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Elizabeth Marrett,1 Changgeng Zhao,1 Ning Jackie Zhang,2 Qiaoyi Zhang,1 Dena R Ramey,1 Joanne E Tomassini,1 Andrew M Tershakovec,1 David R Neff11Merck & Co, Inc., Whitehouse Station, NJ, USA; 2College of Health and Public Affairs, University of Central Florida, Orlando, FL, USABackground: Guidelines endorse statin therapy for lowering low-density lipoprotein cholesterol (LDL-C) to recommended levels, in patients with cardiovascular disease (CVD) risk, if needed, after lifestyle changes. Atorvastatin is a common statin with greater LDL-C lowering efficacy than most other statins; its availability in generic form will likely increase its use. This study assessed attainment of guideline-recommended LDL-C levels in high-risk CVD patients treated with atorvastatin monotherapy.Methods: Analyses of two retrospective US cohorts of patients who received a prescription for atorvastatin monotherapy between January 1, 2008 and December 31, 2010 (index date defined as first prescription date) in the GE Centricity Electronic Medical Record (EMR) (N=10,693) and Humana Medicare (N=16,798) databases. Eligible patients were ≥18 years, diagnosed with coronary heart disease or atherosclerotic vascular disease, with ≥1 LDL-C measurement between 3 months and 1 year postindex date, and continuously enrolled for 1 year prior to and following the index date.Results: Of the eligible patients, 21.8%, 29.6%, 29.9%, and 18.7% (GE Centricity EMR) and 25.4%, 32.9%, 27.8%, and 14.0% (Humana Medicare) received 10, 20, 40, and 80 mg doses of atorvastatin, respectively. The mean ± standard deviation (SD) follow-up LDL-C levels were 2.1±0.8 mmol/L (83±30 mg/dL) and 2.3±0.8 mmol/L (88±31 mg/dL) for the GE Centricity EMR and Humana Medicare cohorts, respectively. Regardless of dose, only 28.3%-34.8% of patients had LDL-C levels 1.8 mmol/L (>70 mg/dL), and of these, 30%-40% had LDL-C levels ≥0.5 mmol/L (≥20 mg/dL) above this, regardless of dose. This suggests that more effective lipid-lowering strategies, such as statin uptitration, switching to a higher efficacy statin, and/or combination therapy, may be required to achieve optimal LDL-C lowering in high-risk patients.Keywords: statin therapy, managed-care, lipid-lowering therapy

JoAnne M Foody,1 Peter P Toth,2 Joanne E Tomassini,3 Shiva Sajjan,3 Dena R Ramey,3 David Neff,3 Andrew M Tershakovec,3 Henry Hu,3 Kaan Tunceli31Brigham and Women's Hospital, Boston, MA, 2CGH Medical Center, Sterling, IL, and University of Illinois College of Medicine, Peoria, IL, 3Merck & Co., Inc., Whitehouse Station, NJ, USABackground: Many high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US.Methods: Eligible patients (n = 17,830), initially on statin monotherapy who were ≥18 years with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy, and on lipid-lowering therapy for ≥42 days, were identified between November 1, 2002 and September 30, 2009. The percent change from baseline in LDL-C levels and the odds ratios for attainment of LDL-C

Background: Canadian and European treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as a primary treatment target for hypercholesterolaemia. Objectives: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high-sensitivity C-reactive protein (hs-CRP) levels. Methods: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL-C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL-C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks. Results: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL-C, most lipids and lipoproteins and/or hs-CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL-C and: Apolipoprotein (Apo) B, total cholesterol (total-C), total-C/high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, Apo B/Apo A-I or hs-CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose. Conclusions: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively. [ABSTRACT FROM AUTHOR]

Improvements in hypertension treatment and control are challenged by the increasing incidence of metabolic risk factors for hypertension, in particular, obesity and insulin resistance. Such risk factors can increase the severity of hypertension and can interact via a multitude of hormonal and inflammatory pathways. Their presence may affect antihypertensive agent choice with regard to antihypertensive efficacy as well as potential synergistic or antagonistic effects on inflammatory status and progression to diabetes. Furthermore, an increasing number of pharmacologic options are available to promote weight loss and insulin sensitivity that may affect blood pressure directly and indirectly. This review considers the metabolic basis for the complex interactions of hypertension with obesity and insulin resistance, and it assesses the clinical evidence for an impact of weight loss and insulin-sensitizing treatment on blood pressure. Awareness of these pathophysiologic interrelations and their implications for treatment are likely to be of increasing importance for successful blood pressure management. [ABSTRACT FROM AUTHOR]

