Janice Pogue

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

BACKGROUND Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events

BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. We compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. METHODS After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. RESULTS Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001). CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (ClinicalTrials.gov number, NCT00153101 [ClinicalTrials.gov].).

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.

Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients

BACKGROUND We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p<O.001). For all five trials the ACE inhibitor group had lower rates of death than the placebo group (1,467/6,391 [23.0%] vs 1,710/6,372 [26.8%]; 0.80 [0.74-0.87]) and lower rates of reinfarction (571 [8.9%] vs 703 [11.0%]; 0.79 [0.70-0.89]), readmission for heart failure (876 [13.7%] vs 1202 [18.9%]; 0.67 [0.61-0.74]), and the composite of these events (2161 [33.8%] vs 2610 [41.0%]; 0.72 [0.67-0.78]; all p<0.0001). The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, benefit was apparent over the range examined.

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

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial

BACKGROUND Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartans effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation

BACKGROUND Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. METHODS A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. RESULTS At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001). CONCLUSIONS In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.)

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.).

Comparison of Candesartan, Enalapril, and Their Combination in Congestive Heart Failure Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study: The RESOLVD Pilot Study Investigators

BACKGROUND We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF). METHODS AND RESULTS Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025+/-0.004) than with candesartan alone (0.015+/-0.004) or enalapril alone(0.015+/-0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8+/-4 mL; ESV 1+/-4 mL; P<0.01) than with candesartan alone (EDV 27+/-4 mL; ESV 18+/-3 mL) or enalapril alone (EDV 23+/-7 mL; ESV 14+/-6 mL). Blood pressure decreased with combination therapy (6+/-1/4+/-1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2+/-5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7+/-7.8 pg/mL) or enalapril (-0.8+/-11. 3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8+/-2.7 pmol/L; P<0.01) compared with candesartan (4. 4+/-3.8 pmol/L) and enalapril alone (4.0+/-5.0 pmol/L). CONCLUSIONS Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.