Correction: Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.

[This corrects the article DOI: 10.1371/journal.pone.0186196.].

Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.

INTRODUCTION: The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all-cause mortality and hospitalization due to cardiovascular events in a high-risk population. METHODS: This prospective registry included high risk adults over 30 years old free of cardiovascular disease (2008-2012). Diagnosis of hypertension, dyslipidemia or diabetes mellitus was inclusion criterion. Lipid biomarkers were evaluated. Primary endpoints were all-cause mortality and hospital admission due to coronary heart disease or stroke. We estimated adjusted rate ratios (aRR), absolute risk differences and population attributable risk associated with adverse lipid profiles. RESULTS: 51,462 subjects were included with a mean age of 62.6 years (47.6% men). During an average follow-up of 3.2 years, 919 deaths, 1666 hospitalizations for coronary heart disease and 1510 hospitalizations for stroke were recorded. The parameters that showed an increased rate for total mortality, coronary heart disease and stroke hospitalization were, respectively, low HDL-Cholesterol: aRR 1.25, 1.29 and 1.23; high Total/HDL-Cholesterol: aRR 1.22, 1.38 and 1.25; and high Triglycerides/HDL-Cholesterol: aRR 1.21, 1.30, 1.09. The parameters that showed highest population attributable risk (%) were, respectively, low HDL-Cholesterol: 7.70, 11.42, 8.40; high Total/HDL-Cholesterol: 6.55, 12.47, 8.73; and high Triglycerides/HDL-Cholesterol: 8.94, 15.09, 6.92. CONCLUSIONS: In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers.

Association Between a Social-Business Eating Pattern and Early Asymptomatic Atherosclerosis.

BACKGROUND: The importance of a healthy diet in relation to cardiovascular health promotion is widely recognized. Identifying specific dietary patterns related to early atherosclerosis would contribute greatly to inform effective primary prevention strategies. OBJECTIVES: This study sought to quantify the association between specific dietary patterns and presence and extent of subclinical atherosclerosis in a population of asymptomatic middle-aged adults. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) study enrolled 4,082 asymptomatic participants 40 to 54 years of age (mean age 45.8 years; 63% male) to evaluate the presence of subclinical atherosclerosis in multiple vascular territories. A fundamental objective of this cohort study was to evaluate the life-style-related determinants, including diet, on atherosclerosis onset and development. We conducted a cross-sectional analysis of baseline data, including detailed information on dietary habits obtained as part of the overall life-style and risk factor assessment, as well as a complete vascular imaging study that was performed blinded to the clinical information. RESULTS: Most PESA participants follow a Mediterranean (40% of participants) or a Western (41%) dietary pattern. A new pattern, identified among 19% of participants, was labeled as a social-business eating pattern, characterized by a high consumption of red meat, pre-made foods, snacks, alcohol, and sugar-sweetened beverages and frequent eating-out behavior. Participants following this pattern presented a significantly worse cardiovascular risk profile and, after adjustment for risk factors, increased odds of presenting subclinical atherosclerosis (odds ratio: 1.31; 95% confidence interval: 1.06 to 1.63) compared with participants following a Mediterranean diet. CONCLUSIONS: A new social-business eating pattern, characterized by high consumption of red and processed meat, alcohol, and sugar-sweetened beverages, and by frequent snacking and eating out as part of an overall unhealthy life-style, is associated with an increased prevalence, burden, and multisite presence of subclinical atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Impact of hypertension on mortality and cardiovascular disease burden in patients with cardiovascular risk factors from a general practice setting: the ESCARVAL-risk study.

OBJECTIVE: To estimate the attributable risk associated to hypertension for all-cause mortality and cardiovascular hospitalization endpoints in a prospective study of patients with at least one cardiovascular risk factors participating in the Estudio Cardiovascular Valencia-risk project, we also evaluated the attributable risk associated with other risk factors and risk factor clustering. METHODS: Prospective electronic health recording-based study in a Mediterranean population that included 52 007 cardiovascular disease-free men and women aged 30 years or older (mean age 62.6 year) with hypertension (79.0%), diabetes mellitus (37.3%), or dyslipidemia (88.2%), who underwent routine health examinations. All-cause mortality and hospitalization records for coronary heart disease (CHD) or stroke were collected. RESULTS: During an average follow-up time of 3.2 years, 928 deaths and 1682 and 1529 hospitalizations for CHD and stroke, respectively, were recorded. In both men and women, hypertension significantly increased the multiadjusted rates of death and CHD and stroke hospitalizations. Hypertension was associated with a substantial amount of avoidable deaths both in men and women, population attributable risks were 41.81 (95% confidence interval 28.02, 53.24)% and 37.84 (5.74, 61.51)%, respectively. Similarly, the population attributable risk of hospitalization for CHD and stroke associated to hypertension was among the highest in both the sexes as compared with the impact of the other main cardiovascular risk factors. Increasing cardiovascular risk factors clustering was associated with increasing burden of disease. CONCLUSION: Our results highlight the relevance of hypertension as main risk factor for mortality and cardiovascular events in a real-life setting. Although our data support the ongoing need of cardiovascular risk factors prevention, intensified actions for primary prevention of hypertension show potential to largely reduce the burden of cardiovascular disease.

Cost-effectiveness and public health benefit of secondary cardiovascular disease prevention from improved adherence using a polypill in the UK.

OBJECTIVE: To evaluate the public health and economic benefits of adherence to a fixed-dose combination polypill for the secondary prevention of cardiovascular (CV) events in adults with a history of myocardial infarction (MI) in the UK. DESIGN: Markov-model-based cost-effectiveness analysis, informed by systematic reviews, which identified efficacy, utilities and adherence data inputs. SETTING: General practice in the UK. PARTICIPANTS: Patients with a mean age of 64.7 years, most of whom are men with a recent or non-recent diagnosis of MI and for whom secondary preventive medication is indicated and well tolerated. INTERVENTION: Fixed-dose combination polypill (100 mg aspirin, 20 mg atorvastatin and 2.5, 5, or 10 mg ramipril) compared with multiple monotherapy. PRIMARY AND SECONDARY OUTCOME MEASURES: CV events prevented per 1000 patients; cost per life-year gained; and cost per quality-adjusted life-year (QALY) gained. RESULTS: The model estimates that for each 10% increase in adherence, an additional 6.7% fatal and non-fatal CV events can be prevented. In the base case, over 10 years, the polypill would improve adherence by ∼20% and thereby prevent 47 of 323 (15%) fatal and non-fatal CV events per 1000 patients compared with multiple monotherapy, with an incremental cost-effectiveness ratio (ICER) of £8200 per QALY gained. Probabilistic sensitivity analyses for the base-case assumptions showed an 81.5% chance of the polypill being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained compared with multiple monotherapy. In scenario analyses that varied structural assumptions, ICERs ranged between cost saving and £21,430 per QALY gained. CONCLUSIONS: Assuming that some 450,000 adults are at risk of MI, a 10 percentage point uptake of the polypill could prevent 3260 CV events and 590 CV deaths over a decade.The polypill appears to be a cost-effective strategy to prevent fatal and non-fatal CV events in the UK.

Prevalence, Vascular Distribution, and Multiterritorial Extent of Subclinical Atherosclerosis in a Middle-Aged Cohort: The PESA (Progression of Early Subclinical Atherosclerosis) Study.

BACKGROUND: Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations. METHODS AND RESULTS: The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2-3 sites), or generalized (4-6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized. CONCLUSIONS: Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01410318.

A polypill strategy to improve adherence: results from the FOCUS project.

BACKGROUND: Adherence to evidence-based cardiovascular (CV) medications after an acute myocardial infarction (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 randomized 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) aimed to elucidate factors that interfere with appropriate adherence to CV medications for secondary prevention after an acute MI. Additionally, 695 patients from Phase 1 were randomized 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 randomized 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 questionnaire (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).

Policomprimido: ¿quimera o realidad? / Polypill: Chimera or Reality?

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A polypill strategy to improve global secondary cardiovascular prevention: from concept to reality.

The prevention of cardiovascular disease (CVD) by using a polypill has gained increasing momentum as a strategy to contain progression of the disease. Since its initial conception just over a decade ago, only a handful of trials have been completed assessing the efficacy and safety of this innovative concept. The results of these trials have supported the viability of the polypill in CVD prevention and management, albeit with a few caveats, essentially related to the lack of evidence on the effect of the polypill to effectively reduce cardiovascular events. The polypill has the potential to control the global health epidemic of CVD by effectively reaching underdeveloped regions of the world, simplifying healthcare delivery, improving cost-effectiveness, increasing medication adherence, and supporting a comprehensive prescription of evidence-based cardioprotective drugs. Major trials underway will provide definitive evidence on the efficacy of the polypill in reducing cardiovascular events in a cost-effective manner. The results of these studies will determine whether a polypill strategy can quell the burgeoning public health challenge of CVD and will potentially provide the evidence to implement an effective, simple, and innovative solution to restrain the global CVD pandemic.

Evolution of the polypill concept and ongoing clinical trials.

Ischemic heart disease and stroke are the leading causes of death worldwide. What was once thought to be an endemic disease of high income countries has become a global epidemic, as low and middle income countries have adopted Western lifestyles, to the point that noncommunicable diseases are now the main cause of death in these regions, above and beyond communicable diseases, malnutrition, and injury. As a result, a large proportion of individuals at high 10-year risk of a cardiovascular event live in low- and middle-income countries, and the most of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, ß-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, however, the efficacy of cardiovascular event prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications, and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy, and how this therapy could improve adherence to treatment, reduce the cost, and improve treatment affordability in low-income countries.

The Progression and Early detection of Subclinical Atherosclerosis (PESA) study: rationale and design.

BACKGROUND: The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly defined. OBJECTIVE: The PESA study examines the presence of subclinical atherosclerosis by means of noninvasive imaging and prospectively analyzes the determinants associated with its development and progression in a middle-aged population. METHODS: The PESA study is an observational, longitudinal and prospective cohort study in a target population of 4000 healthy subjects (40-54 years old, 35% women) based in Madrid (Spain). Recruitment began in June 2010 and will be completed by the end of 2013. Baseline examination consists of (1) assessment for cardiovascular risk factors (including lifestyle and psychosocial factors); (2) screening for subclinical atherosclerosis using 2D/3D ultrasound in carotid, abdominal aorta and iliofemoral arteries, and coronary artery calcium score (CACS) by computed tomography; and (3) blood sampling for determination of traditional risk factors, advanced "omics" and biobanking. In addition, a subgroup of 1300 participants with evidence of atherosclerosis on 2D/3D ultrasound or CACS will undergo a combined (18)F-fluorodeoxyglucose-positron emission tomography/magnetic resonance imaging ((18)FDG PET/MRI) study of carotid and iliofemoral arteries. Follow-up at 3 and 6 years will include a repetition of baseline measurements, except for the (18)FDG PET/MRI study, which will be repeated at 6 years. CONCLUSIONS: The PESA study is expected to identify new imaging and biological factors associated with the presence and progression of atherosclerosis in asymptomatic people and will help to establish a more personalized management of medical care.

Prevention: Polypills for cardiovascular prevention: a step forward?

The effect of a fixed-dose combination drug strategy ('polypill') on patients' adherence to medication was analysed in a series of 2,004 individuals with, or at high risk of, cardiovascular disease in the UMPIRE study. The polypill improved adherence by >20%, but the reduction in blood-pressure and cholesterol levels was modest.

Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial.

BACKGROUND: The effect of ß-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion). METHODS AND RESULTS: Patients with Killip class II or less anterior ST-segment-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were randomized to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The predefined primary end point was infarct size on magnetic resonance imaging performed 5 to 7 days after STEMI. Magnetic resonance imaging was performed in 220 patients (81%). Mean ± SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6 ± 15.3 versus 32.0 ± 22.2 g; adjusted difference, -6.52; 95% confidence interval, -11.39 to -1.78; P=0.012). In patients with pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction grade 0 to 1 flow, the adjusted treatment difference in infarct size was -8.13 (95% confidence interval, -13.10 to -3.16; P=0.0024). Infarct size estimated by peak and area under the curve creatine kinase release was measured in all study populations and was significantly reduced by intravenous metoprolol. Left ventricular ejection fraction was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09-5.21; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21). CONCLUSIONS: In patients with anterior Killip class II or less ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01311700. EUDRACT number: 2010-019939-35.

Systematic review of three decades of Spanish cardiovascular epidemiology: improving translation for a future of prevention.

