Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or Older in the United States Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. Risk score overestimation: the impact of individual cardiovascular risk factors and preventive therapies on the performance of the American Heart Association-American College of Cardiology-Atherosclerotic Cardiovascular Disease risk score in a modern multi-ethnic cohort Extended-release niacin or ezetimibe and carotid intima-media thickness. Lipid-lowering therapy in older persons Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. Prevalence of Dyslipidemia and Lipid Goal Attainment in Statin-Treated Subjects From 3 Data Sources: A Retrospective Analysis Long-Term Safety and Efficacy of a Combination of Niacin Extended Release and Simvastatin in Patients with Dyslipidemia Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy. Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Design and Rationale of the ARBITER 6 Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)-6-HDL and LDL Treatment Strategies in Atherosclerosis (HALTS) Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial. A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets? Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial Reductions in Atherogenic Lipids and Major Cardiovascular Events Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)—A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. The influence of statin-fibrate combination therapy on lipids profile and apolipoprotein A5 in patients with acute coronary syndrome Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin.
Atherosclerotic cardiovascular disease ( ASCVD ) is the leading cause of death , decreased quality of life , and medical costs in the United States . Nearly 1 in 3 Americans die of heart disease and stroke ( 1 ) . Most ASCVD is preventable through a healthy lifestyle and effective treatment of cholesterol and blood pressure . The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults from the American College of Cardiology and American Heart Association ( ACC/AHA ) provides an evidence -based approach to reducing ASCVD risk ( 2 ) . Guideline Development Process In 2008 , the National Heart , Lung , and Blood Institute ( NHLBI ) convened the Adult Treatment Panel ( ATP ) IV to up date the 2001 ATP-III cholesterol guidelines using a rigorous systematic process to identify and review r and omized , controlled trials ( RCTs ) with cardiovascular outcomes and meta-analyses of these RCTs . The panel comprised experts and clinicians from the fields of cardiology , epidemiology , primary care , and endocrinology ( 2 ) and received support from the Lifestyle Management and Risk Assessment Work Groups ( 3 , 4 ) . Systematic evidence review s conducted according to principles recommended by the Institute of Medicine ( 5 ) were performed to answer 3 questions relevant to clinical care . Two questions focused on the evidence supporting low-density lipoprotein cholesterol ( LDL-C ) and nonhigh-density lipoprotein cholesterol ( HDL-C ) levels as targets of treatment . One question examined the reduction in ASCVD events and adverse effects for each cholesterol-lowering drug class . The panel synthesized the evidence from these 3 review s as well as from Lifestyle Management and Risk Assessment Work Groups review s ( 3 , 4 ) that addressed 5 additional critical questions . Systematic electronic search es of relevant data bases of the peer- review ed English- language literature published from 1 January 1995 through 1 December 2009 for each critical question were conducted by an NHLBI-selected independent contractor and focused on RCTs and systematic review s and meta-analyses of RCTs assessed as fair to good quality . In addition , RCTs with ASCVD outcomes that included coronary heart disease , stroke , and cardiovascular deaths published after that date were eligible for consideration through July 2013 . Evidence tables were constructed , and the strength of evidence was rated according to the NHLBI ( Table 1 of the Supplement ) . Recommendations were grade d according to criteria from the NHLBI ( Table 2 of the Supplement ) and ACC/AHA ( Table 3 of the Supplement ) . Because of the inherent differences in grading systems and the clinical questions driving the recommendations , alignment between the NHLBI and ACC/AHA formats was imperfect . A complete description of the methods used and results of the evidence review are provided in the guideline ( 2 ) and the NHLBI evidence report ( www.nhlbi.nih.gov/ guidelines /cholesterol/ser/index.htm ) . Supplement . NHLBI and ACC/AHA Criteria for Rating Strength of Evidence To help clinicians estimate ASCVD risk , the risk assessment working group developed the Pooled Cohort Equations using data from 5 NHLBI-sponsored longitudinal , population -based cohorts of African American and non-Hispanic white men and women to estimate risk for a first myocardial infa rct ion , coronary heart disease death , or fatal or nonfatal stroke on the basis of age , sex , race , smoking status , total cholesterol level , HDL-C level , systolic blood pressure , antihypertensive therapy , and diabetes ( 4 , 6 ) . These equations significantly advance ASCVD risk estimation by providing sex- and race-specific estimates and including stroke as an outcome . The earlier Framingham equations calculated only coronary heart disease risk for non-Hispanic whites . The draft recommendations were review ed by 23 experts and representatives of federal agencies identified by the NHLBI . In September 2013 , the recommendations developed by the panel were transitioned to the ACC/AHA and had additional review by 4 experts nominated by the ACC Foundation and the AHA . The governing bodies of the ACC and AHA approved the guideline , which also received endorsement from the American Association of Cardiovascular and Pulmonary Rehabilitation , American Pharmacists Association , American Society for Preventive Cardiology , Association of Black Cardiologists , Preventive Cardiovascular Nurses Association , and WomenHeart : The National Coalition for Women with Heart Disease . Recommendations The guideline focuses on treatment of blood cholesterol to reduce ASCVD risk in adults . Major recommendations are summarized here and in Table 1 . The guideline report provides a complete listing of recommendations and supporting evidence behind each recommendation ( 2 ) . Table 1 . Major Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults * 1 . Encourage Adherence to a Healthy Lifestyle A healthy lifestyle is the foundation for cardiovascular health . The panel endorsed the 2013 ACC/AHA Lifestyle Management Guideline ( 3 ) for a diet that is low in saturated fat , trans fat , and sodium ; emphasizes vegetables , fruits , whole grains , low-fat dairy products , poultry , fish , legumes , nontropical vegetable oils , and nuts ; and limits sweets , sugar-sweetened beverages , and red meats and engage in regular aerobic physical activity . Adults also should maintain a healthy body weight , avoid smoking , and control hypertension and diabetes when present . 2 . Statin Therapy Is Recommended for Adults in Groups Demonstrated to Benefit Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups : those with clinical ASCVD ( acute coronary syndromes , myocardial infa rct ion , stable angina , coronary or other arterial revascularization , stroke , transient ischemic attack , or peripheral arterial disease of atherosclerotic origin ) when  statins are used for secondary prevention , and those with LDL-C levels 190 mg/dL ; those aged 40 to 75 years with diabetes and LDL-C levels 70 to 189 mg/dL ; and those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk 7.5 % when statins are used for primary prevention . Moderate evidence supports consideration of statin therapy for primary prevention in individuals with a 10-year ASCVD risk of 5 % to < 7.5 % . Routine initiation of statin therapy is not recommended in adults with New York Heart Association heart failure class II to IV or those receiving maintenance hemodialysis . R and omized , controlled trials in these groups showed no reduction in ASCVD . 3 . Statins have an Acceptable Margin of Safety When Used in Properly Selected Individuals and Appropriately Monitored Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessment s in properly selected patients . Adjustment of statin intensity is recommended in individuals older than 75 years with a history of statin intolerance or other characteristics ( 2 ) or those receiving drug therapy that may increase statin adverse events . Routine monitoring of hepatic aminotransferase level or creatine kinase level is not recommended unless clinical ly indicated by symptoms suggesting hepatotoxicity or myopathy . Given the potential for decreasing ASCVD events and death , the relationship of muscle and other symptoms to statin treatment must be confirmed . Therefore , eliciting a history of muscle symptoms before statin initiation and carefully monitoring symptoms during statin discontinuation and rechallenge is recommended . Severe myopathy , rhabdomyolysis , and possibly hemorrhagic stroke are rare complications of statin therapy . Although statin therapy modestly increases the risk for type 2 diabetes , ASCVD risk reduction outweighs the excess risk for diabetes for high-intensity statins in secondary prevention or for 10-year ASCVD risk 7.5 % . Similarly , ASCVD risk reduction outweighs the excess risk for diabetes for moderate-intensity statin therapy in adults with a 10-year ASCVD risk 5 % . 4 . Engage in a ClinicianPatient Discussion Before Initiating Statin Therapy , Especially for Primary Prevention in Patients With Lower ASCVD Risk Decisions to initiate statin therapy in primary prevention should be based on clinical judgment and preferences of informed patients . In adults without clinical ASCVD or diabetes whose LDL-C level is < 190 mg/dL , calculating the estimated 10-year ASCVD risk should be the start of the clinicianpatient discussion and should not automatically lead to statin initiation . As the absolute risk for ASCVD events decreases , so does the net benefit of the intervention . Therefore , discussion of the potential for ASCVD event reduction , adverse effects , drugdrug interactions , and patient preferences is especially important for lower-risk primary prevention . The discussion provides the opportunity to encourage healthy lifestyle habits and control other risk factors . Additional factors may be considered when a risk-based decision is uncertain , including LDL-C levels 160 mg/dL , family history of premature ASCVD , elevated  lifetime ASCVD risk  , high-sensitivity C-reactive protein level 2.0 mg/L ,  coronary artery calcification score  > 300 Agatston units , and anklebrachial index < 0.9 . After age 75 years , comorbid conditions , anticipated longevity , safety considerations , and patient preferences should play a large role in decision making . 5 . Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation ( 4 , 6 ) . Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in underidentifying high-risk and overidentifying low-risk individuals for statin treatment . The Pooled Cohort Equations were developed using recent data from 5 NHLBI-sponsored , longitudinal , population -based cohorts of African American and white men and women ( ARIC [ In 2016 , the American College of Cardiology published the first expert consensus decision pathway ( ECDP ) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease ( ASCVD ) risk . Since the publication of that document , additional evidence and perspectives have emerged from r and omized clinical trials and other sources , particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 ( PCSK9 ) inhibitors in secondary prevention of ASCVD . Most notably , the FOURIER ( Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk ) trial and SPIRE-1 and -2 ( Studies of PCSK9 Inhibition and the Reduction of Vascular Events ) , assessing evolocumab and bococizumab , respectively , have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients . In addition , further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published . Based on results from these important analyses , the ECDP writing committee judged that it would be desirable to provide a focused up date to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities . In the following summary table , changes from the 2016 ECDP to the 2017 ECDP Focused Up date are highlighted , and a brief rationale is provided . The content of the full document has been changed accordingly , with more extensive and detailed guidance regarding decision making provided both in the text and in the up date d algorithms . Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities  on statin therapy for secondary prevention . The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C < 190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes . Based on feedback and further deliberation , the ECDP writing committee down- grade d recommendations regarding bile acid sequestrant use , recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe . For clarification , the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia , based on clinical criteria with and without genetic testing . Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians , unless there was a compelling reason or new evidence , in which case justification is provided Atherosclerotic cardiovascular disease is the most important public health problem of our time in both Europe and the rest of the world , accounting for the greatest expenditure in most healthcare budgets . Achieving consistency of clinical care , incorporating new evidence and their synthesis into practical recommendations for clinicians is the task of various guideline committees throughout the world . Any change in a set of guidelines therefore can have far reaching consequences , particularly if they appear to be at variance with the existing guidelines . The present article discusses the recent American College of Cardiology (ACC)/American Heart Association ( AHA ) guidelines 2013 on the control of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults . When compared with the ESC/EAS guidelines on lipid modification in 2011 , the ACC/AHA guidelines of 2013 differ markedly . Specifically , ( i ) the scope is limited to r and omized trials only , which excludes a significant body of data and promotes essentially a statin centric approach only ; ( ii ) the abolition of low-density lipoprotein cholesterol ( LDL-C ) targets in favour of specific statin regimens that produce a 30 - 50 % reduction in LDL-C we believe will confuse many physicians and miss the opportunity for medication adherence and patient engagement in self-management ; ( iii ) the absence of target LDL-C levels in very high-risk patients with high absolute risk or residual risk factors will discourage clinicians to consider the addition of lipid modification treatments and individualize patient care ; ( iv ) a reduction in the threshold for treatment in primary prevention will result in a greater number of patients being prescribed statin therapy , which is potentially good in young patients with high life time risk , but will result in a very large number of older patients offered therapy ; and ( v ) the mixed pool risk calculator used to asses CVD risk in the guidelines for primary prevention has not been fully evaluated . This article discusses the potential implication s of adopting the ACC/AHA guidelines on patient care in Europe and beyond and concludes with the opinion that the ESC/EAS guidelines from 2011 seem to be the most wide ranging , pragmatic and appropriate choice for European countries Editors ' Notes Context Clinical guidelines provide conflicting recommendations about whether to prescribe statins in persons aged 75 years or older for primary prevention of unwanted cardiovascular outcomes . Contribution This study used information from clinical trials to model the tradeoffs between benefits and harms and found that using  statins  in all persons aged 75 to 94 years would prevent new myocardial infa rct ions and deaths from coronary heart disease at an acceptable cost . Caution Small increases in the frequency or severity of harms would negate the benefits . Implication Additional research is warranted to better underst and the tradeoffs between benefits and harms in this age group . Statins are commonly used in adults aged 75 years or older ( 1 ) . Despite their widespread use , evidence for their effectiveness for primary prevention in elderly adults is unclear , and guidelines for their use in this population are inconsistent . The recently published American College of Cardiology/American Heart Association ( ACC/AHA ) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults gave limited recommendations for statin use for primary prevention in adults aged 75 years or older ( 2 ) , noting that few data were available to indicate an atherosclerotic cardiovascular disease event reduction benefit in primary prevention among individuals > 75 years of age who do not have clinical year atherosclerotic cardiovascular disease , and suggesting that comorbid conditions , safety , and priorities of care are recommended for joint provider and patient decision making . The American Medical Directors Association , a professional group of long-term care providers , recommended that statins not be routinely prescribed in adults aged 70 years or older as part of the American Board of Internal Medicine Choosing Wisely campaign ( 3 ) . This recommendation was based on the lack of an association between high cholesterol levels and outcomes in older adults as well as the potential for an increased risk for statin-related adverse events , including cognitive impairment , falls , neuropathy , and muscle damage ( 3 ) . The variation in these treatment recommendations reflects uncertainty about the balance between the benefits and risks of statin use in older adults compared with younger adults as well as the more limited evidence base in this population . Adults aged 75 years or older have been underrepresented in trials of statins for primary prevention , so the effectiveness of statins is less clear in this population . Results from observational studies suggest that the associations between low-density lipoprotein ( LDL ) cholesterol levels and outcomes are attenuated in older adults ( 47 ) . Although the baseline risk for cardiovascular disease is increased in older adults , their life expectancy is shorter and their risks for competing mortality are greater . Finally , there has been concern about geriatric-specific adverse effects , especially functional limitation due to muscle pain , weakness , and mild cognitive impairment ( 816 ) . In the presence of uncertainty about the riskbenefit tradeoff , computer simulations can provide estimates of the potential benefits of various treatment strategies as well as the costs and potential risk for harms . We evaluated the population benefit and cost-effectiveness of statins in persons aged 75 years or older without a history of cardiovascular disease in the United States . This investigation was conducted using the Cardiovascular Disease Policy Model ( CVDPM ) , a Markov model of the U.S. population ( 17 ) . We simulated the impact of statins for primary prevention based on treatment of the high-risk groups identified by the ACC/AHA guidelines , the associated costs , and potential harms that could offset the potential cardiovascular benefits in the U.S. population of adults aged 75 to 94 years over the next 10 years . Methods The Model The CVDPM is an established state-transition ( Markov ) model of the incidence , prevalence , mortality , and cost of CHD and stroke in U.S. residents aged 35 to 94 years ( 17 ) . The present study was limited to adults aged 75 to 94 years . The model comprises 3 components . First , the demographic-epidemiologic submodel estimates the incidence of coronary heart disease ( CHD ) ( cardiac arrest , myocardial infa rct ion [ MI ] , angina , or CHD death ) , ischemic stroke , and death from other causes on the basis of age , sex , systolic blood pressure , smoking , high-density lipoprotein and LDL cholesterol levels , diabetes , body mass index , and statin use . Second , the bridge submodel characterizes the initial CHD or stroke event and related events in the subsequent 30 days . Third , the disease-history submodel predicts the number of subsequent CHD and stroke events , revascularization procedures , and deaths among patients with cardiovascular disease , stratified according to age , sex , and history of cardiovascular disease events . In addition , persons may exit the model at any stage through a non-CHD , nonstroke mortality function , allowing for competing risk . Modifiable components of the model include population distributions , risk factor levels , risk factor coefficients , event rates , case-fatality rates , costs , and disability adjustments ( 17 ) . Costs for stroke requiring hospitalization , CHD , and acute stroke rehabilitation were estimated using California hospital data ( 18 ) and were deflated using costcharge ratios and the ratio of the U.S. national average costs to the California average ( 19 , 20 ) . Age- and sex-specific background health care costs were estimated using national data ( 21 ) . All model costs were inflated to 2014 costs by using the medical component of the Consumer Price Index ( 22 ) . All disability weights associated with the CHD and stroke event states were based on the Global Burden of Disease Study ( 23 , 24 ) . Additional details are provided in the Appendix . Simulation Inputs We modeled the effect of statins on LDL cholesterol level based on PROSPER ( Prospect i ve Study of Pravastatin in the Elderly at Risk of Vascular Disease ) , a r and omized , placebo-controlled trial of 5804 men and women aged 70 to 82 years ( 25 ) . In that trial , the mean reduction in LDL cholesterol level was 34 % for participants with an average initial level of 147 mg/dL , consistent with the estimated effect of a moderate-dose statin in the 2013 ACC/AHA guideline ( 2 ) . We included 3 estimates for the effectiveness of a decrease in LDL cholesterol level on events . The primary estimates were derived by extrapolating the age-stratified effect sizes of a 1.0-mmol/L reduction in LDL cholesterol level from the Cholesterol Treatment Trialists ' meta- analysis ( 26 ) . We fit a regression line to the 3 age strata reported in that analysis ( 60 years , > 60 to 70 years , and > 70 years ) to estimate the effect sizes at ages 80 and 90 years . In a sensitivity analysis , we used a high estimate based on the age-pooled estimate of effect of a 1.0-mmol/L reduction in LDL cholesterol level on major coronary events in the meta- analysis . We used a low estimate based on the effect size from PROSPER for primary prevention ( 25 ) . Statin costs were derived from the National Average Drug Acquisition Cost ( NADAC ) data base ( 27 ) . Our primary cost estimate ( $ 5.59 for a 30-day supply ) was the average of the NADAC costs for the 4 moderate-dose statins that are available in generic form : atorvastatin , 10 mg ; simvastatin , 20 mg ; pravastatin , 40 mg ; and lovastatin , 40 mg . This cost estimate was $ 5.00 when indexed to 2010 dollars based on the medical component of the Consumer Price Index ( 22 ) . In addition , we used a low cost estimate of $ 4 per month , based on the price of generic statins from multiple discount retailers ( such as Walmart , Target , and Walgreens ) . For a high cost estimate , we used $ 30 for a 30-day supply ; the low and high cost estimates have been used similarly in other contemporary cost-effectiveness analyses ( 28 , 29 ) . Adults aged 65 years or older use a median of 4 medications ; therefore , we estimated the cost of an additional 0.25 physician visit per year for statin use , assuming that medication management could be covered in 1 visit ( 30 , 31 ) . We estimated 1 lipid panel per year for monitoring ( 32 ) . Event rates for myopathy and hemorrhagic stroke were estimated as 0.001 per statin-year of use , based on the ACC/AHA guideline statement ( 2 ) . Although many major and minor adverse effects have been reported to be associated with statin use , we focused on 2 that are important to geriatric population s and that have generated concern in the scientific literature : functional limitation due to muscle pain and weakness , and mild cognitive impairment ( 816 ) . Both are prevalent in older adults and can have a substantial effect on quality of life and the ability to live independently . A recent review of late-life activity limitations in the United States reported data on participants in 5 nationally representative surveys . The prevalence of limitations in activities of daily living was 27 % in adults aged 75 to 84 years and 45 % in those aged 85 years or older ( 33 ) . The population -weighted average of these estimates is 32 % for adults aged 75 to 94 years . Widely varying prevalence estimates for mild cognitive impairment have been reported due to the differential measures of this condition and the differences between population s. A recent review reported prevalence of mild cognitive impairment of 19 % to 28 % in studies of older U.S. adults ; we used the average of the 4 U.S. studies , which was 25 % ( 34 ) . Disability-adjusted life-years for the corresponding states were calculated as 1 minus the disability weights reported in the Global Burden of Disease Study ( 24 ) . Because the statin-associated relative risk for these adverse effects is uncertain , we assumed no elevated risk for these adverse effects in our base-case scenario . The goal of this investigation was not to evaluate the strength of the literature regarding the presence of these adverse International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol ( HDL-C ) and elevated triglycerides for patients at moderately high to high coronary heart disease ( CHD ) risk . Combination therapy is often required to achieve multiple lipid treatment goals , and > or = 50 % reduction in low-density lipoprotein cholesterol ( LDL-C ) is needed in some patients to achieve aggressive LDL-C targets . In this context , we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin ( niacin ER ) , a statin plus ezetimibe , and a highly potent statin alone . This was an open-label , multicenter , 12-week study in 292 patients ( 50 % women ) who qualified for drug therapy based on number of CHD risk factors . Patients were r and omized to four parallel arms , titrated from low to moderate or high doses : atorvastatin/niacin ER , rosuvastatin/niacin ER , simvastatin/ezetimibe , or rosuvastatin alone . Baseline mean values were , for LDL-C 197 mg/dL ( 5.1 mmol/L ) , HDL-C 49 mg/dL ( 1.3 mmol/L ) , triglycerides 168 mg/dL ( 1.9 mmol/L ) . There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment . All groups lowered LDL-C by approximately 50 % or more ( range -49 to -57 % ) , achieving mean levels of 82 - 98 mg/dL ( 2.1 - 2.5 mmol/L ) . Changes in non-HDL-C ( range -46 to -55 % ) mirrored those for LDL-C and did not differ among treatment groups . Statin/niacin ER combination regimens also increased HDL-C and large HDL ( HDL2 ) and lowered triglycerides and lipoprotein ( a ) significantly more than other regimens . No drug-related myopathy or hepatotoxicity was observed . In this study , low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD Importance Recent guidelines have recommended nonfasting for routine testing of lipid levels based on comparisons of nonfasting and fasting population s. However , no previous study has examined the association of cardiovascular outcomes with fasting vs nonfasting lipid levels measured in the same individuals . Objective To compare the association of nonfasting and fasting lipid levels with prospect ively ascertained coronary and vascular outcomes and to evaluate whether a strategy of using nonfasting instead of fasting lipid level measurement would result in misclassification of risk for individuals undergoing evaluation for initiation of statin therapy . Design , Setting , and Participants This post hoc prospect i ve follow-up of a r and omized clinical trial included 8270 of 10 305 participants from the Anglo-Sc and inavian Cardiac Outcomes Trial-Lipid Lowering Arm ( ASCOT-LLA ) with nonfasting and fasting lipid levels measured 4 weeks apart ( including 6855 participants with no prior vascular disease ) ( median follow-up , 3.3 years ; interquartile range , 2.8 - 3.6 years ) . Data were collected from February 1 , 1998 , to December 31 , 2002 , and analyzed from February 1 , 2016 , to November 30 , 2018 . Multivariable Cox models , adjusted for cardiovascular risk factors , were calculated for 40-mg/dL ( 1-mmol/L ) higher values of nonfasting and fasting lipids . Main Outcomes and Measures The trial 's primary end point consisted of major coronary events ( nonfatal myocardial infa rct ion [ MI ] and fatal coronary heart disease [ 212 events ] ) . Secondary analyses examined atherosclerotic cardiovascular disease ( ASCVD ) events ( including MI , stroke , and ASCVD death [ 351 events ] ) . Results Among the 8270 participants ( 82.1 % male ; mean [ SD ] age , 63.4 [ 8.5 ] years ) , nonfasting sample s had modestly higher triglyceride levels and similar cholesterol levels compared to fasting sample s. Associations of  nonfasting lipid levels with coronary events were similar to those for fasting lipid levels . For example , adjusted hazard ratios ( HRs ) per 40-mg/dL of low-density lipoprotein cholesterol were 1.32 ( 95 % CI , 1.08 - 1.61 ; P = .007 ) for nonfasting levels and 1.28 ( 95 % CI , 1.07 - 1.55 ; P = .008 ) for fasting levels . For the primary prevention group , adjusted HRs were 1.42 ( 95 % CI , 1.13 - 1.78 ; P = .003 ) for nonfasting levels and 1.37 ( 95 % CI , 1.11 - 1.69 ; P = .003 ) for fasting levels . Results were consistent by r and omized treatment arm ( atorvastatin calcium , 10 mg/d , or placebo ) and similar for ASCVD events . Concordance of fasting and nonfasting lipid levels for classifying participants into appropriate ASCVD risk categories was high ( 94.8 % ) . Conclusions and Relevance Measurement of nonfasting and fasting lipid levels yields similar results in the same individuals for association with incident coronary and ASCVD events . These results suggest that routine measurement of nonfasting lipid levels may help facilitate ASCVD risk screening and treatment , including consideration of when to initiate statin therapy Aims To evaluate the 2013 American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease ( ASCVD ) risk score among four different race/ethnic groups and to ascertain which factors are most associated with risk overestimation by the AHA-ACC-ASCVD score . Methods and results The Multi-Ethnic Study of Atherosclerosis ( MESA ) , a prospect i ve community-based cohort , was used to examine calibration and discrimination of the AHA-ACC-ASCVD risk score in 6441 White , Black , Chinese , and Hispanic Americans ( aged 45 - 79 years and free of known ASCVD at baseline ) . Using univariable and multivariable absolute risk regression , we modelled the impact of individual risk factors on the discordance between observed and predicted 10-year ASCVD risk . Overestimation was observed in all race/ethnic groups in MESA and was highest among Chinese ( 252 % for women and 314 % for men ) and lowest in White women ( 72 % ) and Hispanic men ( 67 % ) . Higher age , Chinese race/ethnicity ( when compared with White ) , systolic blood pressure ( treated and untreated ) , diabetes , alcohol use , exercise , lipid-lowering medication , and aspirin use were all associated with more risk overestimation , whereas family history was associated with less risk overestimation in a multivariable model ( all P < 0.05 ) . Conclusion The AHA-ACC-ASCVD risk score overestimates ASCVD risk among men , women , and all four race/ethnic groups evaluated in a modern American primary prevention cohort . Clinicians treating patients similar to those in MESA , particularly older individuals and those with factors associated with more risk overestimation , may consider interpreting absolute ASCVD risk estimates with caution BACKGROUND Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein ( HDL ) cholesterol level or further lower the low-density lipoprotein ( LDL ) cholesterol level . METHODS We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent , who were receiving long-term statin therapy , and in whom an LDL cholesterol level under 100 mg per deciliter ( 2.6 mmol per liter ) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women ( 1.3 or 1.4 mmol per liter , respectively ) had been achieved . The patients were r and omly assigned to receive extended-release niacin ( target dose , 2000 mg per day ) or ezetimibe ( 10 mg per day ) . The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months . The trial was terminated early , on the basis of efficacy , according to a prespecified analysis conducted after 208 patients had completed the trial . RESULTS The mean HDL cholesterol level in the niacin group increased by 18.4 % over the 14-month study period , to 50 mg per deciliter ( P < 0.001 ) , and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2 % , to 66 mg per deciliter ( 1.7 mmol per liter ) ( P < 0.001 ) . Niacin therapy significantly reduced LDL cholesterol and triglyceride levels ;  ezetimibe reduced the HDL cholesterol and triglyceride levels . As compared with ezetimibe , niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months ( P = 0.003 ) , leading to significant reduction of both mean ( P = 0.001 ) and maximal carotid intima-media thickness ( P < or = 0.001 for all comparisons ) . Paradoxically , greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness ( R = -0.31 , P < 0.001 ) . The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group ( 1 % vs. 5 % , P = 0.04 by the chi-square test ) . CONCLUSIONS This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe . ( Clinical Trials.gov number , NCT00397657 . Numerous r and omized , double-blind , placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia . The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids , age , or gender . The up date d National Cholesterol Education Program III guidelines state that in very high-risk persons , a serum low-density lipoprotein ( LDL ) cholesterol level of < 70 mg/dl ( 1.8 mmol/l ) is a reasonable clinical strategy for moderately high-risk persons ( 2 or more risk factors and a 10-year risk for coronary artery disease of 10 % to 20 % ) , and the serum LDL cholesterol should be reduced to < 100 mg/dl ( 2.6 mmol/l ) . When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons , the serum LDL cholesterol should be reduced by at least 30 % to 40 % . The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease . Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality 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 , r and omized 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 infa rct ion , unstable angina requiring rehospitalization , coronary revascularization ( ≥30 days after r and omization ) , 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 result ed 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 Clinical Trials.gov number , NCT00202878 . ) BACKGROUND Lipid-lowering therapy with statins reduces the risk of cardiovascular events , but the optimal level of low-density lipoprotein ( LDL ) cholesterol is unclear . METHODS We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40  mg of pravastatin daily ( st and ard therapy ) with 80 mg of atorvastatin daily ( intensive therapy ) . The primary end point was a composite of death from any cause , myocardial infa rct ion , documented unstable angina requiring rehospitalization , revascularization ( performed at least 30 days after r and omization ) , and stroke . The study was design ed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event . Follow-up lasted 18 to 36 months ( mean , 24 ) . RESULTS The median LDL cholesterol level achieved during treatment was 95 mg per deciliter ( 2.46 mmol per liter ) in the st and ard-dose pravastatin group and 62 mg per deciliter ( 1.60 mmol per liter ) in the high-dose atorvastatin group ( P<0.001 ) . Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group , reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin ( P=0.005 ; 95 percent confidence interval , 5 to 26 percent ) . The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen . CONCLUSIONS Among patients who have recently had an acute coronary syndrome , an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a st and ard regimen . These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels Background Evidence -based r and omized clinical trials have shown significant benefit of statin treatment with regard to cardiovascular disease . In anticipation of the National Cholesterol Education Program Adult Treatment Panel IV guidelines , we wanted to assess the current state of lipid goal attainment in the high-risk secondary prevention population in the United States . The objectives of the study were to estimate the proportion of high-risk patients treated with statin monotherapy  who achieved Adult Treatment Panel III – recommended low-density lipoprotein cholesterol ( LDL-C ) goals ( < 100 mg/dL ; optional < 70 mg/dL ) as well as non – high-density lipoprotein cholesterol goals ( < 130 mg/dL ; optional < 100 mg/dL ) . Methods and Results This is a cross-sectional , retrospective study of 3 data sources : electronic medical records ( 2003–September 2010 ) , administrative cl aims data ( 2003–2010 ) , and National Health and Nutrition Examination Survey data ( 2007–2008 ) . High-risk patients ( ≥18 years of age ) were defined as those with a history of coronary heart disease or coronary heart disease risk equivalent who had the latest complete lipid panel measurement and had been treated with statin monotherapy for > 90 days at the time of the lipid panel . Cardiovascular disease , coronary heart disease , and coronary heart disease risk equivalents were defined on the basis of availability , specific to each data source . Across the 3 data sources , 20 % to 26 % of high-risk patients treated with statin monotherapy for > 90 days had LDL-C < 70 mg/dL , and 67 % to 77 % had LDL-C < 100 mg/dL. The percentages of those attaining both LDL-C goals and non – high-density lipoprotein cholesterol goals were quantitatively smaller ( 13.5 % to 19.0 % and 46 % to 70 % ) . Conclusions Across the 3 data sources , there was consistency in the proportion of high-risk patients treated with statin monotherapy who were at LDL-C goal . A significant number of these statin-treated patients had additional dyslipidemias Introduction High-dose HMG-CoA reductase inhibitors ( statins ) fail to prevent approximately two-thirds of cardiovascular events . This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol ( non-HDL-C ) , HDL-C , and triglycerides in national guidelines and has intensified interest in combination therapy . Methods The OCEANS study ( Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia ; Clinical Trials.gov identifier : NCT00080275 ) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin ( NER/S ; SIMCOR ® ) over 52 weeks in 520 patients with mixed dyslipidemia . After a ≥4-week run-in phase of diet modification and simvastatin 40 mg/day , median baseline values ( mg/dL ) were : non-HDL-C = 141 , low-density lipoprotein-cholesterol ( LDL-C ) = 110 , HDL-C = 45 , and triglyceride = 151 . Patients were r and omized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2000/40 mg/day . Results Differences between titration groups in tolerability , safety , and efficacy were minimal ; therefore , all results are for pooled titration groups . The safety of NER/S was consistent with the safety profile of each individual component . Treatment with NER/S was well tolerated : 71 % of patients experienced flushing and 92 % of flushing episodes were mild or moderate in intensity . Overall , 61 % of patients experienced flushing episodes that were rated as mild or moderate in intensity . Flushing decreased over time : < 40 % of those who had flushing during titration experienced flushing during the final 12 weeks . A total of 20 % of patients discontinued treatment because of a treatment-related adverse event , including 7 % who discontinued because of flushing . Median changes from baseline ( following the simvastatin 40 mg/day run-in phase ) to 24 weeks were : non-HDL-C = −27.3 % , LDL-C = −25.0 % , HDL-C = + 23.9 % , and triglycerides = −35.9 % ( all p < 0.0001 vs baseline ) . In lipid-treatment-naive patients , NER/S 2000/40 mg/day decreased non-HDL-C , LDL-C , and triglycerides by approximately 50 % and increased HDL-C by approximately 25 % when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in . All three therapeutic lipid targets ( LDL-C [ risk-adjusted goal ] , HDL-C ≥40 mg/dL , and triglycerides < 150 mg/dL ) were achieved concurrently by 65 % of patients treated with NER/S. Conclusion Treatment with NER/S 2000/40 mg/day is well tolerated , has no unanticipated adverse events , and provides additional , clinical ly relevant improvements in multiple lipid parameters beyond statin monotherapy CONTEXT Interest remains high in cholesteryl ester transfer protein ( CETP ) inhibitors as cardioprotective agents . Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins . OBJECTIVE To examine the biochemical effects , safety , and tolerability of evacetrapib , as monotherapy and in combination with statins , in patients with dyslipidemia . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol ( LDL-C ) or low high-density lipoprotein cholesterol ( HDL-C ) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe . INTERVENTIONS Following dietary lead-in , patients were r and omly assigned to receive placebo ( n = 38 ) ; evacetrapib monotherapy , 30 mg/d ( n = 40 ) , 100 mg/d ( n = 39 ) , or 500 mg/d ( n = 42 ) ; or statin therapy ( n = 239 ) ( simvastatin , 40 mg/d ; atorvastatin , 20 mg/d ; or rosuvastatin , 10 mg/d ) with or without evacetrapib , 100 mg/d , for 12 weeks . MAIN OUTCOME MEASURES The co- primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment . RESULTS The mean baseline HDL-C level was 55.1 ( SD , 15.3 ) mg/dL and the mean baseline LDL-C level was 144.3 ( SD , 26.6 ) mg/dL. As monotherapy , evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL ( 53.6 % to 128.8 % ) compared with a decrease with placebo of -0.7 mg/dL ( -3.0 % ; P < .001 for all compared with placebo ) and decreases in LDL-C of -20.5 to -51.4 mg/dL ( -13.6 % to -35.9 % ) compared with an increase with placebo of 7.2 mg/dL ( 3.9 % ; P < .001 for all compared with placebo ) . In combination with statin therapy , evacetrapib , 100 mg/d , produced increases in HDL-C of 42.1 to 50.5 mg/dL ( 78.5 % to 88.5 % ; P < .001 for all compared with statin monotherapy ) and decreases in LDL-C of -67.1 to -75.8 mg/dL ( -11.2 % to -13.9 % ; P < .001 for all compared with statin monotherapy ) . Compared with evacetrapib monotherapy , the combination of statins and evacetrapib result ed in greater reductions in LDL-C ( P < .001 ) but no greater increase in HDL-C ( P = .39 ) . Although the study was underpowered , no adverse effects were observed . CONCLUSIONS Compared with placebo or statin monotherapy , evacetrapib as monotherapy or in combination with statins  increased HDL-C levels and decreased LDL-C levels . The effects on cardiovascular outcomes require further investigation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01105975 BACKGROUND Niacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy . METHODS In this r and omized , placebo-controlled trial ( n = 75 ) of magnetic resonance imaging of carotid atherosclerosis , we performed a secondary comparison of combination niacin-statin ( simvastatin 20 mg/Niacin-ER 2 G [ S20/N ] ) to monotherapy with moderate ( 20 mg [ S20 ] ) and high-dose ( 80 mg [ S80 ] ) simvastatin on lipids , apolipoproteins ( apo ) , low density lipoprotein ( LDL ) and high density lipoprotein ( HDL ) particle subclasses , and inflammatory markers . RESULTS At baseline , average age was 71 , 72 % were male , 62.5 % used statins , and average LDL-cholesterol was 111 mg/dL. At 12 months , S20/N , compared to S80 , significantly reduced apoB ( -36.6 % vs -11.9 % ; P = .05 ) and lipoprotein(a ) ( -18 % vs + 3.5 % ; P = .001 ) and had at least an equivalent effect on LDL-cholesterol ( -39.3 % vs -24.3 % ; P = .24 ) . The combination reduced the proportion of subjects with atherogenic LDL pattern-B ( 50 % to 11.5 % ) compared to S80 ( 56 % to 56 % ) ( P = .01 ) . Despite increases in plasma free fatty acids ( + 62.4 % ; F = 5.65 , P = .005 vs S20 and S80 ) , plasma triglycerides ( -29.4 % ; F = 6.88 , P = .002 vs S20 and S80 ) , and very-low-density lipoprotein ( -44.2 % ; F = 7.94 , P < .001 vs S20 and S80 ) , levels were reduced by S20/N. S20/N increased HDL-cholesterol levels ( + 18.1 % ) as compared to S20 ( 0 % ) and S80 ( + 5.9 % ) ( P < .001 vs both statin arms ) , largely due to an increase in HDL particle size ( + 4.6 % ; P = .01 vs both statin arms ) . CONCLUSIONS We demonstrate that full-dose niacin/moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins , at least comparable to high-dose simvastatin , while also raising HDL-cholesterol . Results of large clinical trials will inform whether niacin-statin combinations reduce cardiovascular disease events This issue of JAMA contains the latest US Preventive Services Task Force ( USPSTF ) recommendation statement on statins for prevention of cardiovascular disease in adults,1 along with the accompanying evidence report and systematic review 2 on which the recommendations are based . The evidence report summarized data from 19 trials including a total of 71 344 patients and concluded that statin therapy was associated with reduced risk of all-cause and cardiovascular mortality and cardiovascular disease ( CVD ) events . Thus , the task force recommended “ initiating use of lowto moderate-dose statins in adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 10 % or greater ( B recommendation ) ” or “ 7.5 % to 10 % ( C recommendation ) .”1 Although the task force did their usual careful job of review ing the evidence , the evidence for treating asymptomatic persons with statins does not appear to merit a grade B or even a grade C recommendation . The task force evidence report estimated an absolute benefit for use of statins of 0.40 % for all-cause mortality and 0.43 % for cardiovascular mortality and indicated that the absolute benefit was greater for patients at greater baseline risk.2 Notably , the evidence report did not exclude studies that included patients taking statins for secondary prevention , who have a higher baseline risk of cardiac events and death and thus are more likely to benefit from therapy that inflates the benefit attributed to a primary prevention population . The task force did perform a sensitivity analysis that excluded 3 trials with persons for whom there were prior “ hard ” cardiovascular events and obtained similar results of benefits ( eTable 5 in the article by Chou et al2 ) . This sensitivity analysis did not exclude WOSCOPS , which included patients receiving statins for secondary prevention—5 % had angina and 3 % had intermittent claudication,3 accounting for 15 % of the total weight in the meta- analysis . In contrast , a meta- analysis of 11 studies and 65 229 patients receiving statins for primary prevention , in which patients receiving statins for secondary prevention were excluded , found no benefit of statins for reducing all-cause mortality.4 The confidence intervals of these 2 analyses overlap , and the difference between these findings likely reflects differences in studies included . The USPSTF and authors of the evidence report did not have access to the primary data ( clinical study reports and anonymized patient-level data ) from the statin clinical trials . Rather , they had to rely on peer- review ed published reports as the basis for these recommendations . Exacerbating the potential bias , all of the trials included in the task force evidence report2 were industry-sponsored except 1 trial,5 and that trial contributed 0.2 % of the weight to the mortality calculation . Industry-sponsored studies have been shown to report greater benefit and lesser adverse effects than noncommercially sponsored trials of the same drugs.6 Whether this is true for statins and primary prevention of CVD is unknown . Among the 19 r and omized clinical trials of statins vs placebo or no statin included in the evidence report for the task force recommendations , only 15 reported all-cause mortality , 10 reported cardiovascular mortality , 12 reported fatal and nonfatal myocardial infa rct ion  , and 13 reported fatal and nonfatal stroke.2,7  Reliance on selective reporting of the most important outcomes , which are likely included in the clinical trial data , makes reporting bias possible . Furthermore , after allcause mortality , the comparative incidence of serious adverse events between treatment and control groups is arguably the second most important measure of the effect of active therapy in r and omized clinical trials . Underst and ing the evidence base in evaluating harms of statin therapy is also critically important . Although the benefits of any preventive therapy accrue according to risk of disease ( greater benefit in higher-risk patients ) , the harms of therapy usually distribute equally over all risk levels . Thus , persons at low risk have little chance of benefit but equal chance of harms and thus are more likely to have a net harm . The evidence base for harms of statins , despite the introduction of these drugs more than 20 years ago , is incomplete . Many of the trials did not ask about commonly reported statin effects , such as muscle pains and weakness , and only recorded myopathy , for which an increase in creatine kinase levels was required . Because most muscle problems do not involve an increase in creatine kinase levels , this leads to a significant underestimate of muscle problems . Other studies have estimated that closer to 20 % of statin users have muscle problems.8 Additionally , the actual trial data are largely held by the Cholesterol Treatment Trialists ’ Collaboration on behalf of the industry sponsor and have not been made available to other research ers , despite multiple requests over many years.9 Although reported rates of adverse events in clinical trials are low , this does not reflect the experience of clinicians who see patients who are taking statins . For instance , the experience of an NPR reporter with a calculated 2.9 % risk of heart disease over 10 years using the recommended American College of Cardiology/American Heart Association ( ACC/AHA ) risk calculator,10 but still prescribed a statin , and experiencing adverse effects from the medication , is typical of what many Related articles at jama.com BACKGROUND Accurate risk assessment of atherosclerotic cardiovascular disease ( ASCVD ) is essential to effectively balance the risks and benefits of therapy for primary prevention . OBJECTIVE To compare the calibration and discrimination of the new American Heart Association ( AHA ) and American College of Cardiology ( ACC ) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score . DESIGN Prospect i ve epidemiologic study of ASCVD . SETTING MESA ( Multi-Ethnic Study of Atherosclerosis ) , a community-based , sex-balanced , multiethnic cohort . PATIENTS 4227 MESA participants aged 50 to 74 years and without diabetes at baseline . MEASUREMENTS Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores- and their respective end points-in MESA after a 10.2-year follow-up . RESULTS The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37 % to 154 % in men and 8 % to 67 % in women . Overestimation was noted throughout the continuum of risk . In contrast , the Reynolds Risk Score overestimated risk by 9 % in men but underestimated risk by 21 % in women .  Aspirin , lipid-lowering or antihypertensive therapy  , and  interim revascularization  did not explain the overestimation . LIMITATION Comparability of MESA with target population s for primary prevention and possibility of missed events in MESA . CONCLUSION Of the 5 risk scores , 4 , including the new AHA-ACC-ASCVD score , showed overestimation of risk ( 25 % to 115 % ) in a modern , multiethnic cohort without baseline clinical ASCVD . If vali date d , overestimation of ASCVD risk may have substantial implication s for individual patients and the health care system . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute Background Recent evidence on the use of statin therapy indicates the potential for ultra-low levels of LDL-C to provide greater protection from recurrent coronary heart disease events . Guidelines for the treatment of lipid disorders were revised to indicate that an LDL-C treatment goal of 70 mg/dl was optional ( NCEP ATPIII ) . In these same guidelines , low levels of HDL-C are also suggested but not specifically proscribed as a target of therapy . Recently ARBITER 2 ( Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2 ) has provided the first evidence of the potential of raising HDL-C with extended release niacin when added to statin monotherapy in secondary prevention . However , whether this approach would be superior to a strategy in which lower concentrations of LDL-C are targeted is unknown . Material s and methods ARBITER 6-HALTS ( HDL and LDL Treatment Strategies ) will be a r and omized , parallel group , open-label study comparing HDL-C and LDL-C focused strategies of lipid treatments for their effects on atherosclerosis . Up to 400 subjects will be assigned to either  intensified LDL-C lowering therapy with ezetimibe or HDL-C raising therapy with extended-release niacin . The primary endpoint is the mean change in the intima-media thickness of the common carotid artery after 14 months . Secondary endpoints include the change in lipid values and lipid subfractions , drug discontinuation due to adverse effects , change in quality of life , and a composite endpoint consisting of all major adverse cardiovascular events . Conclusion ARBITER 6-HALTS will guide clinicians on whether a lipid treatment strategy of raising HDL-C or further LDL-C reduction is superior in the secondary prevention of coronary heart disease To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol ( LDL-C ) goal ( as per National Cholesterol Education Program Adult Treatment Panel III [ NCEP ATP III ] guidelines ) and in those with low high-density lipoprotein cholesterol ( HDL-C ) . Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70 , ≥100 , ≥130 , or ≥160 mg/dl for very high , high , moderate , and low coronary heart disease risk , respectively , or at LDL-C goal with HDL-C ≤40 mg/dl , were r and omized 1:1:1 , stratified by background therapy use ,  to anacetrapib  100 mg ( n = 153 ) , anacetrapib 25 mg ( n = 152 ) , or placebo ( n = 154 ) for 24 weeks , followed by a 12-week off-drug reversal phase . The primary end points were percent change from baseline in LDL-C ( beta-quantification method ) and HDL-C , as well as the safety profile  of anacetrapib . Both doses of anacetrapib  reduced LDL-C , non-HDL-C , apolipoprotein ( Apo ) B , and lipoprotein a and increased HDL-C and Apo AI versus placebo ( p < 0.001 for all ) . There were no meaningful differences between the anacetrapib 25 mg , 100 mg , and placebo groups in the proportions of discontinuations due to drug-related adverse events ( 0.7 % , 1.3 % vs 1.3 % ) or in abnormalities in liver enzymes ( 0 % , 0 % vs 0.7 % ) , creatine kinase elevations overall ( 0 % , 0.7 % vs 0 % ) or with muscle symptoms ( none seen ) , blood pressure , electrolytes , or adjudicated cardiovascular events ( 0.7 % , 0.7 % vs 1.3 % ) . In conclusion , treatment with anacetrapib result ed in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated BACKGROUND Co-administration of a fibrate and statin is an effective treatment option for patients with multiple lipid abnormalities , yet adequate long-term safety and efficacy data are lacking . OBJECTIVE To evaluate the long-term safety and efficacy of fenofibric acid combined with statins in adults with mixed dyslipidemia . METHODS Three large , 12-week , phase three , double-blind , r and omized , controlled trials evaluated fenofibric acid 135 mg combined with a low- or moderate-dose statin compared to fenofibric acid or statin monotherapy , and a subsequent 52-week open-label extension study evaluated fenofibric acid 135 mg combined with moderate-dose statin ( rosuvastatin 20 mg , simvastatin 40 mg , or atorvastatin 40 mg ) . This prespecified analysis integrated results from these studies to assess the long-term safety and efficacy of combination therapy . RESULTS Across the controlled studies and the extension study , 2201 patients received at least one dose of fenofibric acid + statin  for a median duration of 364 days . The most common adverse events were headache , upper respiratory tract infection , nasopharyngitis , and back pain , with the incidence of all adverse events being similar across all combination therapy treatment groups . Rhabdomyolysis or treatment-related death was not reported in any group . Combination therapy result ed in sustained improvements in multiple lipid parameters , including triglycerides , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , non-high-density lipoprotein cholesterol , very low-density lipoprotein cholesterol , total cholesterol , apolipoprotein B , and high-sensitivity C-reactive protein . CONCLUSION Long-term fenofibric acid + statin combination therapy was generally well tolerated and result ed in comprehensive and sustained improvements in multiple lipid parameters in adults with mixed dyslipidemia OBJECTIVE Evaluate the lipid-altering effects of ezetimibe added to ongoing statin therapy , statin titration , switching from statin monotherapy to a more potent statin or to ezetimibe/simvastatin . METHODS A pooled analysis of patient-level data from 17 double-blind , active or placebo-controlled studies of 8667 hypercholesterolemic adults r and omized to  ezetimibe 10 mg added to ongoing statins , statin titration ( doubling ) , or switching from ongoing statins to rosuvastatin ( 10 mg ) or to ezetimibe/simvastatin ( 10/20 and 40 mg ) . Percent change from baseline in low-density lipoprotein cholesterol ( LDL-C ) was estimated by analysis of variance . Percent of patients who achieved LDL-C and other guideline -recommended targets , and target lipid levels by baseline distance to goal were evaluated . RESULTS LDL-C percent change from baseline was -26.0 for ezetimibe added to ongoing statin therapy , -27.6 for switching from ongoing statin to ezetimibe/simvastatin , -19.7 for switching to rosuvastatin 10 mg , and -9.7 for dose doubling of the ongoing statin . For patients within 0.8 mmol/L ( 30 mg/dL ) of the target at baseline , LDL-C target attainment rates were 75.9 % for adding ezetimibe to ongoing statin , 72.8 % for switching to ezetimibe/simvastatin , 61.8 % for switching to rosuvastatin , and 44.3 % for statin dose-doubling . Similarly , improvements in other lipids and achievement of non-high-density lipoprotein cholesterol and apolipoprotein B targets among this patient group were largest for ezetimibe added to ongoing statins and switching to ezetimibe/simvastatin ; switching to rosuvastatin 10 mg and statin dose-doubling were less effective . CONCLUSIONS Adding ezetimibe to ongoing statin therapy appeared to be an effective option for patients who do not achieve lipid-lowering goals on statins alone AIM Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease ( CVD ) . The st and ard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY ( EMPATHY ) study examines whether intensive lipid-lowering therapy is superior to st and ard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy , but without a history of coronary artery disease . METHODS Patients who had elevated low-density lipoprotein cholesterol ( LDL-C ) and diabetic retinopathy without a history of coronary artery disease were eligible for the study . Patients were r and omly assigned in a 1:1 ratio to receive intensive or st and ard therapy . Patients are being treated with monotherapy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor ( statin ) for a maximum of 5.5 years to achieve the following LDL-C target : ＜70 mg/dL for the intensive therapy group or ≥100 and ＜120 mg/dL for the st and ard therapy group . The primary endpoint is a composite of incidence of CVD and death from CVD . RESULTS Between May 2010 and October 2013 , 5,995 patients were assessed for eligibility , and 5,144 were assigned to the study treatment ( 2,571 and 2,573 in the intensive and st and ard therapy groups , respectively ) , and baseline data were analyzed from 5,107 ( 2,550 in the intensive therapy group and 2,557 in the st and ard therapy group ) . CONCLUSIONS This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting . Furthermore , this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy . CLINICAL TRIAL REGISTRATION NUMBER UMIN000003486 Context Most trials that address lipid management focus on reducing low-density lipoprotein ( LDL ) cholesterol levels rather than increasing high-density lipoprotein ( HDL ) cholesterol levels . Contribution In this double-blind trial , 143 military retirees with low HDL cholesterol levels and coronary artery disease were r and omly assigned to placebo or aggressive HDL cholesterolincreasing therapy with gemfibrozil , niacin , and cholestyramine for 30 months . All participants received diet and exercise counseling . Compared with the placebo group , the treated group had a 20 % decrease in total cholesterol level ; a 36 % increase in HDL cholesterol level ; less focal coronary stenosis ; fewer total cardiovascular events ; and more flushing , skin rashes , and abdominal symptoms . Caution s The small trial had limited ability to assess clinical outcomes . The Editors Large epidemiologic studies have repeatedly demonstrated that cardiovascular risk increases proportionally with increasing total cholesterol and low-density lipoprotein ( LDL ) cholesterol levels and decreasing high-density lipoprotein ( HDL ) cholesterol levels ( 1 , 2 ) . Although many studies have documented that statins , drugs that primarily reduce LDL cholesterol levels , significantly reduce the risk for cardiovascular events ( 3 - 7 ) , prospect i ve studies that examine the clinical effects of increasing HDL cholesterol levels have been more limited . The Coronary Drug Project first reported evidence of a mortality benefit in patients treated with niacin ; however , the difference was seen long after withdrawal of the study drug , making the mechanism of benefit less clear ( 8) . The Helsinki Heart Study ( 9 ) examined the use of gemfibrozil in primary prevention . Coronary events were reduced by 34 % , but the increase in HDL cholesterol level was modest ( only 11 % ) . The Bezafibrate Infa rct ion Prevention Trial failed to show a reduction in cardiovascular events in the composite population , although a recent re analysis of the data suggests an improved outcome in patients experiencing a greater increase in HDL cholesterol level ( 10 ) . The Veterans Affairs HDL Intervention Trial ( VA-HIT ) ( 11 ) demonstrated a modest reduction in coronary events when gemfibrozil was used in patients with normal levels of LDL cholesterol and low levels of HDL cholesterol . The authors ascribed most of the reduction in clinical events to the improvement in HDL cholesterol , although the overall improvement was only approximately 6 % with drug therapy . More recently , a combination of a statin ( simvastatin ) with niacin was found to favorably modify both HDL cholesterol and LDL cholesterol levels and reduce cardiovascular events compared with both placebo therapy and underlying treatment with antioxidants in a cohort of 160 patients with coronary disease ( 12 ) . Despite a significant increase in mean HDL cholesterol levels , the overwhelming treatment effect in this study was the reduction in LDL cholesterol level ( 42 % in the treatment group ) . The most suggestive evidence of benefit from an increase in HDL cholesterol level has come from trials assessing the effect on coronary stenosis . Trials of quantitative angiography after monotherapy with fibrates ( 13 ) , as well as combinations of medications that both reduce LDL cholesterol levels and increase HDL cholesterol levels ( 14 - 18 ) , have shown an attenuation in angiographic progression . Nissen and colleagues ( 19 ) recently took this theory a step further by demonstrating that an infusion of a recombinant form of HDL , apolipoprotein A-I Milano , can lead to regression of angiographic stenosis as assessed by intravascular ultrasonography . We undertook the Armed Forces Regression Study ( AFREGS ) in 1993 to determine whether coronary atherosclerosis , assessed by quantitative coronary angiography and clinical coronary events , would improve when combination drug therapy focused on increasing HDL cholesterol levels in a sample of patients with fairly normal LDL cholesterol levels and low HDL cholesterol levels . A pilot study by Whitney and colleagues ( 20 ) showed the feasibility of this trial design , and the safety of using these drugs in combination has been previously established ( 21 ) . Methods Patients Participants living within a 150-mile radius of Wilford Hall Medical Center in San Antonio , Texas , who could provide written informed consent were eligible for enrollment . We recruited men and women younger than 76 years of age who had established or suspected coronary artery disease ( positive results on an exercise treadmill test or classic angina ) and did not have unstable symptoms . We allowed LDL cholesterol levels up to 4.1 mmol/L ( 160 mg/dL ) with HDL cholesterol levels less than 1.0 mmol/L ( 40 mg/dL ) after adherence to the American Heart Association ( AHA ) step II diet for at least 6 months . We set no lower limit to either HDL cholesterol or LDL cholesterol level . Each patient was required to have measurable stenosis between 30 % and 80 % of the luminal diameter within the coronary tree by caliper inspection . Patients with stenosis greater than 80 % were eligible if they had a favorable prognosis based on functional testing ( ability to exercise for > 9 minutes on a full Bruce protocol exercise treadmill test ) . Exclusions included a major vascular event ( myocardial infa rct ion , cerebrovascular accident , coronary artery bypass grafting , or other coronary catheterbased intervention ) within 6 months , a history of congestive heart failure ( other than in the setting of myocardial infa rct ion ) , or a left ventricular ejection fraction less than 0.4 on ventriculography . Other exclusion criteria included alcohol or substance abuse within the past year , uncontrolled arrhythmias , resistant hypertension , diabetes , uncontrolled gout , uncontrolled thyroid disease , liver or gall bladder disease , renal dysfunction ( creatinine concentration > 176.8 mol/L [ > 2.0 mg/dL ] or proteinuria greater than 2 + by dipstick or 500 mg/24 h ) , uncontrolled peptic ulcer disease , or pancreatic disorders . In addition , we excluded patients taking any lipid-modifying medications within 4 weeks of r and omization , heparin or coumarin-type anticoagulants , long-term oral corticosteroid therapy , or other immunosuppressive agents . We also excluded patients if they had hypersensitivity to or history of intolerance that required cessation of therapy for any component of gemfibrozil , nicotinic acid , cholestyramine , aspirin , or nitrates . Other exclusion criteria were the potential for childbearing , technically inadequate coronary arteriography for stenosis quantification , or any serious condition that we thought would compromise participation in the study or preclude survival for the duration of the study . We thoroughly informed participants of the details of the study . Each patient voluntarily enrolled and signed an informed consent statement that the Wilford Hall Medical Center Institutional Review Board review ed and approved . From screening laboratory records , we identified 1290 participant c and i date s and invited them to participate ( Figure 1 ) . Of the 847 patients who attended the introductory briefing , 671 met LDL cholesterol and HDL cholesterol entry criteria on fasting lipid analysis . Of the 269 participants who eventually provided informed consent , 55 subsequently withdrew for personal reasons , most commonly citing a fear of cardiac catheterization , and an additional 27 met an exclusion criterion . Of the 187 participants who completed the 6-month lifestyle modification phase and underwent coronary angiography  , 44 were excluded after initial coronary arteriography ; 27 had extensive coronary disease necessitating revascularization ( percutaneous coronary intervention in 3 patients and coronary artery bypass grafting in 24 patients ) , and 17 had insignificant coronary disease on angiography . Thus , we eventually r and omly assigned 143 patients ( 11 % of those initially contacted ) to either pharmacologic therapy or placebo . Figure 1 . Flow of patients through the study . Protocol After inclusion and exclusion criteria were met , a 6- to 8-month run-in period was performed to ensure that patients could adhere to the prescribed diet . During this phase , all patients received diet counseling from a study dietitian , exercise guidance from an exercise specialist , and smoking cessation advice . All study participants committed to attending a bimonthly food show for training in the AHA step II diet , with reinforcing presentations from the dietitian , exercise specialist , and cardiologist that discussed cardiac risk factor modification . We r and omly assigned each participant by using a computer-generated r and omization schedule . The central pharmacy held the code , and the information was not shared with physicians or patients until the completion of the protocol . Patients were r and omly assigned to 1 of 2 treatment groups : pharmacologic therapy with gemfibrozil , niacin , and cholestyramine or conventional therapy . The goal of therapy was to increase HDL cholesterol level by at least 25 % . The study was double-blind and placebo-controlled . The pharmaceutical company prepared all medications and placebos , and the central pharmacy dispensed them at 30-day intervals . The pharmacologic therapy group began receiving gemfibrozil , 600 mg twice per day . Short-acting niacin was added in the third month at a dosage of 250 mg/d and was titrated to 3000 mg/d as tolerated . Cholestyramine was added in the sixth month , and the dosage was titrated to 16 g/d as tolerated . The conventional therapy group was maintained on the AHA step II diet and applicable matching placebos for the duration of the investigation . If LDL cholesterol levels exceeded 4.14 mmol/L ( 160 mg/dL ) during the trial , cholestyramine was administered in an open-label fashion . Participants visited 1 clinic on a monthly basis for the duration of the study . At each monthly visit , clinicians measured vital signs and weight , counted unused study drugs , review ed changes in medications or medical status , provided BACKGROUND AND AIMS Substantial residual cardiovascular risks remain despite intensive statin treatment . Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins . K-877 ( pemafibrate ) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy . The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment . METHODS The objectives were investigated in two , multicentre , r and omised , double-blind ,  placebo-controlled  , parallel group comparison clinical trials : ( A ) K-877 0.1 , 0.2 , and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients , ( B ) K-877 0.2 ( fixed dose ) and 0.2 ( 0.4 ) ( conditional up-titration ) mg/day in combination with any statin for 24 weeks in 423 patients . RESULTS In both studies , we found a robust reduction in fasting triglyceride levels by approximately 50 % in all combination therapy groups , which was significant compared to the statin-monotherapy ( placebo ) groups ( p < 0.001 ) . High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy , i.e. small low-density lipoproteins decreased whereas larger ones increased , and larger high-density lipoproteins decreased whereas smaller ones increased . The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies . CONCLUSIONS These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment OBJECTIVES We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose . BACKGROUND Reducing the level of low-density lipoprotein cholesterol ( LDL-C ) with statins induces important pleiotropic effects such as platelet inhibition . An insufficient LDL-C reduction often is treated with ezetimibe , an intestinal cholesterol absorption inhibitor , in combination with a low statin dose . It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy . METHODS Fifty-six patients with coronary artery disease were assigned r and omly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks . The levels of LDL-C , platelet activation markers after stimulation , platelet aggregation , and plasma chemokine levels ( i.e. , regulated on activation normally T-cell expressed and secreted [ RANTES ] ) were measured before and after changing lipid-lowering medication . RESULTS Platelet activation markers ( P-selectin ) after stimulation ( adenosine diphosphate ) were reduced by 40 mg/day of atorvastatin ( -5.2 + /- 1.6 arbitrary units ) but not by ezetimibe plus low-dose atorvastatin ( 2.1 + /- 1.8 arbitrary units ; p < 0.005 ) despite a similar reduction of LDL-C  ( atorvastatin -1.01 + /- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 + /- 0.22 mmol/l , p = NS ) . Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin . CONCLUSIONS Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin . In patients with coronary artery disease , it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects BACKGROUND Improving lipids beyond low-density lipoprotein cholesterol ( LDL-C ) lowering with statin monotherapy may further reduce cardiovascular risk . Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit , but is underutilised because of flushing , mediated primarily by prostagl and in D(2 ) ( PGD(2 ) ) . Laropiprant ( LRPT ) , a PGD(2 ) receptor ( DP1 ) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin ( ERN ) into a fixed-dose tablet . METHODS AND RESULTS Dyslipidaemic patients were r and omised to ERN/LRPT 1 g ( n = 800 ) , ERN 1 g ( n = 543 ) or placebo ( n = 270 ) for 4 weeks . Doses were doubled ( 2 tablets/day ; i.e. 2 g for active treatments ) for 20 weeks . ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C ( -18.4 % ) , high-density lipoprotein cholesterol ( HDL-C ; 20.0 % ) , LDL-C : HDL-C ( -31.2 % ) , non-HDL-C ( -19.8 % ) , triglycerides ( TG ; -25.8 % ) , apolipoprotein ( Apo ) B ( -18.8 % ) , Apo A-I ( 6.9 % ) , total cholesterol ( TC ; -8.5 % ) , TC : HDL-C ( -23.1 % ) and lipoprotein(a ) ( -20.8 % ) across weeks 12 - 24 . ERN/LRPT produced significantly less flushing than ERN during initiation ( week 1 ) and maintenance ( weeks 2 - 24 ) for all prespecified flushing end-points ( incidence , intensity and discontinuation because of flushing ) . Except for flushing , ERN/LRPT had a safety/tolerability profile comparable with ERN . CONCLUSION Extended-release niacin/LRPT 2 g produced significant , durable improvements in multiple lipid/lipoprotein parameters . The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin , a therapy proven to reduce cardiovascular risk The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control . This is a blinded component in a 5,518-patient subset of the ACCORD cohort . These participants were r and omized to either be ( 1 ) treated with simvastatin ( titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [ LDL ] cholesterol level of < 2.59 mmol/L [ 100 mg/dL ] ) plus placebo or ( 2 ) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent ( or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to < 50 mL/min per 1.73 m2 ) . Setting an upper limit of LDL cholesterol qualifying for r and omization excluded patients who would not likely achieve the LDL cholesterol goal . Recruitment for ACCORD began in January 2001 , and follow-up is scheduled to end in June 2009 . Since recruitment began , several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol . This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments . The current protocol is design ed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment st and ards of care IMPORTANCE In phase 2 studies , evolocumab , a fully human monoclonal antibody to PCSK9 , reduced LDL-C levels in patients receiving statin therapy . OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin . DESIGN , SETTING , AND PATIENTS Phase 3 , 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries . INTERVENTIONS Patients ( n = 2067 ) were r and omized to 1 of 24 treatment groups in 2 steps . Patients were initially r and omized to a daily , moderate-intensity ( atorvastatin [ 10 mg ] , simvastatin [ 40 mg ] , or rosuvastatin [ 5 mg ] ) or high-intensity ( atorvastatin [ 80 mg ] , rosuvastatin [ 40 mg ] ) statin . After a 4-week lipid-stabilization period , patients ( n = 1899 ) were r and omized to compare evolocumab ( 140 mg every 2 weeks or 420 mg monthly ) with placebo ( every 2 weeks or monthly ) or ezetimibe ( 10 mg or placebo daily ; atorvastatin patients only ) when added to statin therapies . MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol ( LDL-C ) level at the mean of weeks 10 and 12 and at week 12 . RESULTS Evolocumab  reduced LDL-C levels by 66 % ( 95 % CI , 58 % to 73 % ) to 75 % ( 95 % CI , 65 % to 84 % ) ( every 2 weeks ) and by 63 % ( 95 % CI , 54 % to 71 % ) to 75 % ( 95 % CI , 67 % to 83 % ) ( monthly ) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups ; the LDL-C reductions at week 12 were comparable . For moderate-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36 % , 40 % , and 39 % of evolocumab- , ezetimibe- , and placebo-treated patients , respectively . The most common adverse events in evolocumab-treated patients were back pain , arthralgia , headache , muscle spasms , and pain in extremity ( all < 2 % ) . CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia , evolocumab added to moderate- or high-intensity statin therapy result ed in additional LDL-C lowering . Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01763866 Residual cardiovascular risk persists despite statins , yet outcome studies of lipid‐targeted therapies beyond low‐density lipoprotein cholesterol ( LDL‐C ) have not demonstrated added benefit . Triglyceride elevation is an independent risk factor for cardiovascular events . High‐dose eicosapentaenoic acid ( EPA ) reduces triglyceride‐rich lipoproteins without raising LDL‐C. Omega‐3s have postulated pleiotropic cardioprotective benefits beyond triglyceride‐lowering . To date , no large , multinational , r and omized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes . The Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial ( REDUCE‐IT ; NCT01492361 ) is a phase 3b r and omized , double‐blinded , placebo‐controlled trial of icosapent ethyl , a highly purified ethyl ester of EPA , vs placebo . The main objective is to evaluate whether treatment with icosapent ethyl  reduces ischemic events in statin‐treated patients with high triglycerides at elevated cardiovascular risk . REDUCE‐IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor . R and omization required fasting triglycerides ≥150 mg/dL and < 500 mg/dL and LDL‐C > 40 mg/dL and ≤100 mg/dL with stable statin ( ± ezetimibe ) ≥4 weeks prior to qualifying measurements . The primary endpoint is a composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , coronary revascularization , or unstable angina . The key secondary endpoint is the composite of cardiovascular death , nonfatal myocardial infa rct ion , or nonfatal stroke . Several secondary , tertiary , and exploratory endpoints will be assessed . Approximately 8000 patients have been r and omized at approximately 470 centers worldwide . Follow‐up will continue in this event‐driven trial until approximately 1612 adjudicated primary ‐efficacy endpoint events have occurred Background : A continuous relationship between reductions in low-density lipoprotein cholesterol ( LDL-C ) and major adverse cardiovascular events ( MACE ) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However , it is uncertain whether this relationship extends to LDL-C levels < 50 mg/dL. We assessed the relationship between additional LDL-C , non – high-density lipoprotein cholesterol , and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls ( placebo/ezetimibe )  , mainly as add-on therapy to maximally tolerated statin . Methods : Data were pooled from 10 double-blind trials ( 6699 patient-years of follow-up ) . R and omization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks , added to background statin therapy in 8 trials . This analysis included 4974 patients ( 3182 taking alirocumab , 1174 taking placebo , 618 taking ezetimibe ) . In a post hoc analysis , the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE ( coronary heart disease death , nonfatal myocardial infa rct ion , ischemic stroke , or unstable angina requiring hospitalization ) in multivariable analyses . Results : Overall , 33.1 % of the pooled cohort achieved average LDL-C < 50 mg/dL ( 44.7%–52.6 % allocated to alirocumab , 6.5 % allocated to ezetimibe , and 0 % allocated to placebo ) . In total , 104 patients experienced MACE ( median time to event , 36 weeks ) . For every 39 mg/dL lower achieved LDL-C , the risk of MACE appeared to be 24 % lower ( adjusted hazard ratio , 0.76 ; 95 % confidence interval , 0.63–0.91 ; P=0.0025 ) . Percent reductions in LDL-C from baseline were inversely correlated with MACE rates ( hazard ratio , 0.71 ; 95 % confidence interval , 0.57–0.89 per additional 50 % reduction from baseline ; P=0.003 ) . Strengths of association material ly similar to those described for LDL-C were observed with achieved non – high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions . Conclusions : In a post hoc analysis from 10 ODYSSEY trials , greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE , including very low levels of LDL-C ( < 50 mg/dL ) . These findings require further validation in the ongoing prospect i ve ODYSSEY OUTCOMES trial . Clinical Trial Registration : URL : https://www . clinical trials.gov . Unique identifiers : NCT01507831 , NCT01623115 , NCT01709500 , NCT01617655 , NCT01644175 , NCT01644188 , NCT01644474 , NCT01730040 , NCT01730053 , and NCT01709513 BACKGROUND Reduction in low-density lipoprotein cholesterol ( LDL-C ) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes ( ACSs ) . The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy . The IMProved Reduction of Outcomes : Vytorin Efficacy International Trial ( IMPROVE-IT ) is a multicenter , r and omized , double-blind , active-control trial design ed to test the hypothesis that the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS . STUDY DESIGN The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS . Patients are r and omized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg . Follow-up visits are at 1 and 4 months , and every 4 months thereafter . If consecutive measures of LDL-C are > 79 mg/dL at follow-up visits , the simvastatin dose will be increased to 80 mg in a double-blind manner . The primary end point is the first occurrence of cardiovascular death , nonfatal myocardial infa rct ion , rehospitalization for unstable angina , coronary revascularization ( occurring at least 30 days after r and omization ) , or stroke . Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point . SUMMARY IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS . In addition , the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further BACKGROUND Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction . However , niacin is underutilised because of the side effects of flushing , mediated primarily by prostagl and in D(2 ) ( PGD(2 ) ) . A combination tablet containing extended-release niacin and laropiprant ( ERN/LRPT ) , a PGD(2 ) receptor ( DP1 ) antagonist , offers improved tolerability . This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol ( LDL-C ) goal based on their coronary heart disease risk category ( high , moderate or low ) . METHODS After a 2- to 6-week run-in statin ( simvastatin 10 or 20 mg or atorvastatin 10 mg ) period , 1216 patients were r and omised equally to one of two treatment groups in a double-blind fashion : group 1 received ERN/LRPT ( 1 g ) plus the run-in statin dose and advanced to ERN/LRPT ( 2 g ) after 4 weeks for an additional 8 weeks , with no adjustments to the run-in statin dose ; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks . RESULTS ERN/LRPT added to statin ( pooled across statin and statin dose ) significantly improved key lipid parameters vs. the doubled statin dose ( pooled ) : the between-treatment group difference in least squares mean per cent change [ 95 % confidence interval ( CI ) ] from baseline to week 12 in LDL-C ( primary end-point ) was -4.5 % ( -7.7 , -1.3 ) and in high-density lipoprotein cholesterol ( HDL-C ) was 15.6 % ( 13.4 , 17.9 ) and in median per cent change for triglyceride ( TG ) was -15.4 % ( -19.2 , -11.7 ) . Treatment-related adverse experiences ( AEs ) related to flushing , pruritis , rash , gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled . CONCLUSIONS The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C , HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia . The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin Background Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus , but many of these patients fail to achieve the target LDL-C level . Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin . However , in patients with type 2 diabetes who are already being treated with satins , it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose . Therefore , this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins . Methods The subjects were type 2 diabetic patients under treatment with rosuvastatin ( 2.5 mg daily ) , who had LDL-C levels ≥80 mg/dL. They were r and omly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day ( combination group , n = 40 ) or an increase of the rosuvastatin dose to 5 mg/day ( dose escalation group , n = 39 ) . These two groups were compared at baseline and after 12 weeks of treatment . Results The percent change of LDL-C was −31 % in the combination group and −12 % in the dose escalation group . Both groups showed a significant decrease , but the decrease was greater in the combination group . In both groups , there was a significant decrease in the levels of small dense LDL-C , oxidized LDL and remnant-like lipoprotein cholesterol . For all of these parameters , the percent changes were greater in the combination group . Only the combination group showed a significant decrease of triglycerides . Multivariate analysis was performed to identify factors associated with reaching an LDL-C level < 80 mg/dL. As a result , add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C. Conclusions Compared with increasing the dose of rosuvastatin , the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients , suggesting that this combination could suppress the progression of atherosclerosis . Trial registration Background Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin – based treatment . Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low‐density lipoprotein ( LDL ) cholesterol by around 25 % to 40 % and more than doubles high‐density lipoprotein ( HDL ) cholesterol . However , it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events . Methods The REVEAL study is a r and omized , double‐blind , placebo‐controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL‐lowering treatment with atorvastatin for an average of at least 4 years among patients with preexisting atherosclerotic vascular disease . The primary assessment is an intention‐to‐treat comparison among all r and omized participants of the effects of allocation to anacetrapib on major coronary events ( defined as the occurrence of coronary death , myocardial infa rct ion , or coronary revascularization ) . Results Between August 2011 and October 2013 , 30,449 individuals in Europe , North America , and China were r and omized to receive anacetrapib 100 mg daily or matching placebo .  Mean ( SD ) age was 67 ( 8) years , 84 % were male , 88 % had a history of coronary heart disease , 22 % had cerebrovascular disease , and 37 % had diabetes mellitus . At the r and omization visit ( after at least 8 weeks on a protocol ‐defined atorvastatin regimen ) , mean plasma LDL cholesterol was 61 ( 15 ) mg/dL and HDL cholesterol was 40 ( 10 ) mg/dL. Interpretation The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen . Results are anticipated in 2017 BACKGROUND Despite st and ard statin therapy , a majority of patients retain a high " residual risk " of cardiovascular events . OBJECTIVES The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention ( PCI ) . METHODS This trial was a prospect i ve , r and omized , controlled , multicenter study . Eligible patients who underwent PCI were r and omly assigned to atorvastatin alone or atorvastatin plus ezetimibe ( 10 mg ) daily . Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol ( LDL-C ) < 70 mg/dl . Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients . RESULTS The combination of atorvastatin/ezetimibe result ed in lower levels of LDL-C  than atorvastatin monotherapy ( 63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl ; p < 0.001 ) . For the absolute change in percent atheroma volume ( PAV ) , the mean difference between the 2 groups ( -1.538 % ; 95 % confidence interval [ CI ] : -3.079 % to 0.003 % ) did not exceed the pre-defined noninferiority margin of 3 % , but the absolute change in PAV did show superiority for the dual lipid-lowering strategy ( -1.4 % ; 95 % CI : -3.4 % to -0.1 % vs. -0.3 % ; 95 % CI : -1.9 % to 0.9 % with atorvastatin alone ; p = 0.001 ) . For PAV , a significantly greater percentage of patients who received atorvastatin/ezetimibe  showed coronary plaque regression ( 78 % vs. 58 % ; p = 0.004 ) . Both strategies had acceptable side effect profiles , with a low incidence of laboratory abnormalities and cardiovascular events . CONCLUSIONS Compared with st and ard statin monotherapy , the combination of statin plus ezetimibe showed greater coronary plaque regression , which might be attributed to cholesterol absorption inhibition-induced aggressive lipid lowering . ( Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [ PRECISE-IVUS ] ; NCT01043380 ) Background Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome ( ACS ) complicated by elevated triglycerides ( TG ) and decreased high density lipoprotein cholesterol ( HDL-C ) . The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 ( apoA5 ) level in patients with ACS . Methods One hundred and four patients with ACS were recruited and r and omly assigned into two groups : one was statin group ( n = 52 ) , given atorvastatin ( 20 mg QN ) or other statins with equivalent dosages ; the other was combination group ( n = 52 ) , given the same dose of statin plus bezafibrate ( 200 mg BID ) . Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment . Serum apoA5 levels were determined using a commercial available ELISA kit . Results ( 1 ) Compared with that of statin monotherapy , statin-bezafibrate combination treatment not only result ed in a significant reduction of TG , TC and LDL-C levels , ( all p < 0.05 ) , but also led to increases in HDL-C and apoA5 levels ( p < 0.05).(2 ) The percentage changes of TC , TG , LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks ( all p < 0.05 ) . Similarly , the rates of achieving lipid-control target were higher in statin-bezafibrate combination treatment group than those in statin monotherapy group ( all p < 0.05).(3 ) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG ( r = 0.359 , p = 0.009 ) . However , a negative correlation was observed between apoA5 and TG ( r = -0.329 , p = 0.017 ) after 12 weeks treatment . Conclusions Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients .  Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control BACKGROUND Despite the efficacy of statins in lowering low-density lipoprotein cholesterol ( LDL-C ) levels , many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction . The cholesterol absorption inhibitor , ezetimibe , has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins . This study was performed to compare the efficacy and safety of ezetimibe ( 10 mg ) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease ( CHD ) and are not at their LDL-C goal on the starting dose of atorvastatin . METHODS This was a 14-week , multicenter , r and omized , double-blind , active-controlled study conducted in 113 clinical research centers in 21 countries . Participants were adults with heterozygous familial hypercholesterolemia ( HeFH ) , CHD , or multiple ( > or = 2 ) cardiovascular risk factors , and a LDL-C level > or = 130 mg/dL after a 6- to 10-week dietary stabilization and atorvastatin ( 10 mg/day ) open-label run-in period . Eligible subjects continued to receive atorvastatin ( 10 mg ) and were r and omized to receive blinded treatment with ezetimibe ( 10 mg/day ; n = 305 ) or an additional 10 mg/day of atorvastatin ( n = 316 ) . The atorvastatin dose in both groups was doubled after 4 weeks , 9 weeks , or both when the LDL-C level was not at its goal ( < or = 100 mg/dL ) , so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day . The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14 . A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy . RESULTS The proportion of subjects reaching their target LDL-C level goal of < or = 100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group ( 22 % vs 7 % ; P < .01 ) . At 4 weeks , levels of LDL-C , triglycerides , and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin ( LDL-C -22.8 % versus -8.6 % ; P < .01 ) . The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone . CONCLUSIONS The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone
Population Characteristics and Study Quality of Included Trials , by Combination Therapy Agent and Potency Comparison Long-Term Clinical Outcomes We found insufficient evidence to compare long-term clinical outcomes ( mortality , acute coronary events , cerebrovascular events , and revascularization procedures ) for all combination therapy and statin intensity comparisons .
Figure 1 presents an evidence map of studies that evaluated these
Atherosclerotic cardiovascular disease ( ASCVD ) affects more than 15 million Americans ( 1 ) and is the leading cause of death for both men and women in the United States ( 2 ) .
Trials have demonstrated reductions in low-density lipoprotein ( LDL ) cholesterol levels ( 3 ) and decreased ASCVD risk with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) monotherapy ( 4 ) .
Over the past decade , statins have often been used in combination with other lipid-modifying agents .
Recently , several high-profile r and omized , controlled trials ( RCTs ) have evaluated add-on therapy ( 57 ) , wherein statin monotherapy is compared with the combination of the same statin dose and another lipid-modifying agent .
Add-on combination therapy can lead to superior lipid outcomes , but studies have not shown decreased rates of cardiovascular death , myocardial infa rct ion , revascularization , or stroke ( 57 ) .
Therefore , the 2013 American College of Cardiology ( ACC ) and American Heart Association ( AHA ) guidelines recommend moderate- or high-intensity statin monotherapy as the first-line strategy for ASCVD risk reduction among patients with LDL cholesterol levels of 4.91 mmol/L or greater ( 190 mg/dL ) , preexisting ASCVD , diabetes mellitus ( DM ) , or estimated 10-year ASCVD risk of 7.5 % or greater ( 8) .
Adverse effects are more common with higher-intensity statin regimens ( 9 ) , and musculoskeletal adverse events occur frequently among patients with the C variant in the SLCO1B1 gene ( 10 ) .
The 2013 ACC/AHA guidelines suggest that clinicians consider moderated combination therapy with a lower-intensity statin and another lipid-modifying medication among high-risk patients ( LDL cholesterol level 4.91 mmol/L [ 190 mg/dL ] , preexisting ASCVD , or DM ) who are intolerant of or unresponsive to statins ( evidence grade E : expert opinion ) ( 8) .
Yet , it is unclear whether this strategy results in similar ASCVD risk reductions and fewer adverse effects compared with higher-intensity statin monotherapy .
A 2009 systematic review that examined these questions found insufficient evidence to weigh benefits and risks of moderated combination therapy ( 12 ) .
We aim ed to compare the effectiveness , safety , and tolerability of moderated combination therapy of statin with another lipid-modifying medication ( bile acid sequestrant , ezetimibe , fibrate , niacin , or -3 fatty acid ) with those of higher-intensity statin monotherapy among high-risk patients .
We sought to compare the long-term clinical benefits and short-term lipid effects of moderated combination therapy with those of higher-intensity statin monotherapy , as well as to determine whether these regimens differ in rates of adherence and harms .
Given the recent release of the 2013 ACC/AHA guidelines ( 8) , we narrowed the scope of this manuscript to focus on evidence most relevant to high-risk population s for whom combination therapy might be considered .
Prior studies have suggested schemes to group statins on the basis of their reported LDL cholesterol reduction ( 17 , 18 ) , which are similar to the strategy used by the ACC/AHA committee ( 8) .