European Atherosclerosis Society Consensus Panel Research Articles

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.

Abstract

Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.

AimsTo appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).Methods and resultsWe assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.ConclusionConsistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

Novel Therapies for Familial Hypercholesterolemia.

Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50%. The LDL-C target is adjusted to <100 or <70mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300mg/dL (or >200mg/dL with significant CAD, although now approved for LDL-C as low as 160mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.

A VOYAGER Meta-Analysis of the Impact of Statin Therapy on Low-Density Lipoprotein Cholesterol and Triglyceride Levels in Patients With Hypertriglyceridemia

Elevated triglyceride (TG) levels are associated with increased cardiovascular disease risk. In patients with mild-to-moderate hypertriglyceridemia, defined by the European Atherosclerosis Society Consensus Panel as a TG level of 177 to 885 mg/dl (2.0 to 10.0 mmol/L), low-density lipoprotein cholesterol (LDL-C) reduction remains the primary treatment goal. Using data from the indiVidual patient meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin (VOYAGER) meta-analysis, we analyzed LDL-C and TG reductions in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Least squares mean percentage change from baseline in LDL-C and TG was compared using 15,800 patient exposures to rosuvastatin 5 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 80 mg in patients with baseline TG ≥177 mg/dl (≥2.0 mmol/L). Comparisons were made using mixed-effects models with data only from studies directly comparing treatments by randomized design. Mean LDL-C reductions ranged from -26.9% to -55.5%. Rosuvastatin 10 to 40 mg resulted in significantly greater LDL-C reductions than equal or double doses of atorvastatin and simvastatin (p <0.05). Mean TG reductions ranged from -15.1% to -31.3%. Rosuvastatin 10 mg resulted in significantly greater TG reductions than atorvastatin 10 mg (p <0.05). Rosuvastatin 20 and 40 mg resulted in TG reductions similar to those with equal doses of atorvastatin. Rosuvastatin 10 to 40 mg resulted in significantly greater TG reductions than equal or double doses of simvastatin (p <0.05). In conclusion, in patients with hypertriglyceridemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. TG reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Association of Lipoprotein Subfractions and Coronary Artery Calcium In Patient at Intermediate Cardiovascular Risk

More precise estimation of the atherogenic lipid parameters could improve identification of residual risk beyond what is possible using traditional lipid risk factors. The aim of the present study was to explore the association between advanced analysis of lipoprotein subfractions and the prevalence of coronary artery calcium. Consecutive participants at intermediate cardiovascular risk who were undergoing computed tomographic assessment of coronary calcium (calcium score) were included. Using a validated ultracentrifugation method (the vertical autoprofile II test), cholesterol in eluting lipoprotein subfractions [i.e., low- (LDL), very-low-, intermediate-, and high-density lipoprotein subclasses, lipoprotein (a), and predominant LDL distribution] was directly quantified. A total of 410 patients were included (29% women, mean age 57 years), of whom 297 (72.4%) had coronary artery calcium. LDL pattern B (predominance of small dense particles) emerged as an independent predictor of coronary calcium after adjustment for traditional risk factors (odds ratio 4.46, 95% confidence interval 1.19 to 16.7). However, after additional stratification for dyslipidemia, as defined by conventional lipid profiling, a statistically significant prediction was only retained for high-density lipoprotein subfraction 2 (odds ratio 3.45, 95% confidence interval 2.03 to 50.1) and "real" LDL (odds ratio 6.10, 95% confidence interval 1.26 to 23.41) in the normolipidemia group and for lipoprotein (a) (odds ratio 7.81, 95% confidence interval 1.41 to 43.5) in the dyslipidemic group. In conclusion, advanced assessment of the lipoprotein subfractions [i.e., LDL pattern B, high-density lipoprotein subfraction 2, "real" LDL, and lipoprotein (a)] using the vertical autoprofile II test provided additional information to that of conventional risk factors on the prevalence of coronary artery calcium in patients at intermediate cardiovascular risk.

European guidance on management of dyslipidaemias

British Journal of Cardiac NursingVol. 7, No. 5 Policy UpdateEuropean guidance on management of dyslipidaemiasBelinda LindenBelinda LindenSearch for more papers by this authorBelinda LindenPublished Online:27 Sep 2013https://doi.org/10.12968/bjca.2012.7.5.242AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Reiner Z, Catapano A, de Backer G et al. (2011) ESC/EAS guidelines for the management of dyslipidaemias. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 32: 1769–818 Crossref, Google ScholarChapman MJ, Ginsberg HN, Amarenco P et al. for European Atherosclerosis Society Consensus Panel (2011) Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 32: 1345–1345 Crossref, Google ScholarConroy RM, Pyorala K, Fitzgerald AP et al. (2003) Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 24: 987–987 Crossref, Google ScholarDepartment of Health (2000) National Service Framework for Coronary Heart Disease. Modern Standards and Service Models. DH, London Google ScholarGraham I, Atar D, Borch-Johnsen K et al. for European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG) (2007) European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 28: 2375–2375 Crossref, Google ScholarNational Institute for Health and Clinical Excellence (2008) Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. [Clinical Guideline 67] May 2008 - reissued May 2012. NICE, London Google Scholar FiguresReferencesRelatedDetails 1 May 2012Volume 7Issue 5ISSN (online): 2052-2207 Metrics History Published online 27 September 2013 Published in print 1 May 2012 Information© MA Healthcare LimitedPDF download

Lipoprotein(a): Genotype–Phenotype Relationship and Impact on Atherogenic Risk

In 2010, more than 45 years after the initial discovery of lipoprotein(a) [Lp(a)] by Kare Berg, an European Atherosclerosis Society Consensus Panel recommended screening for elevated Lp(a) in people at moderate to high risk of atherosclerotic cardiovascular disease (CVD). This recommendation was based on extensive epidemiological findings demonstrating a significant association between elevated plasma Lp(a) levels and coronary heart disease, myocardial infarction, and stroke. In addition to those patients considered to be at moderate to high risk of heart disease, statin-treated patients with recurrent heart disease were also identified as targeted for screening of elevated Lp(a) levels. Taken together, recent findings have significantly strengthened the notion of Lp(a) as a causal risk factor for CVD. It is well established that Lp(a) levels are largely determined by the size of the apolipoprotein a [apo(a)] gene; however, recent studies have identified several other LPA gene polymorphisms that have significant associations with an elevated Lp(a) level and a reduced copy number of K4 repeats. In addition, the contribution of other genes in regulating Lp(a) levels has been described. Besides the strong genetic regulation, new evidence has emerged regarding the impact of inflammation as a modulator of Lp(a) risk factor properties. Thus, oxidized phospholipids that possess a strong proinflammatory potential are preferentially carried on Lp(a) particles. Collectively, these findings point to the importance of both phenotypic and genotypic factors in influencing apo(a) proatherogenic properties. Therefore, studies taking both of these factors into account determining the amount of Lp(a) associated with each individual apo(a) size allele are valuable tools when assessing a risk factor role of Lp(a).