Background and Objective: Disease history and clinical features can influence treatment response in patients with acute gout. The purpose of this pooled subgroup analysis was to assess the association of baseline disease and patient characteristics with response to treatment in acute gout using data from two identical studies.Methods: Patients > or = 18 years of age with onset of acute gout within 48 h associated with moderate, severe, or extreme pain involving less than four joints were eligible for inclusion in the primary studies, and were randomized to etoricoxib 120 mg once daily (N = 178) or indomethacin 50 mg three times daily (N = 161). The primary and secondary efficacy endpoints were analyzed using an analysis of covariance model to detect potential differential treatment responses across several subgroups: joint involvement (mono-articular vs. oligo-articular), baseline pain severity (moderate vs. severe), concomitant allopurinol and/or colchicine use (users vs. nonusers), age (< 45, 45-55, and > 55 years), gender, and race (white or other).Results: Overall, etoricoxib and indomethacin demonstrated comparable efficacy across all subgroups. Compared with patients with oligo-articular disease, those with mono-articular disease had significantly greater improvements in patient assessment of pain, patient global assessment of response to therapy (PGART), investigator global assessment of response to therapy (IGART), and study joint tenderness (p < 0.001 for all). Greater improvements were seen in patient assessment of pain (p < 0.001) and study joint tenderness (p < 0.05) for severe/extreme baseline pain compared with moderate baseline pain. Concomitant use of colchicine and/or allopurinol was associated with significantly worse IGART (p < 0.05).Conclusions: This pooled subgroup analysis demonstrated significantly greater response of acute gout to either etoricoxib or indomethacin among those with monoarticular disease, severe/extreme baseline pain, and non-use of colchicine and/or allopurinol. These results should be interpreted in the context of a pooled subgroup analysis with a limited sample size, and with the understanding that associations identified in such analyses do not define causation. Despite limitations, the results provide insights into the types of patients more likely to respond better to anti-inflammatory medication, and reiterate the importance of earlier effective control of the disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5 mg/750 mg (H/A) and placebo in treating pain after arthroscopy of the knee. METHODS: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50 mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24 h. The primary endpoint was total pain relief at 6 h for rofecoxib 50 mg compared with placebo. RESULTS: H/A (p = 0.003), but not rofecoxib (p = 0.256) was significantly more effective than placebo for total pain relief at 6 h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (p < 0.01, p < 0.05, respectively) and placebo (p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (p < 0.001) over 24 h. Rofecoxib also provided better Brief Pain Inventory Severity (p = 0.008) and Interference Domain (p = 0.045) scores at 24 h compared to placebo and had lower 24-h Pain Severity scores than H/A (p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups. CONCLUSIONS: Rofecoxib 50 mg did not provide significantly different pain relief than placebo at 6 h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24 h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model. [ABSTRACT FROM AUTHOR]

BACKGROUND: Obesity is an increasing concern in the United States. Effective prevention of obesity requires the risk factors to be well defined. African Americans have a high risk of obesity. OBJECTIVE: The objective of this study was to identify risk factors, present at birth, for increased adiposity in adulthood in an African American population. DESIGN: In this retrospective analysis of a prospective cohort study, anthropometric and socioeconomic variables were collected at birth. A representative sample of 447 African American subjects was followed up until young adulthood, when skinfold thickness was measured. Associations between the independent variables and increased adiposity (skinfold thickness above the 85th percentile) were explored by using unadjusted and adjusted analyses. RESULTS: Three variables measured at birth were independently associated with adiposity in young adulthood, explaining 12% of the variance. The odds ratios (with 95% CIs) of these variables for increased adiposity were 2.7 (1.2, 6.2) for female sex, 4.0 (1.4, 11. 2) for first-born status, and 1.15 (1.06, 1.25) for each unit increment in maternal prepregnancy body mass index (BMI; in kg/m(2)). After adjustment for these variables, birth weight for gestational age and socioeconomic variables were not associated with adiposity. CONCLUSIONS: This cohort study of African American subjects was the first to identify first-born status as an independent risk factor for increased adiposity in adulthood in a US population. The results of the study strengthen previous reports of the effect of female sex and maternal BMI on adulthood obesity. Identification of risk factors early in life may help target prevention toward high-risk children and allow healthy lifestyles to be established before the onset of obesity. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

OBJECTIVES: This study evaluated retention of the effect of a home-based, practitioner-initiated nutrition education model. METHODS: Children with elevated low-density lipoprotein (LDL) cholesterol levels were randomly assigned to one of two nutrition interventions or to an at-risk control group. Intervention effects were evaluated 3, 6, and 12 months postbaseline. RESULTS: The parent-child autotutorial group demonstrated significant increases in knowledge and, along with the counseling group, decreases in total and saturated fat intake. Also, the autotutorial and counseling groups retained a majority of their initial LDL cholesterol decrease. CONCLUSIONS: Knowledge of heart-healthful eating and dietary fat intake as well as dietary change can be affected and retained via home-based, practitioner-initiated nutrition interventions with hypercholesterolemic children, although some form of ongoing intervention may be necessary to produce lasting decreases in LDL cholesterol levels. [ABSTRACT FROM AUTHOR]

Background: The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin., Objectives: The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS)., Methods: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke., Results: Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints., Conclusions: Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)., Competing Interests: Funding Support and Author Disclosures The IMPROVE-IT trial was supported by Merck and Co. Dr Oyama has received a grant from JSPS Overseas Research Fellowships. Dr Giugliano has received grants from Amgen and Anthos Therapeutics; has received honoraria from Amgen, Centrix, Daiichi-Sankyo, Dr Reddy's Laboratories, Medical Education Resources, Medscape, Menarini, Pfizer, SAJA Pharmaceuticals, Servier, and Voxmedia; and has received consultant fees from Amarin, Amgen, Bayer, CryoLife, Daiichi-Sankyo, Esperion, Gilead, Hengrui, Inari, Pfizer, PhaseBio Pharmaceuticals, St Lukes, and Sanofi. Dr Blazing has received research support from Merck; has received consulting fees from Espirion (<$10,000); and has received indirect support from Sanofi through Duke Clinical Research Institute. Dr Park has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, The Medicines Company, and Zora Biosciences. Dr Tershakovec is a former employee of Merck Sharp and Dohme Corp, a subsidiary of Merck and Co, Inc, and may own stock in the company. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and has received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk. Dr Cannon has received grant support and consulting fees from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Pfizer, and Merck; has received grant support from Daiichi-Sankyo; and has received consulting fees from Aegerion, Alnylam, Amarin, Applied Clinical Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Innovent, Kowa, Eli Lilly, and Rhoshan. Dr Braunwald has received research grants through the Brigham and Women’s Hospital from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; has served as a consultant for Amgen, Cardurion, MyoKardia, NovoNordisk, Boehringer Ingelheim/Lilly, IMMEDIATE, and Verve; and has performed uncompensated consultancies and lectures for The Medicines Company., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial., Objectives: The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)., Methods: Within IMPROVE-IT, 17,708 patients post-acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy., Results: In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68)., Conclusions: Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)., (© 2020 The Authors.)

Background: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies., Objective: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods., Methods: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies., Results: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29-0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P < .01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: -5.0 and -12.0, -2.0 and -5.4, and -1.5 and -12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: -5.0 and -19.9 and -2.0 and -7.3) in second-line studies., Conclusion: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements., (Copyright © 2019. Published by Elsevier Inc.)

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h -1 ) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway., Competing Interests: Conflict of interest: A.H. Morice has received consulting fees from Afferent, Merck Sharp & Dohme, Boehringer Ingelheim, Pfizer, and Proctor & Gamble; lecture fees from Boehringer Ingelheim and AstraZeneca; and grant support from Proctor & Gamble. Conflict of interest: M.M. Kitt is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.P. Ford is a former employee of Afferent Pharmaceuticals and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: A.M. Tershakovec is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock in the company. Conflict of interest: W-C. Wu was an employee of Merck Sharp & Dohme, Corp, during the conduct of the study. Conflict of interest: K. Brindle has nothing to disclose. Conflict of interest: R. Thompson has nothing to disclose. Conflict of interest: S. Thackray-Nocera has nothing to disclose. Conflict of interest: C. Wright has nothing to disclose., (Copyright ©ERS 2019.)

