Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak. The Role of Statins in the Management of Nonalcoholic Fatty Liver Disease. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial. Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) Evaluation of a toolkit to improve cardiovascular disease screening and treatment for people with type 2 diabetes: protocol for a cluster-randomized pragmatic trial Impact of adherence to statins on chronic heart failure in primary prevention. Impact of better adherence to statin agents in the primary prevention of coronary artery disease A tailored lifestyle intervention to reduce the cardiovascular disease risk of individuals with Familial Hypercholesterolemia (FH): design of the PRO-FIT randomised controlled trial The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct Interaction between Mediterranean diet and statins on mortality risk in patients with cardiovascular disease: Findings from the Moli-sani Study. 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. Aspirin for primary prevention: yes or no? Global Risk Assessment to Guide Blood Pressure Management in Cardiovascular Disease Prevention A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk Evaluating the impact of population and high-risk strategies for the primary prevention of cardiovascular disease. Cardiac risk factors and the use of cardioprotective medications in patients with chronic renal insufficiency. Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or Older in the United States Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease History or Cardiovascular Risk Factors: Results of a Pooled Analysis of Phase 3 Clinical Trials Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomised controlled trial Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. 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 Lipoprotein(a) as a cardiovascular risk factor: current status
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 Non-alcoholic fatty liver disease ( NAFLD ) and its advanced form non-alcoholic steatohepatitis ( NASH ) are the most common causes of elevated liver enzymes in the general population . NASH , and to a lesser extent NAFLD have been associated with increased liver-related , cardiovascular disease ( CVD ) , and allcause mortality . No effective treatment is widely acceptable . OBJECTIVE The purpose of this review is to summarize available data on the impact of statins on NAFLD and NASH . METHOD A comprehensive review of the literature was performed to identify studies assessing the effect of statin use in NAFLD/NASH . RESULTS Recent reports have shown that the use of statins in patients with elevated plasma aminotransferases may be beneficial . Post hoc data from three large prospect i ve r and omized clinical trials ( n>11 , 000 ) suggest that specific statins ( mainly atorvastatin ) ameliorate NAFLD/NASH and reduce CVD events twice as much as in those with normal liver function . Several biopsy studies have found that rosuvastatin use is related with significant histological ameliorating effects in the setting of NASH . Statin treatment may also protect from hepatocellular carcinoma ( HCC ) related to NAFLD/NASH . CONCLUSION Since NAFLD/NASH patients have high CVD risk , they will probably require a statin . Thus , why not select a specific statins ( atorvastatin or rosuvastatin , both generic now ) that offer a substantial liver- and CVDrelated adverse event reduction ? The administration of statins in these patients is as safe as in the general population Most patients with type 2 diabetes mellitus develop cardiovascular disease ( CVD ) , with substantial loss of life expectancy . Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes . The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge . Despite the importance of this health problem , there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes . The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial is a r and omized , multicenter , double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors . ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality . All participants are in the glycemia trial , which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin ( HbA1c ) level of < 6.0 % will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9 % . The lipid trial includes 5,518 of the participants , who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether , in the context of good glycemic control , a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo . The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of < 120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of < 140 mm Hg . The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event , specifically nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death . Upon the expected completion of participant follow-up in 2009 , the ACCORD trial should document for the first time the benefits and risks of intensive glucose control , intensive blood pressure control , and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes 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 Background The prognosis for young people diagnosed with diabetes during childhood remains poor and this is mainly related to the long-term risk of developing vascular complications . Microalbuminuria identifies subjects at risk for diabetic nephropathy ( DN ) and cardiovascular disease ( CVD ) . It is often detected in adolescence but is rarely treated before the age of 18 years , as at the end of puberty albumin excretion may decline and in some subjects will return into the normal range . However , evidence indicates that subjects with both transient and persistent microalbuminuria have experienced renal damage during puberty and thus reno-protection to prevent long-term complications is warranted . In adults with diabetes and microalbuminuria , the use of angiotensin converting enzyme inhibitors ( ACEI ) and Statins is increasing , and in order to determine whether these agents are of value in the adolescent population a large r and omized controlled clinical trial is needed . Methods / Design The Adolescent type 1 Diabetes cardio-renal Intervention Trial ( AdDIT ) is a multi-center , r and omized , double-blind , placebo-controlled trial of ACEI and Statin therapy in adolescents with type 1 diabetes . 500 high-risk adolescents , defined on the basis of their albumin excretion , are r and omized to receive either ACEI ( Quinapril ) or Statins ( Atorvastatin ) or combination therapy or placebo for 3 - 4 years . There will also be a parallel open observational study , based on the follow-up of 400 low-risk non-r and omized adolescents . The major endpoint of the study is the change in albumin excretion ; secondary endpoints include markers of CVD , renal function , retinopathy , quality of life combined with assessment of compliance and potential health economic benefits . Discussion AdDIT will provide important data on the potential renal and cardiovascular protective effects of ACEI and Statins in high-risk adolescents . Long-term follow-up of the r and omized subjects will provide direct evidence of disease outcomes , in addition to the data on early surrogate measures of DN and CVD . Follow-up of non-r and omized low-risk subjects will determine the potential impact of intervention on DN and CVD . AdDIT will help to determine whether , in addition to encouraging young people to achieve good glycaemic control , pharmacological cardio-renal protection should also be implemented . EudraCT Number 2007 - 001039 - 72 Trial Registration Number IS RCT Background The gap between the level of care recommended by evidence -based clinical practice guidelines and the actual care delivered to patients in practice has been well established . The Canadian Diabetes Association ( CDA ) created an implementation strategy to improve the implementation of its 2008 guidelines . This study will evaluate the impact of the strategy to improve cardiovascular disease ( CVD ) screening , prevention and treatment for people with diabetes . Design A pragmatic cluster-r and omized trial will be conducted to evaluate the CDA 's CVD Toolkit .  All family physicians in Ontario , Canada were r and omly allocated to receive the Toolkit , which includes several printed educational material s targeting CVD screening , prevention and treatment , either in spring 2009 ( intervention arm ) or in spring 2010 ( control arm ) . R and omization occurred at the level of the practice . Forty family physicians from each arm will be recruited to participate , and the medical records for 20 of their diabetic patients at high risk for CVD will be retrospectively review ed . Outcome measures will be assessed for each patient between July 2009 and March 2010 . The primary outcome will be that the patient is receiving a statin .  