Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial.

Aim: The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and ≤48 h anticoagulation prior to randomization undergoing cardioversion. Methods: One thousand five hundred patients were randomized. The apixaban dose of 5 mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 133 µmol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding. Results: There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events. Conclusions: Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion. Clinical Trials.gov number: NCT02100228.

Apixaban compared with parenteral heparin and/or vitamin K antagonist in patients with nonvalvular atrial fibrillation undergoing cardioversion: Rationale and design of the EMANATE trial.

BACKGROUND: Stroke prevention in anticoagulation-naïve patients with atrial fibrillation undergoing cardioversion has not been systematically studied. OBJECTIVE: To determine outcomes in anticoagulation-naïve patients (defined as those receiving an anticoagulant for <48 hours during the index episode of atrial fibrillation) scheduled for cardioversion. METHODS: This is a randomized, prospective, open-label, real-world study comparing apixaban to heparin plus warfarin. Early image-guided cardioversion is encouraged. For apixaban, the usual dose is 5 mg BID with a dose reduction to 2.5 mg BID if 2 of the following are present: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL. If cardioversion is immediate, a single starting dose of 10 mg (or 5 mg if the dose is down-titrated) of apixaban is administered. Cardioversion may be attempted up to 90 days after randomization. Patients are followed up for 30 days after cardioversion or 90 days postrandomization if cardioversion is not performed within that timeframe. Outcomes are stroke, systemic embolization, major bleeds, clinically relevant nonmajor bleeding, and death, all adjudication-blinded. STATISTICS: The warfarin-naive cohort from the ARISTOTLE study was considered the closest data set to the patients being recruited into this study. The predicted incidence of stroke, systemic embolism, and major bleeding within 30 days after randomization was approximately 0.75%. To adequately power for a noninferiority trial, approximately 48,000 participants would be needed, a number in excess of feasibility. The figure of 1,500 patients was considered clinically meaningful and achievable. CLINICAL CONTEXT: This first prospective cardioversion study of a novel anticoagulant in anticoagulation-naïve patients should influence clinical practice.

Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study.

BACKGROUND: Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this "residual risk" have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors. METHODS AND RESULTS: A total of 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age (adjusted hazard ratio [aHR], 1.13 per 1 SD [8.8 years]; 95% confidence interval [CI], 1.04-1.23), increased body mass index (aHR, 1.09; 95% CI, 1.02-1.17 per 4.5 kg/m(2)), male sex (aHR, 1.33; 95% CI, 1.07-1.65), hypertension (aHR, 1.38; 95% CI, 1.17-1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11-1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11-1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03-1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70-0.94), aspirin use (aHR, 0.67; 95% CI, 0.56-0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84-0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679). CONCLUSIONS: Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00327691.

Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial.

BACKGROUND: High-density lipoproteins have antidiabetic properties in vitro. Furthermore, elevated high-density lipoprotein levels accompanying a genetic deficiency of cholesteryl ester transfer protein are associated with decreased levels of plasma glucose. We now investigate effects on glucose homeostasis of inhibiting cholesteryl ester transfer protein with torcetrapib. METHODS AND RESULTS: A post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was conducted to investigate effects of the cholesteryl ester transfer protein inhibitor torcetrapib on glycemic control in the 6661 diabetic patients in the trial. At baseline, there were no differences between the 2 treatment arms with respect to plasma glucose, insulin, hemoglobin A(1c), or the homeostasis model assessment of insulin resistance. After 3 months, the diabetic subjects taking the combination of torcetrapib plus atorvastatin had plasma glucose levels 0.34 mmol/L lower (P<0.0001) and insulin levels 11.7 µU/mL lower (P<0.0001) than in those receiving atorvastatin alone. Homeostasis model assessment of insulin resistance values decreased from 49.1 to 47.3 (P<0.0001) in the torcetrapib/atorvastatin arm compared with an increase in homeostasis model assessment of insulin resistance in the atorvastatin arm. At the 6-month time point, the mean hemoglobin A(1c) level in the atorvastatin arm was 7.29% compared with 7.06% in the torcetrapib/atorvastatin arm (P<0.0001). These effects of torcetrapib remained apparent for up to 12 months. Torcetrapib also lowered both glucose and insulin levels in the participants without diabetes mellitus, although the effects were not as great as in those with diabetes mellitus. CONCLUSIONS: Treatment with torcetrapib improves glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus. It remains to be determined whether this effect is the consequence of raising high-density lipoprotein.at CLINICAL TRIAL REGISTRATION: http:www.clinicaltrials.gov. Unique identifier: NCT00134264.

