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A medication adherence and persistence comparison of hypertensive patients treated with single-, double- and triple-pill combination therapy Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2018 EXECUTIVE SUMMARY. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2019 EXECUTIVE SUMMARY. Combining Multiple Approaches for the Secondary Prevention of Vascular Events After Stroke: A Quantitative Modeling Study Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. 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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 [ BACKGROUND Cardiovascular disease ( CVD ) is the leading cause of death , and principal reason for the large difference in life expectancy between indigenous Māori and the non-indigenous population in New Zeal and . CVD guidelines recommend that people who are at high risk or who have had previous CVD should be offered aspirin , blood pressure lowering and lipid lowering therapies . However , prescribing and adherence rates are low and CVD events remain high . AIM To assess whether a medication strategy using a fixed dose combination pill ( ' polypill ' ) could improve prescribing and adherence to recommended medications , lower blood pressure and improve lipids compared with current care over 12 months . METHODS IMProving Adherence using Combination Therapy ( IMPACT ) is an open-label r and omised controlled trial comparing a once-daily polypill containing four preventive medications with usual care .  Six hundred participants who have had previous CVD events or are at high risk of CVD will be enrolled , including 300 Māori . Participants are identified , enrolled and prescribed either the polypill or current medications at their usual primary health care practice , with medications ( including the polypill ) dispensed through local community pharmacies . The polypill contains 75 mg aspirin , 40 mg simvastatin , 10 mg lisinopril and either 12.5 mg hydrochlorothiazide or 50 mg atenolol . Primary outcomes are adherence to guidelines -recommended medications and changes in systolic blood pressure and low density lipoprotein at 12 months . Secondary outcomes include other lipids , medication dispensing , barriers to adherence , CVD and other serious adverse events , quality of life and prescriber acceptability . The trial is registered with the Australian New Zeal and Clinical Trial Registry ( ACTRN12606000067572 ) BACKGROUND Accurate risk assessment of atherosclerotic cardiovascular disease ( ASCVD ) is essential to effectively balance the risks and benefits of therapy for primary prevention . OBJECTIVE To compare the calibration and discrimination of the new American Heart Association ( AHA ) and American College of Cardiology ( ACC ) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score . DESIGN Prospect i ve epidemiologic study of ASCVD . SETTING MESA ( Multi-Ethnic Study of Atherosclerosis ) , a community-based , sex-balanced , multiethnic cohort . PATIENTS 4227 MESA participants aged 50 to 74 years and without diabetes at baseline . MEASUREMENTS Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores- and their respective end points-in MESA after a 10.2-year follow-up . RESULTS The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37 % to 154 % in men and 8 % to 67 % in women . Overestimation was noted throughout the continuum of risk . In contrast , the Reynolds Risk Score overestimated risk by 9 % in men but underestimated risk by 21 % in women .  Aspirin , lipid-lowering or antihypertensive therapy  , and  interim revascularization  did not explain the overestimation . LIMITATION Comparability of MESA with target population s for primary prevention and possibility of missed events in MESA . CONCLUSION Of the 5 risk scores , 4 , including the new AHA-ACC-ASCVD score , showed overestimation of risk ( 25 % to 115 % ) in a modern , multiethnic cohort without baseline clinical ASCVD . If vali date d , overestimation of ASCVD risk may have substantial implication s for individual patients and the health care system . PRIMARY FUNDING SOURCE National Heart , Lung , and Blood Institute Purpose of review To review the risk of cardiovascular complications in HIV-infected patients receiving combination antiretroviral treatment .  Recent findings Recent data suggest that patients with chronic HIV infection will require continuous lifelong combination antiretroviral treatment , which may increase the risk of cardiovascular disease in all population s by substantial amounts . Simple , safe and effective interventions to reduce cardiovascular complications in HIV-infected patients will be required . Studies in the general population suggest that the primary prevention of cardiovascular disease with a pill combining blood-pressure-lowering , cholesterol-lowering and antiplatelet treatments ( a polypill ) might decrease cardiovascular events . An HIV polypill study with 8000 HIV-infected patients with a moderate risk of cardiovascular disease r and omized to either a polypill of low-dose pravastatin , aspirin , hydrochlorothiazide and lisinopril or to placebo is described . The primary clinical endpoint would be a composite of cardiovascular mortality , non-fatal myocardial infa rct ion and stroke .  A vanguard study of 400 patients could assess changes in cholesterol , blood pressure and other risk factors . The clinical endpoint study described would have 80 % power to detect a 23 % reduction in the rate of cardiovascular events in the polypill arm . Summary A study of a polypill like that proposed for the general population will provide crucial information on the risks and benefits of primary cardiovascular prevention in HIV-infected patients Importance Recent guidelines have recommended nonfasting for routine testing of lipid levels based on comparisons of nonfasting and fasting population s. However , no previous study has examined the association of cardiovascular outcomes with fasting vs nonfasting lipid levels measured in the same individuals . Objective To compare the association of nonfasting and fasting lipid levels with prospect ively ascertained coronary and vascular outcomes and to evaluate whether a strategy of using nonfasting instead of fasting lipid level measurement would result in misclassification of risk for individuals undergoing evaluation for initiation of statin therapy . Design , Setting , and Participants This post hoc prospect i ve follow-up of a r and omized clinical trial included 8270 of 10 305 participants from the Anglo-Sc and inavian Cardiac Outcomes Trial-Lipid Lowering Arm ( ASCOT-LLA ) with nonfasting and fasting lipid levels measured 4 weeks apart ( including 6855 participants with no prior vascular disease ) ( median follow-up , 3.3 years ; interquartile range , 2.8 - 3.6 years ) . Data were collected from February 1 , 1998 , to December 31 , 2002 , and analyzed from February 1 , 2016 , to November 30 , 2018 . Multivariable Cox models , adjusted for cardiovascular risk factors , were calculated for 40-mg/dL ( 1-mmol/L ) higher values of nonfasting and fasting lipids . Main Outcomes and Measures The trial 's primary end point consisted of major coronary events ( nonfatal myocardial infa rct ion [ MI ] and fatal coronary heart disease [ 212 events ] ) . Secondary analyses examined atherosclerotic cardiovascular disease ( ASCVD ) events ( including MI , stroke , and ASCVD death [ 351 events ] ) . Results Among the 8270 participants ( 82.1 % male ; mean [ SD ] age , 63.4 [ 8.5 ] years ) , nonfasting sample s had modestly higher triglyceride levels and similar cholesterol levels compared to fasting sample s. Associations of  nonfasting lipid levels with coronary events were similar to those for fasting lipid levels . For example , adjusted hazard ratios ( HRs ) per 40-mg/dL of low-density lipoprotein cholesterol were 1.32 ( 95 % CI , 1.08 - 1.61 ; P = .007 ) for nonfasting levels and 1.28 ( 95 % CI , 1.07 - 1.55 ; P = .008 ) for fasting levels . For the primary prevention group , adjusted HRs were 1.42 ( 95 % CI , 1.13 - 1.78 ; P = .003 ) for nonfasting levels and 1.37 ( 95 % CI , 1.11 - 1.69 ; P = .003 ) for fasting levels . Results were consistent by r and omized treatment arm ( atorvastatin calcium , 10 mg/d , or placebo ) and similar for ASCVD events . Concordance of fasting and nonfasting lipid levels for classifying participants into appropriate ASCVD risk categories was high ( 94.8 % ) . Conclusions and Relevance Measurement of nonfasting and fasting lipid levels yields similar results in the same individuals for association with incident coronary and ASCVD events . These results suggest that routine measurement of nonfasting lipid levels may help facilitate ASCVD risk screening and treatment , including consideration of when to initiate statin therapy Background The complexity of treatment regimens , costs and pill burden decrease the medication adherence and contribute to shortfall in cardiovascular preventive drug coverage . The polypill , a fixed dose combination pill of established drugs , is expected to increase adherence and reduce the costs whilst preventing major cardiovascular events ( MCVE ) . Design and methods The PolyIran trial is a pragmatic cluster r and omized trial nested within the Golestan Cohort Study ( GCS ) . Subjects were r and omized to either non-pharmacological preventive interventions alone ( minimal care arm ) or together with a polypill ( polypill arm ) comprising hydrochlorothiazide , aspirin , atorvastatin and either enalapril or valsartan . This study benefits from the infrastructure of the primary health care system in Iran and the interventions are delivered by the local auxiliary health workers ( Behvarz ) to the participants . The primary outcome of the study is the occurrence of first MCVE within five years defined as non-fatal and fatal myocardial infa rct ion , unstable angina , sudden death , heart failure , coronary artery revascularization procedures , and non-fatal and fatal stroke . Trial status From February 2011 to April 2013 , 8410 individuals ( 236 clusters ) attended the eligibility assessment . Of those , 3421 in the polypill arm and 3417 in the minimal care arm were eligible . The study is ongoing . Conclusion The infrastructure of GCS and the primary health care system in Iran enabled the conduct of this pragmatic large-scale trial . If the polypill strategy proves effective , it may be implemented to prevent cardiovascular disease in developing countries Aims To evaluate the 2013 American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease ( ASCVD ) risk score among four different race/ethnic groups and to ascertain which factors are most associated with risk overestimation by the AHA-ACC-ASCVD score . Methods and results The Multi-Ethnic Study of Atherosclerosis ( MESA ) , a prospect i ve community-based cohort , was used to examine calibration and discrimination of the AHA-ACC-ASCVD risk score in 6441 White , Black , Chinese , and Hispanic Americans ( aged 45 - 79 years and free of known ASCVD at baseline ) . Using univariable and multivariable absolute risk regression , we modelled the impact of individual risk factors on the discordance between observed and predicted 10-year ASCVD risk . Overestimation was observed in all race/ethnic groups in MESA and was highest among Chinese ( 252 % for women and 314 % for men ) and lowest in White women ( 72 % ) and Hispanic men ( 67 % ) . Higher age , Chinese race/ethnicity ( when compared with White ) , systolic blood pressure ( treated and untreated ) , diabetes , alcohol use , exercise , lipid-lowering medication , and aspirin use were all associated with more risk overestimation , whereas family history was associated with less risk overestimation in a multivariable model ( all P < 0.05 ) . Conclusion The AHA-ACC-ASCVD risk score overestimates ASCVD risk among men , women , and all four race/ethnic groups evaluated in a modern American primary prevention cohort . Clinicians treating patients similar to those in MESA , particularly older individuals and those with factors associated with more risk overestimation , may consider interpreting absolute ASCVD risk estimates with caution The use of preventive medications in people at high risk of cardiovascular disease is conceptually straightforward , yet in practice the adoption of such measures is disappointingly low , plus there is wide international variation in preventive therapies . Several barriers might explain this shortfall and variation , but the simplicity and economy of a polypill-based strategy might overcome some barriers . The ‘ Use of a Multidrug Pill In Reducing cardiovascular Events ’ ( UMPIRE ) trial assesses whether a polypill strategy ( by combining aspirin , a statin and two blood pressure lowering agents ) would improve adherence to guideline -indicated therapies and would lower both blood pressure and cholesterol , in people with established cardiovascular disease . UMPIRE , running in India and three European countries ( Engl and , Irel and and the Netherl and s ) , is an open , r and omised , controlled trial design ed to include 1000 participants in India and 1000 in Europe , with a followup of 12–24 months . Participants were r and omised to one of two versions of the polypill or relegated to usual care . The primary study outcomes were the self-reported use of aspirin , a statin and at least two blood pressure lowering agents ; as well as changes in blood pressure and cholesterol . Secondary outcomes included : any cardiovascular events , reasons for stopping medications , serious adverse events and perceived changes in quality of life . Interpretation of the study data will be enhanced by health , economic and process-related evaluations . UMPIRE is registered with the European Clinical Trials data base , as EudraCT : 2009 - 016278 - 34 and the Clinical Trials Registry , India as CTRI/2010/091/000250 . The trial was part of the ‘ Single Pill Against Cardiovascular Events ( SPACE ) ’ collaboration , which encompasses the ‘ IMProving Adherence using Combination Therapy ( IMPACT ) ’ and ‘ Kanyini Guidelines Adherence with the Polypill ( Kanyini-GAP ) ’ trials Objective Although many epidemiological