BACKGROUND: In order to improve national cardiovascular disease (CVD) epidemiology and prevention, we systematically reviewed and analyzed the relevant literature produced in the last three decades for Spain. DESIGN: Systematic Review. METHODS: We searched for all the articles aiming to monitor CVD clinical endpoints and risk factors in the Spanish general population that were indexed in MEDLINE and EMBASE. Based on international recommendations, we analyzed each article with a three-level scoring system (low to high) for the following criteria: data quality, representativeness and translation of results into preventive interventions. RESULTS: We reviewed 2565 articles, selecting 314 for in-depth analysis. Articles about diet, blood pressure, obesity and smoking represented 53% of all published CVD studies, whereas those about physical activity or psychosocial factors represented only 5%. Low data quality was found in 67% and 60% of the articles about physical activity and smoking, respectively. High data quality was found in 77% and 61% of the articles dedicated to diet and blood pressure, respectively. Representativeness was low for 41%, 31% and 25% of the studies focusing on diet, smoking and diabetes, respectively. Translation of research results into prevention scored lowest of all three criteria, as 41% of all 314 articles scored low. None of the articles on obesity, diabetes, lipids, physical activity or psychosocial factors identified any specific preventive intervention. CONCLUSION: Future Spanish CVD epidemiology research will benefit from improving not just the quality and representativeness of the data measured, but drastically improving the translation of research results into future preventive interventions. The lack of a translational focus remains the fundamental gap in CVD research.

Myocardial involvement in Chagas disease: insights from cardiac magnetic resonance.

BACKGROUND: Chagas' disease is becoming a public health problem in Europe because of migratory movements. Cardiac magnetic resonance (CMR) has emerged as a non-invasive tool to assess cardiac tissue characteristics. There is scarce data available on CMR in patients with Chagas' disease. OBJECTIVE: To describe CMR findings in patients with Chagas' disease living in a non-endemic area focusing on differentiation from other cardiomyopathies and relation with clinical status. METHODS AND RESULTS: Sixty-seven Chagas' disease patients divided into 3 groups-group 1 (indeterminate form: positive serology without ECG or 2D-echocardiographic abnormalities; N = 27), group 2 (ECG abnormalities of Chagas' disease but normal 2D-echocardiography; N = 19), and group 3 (regional wall motion abnormalities, LV end-diastolic diameter >55 mm or LV ejection fraction <50% on echocardiography; N = 21)--were studied. The presence of wall motion abnormalities and delayed enhancement (DE) by CMR was more frequent in the inferolateral and apical segments. DE distribution in the myocardial wall was heterogeneous (subendocardial 26.8%, midwall 14.0%, subepicardial 22.6%, and transmural 36.0% of total segments with DE) and related to larger cardiac chambers and worse systolic function. CONCLUSION: Pattern of DE in Chagas' disease may mimic that of both ischemic and nonischemic cardiomyopathies, with especial predilection for the apical and inferolateral segments of the left ventricle. These findings support that myocardial involvement in chronic Chagas' cardiomyopathy (CCC) may be due to both microvascular disturbances and chronic myocarditis and may favor CCC in the differential diagnosis of patients with compatible epidemiological history and heart failure of uncertain etiology.

Maximizing therapeutic envelope for prevention of cardiovascular disease: role of polypill.

Cardiovascular-disease prevention is often inadequate due to several factors. Lack of professional adherence to guidelines, unaffordable medication, and lack of patients' adherence to treatment are the most important. It has been suggested that an affordable, fixed-dose combination drug containing evidence-based active compounds could improve cardiovascular prevention by improving patients' adherence to treatment. The available evidence suggests that the polypill strategy can achieve this objective and it will gain a place in the therapeutic armamentarium for the prevention of cardiovascular events in patients at high risk.

Study design for the "effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion" (METOCARD-CNIC): a randomized, controlled parallel-group, observer-blinded clinical trial of early pre-reperfusion metoprolol administration in ST-segment elevation myocardial infarction.

BACKGROUND: Infarct size predicts post-infarction mortality. Oral ß-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early intravenous (IV) ß-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)-based experimental studies, the ß(1)-blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion ß-blocker initiation in STEMI. OBJECTIVE: The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. DESIGN: The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with ß-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. CONCLUSIONS: The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI.