Nancy R. Cook

Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

BACKGROUND Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. METHODS In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. RESULTS Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. CONCLUSIONS In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.

C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events

Background—The metabolic syndrome describes a high-risk population having 3 or more of the following clinical characteristics: upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose. All of these attributes, however, are associated with increased levels of C-reactive protein (CRP). Methods and Results—We evaluated interrelationships between CRP, the metabolic syndrome, and incident cardiovascular events among 14 719 apparently healthy women who were followed up for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death; 24% of the cohort had the metabolic syndrome at study entry. At baseline, median CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (Ptrend <0.0001). Over the 8-year follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk. For example, among those with the metabolic syndrome at study entry, age-adjusted incidence rates of future cardiovascular events were 3.4 and 5.9 per 1000 person-years of exposure for those with baseline CRP levels less than or greater than 3.0 mg/L, respectively. Additive effects for CRP were also observed for those with 4 or 5 characteristics of the metabolic syndrome. The use of different definitions of the metabolic syndrome had minimal impact on these findings. Conclusions—These prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome.

Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction

The c statistic, or area under the receiver operating characteristic (ROC) curve, achieved popularity in diagnostic testing, in which the test characteristics of sensitivity and specificity are relevant to discriminating diseased versus nondiseased patients. The c statistic, however, may not be optimal in assessing models that predict future risk or stratify individuals into risk categories. In this setting, calibration is as important to the accurate assessment of risk. For example, a biomarker with an odds ratio of 3 may have little effect on the c statistic, yet an increased level could shift estimated 10-year cardiovascular risk for an individual patient from 8% to 24%, which would lead to different treatment recommendations under current Adult Treatment Panel III guidelines. Accepted risk factors such as lipids, hypertension, and smoking have only marginal impact on the c statistic individually yet lead to more accurate reclassification of large proportions of patients into higher-risk or lower-risk categories. Perfectly calibrated models for complex disease can, in fact, only achieve values for the c statistic well below the theoretical maximum of 1. Use of the c statistic for model selection could thus naively eliminate established risk factors from cardiovascular risk prediction scores. As novel risk factors are discovered, sole reliance on the c statistic to evaluate their utility as risk predictors thus seems ill-advised.

Assessing the performance of prediction models: a framework for traditional and novel measures.

The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration. Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision–analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions. We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration, we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n = 544 for model development, n = 273 for external validation). We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.

Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP)

Objective To examine the effects of reduction in dietary sodium intake on cardiovascular events using data from two completed randomised trials, TOHP I and TOHP II. Design Long term follow-up assessed 10-15 years after the original trial. Setting 10 clinic sites in 1987-90 (TOHP I) and nine sites in 1990-5 (TOHP II). Central follow-up conducted by post and phone. Participants Adults aged 30-54 years with prehypertension. Intervention Dietary sodium reduction, including comprehensive education and counselling on reducing intake, for 18 months (TOHP I) or 36-48 months (TOHP II). Main outcome measure Cardiovascular disease (myocardial infarction, stroke, coronary revascularisation, or cardiovascular death). Results 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2415 (77%), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P=0.34). Conclusion Sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events.

Physical Activity and Reduced Risk of Cardiovascular Events Potential Mediating Mechanisms

Background— Higher levels of physical activity are associated with fewer cardiovascular disease (CVD) events. Although the precise mechanisms underlying this inverse association are unclear, differences in several cardiovascular risk factors may mediate this effect. Methods and Results— In a prospective study of 27 055 apparently healthy women, we measured baseline levels of hemoglobin A1c, traditional lipids (total, low-density lipoprotein, and high-density lipoprotein cholesterol), novel lipids [lipoprotein(a) and apolipoprotein A1 and B-100], creatinine, homocysteine, and inflammatory/hemostatic biomarkers (high-sensitivity C-reactive protein, fibrinogen, soluble intracellular adhesion molecule-1) and used womens self-reported physical activity, weight, height, hypertension, and diabetes. Mean follow-up was 10.9±1.6 years, and 979 incident CVD events occurred. The risk of CVD decreased linearly with higher levels of activity (P for linear trend <0.001). Using the reference group of <200 kcal/wk of activity yielded age- and treatment-adjusted relative risk reductions associated with 200 to 599, 600 to 1499, and ≥1500 kcal/wk of 27%, 32%, and 41%, respectively. Differences in known risk factors explained a large proportion (59.0%) of the observed inverse association. When sets of risk factors were examined, inflammatory/hemostatic biomarkers made the largest contribution to lower risk (32.6%), followed by blood pressure (27.1%). Novel lipids contributed less to CVD risk reduction compared with traditional lipids (15.5% and 19.1%, respectively). Smaller contributions were attributed to body mass index (10.1%) and hemoglobin A1c/diabetes (8.9%), whereas homocysteine and creatinine had negligible effects (<1%). Conclusions— The inverse association between physical activity and CVD risk is mediated in substantial part by known risk factors, particularly inflammatory/hemostatic factors and blood pressure.

