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The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene. [ABSTRACT FROM AUTHOR]

Abstract Background Higher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants. Methods After 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization. Results Higher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction. Conclusions Higher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients. Highlights • Elevated FGF21 levels at randomization were associated with incident MCVE. • At 1-year, FGF21 levels were lower in 80 mg versus 10 mg atorvastatin group • Elevated FGF21 levels at 1-year were associated with subsequent MCVE. • Changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. • FGF21 provides incremental value in risk prediction in statin-treated patients. [ABSTRACT FROM AUTHOR]

Background Time to benefit (TTB) in clinical trials of cholesterol-lowering drugs is important because it may provide a clue as to the potential mechanism of action of the drug, it is helpful in determining when to stop a trial for futility, and it may inform treatment decisions in subjects with reduced life expectancy. Objective To compare TTB among clinical trials of cholesterol-lowering drugs. Methods We examined TTB in 24 trials of cholesterol-lowering drugs with positive outcomes. Benefit curves were constructed by subtracting the curve for a placebo or comparator drug from the curve for active treatment. Results TTB ranged from 1 to 30 (mean 13.1) months, being shorter in trials of statins (n = 17) compared to nonstatins (n = 7), 10.3 vs 20.0 months. Among statin trials, TTB was shorter with atorvastatin (n = 6) than in trials with other statins (n = 11), 4.75 compared to 11.4 months. Conclusions TTB is variable among trials of cholesterol-lowering drugs, being shorter with statin compared to nonstatin drugs. TTB is shorter with atorvastatin than with other statins. For trials of new cholesterol-lowering drugs, outcome curves that do not separate for up to 30 months do not preclude eventual benefit. [ABSTRACT FROM AUTHOR]

Background Higher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events. Objective The purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease. Methods We assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9 years. Results In the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11–1.21, P < .0001), for triglycerides (HR 1.09, 95% CI 1.04–1.15, P = .0005), and for LDL-cholesterol (HR 1.14, 95% CI 1.09–1.19, P < .0001). Similar results were found for the 3 other measures of variability, standard deviation, coefficient of variability, and variability independent of the mean. Similar results were seen for CV events, stroke, and nonfatal myocardial infarction. Higher variability in triglyceride and LDL-cholesterol, but not HDL-cholesterol, was predictive of incident diabetes. The correlation among the variability of the 3 lipid measurements was weak. Conclusion Visit-to-visit variability in fasting measurements of HDL-cholesterol, triglycerides, and LDL-cholesterol are predictive of coronary events, CV events, and for triglyceride and low-density lipoprotein cholesterol variability, incident diabetes. The mechanisms accounting for these associations remain to be determined. [ABSTRACT FROM AUTHOR]

Background Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease. Objectives The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a). Methods We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo. Results At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (−3.4 ± 10.7 mg/dL [−11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92). Conclusion In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels. [ABSTRACT FROM AUTHOR]

Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p <0.01 in both men and women) over 1 year after randomization. The increase in body weight was greater in patients with NODM than those without NODM (1.6 vs 0.9 kg, p <0.001). The association of change in body weight with NODM risk remained significant after adjusting for confounding factors (hazard ratios 1.33, 1.42, and 1.88 for quartiles 2, 3, and 4 compared with quartile 1, respectively). Similar results were obtained in patients with normal fasting glucose level. In conclusion, 1-year change in body weight is predictive of NODM in patients who underwent statin therapy from the TNT trial. Our study highlights the importance of weight control as a lifestyle measure to prevent statin-related NODM. [ABSTRACT FROM AUTHOR]

