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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Clinical lipidology belongs par excellence to the preventive mode of medical practice. This Roundtable brings two long-time advocates of cardiometabolic prevention and a newly minted preventive cardiologist into a discussion that expands their recent JCL editorial on this topic. Atherosclerosis is a single disease process that leads to approximately 25% of deaths in economically advanced nations and a growing fraction of mortality and morbidity in nations with developing and emerging economies. Our discussants suggest that at least 75% of atherosclerotic cardiovascular disease can be prevented. Diet and lifestyle including physical activity are the cornerstones for this effort. Public and private choices about diet-lifestyle are influenced by economics, education (especially in childhood), inequities, technology, misinformation, and trust. Lipid clinics perform well with pharmacologic treatment of lipid disorders and increasingly give attention to hypertension, obesity, and diabetes as needed. Cardiometabolic prevention in the clinic works best through provider teams. Business considerations and exemplary programs are highlighted.

Background Non-statin lipid lowering therapies (LLTs) provide additional treatment options for patients. Use patterns and patient perceptions of non-statin LLT remain incompletely described. Hypothesis The guideline-recommended statin intensity remains underutilized in patients treated with and without non-statin LLT. Methods The PALM Registry collected LLT information on patients with or at risk of ASCVD treated at 125 US clinics in 2015. We compared patient perceptions, lipid levels and statin use among patients treated with and without non-statin LLT. Results Among 7720 patients, 1930 (25.0%) were treated with a non-statin LLT (1249 fish oil, 417 fibrates, 329 ezetimibe, 196 niacin). Concurrent statin treatment occurred in 73.7%, of which 45.4% were dosed under the guideline-recommended intensity. Compared with patients on statin alone, patients receiving both a statin and non-statin LLT (n = 1423) were more likely to be male, white race and to perceive themselves as higher risk of ASCVD compared with their peers (38.5% vs. 34.9%, p = .047). Only 27.4% of patients treated with non-statin LLT alone perceived themselves at higher risk. Most (75.7%) patients treated with a non-statin LLT alone reported never being treated with a statin, despite ASCVD in 30.8% of these patients. Among those previously treated with a statin, 59.3% reported being willing to try a statin again. Conclusions Non-statin LLT is used in one in four patients with or at risk for ASCVD; its use is frequently in place of statin therapy or in the absence of guideline-recommended statin intensity. More work is needed to establish statins as first line therapy.

Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.

Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6YE361 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6YE361 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6YE361 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6YE361 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6YE361 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361 although no underlying STAT6 mutations were observed in either sample examined. STAT6YE361 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.

G-quadruplexes are pervasive nucleic acid secondary structures in mammalian genomes and transcriptomes that regulate gene expression and genome duplication. Small molecule ligands that modify the stability of G-quadruplexes are widely studied in cancer, but whether G-quadruplex ligands can also be used to manipulate cell function under normal development and homeostatic conditions is largely unexplored. Here we show that two related G-quadruplex ligands (pyridostatin and carboxypyridostatin) can reduce proliferation of adult neural stem cell and progenitor cells derived from the adult mouse subventricular zone both in vitro and in vivo. Studies with neurosphere cultures show that pyridostatin reduces proliferation by a mechanism associated with DNA damage and cell death. By contrast, selectively targeting RNA G-quadruplex stability with carboxypyridostatin diminishes proliferation through a mechanism that promotes cell cycle exit and the production of oligodendrocyte progenitors. The ability to generate oligodendrocyte progenitors by targeting RNA G-quadruplex stability, however, is dependent on the cellular environment. Together, these findings show that ligands that can selectively stabilize RNA G-quadruplexes are an important, new class of molecular tool for neural stem and progenitor cell engineering, whereas ligands that target DNA G-quadruplexes have limited utility due to their toxicity.

Background Familial hypercholesterolemia (FH) affects more than one million Americans, and most individuals have not been formally diagnosed with the condition. Individuals with FH have markedly elevated serum low-density lipoprotein cholesterol (LDL-C) levels from birth that substantially increase their risk for early-onset cardiovascular (CV) events. Guideline-recommended treatments exist to lower LDL-C and reduce the risk of CV events in individuals with FH and hypercholesterolemia. This study seeks to address a significant gap in the care of individuals with FH by systematically developing an effective approach to increase the adoption of guideline-recommended treatments for FH. Methods This developmental study will consist of three aims: 1) determine the barriers to and facilitators of treatment of FH; 2) develop a list of potential implementation strategies to promote the adoption of guideline-recommended treatment of individuals with FH, and 3) pilot one implementation strategy from Aim 2 in one health care system to evaluate implementation outcomes of the strategy. The Practical, Robust Implementation and Sustainability Model will guide this project, including the development of interview questions, implementation strategies, and evaluation of the implementation strategy. The implementation outcomes include: of individuals targeted by the implementation strategy, how many are impacted by it (reach), measure the change in knowledge, attitude, and behavior that is impacted by the implementation strategy (effectiveness), in settings targeted by the implementation strategy, how many adopt it (adoption), and fidelity and cost of the implementation strategy (implementation). Data sources will include electronic health records, administrative databases, surveys, and semi-structured interviews. Discussion The inclusion of patient and organizational stakeholder experiences is a critically important step in developing efficient and effective implementation strategies. Additionally, perspectives from a variety of geographic areas and cultural perspectives should increase feasibility and fidelity of the interventional approach to improve adoption of guideline-recommended practices for FH care.

Aims The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. Methods This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. Results Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (–36.2%) significantly more than placebo (1.8% (placebo-corrected difference –38.0%); P Conclusion The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. Trial Registration ClinicalTrials.gov identifier: NCT03337308.

Acquisition costs and cost-effectiveness have limited access and recommendations to use proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibiting monoclonal antibodies (mAbs). Recently, prices were reduced by 60% for alirocumab and evolocumab. This statement systematically reviewed subgroup analyses from statin and PCSK9 mAb trials to identify higher risk groups for which PCSK9 mAbs at the new price could be considered a reasonable (

Background Black men and women are at higher risk for, and suffer greater morbidity and mortality from, atherosclerotic cardiovascular disease (ASCVD) compared with adults of European Ancestry (EA). Black patients with familial hypercholesterolemia are at particularly high risk for ASCVD complications because of lifelong exposure to elevated levels of low‐density‐lipoprotein cholesterol. Methods and Results This retrospective study analyzed ASCVD prevalence and risk factors in 808 adults with heterozygous familial hypercholesterolemia from 5 US‐based lipid clinics, and compared findings in Black versus EA patients. Multivariate logistic regression models were used to determine the strongest predictors of ASCVD as a function of race. No significant difference was noted in the prevalence of ASCVD in Black versus EA patients with familial hypercholesterolemia (39% versus 32%, respectively; P =0.15). However, Black versus EA patients had significantly greater prevalence of modifiable risk factors, including body mass index (mean, 32±7 kg/m 2 versus 29±6 kg/m 2 ; P P P P =0.006). Black versus EA patients also had significantly lower usage of statins (61% versus 73%; P =0.004) and other lipid‐lowering agents. In a fully adjusted multivariate model, race was not independently associated with ASCVD (odds ratio, 0.92; 95% CI, 0.60–1.49; P =0.72). Conclusions The strongest predictors of ASCVD in Black patients with familial hypercholesterolemia were hypertension and cigarette smoking. These data support wider usage of statins and other lipid‐lowering therapies and greater attention to modifiable risk, specifically blood pressure management and smoking cessation.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in women across all racial and ethnic groups within the USA. Despite robust evidence from randomized controlled trials demonstrating that treatment of hypercholesterolemia in women reduces cardiovascular events, women who are eligible for lipid-lowering therapy are less likely than men to be prescribed guideline-recommended therapy or to have therapy prescribed at the appropriate intensity. Historically, women have been underrepresented in clinical trials. Recent randomized clinical trials have shown that women derive similar benefits as men when treated with lipid-lowering therapy, and recent studies demonstrate potential uses for lipid-lowering therapies that extend beyond their previously well-established indications. In this review, we will discuss lipid-lowering therapies in the context of recent clinical trials with a focus on special considerations in women.

We describe a case of a 59-year-old man with severe heterozygous familial hypercholesterolemia (FH) and elevated lipoprotein(a) presenting with severe aortic stenosis, treated with transcatheter aortic valve replacement (TAVR). His history also includes premature coronary artery disease requiring coronary artery bypass surgery at age 48 and a stroke at age 55. His pre-treatment lipid values include an LDL-Cholesterol (LDL-C) of 458 mg/dL, total cholesterol of 588 mg/dL, and lipoprotein (a) level of 351 nmol/L. Since his FH diagnosis, he has received several lipid-lowering agents including statins, bile acid sequestrants, nicotinic acid derivatives, and PCSK9 inhibitors. This case reflects the association of FH and elevated lipoprotein(a) with aortic stenosis and TAVR as a viable and effective treatment.

Background Numerous implementation strategies to improve utilization of statins in patients with hypercholesterolemia have been utilized, with varying degrees of success. The aim of this systematic review is to determine the state of evidence of implementation strategies on the uptake of statins. Methods and results This systematic review identified and categorized implementation strategies, according to the Expert Recommendations for Implementing Change (ERIC) compilation, used in studies to improve statin use. We searched Ovid MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from inception to October 2018. All included studies were reported in English and had at least one strategy to promote statin uptake that could be categorized using the ERIC compilation. Data extraction was completed independently, in duplicate, and disagreements were resolved by consensus. We extracted LDL-C (concentration and target achievement), statin prescribing, and statin adherence (percentage and target achievement). A total of 258 strategies were used across 86 trials. The median number of strategies used was 3 (SD 2.2, range 1–13). Implementation strategy descriptions often did not include key defining characteristics: temporality was reported in 59%, dose in 52%, affected outcome in 9%, and justification in 6%. Thirty-one trials reported at least 1 of the 3 outcomes of interest: significantly reduced LDL-C (standardized mean difference [SMD] − 0.17, 95% CI − 0.27 to − 0.07, p = 0.0006; odds ratio [OR] 1.33, 95% CI 1.13 to 1.58, p = 0.0008), increased rates of statin prescribing (OR 2.21, 95% CI 1.60 to 3.06, p < 0.0001), and improved statin adherence (SMD 0.13, 95% CI 0.06 to 0.19; p = 0.0002; OR 1.30, 95% CI 1.04 to 1.63, p = 0.023). The number of implementation strategies used per study positively influenced the efficacy outcomes. Conclusion Although studies demonstrated improved statin prescribing, statin adherence, and reduced LDL-C, no single strategy or group of strategies consistently improved outcomes. Trial registration PROSPERO CRD42018114952.

Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. BA has been shown to significantly lower LDL-C by a mean of ~18% in patients receiving background maximally tolerated statins and a mean of ~25% in patients with statin intolerance. Objective: Determine efficacy and safety of BA in statin-intolerant patients receiving no background statin therapy across 4 phase 3 clinical trials. Methods: Data were pooled from 4 randomized (2:1), placebo-controlled studies evaluating oral BA 180 mg once daily vs placebo for 12 to 52 weeks. Primary efficacy endpoint was LDL-C % change from baseline to week 12. Safety assessments included treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI), and laboratory values. For patients who reported SAMs, additional information around etiology and location were collected. Results: Of 3621 patients, 586 (394 BA; 192 placebo) reported intolerance to multiple statins because of SAMS or other AEs and received no statins during the studies. Mean baseline LDL-C was 148.7 mg/dL. After 12 weeks, BA significantly lowered LDL-C vs placebo (placebo-corrected, -26.5%; P < 0.001). Myalgia was the top reason for drug discontinuation, but was less common in the BA arm (17.7%) vs placebo (43.5%). CK > 5 х ULN was uncommon in both groups. Among AESIs (Table) , muscle disorders were reported by 12.7% (BA) vs 14.1% (placebo). Myalgia was less common with BA (4.6%) vs placebo (7.3%). Muscle spasms (4.1% vs 3.6%) and pain in extremity (3.3% vs 2.1%) were comparable between treatment groups. Muscular weakness was rare (0.5% BA, 1% placebo). Conclusion: Among the population of patients unable to use statins, BA significantly lowered LDL-C vs placebo without increasing muscle-related TEAEs. BA may be an appropriate lipid-lowering therapy for patients with hyperlipidemia who are statin intolerant.

Introduction: Black men and women are at higher risk for atherosclerotic cardiovascular disease (ASCVD) and when diagnosed, have greater morbidity and mortality as compared to individuals from European ancestry (EA). In patients with familial hypercholesterolemia (FH), it remains unknown whether Black patients have similarly increased risk for ASCVD. Hypothesis: To characterize the prevalence of ASCVD and to determine the strongest predictors of ASCVD in Black FH patients compared to EAs. Methods: The prevalence of ASCVD in 173 Black adult patients with FH followed in US-based lipid clinics was assessed retrospectively through a multicenter. A multivariate logistic regression model was used to determine the strongest predictors of ASCVD. Covariates included age, sex, diabetes mellitus, hypertension, and current smoking. ASCVD was defined as coronary, peripheral, and cerebrovascular events including angina, myocardial infarction, coronary angioplasty, peripheral arterial surgery, claudication, peripheral angioplasty, transient ischemic attack, stroke, and carotid endarterectomy. Results: Baseline characteristics of the 173 Black adult patients compared to EAs are shown in table 1. Black patients with FH were more likely to have higher BMI, hypertension, diabetes and to be current smokers. The prevalence of ASCVD in Black patients with FH was 38% compared to 30% in EAs, an absolute difference of 8% (p=0.047). The strongest predictors of ASCVD in Black patients with FH were hypertension and current smoking (table 2). Conclusions: Black patients with FH have a significantly higher prevalence of ASCVD when compared to EAs with FH. The strongest predictors of ASCVD in Black patients with FH were hypertension and current smoking. Aggressive primary prevention strategies specifically focused on the management of hypertension and smoking cessation should be tested for impact on the cardiovascular risk profile of Black patients with FH.

Introduction: Bempedoic acid (BA), an ATP-citrate lyase inhibitor, lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. Objective: To report efficacy and safety of BA by sex in patients with elevated LDL-C. Methods: Data were pooled from 4 phase 3 randomized (2:1), double-blind studies investigating oral BA (180 mg once daily) vs placebo for 12 weeks to 52 weeks in adults receiving maximally tolerated statins who required additional LDL-C lowering, analyzed by sex. The primary efficacy endpoint was % change in LDL-C from baseline to week 12. Results were analyzed in cohorts with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (“ASCVD/HeFH on statins pool”, n=3009) or history of statin intolerance (“statin intolerant pool”, n=614). Safety assessments included treatment-emergent adverse events (TEAEs). Results: Of all participants, 34.3% were women. Significant LDL-C lowering from baseline with BA vs placebo was demonstrated in both pools and sexes ( P < 0.001; Table 1 ), with greater lowering in women vs men in the ASCVD/HeFH on statins pool ( P = 0.04). Rates of TEAEs were similar across groups ( Table 2 ). Rates of common TEAEs were similar in both pools and sexes, except urinary tract infection (men: BA, 2.8%; placebo, 3.0%; women: BA, 8.0%; placebo, 10.3%) and pain in extremity (men: BA, 2.5%; placebo, 1.2%; women: BA, 4.2%; placebo, 2.9%), which occurred more frequently in women. Conclusion: BA lowered LDL-C significantly in both women and men, with greater effect in women vs men in both pools, and a safety profile generally comparable to placebo in both sexes.

The funding information in this paper was presented incorrectly. It should be: This study was supported in part by Aegerion, Inc. and REGENXBIO Inc.

Background: Statin-treated patients with diabetes mellitus (DM) are at high cardiovascular (CV) risk. Methods: In REDUCE-IT, icosapent ethyl (IPE; 4 g/day) reduced CV risk vs. placebo in statin-treated patients with either DM plus risk factors or established CV disease. The primary endpoint was CV death, myocardial infarction (MI), stroke, coronary revascularization, or unstable angina. The key secondary endpoint was CV death, MI, or stroke. Key DM analyses were prespecified. Results: 58.5% of patients had DM; 91.0% on ≥1 DM medication, 49.5% on ≥2. IPE reduced primary (Figure) and key secondary first and total (first plus recurrent) events. Patients with and without DM both showed substantial benefits, but patients with DM had 1.5-fold greater rates of the primary endpoint in the placebo group, and a 7% absolute risk reduction in first and a 12.7% reduction in total events (both p Conclusion: IPE 4 g/day provides robust CV benefits in statin-treated patients with DM, with large relative and absolute risk reductions in both first and total CV events. Disclosure D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. E.A. Brinton: Consultant; Self; Esperion Therapeutics, Inc., Medicines Company, Regeneron Pharmaceuticals. Speaker’s Bureau; Self; Amarin Corporation, Amgen, Esperion Therapeutics, Inc. Other Relationship; Self; Amarin Corporation, Kowa Pharmaceuticals America, Inc. M. Miller: Consultant; Self; Amarin Corporation. P.G. Steg: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Idorsia, Mylan, Novartis AG, Pfizer Inc., Sanofi, Servier. Research Support; Self; Amarin Corporation. Speaker’s Bureau; Self; Novo Nordisk A/S. T.A. Jacobson: Consultant; Self; Esperion Therapeutics, Inc., Regeneron Pharmaceuticals, Sanofi US. Other Relationship; Self; Amarin Corporation. S.B. Ketchum: Other Relationship; Self; Amarin Corporation. R.T. Doyle: Other Relationship; Self; Amarin Corporation. R.A. Juliano: Other Relationship; Self; Amarin Corporation. L. Jiao: Other Relationship; Self; Amarin Corporation. C. Granowitz: Other Relationship; Self; Amarin Corporation. O. Ganda: Consultant; Self; Amarin Corporation. Other Relationship; Self; Novo Nordisk A/S. F.K. Welty: Other Relationship; Self; Boehringer Ingelheim International GmbH. R.S. Busch: Research Support; Self; Amarin Corporation, Bayer AG, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen, Esperion Therapeutics, Inc., Novo Nordisk Inc., Sanofi US. A.C. Goldberg: Advisory Panel; Self; Akcea Therapeutics, Esperion Therapeutics, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; Akcea Therapeutics, Amarin Corporation, Amgen, Ionis Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Other Relationship; Self; Merck & Co., Inc. D.M. Herrington: None. M. Budoff: Research Support; Self; Amarin Corporation, General Electric. Speaker’s Bureau; Self; Amarin Corporation. J. Tardif: Research Support; Self; Esperion Therapeutics, Inc., Ionis Pharmaceuticals, Inc., REGENXBIO Inc., Sanofi, Servier. Other Relationship; Self; Amarin Corporation, AstraZeneca, DalCor Pharmaceuticals. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corvidia, Denka-Seiken Co., Ltd., Esperion Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amgen, Esperion Therapeutics, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA. Funding Amarin Pharma Inc

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased "lipotoxicity," improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., "C24:0/C16:0"), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e'. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P

Background The alirocumab expanded use program provided open-label access to alirocumab before its commercial availability to patients with severe hypercholesterolemia not controlled with maximally tolerated doses of standard-of-care lipid-lowering therapy. Objective To describe the safety and lipid-lowering efficacy of alirocumab in high-risk patients who were likely to be early users of proprotein convertase subtilisin/kexin type 9 inhibitors after approval. Methods Patients with heterozygous familial hypercholesterolemia (HeFH) and/or coronary heart disease (CHD) and baseline low-density lipoprotein cholesterol (LDL-C) of ≥160 mg/dL on maximally tolerated lipid-lowering therapy were enrolled and received alirocumab 150 mg every 2 weeks for 24 weeks. Patients were permitted use of all available statins; those not taking any dose of statin could also be enrolled. Results Of 100 enrolled patients, 93 were white, 62 were women, and overall mean age was 58 years; 61 had HeFH, 3 had unknown type of familial hypercholesterolemia, 66 had CHD, and 30 had both familial hypercholesterolemia and CHD. Sixty-four patients were identified by their providers to have some level of statin intolerance; of these, 47 were not on statin. Alirocumab reduced LDL-C on average from 221 mg/dL at baseline to 102 mg/dL by week 24 (−55%). Treatment-emergent adverse events were experienced in 61% of patients and treatment-emergent adverse events leading to permanent treatment discontinuation in 3% of patients; no deaths occurred. Conclusions Safety and efficacy observations from the open-label alirocumab expanded use program of very high-risk patients with HeFH and/or CHD and baseline LDL-C of ≥160 mg/dL uncontrolled by maximally tolerated lipid-lowering therapy were consistent with those in the placebo/ezetimibe-controlled ODYSSEY trials.

The latest cholesterol guidelines have shifted focus from achieving low-density lipoprotein cholesterol (LDL-C) targets toward statin use and intensity guided by atherosclerotic cardiovascular disease (ASCVD) risk.Statin use and intensity were evaluated in 5,905 statin-eligible primary or secondary prevention patients from 138 PALM Registry practices.Overall, 74.7% of eligible adults were on statins; only 42.4% were on guideline-recommended intensity. Relative to primary prevention patients, ASCVD patients were more likely to be on a statin (83.6% vs 63.4%, P.0001) and guideline-recommended intensity (47.3% vs 36.0%, P.0001). Men were more likely than women to be prescribed recommended intensity for primary (odds ratio [OR] 1.87, 95% CI 1.49-2.34) and secondary (OR 1.47, 95% CI 1.26-1.70) prevention. In primary prevention, increasing age, diabetes, obesity, hypertension, and lower 10-year ASCVD risk were associated with increased odds of receiving recommended intensity. Among ASCVD patients, those with coronary artery disease were more likely to be on recommended intensity than cerebrovascular or peripheral vascular disease patients (OR 1.71, 95% CI 1.41-2.09), as were those seen by cardiologists (OR 1.43, 95% CI 1.12-1.83). Median LDL-C levels were highest among patients not on statins (124.0 mg/dL) and slightly higher among those on lower-than-recommended intensity compared with recommended-therapy recipients (88.0 and 84.0 mg/dL, respectively; P≤.0001).In routine contemporary practice, 1 in 4 guideline-eligible patients was not on a statin; less than half were on the recommended statin intensity. Untreated and undertreated patients had significantly higher LDL-C levels than those receiving guideline-directed statin treatment.

Background The previously published ODYSSEY ESCAPE trial demonstrated a significant reduction in the use of lipoprotein apheresis for heterozygous familial hypercholesterolemia (HeFH) patients when placed on alirocumab 150 mg every 2 weeks. In patients with HeFH who have consistently elevated levels of low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy, current lipid guidelines recommend apheresis. Although apheresis reduces LDL-C levels by 50%–75%, it must be repeated, as frequently as every 1–2 weeks. Objective To assess clinical experience with apheresis and alirocumab for patients in a real-world practice setting. Methods This retrospective review included patients from 5 apheresis centers who were treated with apheresis and had started alirocumab therapy. In addition to LDL-C levels, total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, and particle number were evaluated if data were available. Results Eleven of the 25 (44%) patients discontinued apheresis completely after initiation of alirocumab therapy, having achieved LDL-C 50% reduction from baseline levels. Among the 14 patients who remained on apheresis, seven decreased the frequency of apheresis sessions. No significant safety problems were reported. Conclusion Alirocumab lowered LDL-C levels by an average of 55.5% in patients receiving apheresis for elevated LDL-C. Seventy-two percent of patients on alirocumab therapy discontinued or reduced the frequency of apheresis treatment. However, some patients continued to require apheresis due to elevated lipoprotein(a), extremely elevated LDL-C, or if alirocumab therapy was discontinued due to less than anticipated LDL-C reduction.

Pediatric endotracheal intubation is a procedure that can be stress provoking to the emergency physician. Although the need for this core skill is rare, when confronted with this situation, the emergency physician must have knowledge of the anatomic, physiologic, and pathologic components unique to the pediatric airway to optimize success. Furthermore, the emergency physician should be well versed in the various equipment and adjuncts as well as techniques developed to effectively manage the pediatric airway. This review covers the pathophysiology and practice of endotracheal intubation. Figures show a gum elastic bougie; the Mallampati classification; appropriate oropharyngeal, laryngeal, and tracheal axes; advancing the laryngoscope to lift the epiglottis; endotracheal tube position in neonates; and synchronized intermittent mandatory ventilation pressure-regulated volume control mechanical ventilation. Tables list endotracheal tube sizes, neonatal endotracheal tube sizes, pediatric laryngeal mask airway sizes, commonly used induction agents, and endotracheal tube insertion depth guidelines. This review contains 6 figures, 8 tables, and 77 references. Key words: emergent tracheal intubation; endotracheal tube; laryngoscopy; pediatric airway; pediatric airway management; pediatric endotracheal intubation; pediatric laryngeal mask; video laryngoscopy

Background Current treatment guidelines strongly recommend statin therapy for secondary prevention. However, it remains unclear whether patients’ perceptions of cardiovascular risk, beliefs on cholesterol, or the intensity of prescribed statin therapy differs for patients with coronary artery disease ( CAD ) versus cerebrovascular disease (Ce VD ) versus both CAD and Ce VD ( CAD &Ce VD ). Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry collected data on statin use, intensity, and core laboratory low‐density lipoprotein cholesterol levels for 3232 secondary prevention patients treated at 133 US clinics. Among individuals with Ce VD only (n=403), CAD only (n=2202), and Ce VD & CAD (n=627), no significant differences were observed in patient‐perceived cardiovascular disease risk, beliefs on cholesterol lowering, or perceived effectiveness and safety of statin therapy. However, patients with Ce VD only were less likely to receive any statin therapy (76.2% versus 86.2%; adjusted odds ratio 0.64, 95% CI 0.45–0.91), or guideline‐recommended statin intensity (34.6% versus 50.4%; adjusted odds ratio 0.60, 95% CI 0.45–0.81) than those with CAD only. Individuals with Ce VD only were also less likely to achieve low‐density lipoprotein cholesterol dL (59.2% versus 69.7%; adjusted odds ratio 0.79, 95% CI 0.64–0.99) than individuals with CAD alone. There were no significant differences in the use of any statin therapy or guideline‐recommended statin intensity between individuals with CAD &Ce VD and those with CAD only. Conclusions Despite lack of significant differences in patient‐perceived cardiovascular risk or statin beliefs, patients with Ce VD were significantly less likely to receive higher intensity statin or achieve low‐density lipoprotein cholesterol dL than those with CAD only.

