Design and rationale of the ARBITER trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)--a randomized trial comparing the effects of atorvastatin and pravastatin on carotid artery intima-media thickness. Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak. A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization Effectiveness of an intervention designed to optimize statins use: a primary prevention randomized clinical trial Primary prevention of vascular events in patients with high levels of C-reactive protein: the JUPITER study Electronic Health Record-Based Patient Identification and Individualized Mailed Outreach for Primary Cardiovascular Disease Prevention: A Cluster Randomized Trial Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13) on the effectiveness of statins: the GenHAT study Changes in CVD risk factors in the activity counseling trial The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct Rationale and design of assessment of lipophilic vs. hydrophilic statin therapy in acute myocardial infarction (the ALPS-AMI) study. 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. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial The Collaborative Cardiovascular Risk Reduction in Primary Care (CCARP) study. Continuation of statin therapy and primary prevention of nonfatal cardiovascular events. Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial.
BACKGROUND As a class , statins are remarkably effective in reducing low-density lipoprotein ( LDL ) cholesterol , and several of these drugs have now been shown to reduce coronary heart disease morbidity and mortality . However , several important controversies in the use of statins remain to be answered by clinical trials . For example , it is controversial whether marked cholesterol reduction to levels below 100 mg/dL would further reduce the incidence of coronary heart disease . Furthermore , concerns about differences among statins for nonlipid effects has raised the concern that the assumption of a class effect is premature until head-to-head clinical trials are completed . METHODS Arterial Biology for the Investigation for the Treatment Effects of Reducing Cholesterol ( ARBITER ) is a single-center , r and omized , active-controlled study comparing the efficacy of high-dose atorvastatin ( 80 mg/d ) and pravastatin ( 40 mg/d ) in patients being treated for either the primary or secondary prevention of coronary heart disease . This trial will enroll up to 200 patients for the primary end point of the mean change in intima-media thickness of the common carotid artery . This effect will be evaluated over a treatment duration of 12 months . Secondary end points include the effects of statin therapy on inflammatory and hemostatic markers ( C-reactive protein and fibrinogen ) . CONCLUSION ARBITER will provide important data on the role of marked LDL reduction and the " class effect " theory of statin therapy in cardiovascular medicine 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 The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear . More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease ( CVD ) , side effects , improvement in adherence and physician/patient " acceptability " of the Polypill . Methods We conducted an open-label , parallel-group , r and omized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD . The trial compared a Polypill ( 75 mg aspirin , 20 mg simvastatin , 10 mg lisinopril and 12.5 mg hydrochlorothiazide ) to St and ard Practice . After r and omization , patients were followed monthly for three months . Pre-specified primary outcomes included reduction in systolic blood pressure , total cholesterol and estimated 10-year CVD risk . We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients . Results Patients were recruited in a six-month period as planned . Two hundred three patients ( 94.0 % ) completed the treatment program and returned for their three-month follow-up visits . No safety concerns were reported . These findings suggest a high rate of patient acceptability , a finding that is bolstered by the majority of patients completing the trial ( 90 % ) indicating that they would take the Polypill " for life " if proven to be effective in reducing CVD risk . Approximately 86 % of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93 % for secondary prevention of CVD . Both the Polypill and St and ard Practice result ed in marked reductions in systolic blood pressure , total cholesterol and 10-year risk of CVD . However , the differences between the treatment groups were not statistically significant . Conclusions We successfully completed a Polypill feasibility trial in Sri Lanka . We were able to document high acceptability of the Polypill to patients and physicians . We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs . The Polypill was however simpler and achieved comparable risk factor reductions , highlighting its potential usefulness in the prevention of CVD.Trial registration number Clinical trials.gov : Background Although hypercholesterolemia is considered a cardiovascular risk factor , in isolation