The benefits of intensive lipid lowering in patients with stable coronary heart disease with normal or high systolic blood pressure: an analysis of the Treating to New Targets (TNT) study.

This post-hoc analysis of the Treating to New Targets (TNT) study evaluated the joint effects of managing low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on cardiovascular outcomes. Patients (N=9739) with clinically evident, stable coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/d. The primary end point was occurrence of a first major cardiovascular event. At 3 months' follow-up, patients were stratified according to SBP (< 140 mm Hg vs > or = 140 mm Hg) and tertiles of LDL-C. At 4.9 years' median follow-up, the rate of major cardiovascular events was reduced most in patients with lower LDL-C (P < .001) and in patients with SBP < 140 mm Hg (P = .014). A 42% relative risk reduction was observed for patients in the lowest LDL-C tertile with an SBP < 140 mm Hg, compared with patients in the highest LDL-C tertile with an SBP > or = 140 mm Hg. The effect of lower SBP on stroke was most pronounced in the lowest LDL-C tertile.

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

BACKGROUND: Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). METHODS: This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. RESULTS: Enrollment of 641 subjects is complete. The baseline mean data are age 74 +/- 8 years, 53% women, MMSE 22 +/- 3, ADAS-cog 23 +/- 10, AD Functional Assessment and Change Scale (ADFACS) 13 +/- 9, Neuropsychiatric Inventory (NPI) 10 +/- 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 +/- 3. Mean prior donepezil treatment was 409 +/- 407 days. Mean baseline lipid levels are total cholesterol 5.8 +/- 0.8 mmol/L (224 +/- 33 mg/dL), LDL-C 3.7 +/- 0.7 mmol/L (143 +/- 26 mg/dL), triglycerides 1.5 +/- 0.7 mmol/L (132 +/- 64 mg/dL), and high-density lipoprotein cholesterol 1.6 +/- 0.5 mmol/L (64 +/- 18 mg/dL). CONCLUSIONS: LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the treatment of people with AD.

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.

OBJECTIVE: The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS: A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS: End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS: Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia.

BACKGROUND: The efficacy and safety of atorvastatin in children/adolescents aged 10-17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed. OBJECTIVE: To characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6-15 years with HeFH. METHODS: A total of 272 subjects aged 6-15 years with HeFH and low-density lipoprotein cholesterol (LDL-C) ≥4.0 mmol/L (154 mg/dL) were enrolled in a 3-year study (NCT00827606). Subjects were initiated on atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based on LDL-C levels. RESULTS: Mean percentage reductions from baseline in LDL-C at 36 months/early termination were 43.8% for subjects at Tanner stage (TS) 1 and 39.9% for TS ≥2. There was no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged <10 vs ≥10 years, and the treatment had no adverse effect on growth or maturation. Atorvastatin had a favorable safety and tolerability profile, and only 6 (2.2%) subjects discontinued because of adverse events. CONCLUSIONS: Atorvastatin over 3 years was efficacious, had no impact on growth/maturation, and was well tolerated in children and adolescents with HeFH aged 6-15 years.

Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT] Study).

Statins may have nephroprotective as well as cardioprotective effects in patients with cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/day and followed for 4.9 years. The relation between intrastudy change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVEs, defined as CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke) was assessed among 9,500 patients stratified by renal function: improving (change in eGFR more than +2 ml/min/1.73 m(2)), stable (-2 to +2 ml/min/1.73 m(2)), and worsening (less than -2 ml/min/1.73 m(2)). Compared with patients with worsening renal function (1,479 patients, 15.6%), the rate of MCVEs was 28% lower in patients with stable renal function (2,241 patients, 23.6%) (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.60 to 0.87; p = 0.0005) and 64% lower in patients with improving renal function (5,780 patients, 60.8%; HR 0.36; 95% CI 0.30 to 0.43; p <0.0001). For each 1 ml/min/1.73 m(2) increase in eGFR, the absolute reduction in the rate of MCVEs was 2.7% (HR 0.973; 95% CI 0.967 to 0.980; p <0.0001). An absolute MCVE rate reduction per 1 ml/min/1.73 m(2) increase in eGFR of 2.0% was reported with atorvastatin 10 mg and 3.3% with atorvastatin 80 mg. In conclusion, intrastudy stabilization or increase in eGFR in atorvastatin-treated patients with CHD from the TNT study was associated with a reduced rate of MCVEs. Statin-treated CHD patients with progressive renal impairment are at high risk for future cardiovascular events.

Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes.

BACKGROUND: Traditional cardiovascular risk factors, such as hypertension and dyslipidemia, predispose individuals to cardiovascular disease, particularly patients with diabetes. We investigated the predictive value of baseline systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of vascular outcomes in a large population of patients at high risk of future cardiovascular events. METHODS: Data were pooled from the TNT (Treating to New Targets), CARDS (Collaborative Atorvastatin Diabetes Study), and IDEAL (Incremental Decrease in End-Points Through Aggressive Lipid Lowering) trials and included a total of 21,727 patients (TNT: 10,001; CARDS: 2838; IDEAL: 8888). The effect of baseline SBP and LDL-C on cardiovascular events, coronary events, and stroke was evaluated using a multivariate Cox proportional-hazards model. RESULTS: Overall, risk of cardiovascular events was significantly higher for patients with higher baseline SBP or LDL-C. Higher baseline SBP was significantly predictive of stroke but not coronary events. Conversely, higher baseline LDL-C was significantly predictive of coronary events but not stroke. Results from the subgroup with diabetes (5408 patients; TNT: 1501; CARDS: 2838; IDEAL: 1069) were broadly consistent with those of the total cohort: baseline SBP and LDL-C were significantly predictive of cardiovascular events overall, with the association to LDL-C predominantly related to an effect on coronary events. However, baseline SBP was not predictive of either coronary or stroke events in the pooled diabetic population. CONCLUSIONS: In this cohort of high-risk patients, baseline SBP and LDL-C were significantly predictive of cardiovascular outcomes, but this effect may differ between the cerebrovascular and coronary systems. TRIAL REGISTRATION NUMBER: NCT00327691 (TNT); NCT00327418 (CARDS); NCT00159835 (IDEAL).

Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial.

BACKGROUND: Studies demonstrate that lowering low-density lipoprotein cholesterol (LDL-C) using a statin is associated with significant reduction in cardiovascular events. Whether visit-to-visit variability in LDL-C levels affects cardiovascular outcomes is unknown. OBJECTIVES: This study sought to evaluate the role of visit-to-visit variability in LDL-C levels on cardiovascular outcomes. METHODS: We evaluated patients with coronary artery disease and LDL-C <130 mg/dl enrolled in the TNT (Treating to New Targets) trial, randomly assigned to receive atorvastatin 80 mg/day versus 10 mg/day and with at least one post-baseline measurement of LDL-C. Visit-to-visit LDL-C variability was evaluated from 3 months into random assignment through the use of various measurements of LDL-C variability: SD, average successive variability (ASV), coefficient of variation, and variation independent of mean, with the first 2 measurements used as the primary measurements. Primary outcome was any coronary event, and secondary outcomes were any cardiovascular event, death, myocardial infarction, or stroke. RESULTS: Among 9,572 patients, SD and ASV were significantly lower with atorvastatin 80 mg/day versus 10 mg/day (SD: 12.03 ± 9.70 vs. 12.52 ± 7.43; p = 0.005; ASV: 12.84 ± 10.48 vs. 13.76 ± 8.69; p < 0.0001). In the adjusted model, each 1-SD increase in LDL-C variability (by ASV) increased the risk of any coronary event by 16% (hazard ratio [HR]: 1.16; 95% confidence interval [CI]: 1.10 to 1.23; p < 0.0001), any cardiovascular event by 11% (HR: 1.11; 95% CI: 1.07 to 1.15; p < 0.0001), death by 23% (HR: 1.23; 95% CI: 1.14 to 1.34; p < 0.0001), myocardial infarction by 10% (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02), and stroke by 17% (HR: 1.17; 95% CI: 1.04 to 1.31; p = 0.01), independent of treatment effect and achieved LDL-C levels. Results were largely consistent when adjusted for medication adherence. CONCLUSIONS: In subjects with coronary artery disease, visit-to-visit LDL-C variability is an independent predictor of cardiovascular events.

Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes.

OBJECTIVES: The purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk. BACKGROUND: Statins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension. METHODS: We compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest. RESULTS: Among 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups. CONCLUSIONS: Compared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.

Relation of improvement in estimated glomerular filtration rate with atorvastatin to reductions in hospitalizations for heart failure (from the Treating to New Targets [TNT] study).

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials).

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.

Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.

OBJECTIVES: We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. BACKGROUND: Statin therapy might modestly increase the risk of new-onset T2DM. METHODS: We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. RESULTS: In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). CONCLUSIONS: High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial).

Analyses of randomized clinical trials are usually restricted to examination of time to first event. However, because many patients have multiple events, this approach precludes much potentially useful clinical and economic data. To assess the effect on overall disease burden in the Treating to New Targets (TNT) study, we evaluated the effect of treatment with atorvastatin 80 versus 10 mg in the period after the occurrence of a first cardiovascular event. In TNT, 10,001 patients with stable coronary heart disease received double-blind therapy with atorvastatin 80 or 10 mg and were followed for 4.9 years. Post hoc time-to-event analysis was used to estimate separate hazard ratios for time to any first, second, third, fourth, and fifth recurrent cardiovascular events. During TNT, 3,082 patients had a first recurrent cardiovascular event, with 1,516, 698, 345, and 197 developing second, third, fourth, and fifth recurrent events, respectively. In patients receiving atorvastatin 80 mg, the relative risk of a first recurrent event was significantly decreased compared to those receiving atorvastatin 10 mg. Significant benefit with the 80-mg dose was also observed for second, third, fourth, and fifth recurrent events. Similar findings were recorded in 5,854 patients with type 2 diabetes mellitus and/or metabolic syndrome and in 3,809 patients > or = 65 years of age compared to younger patients. In conclusion, treatment with atorvastatin 80 mg continued to significantly decrease the risk of any cardiovascular event over time compared to atorvastatin 10 mg in patients who had survived previous events. In TNT, analyses limited to the primary end point significantly underestimated the decrease in total cardiovascular disease burden achieved by intensive low-density lipoprotein cholesterol lowering.

Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart failure, myocardial infarction, and stroke in patients with stable coronary heart disease (Data from the Treating to New Targets [TNT] trial).

The heart rate at rest (HR) is a predictor of cardiovascular (CV) mortality. However, its effect on nonfatal CV events is unknown. The aim of the present post hoc analysis of the Treating New Targets (TNT) trial was to assess the effect of the HR at rest on major CV events in patients with stable coronary heart disease. A total of 9,580 subjects were included in the present analysis and were followed up for a median of 4.9 years. The rate of major CV events was 11.9% in those with a baseline HR of > or =70 beats/min versus 8.8% in those with a baseline HR of <70 beats/min. An increased HR at rest was associated with CV events, even after adjustment for differences in baseline characteristics (unadjusted hazard ratio 1.16 for every 10-beats/min increase, 95% confidence interval [CI] 1.10 to 1.23, p <0.0001; adjusted hazard ratio 1.08 per 10-beats/min increase, 95% CI 1.02 to 1.16, p = 0.018). A HR > or =70 beats/min was a significant independent predictor of all-cause mortality (hazard ratio 1.40, 95% CI 1.14 to 1.71, p = 0.001) and heart failure hospitalization (hazard ratio 2.30, 95% CI 1.80 to 2.95, p > or =0.0001). However, this association was not observed for stroke or myocardial infarction (p = 0.11 and p = 0.68, respectively). In conclusion, in patients with stable coronary heart disease, every 10-beats/min increase in the HR at rest was associated with an 8% increase in major CV events. In particular, a HR at rest of > or =70 beats/min was associated with a 40% increased risk of all-cause mortality and more than doubled the risk of heart failure hospitalization, but not the risk of stroke or myocardial infarction.

Comparison of effectiveness of atorvastatin 10 mg versus 80 mg in reducing major cardiovascular events and repeat revascularization in patients with previous percutaneous coronary intervention (post hoc analysis of the Treating to New Targets [TNT] Study).

The Treating to New Targets (TNT) study demonstrated that intensive atorvastatin therapy to achieve low-density lipoprotein cholesterol concentrations well below recommended target levels provides an incremental clinical benefit in patients with stable coronary artery disease. This post hoc analysis of the TNT study was conducted to investigate whether this benefit extends to patients with previous percutaneous coronary intervention (PCI). A total of 10,001 patients with clinically evident coronary artery disease, including 5,407 patients with previous PCI, were randomized to atorvastatin 10 or 80 mg/day and followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event. Revascularization, a component of a secondary end point, was also examined. In patients with previous PCI, mean low-density lipoprotein cholesterol levels at study end were 79.5 mg/dl in the 80-mg arm and 100.8 mg/dl in the 10-mg arm. First major cardiovascular events occurred in 230 patients (8.6%) receiving high-dose atorvastatin and 289 patients (10.6%) receiving low-dose atorvastatin (hazard ratio 0.79, 95% confidence interval 0.67 to 0.94, p = 0.008). Repeat revascularization during follow-up (PCI or coronary artery bypass grafting) was performed in 466 patients (17.3%) in the 80-mg arm and 624 patients (22.9%) in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.65 to 0.82, p <0.0001). In conclusion, intensive lipid lowering to a mean low-density lipoprotein cholesterol level of 79.5 mg/dl (2.1 mmol/L) with atorvastatin 80 mg/day in patients with previous PCI reduces major cardiovascular events by 21% and repeat revascularizations by 27% compared with a less intensive lipid-lowering regimen.

Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study.

OBJECTIVES: This subanalysis of the TNT (Treating to New Targets) study investigates the effects of intensive lipid lowering with atorvastatin in patients with coronary heart disease (CHD) with and without pre-existing chronic kidney disease (CKD). BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD. METHODS: A total of 10,001 patients with CHD were randomized to double-blind therapy with atorvastatin 80 mg/day or 10 mg/day. Patients with CKD were identified at baseline on the basis of an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) using the Modification of Diet in Renal Disease equation. The primary efficacy outcome was time to first major cardiovascular event. RESULTS: Of 9,656 patients with complete renal data, 3,107 had CKD at baseline and demonstrated greater cardiovascular comorbidity than those with normal eGFR (n = 6,549). After a median follow-up of 5.0 years, 351 patients with CKD (11.3%) experienced a major cardiovascular event, compared with 561 patients with normal eGFR (8.6%) (hazard ratio [HR] = 1.35; 95% confidence interval [CI] 1.18 to 1.54; p < 0.0001). Compared with atorvastatin 10 mg, atorvastatin 80 mg reduced the relative risk of major cardiovascular events by 32% in patients with CKD (HR = 0.68; 95% CI 0.55 to 0.84; p = 0.0003) and 15% in patients with normal eGFR (HR = 0.85; 95% CI 0.72 to 1.00; p = 0.049). Both doses of atorvastatin were well tolerated in patients with CKD. CONCLUSIONS: Aggressive lipid lowering with atorvastatin 80 mg was both safe and effective in reducing the excess of cardiovascular events in a high-risk population with CKD and CHD.

Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease.

OBJECTIVE: To investigate the effect of intensive lipid lowering with high-dose atorvastatin on the incidence of major cardiovascular events compared with low-dose atorvastatin in patients with coronary artery disease and type 2 diabetes, with and without chronic kidney disease (CKD). PATIENTS AND METHODS: Following 8 weeks' open-label therapy with atorvastatin (10 mg/d), 10,001 patients with coronary artery disease were randomized to receive double-blind therapy with either 80 mg/d or 10 mg/d of atorvastatin between July 1, 1998, and December 31, 1999. Of 1501 patients with diabetes, renal data were available for 1431. Patients with CKD were defined as having a baseline estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2, using the Modification of Diet in Renal Disease equation. RESULTS: After a median follow-up of 4.8 years, 95 (17.4%) of 546 patients with diabetes and CKD experienced a major cardiovascular event vs 119 (13.4%) of 885 patients with diabetes and normal eGFRs (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.00-1.72; P<.05). Compared with 10 mg of atorvastatin, 80 mg of atorvastatin reduced the relative risk of major cardiovascular events by 35% in patients with diabetes and CKD (20.9% [57/273] vs 13.9% [38/273]; HR, 0.65; 95% CI, 0.43-0.98; P=.04) and by 10% in patients with diabetes and normal eGFR (14.1% [62/441] vs 12.8% [57/444]; HR, 0.90; 95% CI, 0.63-1.29; P=.56). The absolute risk reduction in patients with diabetes and CKD was substantial, yielding a number needed to treat of 14 to prevent 1 major cardiovascular event over 4.8 years. Both treatments were well tolerated. CONCLUSION: Patients with diabetes, stable coronary artery disease, and mild to moderate CKD experience marked reduction in cardiovascular events with intensive lipid lowering, in contrast to previous observations in patients with diabetes and end-stage renal disease. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00327691.