Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors

Context  Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown. Objective  To compare traditional and novel risk factors as predictors of cardiovascular mortality. Design, Setting, and Patients  A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years. Main Outcome Measures  Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m². Results  Among the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15). Conclusions  Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.      

Risk of subsequent fracture after low-trauma fracture in men and women

Context  There are few published long-term data on absolute risk of subsequent fracture (refracture) following initial low-trauma fracture in women and fewer in men. Objective  To examine long-term risk of subsequent fracture following initial osteoporotic fracture in men and women. Design, Setting, and Participants  Prospective cohort study (Dubbo Osteoporosis Epidemiology Study) in Australia of 2245 community-dwelling women and 1760 men aged 60 years or older followed up for 16 years from July 1989 through April 2005. Main Outcome Measure  Incidence of first (initial) fracture and incidence of subsequent fracture according to sex, age group, and time since first fracture. Relative risk was determined by comparing risk of subsequent fracture with risk of initial fracture. Results  There were 905 women and 337 men with an initial fracture, of whom 253 women and 71 men experienced a subsequent fracture. Relative risk (RR) of subsequent fracture in women was 1.95 (95% confidence interval [CI], 1.70-2.25) and in men was 3.47 (95% CI, 2.68-4.48). As a result, absolute risk of subsequent fracture was similar in women and men and at least as great as the initial fracture risk for a woman 10 years older. Thus, women and men aged 60 to 69 years had absolute refracture rates of 36/1000 person-years (95% CI, 26-48/1000) and 37/1000 person-years (95% CI, 23-59/1000), respectively. The increase in absolute fracture risk remained for up to 10 years, by which time 40% to 60% of surviving women and men experienced a subsequent fracture. All fracture locations apart from rib (men) and ankle (women) resulted in increased subsequent fracture risk, with highest RRs following hip (RR, 9.97; 95% CI, 1.38-71.98) and clinical vertebral (RR, 15.12; 95% CI, 6.06-37.69) fractures in younger men. In multivariate analyses, femoral neck bone mineral density, age, and smoking were predictors of subsequent fracture in women and femoral neck bone mineral density, physical activity, and calcium intake were predictors in men. Conclusion  After an initial low-trauma fracture, absolute risk of subsequent fracture was similar for men and women. This increased risk occurred for virtually all clinical fractures and persisted for up to 10 years.      

20-year outcomes following conservative management of clinically localized prostate cancer

Context  The appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent study suggested an increasing prostate cancer mortality rate for men who are alive more than 15 years following diagnosis. Objective  To estimate 20-year survival based on a competing risk analysis of men who were diagnosed with clinically localized prostate cancer and treated with observation or androgen withdrawal therapy alone, stratified by age at diagnosis and histological findings. Design, Setting, and Patients  A retrospective population-based cohort study using Connecticut Tumor Registry data supplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. Main Outcome Measures  Probability of mortality from prostate cancer or other competing medical conditions, given a patient’s age at diagnosis and tumor grade. Results  The prostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95% confidence interval [CI], 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI, 10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjusting for differences in tumor histology (rate ratio, 1.1; 95% CI, 0.6-1.9). Men with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6 deaths per 1000 person-years; 95% CI, 2-11). Men with high-grade prostate cancers have a high probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000 person-years; 95% CI, 90-156). Men with Gleason score of 5 or 6 tumors have an intermediate risk of prostate cancer death. Conclusion  The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis, which does not support aggressive treatment for localized low-grade prostate cancer.      

