title: Additive Beneficial Effects of Valsartan Combined with Rosuvastatin in the Treatment of Hypercholesterolemic Hypertensive Patients Proactive Multifactorial Intervention Strategy Reduces the Risk of Cardiovascular Disease Estimated with Region-Specific Risk Assessment Models in Pacific Asian Patients Participating in the CRUCIAL Trial A polypill strategy to improve adherence: results from the FOCUS project. The combined use of aspirin, a statin, and blood pressure-lowering agents (polypill components) and the risk of vascular morbidity and mortality in patients with coronary artery disease. Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: an 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong) Simplified therapeutic intervention to control hypertension and hypercholesterolemia: a cluster randomized controlled trial (STITCH2) Rationale and design of the Kanyini guidelines adherence with the polypill (Kanyini-GAP) study: a randomised controlled trial of a polypill-based strategy amongst Indigenous and non Indigenous people at high cardiovascular risk Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial An International Randomised Placebo-Controlled Trial of a Four-Component Combination Pill (“Polypill”) in People with Raised Cardiovascular Risk Impact of switching from different treatment regimens to a fixed-dose combination pill (polypill) in patients with cardiovascular disease or similarly high risk Reduction in cardiovascular risk using a proactive multifactorial intervention is consistent among patients residing in Pacific Asian and non-Pacific Asian regions: a CRUCIAL trial subanalysis Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study Recruiting equal numbers of indigenous and non-indigenous participants to a ‘polypill’ randomized trial Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives. A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization Slovak Trial on Cardiovascular Risk Reduction Following National Guidelines with CaDUET® (The STRONG DUET Study) Pharmacokinetics of a telmisartan/rosuvastatin fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects. Zofenopril Plus Hydrochlorothiazide and Irbesartan Plus Hydrochlorothiazide in Previously Treated and Uncontrolled Diabetic and Non-diabetic Essential Hypertensive Patients Randomized Polypill Crossover Trial in People Aged 50 and Over INterpreting the Processes of the UMPIRE Trial (INPUT): protocol for a qualitative process evaluation study of a fixed-dose combination (FDC) strategy to improve adherence to cardiovascular medications An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes Cardiovascular disease risk reduction in rural China: a clustered randomized controlled trial in Zhejiang Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation The Effect of a Cardiovascular Polypill Strategy on Pill Burden. Effects of an optimised POCT guided diagnostic and treatment strategy for symptoms of uncomplicated UTI on use of appropriate antibiotics and uptake into primary care practice Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo-controlled, multicenter study. Effects of renin-angiotensin blockers/inhibitors and statins on mortality and functional impairment in polypathological patients. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors. Proactive multiple cardiovascular risk factor management compared with usual care in patients with hypertension and additional risk factors: the CRUCIAL trial Patients’ and Providers’ Perspectives of a Polypill Strategy to Improve Cardiovascular Prevention in Australian Primary Health Care: A Qualitative Study Set Within a Pragmatic Randomized, Controlled Trial Pharmacokinetics of rosuvastatin/olmesartan fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects. Reduction in cardiovascular risk using proactive multifactorial intervention versus usual care in younger (<65 years) and older (≥65 years) patients in the CRUCIAL trial Characteristics and lipid distribution of a large, high-risk, hypertensive population: the lipid-lowering component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The Evening versus Morning Polypill Utilization Study: the TEMPUS rationale and design PolyPill for Prevention of Cardiovascular Disease in an Urban Iranian Population with Special Focus on Nonalcoholic Steatohepatitis: A Pragmatic Randomized Controlled Trial within a Cohort (PolyIran - Liver) - Study Protocol. Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Cardiovascular complications of HIV: an overview of risk and a novel approach to prevention – the HIV polypill study Reliability Analysis of a Newly Developed Questionnaire for Quality Control of Follow-up Visits in PolyIran Study. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial An economic case for a cardiovascular polypill? A cost analysis of the Kanyini GAP trial. A randomized, placebo-controlled trial to evaluate the efficacy, safety, and pharmacodynamic interaction of coadministered amlodipine and atorvastatin in 1660 patients with concomitant hypertension and dyslipidemia: the respond trial. Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE): rationale and design of a randomised controlled trial of a cardiovascular preventive polypill-based strategy in India and Europe Polypill-based therapy likely to reduce ethnic inequities in use of cardiovascular preventive medications: Findings from a pragmatic randomised controlled trial Facilitators and barriers to implementation of a pragmatic clinical trial in Aboriginal health services. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care IMProving Adherence using Combination Therapy (IMPACT): design and protocol of a randomised controlled trial in primary care. Changes in calculated coronary heart disease risk using proactive multifactorial intervention versus continued usual care in Latin-American and non-Latin-American patients enrolled in the CRUCIAL trial Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. Efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia: results of the AVALON trial. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Greater cardiovascular risk reduction with once-daily fixed combination of three antihypertensive agents and statin versus free-drug combination: The ALL-IN-ONE trial. Is there a BP benefit of changing the time of aspirin administration in treated hypertensive patients?
abstract: Background and Objectives We compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients . Subjects and Methods Patients who met inclusion criteria were r and omized to receive 1 of the following 2-month drug regimens :  valsartan 160 mg plus rosuvastatin 20 mg , valsartan 160 mg plus placebo , or rosuvastatin 20 mg plus placebo . The primary efficacy variables were change in sitting diastolic blood pressure ( sitDBP ) and sitting systolic blood pressure ( sitSBP ) , and percentage change in low-density lipoprotein-cholesterol ( LDL-C ) in the combination , valsartan , and rosuvastatin groups . Adverse events ( AEs ) during the study were analyzed . Results A total of 354 patients were screened and 123 of them were finally r and omized .  Changes of sitDBP by least squares mean ( LSM ) were -11.1 , -7.2 , and -3.6 mm Hg , respectively , and was greater in the combination , as compared to both valsartan ( p=0.02 ) and rosuvastatin ( p<0.001 ) . Changes of sitSBP by LSM were -13.2 , -10.8 , and -4.9 mm Hg , and was greater in the combination , as compared to rosuvastatin ( p=0.006 ) and not valsartan ( p=0.42 ) . Percentage changes of LDL-C by LSM were -52 , -4 , and -47 % in each group , and was greater in the combination , as compared to valsartan ( p<0.001 ) , similar to rosuvastatin ( p=0.16 ) . Most AEs were mild and resolved by the end of the study . Conclusion Combination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability , as compared to valsartan monotherapy . Its lipid lowering effect was similar to rosuvatatin monotherapy Despite race , ethnic , and regional differences in cardiovascular disease risk , many worldwide hypertension management guidelines recommend the use of the Framingham coronary heart disease ( CHD ) risk equation to guide treatment decisions . This sub analysis of the recently published CRUCIAL trial compared the treatment-related reductions in calculated CHD and stroke risk among Pacific Asian ( PA ) patients using a variety of region-specific risk assessment models . As a result , greater reductions in systolic and diastolic blood pressure , low-density lipoprotein cholesterol , and triglycerides were observed in the proactive multifactorial intervention ( PMI ) arm compared with the usual care arm at Week 52 for PA patients . The relative percentage change in 10-yr CHD risk between baseline and Week 52 in the PMI versus usual care arms was greatest using the NIPPON DATA 80 fatal CHD model ( LS [ least square ] mean difference -42.6 % ) , and similar in the SCORE fatal CHD and Framingham total CHD models ( LS mean difference -29.4 % and -30.8 % , respectively ) . The single-pill based PMI approach is consistently effective in reducing cardiovascular disease risk , evaluated using a variety of risk assessment models . ( Clinical Trials.gov registration number : NCT00407537 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 ) 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 The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance . This study aim ed to evaluate the efficacy and safety of fixed-dose combination ( FDC ) therapy with olmesartan medoxomil ( 40 mg ) and rosuvastatin ( 20 mg ) in Korean patients with mild to moderate hypertension and dyslipidemia . This multicenter , r and omized , double-blind , factorial- design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia . Patients were r and omly assigned to receive FDC therapy ( 40 mg olmesartan medoxomil , 20 mg rosuvastatin ) , 40 mg olmesartan medoxomil , 20 mg rosuvastatin , or a placebo . The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil , and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment . A total of 162 patients were included . The least square mean percentage