Low-density lipoprotein cholesterol (LDL-C) has been identified as a causative factor for atherosclerosis and related coronary heart disease, and as the main target for cholesterol- and lipid-lowering therapy. Statin drugs inhibit cholesterol synthesis in the liver and are typically the first line of therapy to lower elevated levels of LDL-C. On the other hand, a different drug, Ezetimibe, inhibits the absorption of cholesterol by the small intestine and provides a different mechanism of action. Many clinical trials have been carried out on safety and efficacy evaluation of cholesterol lowering drugs. To synthesize the results from different clinical trials, we examine treatment level (aggregate) network meta-data from 29 double-blind, randomized, active, or placebo-controlled statins +/$-$ Ezetimibe clinical trials on adult treatment-naïve patients with primary hypercholesterolemia. In this article, we propose a new approach to carry out Bayesian inference for arm-based network meta-regression. Specifically, we develop a new strategy of grouping the variances of random effects, in which we first formulate possible sets of the groups of the treatments based on their clinical mechanisms of action and then use Bayesian model comparison criteria to select the best set of groups. The proposed approach is especially useful when some treatment arms are involved in only a single trial. In addition, a Markov chain Monte Carlo sampling algorithm is developed to carry out the posterior computations. In particular, the correlation matrix is generated from its full conditional distribution via partial correlations. The proposed methodology is further applied to analyze the network meta-data from 29 trials with 11 treatment arms., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials., Methods and Results: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates., Conclusions: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) vs simvastatin (40 mg). Subjects were divided into 3 groups: pre-existing HF (i.e., defined by past medical history), de novo HF (i.e., defined by Killip class II or greater during index admission), and no HF. The final analytical cohort included 14,792 patients (82%) with HF status recorded at baseline. In total, 790 patients (5.3%) reported a pre-existing diagnosis of HF and 1374 patients (9.3%) experienced de novo HF. Patients with pre-existing or de novo HF were older, more likely to be woman, and had a greater prevalence of atrial fibrillation and diabetes mellitus. The incidences of death/HF-hospitalizations at 5 years were 32%/20% for pre-existing HF, 18%/7% for de novo HF, and 8%/3% for no HF. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death (pre-existing HF: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.68 to 2.22, p < 0.001; de novo HF: HR 1.51, 95% CI 1.33 to 1.72, p < 0.001) and hospitalizations for HF (pre-existing HF: HR 2.96, 95% CI 2.36 to 3.71, p < 0.001; de novo HF: HR 1.88, 95% CI 1.49 to 2.38, p < 0.001). There was no interaction among baseline HF status (i.e., pre-existing or de novo), lipid lowering therapy (i.e., simvastatin/ezetimibe vs simvastatin alone), and clinical outcomes. In conclusion, patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities. In conclusion, HF was independently associated with increased risk of long-term morbidity and mortality with the pre-existing HF cohort demonstrating the highest overall risk., (Copyright © 2018. Published by Elsevier Inc.)

Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization., Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years., Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; P =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; P =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; P =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; P =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; P =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; P =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; P =0.011) with ezetimibe added to simvastatin therapy., Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878., (© 2017 American Heart Association, Inc.)

Background: Understanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS)., Methods and Results: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) and ST-segment elevation myocardial infarction (STEMI), in those <65 and ≥65 years old, and males and females, over 7 years of follow-up. Of 18 131 patients, the presenting event was STEMI for 5190 (29%) and UA/NSTEMI for 12 941 (71%); 10 173 (56%) patients were <65 years old and 7971 (44%) were ≥65 years old at presentation. UA/NSTEMI patients were older than STEMI patients, with more cardiovascular and noncardiovascular risk factors. In STEMI patients, the cumulative incidence of cardiovascular death was higher for ∼4 years following the index event, after which noncardiovascular death predominated. In UA/NSTEMI patients, the cumulative incidence of cardiovascular death remained higher than noncardiovascular death over the full follow-up period. Patients ≥65 years old and <65 years old had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow-up. Female patients had a higher incidence of cardiovascular death than noncardiovascular death for ∼6 years following the index event; male patients had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow-up., Conclusions: Among post-ACS patients enrolled in a long-term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age. These findings further delineate long-term prognosis after ACS and should inform the design of future cardiovascular outcomes trials., (© 2017 The Authors and Merck Sharp & Dohme Corp. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The 2008 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study demonstrated ezetimibe + simvastatin vs simvastatin alone had a neutral effect on the surrogate endpoint of carotid intima-media thickness. Subsequent media portrayal of the study prompted ezetimibe discontinuation in many patients., Objective: The objective of the study was to assess the impact of ENHANCE reporting on ezetimibe discontinuation, low-density lipoprotein cholesterol (LDL-C) changes, and potential cardiovascular disease (CVD) risk., Methods: This analysis used claims data in a retrospective, observational study of patients receiving ezetimibe + statin and compared LDL-C for patients who discontinued ezetimibe (n = 970) vs those who continued ezetimibe + statins (n = 3706) after ENHANCE results disclosure. Change in relative CVD risk was estimated from the absolute LDL-C difference between groups per the Cholesterol Treatment Trialists' meta-analysis of statin trials., Results: The rate of ezetimibe discontinuation was 2% in the 6 months before and 21% in the 6 months after reporting of ENHANCE results. Among patients who ultimately discontinued vs continued ezetimibe, respective mean LDL-C levels were 79.8 and 78.3 mg/dL 6 months before reporting of the ENHANCE results and 93.5 and 78.1 mg/dL 6 months after reporting of ENHANCE. Predictive application of the Cholesterol Treatment Trialists' meta-analysis suggested the 13.9 mg/dL increase in mean LDL-C translated to a 9.4% increase in relative CVD risk for those who discontinued ezetimibe., Conclusion: After reporting of the neutral ENHANCE results, ezetimibe discontinuation rate increased, LDL-C levels increased, and predicted CVD risk increased among those who discontinued ezetimibe. Characterization of clinical outcomes regarding lipid-altering agents based on surrogate biomarker studies not designed to assess CVD outcomes may be misleading, potentially placing patients at increased CVD risk., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Importance: In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown., Objective: To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial., Design, Setting, and Participants: This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017., Main Outcomes and Measures: Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial., Results: Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater., Conclusions and Relevance: Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels., Trial Registration: clinicaltrials.gov Identifier: NCT00202878.

Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7 mg/dl with ezetimibe/statin; 0.2 to 4.6 mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4 mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG ≥126 mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy., (Copyright © 2016 The Authors and Merck Sharp & Dohme Corp. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment analysis., Methods: We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol values between 50 and 125 mg/dL and who received Ez 10 mg/d with S 40 mg/d (Ez/S) or placebo with simvastatin 40 mg/d (P/S). The primary composite end point was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization ≥30 days postrandomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary end point or noncardiovascular death within 30 days of drug discontinuation., Results: Mean low-density lipoprotein cholesterol values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference -17 mg/dL = -24%; P < .001). The 7-year Kaplan-Meier estimate of the primary end point occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HR adj 0.92 [95% CI 0.87-0.98]; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT., Conclusions: This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In numerous clinical trials, lowering LDL-C with statin therapy has been demonstrated to reduce the risk of cardiovascular disease (CVD) in primary and secondary prevention settings. Guidelines recommend statins for first-line therapy in cholesterol-lowering management of patients with CVD risk. Despite increased statin monotherapy use over the last decade, a number of patients with high CVD risk do not achieve optimal LDL-C lowering. Guidelines recommend consideration of statin combination therapy with nonstatin agents for these patients. However, combination therapy approaches have been hampered by neutral findings. Recently, ezetimibe added to simvastatin therapy reduced cardiovascular events in acute coronary syndrome patients, more than simvastatin alone. This article provides an overview of various agents in combination with statin therapy on cardiovascular outcomes. Other lipid-lowering agents in development, including PCSK9 and CETP inhibitors in development, are also described.

Objectives: Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed., Methods: This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988-2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed., Results: Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (-0.0119 mm/year) than after 2000 (-0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (≥ 2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar., Conclusion: Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin., Objectives: This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy., Methods: All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis., Results: Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005)., Conclusions: Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Little is known regarding relationships between high-sensitivity C-reactive protein (hsCRP) and lipoproteins other than low-density lipoprotein cholesterol (LDL-C). High-density lipoprotein (HDL), with both anti-inflammatory and cholesterol-mediating effects, is of particular interest. This exploratory analysis assessed associations between hsCRP and lipids in older (>65 years) patients with moderate and/or high cardiovascular disease risk, before and after treatment with ezetimibe/simvastatin (E/S) or atorvastatin (ATV)., Methods: An analysis of a multicenter, randomized, double-blind, 12-week study. Correlations were assessed in 1054 patients with both baseline and 12-week hsCRP ≤ 10 mg/L, pooled across doses of E/S (10/20 and 10/40 mg) and ATV (10, 20, and 40 mg), and combined E/S + ATV treatments. Because of multiple comparisons, observed relationships were considered significant only if P values were < .01., Results: Correlations between baseline levels of hsCRP and either LDL-C, non-HDL-C, or apolipoprotein B were weak and nonsignificant in the E/S, ATV, and E/S + ATV groups. After 12 weeks of treatment, these correlations increased slightly and significantly in all groups, except for LDL-C in the ATV group. HDL-C was significantly but inversely correlated with hsCRP in the ATV and E/S + ATV groups at baseline, and in all groups at 12 weeks. Only with HDL-C did change correlate with change in hsCRP in both the E/S and combined groups., Conclusions: Relationships between hsCRP and lipid factors in older patients were weak at baseline and somewhat stronger after treatment. HDL-C was inversely and consistently correlated with baseline and 12-week on-treatment hsCRP and with therapy-induced changes in HDL-C and hsCRP., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

This brief article provides complementary data supporting the results reported in "Changing Characteristics of Statin-related cIMT Trials from 1988 to 2006" [1]. That article described time-related trends in baseline factors and study characteristics that may have influenced the variability of carotid intima media thickness (cIMT) endpoints (mean of mean and maximum common carotid artery [CCA]/cIMT) in published statin trials. In this brief report, additional details for the studies included in the analysis, and further supporting data, including mean of the maximum CCA/cIMT changes and subgroup data (mean and maximum CCA/cIMT) are provided. For the analysis, study-level data was extracted from 17 statin cIMT trials conducted during 1988-2006, selected on the basis of having at least one statin monotherapy arm in the absence of mixed therapy, and baseline- and study-end values for mean mean and mean maximum CCA/cIMT endpoints. The baseline mean CCA/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Interestingly, all 8 studies conducted before 2000 were significant for cIMT change in which patients did not receive prior LLT; whereas after 2000, the results were more variable and in 4 of 6 trials that did not show a significant cIMT change, patients had received prior treatment. Baseline mean maximum cIMT and LDL-C levels, and annualized changes in studies conducted before 2000 were higher than those conducted after 2000, similar to the results reported in the original article for the mean mean cIMT endpoint. These findings were consistent across study populations of patients with CHD risk versus those without, and in studies with greater LDL-C reductions and with thickened baseline cIMT at study entry for both mean and maximum cIMT changes. Taken together, these results are consistent with trends in recent years toward greater use of lipid-lowering therapy and control of LDL-C that may have impacted the variability in the results of cIMT studies.

Background: Patients with diabetes mellitus and cardiovascular disease may not achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on statin monotherapy, attributed partly to atherogenic dyslipidemia. More intensive LDL-C-lowering therapy can be considered for these patients. A previous randomized, controlled study demonstrated greater LDL-C lowering in diabetic patients with symptomatic cardiovascular disease who switched from simvastatin 20 mg (S20) or atorvastatin 10 mg (A10) to combination ezetimibe/simvastatin 10/20 mg (ES10/20) therapy, compared with statin dose-doubling (to S40 or A20) or switching to rosuvastatin 10 mg (R10). The effect of these regimens on novel biomarkers of atherogenic dyslipidemia (low- and high-density lipoprotein particle number and lipoprotein-associated phospholipase A2 [Lp-PLA2]) was assessed., Methods and Results: Treatment effects on low- and high-density lipoprotein particle number (by NMR) and Lp-PLA2 (by ELISA) were evaluated using plasma samples available from 358 subjects in the study. Switching to ES10/20 reduced low-density lipoprotein-particle number numerically more than did statin dose-doubling and was comparable with R10 (-133.3, -94.4, and -56.3 nmol/L, respectively; P>0.05). Increases in high-density lipoprotein particle number were significantly greater with switches to ES10/20 versus statin dose-doubling (1.5 and -0.5 μmol/L; P<0.05) and comparable with R10 (0.7 μmol/L; P>0.05). Percentages of patients attaining low-density lipoprotein particle number levels <990 nmol/L were 62.4% for ES10/20, 54.1% for statin dose-doubling, and 57.0% for R10. Switching to ES10/20 reduced Lp-PLA2 activity significantly more than did statin dose-doubling (-28.0 versus -3.8 nmol/min per mL, P<0.05) and was comparable with R10 (-28.0 versus -18.6 nmol/min per mL; P>0.05); effects on Lp-PLA2 concentration were modest., Conclusions: In diabetic patients with dyslipidemia, switching from statins to combination ES10/20 therapy generally improved lipoprotein subclass profile and Lp-PLA2 activity more than did statin dose-doubling and was comparable with R10, consistent with its lipid effects., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251., (© 2015 The Authors. [Ngoc‐Anh Le and Peter W. F. Wilson] and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All rights reserved. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)., Methods and Results: The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets., Conclusions: Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment., Clinical Trial Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878., (© 2015 American Heart Association, Inc.)

Background: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS., Methods: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg)., Results: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups., Conclusion: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).

Background: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known., Methods: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years., Results: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups., Conclusions: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).