it is not necessarily sufficient cause for a cardiovascular event . To improve event prediction , cardiovascular risk calculators have been developed ; the REGICOR calculator has been vali date d for use in our population . The objective of this project is to develop an intervention with general practitioners ( GPs ) and evaluate its impact on prescription adequacy of cholesterol-lowering drugs in primary prevention of cardiovascular disease and in controlling the costs associated with this disease . Methods This nonblinded , cluster-r and omized clinical trial analyzes data from primary care electronic medical records ( ECAP ) and other data bases . Inclusion criteria are patients aged 35 to 74 years with no known cardiovascular disease and a new prescription for cholesterol-lowering drugs during the 2-year study period . Dependent variables include the following : RETIRA , defined as new cholesterol-lowering drugs initiated during the year preceding the intervention , considered inadequate , and withdrawn during the study period ; EVITA , defined as new cholesterol-lowering drugs initiated during the study period and considered inadequate ; COST , defined as the total cost of inadequate new treatments prescribed ; and REGISTER , defined as the recording of cardiovascular risk factors . Independent variables include the  GP ’s quality -of-care indicators and r and omly assigned study group ( intervention vs control )  , patient demographics , and clinical variables . Aggregated descriptive analysis will be done at the GP level and multilevel analysis will be performed to estimate the intervention effect , adjusted for individual and GP variables . Discussion The study objective is to generate evidence about the effectiveness of implementing feedback information programs directed to GPs in the context of Primary Care . The goal is to improve the prescription adequacy of lipid-lowering therapies for primary prevention . Trial registration Clinical Trials.gov Identifier : NCT01997671 . November 28 , 2013 The Justification for the Use of Statins in Primary Prevention : An Intervention Trial Evaluating Rosuvastatin ( JUPITER ) study was the first large-scale , prospect i ve study to examine the benefits of statin therapy in subjects with elevated levels of high-sensitivity C-reactive protein but with low-to-normal LDL-cholesterol levels , who were not qualified for lipid-lowering treatment according to the current guidelines for primary prevention . The JUPITER study aim ed to determine whether rosuvastatin 20 mg daily would reduce the rate of first major cardiovascular events , including cardiovascular death , nonfatal stroke , nonfatal myocardial infa rct ion , hospitalization for unstable angina or arterial revascularization .  Rosuvastatin reduced LDL-cholesterol levels by 50 % and high-sensitivity C-reactive protein by 37 % . Compared with placebo , the combined primary end point was reduced in 44 % ( p < 0.00001 ) , and total mortality in 20 % ( p = 0.02 ) . The trial confirmed the relationship between the rates of major cardiovascular events with both high-sensitivity C-reactive protein and LDL-cholesterol levels achieved after statin treatment . Interestingly , this was the first large , prospect i ve statin trial to show benefit in the reduction of venous thromboembolism ABSTRACT BACKGROUND Many individuals at higher risk for cardiovascular disease ( CVD ) do not receive recommended treatments . Prior interventions using personalized risk information to promote prevention did not test clinic-wide effectiveness . OBJECTIVE AND DESIGN To perform a 9-month cluster-r and omized trial , comparing a strategy of electronic health record-based identification of patients with increased CVD risk and individualized mailed outreach to usual care . PARTICIPANTS Patients of participating physicians with a Framingham Risk Score of at least 5 % , low-density lipoprotein (LDL)-cholesterol level above guideline threshold for drug treatment , and not prescribed a lipid-lowering medication were included in the intention-to-treat analysis .INTERVENTION Patients of physicians r and omized to the intervention group were mailed individualized CVD risk messages that described benefits of using a statin ( and controlling hypertension or quitting smoking when relevant).MAIN MEASURES The primary outcome was occurrence of a LDL-cholesterol level , repeated in routine practice , that was at least 30 mg/dl lower than prior . A secondary outcome was lipid-lowering drug prescribing . Clinical trials.gov identifier : NCT01286311.KEY RESULTS Fourteen physicians with 218 patients were r and omized to intervention , and 15 physicians with 217 patients to control . The mean patient age was 60.7 years and 77 % were male . There was no difference in the primary outcome ( 11.0 % vs. 11.1 % , OR 0.99 , 95 % CI 0.56–1.74 , P = 0.96 ) , but intervention group patients were twice as likely to receive a prescription for lipid-lowering medication ( 11.9 % , vs. 6.0 % , OR 2.13 , 95 % CI 1.05–4.32 , p = 0.038 ) . In post hoc analysis with extended follow-up to 18 months , the