studies have suggested that increased serum uric acid levels are a risk factor for mortality , this relationship remains uncertain . This cohort study examined the effects of serum uric acid level on death from cancer , atherosclerotic cardiovascular disease ( ASCVD ) or all causes in men . Method A 9-year , prospect i ve cohort study was carried out with 22 698 Korean men , aged 30 to 77 years , who received health insurance from the National Health Insurance Corporation and who underwent biennial , secondary medical evaluations in 1992–1996 . The main outcome measures were death from cancer , ASCVD or all causes , compared by quintiles of serum uric acid level . At baseline , the mean ( SD ) level of serum uric acid was 354.4 ( 98.1 ) μmol/l . Results During 199 746 person-years of follow-up , there were 387 cancer deaths , 323 ASCVD ( 99 ischaemic heart disease , 192 stroke ) deaths and 1625 all-cause deaths . In multivariate Cox proportional hazards models , having controlled for age , current smoking , diabetes , hypertension and hypercholesterolaemia , uric acid levels were not associated with mortality from cancer , ASCVD or all causes . However , for those with diabetes , uric acid levels were associated with mortality from all causes even after full adjustment of the covariates . When the interaction term was included in the multivariate model , there was significant interactive effect of uric acid with diabetes ( RR = 1.26 , 95 % confidence interval 1.02–1.55 ) on the risk of all cause of death , whereas the effects of uric acid itself did not attain significance . Conclusion These findings indicate that uric acid level is not an independent risk factor for death from cancer , ASCVD or all causes OBJECTIVES The purpose of this study was to determine the prognostic accuracy of electron beam computed tomographic ( CT ) scanning of the coronary arteries and the relationship of coronary calcification to st and ard coronary disease risk factors and C-reactive protein ( CRP ) in the prediction of atherosclerotic cardiovascular disease ( ASCVD ) events in apparently healthy middle-age persons . BACKGROUND As a screening test for coronary artery disease ( CAD ) , electron beam CT scanning remains controversial . METHODS In a prospect i ve , population -based study , 4,903 asymptomatic persons age 50 to 70 years underwent  electron beam CT scanning of the coronary arteries . RESULTS At 4.3 years , follow-up was available in 4,613 participants ( 94 % ) , and 119 had sustained at least one ASCVD event . Subjects with ASCVD events had higher baseline coronary calcium scores ( median [ interquartile range ] , Agatston method ) than those without events : 384 ( 127 , 800 ) versus 10 ( 0 , 86 ) ( p < 0.0001 ) . For coronary calcium score threshold > or = 100 versus < 100 , relative risk ( 95 % confidence interval ) was 9.6 ( 6.7 to 13.9 ) for all ASCVD events , 11.1 ( 7.3 to 16.7 ) for all CAD events , and 9.2 ( 4.9 to 17.3 ) for non-fatal myocardial infa rct ion and death . The coronary calcium score predicted CAD events independently of st and ard risk factors and CRP ( p = 0.004 ) , was superior to the Framingham risk index in the prediction of events ( area under the receiver-operating characteristic curve of 0.79 + /- 0.03 vs. 0.69 + /- 0.03 , p = 0.0006 ) , and enhanced stratification of those falling into the Framingham categories of low , intermediate , and high risk ( p < 0.0001 ) . CONCLUSIONS The electron beam CT coronary calcium score predicts CAD events independent of st and ard risk factors , more accurately than st and ard risk factors and CRP , and refines Framingham risk stratification BACKGROUND Adherence to evidence -based cardiovascular ( CV ) medications after an acute myocardial infa rct ion ( MI ) is low after the first 6 months . The use of fixed-dose combinations ( FDC ) has been shown to improve treatment adherence and risk factor control . However , no previous r and omized trial has analyzed the impact of a polypill strategy on adherence in post-MI patients . OBJECTIVES The cross-sectional FOCUS ( Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention ) study ( Phase 1 ) aim ed to eluci date factors that interfere with appropriate adherence to CV medications for secondary prevention after an acute MI . Additionally , 695 patients from Phase 1 were r and omized into a controlled trial ( Phase 2 ) to test the effect of a polypill ( containing aspirin 100 mg , simvastatin 40 mg , and ramipril 2.5 , 5 , or 10 mg ) compared with the 3 drugs given separately on adherence , blood pressure , and low-density lipoprotein cholesterol , as well as safety and tolerability over a period of 9 months of follow-up . METHODS In Phase 1 , a 5-country cohort of 2,118 patients was analyzed . Patients were r and omized to either the polypill or 3 drugs separately for Phase 2 . Primary endpoint was adherence to the treatment measured at the final visit by the self-reported Morisky-Green question naire ( MAQ ) and pill count ( patients had to meet both criteria for adherence at the in-person visit to be considered adherent ) . RESULTS In Phase 1 , overall CV medication adherence , defined as an MAQ score of 20 , was 45.5 % . In a multivariable regression model , the risk of being nonadherent ( MAQ < 20 ) was associated with younger age , depression , being on a complex medication regimen , poorer health insurance coverage , and a lower level of social support , with consistent findings across countries . In Phase 2 , the polypill group showed improved adherence compared with the group receiving separate medications after 9 months of follow-up : 50.8 % versus 41 % ( p = 0.019 ; intention-to-treat population ) and 65.7 % versus 55.7 % ( p = 0.012 ; per protocol population ) when using the primary endpoint , attending the final visit with MAQ = 20 and high pill count ( 80 % to 110 % ) combined , to assess adherence . Adherence also was higher in the FDC group when measured by MAQ alone ( 68 % vs. 59 % , p = 0.049 ) . No treatment difference was found at follow-up in mean systolic blood pressure ( 129.6 mm Hg vs. 128.6 mm Hg ) , mean low-density lipoprotein cholesterol levels ( 89.9 mg/dl vs. 91.7 mg/dl ) , serious adverse events ( 23 vs. 21 ) , or death ( 1 , 0.3 % in each group ) . CONCLUSIONS For secondary prevention following acute MI , younger age , depression , and a complex drug treatment plan are associated with lower medication adherence . Meanwhile , adherence is increased in patients with higher insurance coverage levels and social support . Compared with the 3 drugs given separately , the use of a polypill strategy met the primary endpoint for adherence for secondary prevention following an acute MI . ( Fixed Dose Combination Drug [ Polypill ] for Secondary Cardiovascular Prevention [ FOCUS ] ; NCT01321255 ) 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 Objective To evaluate whether provision of fixed dose combination treatment improves adherence and risk factor control compared with usual care of patients at high risk of cardiovascular disease in primary care . Design Open label r and omised control trial : IMPACT ( IMProving Adherence using Combination Therapy ) . Setting 54 general practice s in the Auckl and and Waikato regions of New Zeal and , July 2010 to August 2013 . Participants 513 adults ( including 257 indigenous Māori ) at high risk of cardiovascular disease ( established cardiovascular disease or five year risk ≥15 % ) who were recommended for treatment with antiplatelet , statin , and two or more blood pressure lowering drugs . 497 ( 97 % ) completed 12 months ’ follow-up . Interventions Participants were r and omised to continued usual care or to fixed dose combination treatment ( with two versions available : aspirin 75 mg , simvastatin 40 mg , and lisinopril 10 mg with either atenolol 50 mg or hydrochlorothiazide 12.5 mg ) . All drugs in both treatment arms were prescribed by their usual general practitioners and dispensed by local community pharmacists . Main outcome measures Primary outcomes were self reported adherence to recommended drugs ( antiplatelet , statin , and two or more blood pressure lowering agents ) and mean change in blood pressure and low density lipoprotein cholesterol at 12 months . Results Adherence to all four recommended drugs was greater among fixed dose combination than usual care participants at 12 months ( 81 % v 46 % ; relative risk 1.75 , 95 % confidence interval 1.52 to 2.03 , P<0.001 ; number needed to treat 2.9 , 95 % confidence interval 2.3 to 3.7 ) . Adherence for each drug type at 12 months was high in both groups but especially in the fixed dose combination group : for antiplatelet treatment it was 93 % fixed dose combination v 83 % usual care ( P<0.001 ) , for statin 94 % v 89 % ( P=0.06 ) , for combination blood pressure lowering 89 % v 59 % ( P<0.001 ) , and for any blood pressure lowering 96 % v 91 % ( P=0.02 ) . Self reported adherence was highly concordant with dispensing data ( dispensing of all four recommended drugs 79 % fixed dose combination v 47 % usual care , relative risk 1.67 , 95 % confidence interval 1.44 to 1.93 , P<0.001 ) . There was no statistically significant improvement in risk factor control between the fixed dose combination and usual care groups over 12 months : the difference in systolic blood pressure was −2.2 mm Hg ( −4.5 v −2.3 , 95 % confidence interval −5.6 to 1.2 , P=0.21 ) , in diastolic blood pressure −1.2 mm Hg ( −2.1 v −0.9 , −3.2 to 0.8 , P=0.22 ) and in low density lipoprotein cholesterol −0.05 mmol/L ( −0.20 v −0.15 , −0.17 to 0.08 , P=0.46 ) . The number of participants with cardiovascular events or serious adverse events was similar in both treatment groups ( fixed dose combination 16 v usual care 18 ( P=0.73 ) , 99 v 93 ( P=0.56 ) , respectively ) . Fixed dose combination treatment was discontinued in 94 participants ( 37 % ) . The most commonly reported reason for discontinuation was a side effect ( 54/75 , 72 % ) . Overall , 89 % ( 227/256 ) of fixed dose combination participants ’ general practitioners completed a post-trial survey , and the fixed dose combination strategy was rated as satisfactory or very satisfactory for starting treatment ( 206/227 , 91 % ) , blood pressure control ( 180/220 , 82 % ) , cholesterol control ( 170/218 , 78 % ) , tolerability ( 181/223 , 81 % ) , and prescribing according to local guidelines ( 185/219 , 84 % ) . When participants were asked at 12 months how easy they found taking their prescribed drugs , most responded very easy or easy ( 224/246 , 91 % fixed dose combination v 212/246 , 86 % usual care , P=0.09 ) . At 12 months the change in other lipid fractions , difference in EuroQol-5D , and difference in barriers to adherence did not differ significantly between the treatment groups . Conclusions Among this well treated primary care  population  , fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance . Acceptability was high for both general practitioners and patients , although the discontinuation rate was high . Trial registration Australian New Zeal and Clinical Trial Registry ACTRN12606000067572 OBJECTIVES We sought to determine whether lipid-lowering therapy and antioxidants retard the progression of coronary calcification and prevent atherosclerotic cardiovascular disease ( ASCVD ) events . BACKGROUND The electron beam computed tomography-derived coronary calcium score predicts coronary disease events . Small , uncontrolled studies suggest that vigorous lipid-lowering therapy slows progression of coronary calcification and prevents coronary artery disease events , but controlled , scientific demonstration of these effects is lacking . METHODS We conducted a double-blind , placebo-controlled r and omized clinical trial of atorvastatin 20 mg daily , vitamin C 1 g daily , and vitamin E ( alpha-tocopherol ) 1,000 U daily , versus matching placebos in 1,005 asymptomatic , apparently healthy men and women age 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender . All study participants also received aspirin 81 mg daily . Mean duration of treatment was 4.3 years . RESULTS Treatment reduced total cholesterol by 26.5 % to 30.4 % ( p < 0.0001 ) , low-density lipoprotein cholesterol by 39.1 % to 43.4 % ( p < 0.0001 ) , and triglycerides by 11.2 % to 17.0 % ( p < or = 0.02 ) but had no effect ( p = 0.80 ) on progression of coronary calcium score ( Agatston method ) . Treatment also failed to significantly reduce the primary end point , a composite of all ASCVD events ( 6.9 % vs. 9.9 % , p = 0.08 ) . Event rates were related to baseline calcium score ( pre-specified analysis ) and may have been reduced in a subgroup of participants with baseline calcium score > 400 ( 8.7 % vs. 15.0 % , p = 0.046 [ not a pre-specified analysis ] ) . CONCLUSIONS Treatment with alpha-tocopherol , vitamin C , and low doses of atorvastatin ( 20 mg once daily ) did not affect the progression of coronary calcification . Treatment may have reduced ASCVD events , especially in subjects with calcium scores > 400 , but these effects did not achieve conventional levels of statistical significance OBJECTIVES The goal of this study was to determine whether the level of kidney function  is an independent risk factor for atherosclerotic cardiovascular disease ( ASCVD ) outcomes in the Atherosclerosis Risk in Communities ( ARIC ) study , a prospect i ve cohort study of subjects aged 45 to 64 years . BACKGROUND The level of kidney function is now recognized as a risk factor for ASCVD outcomes in patients at high risk for ASCVD , but it remains unknown whether the level of kidney function is a risk factor for ASCVD outcomes in the community . METHODS Cox proportional-hazards regression was used to evaluate the association of glomerular filtration rate ( GFR ) with ASCVD after adjustment for the major ASCVD risk factors in 15,350 subjects . We search ed for nonlinear relationships between GFR and ASCVD . RESULTS During a mean follow-up time of 6.2 years , 965 ( 6.3 % ) of subjects had ASCVD events . Subjects with GFR of 15 to 59 ml/min/1.73 m(2 ) ( n = 444 , hazard ratio 1.38 [ 1.02 , 1.87 ] ) and 60 to 89 ml/min/1.73 m(2 ) ( n = 7,665 , hazard ratio 1.16 [ 1.00 , 1.34 ] ) had an increased adjusted risk of ASCVD compared with subjects with GFR of 90 to 150 ml/min/1.73 m(2 ) . Each 10 ml/min/1.73 m(2 ) lower GFR was associated with an adjusted hazard ratio of 1.05 ( 1.02 , 1.09 ) , 1.07 ( 1.01 , 1.12 ) , and 1.06 ( 0.99 , 1.13 ) for ASCVD , de novo ASCVD , and recurrent ASCVD , respectively . A nonlinear model did not fit the data better than a linear model . CONCLUSIONS The level of GFR is an independent risk factor for ASCVD and de novo ASCVD in the ARIC study BACKGROUND Blood pressure shows an inverse association with mortality in patients with chronic kidney disease ( CKD ) on dialysis .  It is unclear if the same phenomenon exists in patients with CKD not yet on dialysis . METHODS We examined the association of  systolic ( SBP ) and diastolic ( DBP ) blood pressure  with  all-cause mortality  in a historical prospect i ve cohort of 860 patients ( age 68.1+/-10.1 years , 99.1 % male , 24.4 % black ) with estimated glomerular filtration rate ( GFR ) < 60 ml/min/1.73 m2 . We used Cox models to adjust for the effects of age , race , diabetes mellitus , atherosclerotic cardiovascular disease ( ASCVD ) , congestive heart failure , smoking , antihypertensive medications , body mass index , GFR , albumin , cholesterol , haemoglobin and proteinuria . To examine the role of comorbidities , we performed subgroup analyses based on prevalent ASCVD status and level of estimated GFR . RESULTS Higher SBP and higher DBP were both associated with lower mortality [ adjusted hazard ratio ( 95 % confidence interval ) for SBP 133 - 154 , 155 - 170 and > 170 mmHg , compared with < 133 mmHg , respectively : 0.61 ( 0.44 - 0.85 ) , 0.62 ( 0.45 - 0.87 ) and 0.68 ( 0.49 - 0.96 ) ; and for DBP 65 - 75 , 76 - 86 and > 86 mmHg , compared with < 65 mmHg : 0.85 ( 0.62 - 1.18 ) , 0.72 ( 0.52 - 1.00 ) and 0.60 ( 0.41 - 0.86 ) ] . The same association was present for both SBP and DBP only in subgroups with GFR < or = 30 ml/min/1.73 m2 and for DBP only in the subgroup with ASCVD . CONCLUSIONS Lower blood pressure is associated with higher mortality in patients with moderate to severe CKD , but interactions with kidney function and with ASCVD suggest that blood pressure may play a surrogate rather than a causative role in this association AIM Our objective was to investigate the effects and tolerability of fixed-dose combination therapy on blood pressure and LDL in adults without elevated blood pressure or lipid levels . METHODS This was a double-blind r and omised placebo-controlled trial in residents of Kalaleh , Golestan , Iran . Following an 8-week placebo run-in period , 475 participants , aged 50 to 79 years , without cardiovascular disease , hypertension or hyperlipidaemia were r and omised to fixed-dose combination therapy with aspirin 81 mg , enalapril 2.5 mg , atorvastatin 20 mg and hydrochlorothiazide 12.5 mg ( polypill ) or placebo for a period of 12 months . The primary outcomes were changes in LDL-cholesterol , systolic and diastolic blood pressure and adverse reactions . Analysis was by intention-to-treat basis . RESULTS At baseline , there were differences in systolic blood pressure ( 6 mmHg ) . Taking account of baseline differences , at 12 months , polypill was associated with statistically significant reductions in blood pressure ( 4.5/1.6 mmHg ) and LDL-cholesterol ( 0.46 mmol/l ) . The study drug was well tolerated , but result ed in the modest reductions in blood pressure and lipid levels . CONCLUSION The effects of the polypill on blood pressure and lipid levels were less than anticipated , raising questions about the reliability of the reported compliance . There is a case for a fully powered trial of a polypill for the prevention of cardiovascular disease BACKGROUND AND AIMS Patients with established coronary artery disease ( CAD ) are likely to receive a combination of aspirin , a statin , and blood pressure (BP)-lowering agents . Combining these pharmacologic agents into a cardiovascular combination pill , such as a polypill , could be considered to reduce prescription gaps and nonadherence in high-risk patients . We aim ed to evaluate the effect of the concomitant use of aspirin , a statin , and BP-lowering agent(s ) in patients with CAD on vascular morbidity and mortality  in current clinical practice in an observational study to provide insights in the combination pill concept related to feasibility and applicability . METHODS In total , 2,706 patients with CAD enrolled in the Second Manifestations of ARTerial disease study were followed for the occurrence of a subsequent vascular event ( ie , myocardial infa rct ion , ischemic cerebrovascular accident , vascular death ) and all-cause mortality . The relationship between combination therapy and cardiovascular events and all-cause mortality was assessed using Cox proportional hazards regression models to calculate hazards ratios ( HRs ) with a 95 % CI . Both covariate and propensity score adjusting methods were used to reduce confounding by indication . RESULTS A combination of aspirin , a statin , and ≥1 BP-lowering agent(s ) was used by 67 % of the patients . During a median of 5.0 years ( interquartile range 2.4 - 10.2 years ) , 347 vascular events occurred and 162 patients died . Combination therapy with aspirin , statin , and ≥1 BP-lowering agent was associated with a lower risk of myocardial infa rct ion ( HR 0.68 , 95 % CI 0.49 - 0.96 ) , ischemic cerebrovascular accident ( HR 0.37 , 95 % CI 0.16 - 0.84 ) , composite vascular end point ( HR 0.66 , 95 % CI 0.49 - 0.88 ) , vascular mortality ( HR 0.53 , 95 % CI 0.33 - 0.85 ) , and all-cause mortality ( HR 0.69 , 95 % CI 0.49 - 0.96 ) compared with the absence of combination therapy , after adjusting for confounding covariates in a propensity score . The use of 1 or only 2 components of combination therapy was associated with a higher risk for cardiovascular events compared with the combined use of aspirin , a statin , and ≥1 BP-lowering agent(s ) . CONCLUSION Two-thirds of the patients with CAD use a combination of aspirin , a statin , and ≥1 BP-lowering agent(s ) , components of a cardiovascular fixed-dose combination pill . Combination therapy with these agents is associated with a lower risk of vascular events and total mortality . Although treatment effect in observational studies should be interpreted with caution , the results of this study support supposed benefits from combination therapy . However , the effect of fixed-dose combination pill on clinical outcome needs to be demonstrated in r and omized clinical trials Introduction This paper describes a planned process evaluation of the Use of a Multidrug Pill In Reducing Cardiovascular Events ( UMPIRE ) trial , one of several r and omised clinical trials taking place globally to assess the potential of cardiovascular drugs as a fixed-dose combination ( polypill ) in cardiovascular disease prevention . A fixed-dose combination may be a promising strategy for promoting adherence to medication ; alleviating pill burden through simplifying regimens and reducing cost . This process evaluation will complement the UMPIRE trial by using qualitative research methods to inform underst and ing of the complex interplay of factors that underpin trial outcomes . Methods A series of semistructured , in-depth interviews with local health professionals and UMPIRE trial participants in India and the UK will be undertaken . The aim is to underst and their views and experiences of the trial context and of day-to-day use of medications more generally . The grounded theory approach will be used to analyse data and help inform the processes of the UMPIRE trial . Ethics and dissemination The study has received ethical approval for all sites in the UK and India where trial participant interviews will be undertaken . The process evaluation will help inform and enhance the underst and ing of the UMPIRE trial results and its applicability to clinical practice as well as shaping policy regarding strategies for improving cardiovascular medication adherence 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 BACKGROUND Identification of the population at high risk of developing  atherosclerotic cardiovascular disease ( ASCVD ) is critical for its prevention . The aim of the present study was to evaluate the use of  fasting blood glucose ( FBG )  to predict ASCVD . METHODS In all , 18 610 participants , aged 35 - 74 years at enrollment , were included in this prospect i ve study . Baseline information was collected using a st and ardized question naire , physical examinations , and laboratory tests . During follow-up , disease status and vital information were up date d. Cox proportional hazards regression analysis was used to estimate associations , with normal FBG ( 70 - 99 mg/dL ) as the reference group . Anthropometric measurements , socioeconomic status , and conventional cardiovascular risk factors were included in the multivariate-adjusted model . RESULTS After 7.8 years follow-up ( 145 223 person-years ) , there were 519 cases of ASCVD . The multivariate-adjusted hazard ratios ( HR ) , with 95 % confidence intervals ( CI ) , for ASCVD in patients with low FBG ( < 70 mg/dL ) , impaired fasting glucose ( IFG ; 100 - 125 mg/dL ) , and diabetes ( ≥126 mg/dL , use of antidiabetic medication and /or self-report ) were 1.35 ( 0.84 , 2.15 ) , 1.02 ( 0.81 , 1.27 ) , and 1.68 ( 1.26 , 2.23 ) , respectively . Although IFG was associated with the development of diabetes ( multivariate-adjusted HR 3.67 ; 95 % CI 3.20 , 4.21 ) , it was only associated with incident ASCVD in the univariate model ( HR 1.52 ; 95 % CI 1.23 , 1.88 ) . The association of diabetes with coronary heart disease was more pronounced than that with stroke . Gender and residential differences were also identified . CONCLUSIONS In the present study , IFG was associated with the development of diabetes but not incident ASCVD . Prevention strategies to reduce the development of diabetes in people with IFG are critical to improve cardiovascular health Background : Dapagliflozin is a sodium‐glucose co‐transporter‐2 ( SGLT‐2 ) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus ( T2DM ) by promoting glycosuria via inhibiting urinary glucose reabsorption . In addition to improving blood glucose control , treatment with dapagliflozin results in glucose‐induced osmotic diuresis , weight loss , and blood pressure lowering . Previous trials of SGLT‐2 inhibitors showed reductions in cardiovascular ( CV ) events , including CV death and hospitalization for heart failure , and ischemic events in patients with atherosclerotic cardiovascular disease ( ASCVD ) . Research design and methods : DECLARE – TIMI 58 ( NCT01730534 ) is a phase 3b r and omized , double‐blind , placebo‐controlled trial design ed to evaluate the CV safety and efficacy of dapagliflozin that has completed r and omization of 17,160 patients with T2DM and a history of either established ASCVD ( n = 6,971 ) or multiple risk factors for ASCVD ( n = 10,189 ) . Patients were r and omized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo . The primary safety outcome is the time to the first event of the composite of CV death , myocardial infa rct ion , or ischemic stroke ( major adverse cardiovascular events ; MACEs ) . The co‐ primary efficacy outcomes are the composite of CV death , myocardial infa rct ion , or ischemic stroke and the composite of CV death or hospitalization for heart failure . This event‐driven trial will continue until at least 1,390 subjects have a MACE outcome , thereby providing > 99 % power to test for the primary outcome of safety  of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI > 1.3 for the primary outcome of MACE , as well as 85 % power to detect a 15 % relative risk reduction in MACE and an estimated 87 % power to detect a 20 % reduction in the composite of CV death or hospitalization for heart failure at a 1‐sided & agr ; level of .0231 . Conclusion : The DECLARE – TIMI 58 trial is testing the hypotheses that dapagliflozin is safe ( does not increase ) and may reduce the occurrence of major CV events . DECLARE – TIMI 58 is the largest study to address this question with an SGLT‐2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors Background : The accurate assessment of individual risk can be of great value to guiding and facilitating the prevention of atherosclerotic cardiovascular disease ( ASCVD ) . However , prediction models in common use were formulated primarily in white population s. The China-PAR project ( Prediction for ASCVD Risk in China ) is aim ed at developing and validating 10-year risk prediction equations for ASCVD from 4 contemporary Chinese cohorts . Methods : Two prospect i ve studies followed up together with a unified protocol were used as the derivation cohort to develop 10-year ASCVD risk equations in 21 320 Chinese participants . The external validation was evaluated in 2 independent Chinese cohorts with 14 123 and 70 838 participants . Furthermore , model performance was compared with the Pooled Cohort Equations reported in the American College of Cardiology/American Heart Association guideline . Results : Over 12 years of follow-up in the derivation cohort with 21 320 Chinese participants , 1048 subjects developed a first ASCVD event . Sex-specific equations had C statistics of 0.794 ( 95 % confidence interval , 0.775–0.814 ) for men and 0.811 ( 95 % confidence interval , 0.787–0.835 ) for women . The predicted rates were similar to the observed rates , as indicated by a calibration & khgr;2 of 13.1 for men ( P=0.16 ) and 12.8 for women ( P=0.17 ) . Good internal and external validations of our equations were achieved in subsequent analyses . Compared with the Chinese equations , the Pooled Cohort Equations had lower C statistics and much higher calibration & khgr;2 values in men . Conclusions : Our project developed effective tools with good performance for 10-year ASCVD risk prediction among a Chinese population that will help to improve the primary prevention and management of cardiovascular disease Aims Recent data indicate that fixed-dose combination ( FDC ) pills , polypills , can produce sizeable risk factor reductions . There are very few published data on the consistency of the effects of a polypill in different patient population s. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels . The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol , blood pressure ( BP ) , calculated cardiovascular relative risk reduction and adverse events . Methods This paper describes a post-hoc analysis of a r and omised , placebo-controlled trial of a polypill ( containing aspirin 75 mg , simvastatin 20 mg , lisinopril 10 mg and hydrochlorothiazide 12.5 mg ) in 378 individuals without an indication for any component of the polypill , but who had an estimated five-year risk for cardiovascular disease ≥7.5 % . The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol , systolic BP , calculated cardiovascular relative risk reduction and adverse events . Results The mean LDL-cholesterol in the polypill group was 0.9 mmol/l ( 95 % confidence interval ( CI ) : 0.8–1.0 ) lower compared with the placebo group during follow-up . Those with a baseline LDL-cholesterol > 3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo , than patients with an LDL-cholesterol ≤3.6 mmol/l ( −1.1 versus −0.6 mmol/l , respectively ) . The mean systolic BP was 10 mm Hg ( 95 % CI : 8–12 ) lower in the polypill group . In participants with a baseline systolic BP > 135 mm Hg the polypill result ed in a greater absolute systolic BP reduction with the polypill compared with placebo , than participants with a systolic BP ≤ 135 mm Hg ( −12 versus −7 mm Hg , respectively ) . Calculated from individual risk factor reductions , the mean cardiovascular relative risk reduction was 48 % ( 95 % CI : 43–52 ) in the polypill group . Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill . Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk . Conclusion This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors . Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction , suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill AIMS Recent trials of cardiovascular polypills in high-risk population s show improvements in the use of cardiovascular preventive treatments , compared to usual care . We describe patterns of pill burden in Australian practice , define the impact of polypill therapy on pill burden , and explore how physicians add medication to polypill therapy . METHODS The Kanyini Guidelines Adherence with the Polypill Study was an open-label trial involving 623 participants in Australia which r and omized participants to a polypill strategy ( containing a statin , antiplatelet agent , and two blood-pressure-lowering medications ) or usual care . Participants either had established cardiovascular disease or were at high calculated risk ( ≥15 % over 5 years ) . Current medications , daily pill burden , and self-reported use of combination treatment were recorded prior to r and omization and at study end . Median pill burden at baseline and study end was compared in both arms . Subgroup analysis of the polypill strategy on trial primary outcomes was conducted by pill burden at baseline . RESULTS Median total and cardiovascular pill burdens of the polypill group decreased from 7 to 5 and from 4 to 2 , respectively ( median change -2 ; IQR -3 , 0 ) , with no change in the usual care group ( comparison of change ; P < 0.001 ) . No change was seen for noncardiovascular medications . Of those still using the polypill at study end , 43.8 % were prescribed additional medications ; 84.5 % of these additional medications were blood-pressure-lowering medications . Within the polypill group , lower pill burden at baseline was associated with greater increases in the use of indicated cardiovascular preventive medications at study end compared to those with higher pill burdens . No trend was observed between the level of baseline pill burden and the effect of poylpill treatment on systolic blood pressure or total cholesterol . CONCLUSION A cardiovascular polypill in contemporary Australian practice reduces cardiovascular and total pill burdens , despite frequent prescription of additional medications Status epilepticus ( SE ) is a common neurological and medical emergency . Despite the significant mortality associated with SE , no human data have been available regarding cardiovascular changes prior to death in patients with this condition . This study was conducted to measure hemodynamic trends in the 24 h prior to death in a series of 24 prospect ively evaluated SE patients . Two distinct cardiovascular patterns of mean arterial pressure ( MAP ) and heart rate ( HR ) were observed . Ten patients had a gradual decline in MAP and /or HR , and this group was design ated as having gradual cardiac decompensation ( GCD ) . The remaining 14 patients showed no significant changes in either MAP or HR up to the time of death . This group of patients was design ated as having acute cardiac decompensation ( ACD ) . The changes in MAP and HR over the last 24 h prior to death between the GCD and ACD groups were statistically significant . Ninety percent of the GCD patients had a history of multiple risk factors for arteriosclerotic cardiovascular disease ( ASCVD ) , while only 30 % of the ACD group had a history of multiple risk factors for ASCVD . The results provide the first human data of cardiovascular events immediately preceding death in SE patients . We propose that further investigation of the cardiovascular pathophysiology of SE may provide new therapeutic interventions which could decrease the significant mortality associated with SE Aims Cardiovascular fixed-dose combination pills , or polypills , may help address the widespread lack of access and adherence to proven medicines . Initiation of polypill-based care typically entails switching from current separately taken medications . Given the heterogeneity in usual care , there is interest in the impact of polypill treatment across different patterns of prior medication regimen . Methods A total of 2004 participants with established cardiovascular disease or estimated 5-year cardiovascular risk of over 15 % were r and omised to polypill-based treatment ( aspirin 75 mg , simvastatin 40 mg , lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide 12.5 mg ) or usual care . Baseline medications were classified by potency relative to polypill components . Estimated cardiovascular risk reduction was calculated by combining risk factor changes with results seen in meta-analyses of previous r and omised trials . Results For cholesterol reduction conferred by polypills , there was a dose response across baseline statin groups , with mean low-density lipoprotein (LDL)-cholesterol differences of 0.37 , 0.22 , 0.14 and 0.07 mmol/L among patients taking no statin , less potent , equipotent and more potent statin at baseline , respectively . Similarly there were differences in mean systolic BP of 5.4 , 6.2 , 3.3 and 1.8 mmHg among patients taking 0 , 1 , 2 or 3 BP-lowering agents . Among patients taking more potent statins at baseline , there was no significant difference in LDL-cholesterol but there were benefits for BP and aspirin adherence . Similar results were seen among patients taking 3 BP-lowering agents at baseline . Switching to a polypill-based strategy result ed in estimated cardiovascular relative risk reductions across a wide range of usual care patterns of antiplatelet , statin and BP-lowering therapy prescribing . Conclusion Adherence benefits from switching to a polypill result ed in risk factor changes that were at least as good as usual care across a wide variety of treatment patterns , including equally potent or more potent regimens . The benefits of switching to polypill-based care were greatest among those stepped up from partial treatment or less potent treatment Background The Pooled Cohort Risk Equation was introduced by the American College of Cardiology ( ACC ) and American Heart Association ( AHA ) 2013 in their Blood Cholesterol Guideline to estimate the 10-year atherosclerotic cardiovascular disease ( ASCVD ) risk . However , absence of Asian ethnicity in the contemporary cohorts and limited studies to examine the use of the risk score limit the applicability of the equation in an Asian population . This study examines the validity of the pooled cohort risk score in a primary care setting and compares the cardiovascular risk using both the pooled cohort risk score and the Framingham General Cardiovascular Disease ( CVD ) risk score . Methods This is a 10-year retrospective cohort study of r and omly selected patients aged 40–79 years . Baseline demographic data , co-morbidities and cardiovascular ( CV ) risk parameters were captured from patient records in 1998 . Pooled cohort  risk score and Framingham General CVD risk score for each patient were computed . All ASCVD events ( nonfatal myocardial infa rct ion , coronary heart disease ( CHD ) death , fatal and nonfatal stroke ) occurring from 1998–2007 were recorded . Results A total of 922 patients were studied . In 1998 , mean age was 57.5 ± 8.8 years with 66.7 % female . There were 47 % diabetic patients and 59.9 % patients receiving anti-hypertensive treatment . More than 98 % of patients with pooled cohort risk score ≥7.5 % had FRS > 10 % . A total of 45 CVD events occurred , 22 ( 7.2 % ) in males and 23 ( 3.7 % ) in females . The median pooled cohort risk score for the population was 10.1 ( IQR 4.7 - 20.6 ) while the actual ASCVD events that occurred was 4.9 % ( 45/922 ) . Our study showed moderate discrimination with AUC of 0.63 . There was good calibration with Hosmer-Lemeshow test χ2 = 12.6 , P = 0.12 . Conclusions The pooled cohort risk score appears to overestimate CV risk but this apparent over-prediction could be a result of treatment . In the absence of a vali date d score in an untreated population , the pooled cohort risk score appears to be appropriate for use in a primary care setting In spite of advances in prevention and treatment , the burden of cardiovascular diseases is increasing . A fixed-dose combination ( FDC ) pill , or " polypill , " composed of evidence -based drugs has been proposed as a means of improving cardiovascular prevention by reducing cost and increasing patient adherence to treatment . The aim of the FOCUS project , funded by the 7th Framework Programme of the European Commission , is to characterize the factors that underlie inadequate secondary prevention and to test a new FDC . To achieve these goals , a 9-member consortium has been constituted , including institutions from Argentina , France , Italy , Spain , and Switzerl and . FOCUS Phase-1 will examine factors potentially related to lack of adequate secondary prevention in 4,000 post-myocardial infa rct ion ( MI ) patients and analyze the relationship between these factors and patient treatment adherence . Primary end points will be ( 1 ) the percentage of patients receiving aspirin , angiotensin-converting enzyme inhibitors , and statins and ( 2 ) adherence to treatment measured by the Morisky-Green test . FOCUS Phase-2 is a r and omized trial that will compare adherence to treatment in 1,340 post-myocardial infa rct ion patients either receiving an FDC comprising aspirin ( 100 mg ) , ramipril ( 2.5 , 5 , or 10 mg ) , and simvastatin ( 40 mg ) or receiving the same 3 drugs separately BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy Background —This study explores health provider and patient attitudes toward the use of a cardiovascular polypill as a health service strategy to improve cardiovascular prevention . Methods and Results —In-depth , semistructured interviews ( n=94 ) were conducted with health providers and patients from Australian general practice , Aboriginal community-controlled and government-run Indigenous Health Services participating in a pragmatic r and omized controlled trial evaluating a polypill-based strategy for high-risk primary and secondary cardiovascular disease prevention . Interview topics included polypill strategy acceptability , factors affecting adherence , and trial implementation . Transcribed interview data were analyzed thematically and interpretively .  Polypill patients commented frequently on cost-savings , ease , and convenience of a daily-dosing pill . Most providers considered a polypill strategy to facilitate improved patient medication use . Indigenous Health Services providers and indigenous patients thought the strategy acceptable and beneficial for indigenous patients given the high disease burden . Providers noted the inflexibility of the fixed dose regimen , with dosages sometimes inappropriate for patients with complex management considerations . Future polypill formulations with varied strengths and classes of medications may overcome this barrier . Many providers suggested the polypill strategy , in its current formulations , might be more suited to high-risk primary prevention patients . Conclusions —The polypill strategy was generally acceptable to patients and providers in cardiovascular prevention . Limitations to provider acceptability of this particular polypill were revealed , as was a perception it might be more suitable for high-risk primary prevention patients , though future combinations could facilitate its use in secondary prevention . Participants suggested a polypill-based strategy as particularly appropriate for lowering the high cardiovascular burden  in indigenous population s. Clinical Trial Registration —URL : http://www.anzctr.org.au . ANZCTRN : 12608000583347 Given the substantially increasing geriatric population , the need for evidence -based strategies to address the medical and societal consequences of these demographic trends has never been greater . In this context , statins for primary prevention of atherosclerotic cardiovascular disease ( ASCVD ) provide substantial potential social value by improving health and survival . However , using statins for primary prevention in older adults presents a clinical dilemma . Even though compelling evidence exists supporting statins for secondary prevention in individuals older than 75 years with clinical ASCVD , the same can not be said for primary prevention . In this Viewpoint , we describe existing evidence on the benefits of statins for primary prevention in older adults , uncertainties about risks , and the need for a r and omized trial before non– evidence -based prescribing patterns become irreversibly incorporated into practice 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 Ertugliflozin is an inhibitor of sodium‐glucose co‐transporter‐2 ( SGLT2 ) , approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus ( T2DM ) . The VERTIS cardiovascular ( CV ) outcomes trial ( NCT01986881 ) has a primary objective to demonstrate non‐inferiority of ertugliflozin versus placebo on major adverse CV events : time to the first event of CV death , nonfatal myocardial infa rct ion , or nonfatal stroke . Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to : 1 ) the composite outcome of CV death or hospitalization for heart failure ( HF ) ; 2 ) CV death ; and 3 ) the composite outcome of renal death , dialysis/transplant , or doubling of serum creatinine from baseline . Methods Patients ≥40 years old with T2DM ( HbA1c 7.0–10.5 % ) and established atherosclerotic cardiovascular disease ( ASCVD ) of the coronary , cerebral , and /or peripheral arterial systems , were r and omized 1:1:1 to once daily double‐blind placebo , ertugliflozin 5 mg or 15 mg added to existing therapy . Results 8246 patients were r and omized and 8238 received at least 1 dose of investigational product . Mean age was 64.4 years , 11.0 % were ≥75 years old , and mean diabetes duration was 12.9 years with screening HbA1c of 8.3 % . At entry , coronary artery disease , cerebrovascular disease , and peripheral arterial disease were present in 76.3 % , 23.1 % , and 18.8 % of patients , respectively . HF was present in 23.1 % , and Stage 3 kidney disease in 21.6 % of patients . Conclusion The results from the VERTIS‐CV trial will define the CV and renal safety and efficacy  of ertugliflozin in patients with T2DM and ASCVD Background The Kanyini Guidelines Adherence with the Polypill ( Kanyini-GAP ) Study aims to examine whether a polypill-based strategy ( using a single capsule containing aspirin , a statin and two blood pressure-lowering agents ) amongst Indigenous and non-Indigenous people at high risk of experiencing a cardiovascular event will improve adherence to guideline -indicated therapies , and lower blood pressure and cholesterol levels . Methods / Design The study is an open , r and omised , controlled , multi-centre trial involving 1000 participants at high risk of cardiovascular events recruited from mainstream general practice s and Aboriginal Medical Services , followed for an average of 18 months . The participants will be r and omised to one of two  versions  of  the polypill  , the version chosen by the treating health professional according to clinical features of the patient , or to usual care . The primary study outcomes will be changes , from baseline measures , in serum cholesterol and systolic blood pressure and self-reported current use of aspirin , a statin and at least two blood pressure lowering agents . Secondary study outcomes include cardiovascular events , renal outcomes , self-reported barriers to indicated therapy , prescription of indicated therapy , occurrence of serious adverse events and changes in quality -of-life . The trial will be supplemented by formal economic and process evaluations . Discussion The Kanyini-GAP trial will provide new evidence as to whether or not a polypill-based strategy improves adherence to effective cardiovascular medications amongst individuals in whom these treatments are indicated . Trial Registration This trial is registered with the Australian New Zeal and Clinical Trial Registry ACTRN126080005833347 BACKGROUND Cardiovascular disease ( CVD ) is among the most common causes of mortality in all population s. Nonalcoholic steatohepatitis is a common finding in patients with CVD . Prevention of CVD in individual patients typically requires periodic clinical evaluation , as well as diagnosis and management of risk factors such as hypertension and hyperlipidemia . However , this is re source consuming and hard to implement , especially in developing countries . We design ed a study to investigate the effects of a simpler strategy : a fixed-dose combination pill consisting of aspirin , valsartan , atorvastatin and hydrochlorthiazide ( PolyPill ) in an unselected group of persons aged over 50 years . DESIGN The PolyIran-Liver study was performed in Gonbad city as an open label pragmatic r and omized controlled trial nested within the Golestan Cohort Study . We r and omly selected 2,400 cohort study participants aged above 50 years , r and omly assigned them to intervention or usual care and invited them to participate in an additional measurement study ( if they met the eligibility criteria ) to measure liver related outcomes . Those agreeing and r and omized to the intervention arm were offered a daily single dose of PolyPill . We will follow participants for 5 years . The primary outcome is major cardiovascular events , secondary outcomes include all-cause mortality and liver related outcomes : liver stiffness and liver enzyme levels . Cardiovascular outcomes and mortality will be determined from the cohort study and liver-related outcomes in those consenting to follow up . Analysis will be by allocated group . TRIAL STATUS Between October and December 2011 , 1,320 intervention and 1,080 control participants were invited to participate in the additional measurement study . For all these participants , the major cardiovascular events will be determined using blind assessment of outcomes through the cohort study . In the intervention and control arms , 875 ( 66 % ) and 721 ( 67 % ) respectively , met the eligibility criteria and agreed to participate in the additional measurement study . Liver related outcomes will be measured in these participants . Of the 1,320 participants r and omized to the intervention , 787 ( 60 % ) accepted the PolyPill . CONCLUSION The PolyIran-liver urban study will provide us with important information on the effectiveness of PolyPill on major cardiovascular events , all-cause mortality and liver related outcomes . ( Clinical Trials.gov ID : NCT01245608 ) BACKGROUND A combination of medications that simultaneously reduce several cardiovascular risk factors in people above a specified age , without selection based on risk factor measurement , has been proposed as a simple strategy for reducing the risk of cardiovascular disease and shown to be effective in r and omized trials ( the Polypill approach ) . AIMS To assess acceptance of the Polypill approach and adherence to preventive treatment among individuals taking part in a cardiovascular disease prevention service . METHODS Daily treatment with simvastatin ( 40 mg ) , amlodipine ( 2.5 mg ) , bendroflumethiazide ( 1.25 mg ) , lisinopril ( 5 mg ) [ or c and esartan ( 4 mg ) if cough was reported ] and folic acid ( 0.8 mg ) was offered , as separate components , to people ≥ 55 years with no history of cardiovascular , renal or liver disease . An audit of adverse effects , adherence and requests for blood pressure and cholesterol measurement was determined by telephone consultation . RESULTS Between 2006 and 2010 , 269 participants started treatment with the Polypill components . Follow-up ranged from 3 to 48 months ( mean 20 ) . A total of 222 participants ( 83 % ) adhered to treatment , including 30 ( 11 % ) who switched from the angiotensin-converting enzyme inhibitor ( lisinopril ) to the angiotensin receptor blocker ( c and esartan ) because of cough . Ten participants ( 4 % ) continued to take treatment but stopped taking one or more drugs because of other symptoms , and 37 ( 14 % ) stopped all treatment , eight because of adverse effects and 29 for non-medical reasons . No one requested a blood pressure or cholesterol measurement . CONCLUSION This is the first demonstration of the application of the Polypill approach in practice . The method was accepted and the Polypill components were well tolerated , with good adherence and no dem and for information about risk factors Background South Asians ( Asian Indians and Pakistanis ) are the second fastest growing ethnic group in the United States ( U.S. ) and have an increased risk of atherosclerotic cardiovascular disease ( ASCVD ) . This pilot study evaluated a culturally-salient , community-based healthy lifestyle intervention to reduce ASCVD risk among South Asians . Methods Through an academic-community partnership , medically underserved South Asian immigrants at risk for ASCVD were r and omized into the South Asian Heart Lifestyle Intervention ( SAHELI ) study . The intervention group attended 6 interactive group classes focused on increasing physical activity , healthful diet , weight , and stress management . They also received follow-up telephone support calls . The control group received translated print education material s about ASCVD and healthy behaviors . Primary outcomes were feasibility and initial efficacy , measured as change in moderate/vigorous physical activity and dietary saturated fat intake at 3- and 6-months . Secondary clinical and psychosocial outcomes were also measured . Results Participants ’ ( n = 63 ) average age was 50 ( SD = 8) years , 63 % were female , 27 % had less than or equal to a high school education , one-third were limited English proficient , and mean BMI was 30 kg/m2 ( SD ± 5 ) . There were no significant differences in change in physical activity or saturated fat intake between the intervention and control group . Compared to the control group , the intervention group showed significant weight loss ( −1.5 kg , p-value = 0.04 ) and had a greater sex-adjusted decrease in hemoglobin A1C ( −0.43 % , p-value < 0.01 ) at 6 months . Study retention was 100 % . Conclusions This pilot study suggests that a culturally-salient , community-based lifestyle intervention was feasible for engaging medically underserved South Asian immigrants and more effective at addressing ASCVD risk factors than print health education material s . Trial registration NCT01647438 , Date of Trial Registration : July 19 , Cost-effective strategies to maintain healthy active lifestyle in aging population s are required to address the global burden of age-related diseases . ASPREE will examine whether the potential primary prevention benefits of low dose aspirin outweigh the risks in older healthy individuals . Our primary hypothesis is that daily oral 100 mg enteric-coated aspirin will extend a composite primary endpoint termed ' disability-free life ' including onset of dementia , total mortality , or persistent disability in at least one of the Katz Activities of Daily Living in 19,000 healthy participants aged 65 years and above ( ' US minorities ' ) and 70 years and above ( non-'US minorities ' ) . ASPREE is a double-blind , r and omized , placebo-controlled trial of oral 100 mg enteric-coated acetyl salicylic acid ( ASA ) or matching placebo being conducted in Australian and US community setting s on individuals free of dementia , disability and cardiovascular disease ( CVD ) events . Secondary endpoints are all-cause and cause specific mortality , fatal and non-fatal cardiovascular events , fatal and non-fatal cancer ( excluding non-melanoma skin cancer ) , dementia , mild cognitive impairment , depression , physical disability , and clinical ly significant bleeding .  To 20 September 2013 14,383 participants have been recruited . Recruitment and study completion are anticipated in July 2014 and December 2018 respectively . In contrast to other aspirin trials that have largely focused on cardiovascular endpoints , ASPREE has a unique composite primary endpoint to better capture the overall risk and benefit of aspirin to extend healthy independent lifespan in older adults in the US and Australia Abstract Objective : To determine whether a low ankle brachial pressure index is associated with an increased risk of cardiovascular events and death , and whether the prediction of such events could be improved by including this index . Design : Cohort study . Setting : 11 practice s in Edinburgh , Scotl and . Subjects : 1592 men and women aged 55–74 years selected at r and om from the age-sex registers of 11 general practice s and followed up for 5 years . Main outcome measures : Incidence of fatal and non-fatal cardiovascular events and all cause mortality . Results : At baseline 90 ( 5.7 % ) of subjects had an ankle brachial pressure index < /=0.7 , 288 ( 18.2 % ) had an index < /=0.9 , and 566 ( 35.6 % ) < /=1.0 . After five years subjects with an index < /=0.9 at baseline had an increased risk of non-fatal myocardial infa rct ion ( relative risk 1.38 , 95 % confidence interval 0.88 to 2.16 ) , stroke ( 1.98 , 1.05 to 3.77 ) , cardiovascular death ( 1.85 , 1.15 to 2.97 ) , and all cause mortality ( 1.58 , 1.14 to 2.18 ) after adjustment for age , sex , coronary disease , and diabetes at baseline . The ability to predict subsequent events was greatly increased by combining the index with other risk factors — for example , hypertensive smokers with normal cholesterol concentrations had a positive predictive value of 25.0 % , increasing to 43.8 % in subjects with a low index and decreasing to 15.6 % in those with a normal index . Conclusion : The ankle brachial pressure index is a good predictor of subsequent cardiovascular events , and improves on predictions by conventional risk factors alone . It is simple and accurate and could be included in routine screening of cardiovascular status . Key messages In this study individuals with a low ankle brachial pressure index had an increased risk of fatal and non-fatal cardiovascular events The index was a good predictor of subsequent cardiovascular events , and improved that of conventional risk factors alone The ankle brachial pressure index could be included in routine screening of cardiovascular status Individuals with a low ankle brachial pressure index require additional monitoring , and might benefit from aspirin or other secondary preventive BACKGROUND The combination of three blood-pressure-lowering drugs at low doses , with a statin , aspirin , and folic acid ( the polypill ) , could reduce cardiovascular events by more than 80 % in healthy individuals . We examined the effect of the Polycap on blood pressure , lipids , heart rate , and urinary thromboxane B2 , and assessed its tolerability . METHODS In a double-blind trial in 50 centres in India , 2053 individuals without cardiovascular disease , aged 45 - 80 years , and with one risk factor were r and omly assigned , by a central secure website , to the Polycap ( n=412 ) consisting of low doses of thiazide ( 12.5 mg ) , atenolol ( 50 mg ) , ramipril ( 5 mg ) , simvastatin ( 20 mg ) , and aspirin ( 100 mg ) per day , or to eight other groups , each with about 200 individuals , of aspirin alone , simvastatin alone , hydrochlorthiazide alone , three combinations of the two blood-pressure-lowering drugs , three blood-pressure-lowering drugs alone , or three blood-pressure-lowering drugs plus aspirin . The primary outcomes were LDL for the effect of lipids , blood pressure for antihypertensive drugs , heart rate for the effects of atenolol , urinary 11-dehydrothromboxane B2 for the antiplatelet effects of  aspirin , and rates of discontinuation of drugs for safety . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00443794 . FINDINGS Compared with groups not receiving blood-pressure-lowering drugs , the Polycap reduced systolic blood pressure by 7.4 mm Hg ( 95 % CI 6.1 - 8.1 ) and diastolic blood pressure by 5.6 mm Hg ( 4.7 - 6.4 ) , which was similar when three blood-pressure-lowering drugs were used , with or without aspirin . Reductions in blood pressure increased with the number of drugs used ( 2.2/1.3 mm Hg with one drug , 4.7/3.6 mm Hg with two drugs , and 6.3/4.5 mm Hg with three drugs ) . Polycap reduced LDL cholesterol by 0.70 mmol/L ( 95 % CI 0.62 - 0.78 ) , which was less than that with simvastatin alone ( 0.83 mmol/L , 0.72 - 0.93 ; p=0.04 ) ; both reductions were greater than for groups without simvastatin ( p<0.0001 ) . The reductions in heart rate with Polycap and other groups using atenolol were similar ( 7.0 beats per min ) , and both were significantly greater than that in groups without atenolol ( p<0.0001 ) . The reductions in 11-dehydrothromboxane B2 were similar with the Polycap ( 283.1 ng/mmol creatinine , 95 % CI 229.1 - 337.0 ) compared with the three blood-pressure-lowering drugs plus aspirin ( 350.0 ng/mmol creatinine , 294.6 - 404.0 ) , and aspirin alone ( 348.8 ng/mmol creatinine , 277.6 - 419.9 ) compared with groups without aspirin . Tolerability of the Polycap was similar to that of other treatments , with no evidence of increasing intolerability with increasing number of active components in one pill . INTERPRETATION This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk AIM In patients with coronary artery disease ( CAD ) , a J-curve relationship has been reported between blood pressure ( BP ) and future cardiovascular events . However , this is controversial . The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD . METHODS AND RESULTS We evaluated 10 001 patients with CAD and a low-density lipoprotein ( LDL ) cholesterol level < 130 mg/dL , r and omized to atorvastatin 80 vs. 10 mg , enrolled in the TNT trial . The post-baseline , time-dependent BPs [ systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) ] were categorized into 10 mmHg increments . The primary outcome was a composite of death from coronary disease , non-fatal myocardial infa rct ion ( MI ) , resuscitated cardiac arrest , and fatal or non-fatal stroke . Among the 10 001 patients , 982 ( 9.82 % ) experienced a primary outcome at 4.9 years ( median ) of follow-up . The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range , both unadjusted and adjusted ( for baseline covariates , treatment effect , and LDL levels ) . A time-dependent , non-linear , multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest . A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality , cardiovascular mortality , non-fatal MI , or angina . However , for the outcome of stroke , lower was better for SBP . CONCLUSION In patients with CAD , a low BP ( < 110 - 120/<60 - 70 mmHg ) portends an increased risk of future cardiovascular events ( except stroke ) BACKGROUND The majority of cardiovascular events and deaths attributable to both raised blood pressure and dyslipidaemia occur in subjects with relatively " normal " blood pressure and lipid levels respectively . The study was design ed to evaluate the potential benefits of cholesterol lowering in the primary prevention of coronary heart disease in hypertensive subjects with average and below average levels of serum cholesterol . MATERIAL AND METHODS Out of 19 342 hypertensive subjects ( aged 40 - 79 ) who were initially r and omized to one of two antihypertensive treatment strategies in the Anglo-Sc and inavian Cardiac Outcomes Trial ( ASCOT ) , 10 305 subjects with total cholesterol levels < or = 6.5 mmol/L were additionally r and omized to either 10 mg atorvastatin or placebo . The primary endpoint was non-fatal myocardial infa rct ion or fatal coronary heart disease . RESULTS The lipid arm of the study was prematurely stopped after a median follow-up period of 3.3 years . One hundred events occurred in those r and omized to atorvastatin compared to 154 events in those receiving placebo , a 36 % relative risk reduction ( p = 0.0005 ) in the primary endpoint . Among secondary and tertiary endpoints , stroke was reduced with 27 % ( p = 0.02 ) . There was a non-significant 13 % reduction in total mortality . Non-cardiovascular mortality was similar in the two treatment limbs of the trial . After three years of follow-up , atorvastatin lowered total serum cholesterol by 1.1 mmol/L compared with placebo . INTERPRETATION Treatment with 10 mg atorvastatin o.d . in hypertensive patients at moderate risk gives a significant risk reduction of coronary heart disease , independent of baseline level of total cholesterol BACKGROUND Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation ( AF ) . However , this treatment carries a risk of bleeding and the need for frequent medical monitoring . We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism . METHODS 1044 patients with AF and with at least one thromboembolic risk factor ( congestive heart failure or left ventricular fractional shortening < or = 25 % , previous thromboembolism , systolic blood pressure of more than 160 mm Hg at study enrollment , or being a woman aged over 75 years ) were r and omly assigned either a combination of low-intensity , fixed-dose warfarin ( international normalised ratio [ INR ] 1.2 - 1.5 for initial dose adjustment ) and aspirin ( 325 mg/day ) or adjusted-dose warfarin ( INR 2.0 - 3.0 ) . Drugs were given open-labelled . FINDINGS The mean INR during follow-up of patients taking combination therapy ( n = 521 ) was 1.3 , compared with 2.4 for those taking adjusted-dose warfarin ( n = 523 ) . During follow-up , 54 % of INRs in patients taking combination therapy were 1.2 - 1.5 and 34 % were less than 1.2 . The trial was stopped after a mean , follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism ( primary events ) in patients given combination therapy ( 7.9 % per year ) was significantly higher than in those given adjusted-dose warfarin ( 1.9 % per year ) at an interim analysis ( p < 0.0001 ) , an absolute reduction of 6.0 % per year ( 95 % Cl 3.4 , 8.6 ) by adjusted-dose warfarin . The annual rates of disabling stroke ( 5.6 % vs 1.7 % , p = 0.0007 ) and of primary event or vascular death ( 11.8 % vs 6.4 % , p = 0.002 ) , were also higher with combination therapy . The rates of major bleeding were similar in both treatment groups . INTERPRETATION Low-intensity , fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism ; adjusted-dose warfarin ( target INR 2.0 - 3.0 ) importantly reduces stroke for high-risk patients Background Cardiovascular diseases ( CVD ) are responsible for significant morbidity , premature mortality , and economic burden . Despite established evidence that supports the use of preventive medications among patients at high CVD risk , treatment gaps remain . Building on prior evidence and a theoretical framework , a complex intervention has been design ed to address these gaps among high-risk , under-treated patients in the Australian primary care setting . This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities ; availability of a range of CVD polypills ( fixed-dose combinations of two blood pressure lowering agents , a statin ± aspirin ) for prescription when appropriate ; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification . Methods Following a systematic development process , the intervention will be evaluated in a pragmatic cluster r and omized controlled trial including 70 general practice s for a median period of 18 months . The 35 general practice s in the intervention group  will work with a nominated partner pharmacy , whereas those in the control group will provide usual care without access to the intervention tools . The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure ( BP ) and low-density lipoprotein cholesterol ( LDL-C ) levels at the study end . The outcomes will be analyzed using data from electronic medical records , utilizing a vali date d extraction tool . Detailed process and economic evaluations will also be performed . Discussion The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients , pharmacists , and general practitioners ( GPs ) for CVD prevention . Trial registration Australian New Zeal and Clinical Trials Registry OBJECTIVE To determine the cost-effectiveness of routine administration , irrespective of blood pressure ( BP ) , of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus . DESIGN , SETTING AND PARTICIPANTS Prospect i ve cost-effectiveness analysis within the Action in Diabetes and Vascular Disease : Preterax and Diamicron-MR Controlled Evaluation ( ADVANCE ) trial , an international , multicentre , r and omised controlled trial of 11,140 participants with type 2 diabetes r and omly allocated to receive perindopril plus indapamide ( 4 mg-1.25 mg/day ) or placebo . MAIN OUTCOME MEASURES Health-related quality -of-life measured by the EuroQol-5D , re source utilisation , and cost-effectiveness ( cost per death averted at 4.3 years ' average follow-up , and estimated cost per life-year gained , by extrapolation ) . RESULTS The mean health-related quality -of-life score of survivors was 0.80 ( on a 0 - 1 scale [ death to full health ] ) , with no difference between treatment groups . Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5 % . For the Australian participants , perindopril-indapamide cost A$ 1368 per patient during the trial period , but reduced total hospitalisation costs by A$ 410 and other medication costs ( mainly other BP-lowering drugs ) by A$ 332 . The absolute reduction in all-cause mortality for the active treatment group was 1.1 % , giving a cost per life saved of A$ 49,200 . Lifetime extrapolation gave an estimated cost per life-year saved of A$ 10,040 ( discounted at 5 % per year ) . CONCLUSION The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective . TRIAL REGISTRATION United States National Library of Medicine NCT00145925 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 AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation ( AF ) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF , among individuals with type 2 diabetes . METHODS AND RESULTS About 11 140 patients with type 2 diabetes ( 7.6 % of whom had AF at baseline ) were r and omized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . We compared total mortality and cardiovascular disease outcomes and effects of r and omized treatment for 4.3 years on such outcomes between patients with and without AF at baseline . After multiple adjustments , AF was associated with a 61 % ( 95 % confidence interval 31 - 96 , P < 0.0001 ) greater risk of all-cause mortality and comparable higher risks of cardiovascular death , stroke , and heart failure ( all P < 0.001 ) . Routine treatment with a fixed combination of perindopril and indapamide produced similar relative , but greater absolute , risk reductions for all-cause and cardiovascular mortalities in patients with AF , compared with those without AF . The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline . CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes . This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment . Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors Higher doses of angiotensin II receptor blockers ( ARBs ) are expected to exert more protective effects against cardiovascular diseases . However , the significance of treatment of hypertension with high-dose ARB remains to be defined . The OlmeSartan and Calcium Antagonists R and omized ( OSCAR ) Study was design ed to determine whether high-dose ARB monotherapy is superior to the combination therapy of ARB plus calcium channel blocker ( CCB ) in the prevention of cardiovascular morbidity/mortality in Japanese elderly high-risk hypertensive patients . The OSCAR study is a multicenter , active-controlled , two-arm parallel group comparison , using the prospect i ve r and omized open-blinded end-point method . In the ‘ Step 1 ’ period , elderly hypertensive patients with diabetes or cardiovascular disease received monotherapy with ARB olmesartan medoxomil at a dose of 20 mg day−1 . If the target blood pressure control ( less than 140/90 mm Hg ) was not achieved by ARB monotherapy , the patients were r and omized to receive either ( 1 ) the increased dose of olmesartan at 40 mg day−1 ( high-dose ARB monotherapy ) or ( 2 ) the addition of a CCB ( amlodipine or azelnidipine ) to 20 mg day−1 olmesartan ( ARB plus CCB combination ) in the ‘ Step 2 ’ period . The follow-up duration will be 3 years . The primary end points will be the composite of fatal and non-fatal cardiovascular events , and death from any cause .  