Secondary outcomes will include 1 ) the receipt of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker , 2 ) various intermediate measures ( A1c , blood pressure , LDL-cholesterol , total-/HDL-cholesterol ratio , body mass index and waist circumference ) , and 3 ) clinical inertia ( the failure to change therapy in response to an abnormal A1c , blood pressure or cholesterol reading ) . The analysis will be carried out using multilevel hierarchical logistic regression models to account for the clustered nature of the data . The group assignment will be a physician-level variable . In addition , a process evaluation study with six focus groups of family physicians will assess the acceptability of the CDA 's Toolkit and will explore factors contributing to any change or lack of change in behaviour , from the perspectives of family physicians . Discussion Printed educational material s for physicians have been shown to exert small-to-moderate changes in patient care . The CDA 's CVD Toolkit is an example of a practice guideline implementation strategy that can be disseminated to a wide audience relatively inexpensively , and so demonstrating its effectiveness at improving diabetes care could have important consequences for guideline developers , policy makers and clinicians . Trial Registration The trial is registered with http://www . clinical trials.gov , ID # AIMS Statins are effective in the prevention of an atherosclerotic event , e.g. coronary artery disease and cerebrovascular disease . Patients at high risk of cardiovascular disease ( CVD ) , such as chronic heart failure ( CHF ) , might benefit from the effects of statin therapy . However , one question that has not yet been answered and that may clarify the role of statins in CHF is whether statins prevent the development of CHF in patients with a low risk of CVD . Our aim was to evaluate the impact of adherence to statins on the incidence of CHF . METHODS A cohort of 111,481 patients was reconstructed using the Régie de l'Assurance Maladie du Québec data bases . Patients were eligible if they were between 45 and 85 years old , without CVD , and newly treated with statins between 1999 and 2004 . A nested case-control design was used to study CHF . Every case of CHF was matched for age and duration of follow-up in up to 15 r and omly selected controls . The adherence level was measured by calculating the medication possession ratio . Rate ratios ( RR ) of CHF were estimated by conditional logistic regression adjusting for several covariables . RESULTS The mean patient age was 63 years , 49 % had hypertension , 21 % had diabetes and 41 % were male . A high level of adherence to statins was associated with a reduction of CHF ( RR 0.81 ; 0.71 , 0.91 ) . The risks associated with CHF were the development of CVD during follow-up , being a social-aid recipient , and suffering from hypertension , diabetes mellitus , or having a higher chronic disease score . CONCLUSION Our study indicates that better adherence to statins is associated with a reduced risk of CHF Background Statins reduce cardiovascular morbidity and mortality after continuous treatment . Studies have shown that less than 50 % of patients take 80 % or more of prescribed doses 1 year after starting therapy . Objective To evaluate the impact of statin adherence on the incidence of coronary artery disease ( CAD ) . Methods A cohort of 115,290 patients was reconstructed using the Régie de l’assurance maladie du Québec data bases . Patients aged 45 to 85 years , without indication of cardiovascular disease ( CVD ) , and newly treated with statins between 1999 and 2004 were eligible . A nested case-control design was used to study CAD . Every case was matched for age and duration of follow-up with r and omly selected controls . The adherence level was measured by calculating the medication possession ratio . Rate ratios ( RR ) of CAD were determined through conditional logistic regression adjusted for several covariates . Results The mean patient age was 63 years , 54 % had hypertension , 26 % had diabetes , and 41 % were males . The proportion of patients with high adherence level to statins  ( ≥ 80 % ) was 74 % during the first year and 53 % after 1 year of follow-up . High adherence was associated with a risk reduction of 18 % [ RR : 0.82 ( 95 % CI : 0.77 - 0.87 ) ] compared to an adherence level of < 20 % . Developing a CVD during follow-up , being male , having been diagnosed with hypertension or diabetes , or having a high chronic disease score increased the risk of CAD . Conclusion Our study suggests that better adherence to statin agents is associated with a significant risk reduction of CAD . Adherence to statin agents needs to be improved so that patients can benefit from the full protective effects of statin therapies Background Because of a high cardiovascular disease ( CVD ) risk in people with Familial Hypercholesterolemia ( FH ) , early prevention of cardiovascular disease is important for health gain and cost reduction . This project focuses on the development and evaluation of an innovative intervention aim ing to reduce CVD risk by promoting a healthy lifestyle among people with FH . Methods This project is design ed as a r and omised controlled trial in which individuals with FH will be assigned r and omly to a control or intervention group . In the intervention group ( n = 200 ) , participants will receive a personalized intervention which is a combination of web-based tailored lifestyle advice and personal counselling by a lifestyle coach .  