primary outcome occurred more often in the intervention group ( 22.5 % vs. 16.1 % , OR 1.59 , 95 % CI 1.05–2.41 , P = 0.029 ) . CONCLUSIONS In this effectiveness trial , individualized mailed CVD risk messages increased the frequency of new lipid-lowering drug prescriptions , but we observed no difference in proportions lowering LDL-cholesterol after 9 months . With longer follow-up , the intervention ’s effect on LDL-cholesterol levels was apparent Context While the benefits of statins in the primary and secondary prevention of coronary artery disease are clear , the value of statin therapy in acute coronary syndromes is uncertain . Contribution Analyzing data from a large , international observational study of acute coronary syndromes , these investigators identified associations between statin use before and during acute coronary events and favorable outcomes . Caution s While these data suggest a potential benefit of statins during acute coronary events , trials are necessary to determine the most appropriate use of statins in the treatment of acute coronary events . The Editors Data from r and omized clinical trials support the efficacy of lipid-lowering medications , particularly statins , in the primary and secondary prevention of coronary artery disease ( 1 - 3 ) . The benefits of statins , however , were not readily apparent until after several months of therapy , suggesting that the drugs ' lipid-lowering capabilities were largely responsible . In vitro work has suggested that statins may have an abundance of pleiotropic effects ( 4 ) . These include modulation of inflammation , inhibition of platelet function and thrombosis , and enhancement of endothelial cell function . The demonstrated ability of statins to immediately affect basic pathophysiologic mechanisms has result ed in increased interest in their potential role in the setting of acute coronary syndromes . The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering ( MIRACL ) trial found that early treatment with high-dose atorvastatin modestly reduced event rates of recurrent ischemia in statin-naive patients presenting with an acute coronary syndrome ( 5 ) . These observations , while intriguing , did not conclusively establish the role of statins in patients with acute coronary syndromes . In the MIRACL trial , the failure of statins to significantly affect more concrete trial end points ( for example , death or recurrent myocardial infa rct ion [ MI ] ) was disappointing . Whether this reflected a true lack of physiologic impact of early statin treatment or merely indicated that the study was underpowered to detect differences in these end points remains unclear . In a sub study using data from the Platelet Receptor Inhibition for Ischemic Syndrome Management ( PRISM ) trial in patients with acute coronary syndromes , patients already taking statins  had better short-term outcomes ( decreased risk for death or nonfatal MI ) than those not previously receiving statin therapy , unless statin therapy was discontinued in the hospital ( 6 ) . Initiation of statin therapy after the onset of an acute coronary syndrome appeared to be less effective than treatment with statins before symptom onset . Using data from the Global Registry of Acute Coronary Events ( GRACE ) project , a large , multinational , observational study of patients with acute coronary syndromes , we examined the association between previous statin therapy  , presentation characteristics of acute coronary syndromes , and hospital outcomes . We also examined the effect of early in-hospital statin therapy ( or withdrawal of statins ) on important hospital outcomes , including death or the development of recurrent MI or stroke . Methods Full details of the GRACE rationale and methods have been published elsewhere and are outlined below ( 7 - 9 ) . Site Selection The GRACE project is design ed to reflect an unbiased population of patients with acute coronary syndromes , regardless of geographic region . Currently , 94 hospitals located in 14 countries ( Argentina , Australia , Austria , Belgium , Brazil , Canada , France , Germany , Italy , New Zeal and , Pol and , Spain , the United Kingdom , and the United States ) are participating in this observational study . Patients entered in the registry must be at least 18 years of age and alive at the time of hospital presentation ; be admitted with an acute coronary syndrome as a presumptive diagnosis ( that is , have symptoms consistent with acute ischemia ) ; and have at least 1 of the following : electrocardiographic changes consistent with an acute coronary syndrome , serial increases in serum biochemical markers of cardiac necrosis , or documentation of coronary artery disease ( 7 - 9 ) . The qualifying acute coronary syndrome must not be precipitated by a significant noncardiovascular comorbid condition ( for example , trauma or surgery ) . To ensure the enrollment of an unbiased sample , the first 10 to 20 consecutive patients ( depending on each site 's patient volume ) are recruited from each site on a monthly basis . Where required , study investigators received approval from their local hospital ethics or institutional review board . Data Collection At each site , a trained coordinator collected data using a st and ardized case-report form . Data on demographic characteristics , medical history , presenting symptoms , duration of prehospital delay , biochemical and electrocardiographic findings , treatment practice s , and hospital outcome were collected . St and ardized definitions of all patient-related variables and clinical diagnoses were used . All cases were assigned to 1 of the following categories : ST-segment elevation MI , nonST-segment elevation MI , unstable angina , and other cardiac or noncardiac diagnoses that have been previously described ( 7 - 9 ) . St and ardized definitions were also used for selected hospital complications and outcomes . Patient Sample For the current study , patients who were subsequently found to have noncardiac or other cardiac ( nonacute coronary syndrome ) primary diagnoses and those who transferred into or out of GRACE registry hospitals were excluded from further consideration . Treatments defined as previous use were those taken by the patient on a long-term basis at home and within 7 days of the presenting event , based on the review of information contained in medical records and abstract ed by trained study physicians and nurses . Treatments received in the hospital ( within the first 24 hours or thereafter ) were categorized as within hospital . Agents prescribed for use after discharge from participating hospitals were categorized as at discharge . Patient treatment categories were defined according to the following groupings : no previous treatment with statins and no treatment with statins during hospitalization , no previous therapy with statins but statin therapy  instituted during hospitalization , previous therapy with statins and statin therapy continued during hospitalization , and previous  therapy with statins but statin therapy not continued during the index hospitalization . Statistical Analysis We used the chi-square tests for discrete variables to analyze differences in demographic and clinical characteristics , treatment practice s , clinical presentation ( ST-segment elevation vs. nonST-segment elevation , large infa rct [ creatine phosphokinase level > 2 times the upper limit of normal ] vs. small infa rct ) , subsequent diagnosis ( ST-segment elevation MI , nonST-segment elevation MI , unstable angina ) , and hospital complications ( death , congestive heart failure or pulmonary edema , cardiogenic shock , stroke , ventricular tachycardia or ventricular fibrillation , and cardiac arrest ) in relation to statin use . The Wilcoxon rank-sum test was used to analyze differences between respective comparison groups for continuous variables . While controlling for potentially confounding variables , we performed multivariate regression analyses to examine the association between previous statin therapy and hospital presentation ( ST-segment elevation vs. no ST-segment elevation , creatine phosphokinase level 2 times normal vs. creatine phosphokinase level < 2 times the upper limit of normal ) , as well as any association between previous or in-hospital statin therapy and hospital outcomes ( death , recurrent MI or MI after 24 hours , and stroke ) or a composite end point of all 3 outcomes . C and i date variables for inclusion in the regression models evaluating previous statin use and hospital presentation included patient age , sex , smoking status , diabetes , history of vascular disease ( previous MI , stroke , positive angiogram , peripheral vascular disease , percutaneous coronary intervention , or coronary artery bypass graft surgery ) , hypertension , hyperlipidemia , and previous therapies ( aspirin , angiotensin-converting enzyme [ ACE ] inhibitors , -blockers , and other lipid-lowering agents ) . C and i date variables for regression models evaluating previous or in-hospital statin use and hospital outcomes included all of the previously listed characteristics plus characteristics present at the time of hospital admission ( heart rate , systolic blood pressure , Killip class , ST-segment elevation or left bundle-branch block pattern , and positive cardiac enzymes ) and receipt of in-hospital therapies ( aspirin and other antiplatelet agents , -blockers , unfractionated heparin , low-molecular-weight heparin , glycoprotein IIb/IIIa inhibitors , cardiac catheterization , percutaneous coronary intervention , or coronary artery bypass graft surgery ) . C and i date variables possibly associated with the outcomes of interest ( P < 0.25 after univariate analysis ) were included in the multivariate models . Variables for which the P value exceeded 0.05 were eliminated in a stepwise fashion so that only those that had a statistically significant association with the outcome of interest were included in the final regression models . Because of their clinical relevance and potential importance , age , sex , and history of hyperlipidemia were retained in the final multivariable models for clinical outcomes regardless of statistical significance . Final models were evaluated for goodness of fit by the HosmerLemeshow test . Because between-hospital variation in use of statin treatment could be considerable and potentially affect our study results , we adjusted for hospital r and om effects on the observed outcomes . We used a generalized estimating equation modeling technique , assuming patients were repeated measures within each hospital . Variable Background Pharmacogenetic research has shown that genetic variation may influence statin responsiveness . Statins exert a variety of beneficial effects beyond lipid lowering , including antithrombotic effects , which contribute to the risk reduction of cardiovascular disease . Statins have been shown to influence the expression of coagulation factors II , V , VII , XII and XIII . Aim Data from a large r and omized clinical trial of pravastatin , design ed to show efficacy relative to usual care , were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II , V , VII , XII and XIII is associated with reduced fatal coronary heart disease ( CHD ) and nonfatal myocardial infa rct ion , combined CHD and all-cause mortality . Methods The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial . The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants r and omly assigned to pravastatin or to usual care .  The efficacy of pravastatin in reducing risk of all-cause mortality , CHD and nonfatal myocardial infa rct ion and combined CHD , was compared among genotype strata by examining an interaction term in a proportional hazards model . Results None of the polymorphisms were associated with the clinical outcomes . For the F7 ( –323 ) ins/del polymorphism there was no interaction with pravastatin for either outcome . For both the F5 Arg506Gln G > A ( rs6025 ) polymorphism and F7 Arg353Gln G > A ( rs6046 ) polymorphism there were no interactions with pravastatin in relation to all-cause mortality , but there were significant interactions with combined CHD [ interaction hazard ratio = 1.33 , 95 % confidence interval ( 1.01–1.76 ) and interaction hazard ratio = 1.92 , 95 % confidence interval ( 1.00–3.65 ) , respectively ] . There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome . Conclusion Polymorphisms in anticoagulation genes ( F5 and F7 ) seem to modify the efficacy of  pravastatin in reducing risk of cardiovascular events Primary care facilities may be a natural setting for delivering interventions that focus on behaviors that improve cardiovascular disease ( CVD ) risk factors . The purpose of this study was to examine the 24-month effects of the Activity Counseling Trial ( ACT ) on CVD risk factors , to examine whether changes in CVD risk factors differed according to baseline risk factor status , and to examine whether changes in fitness were associated with changes in CVD risk factors . ACT was a 24-month multicenter r and omized controlled trial to increase physical activity .  Participants were 874 inactive men and women aged 35–74 years . Participants were r and omly assigned to one of three arms that varied by level of counseling , intensity , and re source requirements . Because there were no significant differences in change over time between arms on any of the CVD risk factors examined , all arms were combined , and the effects of time , independent of arm , were examined separately for men and women . Time × Baseline risk factor status interactions examined whether changes in CVD risk factors differed according to baseline risk factor status . Significant improvements in total cholesterol , high-density lipoprotein cholesterol ( HDL-C ) and low-density lipoprotein cholesterol , the ratio of total cholesterol to HDL-C , and triglycerides were seen in both men and women who had high ( or low for HDL-C ) baseline levels of risk factors , whereas significant improvements in diastolic blood pressure were seen only in those men with high baseline levels . There were no improvements in any risk factors among participants with normal baseline levels . Changes in fitness were associated with changes in a number of CVD risk factors . However , most relationships disappeared after controlling for changes in body weight . Improvements in lipids from the ACT interventions could reduce the risk of coronary heart disease in people with already high levels of lipids by 16%–26 % in men and 11%–16 % in women . Interventions that can be implemented in health care setting s nationwide and result in meaningful population -wide changes in CVD risk factors are needed . The ACT physical activity interventions produced substantial improvements among men and women with elevated CVD risk factors 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 reduce the incidence of cardiovascular events in patients with acute myocardial infa rct ion ( AMI ) . Although all statins are equally effective in secondary prevention , there might be certain differences in the effects of lipophilic and hydrophilic statins . Therefore , our aim is to compare the effectiveness of lipophilic atorvastatin and hydrophilic pravastatin in secondary prevention after AMI . METHODS AND RESULTS This study is a prospect i ve , r and omized , open-label , multicenter study of 500 patients with AMI . Patients that have undergone successful percutaneous coronary intervention will be r and omly allocated to receive either atorvastatin or pravastatin with the treatment goal of lowering their low-density lipoprotein-cholesterol level below 100 mg/dl for 2 years . The primary endpoint will be death due to any cause , nonfatal MI , nonfatal stroke , unstable angina , or congestive heart failure requiring hospital admission , or any type of coronary revascularization . CONCLUSION This is the first multicenter trial to compare the effects and safety of lipophilic and hydrophilic statin therapy in Japanese patients with AMI . It addresses an important issue and could influence the use of statin treatment in the secondary prevention of coronary artery disease 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 OBJECTIVES The purpose of this study was to determine if statins ( hydroxymethylglutaryl CoA reductase inhibitors [ HMG-CoA ] ) , angiotensin-converting enzyme ( ACE ) inhibitors , and angiotensin receptor blockers ( ARBs ) reduce cardiovascular ( CV ) events and pulmonary morbidity in chronic obstructive pulmonary disease ( COPD ) patients . BACKGROUND Few current COPD therapies alter prognosis . Although statins , ACE inhibitors , and ARBs improve outcomes in CV population s , their benefits in COPD patients both with and without concomitant heart disease has not previously been studied . METHODS A time-matched nested case-control study of two population -based retrospective cohorts was undertaken : 1 ) COPD patients having undergone coronary revascularization ( high CV risk cohort ) ; and 2 ) COPD patients without previous myocardial infa rct ion ( MI ) and newly treated with nonsteroidal anti-inflammatory drugs ( low CV risk cohort ) . Prespecified outcomes were COPD hospitalization , MI , and total mortality . RESULTS These drugs reduced both CV and pulmonary outcomes , with the largest benefits occurring with the combination of statins and either ACE inhibitors or ARBs . This combination was associated with a reduction in COPD hospitalization ( risk ratio [ RR ] 0.66 , 95 % confidence interval [ CI ] 0.51 to 0.85 ) and total mortality ( RR 0.42 , 95 % CI 0.33 to 0.52 ) not only in the high CV risk cohort but also in the low CV risk cohort ( RR 0.77 , 95 % CI 0.67 to 0.87 , and RR 0.36 , 95 % CI 0.28 to 0.45 , respectively ) . The combination also reduced MI in the high CV risk cohort ( RR 0.39 , 95 % CI 0.31 to 0.49 ) . Benefits were similar when steroid users were included . CONCLUSIONS These agents may have dual cardiopulmonary protective properties , thereby substantially altering prognosis of patients with COPD . These findings need confirmation in r and omized clinical trials BACKGROUND In view of evidence that statin therapy increases risk of diabetes , the balance of benefit and risk of these drugs in primary prevention has become controversial . We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use . METHODS In the r and omised , double-blind JUPITER trial , 17,603 men and women without previous cardiovascular disease or diabetes were r and omly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint ( myocardial infa rct ion , stroke , admission to hospital for unstable angina , arterial revascularisation , or cardiovascular death ) and the protocol -prespecified secondary endpoints of venous thromboembolism , all-cause mortality , and incident physician-reported diabetes . In this analysis , participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes : metabolic syndrome , impaired fasting glucose , body-mass index 30 kg/m(2 ) or higher , or glycated haemoglobin A(1c ) greater than 6 % . The trial is registered at Clinical Trials.gov , NCT00239681 . FINDINGS Trial participants with one or more major diabetes risk factor ( n=11,508 ) were at higher risk of developing diabetes than were those without a major risk factor ( n=6095 ) . In individuals with one or more risk factors , statin allocation was associated with a 39 % reduction in the primary endpoint ( hazard ratio [ HR ] 0·61 , 95 % CI 0·47 - 0·79 , p=0·0001 ) , a 36 % reduction in venous thromboembolism ( 0·64 , 0·39 - 1·06 , p=0·08 ) , a 17 % reduction in total mortality ( 0·83 , 0·64 - 1·07 , p=0·15 ) , and a 28 % increase in diabetes ( 1·28 , 1·07 - 1·54 , p=0·01 ) . Thus , for those with diabetes risk factors , a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed . For trial participants with no major diabetes risk factors  , statin allocation was associated with a 52 % reduction in the primary endpoint ( HR 0·48 , 95 % CI 0·33 - 0·68 , p=0·0001 ) , a 53 % reduction in venous thromboembolism ( 0·47 , 0·21 - 1·03 , p=0·05 ) , a 22 % reduction in total mortality ( 0·78 , 0·59 - 1·03 , p=0·08 ) , and no increase in diabetes ( 0·99 , 0·45 - 2·21 , p=0·99 ) . For such individuals , a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed . In analysis limited to the 486 participants who developed diabetes during follow-up ( 270 on rosuvastatin vs 216 on placebo ; HR 1·25 , 95 % CI 1·05 - 1·49 , p=0·01 ) , the point estimate of cardiovascular risk reduction  associated with statin therapy ( HR 0·63 , 95 % CI 0·25 - 1·60 ) was consistent with that for the trial as a whole ( 0·56 , 0·46 - 0·69 ) . By comparison with placebo , statins  accelerated the average time to diagnosis of diabetes by 5·4 weeks ( 84·3 [ SD 47·8 ] weeks on rosuvastatin vs 89·7 [ 50·4 ] weeks on placebo ) . INTERPRETATION In the JUPITER primary prevention trial , the cardiovascular and mortality benefits  of statin therapy exceed the diabetes hazard , including in participants at high risk of developing diabetes . FUNDING AstraZeneca STUDY OBJECTIVE To evaluate whether a simple pharmacist protocol , consisting of patient screening and cardiovascular risk stratification , identification and reminders about uncontrolled risk factors , and drug adherence support , can significantly reduce cardiovascular risk . DESIGN Prospect i ve , r and omized , controlled pilot study . SETTING Large primary care medical clinic in Saskatoon , Saskatchewan , Canada . PATIENTS One hundred seventy-six adult patients ( mean age 60 yrs ) who exhibited a 10-year Framingham risk score of 15 % or greater , or a coronary artery disease risk equivalent ( coronary artery disease , peripheral artery disease , cerebrovascular disease , or diabetes mellitus ) . INTERVENTION Eligible patients initially met with the pharmacist to receive general counselling about cardiovascular disease and were then r and omly assigned to receive ongoing follow-up by the pharmacist ( follow-up group [ 88 patients ] ) or to return to usual care ( single-contact group [ 88 patients ] ) for a minimum of 6 months . MEASUREMENTS AND MAIN RESULTS The primary end point was mean reduction in the 10-year Framingham risk score . Secondary end points included individual modifiable risk factors ( systolic and diastolic blood pressures ; total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol [ HDL ] , and triglyceride levels ; total cholesterol : HDL ratio ; and hemoglobin A(1c ) value ) , as well as statin utilization , initiation , and adherence rates . Baseline characteristics were similar across both groups . Neither the mean reduction in 10-year risk ( -2.68 for the follow-up group and -1.25 for the single-contact group , one-tailed p=0.098 ) nor individual risk factors were significantly different between groups . The proportion of patients exhibiting statin adherence of 80 % or greater did not significantly differ between groups at study end ( 73.1 % [ 57/78 ] and 80.0 % [ 52/65 ] , respectively , p=0.333 ) . However , 85.2 % ( 75/88 ) in the follow-up group continued with statin therapy at the end of the study compared with 67.0 % ( 59/88 ) in the single-contact group ( p=0.005 ) . Statin initiations were more frequent in the follow-up group than in the single-contact group ( 75.0 % [ 30/40 ) vs 48.9 % [ 22/45 ] , p=0.013 ) . CONCLUSION This simple cardiovascular care protocol for nonspecialist pharmacists did not result in a clear improvement to cardiovascular risk reduction success among patients in a primary care medical clinic . The intervention did , however , appear to improve statin utilization Although the beneficial effect of statins in secondary prevention of cardiac events is well established , their effectiveness in primary prevention is question able when most evidence derives from r and omized controlled trials and not " real-life " data . To evaluate the association between persistent use of statins and risk of acute nonfatal cardiovascular events  in primary prevention patients in community setting s , we retrospectively analyzed a cohort of 171,535 adults 45 to 75 years old with no indication of cardiovascular disease who began statin therapy from 1998 to 2009 in a large health maintenance organization in Israel . Persistence with statins was measured by the proportion of days covered with dispensed prescriptions of statins during the follow-up period . Main outcome measurements were occurrence of myocardial infa rct ion or performance of a cardiac revascularization procedure . Incidence of acute cardiovascular events during the follow-up period ( 993,519 person-years ) was 10.22 per 1,000 person-years . Persistence with statins was associated with a lower risk of incident cardiac events ( p for trend < 0.01 ) . The most persistent users ( covered with statins for ≥80 % of their follow-up time ) had a hazard ratio of 0.58 ( 95 % confidence interval 0.55 to 0.62 ) compared to nonpersistent users ( proportion of days covered < 20 % ) . Similar results were found when analyses were limited to patients with > 5 years of follow-up . Treatment with high efficacy statins was associated with a lower risk of cardiac events . In conclusion , our large and unselected community-based study supports the results of r and omized controlled trials regarding the beneficial effect of statins in the primary prevention of acute cardiac events 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
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 .