change ( st and ard error ) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group ( −52.3 % [ 2.8 % ] vs −0.6 % [ 3.5 % ] , P<0.0001 ) , and the difference was −51.7 % ( 4.1 % ) ( 95 % confidence interval : −59.8 % to −43.6 % ) . The least square mean change ( st and ard error ) from baseline in diastolic blood pressure 8 weeks after treatment was significantly greater in the FDC group than in the rosuvastatin group ( −10.4 [ 1.2 ] mmHg vs 0.1 [ 1.6 ] mmHg , P<0.0001 ) , and the difference was −10.5 ( 1.8 ) mmHg ( 95 % confidence interval : −14.1 to −6.9 mmHg ) . There were 50 adverse events in 41 patients ( 22.7 % ) and eight adverse drug reactions in five patients ( 2.8 % ) . The study found that FDC therapy with olmesartan medoxomil and rosuvastatin is an effective , safe treatment for patients with hypertension and dyslipidemia . This combination may improve medication compliance in patients with a large pill burden Background : Notwithst and ing improving rates of hypertension control in North America , management of patients with both hypertension and dyslipidemia remains problematic . Based on evidence of improved control utilizing a simplified algorithm for management of hypertension ( STITCH ) , we question ed whether a simplified comprehensive treatment algorithm featuring initial use of single-pill combinations ( SPCs ) would improve management of participants with both hypertension and dyslipidemia . Method : We r and omized 35 primary care practice s in Ontario to either Guidelines -care (  following current Canadian guidelines ) or STITCH2-care ( following a treatment algorithm featuring SPCs ) . Practice s each enrolled up to 50 participants with at least one risk factor above target at entry based on Canadian guidelines for BP and LDL-cholesterol control . The primary endpoint was achieving targets for both hypertension and dyslipidemia control after 6 months , assessed at the practice level . Results : The primary endpoint was achieved in 31.3 % of participants in STITCH2-care practice s , compared with 28.1 % in Guidelines -care practice s , yielding a difference of 3.2 % ( P = 0.63 ) . Notably , STITCH2-care practice s had a significantly greater reduction in SBP while LDL-cholesterol reduction was only marginally greater in STITCH2 practice s. Conclusion : The STITCH2 algorithm result ed in significantly greater use of any SPC compared with Guidelines -care and greater use of the SPC of calcium channel blocker/statin . Unwillingness of the prescribing physician to advance treatment beyond a monotherapy threshold was found to be an important determinant for failing to achieve blood pressure control . In contrast , the more important determinant for failing to achieve LDL control appeared to be the unwillingness of the prescribing physician to initiate therapy with a statin 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 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 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 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 Few trials have compared different approaches to cardiovascular disease prevention among Pacific Asian ( PA ) population s. The Cluster R and omized Usual Care versus Caduet Investigation Assessing Long-term-risk ( CRUCIAL ) trial demonstrated that a proactive multifactorial intervention ( PMI ) approach ( based on single-pill amlodipine/atorvastatin ) result ed in a greater reduction in calculated Framingham 10-year coronary heart disease ( CHD ) risk compared with usual care ( UC ) among hypertensive patients with additional risk factors . One-third of CRUCIAL patients resided in the PA region . The aim of this sub analysis was to compare two approaches to cardiovascular risk factor management ( PMI versus UC ) among patients residing in PA and non-PA regions . Methods This sub analysis of the CRUCIAL trial compared treatment-related changes in calculated CHD risk among patients residing in PA and non-PA regions . Sensitivity analyses were conducted among men and women and those with and without diabetes . Results Overall , 448 patients ( 31.6 % ) resided in the PA region and 969 patients ( 68.4 % ) resided in non-PA regions . The PMI approach was more effective in reducing calculated CHD risk versus UC in both PA ( −37.1 % versus −3.5 % ; P<0.001 ) and non-PA regions ( −31.1 % versus −4.2 % ; P<0.001 ) ; region interaction P=0.131 . PA patients had slightly greater reductions in total cholesterol compared with non-PA patients . PA patients without diabetes had slightly greater reductions in CHD risk compared with non-PA patients . Treatment effects were similar in men and women and those with diabetes . Conclusion The PMI approach was more effective in reducing calculated Framingham 10-year CHD risk compared with UC among men and women with and without diabetes residing in the PA and non-PA region Objective Despite antihypertensive treatment , most hypertensive patients still have high blood pressure ( BP ) , notably high systolic blood pressure ( SBP ) . The EFFICIENT study examines the efficacy and acceptability of a single-pill combination of sustained-release ( SR ) indapamide , a thiazide-like diuretic , and amlodipine , a calcium channel blocker ( CCB ) , in the management of hypertension . Methods Patients who were previously uncontrolled on CCB monotherapy ( BP≥140/90 mm Hg ) or were previously untreated with grade 2 or 3 essential hypertension ( BP≥160/100 mm Hg ) received a single-pill combination tablet containing indapamide SR 1.5 mg and amlodipine 5 mg daily for 45 days , in this multicenter prospect i ve phase 4 study . The primary outcome was mean change in BP from baseline ; percentage of patients achieving BP control ( BP<140/90 mm Hg ) was a secondary endpoint . SBP reduction ( ΔSBP ) versus diastolic BP reduction ( ΔDBP ) was evaluated ( ΔSBP/ΔDBP ) from baseline to day 45 . Safety and tolerability were also assessed . Results Mean baseline BP of 196 patients ( mean age 52.3 years ) was 160.2/97.9 mm Hg . After 45 days , mean SBP decreased by 28.5 mm Hg ( 95 % CI , 26.4 to 30.6 ) , while diastolic BP decreased by 15.6 mm Hg ( 95 % CI , 14.5 to 16.7 ) . BP control ( < 140/90 mm Hg ) was achieved in 85 % patients . ΔSBP/ΔDBP was 1.82 in the overall population . Few patients ( n = 3 [ 2 % ] ) reported side effects , and most ( n = 194 [ 99 % ] ) adhered to treatment . Conclusion In patients who were previously uncontrolled on CCB monotherapy or untreated with grade 2 or 3 hypertension , single-pill combination indapamide SR/amlodipine  reduced BP effectively — especially SBP— over 45 days , and was safe and well tolerated . Trial Registration Clinical Trial Registry – India Introduction Māori are disproportionately affected by cardiovascular disease ( CVD ) , which is the main reason for the eight year difference in life expectancy between Māori and non-Māori . The primary care-based IMPACT ( IMProving Adherence using Combination Therapy ) trial evaluates whether fixed dose combination therapy ( a “ polypill ” ) improves adherence to guideline -based therapy compared with current care among people at high risk of CVD . Interventions shown in trials to be effective do not necessarily reduce ethnic disparities , and may in fact widen them . Indigenous population s with poorer health outcomes are often under-represented in trials so the effect of interventions can not be assessed for them , specifically . Therefore , the IMPACT trial aim ed to recruit as many Māori as non-Māori to assess the consistency of the effect of the polypill . This paper describes the methods and results of the recruitment strategy used to achieve this . Methods Experienced Māori research ers were involved in trial governance throughout trial development and conduct . The trial Steering Committee included leading Māori research ers and was committed to equal recruitment of Māori and non-Māori . Additional funding and Māori research nurses were sought to allow home-based assessment , establishment of the relationship between research nurse and participant , more family involvement prior to enrollment , continuity of the research nurse-participant relationship , and acknowledgement of other Māori culturally important procedures , interactions , language and manners . Primary care practice s with high enrollment of Māori were targeted , with over-sampling of potentially eligible Māori patients , lower thresholds for screening of Māori and 6 months continued Māori recruitment after non-Māori recruitment had finished . Results A total of 257 Māori and 256 non-Māori participants were r and omized . Four Māori and eight non-Māori participants were r and omized per research nurse per month . Potentially eligible Māori were more likely than non-Māori to proceed to subsequent stages of recruitment . Differences between r and omized Māori and non-Māori were evident ( e.g. Maori were less likely to have established coronary artery disease ) . Conclusions Recruitment of equal numbers of indigenous and non-indigenous participants is possible if it is prioritised , adequately re source d and self-determination is supported . Trial registration The trial is registered with the Australian New Zeal and Clinical Trial Registry 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 BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . METHODS Of 19342 hypertensive patients ( aged 40 - 79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . FINDINGS Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50 - 0.83 ] , p=0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56 - 0.96 ] , p=0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69 - 0.90 ] , p=0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59 - 0.86 ] , p=0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71 - 1.06 ] , p=0.16 ) . Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines A line of epidemiological studies suggests that the accumulation of coronary risk factors promotes the progression of coronary atherosclerosis . Recent clinical studies showed that aggressive low-density lipoprotein ( LDL ) cholesterol-lowering therapy using statins could regress coronary atheroma and reduce major cardiovascular events . Additionally , therapy that controlled amlodipine-based blood pressure reduced major cardiovascular events in patients with hypertension compared with an atenolol-based regimen . An open-label r and omized multicenter study is primarily planned to evaluate the changes in coronary atheroma volume using intravascular ultrasonography 18–24 months after intensive lowering of LDL-cholesterol and blood pressure compared with a st and ard therapy indicated by current guidelines in Japanese patients with coronary artery disease ( CAD ) . The secondary endpoints include changes in serum lipid levels , inflammatory markers , glucose markers and blood pressure .  In total , 100 subjects with CAD who are undergoing percutaneous coronary intervention will be tested . The MILLION study will provide new evidence and therapeutic st and ards for the prevention of CAD in Japanese patients by controlling both LDL-C levels and blood pressure 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 The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear . More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease ( CVD ) , side effects , improvement in adherence and physician/patient " acceptability " of the Polypill . Methods We conducted an open-label , parallel-group , r and omized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD . The trial compared a Polypill ( 75 mg aspirin , 20 mg simvastatin , 10 mg lisinopril and 12.5 mg hydrochlorothiazide ) to St and ard Practice . After r and omization , patients were followed monthly for three months . Pre-specified primary outcomes included reduction in systolic blood pressure , total cholesterol and estimated 10-year CVD risk . We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients . Results Patients were recruited in a six-month period as planned . Two hundred three patients ( 94.0 % ) completed the treatment program and returned for their three-month follow-up visits . No safety concerns were reported . These findings suggest a high rate of patient acceptability , a finding that is bolstered by the majority of patients completing the trial ( 90 % ) indicating that they would take the Polypill " for life " if proven to be effective in reducing CVD risk . Approximately 86 % of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93 % for secondary prevention of CVD . Both the Polypill and St and ard Practice result ed in marked reductions in systolic blood pressure , total cholesterol and 10-year risk of CVD . However , the differences between the treatment groups were not statistically significant . Conclusions We successfully completed a Polypill feasibility trial in Sri Lanka . We were able to document high acceptability of the Polypill to patients and physicians . We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs . The Polypill was however simpler and achieved comparable risk factor reductions , highlighting its potential usefulness in the prevention of CVD.Trial registration number Clinical trials.gov : Introduction The efficacy and safety of single-pill amlodipine/atorvastatin for reducing blood pressure ( BP ) , low-density lipoprotein cholesterol ( LDLC ) , and predicted 10-year cardiovascular ( CV ) risk have been demonstrated in low CV risk countries . The Slovak Trial on Cardiovascular Risk Reduction Following National Guidelines with CaDUET ® ( amlodipine besylate/atorvastatin calcium ; Pfizer , Morrisville , PA , USA ; STRONG DUET ) study evaluated its clinical utility in Slovakia , one of the highest CV risk regions in Europe . Methods This was a two-phase study involving 100 outpatient cardiologist and internist departments in Slovakia . Phase 1 assessed BP control and CV risk profiles in adults with treated hypertension , and phase 2 was an open-label , multicenter , observational study . In the phase 2 study , patients with treated but uncontrolled hypertension and three or more coronary heart disease risk factors received single-pill amlodipine/atorvastatin ( 5/10 or 10/10 mg ) for 12 weeks . Major outcomes were the percentage of patients achieving target BP ( ≤140/90 mmHg ) and /or LDL-C ( ≤3 mmol/L ) and reductions in predicted 10-year CV risk . Results Of the 4,672 phase 1 patients , 80.8 % had uncontrolled hypertension and 61.4 % had dyslipidemia . Of the 1,406 phase 2 patients , 90.3 % of patients achieved target BP at week 12 , 66.3 % achieved target LDL-C , and 60.7 % achieved both . The mean 10-year CV risk was reduced by 49 % ( P < 0.0001 ) ; treatment was well-tolerated and safe . ConclusionS ingle-pill amlodipine/atorvastatin was associated with significant improvements in BP , LDL-C target attainment , and 10-year CV risk in patients with uncontrolled hypertension in Slovakia . The treatment was well-tolerated and safe . Use of single-pill amlodipine/atorvastatin in high CV-risk countries could lead to significant improvements in CV risk management OBJECTIVE As hypertension and dyslipidemia are frequent comorbidities , antihypertensive drugs and lipid-lowering agents are often prescribed together for their treatment . Telmisartan and rosuvastatin are widely used together to treat hypertension and dyslipidemia . A combination formulation of these two drugs would improve patient compliance due to ease of dosing . The purpose of this study was to assess bioequivalence of single-dose administration of a newly-developed fixed-dose combination ( FDC ) tablet containing telmisartan/rosuvastatin 80/20 mg ( test treatment ) and coadministration of a telmisartan 80-mg tablet and a rosuvastatin 20-mg tablet ( reference treatment ) in healthy Korean male volunteers . METHODS This was a single-dose , r and omized , open-label , 2-period crossover study enrolling healthy males aged 20 - 50 years with BMI between 18.5 and 25 kg/m2 . Each subject received a single dose of the reference and test treatments with a 14-day washout period . Blood sampling was performed at prespecified intervals for up to 72 hours after dosing . Primary pharmacokinetic parameters were Cmax , AUClast , and AUC0-∞ of telmisartan , rosuvastatin , and N-desmethyl rosuvastatin . Bioequivalence was assessed by determining whether the 90 % confidence intervals ( CIs ) of the geometric mean ratios ( test treatment/reference treatment ) of these parameters were within the st and ard range of 80 % to 125 % . Adverse events were monitored via regular interviews with the subjects and by physical examinations . RESULTS 60 subjects were enrolled and 55 completed the study . The 90 % CIs of the geometric mean ratios of Cmax , AUClast , and AUC00-∞ were 0.9262 - 1.1498 , 0.9294 - 1.0313 , and 0.9312 - 1.0320 for telmisartan , 0.9041 - 1.0428 , 0.9262 - 1.0085 , and 0.9307 - 1.0094 for rosuvastatin , and 0.8718 - 1.0022 , 0.8901 - 0.9904 , and 0.8872 - 0.9767 for N-desmethyl rosuvastatin , respectively . There was no statistical difference in the incidence of adverse events ( AEs ) ( all of which were mild or moderate ) between the reference and test treatments . CONCLUSIONS Our findings suggest that the telmisartan/rosuvastatin FDC is bioequivalent to coadministration of separate tablets , and both treatments were safe and well tolerated . Administration of this FDC tablet is expected to improve patient compliance Introduction In most treated patients with hypertension , a two or more drug combination is required to achieve adequate blood pressure ( BP ) control . In our study we assessed whether the combination of zofenopril + hydrochlorothiazide ( HCTZ ) was at least as effective as irbesartan + HCTZ in essential hypertensives with at least one additional cardiovascular risk factor , uncontrolled by a previous monotherapy . Methods After a 2-week placebo washout , 361 treated hypertensive patients [ office sitting diastolic BP ( DBP ) , ≥90 mmHg ] , aged 18–75 years , were r and omized double blind to 18-week treatment with zofenopril 30 mg plus HCTZ 12.5 mg or irbesartan 150 mg plus HCTZ 12.5 mg once daily , in an international , multicenter study . After the first 6 and 12 weeks , zofenopril and irbesartan doses could be doubled in non-normalized subjects . The primary study end point was the office sitting DBP reduction after 18 weeks of treatment . Secondary end points included office systolic BP ( SBP ) , ambulatory BP and high sensitivity C-reactive protein ( hs-CRP ) . Results The between-treatment difference for office DBP averaged to + 1.0 ( 95 % CI −0.4 , + 0.8 ) mmHg ( P = 0.150 ) , the upper limit of the 95 % confidence interval being inferior to the protocol -defined non-inferiority limit ( 3 mmHg ) . In the subset of patients with valid ambulatory BP , no difference in 24-h average DBP [ n = 181 ; 6.7 ( 8.7 , 4.6 ) zofenopril + HCTZ vs. 6.3 ( 8.8 , 3.7 ) mmHg irbesartan + HCTZ , P = 0.810 ] and SBP reductions [ 11.7 ( 15.4 , 8.0 ) vs. 12.6 ( 17.2 , 8.0 ) mmHg , P = 0.758 ] were observed between the two treatment groups . hs-CRP was reduced by zofenopril + HCTZ [ −0.52 ( −1.05 , 0.01 ) mg/L ] , while it was increased by irbesartan plus HCTZ [ 0.97 ( 0.29 , 1.65 ) mg/L , P = 0.001 between treatments ] . Conclusion In previously monotherapy-treated , uncontrolled patients with hypertension , zofenopril 30–60 mg + HCTZ 12.5 mg is as effective as irbesartan 150–300 mg plus HCTZ 12.5 mg , with the added value of a potential protective effect against vascular inflammation Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone . Its efficacy in reducing cholesterol and blood pressure is uncertain . Methods We conducted a r and omized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50 + without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs . Participants took the Polypill ( amlodipine 2.5 mg , losartan 25 mg , hydrochlorothiazide 12.5 mg and simvastatin 40 mg ) each evening for 12 weeks and a placebo each evening for 12 weeks in r and om sequence . The mean within-person differences in blood pressure and low density lipoprotein ( LDL ) cholesterol at the end of each 12 week period were determined . Results 84 out of 86 participants completed both treatment periods . The mean systolic blood pressure was reduced by 17.9 mmHg ( 95 % CI , 15.7–20.1 ) on the Polypill , diastolic blood pressure by 9.8 mmHg ( 8.1–11.5 ) , and LDL cholesterol by 1.4 mmol/L ( 1.2–1.6 ) , reductions of 12 % , 11 % , and 39 % respectively . The results were almost identical to those predicted ; 18.4 mmHg , 9.7 mmHg , and 1.4 mmol/L respectively . Conclusion The Polypill result ed in the predicted reductions in blood pressure and LDL cholesterol . Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes . Trial Registration Controlled-Trials.com IS RCT 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 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 compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large sub population ( n = 5137 ) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial . Methods Patients had either untreated hypertension or treated hypertension . For those with type II diabetes mellitus , inclusion criteria required at least two additional risk factors . Patients were r and omized to amlodipine with addition of perindopril as required ( amlodipine-based ) or atenolol with addition of thiazide as required ( atenolol-based ) . Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg . Results The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen . In patients with diabetes mellitus , the amlodipine-based treatment reduced the incidence of the composite endpoint – total cardiovascular events and procedures – compared with the atenolol-based regimen ( hazard ratio 0.86 , confidence interval 0.76–0.98 , P = 0.026 ) . Fatal and nonfatal strokes were reduced by 25 % ( P = 0.017 ) , peripheral arterial disease by 48 % ( P = 0.004 ) and noncoronary revascularization procedures by 57 % ( P < 0.001 ) . For the other endpoints included in the composite , the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infa rct ions ( the primary endpoint ) , which were reduced nonsignificantly by 8 % ( hazard ratio 0.92 , confidence interval 0.74–1.15 ) . Conclusion In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Sc and inavian Cardiac Outcomes Trial , the benefits of amlodipine-based treatment , compared with atenolol-based treatment , on the incidence of total cardiovascular events and procedures was significant ( 14 % reduction ) and similar to that observed in the total trial population ( 16 % reduction ) Background Cardiovascular disease ( CVD ) is a major cause of death in China . Despite government efforts , the majority of hypertensive and diabetic patients in China do not receive proper treatment . Reducing CVD events requires long-term care that is proactive , patient-centred , community-based , and sustainable . We have design ed a package of interventions for patients at high risk of CVD to be implemented by family doctors based in township hospitals ( providers of primary care ) in rural Zhejiang , China . This trial aims to determine whether the systematic CVD risk reduction package results in reduced CVD events among patients at risk of CVD compared with usual care , and whether the package is cost-effective and suitable for routine implementation and scale-up . Methods / Design This is a prospect i ve , open-label , cluster r and omized controlled trial ( RCT ) with blinded data analysis . The trial will r and omize 67 township hospitals with 31,708 participants in three counties in Zhejiang Province . Participants will be identified from existing health records and will comprise adults aged 50 to 74 years , with a calculated 10-year CVD risk of 20 % or higher , or diabetes . In the intervention arm , participants will receive a package of interventions including : 1 ) healthy lifestyle counseling ( smoking cessation , and salt , oil , and alcohol reduction ) ; 2 ) prescription of a combination of drugs ( antihypertensives , aspirin , and statin ) ; and 3 ) adherence support for drug compliance and healthy lifestyle change . In the control arm , participants will receive usual care for hypertension and diabetes management at individual clinicians ’ discretion . The primary outcome is the incidence of severe CVD events over 24 months of follow-up . All CVD events will be defined according to the World Health Organization ( WHO ) monitoring of trends and determinants in cardiovascular disease ( MONICA ) definitions , diagnosed at the county hospital or higher level , and reported by the Zhejiang surveillance system . Secondary outcomes include : mean systolic and diastolic blood pressure , blood glucose , serum total cholesterol ( TC ) , and adherence to appointments , and drugs and lifestyle changes . Discussion This trial focuses on risk reduction of CVD rather than specific diseases . It is not design ed to compare therapeutic and healthy lifestyle interventions , but rather their combined effects in primary care setting s. Through the trial , we intend to underst and the effectiveness of the comprehensive CVD reduction package in routine practice . We also intend to underst and the barriers and facilitators to implementing the package , and thus to advise on policy and practice change . Trial registration Current Controlled Trials : IS RCT Background Patients with hypertension and cardiovascular disease ( CVD ) , diabetes , or chronic kidney disease ( CKD ) usually require two or more antihypertensive agents to achieve blood pressure ( BP ) goals . Methods The efficacy/safety of olmesartan ( OM ) 40 mg , amlodipine besylate ( AML ) 10 mg , and hydrochlorothiazide ( HCTZ ) 25 mg versus the component dual-combinations ( OM 40/AML 10 mg , OM 40/HCTZ 25 mg , and AML 10/HCTZ 25 mg ) was evaluated in participants with diabetes , CKD , or chronic CVD in the Triple Therapy with Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) . The primary efficacy end point was least squares ( LS ) mean reduction from baseline in seated diastolic BP ( SeDBP ) at week 12 . Secondary end points included LS mean reduction in SeSBP and proportion of participants achieving BP goal ( < 130/80 mm Hg ) at week 12 ( double-blind r and omized period ) , and LS mean reduction in SeBP and BP goal achievement at week 52/early termination ( open-label period ) . Results At week 12 , OM 40/AML 10/HCTZ 25 mg result ed in significantly greater SeBP reductions in participants with diabetes ( −37.9/22.0 mm Hg vs −28.0/17.6 mm Hg for OM 40/AML 10 mg , −26.4/14.7 mm Hg for OM 40/HCTZ 25 mg , and −27.6/14.8 mm Hg for AML 10/HCTZ 25 mg ) , CKD ( −44.3/25.5 mm Hg vs −39.5/23.8 mm Hg for OM 40/AML 10 mg , −25.3/17.0 mm Hg for OM 40/HCTZ 25 mg , and −33.4/20.6 mm Hg for AML 10/HCTZ 25 mg ) , and chronic CVD ( −37.8/20.6 mm Hg vs −31.7/18.2 mm Hg for OM 40/AML 10 mg , −30.9/17.1 mm Hg for OM 40/HCTZ 25 mg , and −27.5/16.1 mm Hg for AML 10/HCTZ 25 mg ) ( P<0.05 for all subgroups vs dual-component treatments ) . BP goal achievement was greater for participants receiving triple-combination treatment compared with the dual-combination treatments , and was achieved in 41.1 % , 55.0 % , and 38.9 % of participants with diabetes , CKD , and chronic CVD on OM 40/AML 10/HCTZ 25 mg , respectively . At week 52 , there was sustained BP lowering with the OM/AML/HCTZ regimen . Overall , the triple combination was well tolerated . Conclusions In patients with diabetes , CKD , or chronic CVD , short-term ( 12 weeks ) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated , lowered BP more effectively , and enabled more participants to reach BP goal than the corresponding 2-component regimens . Trial Identification Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently 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 Patients presenting with UTI symptoms are among the most frequent clinical presentations in primary care accounting for 15 % of all community antibiotic prescriptions . The diagnostic accuracy of clinical assessment and the most appropriate management of uncomplicated UTI remain unclear . Primary care clinicians are more likely to treat empirically without additional testing . Some advances are being made in the development of novel Point of Care Tests ( POCTs ) for diagnosis of infection and antibiotic resistance in primary care . The incorporation of a test , which enumerates and identifies pathogens and their antibiotic resistance , into a management strategy for UTI has great potential for improving patient outcomes reducing antibiotic use and in turn in reducing the incidence of antimicrobial resistance . While some new promising POCT technologies are being developed , these have not been fully evaluated in primary care . Robust evaluation , providing solid evidence supporting POCT use , which is based on patient benefit , cost-effectiveness , therapeutic choice , microbiological outcomes , and uptake and acceptance into primary care is required . We have design ed a ‘ process-pathway ' model which incorporates acceptability parameters for a POCT in primary care , and incorporates four distinct stages : Stage 1 . Piloting of a novel POCT for diagnosis of UTI in primary care . Stage 2 . An observational stage to describe current primary care management of  uncomplicated UTI  and incidence of uropathogens Stage 3 . A r and omised controlled trial rigorously evaluating the POCT as part of a rapid diagnostic and treatment regime for uncomplicated UTI . Stage 4 . Evaluating the uptake of the POCT in general practice 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 BACKGROUND Although most cardiovascular disease occurs in low-income and middle-income countries , little is known about the use of effective secondary prevention medications in these communities . We aim ed to assess use of proven effective secondary preventive drugs ( antiplatelet drugs , β blockers , angiotensin-converting-enzyme [ ACE ] inhibitors or angiotensin-receptor blockers [ ARBs ] , and statins ) in individuals with a history of coronary heart disease or stroke . METHODS In the Prospect i ve Urban Rural Epidemiological ( PURE ) study , we recruited individuals aged 35 - 70 years from rural and urban communities in countries at various stages of economic development . We assessed rates of previous cardiovascular disease ( coronary heart disease or stroke ) and use of proven effective  secondary preventive drugs  and blood-pressure-lowering drugs with st and ardised question naires , which were completed by telephone interviews , household visits , or on patient 's presentation to clinics . We report estimates of drug use at national , community , and individual levels . FINDINGS We enrolled 153,996 adults from 628 urban and rural communities in countries with incomes classified as high ( three countries ) , upper-middle ( seven ) , lower-middle ( three ) , or low ( four ) between January , 2003 , and December , 2009 . 