Exercise type and intensity in relation to coronary heart disease in men

Context  Studies have shown an inverse relationship between exercise and risk of coronary heart disease (CHD), but data on type and intensity are sparse. Objective  To assess the amount, type, and intensity of physical activity in relation to risk of CHD among men. Design, Setting, and Participants  A cohort of 44 452 US men enrolled in the Health Professionals' Follow-up Study, followed up at 2-year intervals from 1986 through January 31, 1998, to assess potential CHD risk factors, identify newly diagnosed cases of CHD, and assess levels of leisure-time physical activity. Main Outcome Measure  Incident nonfatal myocardial infarction or fatal CHD occurring during the follow-up period. Results  During 475 755 person-years, we documented 1700 new cases of CHD. Total physical activity, running, weight training, and rowing were each inversely associated with risk of CHD. The RRs (95% confidence intervals [CIs]) corresponding to quintiles of metabolic equivalent tasks (METs) for total physical activity adjusted for age, smoking, and other cardiovascular risk factors were 1.0, 0.90 (0.78-1.04), 0.87 (0.75-1.00), 0.83 (0.71-0.96), and 0.70 (0.59-0.82) (P<.001 for trend). Men who ran for an hour or more per week had a 42% risk reduction (RR, 0.58; 95% CI, 0.44-0.77) compared with men who did not run (P<.001 for trend). Men who trained with weights for 30 minutes or more per week had a 23% risk reduction (RR, 0.77; 95% CI, 0.61-0.98) compared with men who did not train with weights (P = .03 for trend). Rowing for 1 hour or more per week was associated with an 18% risk reduction (RR, 0.82; 05% CI, 0.68-0.99). Average exercise intensity was associated with reduced CHD risk independent of the total volume of physical activity. The RRs (95% CIs) corresponding to moderate (4-6 METs) and high (6-12 METs) activity intensities were 0.94 (0.83-1.04) and 0.83 (0.72-0.97) compared with low activity intensity (<4 METs) (P = .02 for trend). A half-hour per day or more of brisk walking was associated with an 18% risk reduction (RR, 0.82; 95% CI, 0.67-1.00). Walking pace was associated with reduced CHD risk independent of the number of walking hours. Conclusions  Total physical activity, running, weight training, and walking were each associated with reduced CHD risk. Average exercise intensity was associated with reduced risk independent of the number of MET-hours spent in physical activity.      

Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study

Context  Women who are physically active have a decreased risk for breast cancer, but the types, amounts, and timing of activity needed are unknown. Objective  To prospectively examine the association between current and past recreational physical activity and incidence of breast cancer in postmenopausal women. Design, Setting, and Patients  Prospective cohort study in 74 171 women aged 50 to 79 years who were recruited by 40 US clinical centers from 1993 through 1998. Main Outcome Measure  Incident invasive and in situ breast cancer. Results  We documented 1780 newly diagnosed cases of breast cancer over a mean follow-up of 4.7 years. Compared with less active women, women who engaged in regular strenuous physical activity at age 35 years had a 14% decreased risk of breast cancer (relative risk [RR], 0.86; 95% confidence interval [CI], 0.78-0.95). Similar but attenuated findings were observed for strenuous physical activity at ages 18 years and 50 years. An increasing total current physical activity score was associated with a reduced risk for breast cancer (P = .03 for trend). Women who engaged in the equivalent of 1.25 to 2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR, 0.82; 95% CI, 0.68-0.97) compared with inactive women. Slightly greater reduction in risk was observed for women who engaged in the equivalent of 10 hours or more per week of brisk walking. The effect of exercise was most pronounced in women in the lowest tertile of body mass index (BMI) (<24.1), but also was observed for women in the middle tertile of BMI (24.1-28.4). Conclusions  These data suggest that increased physical activity is associated with reduced risk for breast cancer in postmenopausal women, longer duration provides most benefit, and that such activity need not be strenuous.      

Folate intake and the risk of incident hypertension among US women

Context  Folate has important beneficial effects on endothelial function, but there is limited information about folate intake and risk of incident hypertension. Objective  To determine whether higher folate intake is associated with a lower risk of incident hypertension. Design, Setting, and Participants  Two prospective cohort studies of 93 803 younger women aged 27 to 44 years in the Nurses’ Health Study II (1991-1999) and 62 260 older women aged 43 to 70 years in the Nurses’ Health Study I (1990-1998), who did not have a history of hypertension. Baseline information on dietary folate and supplemental folic acid intake was derived from semiquantitative food frequency questionnaires and was updated every 4 years. Main Outcome Measure  Relative risk of incident self-reported hypertension during 8 years of follow-up. Results  We identified 7373 incident cases of hypertension in younger women and 12 347 cases in older women. After adjusting for multiple potential confounders, younger women who consumed at least 1000 µg/d of total folate (dietary plus supplemental) had a decreased risk of hypertension (relative risk [RR], 0.54; 95% confidence interval [CI], 0.45-0.66; P for trend <.001) compared with those who consumed less than 200 µg/d. Younger women’s absolute risk reduction (ARR) was approximately 8 cases per 1000 person-years (6.7 vs 14.8 cases). The multivariable RR for the same comparison in older women was 0.82 (95% CI, 0.69-0.97; P for trend = .05). Older women’s ARR was approximately 6 cases per 1000 person-years (34.7 vs 40.4 cases). When the analysis was restricted to women with low dietary folate intake (<200 µg/d), the multivariable RR for younger women with total folate intake at least 800 µg/d compared with less than 200 µg/d was 0.55 (95% CI, 0.32-0.94; P for trend = .03), and 0.61 (95% CI, 0.34-1.11; P for trend = .05) in the older cohort. Among women who did not take folic acid–containing supplements, dietary folate intake of 400 µg/d or more was not significantly associated with risk of hypertension. Conclusion  Higher total folate intake was associated with a decreased risk of incident hypertension, particularly in younger women.      

A Prospective Study of Coffee Consumption and the Risk of Symptomatic Gallstone Disease in Men

Context  Coffee has several metabolic effects that could reduce the risk of gallstone formation. Objective  To examine the association between coffee consumption and the risk of symptomatic gallstone disease in men. Design and Setting  The Health Professionals Follow-up Study, a prospective cohort study, in which the consumption of coffee and other caffeinated drinks was assessed starting in 1986 as part of the 131-item food frequency questionnaire given to US male health professionals with follow-up through 1996. Participants  A total of 46,008 men, aged 40 to 75 years in 1986, without history of gallstone disease. Main Outcome Measures  Newly symptomatic gallstone disease (diagnosed by ultrasonography or x-ray) or a cholecystectomy. Results  During 404,166 person-years of follow-up, 1081 subjects reported symptomatic gallstone disease, of whom 885 required cholecystectomy. After adjusting for other known or suspected risk factors, compared with men who did not consume regular coffee in 1986 and 1990, the adjusted relative risk (RR) for those who consistently drank 2 to 3 cups of regular coffee per day was 0.60 (95% confidence interval [CI], 0.42-0.86) and for those who drank 4 or more cups per day the RR was 0.55 (95% CI, 0.33-0.92). All coffee brewing methods showed a decreased risk. The risk of symptomatic gallstone disease also declined with increasing caffeine intake (P for trend=.005). After controlling for known or suspected risk factors, the RR for men in the highest category of caffeine intake (>800 mg/d) compared with men in the lowest category (25 mg/d) was 0.55 (95% CI, 0.35-0.87). In contrast, decaffeinated coffee was not associated with a decreased risk. Conclusions  In this cohort of US men, coffee consumption may have helped to prevent symptomatic gallstone disease.      

Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability

Context  Aerobic fitness, an important predictor of cardiovascular disease and mortality, is difficult to assess by maximal exercise testing in older adults. Extended walking tests have been examined as outcome predictors in medically ill populations but not in community-dwelling older adults. Objective  To determine whether an extended walking test predicts poor outcomes in older adults. Design, Setting, and Participants  Observational cohort study enrolling 3075 community-dwelling adults aged 70 to 79 years living in Pittsburgh, Pa, or Memphis, Tenn. Of those participating in the Health, Aging, and Body Composition Study, 1584 (52%) were women and 1281 (42%) were black. Participants enrolled from March 1997 to April 1998. Ability to complete the long-distance corridor walk and total performance time was assessed at the baseline examination. Main Outcome Measures  Total mortality, incident cardiovascular disease, incident mobility limitation, and mobility disability were ascertained after a mean (SD) of 4.9 (0.9) years. Results  Among patients eligible to exercise, 351 died, 308 had episodes of incident cardiovascular disease, 1116 had occurrences of mobility limitation, and 509 had occurrences of mobility disability. Inability to complete walking 400 m tended to be associated with a higher risk of mortality and incident cardiovascular disease and, after accounting for potential confounders, was associated with incident mobility limitation (212.6 vs 79.1 events/1000 person-years; adjusted hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.58-2.18; P<.001) and mobility disability (85.2 vs 28.8 events/1000 person-years; adjusted HR, 1.95; 95% CI, 1.56-2.44; P<.001). Of those who completed 400 m, each additional minute of performance time was associated with an adjusted HR of 1.29 (95% CI, 1.12-1.48) for mortality, 1.20 (95% CI, 1.01-1.42) for incident cardiovascular disease, 1.52 (95% CI, 1.41-1.63) for mobility limitation, and 1.52 (95% CI, 1.37-1.70) for disability after adjustment for demographics, health behaviors, clinical and subclinical disease, and cardiovascular disease risk factors. Findings were consistent in both men and women and blacks and whites. Among participants who completed the test and after adjusting for potential confounders, those in the poorest quartile of functional capacity (walk time >362 seconds) had a higher risk of death than those in the best quartile (walk time <290 seconds; adjusted HR, 3.23; 95% CI, 2.11-4.94; P<.001). Conclusions  Older adults in the community who reported no difficulty walking had a wide range of performance on this extended walking test. Ability to do the test and performance were important prognostic factors for total mortality, cardiovascular disease, mobility limitation, and mobility disability in persons in their eighth decade.      

Diurnal blood pressure pattern and risk of congestive heart failure

Context  High blood pressure is the most important risk factor for congestive heart failure (CHF) at a population level, but the relationship of an altered diurnal blood pressure pattern to risk of subsequent CHF is unknown. Objectives  To explore 24-hour ambulatory blood pressure characteristics as predictors of CHF incidence and to investigate whether altered diurnal blood pressure patterns confer any additional risk information beyond that provided by conventional office blood pressure measurements. Design, Setting, and Participants  Prospective, community-based, observational cohort in Uppsala, Sweden, including 951 elderly men free of CHF, valvular disease, and left ventricular hypertrophy at baseline between 1990 and 1995, followed up until the end of 2002. Twenty-four-hour ambulatory blood pressure monitoring was performed at baseline, and the blood pressure variables were analyzed as predictors of subsequent CHF. Main Outcome Measure  First hospitalization for CHF. Results  Seventy men developed heart failure during follow-up, with an incidence rate of 8.6 per 1000 person-years at risk. In multivariable Cox proportional hazards models adjusted for antihypertensive treatment and established risk factors for CHF (myocardial infarction, diabetes, smoking, body mass index, and serum cholesterol level), a 1-SD (9–mm Hg) increase in nighttime ambulatory diastolic blood pressure (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.02-1.55) and the presence of "nondipping" blood pressure (night-day ambulatory blood pressure ratio 1; HR, 2.29; 95% CI, 1.16-4.52) were associated with an increased risk of CHF. After adjusting for office-measured systolic and diastolic blood pressures, nondipping blood pressure remained a significant predictor of CHF (HR, 2.21; 95% CI, 1.12-4.36 vs normal night-day pattern). Nighttime ambulatory diastolic blood pressure and nondipping blood pressure were also significant predictors of CHF after exclusion of all participants who had an acute myocardial infarction before baseline or during follow-up. Conclusions  Nighttime blood pressure appears to convey additional risk information about CHF beyond office-measured blood pressure and other established risk factors for CHF. The clinical value of this association remains to be established in future studies.      

New parents and mental disorders: a population-based register study

Context  Studies on postpartum mental disorders among mothers have primarily focused on either depression or psychoses and have generally not included the broader spectrum of mental disorders. A few studies have found that some men have symptoms of depression after becoming fathers, but these studies have not documented whether this exceeds the morbidity among men in general. Objectives  To estimate the risk of postpartum mental disorders necessitating hospital admission or outpatient contact for mothers as well as fathers during a 1-year postnatal follow-up period after birth of first live-born child and to investigate whether parents in general differ from nonparents in the risk of admission with a mental disorder and how this difference varies with age. Design, Setting, and Patients  Register-based cohort formed by linking information from Danish health and civil service registers. A total of 2 357 942 Danish-born persons were followed up from their 15th birthday or January 1, 1973, whichever came later, until date of onset of the disorder in question, date of death, date of emigration from Denmark, or July 1, 2005, whichever came first. From 1973 to 2005, a total of 630 373 women and 547 431 men became parents for the first time, and during the first year after childbirth, these parents contributed 1 115 639 person-years at risk. Main Outcome Measure  First-time psychiatric hospital admission or outpatient contact 0 to 12 months after becoming a parent. Results  A total of 1171 mothers and 658 fathers were admitted with a mental disorder to a psychiatric hospital during the first 12 months after parenthood, and the corresponding prevalence of severe mental disorders through the first 3 months after childbirth was 1.03 per 1000 births for mothers and 0.37 per 1000 births for fathers. Compared with women who had given birth 11 to 12 months prior, primiparous women had an increased risk of incident hospital admission with any mental disorder through the first 3 months after childbirth, with the highest risk 10 to 19 days postpartum (relative risk [RR], 7.31; 95% confidence interval [CI], 5.44-9.81). Among mothers, risk was also increased for psychiatric outpatient contacts through the first 3 months after childbirth, also with the highest risk occurring 10 to 19 days postpartum (RR, 2.67; 95% CI, 1.99-3.59). Unlike motherhood, fatherhood was not associated with any increased risk of hospital admission or outpatient contact. Conclusion  In Denmark, the risk of postpartum mental disorders among primiparous mothers is increased for several months after childbirth, but among fathers there is no excess of severe mental disorders necessitating admission or outpatient contacts.      

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      

Prospective study of alcohol consumption and risk of dementia in older adults

Context  Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear. Objective  To determine the prospective relationship of alcohol consumption and risk of dementia among older adults. Design, Setting, and Participants  Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999. Main Outcome Measures  Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI. Results  Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95% CI, 0.60-2.49; P for quadratic term = .001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E 4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia. Conclusions  Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.      

Effect of estrogen therapy on gallbladder disease

Context  Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials. Objective  To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes. Design, Setting, and Participants  Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. The volunteer sample was 22 579 community-dwelling women aged 50 to 79 years without prior cholecystectomy. Intervention  Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E + P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14 203). Main Outcome Measures  Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods. Results  The CEE and the E + P groups were similar to their respective placebo groups at baseline. The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials, respectively. The annual incidence rate for any gallbladder event was 78 events per 10 000 person-years for the CEE group (vs 47/10 000 person-years for placebo) and 55 per 10 000 person-years for E + P (vs 35/10 000 person-years for placebo). Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06; E + P: HR, 1.59; 95% CI, 1.28-1.97). Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28; E + P: HR, 1.54; 95% CI 1.22-1.94); and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1.48-2.35; E + P: HR, 1.68; 95% CI, 1.34-2.11) for estrogen users. Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44; E + P: HR, 1.67; 95% CI, 1.32-2.11), but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04; E + P: HR, 1.49; 95% CI, 0.78-2.84). Conclusions  These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy. The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.      

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.      

Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level

Context  Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. Objective  To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. Design, Setting, and Participants  Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. Main Outcome Measure  Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. Results  There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41 779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100 000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100 000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P<.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk. Conclusion  Elevated serum HBV DNA level (10 000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.      

Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial

Context  Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy. Objective  To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo. Design, Setting, and Participants  The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS. Intervention  Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303). Main Outcome Measures  Incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment. Results  The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs 22 per 10 000 person-years; P = .01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000 person-years; P = .72). Conclusions  Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.      

Obesity and the risk of new-onset atrial fibrillation

Context  Obesity is associated with atrial enlargement and ventricular diastolic dysfunction, both known predictors of atrial fibrillation (AF). However, it is unclear whether obesity is a risk factor for AF. Objective  To examine the association between body mass index (BMI) and the risk of developing AF. Design, Setting, and Participants  Prospective, community-based observational cohort in Framingham, Mass. We studied 5282 participants (mean age, 57 [SD, 13] years; 2898 women [55%]) without baseline AF (electrocardiographic AF or arterial flutter). Body mass index (calculated as weight in kilograms divided by square of height in meters) was evaluated as both a continuous and a categorical variable (normal defined as <25.0; overweight, 25.0 to <30.0; and obese, 30.0). In addition to adjusting for clinical confounders by multivariable techniques, we also examined models including echocardiographic left atrial diameter to examine whether the influence of obesity was mediated by changes in left atrial dimensions. Main Outcome Measure  Association between BMI or BMI category and risk of developing new-onset AF. Results  During a mean follow-up of 13.7 years, 526 participants (234 women) developed AF. Age-adjusted incidence rates for AF increased across the 3 BMI categories in men (9.7, 10.7, and 14.3 per 1000 person-years) and women (5.1, 8.6, and 9.9 per 1000 person-years). In multivariable models adjusted for cardiovascular risk factors and interim myocardial infarction or heart failure, a 4% increase in AF risk per 1-unit increase in BMI was observed in men (95% confidence interval [CI], 1%-7%; P = .02) and in women (95% CI, 1%-7%; P = .009). Adjusted hazard ratios for AF associated with obesity were 1.52 (95% CI, 1.09-2.13; P = .02) and 1.46 (95% CI, 1.03-2.07; P = .03) for men and women, respectively, compared with individuals with normal BMI. After adjustment for echocardiographic left atrial diameter in addition to clinical risk factors, BMI was no longer associated with AF risk (adjusted hazard ratios per 1-unit increase in BMI, 1.00 [95% CI, 0.97-1.04], P = .84 in men; 0.99 [95% CI, 0.96-1.02], P = .56 in women). Conclusions  Obesity is an important, potentially modifiable risk factor for AF. The excess risk of AF associated with obesity appears to be mediated by left atrial dilatation. These prospective data raise the possibility that interventions to promote normal weight may reduce the population burden of AF.      

Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years

Context  Prior estimates of long-term trends in the incidence and severity of stroke have varied; trends in lifetime risk have not been reported. Objective  To determine long-term trends in the incidence, lifetime risk, severity, and 30-day mortality of clinical stroke. Design, Setting, and Participants  Prospective evaluation of the community-based Framingham Study original and offspring cohorts. Participants were 9152 men and women free of prevalent stroke and undergoing follow-up for up to 50 years over 3 consecutive periods (1950-1977, 1978-1989, and 1990-2004), with biennial ascertainment of stroke risk factor data and active surveillance for incident clinical stroke and cause-specific mortality. Main Outcome Measures  Incidence (age-adjusted, sex-specific), severity, 30-day mortality, and mortality-adjusted 10-year and lifetime risk of stroke in each of the specified periods. Results  There were 1030 incident clinical strokes (450 [44%] in men, 629 atherothrombotic brain infarctions [61%]) in 9152 persons 55 years or older over 174 917 person-years of follow-up. The age-adjusted incidence of first stroke per 1000 person-years in each of the 3 periods was 7.6, 6.2, and 5.3, respectively, in men (P = .02 for trend) and 6.2, 5.8, and 5.1 in women (P = .01 for trend). The lifetime risk at age 65 years decreased from 19.5% to 14.5% in men (P = .11) and from 18.0% to 16.1% in women (P = .61). Age-adjusted stroke severity did not vary across periods; however, 30-day mortality decreased significantly in men (from 23% to 14%; P = .01) but not significantly in women (from 21% to 20%; P = .32). Conclusions  In this cohort of men and women free of prevalent clinical stroke at initial examination, incidence of stroke has decreased over the past 50 years but the lifetime risk has not declined to the same degree, perhaps due to improved life expectancy. The results of this study suggest that improved control of risk factors has lowered stroke incidence but emphasize the need for continued primary prevention efforts.      

Risk of hip fracture among dialysis and renal transplant recipients

Context  Renal failure places people at particularly high risk of hip fracture. However, the possible differential impact of dialysis and renal transplantation on this risk is not well understood. Objective  To determine if patients who receive kidney transplants are at greater risk of hip fracture compared with those who continue to undergo dialysis. Design, Setting, and Participants  Cohort study of 101 039 patients with end-stage renal disease placed on the renal transplant waiting list in the United States between January 1, 1990, and December 31, 1999. Main Outcome Measures  Hip fractures, identified from Medicare claims data. Results  Among the patients included in this analysis, 971 hip fractures were observed during the follow-up period of 314 767 person-years. The incidence rate of hip fracture in patients receiving dialysis was 2.9 per 1000 patients per year compared with 3.3 hip fractures per 1000 patients per year in those who had previously received a renal transplant. Initially, the relative risk (RR) of hip fracture associated with transplantation was 1.34-fold greater when compared with dialysis (adjusted RR, 1.34; 95% confidence interval [CI], 1.12-1.61) but then decreased by 1% per month (adjusted RR, 0.99; 95% CI, 0.98-0.99) until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation (adjusted RR, 1.00; 95% CI, 0.87-1.15). Among transplant recipients, risk of fracture was relatively higher in persons with a prolonged period of dialysis before transplantation. Conclusion  The high risk of hip fracture among dialysis patients is exceeded by that among renal transplant patients during the first 1 to 3 years after transplantation.      

Ejaculation frequency and subsequent risk of prostate cancer

Context  Sexual activity has been hypothesized to play a role in the development of prostate cancer, but epidemiological data are virtually limited to case-control studies, which may be prone to bias because recall among individuals with prostate cancer could be distorted as a consequence of prostate malignancy or ongoing therapy. Objective  To examine the association between ejaculation frequency, which includes sexual intercourse, nocturnal emission, and masturbation and risk of prostate cancer. Design, Setting, and Participants  Prospective study using follow-up data from the Health Professionals Follow-up Study (February 1, 1992, through January 31, 2000) of 29 342 US men aged 46 to 81 years, who provided information on history of ejaculation frequency on a self-administered questionnaire in 1992 and responded to follow-up questionnaires every 2 years to 2000. Ejaculation frequency was assessed by asking participants to report the average number of ejaculations they had per month during the ages of 20 to 29 years, 40 to 49 years, and during the past year (1991). Main Outcome Measure  Incidence of total prostate cancer. Results  During 222 426 person-years of follow-up, there were 1449 new cases of total prostate cancer, 953 organ-confined cases, and 147 advanced cases of prostate cancer. Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer. The multivariate relative risks for men reporting 21 or more ejaculations per month compared with men reporting 4 to 7 ejaculations per month at ages 20 to 29 years were 0.89 (95% confidence interval [CI], 0.73-1.10); ages 40 to 49 years, 0.68 (95% CI, 0.53-0.86); previous year, 0.49 (95% CI, 0.27-0.88); and averaged across a lifetime, 0.67 (95% CI, 0.51-0.89). Similar associations were observed for organ-confined prostate cancer. Ejaculation frequency was not statistically significantly associated with risk of advanced prostate cancer. Conclusions  Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer.