Mary Pettinger

Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study.

The Coronary Artery Surgery Study (CASS) randomized 780 patients to an initial strategy of coronary surgery or medical therapy. Of medically randomized patients, 6% had surgery within 6 months and a total of 40% had surgery by 10 years. At 10 years, there was no difference in cumulative survival (medical, 79% vs. surgical, 82%; NS) and no difference in percentage free of death and nonfatal myocardial infarction (medical, 69% vs. surgical, 66%; NS). Patients with an ejection fraction of less than 0.50 exhibited a better survival with initial surgery treatment (medical, 61% vs. surgical, 79%; p = 0.01). Conversely, patients with an ejection fraction greater than or equal to 0.50 exhibited a higher proportion free of death and myocardial infarction with initial medical therapy (medical, 75% vs. surgical, 68%; p = 0.04) although long-term survival remained unaffected (medical, 84% vs. surgical, 83%; p = 0.75). There were no significant differences either in survival and freedom from nonfatal myocardial infarction, whether stratified on presence of heart failure, age, hypertension, or number of vessels diseased. Thus, 10-year follow-up results confirm earlier reports from CASS that patients with left ventricular dysfunction exhibit long-term benefit from an initial strategy of surgical treatment. Patients with mild stable angina and normal left ventricular function randomized to initial medical treatment (with an option for later surgery if symptoms progress) have survival equivalent to those patients randomized to initial surgery.

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS Postmenopausal women (N = 36 282) who were enrolled in a Womens Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

The effect of medical and surgical treatment on subsequent sudden cardiac death in patients with coronary artery disease: a report from the Coronary Artery Surgery Study.

The effect of medical and surgical treatment on subsequent sudden cardiac death was assessed in 13,476 patients in the Coronary Artery Surgery Study registry who had significant coronary artery disease, operable vessels, and no significant valvular disease. (Patients were assigned to medical or surgical therapy on the basis of clinical judgment and not according to a randomization scheme; therefore, biases associated with unknown variables could not be evaluated.) Sudden cardiac death occurred in 452 patients (3.4%) during a mean follow-up of 4.6 years. Five year survival free of sudden death for medically treated patients was 94 +/- 0.3%, and that for surgically treated patients was 98 +/- 0.2% (p less than .0001). Twelve baseline clinical, electrocardiographic, and angiographic variables were significantly different between patients alive at the last follow-up and those suffering sudden death. Data on these variables were available for 11,508 patients. Sudden death occurred in 257 (4.9%) of 5258 medically treated and 101 (1.6%) of 6250 surgically treated patients. In a high-risk patient subset with three-vessel disease and history of congestive heart failure, 91% of surgically treated patients had not suffered sudden death compared with 69% of medically treated patients. After Cox survival analysis was used to correct for baseline variables, surgical treatment had an independent effect on sudden death (p less than .0001). This reduction was most pronounced in high-risk patients.

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause

The authors further analyzed results from the Womens Health Initiative randomized trials (1993-2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Womens Health Initiative observational study (1993-2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.

Validity of self-report for fractures among a multiethnic cohort of postmenopausal women: results from the Women's Health Initiative observational study and clinical trials.

Objective:The purpose of this study is to examine the validity of, and factors associated with, the accuracy of self-report (participant-report and proxy-report) for fractures. Design:Study participants were from the Womens Health Initiative Clinical Trial and Observational Study cohorts. All women were postmenopausal; populations included American Indian, Asian/Pacific Islander, black, Hispanic, and non-Hispanic white. The average length of follow-up was 4.3 years. Self-reported fractures were adjudicated by reviewing medical records. The first adjudicated self-report of fractures for each participant was included in the analysis (n = 6,652). Results:We found substantial variations in validity of self-report by the fracture site. Agreements between self-reports for single-site fractures and medical records were high for hip (78%) and forearm/wrist (81%) but relatively lower for clinical spine fractures (51%). The average confirmation rate for all single-site fractures was 71%. Misidentification of fracture sites by participants or proxy-reporters seemed to be a cause of unconfirmed self-reports. Higher confirmation rates were observed in participant-reports than in proxy-reports. Results of the multivariate analysis indicated that multiple factors, such as ethnicity, a history of osteoporosis or fractures, body mass index, years since menopause, smoking status, and number of falls in the past year were significantly (P < 0.05) related to the validity of self-report. Conclusion:The validity of self-reports for fracture varies by fracture sites and many other factors. The assessed validity in this study is likely conservative because some of the unconfirmed self-reports may be due to poor medical record systems. The validity of self-reports for hip and forearm/wrist fractures is high in this study, supporting their use in epidemiological studies among postmenopausal women.

Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: Results from the women's health initiative randomized trial

Further analyses from the Womens Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture.

Statin Use, Clinical Fracture, and Bone Density in Postmenopausal Women: Results from the Women's Health Initiative Observational Study

Context Some observational studies have shown fewer fractures in patients receiving statins, but other studies have shown no effect. The studies have been small and had limited ability to adjust for potential confounders. Contribution In this subanalysis of the Womens Health Initiative, postmenopausal women had similar rates of hip, lower arm or wrist, and other fractures whether or not they used statins. The authors adjusted for many potential confounders, and the estimates of fracture rates were very precise. Implications Statins do not seem to prevent fractures in postmenopausal women. The Editors The long-term efficacy and safety of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been established in large multicenter trials of cholesterol-lowering for preventing coronary events in both sexes (1-4). Recent laboratory studies have shown that statins stimulate bone formation in cultured osteoblasts, neonatal murine calvaria, and the cortical bone of mice (5). Statins administered orally increased the trabecular bone volume of female rats by 90%. These findings raise the possibility that statin treatment might prevent both coronary and fracture events, two major causes of morbidity in older women, later in life. Early epidemiologic studies examining the association of statin use with risk for hip fracture produced encouraging results (6-9). These studies were limited, however, by either small numbers of fractures (6) or lack of data on important potential confounders (7-9). More recent studies had mixed results (10-12), with some showing no association (11, 12). Few studies have examined associations with both fracture rates and bone density in the same study group. Therefore, we examined the association of statin use with levels of bone density and rates of hip, lower arm or wrist, and other clinical fractures in the Womens Health Initiative (WHI) Observational Study cohort of postmenopausal women. Methods Study Group The study group for this paper is the WHI Observational Study, a prospective cohort study that enrolled 93 716 women ages 50 to 79 years from 1994 to 1998 at 40 clinical centers throughout the United States. Study methods have been described in detail elsewhere (13). Briefly, women were eligible if they were postmenopausal, were unlikely to relocate or die within 3 years, were not enrolled in the WHI Clinical Trial, and were not participating in any other clinical trial. At baseline, women completed screening and enrollment questionnaires by interview and self-report, physical examination, and blood specimen collection. Human subjects review committees at each participating institution reviewed and approved the study. Follow-up and Outcome Ascertainment Women are sent questionnaires annually to report any hospitalization and a wide variety of outcomes, including clinical fractures of any type. Follow-up time ranged from 2 to 6 years per participant as of February 2001 (median duration, 3.9 years). At that time, 2.8% of participants (n = 2632) had withdrawn or were lost to follow-up [2.7% of statin users and 2.8% of nonusers]. Hip fractures are confirmed by central review of radiology reports. Other fractures are counted on the basis of self-report. Nonetheless, in the WHI Clinical Trial, in which all fractures are adjudicated, 81% of self-reported nonhip clinical fractures are confirmed by physician review of medical records, suggesting that the self-report of such fractures is reasonably accurate. For this report, we classified fractures into three mutually exclusive categories: 1) hip fractures, 2) lower arm or wrist fractures, and 3) other clinical fractures. Clinically recognized vertebral fractures were classified as other clinical fractures. Bone mineral density at the total hip, posterioranterior spine, and total body was measured at baseline in three clinical centers among 6442 women (97% of participants enrolled in Pittsburgh, Pennsylvania; Birmingham, Alabama; and Phoenix and Tucson, Arizona) with dual-energy x-ray absorptiometry using a Hologic QDR densitometer (Hologic, Inc., Waltham, Massachusetts). Standard protocols for positioning and analysis were used by technicians who were trained and certified by the University of California, San Francisco, Bone Density Coordinating Center, San Francisco, California. The ongoing quality assurance program includes monitoring spine and hip phantom scans; reviewing a random sample of all scans and flagging scans with specific problems; hardware or software change control, including in vitro and in vivo cross-calibration; and scanning calibration phantoms across instruments and clinical sites. Statin Exposure and Potential Confounders Participants were asked to bring all current prescription medications to their first screening interview. Clinic interviewers entered each medication name directly from the containers into the WHI database, which assigned drug codes using Medispan software (First DataBank, Inc., San Bruno, California). Women reported duration of use for each current medication. Information on dose was not recorded. Current medication use was ascertained by using identical methods at the year 3 clinic visit. Current statin medication use was defined as use of any HMG-CoA reductase inhibitor. Duration of use was examined in three categories (<1 year, 1 to 3 years, or >3 years). Statin medications were further categorized into three groups according to their demonstrated potency for lipid-lowering on the basis of a dose-efficacy trial (14): low potency (fluvastatin and lovastatin), medium potency (pravastatin), and high potency (atorvastatin, simvastatin). Other lipid-lowering medications were fibrate, colestipol, probucol, cholestyramine, niacin, or nicotinic acid. All covariates were ascertained at baseline. Current use of thiazide diuretics, alendronate, corticosteroid, and sedative or hypnotic medications was recorded by using the same procedures described. Current and previous use of hormone replacement therapy was ascertained by interview using a detailed questionnaire that measured type, route of administration, number of pills per day or week, and duration for each hormonal preparation ever taken. For the purposes of this report, hormone replacement therapy was defined as current use of any estrogen with or without progestin. Dietary supplements, including calcium preparations, taken at least twice weekly for the past 2 weeks were also entered into the database. Dietary intake of calcium was measured by using a semi-quantitative food-frequency questionnaire (15). Total calcium intake was defined as the sum of calcium from diet and supplements. Baseline questionnaires ascertained information on race or ethnicity, history of fracture or coronary heart disease (history of myocardial infarction or angina), current and past smoking, coffee consumption (cups per day), and time spent walking outside the home for more than 10 minutes without stopping (minutes per week). Alcohol consumption was estimated from the food-frequency questionnaire. Physical function was measured by using the 10-item Medical Outcomes Study scale (16). Weight was measured to the nearest 0.1 kg on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer. Body mass index was calculated as weight in kg/height in m2. Statistical Analysis The characteristics of women taking a statin medication at baseline were compared with those of women not taking statin medication by using chi-square tests to determine the statistical significance of the differences. Age-adjusted incidence rates of hip, lower arm or wrist, and other clinical fractures per 1000 person-years were calculated according to duration of statin use by the direct method, using the age distribution of the full cohort as the standard population. Women contributed follow-up time until the occurrence of fracture, death, or the end of follow-up, whichever came first. The a priori analysis plan specified selected stratified analyses to determine whether associations between statin use and fracture were apparent in key subgroups of women. For these analyses, women were stratified according to age group (50 to 64 years versus 65 years), current hormone replacement therapy use, body mass index (<25 kg/m2 versus 25 kg/m2, the standard threshold for overweight) (17), history of fracture, and history of coronary disease. Hazard ratios adjusted for age and corresponding 95% CIs were calculated by using Cox proportional-hazards survival models for each fracture category using PHREG in SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). To control for potential confounding factors, hazard ratios and corresponding 95% CIs for categories of duration and potency of statin use were calculated by using multivariate Cox proportional-hazards survival models, using the forced entry approach for variable selection. The multivariate models adjusted for age; race or ethnicity; body mass index; previous fracture; previous coronary disease; current and past hormone replacement therapy use; thiazide, alendronate, corticosteroid, or psychoactive drug use; calcium intake; walking; current and past smoking; coffee intake; and physical function. The multivariate models included individual clinical center as a stratification (or blocking) variable to allow the underlying hazard to be estimated separately for each clinical center. Interaction by clinical center was evaluated by comparing log likelihood statistics (chi-squares) for a model with interaction terms for each clinical center and a reduced model without these terms. Tests for the proportional hazards assumption were conducted by examining plots of the baseline hazard by statin duration categories and by testing interaction terms of statin use by time. Multivariate models were based on 81 896 individuals after exclusion

Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women's Health Initiative Calcium plus Vitamin D Clinical Trial

BACKGROUND It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations. OBJECTIVE The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status. DESIGN A random sample of 3055 postmenopausal women (aged 50-70 y) participating in 3 nested case-control studies of the Womens Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995-2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Womens Health Initiative baseline (1993-1998), were used. RESULTS More than half of the women (57.1%) had deficient (<50 nmol/L) concentrations of 25(OH)D. Distributions of 25(OH)D concentrations by level of latitude of residence, mean annual regional solar irradiance, and intake of vitamin D varied considerably. The predictive model for 25(OH)D explained 21% of the variation in 25(OH)D concentrations. After adjustment for month of blood draw, breast cancer status, colorectal cancer status, fracture status, participation in the hormone therapy trial, and randomization to the dietary modification trial, the predictive model included total vitamin D intake from foods and supplements, waist circumference, recreational physical activity, race-ethnicity, regional solar irradiance, and age. CONCLUSIONS Surrogate markers for 25(OH)D concentrations, although somewhat correlated, do not adequately reflect serum vitamin D measures. These markers and predictive models of blood 25(OH)D concentrations should not be given as much weight in epidemiologic studies of cancer risk.

Assessment of Clinical Validity of a Breast Cancer Risk Model Combining Genetic and Clinical Information

Background The Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment. Methods Seven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case–control cohort of 1664 case patients and 1636 control subjects within the Women’s Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer–Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%–2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided. Results The SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 × 10−5). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10−5). Conclusions Combining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk.

Simulation as a design tool for phase I/II clinical trials: An example from bone marrow transplantation

We discuss the design and analysis of a proposed phase I/II clinical trial in bone marrow transplantation whereby dose modifications that decrease the risk of one complication increase the risk of another. Trials of this type are carried out to determine whether a dose can be found that balances the risks of each complication. Three different scenarios describing potential relationships between each risk and the treatment dose are postulated. The scenarios encompass both favorable situations in which several acceptable doses exist and unfavorable situations in which no acceptable dose exists. The operating characteristics of three sequentially developed trial designs were examined by simulation under each dose-response scenario. The first design was derived from seemingly reasonable rules, but simulations showed that performance fell far short of what was desired, thus motivating modifications. Subsequent designs showed improved performance characteristics compared to the original design. Without close examination of the operating characteristics, the original design would have been implemented, leading to high risk of an erroneous conclusion.