Long-Term Weight Loss and Changes in Blood Pressure: Results of the Trials of Hypertension Prevention, Phase II

Approximately one fourth of the U.S. adult populationnearly 50 million peoplehas hypertension (1, 2). Taking a broader perspective, more than half of the adult population has higher than optimal blood pressure (1), defined as systolic blood pressure greater than 120 mm Hg and diastolic blood pressure greater than 80 mm Hg (2). These persons are at significantly increased risk for cardiovascular disease and stroke (3). Although pharmacologic treatment for hypertension significantly reduces morbidity and mortality from cardiovascular diseases (4, 5), long-term pharmacologic therapy can have undesirable side effects and requires the expense of continuing medical supervision. Furthermore, pharmacologic therapy is not usually initiated when blood pressure is higher than optimal yet below diagnostic thresholds for hypertension. Thus, lifestyle interventions for primary prevention and initial treatment of high blood pressure remain a vital strategy for controlling this highly prevalent condition (2). Weight loss has been shown to reduce blood pressure in overweight hypertensive patients (6-9) and in overweight persons with high-normal blood pressure (10-12). Two reviews of randomized trials of weight reduction to reduce blood pressure examined the results of nine studies (13, 14). Most of these trials were small, only one had more than 500 participants (11), and most had short-term follow-up (1 year or less). Only three studies had follow-up of 3 to 5 years (8, 10, 11). Compared with controls, weight loss averaged nearly 7 kg in the short-term trials and approximately 3 kg in the three longer-term trials. In almost all trials, systolic blood pressure and diastolic blood pressure were reduced in the intervention groups. Since these reviews were published, the Trials of Hypertension Prevention (TOHP) Phase I reported mean weight reduction of 3.9 kg at 18 months in 564 overweight participants with high-normal blood pressure, resulting in significant decreases in systolic blood pressure and diastolic blood pressure compared with a usual care control group (12, 15). To investigate whether nonpharmacologic interventions can prevent hypertension over the long term, TOHP II was initiated. This was a randomized, controlled trial examining the effects of weight loss and dietary sodium reduction, alone and in combination, in reducing blood pressure in overweight adults with high-normal diastolic blood pressure (16). This target population is at high risk for hypertension as they age. The primary outcome paper from this trial (17) provided only a brief overview of the effects of weight loss on blood pressure. Here, we provide more detailed analysis of weight loss and blood pressure in TOHP II. Of special interest are the long-term effects of weight loss on blood pressure, the magnitude of the doseresponse relationship at 36 months, the effect of patterns of weight loss on blood pressure, and the predictors of weight loss and blood pressure response. Methods Participants Participants in TOHP II were overweight adults with nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg. Other eligibility criteria included age 30 to 54 years and a body mass index of 26.1 to 37.4 kg/m2 for men and 24.4 to 37.4 kg/m2 for women, approximately 110% to 165% of ideal weight (18). Principal exclusion criteria were current treatment with medications that might affect blood pressure, clinical or laboratory evidence of cardiovascular disease, diabetes mellitus, renal insufficiency (serum creatinine concentration 150 mol/L [ 1.7 mg/dL] for men and 132 mol/L [ 1.5 mg/dL] for women), and current or planned pregnancy. Detailed descriptions of recruitment and participant characteristics have been published elsewhere (19, 20). The study was reviewed and approved by the institutional review boards at all nine TOHP centers and the coordinating center, and all participants signed informed consent forms. Design Eligible participants were randomly assigned with equal probability to one of four groups: weight loss only, sodium reduction only, combined weight loss and sodium reduction, or usual care (controls). Measurements Age, sex, ethnicity, and years of education were obtained by questionnaire. Baseline blood pressure measurements were taken at three screening visits, each separated by 7 to 45 days. At each visit, three readings of systolic blood pressure and diastolic blood pressure were obtained and averaged. Certified staff obtained measurements in seated participants by using a Hawksley random-zero sphygmomanometer (21). Body weight was measured to the nearest 0.2 kg (0.5 lb) by using a calibrated balance-beam scale; participants wore indoor clothing (without shoes). Blood pressure and weight were measured every 6 months after randomization to the end of follow-up at 36, 42, or 48 months, depending on randomization date. Clinic staff who were blinded to study group assignment