[Inhibitors of PCSK9]. / Inhibiteurs de la PCSK9.

Observational data show a consistent association between elevated low density lipoproteins (LDL-C) and cardiovascular disease (CVD). Reduction of LDL-C reduces the risk of CVD as has been shown by many trials. Statins are currently the most effective drugs for lowering LDL-C, but can present side effects which might limit the prescribed dosage and prevent patients from reaching the recommended LDL levels. Although treated with statins important residual cardiovascular event risk remains in patients in primary and secondary prevention for CVD. The discovery of protein convertase subtilisin kexin 9 antibodies is a very promising new hypolipidemic treatment and the aim of this review is to explain their mechanism of action and to discuss safety and efficacy results of some phase III studies.

Les données d'observation montrent une association cohérente entre une élévation des lipoprotéines de basse densité (LDL-C) et les maladies cardiovasculaires (MCV). Les statines sont actuellement les médicaments les plus efficaces pour abaisser le LDL-C, mais elles peuvent présenter des effets secondaires qui pourraient limiter les patients d'atteindre les niveaux de LDL-C recommandés. Bien que traités par les statines, un important risque résiduel d'événement cardiovasculaire reste chez les patients en préventions primaire et secondaire. La découverte des anticorps contre la protéase convertase subtilisine / kexine 9 est un nouveau traitement antilipémique très prometteur et le but de cet examen est d'expliquer leur mécanisme d'action et de discuter les données de sécurité et d'efficacité de quelques études de phase III.

[Statin treatment in primary and secondary prevention--a statement]. / Traitement des dyslipidémies par les statines en prévention primaire et secondaire.

Although lipid-lowering therapy in patients with established coronary heart disease (secondary prevention) is generally accepted, its benefit is often questioned in asympto- matic patients. The ongoing debate about the usefulness of statin therapy has disturbed many patients, especially in the French- and Italian-speaking parts of Switzerland, which lead too often to treatment discontinuation, even in patients who would benefit the most from it. In the primary prevention, the reduction in LDL cholesterol levels with statins decreases the risk for cardiovascular events. The higher the baseline risk, the greater the benefits in terms of absolute risk reduction; hence, using a scoring tool to evaluate the cardiovascular risk is needed. For patients at low risk, lifestyle interventions are preferable.

Performance evaluation of the Access FT3 and FT4 assays, comparison with Immulite and AxSym, and the relationship to TSH values.

BACKGROUND: Different FT3 and FT4 assays report significantly different results. We compared the distribution of FT3 and FT4 in a cohort of Swiss patients measured with DxI 800, AxSYM, and Immulite 2000. METHODS: TSH, FT3, and FT4 values were measured in 1,938 serum samples. Patients were classified on the basis of their TSH values as low, normal, and high. For each class of TSH values, concordances of FT3 and FT4 results were determined among the three assays. RESULTS: For low TSH values in all three assays FT3 (FT4) concordance of DxI - AxSYM, DxI--Immulite, and AxSYM--Immulite was determined as 83.1%, 76.2% 68.5% (60.8%, 74.6%, 83.1%), for normal TSH as 89.2%, 79.0%, 75.3% (83.9%, 85.5%, 83.1%) and for elevated TSH as 78.0%, 86.0%, 78.0% (84.0%, 90.0%, 90.0%), respectively. Low FT4 concordance rates with DxI 800 were mainly caused by its FT4 upper reference limit of 14.1 pmol/L. Using a cut-off of 16.1 pmol/L concordances with AxSYM and Immulite were improved to 77.7% and 86.9% (low TSH), 92.5% and 96.2% (normal TSH), and 90.0% and 92.2% (high TSH). Low FT3 concordance rates with Immulite were caused by its low FT3 upper reference limit of 6.29 pmol/L as 11.6% of patient samples with normal TSH value showed unusually elevated FT3 results. CONCLUSIONS: We showed an overall good concordance of FT3 and FT4 results, when stratified according to corresponding TSH values and the appropriate reference range is used. However, our data also show that problems of interpretation of results based on numerical values have yet not been solved.

[New european guidelines for dyslipidemia]. / Nouvelles guidelines européennes pour les dyslipidémies.

Lifestyle changes should be considered before anything else in patients with dyslipidemia according to the new guidelines on dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). The guidelines recommend the SCORE system (Systematic Coronary Risk Estimation) to classify cardiovascular risk into four categories (very high, high, medium or low risk) as the basis for treatment decisions. HDL cholesterol, which is inversely proportional to cardiovascular risk, is included to the total risk estimation. In addition to calculating absolute risk, the guidelines contain a table with the relative risk, which could be useful in young patients with a low absolute risk, but high risk compared to individuals of the same age group.

[Pleiotropic Effects of Statins - What Is Their Clinical Significance?] / Pleiotrope Effekte von Statinen ­ Was ist ihre klinische Bedeutung?

Pleiotropic Effects of Statins - What Is Their Clinical Significance? Abstract. Pleiotropic Effects of Statins - What Is Their Clinical Significance? Statins have several pleiotropic effects, such as anti-inflammation, anti-thrombotic effects, inhibition of smooth muscle cell proliferation and apoptosis, inhibition of migration and activation of macrophages. They increase blood glucose with the exception of pitavastatin. The clnical importance of the pleiotropic effects of statins however remains unclear. The lowering of Low Density Lipoprotein cholesterol (LDL-C) has similar effects on the reduction of cardiovascular effects no matter whether this reduction was obtained by statin or by non-statin therapy, indicating that the reduction in LDL-C per se is responsible for the beneficial effect. However, pleiotropic effects of statins might play a role with respect to microvascular events. The difference in pleiotropic effects between the different statins might be a basis for a patient-oriented statin therapy.

Diagnostic accuracy of point-of-care testing for acute coronary syndromes, heart failure and thromboembolic events in primary care: a cluster-randomised controlled trial.

BACKGROUND: Evidence of the clinical benefit of 3-in-1 point-of-care testing (POCT) for cardiac troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and D-dimer in cardiovascular risk stratification at primary care level for diagnosing acute coronary syndromes (ACS), heart failure (HF) and thromboembolic events (TE) is very limited. The aim of this study is to analyse the diagnostic accuracy of POCT in primary care. METHODS: Prospective multicentre controlled trial cluster-randomised to POCT-assisted diagnosis and conventional diagnosis (controls). Men and women presenting in 68 primary care practices in Zurich County (Switzerland) with chest pain or symptoms of dyspnoea or TE were consecutively included after baseline consultation and working diagnosis. A follow-up visit including confirmed diagnosis was performed to determine the accuracy of the working diagnosis, and comparison of working diagnosis accuracy between the two groups. RESULTS: The 218 POCT patients and 151 conventional diagnosis controls were mostly similar in characteristics, symptoms and pre-existing diagnoses, but differed in working diagnosis frequencies. However, the follow-up visit showed no statistical intergroup difference in confirmed diagnosis frequencies. Working diagnoses overall were significantly more correct in the POCT group (75.7% vs 59.6%, p = 0.002), as were the working diagnoses of ACS/HF/TE (69.8% vs 45.2%, p = 0.002). All three biomarker tests showed good sensitivity and specificity. CONCLUSION: POCT confers substantial benefit in primary care by correctly diagnosing significantly more patients. TRIAL REGISTRATION: DRKS: DRKS00000709.

Prevalence of microalbuminuria in the general population of Seychelles and strong association with diabetes and hypertension independent of renal markers.

OBJECTIVE: Few studies have examined microalbuminuria (MAU) in non-western populations. We assessed the prevalence of MAU in the general population of a middle-income country in the African region and relationships between MAU and selected cardiovascular risk factors. METHODS: An examination survey was conducted in a sample representative of the entire population aged 25-64 years in the Seychelles. MAU adjusted for urine creatinine concentration was measured on the second morning urine using a semiquantitative point-of-care analyzer. RESULTS: A total of 1255 persons attended the survey (participation rate of 80.2%). The age-adjusted prevalence of MAU was 11.4%. At age 25-64 years, the prevalence of MAU was 5% in persons without diabetes and hypertension, 20% in persons with either condition and 41% in persons with both conditions. The overall prevalence of stages 3-4 chronic kidney disease was low at 3.2%. In multivariate analysis, MAU was associated with age [odds ratio (OR) 1.24 for a 10-year increase; 95% confidence interval (CI): 1.02-1.52], hypertension stage I (2.0; 1.1-3.8) and stage II (4.5; 2.3-8.6), obesity (1.7; 1.0-2.8) and diabetes (3.0; 1.9-4.9). These associations were virtually unchanged upon further adjustment for markers of renal function such as serum creatinine, serum cystatin C and calculated renal function. CONCLUSION: The prevalence of MAU was high in this population, and MAU was strongly associated with several cardiovascular risk factors independently of renal function markers. These findings suggest that MAU could be a useful marker of cardiovascular risk in this population and help identify persons in need of a specific cardiovascular risk management.

Heparinized blood provides equivalent results to EDTA in the CEDIA and FPIA cyclosporine immunoassays, thus facilitating routine cyclosporine determination.

BACKGROUND: CsA measurements are routinely used to allow adequate CsA dosage adjustments. CsA assays routinely require EDTA anticoagulated whole blood; EDTA has been preferred due to differences seen when using heparinized blood in the past. We hypothesized that with new, robust assays, heparinized blood might be appropriate for measuring CsA levels. METHODS: CsA levels from EDTA samples and heparinized samples were compared using the CEDIA assay on a BeckmanCoulter DXC. Also, CsA levels from heparinized blood were compared using the CEDIA assay (BeckmanCoulter) and the FPIA assay (Abbott Axsym). RESULTS: CsA levels from EDTA blood (x) and heparinized blood (y, n=81) showed very good correlation without deviation from linearity by Passing-Bablok analysis (y=-2.4524+1.0210x). In 187 samples obtained from heparinized blood, CsA levels determined by using the CEDIA assay (x) or the FPIA assay (y) also correlated equally well by Passing-Bablok analysis (y=6.1922+1.0221x), also without deviation from linearity. CONCLUSION: CsA determination from heparinized blood is easy to perform and accurate with the two assays described and evaluated. Using heparinized blood reduces handling time as well as hands on time. We suggest that this methodology be formally evaluated by the manufacturers for inclusion into CE labelling of their products to allow improved laboratory work flow.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

BACKGROUND: The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. OBJECTIVES: The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. PATIENTS AND METHODS: Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. RESULTS: The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. CONCLUSIONS: Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

[What are the biomarkers of atherosclerosis and cardiovascular risk?]. / Quels marqueurs biologiques de l'athérosclérose et du risque cardiovasculaire conseiller?

A large number of novel biomarkers of cardiovascular risk have recently been identified. To be implemented in clinical practice these biomarkers should fulfill certain requirements, such as independance of other risk factors, improvement of the prediction by global risk assessment, and a therapeutic implication (modifiable risk). Some of these new risk markers have shown a clinical importance under certain circumstances (hsCRP, Lp(a), markers of renal insufficiency, or fibrinogen). Among these, only lowering of hsCRP (in addition to the decrease of LDL-cholesterol) by statins has shown a reduction of the risk of cardiovascular events. The use of new biomarkers should be restricted to persons with intermediate global risk since it allows a new risk stratification.

Vitamin D levels in Swiss breast cancer survivors.

BACKGROUND: Cholecalciferol (vitamin D3) is widely supplemented in breast cancer survivors because of the role of vitamin D in multiple health outcomes. METHODS: We conducted an observational study in 332 women in Eastern Switzerland with early, i.e., nonmetastatic breast cancer. Tumour-, patient-related and sociodemographic variables were recorded. Cholecalciferol intake and serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured at the first visit (baseline) and during a follow-up visit in a median of 210 days (range 87-857) after the first visit. Patients presenting 25(OH)D deficiency were advised to take cholecalciferol supplementation. RESULTS: At baseline, 60 (18%) patients had 25(OH)D deficiency (≤50 nmol/l, ≤20 ng/l), and 70 (21%) had insufficiency (50-74 nmol/l, 20-29 ng/l). Out of 121 patients with ongoing cholecalciferol supplementation at baseline, 25(OH)D deficiency and insufficiency was observed in 9 (7%) and 16 (13%) patients, respectively, whereas out of 52 patients with no supplementation, 15 (29%) had deficiency and 19 (37%) had insufficiency. Only 85 (26%) patients had optimal 25(OH)D levels (75-100 nmol/l, 30-40 ng/l) at baseline. Seasonal variation was significant for 25(OH)D (p = 0.042) and 1,25(OH)2D (p = 0.001) levels. Living in a rural area was associated with a higher median 25(OH)D concentration as compared with living in an urban area (87 nmol/l, range 16-216 vs 72 nmol/l, range 17-162; p = 0.001). Regular sporting activity was positively associated with 25(OH)D (p = 0.045). Body mass index was inversely related to both 25(OH)D and 1,25(OH)2D (Spearman's rho = -0.24, p <0.001; rho = -0.23, p <0.001, respectively). The levels of 25(OH)D and 1,25(OH)2D were correlated (rho = 0.21, p <0.001). Age and bone mineral density had no significant correlation with the levels of 25(OH)D. Follow-up 25(OH)D was available for 230 patients, 44 (19%) of whom had 25(OH)D deficiency and 47 (21%) had insufficiency; 25 (41.6%) initially 25(OH)D-deficient patients attained sufficient 25(OH)D levels, whereas 33 (16.5%) patients with sufficient baseline 25(OH)D levels became deficient. Only 67 (30%) patients presented optimal 25(OH)D at the follow-up. CONCLUSION: A remarkable fraction of the patients had serum 25(OH)D below (40%) or above (30%) optimal levels, and only around 30% of patients had optimal levels. Levels of 25(OH)D and 1,25(OH)2D increased on cholecalciferol supplementation, but the usual supplementation regimens were not adequate to bring 25(OH)D to the optimal range for a large proportion of patients. TRIAL REGISTRATION NUMBER: EKSG 08/082/2B.

Treat-to-target versus dose-adapted statin treatment of cholesterol to reduce cardiovascular risk.

Clinical guidelines should be based on the best available evidence and are of great importance for patient care and disease prevention. In this respect, the 2013 American College of Cardiology/American Heart Association report is highly appreciated and well-recognized. The report included critical questions concerning hypercholesterolaemia, but its translation into a clinical guideline initiated intense debate worldwide because of the recommendation to switch from a treat-to-target approach for low-density-lipoprotein-cholesterol to a statin dose-based strategy.

High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.

BACKGROUND: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect. OBJECTIVE: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome. DESIGN: Cross-sectional comparison. SETTING: University hospital in Lausanne, Switzerland. PARTICIPANTS: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated. MEASUREMENTS: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype. RESULTS: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene. CONCLUSION: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Toward a more professional and practical medical education: a novel Central European approach.

We here present an innovative curriculum for a complete medical education that conforms to the current European Bologna system of academic training. The curriculum aims at raising doctors who are excellently prepared for clinical work over as short a time as 5 years; it provides a comprehensive, yet shorter than usual, education that strongly pronounces the importance of increasing the students' practical clinical competences and rigorously excludes superfluous contents. The curriculum encompasses 52 modules, 32 at the bachelor's and 20 at the master's level. Already at the level of the bachelor degree, full employability is given; the students finish the master's course as medical doctors optimally prepared to manage patients at the level of postgraduate medical education. The structure of the curriculum is modular; each modular component is essential for medical education and contains an average of five European Credit Transfer System credits, amounting to 150 hours of education. Depending on the subspecialty, the courses include lectures, seminars, practical laboratory training, and clinical training at varying quantities. In addition to attendance times, sufficient time slots are prepared for self-study in lectures, seminars, and practical work. With our curriculum, we provide an easily applicable backbone for a modern course of medicine that can be installed also at smaller academic institutions.

Statin-induced immunomodulatory effects on human T cells in vivo.

Statins are widely used for treatment of hypercholesterolemia. Recent experimental studies revealed that these drugs also exert anti-inflammatory effects. The aim of this study was to assess immunomodulatory effects of statins in humans in vivo. Twenty-seven healthy volunteers were analyzed for serum cytokines and acute phase proteins, HLA-DR and CD38 expression on T cells and superantigen-mediated T cell activation ex vivo before and after 14 days of statin treatment. First, simvastatin 40 mg was compared to atorvastatin 20 mg. Second, two different doses of simvastatin (20 and 40 mg) were tested. Atorvastatin treatment led to a significant down-regulation of HLA-DR and the CD38 activation marker on peripheral T cells, whereas simvastatin up-regulated both of these molecules. In contrast, superantigen-mediated T cell activation was inhibited by simvastatin and enhanced by atorvastatin. No significant effect of statin treatment on inflammatory serum markers was detected. Thus, immunomodulatory effects of statins on human T cells are first demonstrated in vivo and are differentially induced by two different statins: atorvastatin led to a major histocompatibility class II (MHC II) antigens down-regulation and may therefore be investigated for treatment of chronic transplant rejection; simvastatin inhibited superantigen-mediated T cell activation, which might explain reduced mortality of simvastatin-treated patients with staphylococcal bacteremia.

Lipid-lowering therapy: strategies for improving compliance.

Lowering cholesterol levels is a primary approach for reducing the risk of coronary heart disease (CHD), yet patients rarely achieve the lipid targets recommended by international guidelines. Although high rates of compliance and achievement of lipid targets have been reported in clinical trials, this situation is infrequently reproduced in regular practice. This sub-optimal lipid management has clinical consequences as patients will not gain the full benefit of treatment. Poor compliance with therapeutic lifestyle changes and/or lipid-lowering agents is thought to contribute to the failure of patients in clinical practice to achieve lipid targets, and therefore this problem needs to be addressed. Several approaches may be used to improve compliance, including the prescription of efficacious, well-tolerated agents, educating patients about the necessity of therapy, and regular follow-up to monitor compliance and achievement of goals. However, educating patients to promote compliant behaviour can be time-consuming and therefore the support of other health-care workers, where available, can prove invaluable. Compliance initiatives using educational materials, access to helplines and regular telephone contact with a qualified health-care worker may also improve adherence with therapy. Further studies into the causes of poor compliance and methods of improving adherence with lipid-lowering agents are required.

New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk.

After the publication of the new guidelines of the European Society of Cardiology and the European Atherosclerosis Society for the prevention and treatment of dyslipidemias (Eur Heart J 32:1769-1818, 2011; Eur Heart J 33:1635-1701, 2012), a group of authors has recently published on behalf of the American Heart Association and the American College of Cardiology guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk (Circulation 2013). These new guidelines are supposed to replace the until now widely accepted, at least in the USA, recommendations of the National Cholesterol Education Program Adult Treatment Panel III from the years 2002 (Circulation 106:3143-3421, 2002) and 2004 (Circulation 110:227-39, 2004). Furthermore, they claim to be based mainly on hard evidence derived from the interpretation of results of prospective randomized controlled trials. This Joint Position Statement of the Society for the Prevention of Cardiovascular Diseases e.V. (D.A.CH), the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society of Cardiology concludes that the use of individualized prevention strategies based on specific indications and LDL cholesterol target concentrations, a strategy whose worth has been widely proven and accepted for more than a decade in Europe, should not be given up.