic acid supplement use, history of gallbladder disease, and diabetes mellitus. The treatment groups were divided fairly equally with respect to baseline variables, except for statin use. To analyze the association between postmenopausal hormone therapy and incident gallbladder disease events, we used unadjusted and statin useadjusted proportional hazards models. All risk estimates were derived solely from proportional hazards models. We also estimated KaplanMeier curves for time to occurrence of biliary tract surgery, according to treatment assignment. The number of participants needed to be treated for a new case of biliary tract surgery to occur was calculated by using the incidence rates per person-year of observation. For predictor variables other than treatment assignment, we calculated the hazard ratio and 95% CI by using proportional hazards regression models to estimate the risk for incident biliary tract surgery. We used simple regression models that controlled only for treatment assignment; we also used multivariable regression models that included variables with a previously reported association with gallbladder disease. Our model-fitting methods relied primarily on biological criteria; we began by including factors previously reported to be associated with gallbladder disease. Although the risk for type I errors is always present when candidate predictors are many relative to the number of outcomes, our model-building process accounted for this possibility when we considered the statistical significance of the resulting multivariable model. Results were confirmed by using stepwise and backwards selection methods. We identified one statistically significant interaction between postmenopausal hormone treatment and smoking. Adjustment for this interaction did not substantially affect the hazard ratios for other variables entered in the multivariable models. We performed these analyses by using SAS software (6). A correlation between outcomes at each clinical center could potentially affect the SEs for the relative hazard estimates. Therefore, to control for such potential clustering by center, we used STATA software (7) to generate robust SEs for the proportional hazards models (8). Because site-specific practice patterns could confound the relation of statin use to biliary tract surgery, we also examined statistical models that included clinical center as a fixed effect. We calculated the number of participants needed to be treated to result in one additional biliary tract surgery by using the reciprocal of the absolute risk increase. However, because the 95% CI for the absolute risk increase included zero, the CI for the number needed to treat for harm (NNTH) included . We use a method described by Altman (9) to present the CI in these circumstances. The CI around the NNTH will therefore range from an NNTH to to a number needed to treat for benefit (NNTB). Role of the Funding Source Wyeth-Ayerst Research funded HERS. The study was designed and carried out by the HERS investigators, including scientists from Wyeth-Ayerst Research. Investigators at the HERS Coordinating Center at the University of California, San Francisco, collected the outcome data, supervised the adjudication of outcome events, and analyzed the data. Results Gallbladder disease was particularly prevalent among this cohort of postmenopausal women with coronary artery disease. Twenty-three percent of women reported a history of cholelithiasis or cholecystectomy at baseline (10). With the exception of statin use, which was more prevalent among women assigned to receive placebo (P = 0.01), the distribution of baseline variables was similar in both treatment groups (Table 1). Approximately 23% of the HERS participants had a history of pre-enrollment hormone use; the type and duration did not differ between the treatment groups. Table 1. Selected Baseline Characteristics of Postmenopausal Women Receiving Hormone Therapy or Placebo in the Heart and Estrogen/progestin Replacement Study (HERS) A tot