Jackie Bosch

Vitamin E supplementation and cardiovascular events in high-risk patients

BACKGROUND Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. METHODS We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. RESULTS A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. CONCLUSIONS In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis.We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer.A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E.In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.

BACKGROUND Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drugs ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). INTERPRETATION Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril : the HOPE randomized trial

The future rate of cardiovascular events can be predicted by several well-established risk factors. Even in the absence of classic risk factors, patients with renal disease have an elevated risk for cardiovascular disease (1, 2). This renalcardiovascular association is well established in patients with advanced renal insufficiency (2). It has also been reported in patients in the Hypertension Detection and Follow-up Program (HDFP) (3), in which a serum creatinine concentration greater than 133 mol/L (1.5 mg/dL) was a strong predictor of cardiovascular disease. However, HDFP included only patients with hypertension. In contrast, a recent analysis of data from the Framingham Study did not detect a relationship between mild renal insufficiency (defined as a serum creatinine concentration of 124 to 265 mol/L [1.4 to 3.0 mg/dL]) and cardiovascular events (4). The Heart Outcomes and Prevention Evaluation (HOPE) study investigated the effects of ramipril and vitamin E on major cardiovascular outcomes in 9297 patients at high risk, including those with serum creatinine concentrations up to 200 mol/L (2.3 mg/dL) (5-7). Our study examined the hypothesis that previous evidence of renal disease (that is, an elevated serum creatinine concentration 124 mol/L [ 1.4 mg/dL]) would independently predict future cardiovascular disease. Since the connection between renal and cardiovascular disease is known to exist in patients with diabetes mellitus and those with hypertension, we analyzed nondiabetic and normotensive patients separately. We also examined whether ramipril continued to be effective in patients with impaired renal function. This was done to determine whether the common clinical practice of withholding angiotensin-converting enzyme (ACE) inhibitors in patients with impaired renal excretory function is justified. Methods Patients The design and primary outcomes of the HOPE study have been described elsewhere (5-7). Briefly, men and women at least 55 years of age from 267 centers were included if they had objective evidence of vascular disease or diabetes combined with another cardiovascular risk factor. The main exclusion criteria were heart failure, intolerance of ACE inhibitors or vitamin E, a serum creatinine concentration greater than 200 mol/L (2.3 mg/dL), or dipstick-positive proteinuria (>1+). Patients were treated with ramipril, vitamin E, or placebo in a double-blind, 2 2 factorial design. Follow-up was 3.5 to 5.5 years (median, 4.5 years), and the primary outcome measure was the incidence of cardiovascular death, myocardial infarction, or stroke. Secondary outcome measures included total mortality, hospitalization for heart failure, and revascularization. At the time of randomization, urine albumin level and creatinine concentration were measured once in all patients at four central laboratories. The ratio of urine albumin to creatinine was calculated, and a value of at least 2 mg/mmol was defined as microalbuminuria. Serum creatinine concentration was measured in all patients at local laboratories at the time of randomization. Renal Insufficiency Recent data suggest that in patients older than 55 years of age, a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) is a good indicator of a glomerular filtration rate less than 80 mL/min (8). Therefore, before beginning this post hoc analysis, we used a serum creatinine concentration of at least 124 mol/L (1.4 mg/dL) to differentiate between patients with and those without renal insufficiency. We also estimated creatinine clearance from serum creatinine concentrations by using the CockcroftGault formula (8), which derives the value from creatinine concentration, age, and body weight (140 age [in years] body weight [in kg]/serum creatinine concentration [in mg/dL] 72 [in men] or 0.85 [in women]). For calculated creatinine clearance, an a priori value of 65 mL/min was arbitrarily chosen as a definite indicator of renal insufficiency. Statistical Analysis Baseline serum creatinine values were missing in 10 of 9297 patients who were randomly assigned to receive ramipril, 10 mg/d, or placebo. Only data from the original intention-to-treat analysis (5) were included in our study. We compared baseline characteristics in patients with and those without renal insufficiency by using chi-square tests for discrete variables and t-tests for continuous variables. Because the ratio of albumin to creatinine was not normally distributed, it was compared by using a Wilcoxon test. In the final analysis, time-to-event in each group was estimated by using Cox regression stratified by center; this was done because rates of renal insufficiency varied significantly by center (P=0.006) but event rates did not. Association by center was tested by using logistic regression for renal insufficiency and Cox regression for events. Center was treated as a fixed effect in these models (9). Multivariate models to predict events were developed by using Cox regression and a backward elimination technique, beginning with univariate significant risk factors, including age; sex; waist-to-hip ratio; body mass index; and history of hypertension, diabetes, coronary artery disease, peripheral vascular disease, smoking, ramipril use, and renal insufficiency. Age, body mass index, waist-to-hip ratio, and blood pressure were treated as continuous variables. All covariates were tested for possible confounding with renal insufficiency, but no such pattern was found. We used Cox regression models to assess the effect of randomization to ramipril after controlling for serum creatinine concentration. Statistical tests for interaction were done in the Cox regression analysis to determine whether the effect of ramipril differed in patients with and those without renal insufficiency. We classified patients according to quartiles of serum creatinine concentration and then determined the effect of renal insufficiency on risk for the primary outcome. To do this, we analyzed the rate of the primary outcome across quartiles using Cox regression and testing linearity of the hazard ratios (HRs). Creatinine clearance was also estimated from serum creatinine concentration by using the CockcroftGault formula (8). Because age is used to calculate this value, age was excluded from all multivariate analyses that included creatinine clearance as a variable. All analyses were done by using SAS software for Unix, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Baseline Characteristics of Patients with Renal Disease As shown in Table 1, 980 patients had a serum creatinine concentration at least 124 mol/L (1.4 mg/dL) and 8307 patients did not. Baseline variables did not differ between the placebo and ramipril subgroups. Compared with patients who had no evidence of renal insufficiency, those with renal insufficiency were older; were more likely to be male; and had a higher baseline prevalence of hypertension, coronary artery disease, peripheral vascular disease, low high-density lipoprotein cholesterol level, and use of antiplatelet and antihypertensive agents. Systolic blood pressure, urine albumin level, and waist-to-hip ratio were also higher in this group. Table 1. Baseline Characteristics of Patients with and Those without Renal Insufficiency Event Rates in Patients with Renal Insufficiency Renal insufficiency was an important predictor of the primary outcome for all patients, as well as for the ramipril and placebo groups separately. The extent to which renal insufficiency was associated with the primary outcome is shown in Figure 1 and Table 2. Most impressive is the fact that cardiovascular and all-cause mortality rates were nearly twice as high in patients with renal insufficiency (HR, 1.90 [95% CI, 1.53 to 2.36] and 1.83 [CI, 1.54 to 2.17], respectively, by Cox regression controlling for ramipril use; P<0.001 for both comparisons), as were hospitalizations for heart failure (HR, 2.11 [CI, 1.56 to 2.81]; P<0.001). This effect of renal insufficiency was also observed when calculated creatinine clearance was used instead of serum creatinine concentration (Table 3). Figure 1. Primary outcome, myocardial infarction, cardiovascular death, and all death for patients with a serum creatinine concentration less than 1.4 mg/dL (<124 mol/L) or at least 1.4 mg/dL ( 124 mol/L). Table 2. Outcomes in Patients with and Those without Renal Insufficiency Table 3. Outcomes in Patients with a Creatinine Clearance 65 mL/min or > 65 mL/min Analysis of the group risk for the primary outcome clearly showed that as serum creatinine concentration increases, so does cardiovascular risk. As shown in Figure 2, the incidence of the primary outcome increased with each quartile of serum creatinine concentration (P<0.001 for linear trend of HR across quartiles). Figure 2. Primary outcome according to quartiles of serum creatinine concentration. P P We performed a multivariate analysis to determine whether the observed relationship between the incidence of the primary outcome and renal insufficiency could be explained by the association of impaired renal function with the variables identified in Table 1. In this analysis, an elevated serum creatinine concentration and microalbuminuria were highly significant, independent renal risk factors for the aggregate primary outcome of cardiovascular death, myocardial infarction, or stroke (HR, 1.40 [CI, 1.16 to 1.69] and 1.59 [CI, 1.37 to 1.84], respectively; P<0.001 for both comparisons). Other factors that independently and significantly predicted the primary outcome measure were coronary artery disease (HR, 1.51 [CI, 1.22 to 1.85]), peripheral vascular disease (HR, 1.49 [CI, 1.29 to 1.70]), diabetes mellitus (HR, 1.42 [CI, 1.23 to 1.65]), male sex (HR, 1.20 [CI, 1.01 to 1.43]), 1-year increase in age (HR

Basal insulin and cardiovascular and other outcomes in dysglycemia

BACKGROUND The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested. METHODS We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups. RESULTS The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97). CONCLUSIONS When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Effects of Ramipril and Vitamin E on Atherosclerosis The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE)

Background —Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3×2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients. Methods and Results —A total of 732 patients ≥55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-&agr;-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P =0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo. Conclusions —Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia

BACKGROUND The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. METHODS In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. RESULTS During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. CONCLUSIONS Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).

Use of ramipril in preventing stroke: double blind randomised trial

Abstract Objective: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. Design: Randomised controlled trial with 2×2 factorial design. Setting: 267 hospitals in 19 countries. Participants: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. Outcome measures: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. Results: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. Conclusion: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure. What is already known on this topic Treatment with aspirin and lowering blood pressure reduce the incidence of stroke What this study adds Ramipril, an angiotensin converting enzyme inhibitor, reduces strokes in patients at high risk whose blood pressure is not elevated, despite only a modest lowering of blood pressure The benefits are observed even when patients receive aspirin and other blood pressure lowering treatments

Blood-pressure lowering in intermediate-risk persons without cardiovascular disease

BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years. RESULTS The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes). CONCLUSIONS Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).

Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease.

BACKGROUND Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years. RESULTS The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005). CONCLUSIONS Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE-3 ClinicalTrials.gov number, NCT00468923.).

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

BACKGROUND We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS In this double‐blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban‐plus‐aspirin group after a mean follow‐up of 23 months. RESULTS The primary outcome occurred in fewer patients in the rivaroxaban‐plus‐aspirin group than in the aspirin‐alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=‐4.126), but major bleeding events occurred in more patients in the rivaroxaban‐plus‐aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban‐plus‐aspirin group as compared with 378 (4.1%) in the aspirin‐alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban‐alone group than in the aspirin‐alone group, but major bleeding events occurred in more patients in the rivaroxaban‐alone group. CONCLUSIONS Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.)