Recruitment for the OSCAR study ( around 1200 patients ) was completed by the end of May 2007 . The OSCAR study is the first large clinical trial comparing the efficacy of high-dose ARB monotherapy with that of an ARB plus CCB combination therapy in elderly high-risk hypertensive patients Type 2 diabetes mellitus is associated with a marked increase in the risk of coronary heart disease ( CHD ) or stroke ( by a factor of two to three compared with non-diabetic patients ) , and cardiovascular disease ( CVD ) accounts for the majority of deaths among patients with diabetes . A new fixed dose combination containing atorvastatin 10 mg + metformin SR 500 mg is being introduced in the Indian market for the treatment of dyslipidaemia in diabetic patients . The present study was therefore undertaken to assess efficacy , safety and tolerability of a fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg in adult Indian patients with diabetic dyslipidaemia . The final protocol was approved by relevant ethics committee before the initiation of study . Informed consent was obtained from all the patients prior to enrollment in study . The total duration of study was 14 weeks including two weeks dietary run in period . Patients fulfilling the selection criteria received a single oral tablet of fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg once daily for 12 weeks . The primary efficacy parameters were assessed by evaluating reduction in fasting and postpr and ial plasma glucose concentration levels at baseline and thereafter at each follow up visit at 2 , 4 , 8 and 12 weeks and plasma lipid profile and glycosylated Hb levels at baseline and end of study . The secondary efficacy parameters were assessed by evaluating percentage change from baseline at the end of the study ( week 12 ) in the plasma concentration of the various lipid parameters such as total , HDL- , LDL- and very low density (VLDL)-cholesterol , triglycerides , Apo B , Apo A1 , TC/LDL ratio , LDL/ HDL ratio , and percentage of patients achieving LDL-cholesterol goals as per NCEP ATP III guidelines . A total of 213 patients were enrolled in the study . Of these seven patients were lost to follow-up and considered as drop-outs . Therapy with the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg result ed in a significant reduction in the mean plasma fasting and postpr and ial glucose levels ( 35 and 38.8 % respectively ) . There was a steep fall in the HbA1c levels from baseline levels of 8.76 % to 6.74 % ( 23.1 % ) . There was also a significant ( p < 0.05 ) reduction in mean total cholesterol ( 31.2 % ) , LDL cholesterol ( 35.4 % ) , VLDL-cholesterol ( 19.6 % ) and a significant increase HDL-cholesterol ( 9.5 % ) . Thus there appeared to be trend towards reducing atherosclerosis following therapy with the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg . Mean body mass index was significantly reduced in the patients in the present study following therapy with the study drugs . The fixed dose combination of atorvastatin with metformin was well tolerated with mostly gastro-intestinal adverse events being reported in the current study . Moreover , most of the adverse events were mild to moderate in intensity and disappeared with continued treatment . In conclusion , the results of the present study suggest that , the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg is efficacious and well tolerated therapeutic modality in patients with diabetic dyslipidaemia . Furthermore this combination offers dosage convenience to the patient and by virtue of its dual mode of action is a useful addition to the therapeutic armamentarium for patients with diabetic dyslipidaemia Background There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol ( ‘ polypills ’ ) to reduce cardiovascular disease . However , no reliable placebo-controlled data are available on both efficacy and tolerability . Methods We conducted a r and omised , double-blind placebo-controlled trial of a polypill ( containing aspirin 75 mg , lisinopril 10 mg , hydrochlorothiazide 12.5 mg and simvastatin 20 mg ) in 378 individuals without an indication for any component of the polypill , but who had an estimated 5-year cardiovascular disease risk over 7.5 % . The primary outcomes were systolic blood pressure ( SBP ) , LDL-cholesterol and tolerability ( proportion discontinued r and omised therapy ) at 12 weeks follow-up . Findings At baseline , mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks , polypill treatment reduced SBP by 9.9 ( 95 % CI : 7.7 to 12.1 ) mmHg and LDL-cholesterol by 0.8 ( 95 % CI 0.6 to 0.9 ) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23 % vs 18 % ( RR 1.33 , 95 % CI 0.89 to 2.00 , p = 0.2 ) . There was an excess of side effects known to the component medicines ( 58 % vs 42 % , p = 0.001 ) , which was mostly apparent within a few weeks , and usually did not warrant cessation of trial treatment . Conclusions This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people . The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher . Nonetheless , substantial net benefits would be expected among patients at high risk . Trial Registration Australian New Zeal and Clinical Trials Registry Analysing specific non-fatal events in isolation may lead to spurious conclusions about efficacy unless the events considered are combined with all-cause mortality . The use of combined endpoints has therefore become widespread , at least in cardiovascular disease trials . Combining all-cause mortality with selected non-fatal events is useful because event-free survival , an important criterion in therapy evaluation , is addressed in this manner . In many clinical trials , symptoms , signs or para clinical measures ( for example , blood pressure , exercise duration , quality of life scores ) are used as endpoints . If the patient died before the endpoint was measured , or it was otherwise not possible to perform follow-up assessment s as planned , the effect of treatment on these endpoints may be distorted if the patients concerned are ignored in the analysis . Examples are given of how distortion can be avoided by including all patients r and omized in an analysis that uses a ranked combined endpoint based both on clinical events and on para clinical measures . A distinction is made between a pseudo intention-to-treat analysis that disregards study medication status at the time of endpoint assessment but is confined to patients with data , and a true intention-to-treat analysis that takes into account all patients r and omized based on a ranked combined endpoint CONTEXT Previous trials have investigated the effects of low-dose aspirin on primary prevention of cardiovascular events , but not in patients with type 2 diabetes . OBJECTIVE To examine the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in patients with type 2 diabetes . DESIGN , SETTING , AND PARTICIPANTS Multicenter , prospect i ve , r and omized , open-label , blinded , end-point trial conducted from December 2002 through April 2008 at 163 institutions throughout Japan , which enrolled 2539 patients with type 2 diabetes without a history of atherosclerotic disease and had a median follow-up of 4.37 years . INTERVENTIONS Patients were assigned to the low-dose aspirin group ( 81 or 100 mg per day ) or the nonaspirin group . MAIN OUTCOME MEASURES Primary end points were atherosclerotic events , including fatal or nonfatal ischemic heart disease , fatal or nonfatal stroke , and peripheral arterial disease . Secondary end points included each primary end point and combinations of primary end points as well as death from any cause . RESULTS A total of 154 atherosclerotic events occurred : 68 in the aspirin group ( 13.6 per 1000 person-years ) and 86 in the nonaspirin group ( 17.0 per 1000 person-years ) ( hazard ratio [ HR ] , 0.80 ; 95 % confidence interval [ CI ] , 0.58 - 1.10 ; log-rank test , P = .16 ) . The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient ( stroke ) in the aspirin group and 10 patients ( 5 fatal myocardial infa rct ions and 5 fatal strokes ) in the nonaspirin group ( HR , 0.10 ; 95 % CI , 0.01 - 0.79 ; P = .0037 ) . A total of 34 patients in the aspirin group and 38 patients in the nonaspirin group died from any cause ( HR , 0.90 ; 95 % CI , 0.57 - 1.14 ; log-rank test , P = .67 ) . The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and nonaspirin groups . CONCLUSION In this study of patients with type 2 diabetes , low-dose aspirin as primary prevention did not reduce the risk of cardiovascular events . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00110448 Treatment adherence is a vital determinant to achieving successful outcomes for patients using long-term therapy for a chronic disease . Poor adherence to treatment of chronic diseases is a worldwide problem and a key factor impacting the real-life effectiveness of treatment , as defined by a combination of clinical efficacy , adherence and safety . Over the last 50 years there has been a global shift in disease burden from acute to chronic diseases , according to the World Health Organization ( WHO ) . Therefore , as the prevalence of chronic diseases continues to increase , the challenge of poor adherence is likely to rise in magnitude . Adherence is a complex issue that can have a significant impact on quality of life for patients and methods aim ing to improve the patient experience are widely sought . There has been a transition over time from a more traditional ‘ compliance’-focused medical environment to one of ‘ adherence ’ , which actively involves the patient in their care regimen and this change is promoted by WHO as part of a multifaceted approach . In a study investigating the redemption of initial prescriptions of topical and systemic treatments for dermatologic conditions , psoriasis patients appeared to be least adherent with nearly 50 % of prescriptions unfilled . To maximize positive patient outcomes to therapy for psoriasis , it is essential that we underst and the reasons underlying non-adherence . In psoriasis , adherence has been linked with factors including efficacy , safety perceptions , ease of use , and the healthcare professional – patient relationship . For topical products , non-adherence may be further exacerbated by the necessity of application , which can be cumbersome and time consuming ; this is combined with patients ’ poor acceptability of certain treatment vehicles , such as ointments , that tend to be perceived as messy . Psoriasis , although generally not life-threatening , can have a significant impact on physical , psychological and social wellbeing , particularly related to the overt appearance of skin lesions and the psychological burden of stigma . Nonadherence and the challenges that ensue are discussed in greater depth with respect to topical psoriasis treatment in the article entitled , ‘ Non-adherence and measures to improve adherence in the topical treatment of psoriasis ’ , pages 4–9 within this supplement . Current guidelines for the first-line treatment of mild-tomoderate psoriasis recommend the topical use of vitamin D analogues and corticosteroids . The development of a fixeddose combination topical gel containing the vitamin D analogue calcipotriol and the corticosteroid betamethasone dipropionate has provided a user-friendly once-daily therapy option and shows superior efficacy over the individual active components administered as monotherapies and is well tolerated in patients with mild-to-moderate psoriasis .  Safety concerns associated with the single agents are also attenuated as the steroid component of the fixed combination gel lowers the incidence of skin irritation sometimes experienced with use of vitamin D analogues , and calcipotriol potentially reduces steroid-induced skin atrophy . Twelve clinical trials have evaluated the efficacy and safety of calcipotriol plus betamethasone dipropionate gel ( referred to here as a ‘ fixed combination ’ gel ) , for the treatment of psoriasis of the scalp ( seven studies ) and body ( five studies ) , with 3767 patients receiving this treatment in total . All studies demonstrated improved efficacy of the fixed combination gel versus active and vehicle comparators with a favourable safety and tolerability profile . Four international , Phase 3 trials ( two each for scalp and body psoriasis ) assessed short-term ( 8-week ) treatment , and an additional Phase 3 study in scalp psoriasis assessed the safety of long-term ( 52-week ) treatment . Across all clinical trials , increased efficacy over time ( week 8 versus week 4 ) has been demonstrated with the fixed combination gel for treatment of psoriasis of both body and scalp . A recent , pooled analysis of 8-week safety data from 9 of these 12 clinical trials evaluating once-daily fixed combination gel treatment of the scalp ( six studies ) and body ( three studies ) , is presented in an article within this supplement by Kragballe and van de Kerkhof , pages 10–21 . The incidence of adverse events and adverse drug reactions is consistently low in patients treated with the fixed combination gel , providing evidence for the good overall tolerability of this topical treatment for psoriasis . Accompanying pharmacovigilance data supports the favourable tolerability profile demonstrated in the clinical trials for the fixed combination gel and also its use in a real-world setting . The notion of real-life effectiveness of treatment has been described as a product of clinical efficacy , adherence and safety . However , in a real-life setting , less constrained by clinical rigours , there is a paucity of data to shed light on effectiveness . As described in the article on expert recommendations , of which we are co- authors , pages 22–32 , only two prospect i ve , short-term ( 4-week ) , non-interventional studies assessing the effectiveness of the fixed combination gel in daily practice ( both in Germany ) have been published to date . By the end of treatment there was an approximate decrease of 60–70 % in the proportions of patients presenting with at least moderate severity scalp psoriasis , as assessed by the investigator ’s global assessment ( IGA ) Abstract Objective : Fixed-dose combination therapy reduces pill burden and may , therefore , improve medication adherence and health outcomes . This study compared adherence to and persistence with single- , double- , and triple-pill treatment regimens among hypertensive patients in a US clinical practice setting . Methods : Adults with hypertension treated with three anti-hypertensive medications were identified . Index date was the first occurrence of a single- , double- , or triple-pill regimen with olmesartan or valsartan plus amlodipine and hydrochlorothiazide from July 2010 to September 2011 . Patients were followed for 12 months to assess adherence ( proportion of days covered [ PDC ] ≥ 80 % ) and time to discontinuation ( medication gap ≥60 days ) of the index regimen . Multivariate regression models were used to compare adjusted outcomes . Results : The number of prescribed pills in the index regimen was monotonically related to adherence with 55.3 % , 40.4 % and 32.6 % of patients having PDC ≥80 % in the single- , double- and triple-pill cohorts , respectively . In adjusted analysis , patients in the double- ( odds ratio [ OR ] : 0.45 ; 95 % confidence interval [ CI ] : 0.42–0.48 ) and triple-pill ( OR : 0.26 ; 95 % CI : 0.22–0.30 ) cohorts were less likely to be adherent to their index regimens than those in the single-pill cohort . Double-pill ( hazard ratio [ HR ] : 1.89 ; 95 % CI : 1.74–2.06 ) and triple-pill patients ( HR : 2.49 ; 95 % CI : 2.14–2.88 ) were more likely to discontinue treatment than single-pill patients . Conclusions : Greater pill burden was directly and significantly associated with decreased adherence and persistence with antihypertensive therapies in real- practice setting s. Use of fixed-dose combinations that reduce pill burden could help patients to continue treatment and may result in improved clinical outcomes . Typical of observational studies , the potential for residual confounding of adherence estimates remains due to lack of r and omization of treatment groups The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events ( OPERA ) trial is a large clinical trial of omapatrilat , a vasopeptidase inhibitor , in patients with stage 1 isolated systolic hypertension ( ISH ) . OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition . This 5-year multinational , r and omized , double-blind , parallel-group , placebo-controlled , forced-titration study will be conducted in approximately 12,600 subjects r and omized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years . The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat ( target dose 40 mg ) will reduce cardiovascular ( CV ) morbidity and mortality in older ( > or = 65 years ) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence -based requirement for treatment .  Blood pressure inclusion criteria are  systolic blood pressure ( SBP ) 140 to 159 mm Hg ( SBP 125 to 139 mm Hg in diabetic individuals ) and diastolic blood pressure ( DBP ) < 90 mm Hg . The primary end point is defined as the composite of fatal/nonfatal stroke , fatal/nonfatal myocardial infa rct ion , fatal/nonfatal heart failure , and other CV mortality . Secondary end points include the individual components of the primary end point , CV mortality , and major cardiovascular end points , as well as effects on cognitive function and initiation of treatment for diabetes . Additional analyses will be conducted in men and women , in diabetic patients , in different risk classes and according to prior evidence of vascular disease Objective To compare the incidence of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy  , and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials . Methods The Felodipine Event Reduction ( FEVER ) trial was an investigator- design ed , prospect i ve , multicentre , double-blind , r and omized , placebo-controlled , parallel group trial . It enrolled 9800 Chinese patients , of either sex , aged 50–79 years , with one or two additional cardiovascular risk factors or disease , whose blood pressure , 6 weeks after switching from previous antihypertensive therapy to low-dose ( 12.5 mg a day ) hydrochlorothiazide , was in the range 140–180 mmHg ( systolic ) or 90–100 mmHg ( diastolic ) . These patients were r and omly assigned either to low-dose felodipine extended release or placebo , and followed at 3-month intervals for an average of 40 months . Results The intention-to-treat analysis included 9711 r and omly selected patients with only 30 ( 0.3 % ) lost to follow-up . A total of 31 842 patient-years of follow-up were accumulated , with 85.9 % of patients remaining on blinded r and omized treatment . Add-on therapy was given to 33.9 % of the hydrochlorothiazide – felodipine patients and to 42.3 % of the hydrochlorothiazide – placebo patients . In the felodipine  group , systolic blood pressure (SBP)/diastolic blood pressure ( DBP ) decreased ( from r and omization to study end ) from 154.2/91.0 to 137.3/82.5 mmHg , and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg , with an average difference throughout the trial of 4.2/2.1 mmHg . In the felodipine group , the primary endpoint ( fatal and non-fatal stroke ) was reduced by 27 % ( P = 0.001 ) . Among secondary endpoints , all cardiovascular events were reduced by 27 % ( P < 0.001 ) , all cardiac events by 35 % ( P = 0.012 ) , death by any cause by 31 % ( P = 0.006 ) , coronary events by 32 % ( P = 0.024 ) , heart failure by 30 % ( P = 0.239 ) , cardiovascular death by 33 % ( P = 0.019 ) , cancer by 36 % ( P = 0.017 ) in the felodipine group . No significant differences were found in new-onset diabetes . Both treatments were very well tolerated . Conclusions In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg , such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide , is associated with very substantial reductions in the incidence of most types of cardiovascular events . As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg , and SBP in the placebo group was slightly above that level , FEVER provides the required evidence in support of the guidelines recommended goal , even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACEI = angiotensin-converting enzyme inhibitor ; ADVANCE = Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BCR-QR = bromocriptine quick release ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CHD = coronary heart disease ; CKD = chronic kidney disease ; CVD = cardiovascular disease ; DASH = Dietary Approaches to Stop Hypertension ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ;  HDL-C = high-density lipoprotein cholesterol ; IMPROVE-IT = Improved Reduction of Outcomes : Vytorin Efficacy International Trial ; LDL-C = low-density lipoprotein cholesterol ; LDL-P = low-density lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium glucose cotransporter-2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione ; VADT = Veterans Affairs Diabetes Trial ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACE = American College of Endocrinology ; ACEI = angiotensin-converting enzyme inhibitor ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ARB = angiotensin II receptor blocker ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CGM = continuous glucose monitoring ; CHD = coronary heart disease ; CKD = chronic kidney disease ; DKA = diabetic ketoacidosis ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; EPA = eicosapentaenoic acid ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ;  HDL-C = high-density-lipoprotein cholesterol ; HeFH = heterozygous familial hypercholesterolemia ; LDL-C = low-density-lipoprotein cholesterol ; LDL-P = low-density-lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium-glucose cotransporter 2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione Background and Purpose — Numerous effective strategies for the secondary prevention of cardiovascular events in high-risk patients have now been established . We sought to calculate the cumulative benefit of combining multiple strategies for preventing recurrent events in patients with a history of ischemic stroke or transient ischemic attack . Methods — A comprehensive literature search was undertaken to identify meta-analyses of r and omized controlled trials reporting on the efficacy of secondary prevention strategies . The baseline incidence of vascular events was modeled from the Life Long After Cerebral Ischemia study . Strategies were combined on a multiplicative scale and cumulative risk reductions were computed over a 5-year interval . Results — The combination of 5 proven strategies applied to survivors of an initial stroke or transient ischemic attack — dietary modification , exercise , aspirin , a statin , and an antihypertensive agent — could result in a cumulative relative risk reduction of 80 % . Given a 5-year major cardiovascular event rate of 24 % , this translates to a number needed to treat of about 5 . Further gains would result from applying multimodality therapy over longer intervals and enriching the base strategy with dual antiplatelet therapy , high-dose statins , and more intensive blood pressure – lowering . Even more benefit would be present in high-risk subgroups with the addition , where appropriate , of carotid endarterectomy , moderate intensity oral anticoagulants , glycemic control , and smoking cessation . Conclusions — At least four-fifths of recurrent vascular events in patients with cerebrovascular disease might be prevented by application of a comprehensive , multifactorial approach 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 Objective The purpose of this study was to investigate the consistency of the proportional effect of fixed-dose combination therapy ( the ‘ polypill ’ ) on the use of recommended cardiovascular preventative medications among indigenous Māori and non-indigenous adults in New Zeal and . Methods We r and omised Māori and non-Māori primary care patients at high risk of cardiovascular disease ( either because of a prior event or with an estimated 5-year risk of a first event of at least 15 % ) to a polypill ( containing aspirin , statin and two antihypertensives ) or usual care for a minimum of 12 months . All patients had indications for all polypill components according to their general practitioner , and all medications ( including the polypill )  were prescribed by the patient ’s general practitioner and dispensed at community pharmacies . The main outcome for this study was the use of all recommended medications ( antiplatelet , statin and two antihypertensives ) at 12 months . Heterogeneity in the effect of polypill-based care compared with usual care on this outcome by ethnicity was assessed by logistic regression . Results Baseline use of recommended medications was 36 % ( 93/257 ) among Māori and 51 % ( 130/156 ) among non-Māori participants .  Polypill-based care was associated with an increase in the use of recommended medications among Māori ( relative risk [ RR ] : 1.87 ; 95 % confidence interval [ CI ] : 1.50–2.34 ) and non-Māori ( RR : 1.66 ; 95 % CI : 1.37–2.00 ) when compared with usual care at 12 months , and there was no statistically significant heterogeneity in this outcome by ethnicity ( p = 0.92 ) . Conclusion Polypill-based care is likely to reduce absolute inequities between Māori and non-Māori in the use of recommended cardiovascular preventative medications given baseline absolute differences and the consistency of the proportional effect of this intervention by ethnicity in this pragmatic trial in primary care Diabetes incidence is increasing rapidly in the United States . Diabetes increases the risk for cardiovascular disease , the major cause of death in diabetic individuals . The conventional cardiovascular risk factors of hyperlipidemia and hypertension worsen diabetic vascular disease . Treatment targets for low-density lipoprotein cholesterol ( LDL-C ) and blood pressure in diabetic individuals are being debated . The S AND S is a r and omized , open-label , 3-year trial to examine the effects of aggressive LDL-C ( goal < 70 mg/dL ) and blood pressure ( BP ) ( goal < 115/75 mm Hg ) reduction versus the st and ard goals of < 100 mg/dL for LDL-C and < 130/85 mm Hg for BP .  Five hundred forty-nine American-Indian men and women > 40 years old with type 2 diabetes were r and omized to 1 of 2 groups . Lipids and BP are managed using Food and Drug Administration-approved medications in an algorithmic approach . The presence and progression of atherosclerosis are evaluated by carotid ultrasonography ; echocardiography assesses cardiac function . The primary end point is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events . These outcomes are combined by using a ranked analysis for carotid thickness and assigning a " worst rank " for a cardiovascular event . Secondary end points include carotid plaque score , left ventricular geometry and function , serum C-reactive protein , and safety measures . Unique aspects of the study design and analysis plan involve the use of a composite outcome and changes during the trial of LDL-C treatment goals for participants with baseline or incident cardiovascular disease in the conventional group because of changes in the st and ard of care . Study results will further underst and ing of the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in US population s and will help determine optimal LDL-C and BP treatment goals for diabetic patients 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
The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain .
A limited number of trials reported these outcomes , and the included trials were primarily design ed to observe changes in ASCVD risk factor levels rather than clinical events , which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials .
Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo , active comparator , or usual care but may be associated with improved adherence to a multidrug regimen .
Ongoing , longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes
BACKGROUND Atherosclerotic cardiovascular disease ( ASCVD ) is the leading cause of death and disability worldwide , yet ASCVD risk factor control and secondary prevention rates remain low .
A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill , or polypill , has been proposed as one strategy to reduce the global burden of ASCVD .
OBJECTIVES To determine the effect of fixed-dose combination therapy on all-cause mortality , fatal and non-fatal ASCVD events , and adverse events .
We also sought to determine the effect of fixed-dose combination therapy on blood pressure , lipids , adherence , discontinuation rates , health-related quality of life , and costs .