The control group ( n = 200 ) will receive care as usual . Primary outcomes are biological indicators of CVD risk : systolic blood pressure , glucose , BMI , waist circumference and lipids ( triglycerides , total , LDL and HDL cholesterol ) . Secondary outcomes are : healthy lifestyle behaviour ( with regard to smoking , physical activity , dietary pattern and compliance to statin therapy ) and psychological correlates and determinants of healthy lifestyle behaviour ( knowledge , attitude , risk perception , social influence , self-efficacy , cues to action , intention and autonomy ) . Measurement will take place at baseline , and at 3 and 12 months after r and omisation . Additionally , a throughout process-evaluation will be conducted to assess and monitor intervention implementation during the trial . Discussion Results of the PRO-FIT project will provide information about the effects and implementation of a healthy lifestyle intervention for individuals with FH . Our experiences with this intervention will be indicative about the suitability , feasibility and benefits of this approach for future interventions in other high-risk groups , such as Familial Combined Hypercholesterolemia ( FCH ) and diabetes . Trial registration Background It is hypothesized that in individuals without clinical cardiovascular disease ( CVD ) , but at increased CVD risk , a 50 % to 60 % reduction in CVD risk could be achieved using fixed dose combination ( FDC ) therapy ( usually comprised of multiple blood‐pressure agents and a statin [ with or without aspirin ] ) in a single “ polypill ” . However , the impact of a polypill in preventing clinical CV events has not been evaluated in a large r and omized controlled trial . Methods TIPS‐3 is a 2x2x2 factorial r and omized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population . This study aims to determine whether the Polycap ( comprised of atenolol , ramipril , hydrochlorothiazide , and a statin )  reduces CV events in persons without a history of CVD , but who are at least at intermediate CVD risk . Additional interventions in the factorial design of the study will compare the effect of ( 1 ) aspirin versus placebo on CV events ( and cancer ) , ( 2 ) vitamin D versus placebo on the risk of fractures , and ( 3 ) the combined effect of aspirin and the Polycap on CV events . Results The study has r and omized 5713 participants across 9 countries . Mean age of the study population is 63.9 years , and 53 % are female . Mean INTERHEART risk score is 16.8 , which is consistent with a study population at intermediate CVD risk . Conclusion Results of the TIP‐3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD BACKGROUND Statins are prescribed for patients with cardiovascular disease ( CVD ) , along with the recommendation of adopting healthy diets . We evaluated the independent and the combined effect of statins and Mediterranean diet ( MD ) towards mortality risk in patients with previous CVD by using real-life data from a population -based prospect i ve cohort . METHODS Longitudinal analysis on 1180 subjects ( mean age 67.7 ± 10 ) with prior CVD at enrollment in the Moli-sani Study and followed up for 7.9 y ( median ) .  Adherence to MD was appraised by a Mediterranean diet score .  Hazard ratios ( HR ) with 95 % confidence intervals ( 95 % CI ) were calculated by multivariable Cox regression and competing risk models . RESULTS Multivariable risk estimates associated with a 2-point increase in MD score were 0.84 ( 95 % CI 0.70 - 1.00 ) , 0.77 ( 0.61 - 0.97 ) and 0.70 ( 0.52 - 0.93 ) for overall , cardiovascular and coronary artery disease (CAD)/cerebrovascular deaths , respectively  . Statins were not associated with death risk . Subjects combining statins and average-high adherence to MD had much lower than expected risk of cardiovascular and CAD/cerebrovascular mortality ( p for interaction = 0.045 and 0.0015 , respectively ) as compared to those neither using statins nor having average-high MD . The combination of average-high MD and statins was associated in a likely synergistic way with reduced low- grade inflammation , but not with blood cholesterol . CONCLUSIONS MD lowered the risk of all-cause , cardiovascular and CAD/cerebrovascular mortality CVD patients , net of statins . In the same population , statins  reduced CVD death risk only in combination with MD . Low- grade inflammation , rather than lipids , is likely to be on the pathway of the interaction between MD and statins towards mortality risk 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 AIM To assess benefit versus harm of aspirin for cardiovascular disease ( CVD ) primary prevention by age group , gender and risk category and to interpret these results in light of current New Zeal and CVD risk assessment and management guidelines . METHODS Rates of benefit ( avoided vascular events ) and harm ( additional major extracranial bleeds ) for each gender and age group were calculated from data from the six r and omised controlled trials included in the Anti-Thrombotic Trialists ' ( ATT ) Collaboration meta- analysis . These rates were applied to CVD risk categories to calculate the net benefit or net harm likely to occur from the use of aspirin in primary prevention of CVD as monotherapy and when added to lipid and blood pressure-loweringtherapies . RESULTS Benefits of aspirin monotherapy outweigh the harms for both men and women aged up to 80 years with calculated five-year CVD risk > 15 % in primary prevention . Harm may outweigh benefit for primary prevention for those over 80 years . For men 70 - 79 years the benefit of aspirin in primary prevention is marginal when added to lipid and blood pressure-lowering therapies . DISCUSSION The recent ATT Collaboration meta- analysis has raised doubts about the relative safety of aspirin in primary prevention of CVD . However , modelling by risk category and age group suggests that current guidelines are justified in recommending aspirin for primary prevention of CVD in those with five-year CVD risk > or = 15 % up to the age of 80 years . For men 70 - 79 , consider lipid and blood pressure-lowering therapies first then reassess whether aspirin adds additional net benefit Elevated blood pressure ( BP ) is a causal risk factor for cardiovascular disease ( CVD ) . Epidemiological analyses have established the grade d and continuous association between higher BP and CVD . Moreover , r and omized clinical trials among individuals with hypertension have demonstrated , in aggregate , a reduction in CVD events by 20 % , coronary heart disease ( CHD ) by 17 % , stroke by 27 % , and heart failure by 28 % for every 10 mm Hg systolic BP ( SBP ) lowering with medical therapy.1 Therefore , prevention , detection , treatment , and control of elevated BP , and its clinical correlate hypertension , is an important public health priority and a primary target for CVD prevention . Although national health surveys have demonstrated improvements in hypertension awareness and treatment , strategic opportunities to improve the efficiency and efficacy of applying BP-lowering therapy in patients most likely to benefit remain.2 Global CVD risk assessment , using multivariable prediction models that estimate absolute CVD risk from routinely measured clinical variables , has been promulgated in several CVD prevention guidelines for cholesterol management to target the most intensive preventive therapies to those at highest absolute CVD risk.3–5 Hypertension guidelines , however , have instead relied solely on isolated BP thresholds and BP goals to guide treatment initiation and intensity . In this review , we provide a rationale for incorporating global CVD risk assessment in BP treatment decision-making and propose a framework to guide its implementation in future CVD prevention guidelines . Epidemiological analyses have firmly established that CVD is a multifactorial condition and that modest increases of several CVD risk factors can often lead to greater overall risk than a severe elevation of a Background Most individuals at high cardiovascular disease ( CVD ) risk worldwide do not receive any or optimal preventive drugs . We aim ed to determine whether fixed dose combinations of generic drugs ( ‘ polypills ’ ) would promote use of such medications . Methods We conducted a r and omized , open-label trial involving 623 participants from Australian general practice s. Participants had established CVD or an estimated five-year CVD risk of ≥15 % , with indications for antiplatelet , statin and ≥2 blood pressure lowering drugs ( ‘ combination treatment ’ ) . Participants r and omized to the ‘ polypill-based strategy ’  received a polypill containing aspirin 75 mg , simvastatin 40 mg , lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide 12.5 mg . Participants r and omized to ‘ usual care ’ continued with separate medications and doses as prescribed by their doctor . Primary outcomes were self-reported combination treatment use , systolic blood pressure and total cholesterol . Results After a median of 18 months , the polypill-based strategy was associated with greater use of combination treatment ( 70 % vs. 47 % ; relative risk 1.49 , ( 95 % confidence interval ( CI ) 1.30 to 1.72 ) p < 0.0001 ; number needed to treat = 4.4 ( 3.3 to 6.6 ) ) without differences in systolic blood pressure ( −1.5 mmHg ( 95 % CI −4.0 to 1.0 ) p = 0.24 ) or total cholesterol ( 0.08 mmol/l ( 95 % CI −0.06 to 0.22 ) p = 0.26 ) . At study end , 17 % and 67 % of participants in polypill and usual care groups , respectively , were taking  atorvastatin  or rosuvastatin . Conclusion Provision of a polypill improved self-reported use of indicated preventive treatments . The lack of differences in blood pressure and cholesterol may reflect limited study power , although for cholesterol , improved statin use in the polypill group counter-balanced use of more potent statins with usual care AIMS To estimate the potential effectiveness of different " high-risk " and " population " approaches to the primary prevention of  cardiovascular disease ( CVD ) in middle-aged British men , after correction for regression dilution bias . METHODS AND RESULTS We used a combination of cohort and r and omised controlled trial evidence to estimate the effectiveness of high-risk strategies , based on the identification of high-risk factors or high absolute risk , and strategies based on population -wide reductions in cholesterol and blood pressure . High-risk strategies were potentially effective but would need to be used widely to have a substantial effect on CVD in the population . Aggressive pharmacological treatment ( using statins , beta-blockers , ACE-inhibitors and aspirin ) in individuals with a 10-year Framingham event risk of > or=30 % ( 6 % of population ) would have reduced major CVD by at most 11 % . This figure increased to 34 % at a > or=20 % treatment threshold ( 26 % of population ) . In contrast , modest downwards shifts in the population distributions of serum total cholesterol and systolic blood pressure led to marked expected reductions in major CVD . Taking regression dilution bias into account , 10 % reductions in long-term mean blood cholesterol and blood pressure could have reduced major CVD by 45 % . CONCLUSIONS If high-risk strategies are to have a major impact on CVD in the population , they need to be more widely used than previously envisaged . Population -wide reduction of major risk factors is needed if CVD is to be substantially reduced Cardiovascular disease ( CVD ) is a major cause of morbidity and mortality among patients with chronic renal insufficiency ( CRI ) .  beta-Adrenergic blockers , acetylsalicylic acid ( ASA ) , angiotensin-converting enzyme ( ACE ) inhibitors , and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ( statins ) all reduce CVD mortality , but little is known about the extent to which these medications are used in patients with CRI . This study , a prospect i ve cross-sectional study of consecutive patients seen by nephrologists in four Canadian centers for follow-up of progressive CRI in 1999 , was performed to investigate the prevalence of coronary risk factors and use of cardioprotective medications among patients with CRI . Patients had creatinine clearances of 75 mL/min or less but were not on dialysis therapy . Three hundred four consecutive patients meeting the inclusion criteria were enrolled . Mean age was 60.8 + /- 15.7 years , mean creatinine clearance was 30.3 + /- 18 mL/min , and the case mix of kidney diseases was similar to that in the Canadian Organ Replacement Registry data . One hundred seventeen of 304 patients ( 38.5 % ) had a history of previous CVD , and the prevalence of CVD was greater in patients with more severe CRI . Two hundred forty-three patients ( 79.9 % ) had a history of hypertension , 132 patients ( 43.4 % ) had hyperlipidemia , 114 patients ( 37.5 % ) had diabetes mellitus , and 71 patients ( 27.3 % ) were smokers . Thirty-five percent of the patients with CVD had blood pressures greater than 140/90 mm Hg ; 103 patients ( 33.9 % ) were administered beta-blockers ; 196 patients ( 64.5 % ) , ACE inhibitors or angiotensin-receptor blockers ; 83 patients ( 27.3 % ) , ASA ; and 56 patients ( 18.4 % ) , statins . Patients with diabetes were not more likely than those without diabetes to be prescribed cardioprotective medications . CVD is common in the predialysis population , and its prevalence increases with more severe kidney failure . Despite this , the use of cardioprotective medications  is relatively low , and many patients had suboptimal blood pressure control . Given the high burden of disease in these patients , beta-blockers and ACE inhibitors should be used to control hypertension and /or for cardioprotection , and the increased use of ASA and statins should be considered 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 Abstract Objective : This post hoc analysis sought to assess the efficacy , safety , and tolerability of saxagliptin in patients with type 2 diabetes mellitus and cardiovascular ( CV ) risk factors or disease ( CVD ) . Methods : Data from 5 r and omized controlled trials were pooled to compare saxagliptin 5 mg with placebo : 2 studies of saxagliptin as monotherapy in drug-naïve patients and 1 each of saxagliptin as add-on therapy to metformin , glyburide , or a thiazolidinedione . Analysis was performed according to the following baseline/trial entry criteria : 1 ) history /no history of CVD ; 2 ) ≥ 2 versus 0 to 1 CV risk factors ; 3 ) statin use versus no statin use ; and 4 ) hypertension versus no hypertension . Change from baseline glycated hemoglobin ( HbA1c ) , fasting plasma glucose , and postpr and ial glucose levels ; and the proportion of patients achieving an HbA1c level < 7 % were analyzed ( week 24 ) . Safety was assessed by adverse events , hypoglycemia , and body weight . Results : In total , 882 patients received saxagliptin 5 mg and 799 received placebo . Differences in adjusted mean change from baseline HbA1c ( 95 % CI ) were greater with saxagliptin compared with placebo in patients with a history of CVD ( −0.64 % [ −0.90 to −0.38 ] ) and no history of CVD ( −0.68 % [ −0.78 to −0.58 ] ) ; with ≥ 2 CV risk factors ( −0.73 % [ −0.85 to −0.60 ] ) and 0 to 1 CV risk factor ( −0.62 % [ −0.75 to −0.48 ] ) ; with statin use ( −0.70 % [ −0.89 to −0.52 ] ) and no statin use ( −0.66 % [ −0.77 to −0.56 ] ) ; and with hypertension ( −0.69 % [ −0.82 to −0.57 ] ) and no hypertension ( −0.66 % [ −0.80 to −0.52 ] ) . Saxagliptin was well tolerated , with similar adverse event rates and types compared with placebo . There was a < 1 % rate of confirmed hypoglycemia in all groups except in patients with CV history who received placebo ( 2.1 % ) . Conclusion : Saxagliptin improved glycemic measures , result ed in low rates of confirmed hypoglycemia , and was well tolerated in patients with or without CVD and CV risk factors Abstract Aims /hypothesisThe aim of the study was to examine the impact of statin or omega-3-acid ethyl esters 90 ( omega-3 EE90 ; omega-3-acid ethyl esters 90 refers to a mixture of ethyl esters of n-3 fatty acids ) on estimated cardiovascular disease ( CVD ) risk in community-based people with type 2 diabetes but without known CVD and not taking lipid-lowering therapy . Methods A central computer r and omised 800 patients in 59 UK general practice s to atorvastatin ( n = 401 , 20 mg/day ) or placebo ( n = 399 ) and omega-3 EE90 ( n = 397 , 2 g/day ) or placebo  ( n = 403 ) in a concealed factorial manner . Participants with LDL-cholesterol < 2.6 mmol/l , triacylglycerol < 1.5 mmol/l and estimated 10-year CVD risk < 20 % were compared at 4 months . Results Mean ( SD ) age was 63.5 ( 11.7 ) years , HbA1c 6.9 ( 1.1 ) % and known diabetes duration ( median [ interquartile range ] ) was 4 ( 2–8 ) years . Fifty-seven per cent were men , 90 % white and 74 % had an estimated 10-year CVD risk ≥20 % . Of 732 patients with 4-month data , more allocated atorvastatin ( n = 371 ) compared with placebo ( n = 361 ) achieved LDL-cholesterol < 2.6 mmol/l ( 91 % vs 24 % , p < 0.001 ) and had estimated 10-year CVD risks < 20 % ( 38 % vs 26 % , p < 0.001 ) . No differences were seen between those allocated omega-3 EE90 ( n = 371 ) compared with placebo ( n = 361 ) for participants achieving triacylglycerol < 1.5 mmol/l ( 65 % vs 60 % , p = 0.18 ) or estimated 10-year CVD risks < 20 % ( 34 % vs 30 % , p = 0.18 ) . There were no side effects of note . Conclusions /interpretationMany community-based diabetic patients without known CVD remain at high CVD risk despite statin treatment and require additional risk-reduction strategies . The impact of omega-3 EE90 on CVD risk will remain uncertain until clinical endpoint trial results are available . Trial registration : IS RCT no. 76737502 Funding : The study was funded by Pfizer IMPORTANCE Most patients with cardiovascular disease ( CVD ) do not take recommended medications long-term . The use of fixed-dose combinations ( FDCs ) improves adherence in several clinical areas . Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment . OBJECTIVE To assess whether FDC delivery of aspirin , statin , and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors , systolic blood pressure ( SBP ) and low-density lipoprotein cholesterol ( LDL-C ) . DESIGN , SETTING , AND PARTICIPANTS The UMPIRE trial , a r and omized , open-label , blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe . The trial follow-up concluded in July 2012 . INTERVENTIONS Participants were r and omly assigned ( 1:1 ) to an FDC-based strategy  ( n=1002 ) containing either ( 1 ) 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril , and 50 mg atenolol or ( 2 ) 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril , and 12.5 mg hydrochlorothiazide or to usual care ( n=1002 ) . MAIN OUTCOMES AND MEASURES Adherence to medication ( defined as self-reported use of antiplatelet , statin , and ≥2 BP-lowering medications ) and changes in SBP and LDL-C from baseline . RESULTS At baseline , mean BP was 137/78 mm Hg , LDL-C was 91.5 mg/dL , and 1233 ( 61.5 % ) of 2004 participants reported use of antiplatelet , statin , and 2 or more BP-lowering medications . Median follow-up was 15 months ( interquartile range , 12 - 18 months ) . The FDC group had improved adherence vs usual care ( 86 % vs 65 % ; relative risk [ RR ] of being adherent , 1.33 ; 95 % CI , 1.26 - 1.41 ; P < .001 ) with concurrent reductions in SBP ( -2.6 mm Hg ; 95 % CI , -4.0 to -1.1 mm Hg ; P < .001 ) and LDL-C ( -4.2 mg/dL ; 95 % CI , -6.6 to -1.9 mg/dL ; P < .001 ) at the end of the study . Although there was consistency of effects across predefined subgroups , evidence existed of larger benefits in patients with lower adherence at baseline . In this subgroup of 727 participants ( 36 % ) , adherence at the end of study was 77 % vs 23 % ( RR , 3.35 ; 95 % CI , 2.74 - 4.09 ; P < .001 for interaction ) , SBP was reduced by 4.9 mm Hg ( 95 % CI 7.3 - 2.6 mm Hg ; P = .01 for interaction ) , and LDL-C was reduced by 6.7 mg/dL ( 95 % CI , 10.5 - 2.8 mg/dL ; P = .11 for interaction ) . There were no significant differences in serious adverse events or cardiovascular events ( 50 [ 5 % ] in the FDC group and 35 [ 3.5 % ] in the usual care group ; RR , 1.45 ; 95 % CI , 0.94 - 2.24 ; P=.09 ) between the groups . CONCLUSIONS AND RELEVANCE Among patients with or at high risk of CVD , use of an FDC strategy for blood pressure , cholesterol , and platelet control vs usual care result ed in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION clinical trials.gov Identifier : NCT01057537 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 [ Aims The aims of the study were , first , to critically evaluate lipoprotein(a ) [ Lp(a ) ] as a cardiovascular risk factor and , second , to advise on screening for elevated plasma Lp(a ) , on desirable levels , and on therapeutic strategies . Methods and results The robust and specific association between elevated Lp(a ) levels and increased cardiovascular disease (CVD)/coronary heart disease ( CHD ) risk , together with recent genetic findings , indicates that elevated Lp(a ) , like elevated LDL-cholesterol , is causally related to premature CVD/CHD . The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels . Mechanistically , elevated Lp(a ) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a ) resembles both plasminogen and plasmin but has no fibrinolytic activity , or may accelerate atherosclerosis because , like LDL , the Lp(a ) particle is cholesterol-rich , or both . We advise that Lp(a ) be measured once , using an isoform-insensitive assay , in subjects at intermediate or high CVD/CHD risk with premature CVD , familial hypercholesterolaemia , a family history of premature CVD and /or elevated Lp(a ) , recurrent CVD despite statin treatment , ≥3 % 10-year risk of fatal CVD according to European guidelines , and /or ≥10 % 10-year risk of fatal + non-fatal CHD according to US guidelines . As a secondary priority after LDL-cholesterol reduction , we recommend a desirable level for Lp(a ) < 80th percentile ( less than ∼50 mg/dL ) . Treatment should primarily be niacin 1–3 g/day , as a meta- analysis of r and omized , controlled intervention trials demonstrates reduced CVD  by niacin treatment . In extreme cases , LDL-apheresis is efficacious in removing Lp(a ) . Conclusion We recommend screening for elevated Lp(a ) in those at intermediate or high CVD/CHD risk , a desirable level < 50 mg/dL as a function of global cardiovascular risk , and use of niacin for Lp(a ) and CVD/CHD risk reduction
Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects .
There was no evidence of any serious harm caused by statin prescription .
Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life .
Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta- analysis indicate that these benefits are similar in people at lower ( < 1 % per year ) risk of a major cardiovascular event .
AUTHORS ' CONCLUSIONS Reductions in all-cause mortality , major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins
BACKGROUND Reducing high blood cholesterol , a risk factor for cardiovascular disease ( CVD ) events in people with and without a past history of CVD is an important goal of pharmacotherapy .
Statins are the first-choice agents .
Previous review s of the effects of statins have highlighted their benefits in people with CVD .
The case for primary prevention was uncertain when the last version of this review was published ( 2011 ) and in light of new data an up date of this review is required .
OBJECTIVES To assess the effects , both harms and benefits , of statins in people with no history of CVD .