made these assessments. Blood pressure measurements were obtained during a single visit at all follow-up points except for 18 and 36 months, when measurements were taken at a series of three visits approximately 1 week apart. Multiple measurements were taken at 18 and 36 months to provide a more precise assessment of average blood pressures at these primary outcome points. Dietary intake was assessed by 24-hour recall, and physical activity was assessed by questionnaire. Intervention Participants assigned to the weight loss intervention group sought to lose at least 4.5 kg (10 lb) during the first 6 months of the intervention and to maintain their weight loss for the remainder of the trial. A brief description of the intervention methods is presented here; a more detailed description has been published elsewhere (22). The intervention started with an individual counseling session, followed by 14 weekly group meetings led by dietitians or health educators. After this 14-week intensive phase, participants attended six biweekly group meetings and then monthly group meetings. Beginning in the 18th month, participants were offered a variety of options to keep them involved in the intervention, including individual counseling sessions and special group sessions focused on selected weight loss topics. The intervention focused on self-directed behavior change (behavioral self-management), nutrition education, information on physical activity, and social support for making and maintaining behavior changes. Specific behavior change techniques included self-monitoring (food diaries and graphs of minutes of physical activity per day), setting explicit short-term goals and developing specific action plans to achieve those objectives, and developing alternative strategies for situations that trigger problem eating. The dietary intervention focused on reducing caloric intake by decreasing consumption of excess fat, sugar, and alcohol. Keeping daily food diaries was emphasized for monitoring intake and assessing progress. With experience, the participants determined the caloric intake that produced moderate weight loss for them. It was suggested that men not consume less than 1500 kcal/d and women not less than 1200 kcal/d. Weight loss of more than 0.9 kg (2 lb) per week was discouraged. The physical activity goal was to gradually increase activity to 30 to 45 minutes per day, four to five days per week. Exercise intensity was moderate, approximately 40% to 55% of heart rate reserve, and consisted primarily of brisk walking. Statistical Analysis Baseline characteristics of the weight loss and usual care groups were compared overall and by sex by using t-tests for means and chi-square tests for proportions. Although weight and blood pressure data were collected every 6 months, special efforts were made to achieve high follow-up rates at 18 and 36 months; at each of these two time points, nine blood pressure readings were collected over three visits and were averaged. For participants prescribed antihypertensive medication, follow-up blood pressure for all subsequent visits was taken to be the last study blood pressure before therapy was started. Participants receiving medications that affect blood pressure for reasons other than hypertension or who became pregnant were treated as missing at that visit. We used two-sample t-tests to compare changes in weight and blood pressure from baseline in the weight loss intervention and usual care groups overall, by sex, by ethnicity, and by sex and ethnicity. The effects of the intervention in terms of changes in weight and blood pressure were examined overall and in subgroups defined by sex, ethnicity, and sex and ethnicity. Subgroup differences were tested by using terms for the interaction of treatment group with sex and with ethnicity in multiple linear regression models. Regression analyses were also used to analyze the doseresponse relationship between change in weight and change in blood pressure, overall and within sex and ethnicity subgroups. Differences in dose response were tested by using interaction terms in linear regression models. All regressions were adjusted for age and baseline weight. We also adjusted for baseline blood pressure in the blood pressure regression models. Change in blood pressure was also examined in relation to quintile of weight loss. Quintiles were computed by using the distribution of weight change in the weight loss intervention group. Additional multiple regression analyses were performed in which weight loss participants were categorized according to patterns of weight loss at 6 and 36 months. The PROC MIXED function of SAS software (SAS Institute, Inc., Cary, North Carolina) was used to perform repeated-measures analyses that tested differences over time by pattern of weight loss. Cox proportional-hazards models were used for survival analyses, with onset of hypertension as the outcome. Results Baseline Findings The baseline characteristics of participants assigned to th

The Effect of Including C-Reactive Protein in Cardiovascular Risk Prediction Models for Women

Context The value of adding high-sensitivity C-reactive protein (hsCRP) to a global risk assessment model is unknown. Contribution The authors used the Womens Health Study, a nationwide cohort of 15048 initially healthy women, to develop a cardiovascular disease (CVD) risk prediction model using hsCRP and Framingham risk model predictors. While hsCRP improved overall model fit, the clinical utility of hsCRP in terms of reclassification was most substantial for those with a 5% or greater 10-year risk based on traditional risk factors. Cautions The study does not address the clinical value of lowering hsCRP level. Implications In this largely low-risk population, adding hsCRP to the Framingham model reclassified patients into groups that better reflected their actual CVD risk. This effect was most clinically relevant for those at intermediate risk. The Editors The Framingham risk model (1) is used extensively for detecting risk for coronary heart disease and has been adapted by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (2). The traditional risk factors included are strong predictors of cardiovascular risk, and the model has been validated in several populations (3). However, despite the models success, up to 20% of all coronary events occur in the absence of any major risk factor (4, 5). In addition, most individuals who do not develop coronary heart disease have at least 1 clinically elevated Framingham risk factor (6). Given these modest levels of sensitivity and specificity, research over the past decade has focused on novel blood-based atherosclerotic risk factors that, like cholesterol, can be inexpensively obtained and interpreted in the primary care setting. One of the most promising of these is high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammation that has consistently been shown to predict incident myocardial infarction, stroke, and cardiovascular death among apparently healthy men and women after adjustment for all components of the Framingham risk score (7-16). Blood levels of hsCRP also correlate with hypofibrinolysis and abnormal glucose metabolism, and thus reflect pathophysiologic processes that are related to vascular occlusion but are not easily measured with traditional risk factors (17-20). On that basis, in 2003 the Centers for Disease Control and Prevention and the American Heart Association published the first set of guidelines to endorse the use of hsCRP as a potential adjunct to traditional risk factor screening (21). Despite these data, no simple clinical algorithm that includes Framingham covariables and hsCRP has been developed, and thus it has not been possible to determine whether individuals might be more accurately classified if hsCRP were added to global risk prediction models for major cardiovascular disease (CVD), including myocardial infarction, coronary revascularization, stroke, and cardiovascular death (22). Methods We compared the clinical utility of global cardiovascular risk prediction models based on Framingham covariables with and without hsCRP among participants in the Womens Health Study (WHS) (23-25), a large-scale, nationwide cohort of U.S. women age 45 years and older who were free of CVD and cancer at study entry. Women were followed annually for the development of CVD, with an average follow-up of 10 years. All reported CVD outcomes, including myocardial infarction, ischemic stroke, coronary revascularization procedures, and deaths from cardiovascular causes, were adjudicated by an end points committee after medical record review. All study participants provided written informed consent, and the study protocol was approved by the institutional review board of Brigham and Womens Hospital in Boston, Massachusetts. Baseline blood samples were assayed for C-reactive protein with a validated, high-sensitivity assay (Denka Seiken, Tokyo, Japan) and for total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol with direct-measurement assays (Roche Diagnostics, Basel, Switzerland). Women who were diabetic at baseline were excluded from predictive modeling because ATP III labeling considers diabetes to be a risk equivalent for coronary heart disease (2). In parallel with guidelines established for lipid evaluation (26), models were initially fitted in a derivation cohort limited to women not taking hormone replacement therapy at baseline (n= 15048 with data on all variables) and were then applied to all nondiabetic women (n= 26927) for clinical risk prediction. Development of Risk Prediction Models Models were fitted by using Cox proportional hazards models (27), restricting predictors to components of the Framingham risk score (including either total or LDL cholesterol as well as HDL cholesterol), and adding hsCRP. To determine the functional form used for each predictor, we examined spline plots and fitted power functions to determine the best fit for each variable. When fit was similar, we chose the simplest form, usually a linear term or log transformation, especially when supported by previous data from existing ATP III algorithms. To model blood pressure more fully, we included a nonlinear term for systolic blood pressure. As in the Framingham score, we included antihypertensive medication use and considered its interaction with blood pressure. At baseline in the WHS, use of cholesterol-lowering medications was rare, was not composed of statins, and was not statistically significant in these models. As also in the Framingham score, current but not past smoking was included. We considered interactions of all predictors with smoking and age, particularly on the basis of inclusion in the ATP III risk score. To enhance model simplicity, these were not included when they were only of marginal statistical significance. Of interest, when body mass index was added to the final model, it was not a statistically significant predictor of CVD in these data, an observation consistent with its absence from the Framingham risk score. In addition to comparing the performance of the final model derived from the WHS data with hsCRP to the WHS model without hsCRP, we also compared the performance of the formal ATP III model (2), with and without hsCRP (Appendix). The ATP III model includes terms for the natural logarithms of age, of total and HDL cholesterol, and of systolic blood pressure and was developed for the prediction of hard coronary heart disease events, including myocardial infarction and death from coronary heart disease. Total CVD, including ischemic stroke as well as revascularization procedures, was used as the end point in these analyses. To be conservative and allow the best possible fit for all traditional covariables, we recalculated -coefficients for the ATP III model in the WHS data before evaluating any additive effects of hsCRP. Measures of Model Fit The primary means of comparing predictive models based on Framingham covariables with and without hsCRP was the Bayes information criterion, a likelihood-based measure that adds a penalty for model complexity (28, 29). Lower values indicate better fit. Because of its common use in the medical literature, we also computed the c-index (28), or concordance probability, which is a generalization of the c-statistic, or the area under the receiver-operating characteristic curve (30), that allows for censored data. For these analyses, the c-index was computed and adjusted for optimism due to overfitting with bootstrap sampling (31) using the Design library in S-PLUS software (Insightful Corp., Seattle, Washington) (28). For comparison, we also computed several other measures of global model fit (provided in the Appendix), including other likelihood-based measures such as model weights for the Bayes information criterion, which provide an estimate of the posterior probability of each model given the set of candidate models considered (29, 32); the Akaike information criterion and its corresponding model weights (32); and Nagelkerkes generalized model R2 (33, 34). We computed the D-statistic of Royston and Sauerbrei (35), based on the separation of survival curves by predictor variables, and again adjusted for optimism. Differences in statistics between nested models were tested with a 1-sided test using bootstrap sampling (31). We also calculated the Brier score (28), which directly compares the observed outcomes with the fitted probabilities. To assess model calibration, or how closely the predicted probabilities reflect actual risk, observed risk was calculated on the basis of 8 years of follow-up (available for all participants) and was extrapolated to 10 years for display purposes. We computed the HosmerLemeshow calibration statistic (36) comparing observed and predicted risk using 10 categories based on 2percentage point increments in predicted risk, ranging from less than 2% to 18% or greater. We also computed this statistic using decile categories of predicted probabilities. To address clinical utility, we directly compared predicted risk estimates that are based on models using Framingham covariables with and without hsCRP with actual risk that was observed during study follow-up among all 26927 women for whom data were available. We used weighted statistics (37) to compare the predicted probabilities with and without hsCRP. To approximate clinical criteria commonly used in current treatment guidelines (2, 38), we grouped the predicted probabilities into 10-year risk categories of 0% to less than 5%, 5% to less than 10%, 10% to less than 20%, and 20% or greater. Finally, to address the generalizability of the final WHS risk prediction model with hsCRP, we calibrated the predicted probabilities to observed risk in the Framingham Heart Study, using a limited-access data set available from the National Heart, Lung, and Blood Institute at www.nhlbi.nih.gov/resources/deca/default.htm. Mean values among women age 47 years and o

Clinical Usefulness of Very High and Very Low Levels of C-Reactive Protein Across the Full Range of Framingham Risk Scores

Background—High-sensitivity C-reactive protein (hsCRP) is a strong independent risk factor for cardiovascular events, and levels of hsCRP of <1, 1 to <3, and ≥3 mg/L have been suggested to define low-, moderate-, and high-risk groups. However, the positive predictive value of very low (<0.5 mg/L) and very high levels of hsCRP (>10.0 mg/L) is uncertain. Methods and Results—Baseline levels of hsCRP were evaluated among 27 939 apparently healthy women who were followed up for myocardial infarction, stroke, coronary revascularization, or cardiovascular death. Crude and Framingham Risk Score (FRS)–adjusted relative risks (RRs) of incident cardiovascular events were calculated across a full range of hsCRP levels. Cardiovascular risks increased linearly from the very lowest (referent) to the very highest levels of hsCRP. Crude RRs for those with baseline hsCRP levels of <0.5, 0.5 to <1.0, 1.0 to <2.0, 2.0 to <3.0, 3.0 to <4.0, 4.0 to <5.0, 5.0 to <10.0, 10.0 to <20.0, and ≥20.0 mg/L were 1.0, 2.2, 2.5, 3.1, 3.7, 4.2, 4.9, 6.3, and 7.6, respectively (P for trend <0.001). After adjustment for FRS, these risks were 1.0, 1.6, 1.6, 1.7, 1.9, 2.2, 2.3, 2.8, and 3.1 (P for trend <0.001). All risk estimates remained significant in analyses stratified by FRS and after control for diabetes. Of the total cohort, 15.1% had hsCRP <0.50 mg/L, and 5.4% had hsCRP >10.0 mg/L. Conclusions—Both very low (<0.5 mg/L) and very high (>10 mg/L) levels of hsCRP provide important prognostic information on cardiovascular risk. hsCRP is clinically useful for risk prediction across a full range of values and across a full range of FRS.

Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease: A Randomized Trial

CONTEXT Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials. OBJECTIVE To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. DESIGN, SETTING, AND PARTICIPANTS Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. INTERVENTION Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12. MAIN OUTCOME MEASURES A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality. RESULTS Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L). CONCLUSION After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000541.