Background: Female patients have historically received less aggressive lipid management than male patients. Contemporary care patterns and the potential causes for these differences are unknown. Methods and Results: Examining the Patient and Provider Assessment of Lipid Management Registry—a nationwide registry of outpatients with or at risk for atherosclerotic cardiovascular disease—we compared the use of statin therapy, guideline-recommended statin dosing, and reasons for undertreatment. We specifically analyzed sex differences in statin treatment and guideline-recommended statin dosing using multivariable logistic regression. Among 5693 participants (43% women) eligible for 2013 American College of Cardiology/American Heart Association Cholesterol Guideline–recommended statin treatment, women were less likely than men to be prescribed any statin therapy (67.0% versus 78.4%; P P P P P P P P P P Conclusions: Women eligible for statin therapy were less likely than men to be treated with any statin or guideline-recommended statin intensity. A combination of women being offered statin therapy less frequently, while declining and discontinuing treatment more frequently, accounted for these sex differences in statin use.

A Correction to this paper has been published: 10.1007/s10557-021-07188-w

The following article represents material presented and discussed at a symposium hosted by the National Lipid Association hosted entitled "Managing the Challenging Homozygous Familial Hypercholesterolemia Patient-Academic Insights and Practical Approaches for a Severe Dyslipidemia" on November 7, 2015 in Orlando, FL. Presenters included G.K.H., A.C.G, and P.M.M. The diagnosis and genetic causes of extremely high low-density lipoprotein (LDL) cholesterol, which has become known as homozygous familial hypercholesterolemia, were discussed. This disorder in adults manifest often by LDL cholesterol in excess of 500 occurs in several populations with a prevalence of 1 in 300,000. In more sequestered areas, the frequency may be much greater due to founder effects of specific settlers carrying the responsible alleles. Although the great majority of these patients have a variant sequences in the LDL receptor gene, variants in the apolipoprotein B, proprotein convertase subtilisin kexin type 9, or LDL receptor adaptor protein gene loci can also be causative. Some individuals have additional genetic abnormalities, which have not been fully revealed. In most studies, the diagnosis has depended on predefined clinical findings in association with the very elevated LDL cholesterol. Standard lipid-lowering drugs such as statins, ezetimibe, or bile acid-binding resins are usually only partially beneficial and leave the patients at high risk. Lipoprotein apheresis has been a more effective therapy and is a mainstay in treatment of many patients. New therapies such as mipomersen and lomitapide have reduced LDL dramatically in some but are often ineffective in others. Inhibitors of proprotein convertase subtilisin kexin type 9 can reduce LDL dramatically but in those with null genes for the LDL receptor, they are also ineffective. The availability of this battery of drugs has markedly improved the potential of pharmacotherapy to control LDL values and prolong the life of these patients.

The present study investigated the contributions of an overall personality taxonomy (HEXACO) and boredom proneness to creativity and curiosity. Past research has indicated that creativity and curiosity are related processes that are informed by personality variables. Prior, largely theoretical, work also suggests that the tendency to experience boredom may be linked to creativity and curiosity. In the present study, hierarchical multiple regressions were used to evaluate the role of personality and boredom proneness in the prediction of creativity and curiosity. The results confirmed the importance of personality (especially Openness to Experience) as an important predictor of creativity and curiosity. Furthermore, we found that boredom proneness was a positive predictor of curiosity in several forms once its shared variance with overall personality structure was partialled out. In addition, while the literature has found that boredom as a state triggers creativity, the results of this study indicate that boredom as a personality trait is not predictive of creativity. These findings suggest several interesting possibilities. Of note, if its inhibited qualities could be overcome, boredom proneness might be able to play a positive role in curiosity.

One of the key diagnostic criteria for autism spectrum disorder includes impairments in social interactions. This study compared the extent to which boys with high-functioning autism and typically developing boys “value” engaging in activities with a parent or alone. Two different assessments that can empirically determine the relative reinforcing value of social and non-social stimuli were employed: paired-choice preference assessments and progressive-ratio schedules. There were no significant differences between boys with high-functioning autism and typically developing boys on either measure. Moreover, there was a strong correspondence in performance across these two measures for participants in each group. These results suggest that the relative reinforcing value of engaging in activities with a primary caregiver is not diminished for children with autism spectrum disorder.

Atherosclerotic cardiovascular disease is the leading cause of death in developed and developing countries. LDL lowering therapies have a major role in reduction of cardiovascular events. Statins have been the mainstay of LDL lowering therapies with 20-60% reductions in LDL cholesterol. Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9) represent a new therapeutic option, reducing LDL cholesterol by an additional 40-70% on top of other lipid lowering therapies. This is likely to produce significant cardiovascular risk reduction, although clinical cardiovascular outcomes trials are still in progress. HDL cholesterol raising and triglyceride lowering therapies have not yet shown unequivocal benefits for cardiovascular risk reduction. New therapies in these areas are in development, and their future promise remains to be demonstrated.

Background Many adults eligible for statin therapy for cardiovascular disease prevention are untreated. Our objective was to investigate patient‐reported reasons for statin underutilization, including noninitiation, refusal, and discontinuation. Methods and Results This study included the 5693 adults recommended for statin therapy in the PALM (Patient and Provider Assessment of Lipid Management) registry. Patient surveys evaluated statin experience, reasons for declining or discontinuing statins, and beliefs about statins and cardiovascular disease risk. Overall, 1511 of 5693 adults (26.5%) were not on treatment. Of those not on a statin, 894 (59.2%) reported never being offered a statin, 153 (10.1%) declined a statin, and 464 (30.7%) had discontinued therapy. Women (relative risk: 1.22), black adults (relative risk: 1.48), and those without insurance (relative risk: 1.38) were most likely to report never being offered a statin. Fear of side effects and perceived side effects were the most common reasons cited for declining or discontinuing a statin. Compared with statin users, those who declined or discontinued statins were less likely to believe statins are safe (70.4% of current users vs. 36.9% of those who declined and 37.4% of those who discontinued) or effective (86.3%, 67.4%, and 69.1%, respectively). Willingness to take a statin was high; 67.7% of those never offered and 59.7% of patients who discontinued a statin would consider initiating or retrying a statin. Conclusions More than half of patients eligible for statin therapy but not on treatment reported never being offered one by their doctor. Concern about side effects was the leading reason for statin refusal or discontinuation. Many patients were willing to reconsider statin therapy if offered., See Editorial by Braun

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMT) and an upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including the Zeb2, as well as long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. In mouse models of either contusive spinal cord injury or transient ischemic stroke, the conditional knockout of Zeb2 in astrocytes attenuates astrogliosis, generates larger lesions, and delays recovery of motor function. These findings reveal ZEB2 as an important regulator of the astrocytic response to injury and suggest that astrogliosis is an EMT-like process, which provides a conceptual connection for the molecular and cellular similarities between astrogliosis and wound-healing responses in non-neural tissue.

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A.

BACKGROUND: Adherence to guideline-recommended statin recommendations in the United States (U.S.) is suboptimal. Patients’ likelihood to be treated according to guidelines may vary by the practice in which they are treated. METHODS: Variation in the use of statin therapy in 5,445 patients, with known or at high risk for atherosclerotic cardiovascular disease (ASCVD) and meeting a statin treatment indication, was examined across 74 U.S. Patient and Provider Assessment of Lipid Management (PALM) Registry clinics. Multivariable generalized linear mixed modeling was used to determine the median odds ratio (MOR) for statin use and 2013 American College of Cardiology/American Heart Association guideline-recommended statin intensity by practice. MOR quantifies between-practice variation by comparing the odds of receiving guideline-recommended statin treatment in a patient from a randomly selected practice with a similar patient from another random practice. Risk-adjusted low-density lipoprotein cholesterol (LDL-C) control (

Guideline implementation requires clinician knowledge but may be influenced by pre-existing beliefs and biases. We assessed the association of these clinician factors with lipid management following the release of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. In the PALM registry, 774 clinicians completed a survey to assess their knowledge of the 2013 American College of Cardiology/American Heart Association guidelines, belief in statin benefit, and statin safety concerns. The association of these factors with statin use, statin dosing, and low-density lipoprotein cholesterol (LDL-C) levels were assessed in the 6,839 patients treated by these clinicians between May and November 2015. Overall, 63.9% of clinicians responded to at least 3 out of 4 hypothetical scenarios in concordance with guideline recommendations (good tested knowledge), 88.4% reported belief in statin benefit, and 15.4% raised concerns about statin safety. Belief in statin benefit was more prevalent among cardiologists, who represented 48.8% of the clinicians surveyed, and concerns regarding statin safety were higher among noncardiologists and clinicians in an academic setting. Guideline knowledge was not associated with a difference in statin use (74.1% vs 73.8%, p = 0.84) and achievement of LDL-C level100 mg/dl (54.7% vs 52.4%, p = 0.07). However, patients treated by clinicians who reported belief in statin benefit were more likely to receive guideline-recommended statin intensity (41.9% vs 36.9%, p = 0.03), whereas patients treated by clinicians expressing statin safety concerns were less likely receive statins of at least guideline-recommended intensity (36.8% vs 42.5%, p = 0.001) and to achieve an LDL-C100 mg/dl (44.1% vs 56.1%, p0.001); the latter persisted after multivariable adjustment (odds ratio 0.75, 95% confidence interval 0.63 to 0.89). In conclusion, clinician beliefs regarding benefits and risks of statins were significantly associated with guideline adherence and patients' achieved LDL-C levels, whereas clinician knowledge of guideline recommendations was not.

INTRODUCTION: Familial Hypercholesterolemia (FH) is an inherited disorder characterized by a defect in the binding and internalization of low-density lipoprotein (LDL) particles, resulting in markedly elevated LDL levels and premature atherosclerosis. It is one of the most common inherited disorders of lipid metabolism. Many FH patients, especially those with homozygous FH do not reach LDL goals with traditional LDL therapies and may require additional, less often used, therapies. AREAS COVERED: Mipomersen is an anti-sense oligonucleotide that prevents production of apolipoprotein B leading to decreased levels of very low-density lipoprotein (VLDL) and LDL. In this review the authors discuss the pharmacokinetics of the drug, the clinical trials evaluating its efficacy and safety, and risks and challenges associated with its clinical implementation. Its use as therapy for the treatment of FH is also discussed. EXPERT OPINION: Mipomersen is approved for use only in homozygous FH. It has frequent adverse effects, such as injection site reactions, flu-like symptoms and hepatoxicity. It is useful only in patients who have failed other therapies, and it faces competition from other medications that have more tolerable side effect profiles.

Background The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommended testing low‐density lipoprotein cholesterol ( LDL ‐C) to identify untreated patients with LDL ‐C ≥190 mg/dL, assess lipid‐lowering therapy adherence, and consider nonstatin therapy. We sought to determine whether clinician lipid testing practices were consistent with these guidelines. Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry enrolled primary and secondary prevention patients from 140 US cardiology, endocrinology, and primary care offices in 2015 and captured demographic data, lipid treatment history, and the highest LDL ‐C level in the past 2 years. Core laboratory lipid levels were drawn at enrollment. Among 7627 patients, 2787 (36.5%) had no LDL ‐C levels measured in the 2 years before enrollment. Patients without chart‐documented LDL ‐C levels were more often women, nonwhite, uninsured, and non–college graduates (all P P =0.0034), a high‐intensity statin (21.5% versus 24.3%; P =0.016), nonstatin lipid‐lowering therapy (24.8% versus 27.3%; P =0.037), and had higher core laboratory LDL ‐C levels at enrollment (median 97 versus 92 mg/dL; P LDL ‐C testing. Of 166 individuals with core laboratory LDL ‐C levels ≥190 mg/dL, 36.1% had no LDL ‐C measurement in the prior 2 years, and 57.2% were not on a statin at the time of enrollment. Conclusions In routine clinical practice, LDL ‐C testing is associated with higher‐intensity lipid‐lowering treatment and lower achieved LDL ‐C levels.

African American individuals face higher atherosclerotic cardiovascular disease risk than white individuals; reasons for these differences, including potential differences in patient beliefs regarding preventive care, remain unknown.To evaluate differences in statin use between white and African American patients and identify the potential causes for any observed differences.Using the 2015 Patient and Provider Assessment of Lipid Management (PALM) Registry data, we compared statin use and dosing between African American and white outpatient adults who were potentially eligible for primary or secondary prevention statins. A total of 138 US community health care practices contributed to the data. Data analysis was conducted from March 2017 to May 2018.Primary outcomes were use and dosing of statin therapy according to the 2013 American College of Cardiology/American Heart Association guideline by African American or white race. Secondary outcomes included lipid levels and patient-reported beliefs. Poisson regression was used to evaluate the association between race and statin undertreatment, a category combining people who were not taking a statin or those taking a dose intensity lower than recommended.A total of 5689 patients (806 [14.2%] African American) in the PALM registry were eligible for statin therapy. African American individuals were less likely than white individuals to be treated with a statin (570/807 [70.6%] vs 3654/4883 [74.8%]; P = .02). Among those treated, African American patients were less likely than white patients to receive a statin at guideline-recommended intensity (269 [33.3%] vs 2145 [43.9%], respectively; P .001; relative risk, 1.07 [95% CI, 1.00-1.15]; P = .05, after adjustment for demographic and clinical factors). The median (interquartile range) low-density lipoprotein cholesterol levels of patients receiving treatment were higher among African American than white individuals (97.0 [76.0-121.0] mg/dL vs 85.0 [68.0-105.0] mg/dL; P .001). African American individuals were less likely than white individuals to believe statins were safe (292 [36.2%] vs 2800 [57.3%]; P .001) or effective (564 [70.0%] vs 3635 [74.4%]; P = .008) and were less likely to trust their clinician (663 [82.3%] vs 4579 [93.8%]; P .001). Group differences in statin undertreatment were not significant after adjusting for demographic, clinical, and clinician factors, socioeconomic status, and patient beliefs (final adjusted relative risk, 1.03 [95% CI 0.96-1.11]; P = .35).African American individuals were less likely to receive guideline-recommended statin therapy. Demographic, clinical, socioeconomic, belief-related, and clinician differences contributed to observed differences and represent potential targets for intervention.

Background Current statin use and symptoms among older adults in routine community practice have not been well characterized since the release of the 2013 American College of Cardiology/American Heart Association guideline. Methods and Results We compared statin use and dosing between adults >75 and ≤75 years old who were eligible for primary or secondary prevention statin use without considering guideline‐recommended age criteria. The patients were treated at 138 US practices in the Patient and Provider Assessment of Lipid Management (PALM) registry in 2015. Patient surveys also evaluated reported symptoms while taking statins. Multivariable logistic regression models examined the association between older age and statin use and dosing. Among 6717 people enrolled, 1704 (25%) were >75 years old. For primary prevention, use of any statin or high‐dose statin did not vary by age group: any statin, 62.6% in those >75 years old versus 63.1% in those ≤75 years old ( P =0.83); high‐dose statin, 10.2% versus 12.3% in the same groups ( P =0.14). For secondary prevention, older patients were slightly less likely to receive any statin (80.1% versus 84.2% [ P =0.003]; adjusted odds ratio, 0.81; 95% confidence interval, 0.66–1.01 [ P =0.06]), but were much less likely to receive a high‐intensity statin (23.5% versus 36.2% [ P P =0.0001]). Among current statin users, older patients were slightly less likely to report any symptoms (41.3% versus 46.6%; P =0.003) or myalgias (27.3% versus 33.3%; P Conclusions Overall use of statins was similar for primary prevention in those aged >75 years versus younger patients, yet older patients were less likely to receive high‐intensity statins for secondary prevention. Statins appear to be similarly tolerated in older and younger adults.