The prevalence of type 2 diabetes is increasing worldwide, and diabetes is a strong adverse prognostic factor among patients with cardiovascular (CV) disease. Four classes of drugs that are commonly used for CV risk reduction, statins, niacin, thiazide diuretics, and ß-blockers, have been shown to increase the risk of new-onset diabetes (NOD) by 9% to 43% in meta-analyses or large-scale clinical trials. Clinical predictors for drug-related NOD appear to be similar to the predictors that have been described for NOD unrelated to drugs: fasting blood glucose >100 mg/dL and features of the metabolic syndrome such as body mass index >30 kg/m2, serum triglycerides >150 mg/dL, and elevated blood pressure, among others. The mechanisms whereby these drugs increase the risk of NOD are incompletely understood, although different hypotheses have been suggested. Lifestyle intervention consisting of diet and exercise has been shown in multiple studies to reduce the risk of NOD by approximately 50%, with persistent benefit during long-term follow-up. In patients at high risk for NOD, niacin should be avoided, and for hypertension, an angiotensin-converting enzyme inhibitor or even a ß1-selective blocker might be a better choice than a standard ß-blocker. For thiazide diuretics and particularly statins, benefit in terms of CV event reduction outweighs the risk of NOD. [Copyright &y& Elsevier]

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/m2, 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. [Copyright &y& Elsevier]

Abstract: Objective: This study evaluated the success in attaining non-HDL-cholesterol (non-HDL-C) goals in the multinational L-TAP 2 study. Methods: 9955 patients ≥20 years of age with dyslipidemia on stable lipid-lowering therapy were enrolled from nine countries. Results: Success rates for non-HDL-C goals were 86% in low, 70% in moderate, and 52% in high-risk patients (63% overall). In patients with triglycerides of >200 mg/dL success rates for non-HDL-C goals were 35% vs. 69% in those with ≤200 mg/dL (p < 0.0001). Among patients attaining their LDL-C goal, 18% did not attain their non-HDL-C goal. In those with coronary disease and at least two risk factors, only 34% and 30% attained respectively their non-HDL-C and LDL-C goals. Rates of failure in attaining both LDL-C and non-HDL-C goals were highest in Latin America. Conclusions: Non-HDL-C goal attainment lagged behind LDL-C goal attainment; this gap was greatest in higher-risk patients. [Copyright &y& Elsevier]

Background: This post hoc nested case-control analysis of the TNT study was designed to investigate whether baseline vitamin D level is a significant predictor of cardiovascular risk among statin-treated patients and whether changes in vitamin D after treatment with atorvastatin are associated with improved cardiovascular outcomes. Methods: A total of 10,001 patients with stable coronary heart disease were randomized to atorvastatin 80 or 10 mg for a median of 4.9 years. This analysis included 1,509 patients (497 with a subsequent cardiovascular event and 1,012 without an event) with vitamin D levels determined at baseline and 1 year. Event rates were analyzed by Cox proportional hazard model by baseline vitamin D levels, with vitamin D as a continuous variable, and with change in vitamin D level as the predictor. Results: Vitamin D deficiency (<15 ng/mL) or insufficiency (15- <30 ng/mL) was present in 108 (7.2%) of 1,509 and 625 (41.4%) of 1,509 of patients, whereas 46 (3.0%) of 1,509 had elevated vitamin D. There was no relationship between baseline vitamin D levels or change in vitamin D levels and cardiovascular events or mortality. Modeling of events with vitamin D as a continuous variable similarly showed no relationship of vitamin D to events. These findings held true after adjustment for seasonal variations in vitamin D and other confounders. Conclusion: In statin-treated patients with stable coronary heart disease, vitamin D levels did not predict cardiovascular risk. Changes in plasma concentrations of vitamin D after 1 year of treatment made no contribution to the efficacy of atorvastatin therapy. [ABSTRACT FROM AUTHOR]

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 m2 (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 m2, p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m2 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Statins have been shown to reduce cardiovascular events across a broad spectrum of patients at risk, irrespective of baseline LDL-cholesterol levels. In a meta-analysis of 14 statin trials involving more than 90,000 participants, statin therapy reduced the 5-year incidence of cardiovascular events by about 20% for each mmol/L of LDL-cholesterol reduction. The results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study suggest that the degree of reduction in Japanese subjects may be greater than this for the same degree of LDL-cholesterol reduction. Given the success of statins in preventing cardiovascular events, it is not surprising that they have been tested in a variety of related conditions, three of which are discussed in this article. Heart failure is characterized by inflammation, endothelial dysfunction and neurohumeral activation, conditions that are ameliorated by statin therapy. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) showed no significant benefit of rosuvastatin upon the primary endpoint, cardiovascular death, myocardial infarction and stroke. However, subgroups identified by the biomarkers plasma amino-terminal pro-brain natriuretic and C-reactive protein showed a reduction in events. Aortic stenosis and atherosclerosis share common risk factors, including hypertension and hypercholesterolemia. Although non-randomized cohort studies have suggested that statins slow the progression of aortic stenosis, this was not shown in either of the two randomized placebo-controlled trials testing this hypothesis. Similarly, Alzheimer''s disease shares many risk factors with atherosclerosis, and several observational studies have reported a lower risk of developing this condition in patients taking statins. However, two recently completed clinical trials indicate that neither atorvastatin nor simvastatin slow the progression of early Alzheimer''s disease. In conclusion, although statins are effective, established therapy for the prevention of vascular events in patients at risk, they have as yet not proven to be successful for these newer indications. [Copyright &y& Elsevier]

Background: Differences between women and men have been documented for both diagnostic testing and treatment in cardiology. This analysis evaluates whether low-density lipoprotein cholesterol (LDL-C) success rates according to current guidelines and high-density lipoprotein cholesterol (HDL-C) levels differ by gender in the L-TAP 2 population. Methods: Patients aged ≥20 years with dyslipidemia on stable lipid-lowering therapy were assessed in 9 countries between September 2006 and April 2007. Low-density lipoprotein cholesterol goal attainment by cardiovascular risk level and region and determinants of low HDL-C were compared between genders. Results: Of 9,955 patients (45.3% women) evaluated, women had a significantly lower overall LDL-C success rate than men (71.5% vs 73.7%, P = .014), due entirely to the difference in the high-risk/coronary heart disease (CHD) group (LDL-C goal <100 mg/dL, 62.6% vs 70.6%, P < .0001) Among CHD patients with ≥2 additional risk factors, only 26.7% of women and 31.5% of men (P = .021) attained the optional LDL-C goal of <70 mg/dL. High-density lipoprotein cholesterol was <50 mg/dL in 32.2% of women and <40 mg/dL in 26.8% of men (P < .0001), including 38.2% of women and 29.8% of men in the high risk/CHD group (P < .0001). Predictors of low HDL-C in women included diabetes, smoking, waist circumference, and hypertension. Conclusions: Cholesterol treatment has improved substantially since the original L-TAP a decade ago, when only 39% of women attained their LDL-C goal. However, high-risk women are undertreated compared to men, and a substantial opportunity remains to reduce their cardiovascular risk. [Copyright &y& Elsevier]

That statins should be prescribed for patients before hospital discharge after an episode of acute coronary syndrome (ACS) is a Level of Evidence: 1A recommendation of the American College of Cardiology/American Heart Association Joint Task Force. This level of recommendation is based upon 2 clinical trials: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trials. In the MIRACL trial, 3,086 patients with unstable angina or non–Q-wave myocardial infarction were randomized within 4 days of the event to atorvastatin 80 mg/day or to placebo and followed for 16 weeks. The primary composite end point occurred in 14.8% of atorvastatin patients and 17.4% of placebo patients, a 16% relative risk reduction (p = 0.048). In the PROVE-IT trial, 4,162 patients hospitalized with an ACS within the preceding 10 days were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and were followed for a mean of 24 months. The primary event rate was 22.4% in the atorvastatin group and 26.3% in the pravastatin group, a 16% relative risk reduction (p = 0.005). A strong trend toward a reduction in total mortality was seen in the atorvastatin group (2.2% vs. 3.2%, p = 0.07). Using a composite end point of death, myocardial infarction, and rehospitalization for ACS, the difference between the treatment groups is already statistically significant at 30 days and remains so throughout the follow-up period. Comprehensive treatment programs in ACS patients that include initiation of statins before hospital discharge have been shown to improve outcomes such as recurrent myocardial infarction and total mortality at 1 year. Guidelines prove their utility when their implementation improves outcomes across a broad population at risk, such as in this instance. [Copyright &y& Elsevier]

The Treating to New Targets (TNT) trial enrolled 10,001 patients with coronary disease to treatment with atorvastatin, 80 or 10 mg/d, and observed them for a median of 4.9 years. Mean low-density lipoprotein cholesterol (LDL-C) levels were 77 mg/dL in the 80-mg group and 101 mg/dL in the 10-mg group. The primary end point, a composite of cardiovascular death, myocardial infraction, resuscitated cardiac arrest, and stroke, occurred in 10.9% of patients in the 10-mg and 8.7% of patients in the 80-mg group (P = .0002). In large subgroups of patients in TNT, specifically those with diabetes, the metabolic syndrome, chronic kidney disease, or previous coronary bypass (CABG) surgery, the risk of an event was significantly higher than in patients without these features. The absolute risk reduction in the 80-mg group was greater in each of these subgroups than in other TNT patients. The rates of stroke and hospitalization for heart failure were significantly lower in the more aggressively treated patients. A total of 18,696 patients have taken 80 mg of atorvastatin in clinical trials, usually for 4 to 5 years, with an excellent safety record. Pharmacoeconomic studies indicate that treatment with the 80-mg dose instead of the 10-mg dose almost costs neutral in US TNT-like patients (additional cost $181 for 5 years). In summary, wider use of the 80-mg dose of atorvastatin in patients with stable coronary disease is safe, cost-effective, and provides an incremental reduction in coronary events. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Objectives: The aim of this post hoc analysis from the TNT (Treating to New Targets) trial is to determine whether patients with previous coronary artery bypass grafting (CABG) surgery achieved clinical benefit from intensive low-density lipoprotein (LDL)-cholesterol lowering. Background: The development and progression of atherosclerosis is accelerated in coronary venous bypass grafts. Methods: A total of 10,001 patients with documented coronary disease, including 4,654 with previous CABG, were randomized to atorvastatin 80 or 10 mg/day and were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event (cardiac death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke). Results: A first major cardiovascular event occurred in 11.4% of the patients with prior CABG and 8.5% of those without prior CABG (p < 0.001). In CABG patients, mean LDL-cholesterol levels at study end were 79 mg/dl in the 80-mg arm and 101 mg/dl in the 10-mg arm, and the primary event rate was 9.7% in the 80-mg arm and 13.0% in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.62 to 0.87, p = 0.0004). Repeat revascularization during follow-up, either CABG or percutaneous coronary intervention, was performed in 11.3% of the CABG patients in the 80-mg arm and 15.9% in the 10-mg arm (hazard ratio 0.70, 95% confidence interval 0.60 to 0.82, p < 0.0001). Conclusions: Intensive LDL-cholesterol lowering to a mean of 79 mg/dl with atorvastatin 80 mg/day in patients with previous CABG reduces major cardiovascular events by 27% and the need for repeat coronary revascularization by 30%, compared with less intensive cholesterol-lowering to a mean of 101 mg/dl with atorvastatin 10 mg/day. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691) [Copyright &y& Elsevier]

Objective: We sought to assess the effects on cerebrovascular events of treating patients with stable coronary disease with low-density lipoprotein cholesterol (LDL-C) levels substantially below 100 mg/dl. Background: Lowering LDL-C with statins has been shown to reduce the risk of stroke in patients with stable coronary disease. In observational studies, naturally low cholesterol levels have been associated with an increased risk of hemorrhagic stroke. The cerebrovascular benefits of treating patients with stable coronary disease to LDL-C levels substantially below 100 mg/dl have not been previously investigated. Methods: We describe an analysis of cerebrovascular events in the Treating to New Targets study, a trial where 10,001 patients with documented coronary disease were randomized to treatment with atorvastatin at 10 mg/day or 80 mg/day and followed for a median of 4.9 years. Results: Mean LDL-C levels were 101 mg/dl on 10 mg atorvastatin and 77 mg/dl on 80 mg. In addition to the reduction in major cardiovascular events (hazard ratio 0.78, 95% confidence interval [CI] 0.69 to 0.89; p = 0.0002), the primary end point of the trial, patients in the 80-mg arm experienced a reduction in cerebrovascular events (hazard ratio 0.77, 95% CI 0.64 to 0.93; p = 0.007) and stroke (hazard ratio 0.75, 95% CI 0.59 to 0.96; p = 0.02). Each 1-mg/dl reduction in LDL-C with treatment was associated with a 0.6% relative risk reduction in cerebrovascular events (p = 0.002) and a 0.5% relative risk reduction in stroke (p = 0.041). The incidence of hemorrhagic stroke was similar in the 80-mg and 10-mg groups, 16 and 18 respectively, and the hemorrhagic strokes were distributed evenly across quintiles of achieved LDL-C during treatment. Conclusions: Among patients with established coronary disease, treating to an LDL-cholesterol substantially below 100 mg/dl with 80 mg/day atorvastatin reduces both stroke and cerebrovascular events by an additional 20% to 25% compared with the 10 mg/day dose. An increase in hemorrhagic stroke was not seen at low LDL-C levels. (Treating to New Targets; http://www.clinicaltrials.gov; NCT00327691). [Copyright &y& Elsevier]

Abstract: Background: Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure—a physiologic state characterized by systemic inflammation and endothelial dysfunction. Methods and Results: This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF. Conclusion: Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic. [Copyright &y& Elsevier]

It has taken a century since Anitschkow began feeding cholesterol to rabbits to study the role of cholesterol in atherosclerosis to be fully appreciated and for the potential of cholesterol reduction to prevent cardiovascular events to be fully realized. The body of clinical trial data testing the effects of statins on coronary heart disease is extensive and convincing. A 1% reduction in low-density lipoprotein cholesterol reduces coronary events by approximately 1%. With large doses of potent statins, low-density lipoprotein cholesterol levels and coronary events can thus be reduced by approximately 50%. The anti-inflammatory effects of large doses of atorvastatin likely contribute to the early event reduction seen early after acute coronary syndromes. Translating this information into clinical practice presents a challenge: many patients who would benefit from statins remain untreated or undertreated or discontinue treatment soon after it is initiated. [Copyright &y& Elsevier]

This article reviews the safety of statins, with emphasis on high-dose atorvastatin (80 mg), the agent with the most efficacy data for clinical outcomes. Although elevated levels of hepatic enzymes were of concern when statins were first introduced, a review of data from large clinical trials shows that elevations in hepatic enzymes are rare and do not lead to clinically significant liver disease. Despite the withdrawal of cerivastatin because of fatal rhabdomyolysis, the risk of this complication with other statins is extremely low. Mild and often transient myalgia is more commonly reported. The safety of high-dose atorvastatin has been evaluated in >11,000 patients, and rates of clinically significant myopathy and elevated hepatic enzymes were extremely low. Simvastatin at doses up to 40 mg is also associated with low rates of elevated hepatic enzymes and myopathy. However, the 80-mg dose of simvastatin carries a risk of myopathy (muscle symptoms and creatine kinase levels >10,000 U/L) of approximately 1 in 250. The clinical benefits of preventing vascular events, myocardial infarction, stroke, and need for revascularization outweigh the low rates of adverse events associated with high-dose statin therapy in high- and intermediate-risk patients. [Copyright &y& Elsevier]

Atherosclerosis is increasingly viewed as an inflammatory process. A number of infectious agents have been implicated in the pathogenesis of coronary artery disease. Chlamydia pneumoniae has been the most popular and well-studied of these pathogens. It is difficult to prove a causal relationship which requires the fulfillment of Koch''s postulates, first developed in the late 1800s, to establish an infectious agent as the cause of a disease process. This paper reviews the evidence for and against Chlamydia pneumoniae infection as a contributing factor to atherosclerosis disease. It examines seroepidemiologic and histopathologic studies as well as animal models using Koch''s postulates and then provides an analysis of current clinical trial data. [Copyright &y& Elsevier]

To evaluate the contribution of hematologic factors and long-term inflammation to the development of myocardial infarction at a young age, we measured hematologic variables, including soluble fibrin and high-sensitivity C-reactive protein, in 90 patients who had myocardial infarction and 138 controls ≤45 years of age. Plasma levels of soluble fibrin and C-reactive protein were significantly higher in patients than in controls. On multivariate regression analysis, soluble fibrin was the strongest predictor of myocardial infarction at a young age. [Copyright &y& Elsevier]

The Treating to New Targets (TNT) trial is a parallel-group study that has randomized 10,003 patients from 14 countries to double-blind treatment with either atorvastatin 10 or 80 mg. During the double-blind period, low-density lipoprotein (LDL) cholesterol levels are expected to reach approximate mean values of 100 mg/dl (2.6 mmol/L) for the low-dose atorvastatin group and 75 mg/dl (1.9 mmol/L) for the high-dose group. Randomized patients are expected to be followed for an average of 5 years. The primary end point is the time to occurrence of a major cardiovascular event, defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. The large patient numbers in the TNT study and long follow-up should ensure that there is adequate power to definitively determine if reducing LDL cholesterol levels to approximately 75 mg/dl (1.9 mmol/L) can provide additional clinical benefit. [Copyright &y& Elsevier]

Remarkable therapeutic advances in the treatment of acute coronary syndromes (ACS) have been made with antiplatelet and antithrombotic therapy. However, these therapies alone do not appear to completely stabilize culprit lesions. Evidence from a variety of sources suggests that intensive cholesterol lowering with statins favorably influences culprit lesion stabilization in patients with ACS. Potential mechanisms of benefit include improvements in endothelial function, decreased propensity for platelet thrombus formation, and reduction in inflammation at the site of the lesion. The Myocardial Ischemia with Aggressive Cholesterol Lowering (MIRACL) study is the first large-scale clinical trial to examine whether these mechanisms translate into clinical-event reduction in patients with ACS as well as the substantial proved benefits in the chronic coronary syndromes. In this trial, early initiation of atorvastatin after an episode of unstable angina or non-Q-wave myocardial infarction reduced events over the ensuing 16 weeks. It is hoped that a growing awareness of the benefits of early statin therapy to stabilize culprit lesions in ACS will lead to an increase in the proportion of coronary patients who will receive this beneficial therapy. [ABSTRACT FROM AUTHOR]

Examines the role of intensive cholesterol lowering in the treatment of acute coronary syndromes in the United States. Treatment with statins after an acute coronary event; Comparison between unstable and stable coronary disease; Treatment strategies in acute coronary syndromes.

Assesses the efficacy of statin therapy in preventing cardiovascular risk. Statin trials for primary and secondary prevention of coronary artery disease; Effect of statin on low-density lipoprotein cholesterol levels; Treatment decision based on low-density lipoprotein cholesterol level.

Women presenting with acute myocardial infarction (AMI) have a higher mortality with conventional medical and thrombolytic therapy when compared with men. The outcome after primary percutaneous transluminal mechanical revascularization has not yet been fully investigated. This study was performed to compare the characteristics and the short- and medium-term outcomes of women and men with AMI treated with primary percutaneous revascularization. A total of 182 consecutive patients (62 women and 120 men) were included. Baseline clinical characteristics were similar except that women were older than men, presented more often in cardiogenic shock, and had smaller reference vessel diameters. Stents and abciximab were used equally, but abciximab was stopped more often in women before completion of the 12-hour infusion because of higher bleeding rates. Acute procedural success rates were similar (92% and 97%) but mortality was much higher in women, both at 30-day follow-up (100% vs 0.9%; p <0.05) and during a mean follow-up of 6.9 +/- 4.1 months (15% vs 4.4%; p <0.05). Women also experienced more unfavorable cardiovascular events (recurrent unstable angina or AMI, target vessel revascularization) than men. However, after control for baseline clinical differences in a multivariate analysis, gender was not an independent predictor of survival, whereas age, cardiogenic shock, and completion of a 12-hour abciximab infusion were. [ABSTRACT FROM AUTHOR]