5650 participants had a self-reported coronary heart disease event ( median 5·0 years previously [ IQR 2·0 - 10·0 ] ) and 2292 had stroke ( 4·0 years previously [ 2·0 - 8·0 ] ) . Overall , few individuals with cardiovascular disease took antiplatelet drugs  ( 25·3 % ) , β blockers ( 17·4 % ) , ACE inhibitors or ARBs ( 19·5 % ) , or statins ( 14·6 % ) . Use was highest in high-income countries ( antiplatelet drugs 62·0 % , β blockers 40·0 % , ACE inhibitors or ARBs 49·8 % , and statins 66·5 % ) , lowest in low-income countries ( 8·8 % , 9·7 % , 5·2 % , and 3·3 % , respectively ) , and decreased in line with reduction of country economic status ( p(trend)<0·0001 for every drug type ) . Fewest patients received no drugs in high-income countries ( 11·2 % ) , compared with 45·1 % in upper middle-income countries , 69·3 % in lower middle-income countries , and 80·2 % in low-income countries . Drug use was higher in urban than rural areas ( antiplatelet drugs 28·7 % urban vs 21·3 % rural , β blockers 23·5%vs 15·6 % , ACE inhibitors or ARBs 22·8%vs 15·5 % , and statins 19·9%vs 11·6 % ; all p<0·0001 ) , with greatest variation in poorest countries ( p(interaction)<0·0001 for urban vs rural differences by country economic status ) . Country-level factors ( eg , economic status ) affected rates of drug use more than did individual-level factors ( eg , age , sex , education , smoking status , body-mass index , and hypertension and diabetes statuses ) . INTERPRETATION Because use of secondary prevention medications is low worldwide-especially in low-income countries and rural areas - systematic approaches are needed to improve the long-term use of basic , inexpensive , and effective drugs . FUNDING Full funding sources listed at end of paper ( see Acknowledgments ) 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 Poor control of hypertension or dyslipidemia may at least in part be due to these risk factors being treated in isolation . The Caduet in Untreated Subjects Population ( CUSP ) trial was an 8-week , r and omized , double-blind , placebo-controlled trial evaluating the efficacy/safety of the combination of a calcium channel blocker ( amlodipine besylate ) and a statin ( atorvastatin calcium ) in a single-pill form ( 5/20 mg ) plus therapeutic lifestyle changes ( TLC ) compared with placebo plus TLC in patients with comorbid hypertension and dyslipidemia without evidence of cardiovascular disease . At week 4 , additional antihypertensive/lipid-lowering medication was permitted . The primary end point was the proportion of patients in whom the dual goal of blood pressure ( < 140/90 mm Hg ) and low-density lipoprotein cholesterol control ( < 100 mg/dL ) was met at week 4 . This dual goal attainment was significantly greater with amlodipine/atorvastatin plus TLC compared with placebo plus TLC at week 4 ( 47.6 % vs 1.7 % ; P<.001 ) , with further improvements at week 8 . Most adverse events were mild to moderate . Therapy with single-pill amlodipine/atorvastatin plus TLC in these patients significantly increased dual blood pressure/low-density lipoprotein cholesterol goal attainment compared with placebo plus TLC BACKGROUND Frail and polypathological patients ( PP ) are often undertreated with evidence -based cardiovascular drugs , as their benefits are uncertain in this population . OBJECTIVES To determine the effects of treatment with renin-angiotensin system blockers/inhibitors ( ACEI/ARB ) , statins and /or beta-blockers on survival rates and functional decline in PP with evidence -based clinical indications for treatment with any of these drug families . METHOD Prospect i ve observational multicentre cohort study with a 12-month follow-up period . We selected PP with any condition of the following : chronic heart failure , coronary heart disease , chronic renal disease , cerebrovascular disease , peripheral artery disease , diabetes mellitus with any visceral involvement , hypertension , and dyslipidaemia . Clinical , functional ( Barthel index ) , socio-familial risk data and drug prescriptions were measured at baseline . Multivariate Cox proportional hazards and logistic regression models were used to identify variables independently associated with survival and functional decline . RESULTS The analysis included 1260 PP . The mean age was 79±9.5 years . The mortality rate was 34.5 % . Statin ( aHR 0.671 ; P=0.001 ) , beta-blocker plus statin ( aHR 0.645 ; P=0.007 ) , ACEI/ARB plus statin ( aHR 0.680 ; P=0.002 ) , or combined ACEI/ARB plus statin plus beta-blocker ( aHR 0.541 ; P=0.000 ) prescriptions were associated with longer survival times . Additionally , PP whose Barthel index was ≥60 showed a lower risk of disability progression if treated with statins ( aOR=0.476 ; P=0.000 ) , or their combinations , mainly with ACEI/ARB plus beta-blockers ( aOR 0.563 ; P=0.031 ) . CONCLUSIONS The prescription of statins , alone or in combination with other drugs , may impact the survival and functional decline  in polypathological patients . Further prospect i ve blinded r and omised assays are needed to confirm these observations 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 Abstract Objective : To investigate whether a proactive multifactorial risk factor intervention strategy using single-pill amlodipine/atorvastatin ( 5/10 , 10/10 mg ) in addition to other antihypertensive and lipid-lowering therapy , as required , result ed in greater reduction in calculated Framingham 10-year coronary heart disease ( CHD ) risk compared with usual care ( UC ) after 52-weeks treatment . Research design and methods : Prospect i ve , multinational , open-label , cluster r and omized trial , with the investigator as the unit of r and omization . Eligible hypertensive patients were 35–79 years of age , with ≥3 additional cardiovascular risk factors , but no history of CHD and baseline total cholesterol ( TC ) ≤6.5 mmol/l . Clinical trial registration : Trial registration : Clinical Trials.gov identifier : NCT00407537 . Main outcome measure : The primary endpoint was calculated Framingham 10-year CHD risk at 52 weeks . Results : Of the 140 r and omized sites , 136 sites contributed 1461 patients . Mean baseline age and low-density lipoprotein cholesterol ( LDL-C ) were comparable between treatment arms . Mean baseline BP ( 150.3/89.7 vs. 144.3/86.5 mmHg ) and Framingham CHD risk ( 20.0 vs. 18.1 % ) were higher in the proactive intervention versus the UC arm ( p < 0.002 for both ) . At week 52 , mean CHD risk was 12.5 % in the proactive intervention arm and 16.3 % in the UC arm ( p < 0.001 ) . The difference , observed at weeks 16 and 52 , was primarily driven by significant differences in systolic BP and in TC between the two arms . Overall , adverse events ( AEs ) were reported in 48.8 % and 44.0 % of patients in the proactive intervention and the UC arm , respectively . Although there were differences in the incidence of AEs between the treatment arms , the AE profile in the proactive intervention arm was consistent with previous safety experience for this medication . Conclusions : A proactive multifactorial risk factor intervention strategy that simultaneously treated both BP and cholesterol regardless of individual risk factors per se , is more effective in reducing calculated Framingham 10-year CHD risk than UC in patients with hypertension and additional risk factors 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 BACKGROUND Rosuvastatin , a lipid-lowering agent , has been widely used with olmesartan , a long-acting angiotensin II receptor blocker , indicated for the treatment of dyslipidemia accompanied by hypertension . A fixed-dose combination ( FDC ) tablet of these 2 drugs was recently developed to enhance the dosing convenience and to increase patient compliance while yielding pharmacokinetic profiles comparable to coadministration of each drug as individual tablets . OBJECTIVE The goal of present study was to compare the pharmacokinetic profiles of single-dose administration of an FDC tablet containing rosuvastatin/olmesartan 20/40 mg ( test formulation ) with coadministration of a rosuvastatin 20-mg tablet and a olmesartan 40-mg tablet ( reference formulation ) in healthy Korean male volunteers , for the purpose of determining bioequivalence . METHODS This single-dose , r and omized , open-label , 2-period crossover study enrolled subjects aged 20 to 50 years and within 20 % of ideal body weight . Each subject received a single dose of the test and reference formulations orally in a fasted state , with a 7-day washout period between the administrations . Blood sample s were collected up to 72 hours after dosing , and pharmacokinetic parameters were determined for rosuvastatin , its active metabolite ( N-desmethyl rosuvastatin ) , and olmesartan . Bioequivalence was concluded if the 90 % CIs of the geometric mean ratios for the primary pharmacokinetic parameters were within the predetermined range of 80 % to 125 % . Adverse events ( AEs ) were evaluated based on subject interviews and physical examinations . RESULTS Among the 58 enrolled subjects , 54 completed the study . The 90 % CIs of the geometric mean ratios of the primary pharmacokinetic parameters were as follows : rosuvastatin : AUC(last ) , 85.60 % to 97.40 % and C(max ) , 83.16 % to 98.21 % ; N-desmethyl rosuvastatin : AUC(last ) , 82.08 % to 93.45 % and C(max ) , 79.23 % to 93.41 % ; and olmesartan : AUC(last ) , 97.69 % to 105.69 % and C(max ) , 100.35 % to 109.42 % . The most frequently noted AE was headache , occurring in 3 and 6 patients with the test and reference formulations , respectively . All of the AEs were expected , and there was no significant difference in the prevalences of AEs between the 2 formulations . CONCLUSIONS The pharmacokinetic properties of the newly developed FDC tablet of rosuvastatin/olmesartan 20/40 mg suggest that it is bioequivalent to co-administration of each drug as individual tablets in these healthy Korean male subjects . The two formulations were well tolerated , with no serious AEs observed . Clinical Trials.gov identifier : NCT01823900 Abstract Objective : To compare the reduction in calculated Framingham 10 year coronary heart disease ( CHD ) risk after 52 weeks ’ intervention with a proactive multifactorial intervention ( PMI ) strategy ( based on single-pill amlodipine/atorvastatin [ SPAA ] ) versus continuing usual care ( UC ) ( based on investigators ' best clinical judgment ) among younger ( < 65 years ) and older ( ≥65 years ) patients . Research design and methods : Sub- analysis of the Cluster R and omized Usual Care versus Caduet Investigation Assessing Long-term risk ( CRUCIAL ) trial . Eligible patients had hypertension and ≥3 cardiovascular risk factors . Main outcome measure : Treatment-related reduction in calculated Framingham 10 year CHD risk between baseline and Week 52 in younger and older patients . Results : Nine hundred patients ( 63.5 % ) were < 65 years ( mean age 54.2 years , 57.4 % men ) and 517 patients ( 36.5 % ) were ≥65 years ( mean age 70.5 years , 42.7 % men ) . Younger patients had  lower mean baseline CHD risk  versus older patients ( 17.1 % vs. 22.6 % ) . A greater reduction in calculated CHD risk at Week 52 was observed in the PMI versus the UC arm in both younger ( −33.2 % vs. −2.9 % , p < 0.001 ) and older ( −32.7 % vs. −5.7 % , p < 0.001 ) patients . Least-squares mean treatment differences ( PMI vs. UC ) in percentage change from baseline in calculated CHD risk were similar in younger and older patients ( −26.3 % vs. −25.7 % , age interaction p = 0.887 ) . CHD risk reduction was slightly greater among younger men than younger women ( −29.3 vs. −23.9 , gender interaction p = 0.062 ) . A low proportion of patients discontinued the PMI strategy due to adverse events in both age groups ( 5.8 % vs. 6.1 % , respectively ) . Study limitations included ad-hoc ( not pre-specified ) sub-group analysis and short duration of follow-up . Conclusions : The PMI strategy based on the inclusion of SPAA in the treatment regimen is more effective than UC in reducing calculated CHD risk . This strategy may be considered as the treatment of choice in younger and older hypertensive patients with additional cardiovascular risk factors The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) consisted of 42,418 participants r and omized to one of four antihypertensive treatment groups : chlorthalidone , amlodipine , lisinopril , or doxazosin .  A subset of these participants with fasting low-density lipoprotein cholesterol levels 100 - 189 mg/dL were r and omized into a lipid-lowering component : 5170 to receive pravastatin ( 40 mg daily ) and 5185 to receive usual care . This report describes the characteristics and lipid distribution of these participants . There were no important differences between the r and omized treatment groups . Women had higher total cholesterol , low-density lipoprotein cholesterol , and high-density lipoprotein cholesterol than men . There was a similar finding for black participants compared with whites , except blacks had lower triglycerides . Diabetics had lower high-density lipoprotein cholesterol and higher triglycerides than nondiabetics , and patients with body mass index < 25 kg/m(2 ) had higher high-density lipoprotein cholesterol but lower low-density lipoprotein cholesterol and triglycerides than patients with higher body mass index . The success of the r and omization of this large , diverse population and the differences in the lipid distributions among its subgroups will allow further underst and ing of optimal lipid-lowering treatment Background and rationale In clinical practice , blood pressure (BP)-lowering agents are generally prescribed for use in the morning , whereas ( short-acting ) statins are recommended for use in the evening . There is evidence that the reduction in LDL cholesterol ( LDL-c ) achieved with short-acting statins is superior when taken in the evening and reported improvement in BP control when aspirin and BP-lowering agents are taken in the evening . However , it is unclear whether the additional reduction in LDL-c and BP is offset by a reduction in adherence , given that taking medication in the evening may be less typical or convenient . There is therefore uncertainty concerning the best timing of administration of a cardiovascular combination pill such as the polypill . Aim The aim of TEMPUS ( NCT01506505 ) , a prospect i ve r and omized open blinded endpoint ( PROBE ) crossover trial , is to evaluate whether there is a difference in LDL-c levels or 24-hour ambulatory BP in individuals at increased risk of cardiovascular disease when the cardiovascular polypill is taken in the evening compared to the morning . An additional aim is to assess the effect of the polypill on LDL-c and BP compared to the administration of separate pills of identically dosed components of the polypill . Methods In total 75 participants with established cardiovascular disease or an intermediate to high risk for cardiovascular disease are r and omly allocated to the sequence of three different treatments of 6–8 weeks : ( 1 ) the cardiovascular polypill ( aspirin 75 mg , simvastatin 40 mg , lisinopril 10 mg , and hydrochlorothiazide 12.5 mg ) in the evening ; ( 2 ) the polypill in the morning ; and ( 3 ) the use of the identically dosed agents in separate pills taken at different time points during the day . The primary endpoint is the difference in LDL-c and mean 24-hour ambulatory systolic BP . Secondary outcomes are the difference in relative risk reduction , biochemistry , platelet function and pulse wave analysis , participants ’ adherence , and acceptability . Conclusions TEMPUS will evaluate the effect of timing of the administration of a cardiovascular polypill on LDL-c and BP measurements in patients with an intermediate or high risk for cardiovascular disease 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 ) TOGETHER investigated whether targeting multiple cardiovascular ( CV ) risk factors using single-pill amlodipine/atorvastatin ( AML/ATO ) and therapeutic lifestyle changes ( TLC ) results in greater blood pressure (BP)/lipid control and additional reduction in estimated cardiovascular disease ( CVD ) risk compared with blood pressure intervention only using amlodipine ( AML ) + TLC . TOGETHER was a 6-week , r and omized , double-blind , double-dummy trial using hypertensive participants with additional CV risk factors without CVD/diabetes . Participants were r and omized to either AML/ATO ( 5 to 10/20 mg ) + TLC or AML ( 5 to 10 mg ) + TLC . The primary end point was the difference in proportion of participants attaining both BP ( < 140/90 mm Hg ) and low-density lipoprotein cholesterol ( LDL-C ) ( < 100 mg/dL ) goals at week 6 . At week 6 , 67.8 % of participants receiving AML/ATO + TLC attained the combined BP/LDL-C goal versus 9.6 % with AML + TLC ( RD [ A – B ] : 58.2 ; 95 % CI [ 48.1 to 68.4 ] P < 0.001 ; OR : 19.0 ; 95 % CI 9.1 to 39.6 ; P < 0.001 ) . Significant reductions from baseline in LDL-C , total cholesterol and triglycerides and estimated 10-year Framingham risk were also observed . Treatment with AML/ATO was well tolerated . In conclusion , a multifactorial CV management approach is more effective in achieving combined BP/LDL-C targets as well as CV risk reduction compared with BP intervention only in this patient population CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy 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 BACKGROUND The PolyIran study is a large-scale pragmatic cluster r and omized controlled trial of fixed-dose combination therapy ( Polypill ) for prevention of cardiovascular diseases ( CVD ) in Iran . The PolyIran Quality Control Program ( PIQCP ) including a new question naire was developed to assess the quality of data collection during follow-up visits . The aim of this study was to assess the inter-rater reliability of PIQCP question naire . METHODS The study was conducted in 26 ( 11 % ) r and omly selected clusters ( from a total of 236 PolyIran clusters ) . All participants within these 26 clusters were enrolled .  The quality scores were measured according to the PIQCP guidelines by two independent raters . The intraclass correlation coefficients ( ICC ) were measured . In addition , the quality scores were categorized into good ( 70 % ) and poor ( < 70 % ) . The kappa coefficient was used to assess inter-rater agreement for this categorical quality scores . RESULTS A total number of 945 PolyIran participants were enrolled of which , 501 ( 53 % ) were from intervention arm . In 934 participants ( 98.8 % ) , the quality score could be successfully identified by both raters . The ICC ( 95%CI ) of the overall quality scores was 0.985 ( 0.983 - 0.987 ) . It was 0.976 ( 0.972 - 0.980 ) and 0.988 ( 0.986 - 0.990 ) in intervention and control arms , respectively . We found excellent agreement between the two raters in identifying participants with good and poor quality scores ( kappa = 0.988 , P < 0.001 ) . The kappa values were 0.972 ( P < 0.001 ) and 1.000 ( P < 0.001 ) in intervention and control arms , respectively . DISCUSSION Our results suggested that the PIQCP question naire is a reliable tool for assessing quality of data collection in PolyIran follow-up visits . Using this measure will help us in efficient monitoring of the PolyIran follow-ups and may ensure high quality data BACKGROUND Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease , but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined . We aim ed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol . METHODS 2838 patients aged 40 - 75 years in 132 centres in the UK and Irel and were r and omised to placebo  ( n=1410 ) or atorvastatin 10 mg daily ( n=1428 ) . Study entrants had no documented previous history of cardiovascular disease , an LDL-cholesterol concentration of 4.14 mmol/L or lower , a fasting triglyceride amount of 6.78 mmol/L or less , and at least one of the following : retinopathy , albuminuria , current smoking , or hypertension . The primary endpoint was time to first occurrence of the following : acute coronary heart disease events , coronary revascularisation , or stroke . Analysis was by intention to treat . FINDINGS The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met . Median duration of follow-up was 3.9 years ( IQR 3.0 - 4.7 ) . 127 patients allocated placebo ( 2.46 per 100 person-years at risk ) and 83 allocated atorvastatin ( 1.54 per 100 person-years at risk ) had at least one major cardiovascular event ( rate reduction 37 % [ 95 % CI -52 to -17 ] , p=0.001 ) . Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years . Assessed separately , acute coronary heart disease events were reduced by 36 % ( -55 to -9 ) , coronary revascularisations by 31 % ( -59 to 16 ) , and rate of stroke by 48 % ( -69 to -11 ) . Atorvastatin reduced the death rate by 27 % ( -48 to 1 , p=0.059 ) . No excess of adverse events was noted in the atorvastatin group . INTERPRETATION Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events , including stroke , in patients with type 2 diabetes without high LDL-cholesterol . No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins . The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld OBJECTIVE To measure the costs of a polypill strategy and compare them with those of usual care in people with established cardiovascular disease ( CVD ) or at similarly high cardiovascular risk . DESIGN A within-trial cost analysis of polypill-based care versus usual care with separate medications , using data from the Kanyini Guidelines Adherence with the Polypill ( GAP ) trial and linked health service and medication administrative cl aims data . PARTICIPANTS Kanyini GAP participants who consented to Australian Medicare record access . MAIN OUTCOME MEASURES Mean health service and pharmaceutical expenditure per patient per year , estimated with generalised linear models . Costs during the trial ( r and omisation January 2010 - May 2012 , median follow-up 19 months , maximum follow-up 36 months ) were inflated to 2012 costs . RESULTS Our analysis showed a statistically significantly lower mean pharmaceutical expenditure of $ 989 ( 95 % CI , $ 648-$1331 ) per patient per year in the polypill arm compared with usual care ( P < 0.001 ; adjusted , excluding polypill cost ) . No significant difference was shown in health service expenditure . CONCLUSIONS This study provides evidence of significant cost savings to the taxpayer and Australian Government through the introduction of a CVD polypill strategy . The savings will be less now than during the trial due to subsequent reductions in the costs of usual care . Nonetheless , given the prevalence of CVD in Australia , the introduction of this polypill could increase considerably the efficiency of health care expenditure in Australia . TRIAL REGISTRATION Australian New Zeal and Clinical Trials Registry ACTRN126080005833347 Guidelines stress the importance of the simultaneous management of multiple cardiovascular risk factors . This can in part be achieved by coadministration of lipid-lowering and antihypertensive treatments . Potential pharmacodynamic interaction between drugs should be investigated as part of developing single-pill combinations . The Respond trial assessed whether combining amlodipine to treat hypertension and atorvastatin to treat dyslipidemia affected the action of either monotherapy . A total of 1660 hypertensive patients with dyslipidemia received 1 of 15 combinations of amlodipine ( placebo , 5 , or 10 mg ) and atorvastatin ( placebo , 10 , 20 , 40 , or 80 mg ) in a 3 x 5 factorial r and omized , placebo-controlled design . At 8 weeks , combination-treated patients experienced dose-related and statistically significant reductions in systolic blood pressure , low-density lipoprotein cholesterol , and Framingham risk score . Overall , coadministered atorvastatin and amlodipine was well tolerated and without adverse pharmacodynamic interaction ; combination treatment did not affect the low-density lipoprotein cholesterol-lowering efficacy and safety of atorvastatin , or the systolic blood pressure-lowering efficacy and safety of amlodipine 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 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 OBJECTIVE To identify facilitators and barriers to clinical trial implementation in Aboriginal health services . DESIGN Indepth interview study with thematic analysis . SETTING Six Aboriginal community-controlled health services and one government-run service involved in the Kanyini Guidelines Adherence with the Polypill ( KGAP ) study , a pragmatic r and omised controlled trial that aim ed to improve adherence to indicated drug treatments for people at high risk of cardiovascular disease . PARTICIPANTS 32 health care providers and 21 Aboriginal and Torres Strait Isl and er patients . RESULTS A fundamental enabler was that participants considered the research to be governed and endorsed by the local health service . That the research was perceived to address a health priority for communities was also highly motivating for both providers and patients . Enlisting the support of Aboriginal and Torres Strait Isl and er staff champions who were visible to the community as the main source of information about the trial was particularly important . The major implementation barrier for staff was balancing their service delivery roles with adherence to often highly dem and ing trial-related procedures . This was partially alleviated by the research team 's provision of onsite support and attempts to make trial processes more streamlined . Although more intensive support was highly desired , there were usually insufficient re sources to provide this . CONCLUSION Despite strong community and health service support , major investments in time and re sources are needed to ensure successful implementation and minimal disruption to already overstretched , routine services . Trial budgets will necessarily be inflated as a result . Funding agencies need to consider these additional re source dem and s when supporting trials of a similar nature 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 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 ) Abstract Objective : To compare the change in calculated coronary heart disease ( CHD ) risk using a proactive multifactorial intervention ( PMI ) versus usual care ( UC ) , among Latin-American ( LA ) and non-LA patients enrolled in the CRUCIAL trial . Research design and methods : This is a sub- analysis of the Cluster R and omized Usual Care versus Caduet Investigation Assessing Long-term-risk ( CRUCIAL ) trial . CRUCIAL was a prospect i ve , multinational , open-label , cluster-r and omized trial . Eligible patients had hypertension and ≥3 additional cardiovascular risk factors , but no history of CHD and baseline total cholesterol ≤6.5 mmol/l ( 250 mg/dl ) .  The PMI strategy was implemented by the inclusion of single-pill amlodipine/atorvastatin ( SPAA ) in the patients ’ treatment regimen . Overall , 20 % of patients resided in the LA region . Main outcome measure : Treatment-related change in calculated Framingham 10-year CHD risk between baseline and Week 52 in the LA and non-LA regions . Results : A greater relative reduction in calculated CHD risk after 52 weeks ’ follow-up was observed for patients in the PMI arm compared with UC arm in both LA ( −32.8 % vs. −7.5 % , p = 0.003 ) and non-LA regions ( −33.1 % vs. −3.3 % , p < 0.001 ) , region interaction p = 0.316 . The proportion of patients discontinuing treatment in the PMI arm due to adverse events ( AEs ) was low in both regions ( both 5.9 % ) . Conclusions : The PMI approach based on the inclusion of SPAA in the patients ’ treatment regimen may improve the management of CHD risk among patients residing in LA and non-LA regions . Clinicians may be reassured by the low rate of AEs leading to discontinuation of SPAA in both regions To assess the combined influence of blood pressure ( BP ) , serum cholesterol level , and cigarette smoking on death from coronary heart disease ( CHD ) and to describe how these associations vary with age , data on those factors and on mortality for 316,099 men screened for the Multiple Risk Factor Intervention Trial ( MRFIT ) were examined . Vital status of participants has been determined after an average follow-up of 12 years ; 6327 deaths from CHD have been identified . Strong grade d relationships between serum cholesterol levels above 4.65 mmol/L ( 180 mg/dL ) , systolic BP above 110 mm Hg , and diastolic BP above 70 mm Hg and mortality due to CHD were evident . Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol levels in the lowest quintile . Systolic and diastolic BP , serum cholesterol level , and cigarettes per day were significant predictors of death due to CHD in all age groups . Systolic BP was a stronger predictor than diastolic BP . These results , together with the findings of clinical trials , offer strong support for intensified preventive efforts in all age groups BACKGROUND Cardiovascular morbidity is a major burden in patients with type 2 diabetes . In the Steno-2 Study , we compared the effect of a targeted , intensified , multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria . METHODS The primary end point of this open , parallel trial was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , revascularization , and amputation .  Eighty patients were r and omly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment , with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia , hypertension , dyslipidemia , and microalbuminuria , along with secondary prevention of cardiovascular disease with aspirin . RESULTS The mean age of the patients was 55.1 years , and the mean follow-up was 7.8 years . The decline in glycosylated hemoglobin values , systolic and diastolic blood pressure , serum cholesterol and triglyceride levels measured after an overnight fast , and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group . Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease ( hazard ratio , 0.47 ; 95 percent confidence interval , 0.24 to 0.73 ) , nephropathy ( hazard ratio , 0.39 ; 95 percent confidence interval , 0.17 to 0.87 ) , retinopathy ( hazard ratio , 0.42 ; 95 percent confidence interval , 0.21 to 0.86 ) , and autonomic neuropathy ( hazard ratio , 0.37 ; 95 percent confidence interval , 0.18 to 0.79 ) . CONCLUSIONS A target-driven , long-term , intensified intervention aim ed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent The AVALON study was a r and omized , multicenter trial to assess the efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia . Phase one was an 8-week , double-blind , double-dummy , placebo-controlled period whereby patients received amlodipine 5 mg , atorvastatin 10 mg , amlodipine 5 mg and atorvastatin 10 mg , or placebo . Thereafter , all patients received single-blind amlodipine 5 mg and atorvastatin 10 mg for 8-weeks , followed by 12 weeks of open-label treatment where doses could be titrated to improve low-density lipoprotein cholesterol and blood pressure control .  A total of 847 patients entered the double-blind phase . At Week 8 , 45 % of the patients receiving amlodipine 5 mg and atorvastatin 10 mg reached both their blood pressure and low-density lipoprotein cholesterol goals , compared with 8.3 % with amlodipine ( p < 0.001 ) , 28.6 % with atorvastatin ( p < 0.001 ) , and 3.5 % with placebo . At 28 weeks , 67.1 % of patients coadministered amlodipine and atorvastatin ( mean doses , 7.6 mg and 28.4 mg , respectively ) achieved both targets . Framingham estimated 10-year risk of coronary heart disease declined from baseline levels of 15.1 % to 6.9 % at Week 28 . Following coadministered treatment , the adverse events reported were similar to either agent alone . Concomitant administration of amlodipine and atorvastatin is an effective and well tolerated treatment for coexisting hypertension and dyslipidemia AIMS Cardiovascular polypills are a novel strategy in the prevention of cardiovascular disease . Based on considerations about the effectiveness , the individual pills of a polypill are taken at different times of the day . This study aim ed therefore to compare the use of a polypill in the morning , in the evening or the individual components taken at their usual times on cardiovascular risk factors and patient acceptability . METHODS The study was a r and omized three-period crossover trial . Seventy-eight patients with established cardiovascular disease were r and omly allocated to the use of polypill ( aspirin 75 mg , simvastatin 40 mg , lisinopril 10 mg and hydrochlorothiazide 12.5 mg ) in the morning , in the evening or use of the individual agents taken at different time points ( Trial : NCT01506505 ) . RESULTS Using the polypill in the evening result ed in a 0.2 mmol/L ( 95%-confidence interval ( CI ) : 0.1 to 0.3 ) lower fasting LDL-cholesterol compared to the use in the morning , and not statistically significantly different mean 24-hour systolic BP ( mean difference : 0.7 mmHg ; 95%-CI ; -2.1 to 3.4 ) . Compared to the use of the individual agents , the mean LDL-cholesterol was 0.2 mmol/L ( 95%-CI : 0.1 to 0.3 ) higher when using the polypill in the morning , but not statistically significantly different when used in the evening ( mean difference : -0.1 mmol/L ; 95%-CI : -0.1 to 0.0 ) . Furthermore , there were no differences in mean 24-hour systolic BP with morning use ( mean difference : 0.4 mmHg ; 95%-CI ; -1.5 to 2.3 ) or evening use ( mean difference : 1.0mmHg ; 95%-CI ; -0.8 to 2.8 ) of the polypill compared to the individual agents . The adherence was 5.2 % ( 95%-CI : 1.4 to 9.1 ) higher with morning use of the polypill and 5.0 % ( 95%-CI : 1.5 to 8.5 ) higher with evening use compared to the individual agents . Treatment with the polypill was preferred by 92 % of the participants . CONCLUSION The use of a polypill in the evening was more effective in lowering LDL-cholesterol , and result ed in not statistically significantly different ambulatory BP levels compared to the use of a polypill in the morning . Therapy with a polypill was associated with an increased adherence . The polypill is highly preferred by patients , demonstrating a potential role for the polypill in the prevention of cardiovascular disease CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease , but it is uncertain whether the association is causal . OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12 ) on vascular and nonvascular outcomes . DESIGN , SETTING , AND PATIENTS Double-blind r and omized controlled trial of 12,064 survivors of myocardial infa rct ion in secondary care hospitals in the United Kingdom between 1998 and 2008 . INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12 ) daily vs matching placebo . MAIN OUTCOME MEASURES First major vascular event , defined as major coronary event ( coronary death , myocardial infa rct ion , or coronary revascularization ) , fatal or nonfatal stroke , or noncoronary revascularization . RESULTS Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L ( 28 % ) . During 6.7 years of follow-up , major vascular events occurred in 1537 of 6033 participants ( 25.5 % ) allocated folic acid plus vitamin B(12 ) vs 1493 of 6031 participants ( 24.8 % ) allocated placebo ( risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.97 - 1.12 ; P = .28 ) . There were no apparent effects on major coronary events ( vitamins , 1229 [ 20.4 % ] , vs placebo , 1185 [ 19.6 % ] ; RR , 1.05 ; 95 % CI , 0.97 - 1.13 ) , stroke ( vitamins , 269 [ 4.5 % ] , vs placebo , 265 [ 4.4 % ] ; RR , 1.02 ; 95 % CI , 0.86 - 1.21 ) , or noncoronary revascularizations ( vitamins , 178 [ 3.0 % ] , vs placebo , 152 [ 2.5 % ] ; RR , 1.18 ; 95 % CI , 0.95 - 1.46 ) . Nor were there significant differences in the numbers of deaths attributed to vascular causes ( vitamins , 578 [ 9.6 % ] , vs placebo , 559 [ 9.3 % ] ) or nonvascular causes ( vitamins , 405 [ 6.7 % ] , vs placebo , 392 [ 6.5 % ] ) or in the incidence of any cancer ( vitamins , 678 [ 11.2 % ] , vs placebo , 639 [ 10.6 % ] ) . CONCLUSION Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12 ) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N74348595 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 BACKGROUND The ultimate goal of antihypertensive therapy is cardiovascular risk ( CVR ) reduction . The aim of this study was to compare the efficacy and safety of once-daily fixed combination ( ODFC ) versus free-drug combination ( FDC ) of 3antihypertensive agents and statin . METHODS The ALL-IN-ONE trial was a 12-week r and omized , prospect i ve , multicenter trial . A total of 305 hypertensive patients were r and omized 1:1 . The " fixed group " was given an ODFC of perindropil 10 mg plus indapamide 2.5 mg plus amlodipine 5 or 10 mg plus atorvastatin 20 mg . The " free group " was given a FDC of the 3antihypertensive agents plus atorvastatin 20 mg . Primary end-points were the differences in clinic BP , cholesterol levels and CVR risk between the 2 groups after treatments . Secondary end-points included intragroup differences in clinic BP . Safety and compliance were also assessed . RESULTS At 12-weeks , the fixed group had lower systolic BP and similar diastolic BP compared to the free group . BP targets at week 12 were more commonly reached with fixed than free combination ( 89 % and 80 % respectively , p=0.048 ) . For cholesterol serum in both groups there was a significant reduction of values . Also CVR reduction was greater in those taking ODF . Safety was not significantly different between the 2 groups . Conversely , compliance was significantly greater in the fixed-group vs. the free-group . CONCLUSION This r and omized trial shows that ODF combination of perindropil , indapamide and amlodipine is as safe as free combination of the 3 drugs , but is associated with a greater efficacy in BP control , compliance and , associated with statin , in cholesterol reduction . A better cardiovascular risk control is achieved with ODF combination than with a free administration . Clinical Trials.gov ID : NCT02710539 Background and design : The effects of aspirin on blood pressure ( BP ) are controversial and a chronopharmacological effect of aspirin on 24-hour BP was reported recently in otherwise untreated hypertensive patients . The study was design ed to test the timing effect of aspirin dosing on 24-hour BP in treated hypertensive patients routinely taking aspirin for cardiovascular prevention . Method and results : Seventy-five patients were r and omized into two groups . One group was to receive aspirin in the evening then in the morning for 1 month and the other group in the morning then in the evening , following a cross-over design . The principal assessment criterion was 24-hour systolic BP ( SBP ) measured by 24-hour ambulatory BP monitoring ( ABPM ) . Patients were aged 65 ± 9 years and had been hypertensive for 12 ± 10 years . They were all taking a mean of 2.8 antihypertensive drugs and did not modify their treatment throughout the study . Of the included subjects , 70 % were men and 33 % were diabetics . Mean 24-hour SBP values were clinical ly equivalent and were not statistically different , depending on whether the aspirin was taking in the morning or evening ( 128.3 ± 1.4 vs. 128.3 ± 1.4 mmHg , respectively ) . Neither was there any significant difference in diurnal and nocturnal SBP or in 24-hour , diurnal , and nocturnal diastolic BP ( DBP ) . Conclusion : It does not appear useful to advise patients with long-st and ing hypertension to modify timing of aspirin intake in order to reduce BP values
target: 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: 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 .