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Cardiovascular disease remains the leading cause of death and disability in the United States and globally. Disease burden continues to escalate despite technological advances associated with improved life expectancy and quality of life. As a result, longer life is associated with multiple chronic cardiovascular conditions. Clinical guidelines provide recommendations without considering prevalent scenarios of multimorbidity and health system complexities that affect practical adoption. The diversity of personal preferences, cultures, and lifestyles that make up one's social and environmental context is often overlooked in ongoing care planning for symptom management and health behavior support, hindering adoption and compromising patient outcomes, particularly in groups at high risk. The purpose of this scientific statement was to describe the characteristics and reported outcomes in existing person-centered care delivery models for selected cardiovascular conditions. We conducted a scoping review using Ovid MEDLINE, Embase.com, Web of Science, CINAHL Complete, Cochrane Central Register of Controlled Trials through Ovid, and ClinicalTrials.gov from 2010 to 2022. A range of study designs with a defined aim to systematically evaluate care delivery models for selected cardiovascular conditions were included. Models were selected on the basis of their stated use of evidence-based guidelines, clinical decision support tools, systematic evaluation processes, and inclusion of the patient's perspective in defining the plan of care. Findings reflected variation in methodological approach, outcome measures, and care processes used across models. Evidence to support optimal care delivery models remains limited by inconsistencies in approach, variation in reimbursement, and inability of health systems to meet the needs of patients with chronic, complex cardiovascular conditions.

Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and are associated with increased risk of cardiovascular events that manifest from statin underutilization and discontinuation. The reported frequencies of SAMS are divergent in the literature. The writing group estimates the prevalence of SAMS, namely all muscle symptoms temporally related to statin use but without regard to causality, to be about 10% (range 5% to 25%), and the prevalence of pharmacological SAMS, specifically muscle symptoms resulting from pharmacological properties of the statin, to be about 1-2% (range 0.5% to 4%). In clinical practice, SAMS are likely to result from a combination of pharmacological and nonpharmacological effects, however this does not make the symptoms any less clinically relevant. Regardless of the etiology, SAMS need to be addressed in accordance with patients' preferences and experiences. This clinical perspective reviews the epidemiology and underlying pathophysiology of SAMS, and the cardiovascular consequences resulting from statin discontinuation. We present patient-centered clinical and communication strategies to mitigate SAMS and improve medication adherence and outcomes among statin users. Treatment strategies include 1) optimizing lifestyle interventions, 2) modulating risk factors that may contribute to muscle symptoms, 3) optimizing statin tolerability by dose reduction, decreased dosing frequency, or use of an alternate statin with more favorable pharmacokinetic properties, and 4) use of non-statins, emphasizing those with evidence for atherosclerotic risk reduction, either in combination with or in place of statin therapy depending on the patient's circumstances. The focus of this clinical perspective is sustainable lipoprotein goal achievement, which is important for cardiovascular risk reduction., (Copyright © 2022. Published by Elsevier Inc.)

Patients with homozygous familial hypercholesterolemia (FH) have severe hypercholesterolemia from birth and if untreated may experience very early onset of coronary artery disease in childhood or young adulthood with an aggressive course resulting in early death. Early initiation of aggressive low-density lipoprotein cholesterol (LDL-C) lowering is the mainstay of treatment, which requires the use of a multidrug treatment regimen, often in combination with lipoprotein apheresis, but LDL-C goal achievement is frequently unattainable due to the severity of baseline hypercholesterolemia and hyporesponsiveness to many LDL-C-lowering medications. Evinacumab, a monoclonal antibody that sequesters angiopoietin-like 3 protein and lowers LDL-C by an average of 49% in patients with homozygous FH, was approved by the Food and Drug Administration in February 2021 and is a major advance in treatment of these high-risk patients. In this report, we describe the complementary role of evinacumab in combination with lipoprotein apheresis in two patients with homozygous FH., (© 2022 International Society for Apheresis and Japanese Society for Apheresis.)

Background: Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies., Objective: Evaluate real-world use of bempedoic acid., Methods: Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation., Results: Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common., Conclusions: Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations., Competing Interests: Declaration of Competing Interest BAW reports institutional grant from Akcea. PBD has been a consultant for Akcea, Amryt, Esperion, Kaneka, Regeneron, and has received institutional research grants from Regeneron, Regenxbio, and Retrophin. JQP reports clinical trial work with Amgen, Novartis, and Akcea. SF is an employee of Regeneron and has no current disclosures. Prior disclosures were for single-event consultations with Amarin, Kowa, Novo Nordisk, Esperion, Bio89, and Novartis., (Copyright © 2021. Published by Elsevier Inc.)

Background: Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold., Objectives: The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis., Methods: In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i., Results: In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion., Conclusions: PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (5RO1HL132985). Dr Shapiro has received compensation for advisory activities from Amgen, Esperion, and Novartis. Dr Toth has served as a member of the Speakers Bureau for Amarin, Amgen, Esperion, and Novo Nordisk; and has served as a consultant to Amarin, 89bio, Kowa, Novartis, Resverlogix, and Theravance. Dr Wójcik is a current employee of Amgen; and has served as a consultant for Esperion and The Medicines Company. Dr Duell has performed advisory activities for Akcea, Amryt, Esperion, Kaneka, and Regeneron; and has received institutional grants from Retrophin/Travere, Regeneron, and Regenxbio. Dr Fazio is currently an employee of Regeneron Pharmaceuticals; during the covered period while at OHSU he received compensation for advisory activities from Amarin, Kowa, Novo Nordisk, Novartis, 89bio, and Esperion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Hypercholesterolemia is a leading cause of cardiovascular morbidity and mortality. Accordingly, efforts to lower apolipoprotein B-containing lipoproteins in plasma are the centerpiece of strategies for cardiovascular prevention and treatment in primary and secondary management. Despite the importance of this endeavor, many patients do not achieve appropriate low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) goals, even among those who have experienced atherosclerotic cardiovascular disease. The development of new LDL-C-lowering medications with alternative mechanisms of action will facilitate improved goal achievement in high-risk patients. Inclisiran is a novel small interfering RNA-based drug that is experimental in the United States and approved for clinical use in the European Union. It lowers LDL-C and other apolipoprotein B-containing lipoproteins by reducing production of proprotein convertase subtilisin/kexin Type 9 (PCSK9), a protein that normally contributes to LDL-receptor degradation, thereby increasing LDL-receptor density and recycling in hepatocytes. Although the lipid-lowering efficacy of inclisiran is comparable with results achieved with PCSK9-blocking monoclonal antibodies (alirocumab and evolocumab), there are several important differences between the 2 drug classes. First, inclisiran reduces levels of PCSK9 both intracellularly and extracellularly by blocking translation of and degrading PCSK9 messenger RNA. Second, the long biological half-life of inclisiran produces sustained LDL-C lowering with twice yearly dosing. Third, although PCSK9-blocking monoclonal antibodies drugs are proven to reduce atherosclerotic cardiovascular disease events, clinical outcomes trials with inclisiran are still in progress. In this article, we review the clinical development of inclisiran, its mechanism of action, lipid-lowering efficacy, safety and tolerability, and potential clinical role of this promising new agent., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction : Familial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis, and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies such as lifestyle modification and numerous LDL-C-lowering medications are often insufficient to achieve lipid goals in FH. Areas covered : Angiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described as well as its regulatory journey to an approved therapeutic. Expert opinion : Evinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. The short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events; however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest.

Heart failure with reduced ejection fraction (HFrEF) is a debilitating disease that is associated with substantial morbidity, mortality, and societal costs. The past three decades have brought about significant advancements in the pharmacologic management of HFrEF, and a corresponding reduction in morbidity and mortality. However, the progress to improve clinical outcomes in real-world settings has stalled in recent years, largely due to underutilization of guideline directed medical therapies (GDMT). The discovery of significant cardio-renal protection from sodium-glucose co-transporter 2 inhibitors (SGLT2i) has ushered in a new treatment paradigm for HFrEF management with SGLT2i therapy becoming an essential component of GDMT. Our Preventive Cardiology and Heart Failure services have established an innovative, multi-disciplinary, collaborative protocol to optimize management of cardiovascular risk factors and facilitation SGLT2i use in patients with HFrEF. The goal of this collaboration is to enhance utilization and safety of SGLT2i for HFrEF management by circumventing medication access issues, the major obstacle to therapy initiation. Within this protocol, our heart failure providers identify patients for the addition of SGLT2i to a background of heart failure GDMT. The patient is then referred to preventive cardiology where the team performs a comprehensive cardiovascular risk assessment, optimizes cardiovascular risk factors, and initiates SGLT2i with an emphasis on medication access, cost minimization, and mitigation of potential side effects. The heart failure team assumes responsibility for modification of heart failure-based therapies, and the preventive team manages diabetes, lipid, and metabolic-based therapies. The patient is followed by both cardiology services in a structured fashion, comparing outcome measures at regular intervals and utilizing our patient registry and bio-repository. This clinical practice statement provides a detailed evidentiary review on the cardiovascular and renal benefits of SGLT2i, outlines the rational for creation of a collaborative protocol, details a structured program that may serve as a template for enhanced heart failure management in other health systems, and addresses challenges encountered and recommendations for use., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objective: To determine the real-world use of pharmacotherapy with new evidence-based cardiovascular indications in an academic Preventive Cardiology Clinic., Methods: A retrospective study of patients seen in our Center for Preventive Cardiology (CPC) and who received a new prescription, according to Food and Drug Administration (FDA) approved indications, for one of the following pharmacotherapies with new evidence-based cardiovascular indications from May 2019 to May 2020: proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), eicosapentaenoic acid (EPA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA). Treatment endpoints were prescription patterns, medication access, patient out-of-pocket expenses, medication tolerability, and clinical cardiovascular events while on these therapies., Results: Of the 2390 patients seen in our CPC clinic over the observation period, 532 (22.3%) had already started and 291 (12.2%) were newly initiated on pharmacotherapy with new evidence-based cardiovascular indications with a median treatment duration of 9.1 months. Of these, 291 patients (for a total of 320 separate drug orders) - 93 (29.1%) were prescribed PCSK9i, 131 (40.9%) EPA, 46 (14.4%) SGLT2i, and 50 (15.6%) GLP-1 RA. Nearly 80% of cases required some form of provider intervention post-prescription (authorization, appeal, financial assistance, and/or side effect management). A total of 70% of adult patients with type 2 diabetes on metformin and with an HgbA1C >7% were treated with a SGLT2i and/or GLP-1 RA - either initiated prior to or during the study period. Median monthly drug cost for the total cohort was reduced from $595.00 pre-insurance approval to $70.50 post-insurance approval, to $7.00 post-financial assistance intervention. The medications were well tolerated with any side effect occurring in 28.3%, and discontinuation due to side effects in 5.8% of cases. Clinical cardiovascular events occurred in 2.7%, of which 1.9% was due to ASCVD and 0.8% to hospitalization for heart failure. Differences in medication access, cost, tolerability and clinical cardiovascular events varied widely between the medication classes., Conclusions: Initiation and management of pharmacotherapy with new evidence-based cardiovascular indications in a real-world setting requires substantial provider intervention, a workflow amenable to a multi-disciplinary approach which allows for high rates of medication access and cost minimization, and low rates of medication side effects and clinical cardiovascular events., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2021 The Author(s).)

Objective: To characterize unusual responses to PCSK9 inhibitor (PCSK9i) therapy in a real-world setting, given their extremely low prevalence in clinical trials., Methods: A retrospective study of patients seen in a structured academic PCSK9i clinic who had LDL-C measurements before and after initiation of PCSK9i (up to 12 months). Unusual response was defined as: (1) no response: no changes in LDL-C level at all time points; (2) delayed response: <30% LDL-C reduction by the third dose, but achieving this threshold at a later time; (3) reduced response: <30% LDL-C reduction at all time points; and (4) lost response: ≥30% LDL-C reduction by the third dose, but displaying <30% reduction at a later time., Results: Of the 411 patients meeting inclusion criteria, 54 were initially classified as unusual responders. After excluding those not adherent to prescribed interventions, 31 patients (7.5%) were classified as true unusual responders. These included: 2 with no response, 12 with delayed response, 3 with reduced response, 6 with delayed or reduced response, 4 with lost response, and 4 with delayed and lost response. Response to PCSK9i therapy at all time points revealed higher on-treatment LDL-C values (94-100 vs. 47-51 ​mg/dL, p ​< ​0.001) and lower degree of percent reduction in LDL-C (23.3-34% vs. 61.1-64.5%, p ​< ​0.001) in the unusual versus usual responders. Lipoprotein (a) (Lp[a]) values were consistently higher in the unusual responders (81-92.5 vs. 28.5-52 ​mg/dL, p ​< ​0.01). Fold change in post-versus pre-treatment PCSK9 plasma results was similar between the two cohorts (p ​> ​0.05), suggesting that unusual responses were not due to insufficient plasma PCSK9 blockade. Multiple logistic regression analysis identified clinical FH (OR 2.9, 95% CI 1.27-7.24) and no ezetimibe therapy (OR 0.334, 95% CI 0.150-0.728) as factors related to true unusual response., Conclusions: Unusual responses to PCSK9i in a clinical cohort are more common than reported in clinical trials. Of the suspected unusual responders, nearly half were the result of adherence issues, and thus careful medication reconciliation should be the first step in diagnosing an unusual response., (© 2020 The Author(s).)

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has revolutionized our understanding of cholesterol homeostasis and added to our arsenal against atherosclerotic cardiovascular disease (ASCVD). In a span of approximately 15 years, PCSK9 has morphed from an esoteric and rare cause of familial hypercholesterolemia (FH) into the most efficient cholesterol-lowering target ever known, with the completion of two large scale cardiovascular outcome trials showing positive results. Current Food and Drug Administration (FDA) approved modalities to inhibit PCSK9 are in the form of monoclonal antibodies which display an unparalleled degree of low-density lipoprotein cholesterol (LDL-C) lowering and expand upon the notion that lower LDL-C is better for ASCVD risk reduction. However, the accelerated pace of discovery and therapeutic development has left large gaps in our knowledge regarding the physiology and function of PCSK9. The aim of this review is to provide context to the discovery, history, treatment and current status of PCSK9 and its therapeutic inhibitors and highlight areas of controversy and future directions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chylomicronemia syndrome (CS) is a metabolic condition characterized by severely elevated plasma triglycerides (>880 mg/dL) and high rates of morbidity and mortality. The syndrome can be classified into two major groups: monogenic familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS), the frequencies of which are ill-defined., Objective: The objective of the study was to characterize the prevalence of the most common and rarest subsets of this syndrome, MCS and FCS, respectively, in a single-center, real-world setting., Methods: This was a retrospective cross-sectional study of patients with plasma triglycerides ≥880 mg/dL. The criteria used for identification of patients with FCS were modeled after a Food and Drug Administration endorsed set of parameters. Less stringent criteria that removed the requirement for pancreatitis were used to classify MCS. Full criteria are described in detail in the article., Results: Of the 2,342,136 patient records queried, 578 had triglycerides ≥880 mg/dL (0.025%), of which 86 had a documented history of pancreatitis. Five patients who met the criteria for FCS were identified (three genetically confirmed), resulting in an estimated prevalence of ~1-2 per 1,000,000. On the other hand, MCS was identified in 186 patients, corresponding to an estimated prevalence of ~1 in 12,000. There were 5181 cases of pancreatitis (0.22% of the entire cohort), 86 of which occurred in subjects with triglycerides≥880 mg/dL (1.7% of cases of pancreatitis). Rates of pancreatitis in this subset were elevated at 6.5%, 100%, and 17.8%, among patients with MCS, FCS, and secondary hypertriglyceridemia, respectively., Conclusions: CS is an uncommon condition, but it is associated with significant complications, regardless of etiology. Among patients with CS, MCS was 40- to 60-fold more prevalent than FCS and associated with frequent morbidity. Therefore, disease recognition and treatment should extend to all forms of CS pursuant to the clinical presentation., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. In response, a multidisciplinary team approach, which includes clinical pharmacists, is recommended to improve patient outcomes. The purpose of the study was to describe interventions associated with integration of a clinical pharmacist, with an emphasis on pharmacist-generated patient cost avoidance. Methods: This is a prospective observational study detailing pharmacist-initiated interventions within an academic preventive cardiology service. Interventions targeting pharmacotherapy optimization, side effect management, patient education, medication adherence, and cost avoidance were implemented during shared office visits with providers and/or on provider consultation for remote follow-up. Tabulation of cost avoidance was arranged into 2 formats: clinical interventions implemented by the pharmacist and direct patient out-of-pocket expense reduction. Money saved per clinical intervention was extrapolated from data previously published. Patient out-of-pocket expense prior to and after pharmacist involvement was calculated to assess aggregate yearly patient cost savings. Results: Over 12 months the pharmacist intervened on 974 patients, totaling 3725 interventions. Cost avoidance strategies resulted in yearly savings of $830 748 in aggregate-$149 566 from clinical interventions and $681 182 from patient out-of-pocket expense reduction. Monthly patient out-of-pocket expense was reduced from a median (interquartile range) of $217 ($83.5-$347) before to $5 ($0-$18) after pharmacist intervention. Conclusions : Addition of a clinical pharmacist within an academic preventive cardiology clinic generated substantial pharmacotherapy interventions, resulting in significant cost avoidance for patients. The resulting cost avoidance may result in improved medication adherence and clinical outcomes.

Background: Perioperative bridging in atrial fibrillation (AF) is associated with low thromboembolic rates but high bleeding rates. Recent guidance cautions the practice of bridging except in high risk patients. However, the practice of bridging varies widely and little data exist regarding appropriate anticoagulation intensity when using intravenous unfractionated heparin (UFH)., Hypothesis: To determine if high intensity UFH infusion regimens are associated with increased bleeding rates compared to low intensity regimens for bridging patients with AF., Methods: We conducted a single center retrospective cohort study of admitted patients with non-valvular AF receiving UFH for ≥24 hours. UFH intensities were chosen at the providers' discretion. The primary endpoint was the rate of bleeding defined by the International Society on Thrombosis and Hemostasis during UFH infusion or within 24 hours of discontinuation. The secondary endpoint was a composite of cardiovascular events, arterial thromboembolism, venous thromboembolism, myocardial infarctions and death during UFH infusion., Results: A total of 497 patients were included in this analysis. Warfarin was used in 82.1% and direct acting oral anticoagulants in 14.1% of patients. The rate of any bleed was higher among high intensity compared to low intensity UFH regimens (10.5% vs 4.9%, odds ratio = 2.29, 95% confidence interval = 1.07-4.90). Major bleeding was significantly higher among high intensity compared to low intensity UFH regimens. There was no difference in composite thrombotic events or death., Conclusions: Low intensity UFH infusions, targeting lower anticoagulation targets, were associated with decreased bleeding rates without a signal of increased thromboembolic events in hospitalized AF patients., (© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Purpose of Review: To review the clinical trial data and underlying mechanistic principles in support of the robust cardiovascular (CV) benefits, in particular, heart failure (HF) outcomes association with sodium-glucose co-transporter-2 (SGLT2) inhibitors., Recent Findings: Several large CV outcome trials in patients with type 2 diabetes mellitus (T2DM) and with either established atherosclerotic CV disease (ASCVD) or at high risk for ASCVD reveal that SGLT2 inhibitors cause reductions in CV and HF endpoints. The reduction in ASCVD appears to be confined to those with established ASCVD on the order of ≈ 14%, as does the mortality benefit-all-cause and CV-related. However, hospitalization for HF are reduced by ≈ 33% and occur regardless of baseline patient characteristics. The unprecedented HF outcomes are theorized to occur via several possible mechanisms and include optimization of conventional ASCVD risk factors, improvement in hemodynamics, prevention of cardiac and renal remodeling, inhibition of hormone dysregulation, use of more efficient metabolic substrates, ion channel inhibition, anti-inflammatory effects, and anti-oxidant effects. Recent evidence has unveiled the irrefutable data that SGLT2 inhibitors reduce CV events in patients with T2DM, with a profound effect on reductions in hospitalization for HF. Though several mechanisms conveying this benefit are suggested, most are based in limited data requiring further validation. Nonetheless, the arrival of SGLT2 inhibitors has ushered in a new era of CV risk reductions therapies.

Until 1990, lipid clinics in the United States existed only in academic medical centers, generally in close relationship with laboratory-based research programs. The advent of statin therapy, the success of major clinical trials to prevent or stabilize atherosclerotic cardiovascular disease, and organizational efforts highlighted by regional Lipid Disorders Training Centers and the newly formed National Lipid Association boosted the formation of lipid clinics and preventive cardiology clinics in private and academic settings. This roundtable discussion with 4 experts examines multiple aspects of lipid clinic operations: obtaining referrals, adapting to either the academic or community setting, organizing a team of providers, incorporating diet and lifestyle counseling as well as medication, establishing the pharmacist role, and gaining financial stability. Some issues are as yet unsettled, including the subspecialty home of lipidology, if any, and the diagnostic and management boundaries of practical lipid clinics. Achieving official recognition as a subspecialty has taken some steps forward but remains a challenge. Opportunities for advocacy need to be seized., (Copyright © 2019. Published by Elsevier Inc.)

Background: Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein associated with atherosclerotic cardiovascular disease. Niacin and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) both lower Lp(a)., Objective: The objective of the study was to determine if addition of PCSK9i to background niacin therapy further lowers Lp(a)., Methods: This study is a retrospective analysis of patients who met the following inclusion criteria: initiated PCSK9i therapy, had Lp(a) measurements before and after initiation of PCSK9i, and for the combination therapy group, PCSK9i was added on top of baseline niacin monotherapy. Of the 150 patients included in this study, 136 were on monotherapy (PCSK9i) and 14 were on combination therapy (niacin + PCSK9i). Lp(a) values were assessed in both groups before and after the addition of PCSK9i., Results: Median percent and absolute Lp(a) reductions in the niacin + PCSK9i combination therapy group were -15.3% (interquartile range [IQR] -31.8, -1) and -9 mg/dL (IQR -37.2, -0.5), respectively, from a baseline Lp(a) of 95 mg/dL (IQR 20.5, 171). These reductions were statistically significant or nearly so (P = .04 and P = .05, respectively). Median percent and absolute Lp(a) reductions in the PCSK9i monotherapy group were -17.3% (IQR -34.4, 0) and -6 mg/dL (IQR -16, 0), respectively, from a baseline Lp(a) of 39.5 mg/dL (IQR 15, 117.5). There was no difference in median percent and absolute change in Lp(a) between monotherapy and combination therapy groups (P = .84 and P = .54, respectively)., Conclusions: Our study demonstrates that the addition of PCSK9i to background of niacin therapy is associated with ∼15% reduction in Lp(a) beyond that achieved with background niacin monotherapy., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are set to revolutionize the treatment of hypercholesterolemia in the management of atherosclerotic risk, but numerous reports have detailed unprecedented barriers to access for these drugs. To overcome these challenges, our group created a model to facilitate provision of this new therapy for patients who qualify according to Food and Drug Administration criteria. This report details the real-world follow-up experience of PCSK9i use in a large patient cohort structured to ensure rigor in data collection, analysis, and interpretation. The 271 patients approved and actively followed in our PCSK9i clinic between July 2015 and August 2018 represent a 97% approval rate from insurance, with 28% of prescriptions requiring at least one appeal. Over 50% of patients were statin intolerant. On average, there was a median lapse of 15 days between initial visit and insurance approval. PCSK9i therapy was affordable for most patients, with an average monthly out-of-pocket expense of $58.05 (median $0). Only 2.3% of patients were unable to initiate or continue therapy because of cost. Reductions from baseline in LDL (low-density lipoprotein) cholesterol and Lp(a) (lipoprotein [a])were comparable to published reports with median reductions of 60% and 23% at 1 year, respectively. PCSK9i therapy was well-tolerated overall, though 9% of patients reported adverse events, and 5% of patients discontinued due mostly to musculoskeletal and flu-like symptoms. Our practice model demonstrates that PCSK9i therapy can be accessed easily and affordably for the majority of eligible patients, resulting in dramatic improvement in lipid profile results. Moreover, our registry data suggest that results from the prospective clinical trials of PCSK9i on LDL and Lp(a) reduction and on tolerability are applicable to a real-world cohort.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder typically caused by mutations in genes for lipoprotein lipase (LPL), apolipoprotein C-II (Apo-CII), apolipoprotein A-V (Apo-AV), lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1). FCS is associated with severe morbidity that includes recurrent pancreatitis and other problems. Effective treatment to reliably prevent complications has been unavailable, so there is a quest to identify novel interventions to achieve sustained triglyceride lowering and prevention of pancreatitis. Apolipoprotein C-III (Apo-CIII) interferes with triglyceride clearance by blocking LPL and alternative pathways. Volanesorsen is an experimental antisense oligonucleotide that inhibits translation of Apo-CIII mRNA, thereby substantially lowering plasma levels of Apo-CIII and triglycerides. It is being developed for treatment of patients with FCS and refractory hypertriglyceridemia. Data from a variety of clinical trials have been very encouraging, with documentation of excellent triglyceride-lowering efficacy, but there have been concerns about the risk of drug-related thrombocytopenia and bleeding that contributed to the recent decision by the Food and Drug Administration (FDA) to not approve the drug for clinical use. Clinical trials testing the safety and efficacy of volanesorsen are ongoing, so there is hope that the drug ultimately will be approved and available for treatment of high-risk patients with FCS., (Copyright 2018 Clarivate Analytics.)

Purpose: Medical errors, in particular medication errors, continue to be a troublesome factor in the delivery of safe and effective patient care. Antineoplastic agents represent a group of medications highly susceptible to medication errors due to their complex regimens and narrow therapeutic indices. As the majority of these medication errors are frequently associated with breakdowns in poorly defined systems, developing technologies and evolving workflows seem to be a logical approach to provide added safeguards against medication errors., Summary: This article will review both the pros and cons of today's technologies and their ability to simplify the medication use process, reduce medication errors, improve documentation, improve healthcare costs and increase provider efficiency as relates to the use of antineoplastic therapy throughout the medication use process. Several technologies, mainly computerized provider order entry (CPOE), barcode medication administration (BCMA), smart pumps, electronic medication administration record (eMAR), and telepharmacy, have been well described and proven to reduce medication errors, improve adherence to quality metrics, and/or improve healthcare costs in a broad scope of patients. The utilization of these technologies during antineoplastic therapy is weak at best and lacking for most. Specific to the antineoplastic medication use system, the only technology with data to adequately support a claim of reduced medication errors is CPOE. In addition to the benefits these technologies can provide, it is also important to recognize their potential to induce new types of errors and inefficiencies which can negatively impact patient care., Conclusion: The utilization of technology reduces but does not eliminate the potential for error. The evidence base to support technology in preventing medication errors is limited in general but even more deficient in the realm of antineoplastic therapy. Though CPOE has the best evidence to support its use in the antineoplastic population, benefit from many other technologies may have to be inferred based on data from other patient populations. As health systems begin to widely adopt and implement new technologies it is important to critically assess their effectiveness in improving patient safety., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Purpose: The impact of a pharmacy-managed program for providing education and discharge instructions for patients with heart failure (HF) was evaluated., Methods: A before-and-after quasiexperimental design was used to quantify the effect of a pharmacist-managed HF medication education and discharge instruction program on the incidence of 30-day readmission rates and adherence to targeted Joint Commission core measures for HF (the provision of discharge instructions and the prescribing of an angiotensin-converting-enzyme inhibitor [ACEI]/angiotensin II receptor blocker [ARB] at discharge or documentation of the reason if therapy was not prescribed). Adult patients admitted to Oregon Health and Science University's cardiology unit with systolic HF exacerbation as their primary diagnosis between December 2010 and March 2011 were included. Throughout patients' hospitalization, the pharmacist collaborated with the multidisciplinary team to make treatment and monitoring recommendations; provided discharge medication reconciliation, discharge medication recommendations, and discharge instructions; answered patient-specific questions; and gave the patient a complete discharge medication list., Results: The study enrolled 35 patients and compared results against a historical control group of 115 patients. The frequency of discharge counseling increased significantly (p = 0.007), as did the rate of ACEI/ARB prescribing at discharge (p = 0.02). Both 30-day all-cause and HF-related readmissions were reduced compared with baseline (p = 0.02 and p = 0.11, respectively)., Conclusion: Pharmacist involvement in medication reconciliation and discharge counseling for HF patients was associated with a significant increase in adherence with the Joint Commission's core measures, a significant reduction in 30-day all-cause readmissions, and a positive effect on patient satisfaction.

Antiplatelet therapy is more effective than anticoagulation for the prevention of noncardioembolic ischaemic stroke. The choice of antiplatelet regimen, however, remains contentious. Recent controversies regarding aspirin resistance and the optimal dosing of aspirin, as well as recognition of the variable bioactivation of clopidogrel, have added further confusion to the debate. The American Heart Association (AHA) and American Stroke Association (ASA) recently released their third joint guideline in the past 5 years on secondary stroke prevention. The European Stroke Organisation has published three guidelines on this issue since 2000. These frequent updates have been necessary because of rapidly accumulating data from clinical trials. Careful consideration of the sometimes confusing trial results reveals that the 2011 AHA-ASA guidelines are correct in no longer specifying a 'preferred' antiplatelet regimen from among the choices recently studied. This recommendation does not, however, mean that all antiplatelet regimens should be considered equal. This Review discusses the various antiplatelet regimens, and the trials that led to the rapid evolution of the guidelines for secondary prevention of ischaemic stroke.

We previously demonstrated that black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. To investigate potential mechanisms of this effect, we examined plasma catechins and systemic markers of oxidation, inflammation, and antioxidant protection from 66 subjects enrolled in that study. We collected samples at baseline, 2 h after 450 ml of black tea (acute), after 4 weeks of 900 ml of black tea per day (chronic), and after acute and chronic consumption of water. Total catechins increased 33% after acute tea (P < 0.05) and 29% after chronic tea (P < 0.05). Of individual catechins, plasma epicatechin gallate (ECG) concentration significantly increased with acute tea consumption, and plasma epicatechin (EC) increased with chronic tea consumption. Tea consumption did not improve plasma antioxidant capacity and did not reduce urinary 8-hydroxy-2'-deoxyguanosine, or urinary 8-isoprostane levels. Changes in catechin levels did not correlate with changes in endothelial function, plasma markers of oxidative stress, or C-reactive protein. In contrast, endothelial function at baseline correlated with dietary flavonoid intake (beta = 0.32, P = 0.02) and with baseline plasma EC concentration after adjusting for confounding variables (beta = 0.39, P = 0.03). These findings suggest that the benefits of black tea consumption on endothelial function may not be attributable to tea catechins or a systemic antioxidant or anti-inflammatory effect. Chronic dietary flavonoid status appears to relate to endothelial function, possibly suggesting that other flavonoids or polyphenolic components of tea favorably influence vascular health and risk for cardiovascular disease.

Background: There is a continuing need to examine the relationship between diet quality and health in the population. The Healthy Eating Index (HEI) has been developed as a composite measure of diet quality by the US Department of Agriculture., Objectives: The first objective was to use the HEI to assess the diet quality of a representative sample of the US population and population groups. The second objective was to examine the association between HEI and obesity., Design: Cross-sectional analysis of data from 10 930 adults who participated in the Third National Health and Nutrition Examination Survey. Sociodemographic, physical activity, dietary, and health data were used in the analysis. Diet quality was assessed with the HEI score, ranging from 0 to 100, based on 10 dietary criteria. A low HEI score indicates poor diet., Results: A majority of survey participants had a low HEI score. The percentage of individuals classified as having a poor diet varied by age, gender, race/ethnicity, income, and education. A low HEI score was associated with overweight and obesity. There was a graded increase in the odds ratio of obesity across the HEI category after adjusting for age, gender, race/ethnicity, physical activity, smoking, alcohol use, income, and education., Conclusions: An index of diet quality, such as HEI, may provide a comprehensive assessment of diet in the population. Since the HEI is based on the US Dietary Guidelines, the use of these guidelines as a way to improve health should be emphasized. However, the overall effectiveness of these guidelines in disease prevention needs to be studied further.

Tea consumption has been associated with reduced risk of both cancer and cardiovascular disease in population studies, but clinical data demonstrating bioavailability of the individual catechins and other polyphenolic components of tea are limited. This study assessed the apparent bioavailability of the prominent catechins from black tea in humans drinking tea throughout the day. After 5 d of consuming a low flavonoid diet, subjects drank a black tea preparation containing 15.48, 36.54, 16.74, and 31.14 mg of (-)-epigallocatechin (EGC), (-)-epicatechin (EC), (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG), respectively, at four time points (0, 2, 4 and 6 h). Blood, urine and fecal specimens were collected over a 24- to 72-h period and catechins were quantified by HPLC with coularray detection. Plasma concentrations of EGC, EC and EGCG increased significantly relative to baseline (P < 0.05). Plasma EGC, EC and EGCG peaked after 5 h, whereas ECG peaked at 24 h. Urinary excretion of EGC and EC, which peaked at 5 h, was increased relative to baseline amounts (P < 0.05) and fecal excretion of all four catechins was increased relative to baseline (P < 0.05). Approximately 1.68% of ingested catechins were present in the plasma, urine and feces, and the apparent bioavailability of the gallated catechins was lower than the nongallated forms. Thus, catechins were bioavailable. However, unless they are rapidly metabolized or sequestered, the catechins appeared to be absorbed in amounts that were small relative to intake.

Tea is the most highly consumed beverage in the world, other than water. However, unlike water, tea contains substantial amounts of polyphenols that have unique biological activities and may be responsible for many of the health benefits of tea. As a result, it is essential to be able to measure the various tea-associated polyphenols. Total polyphenol content is currently measured by using methodology based on reducing activity. Several HPLC systems with detectors that, collectively, have wide ranges in sensitivity have been developed for analysis of individual flavonoids in tea and biological samples, and for theaflavins in tea. Catechins also have been measured in plasma by solid phase extraction, addition of a chromophore, and colorimetric quantification. Except for theaflavins in tea, routine and robust methods for the measurement of polyphenol condensation products (dimers and thearubigens) in tea and biological samples have not been developed. Although in vitro and animal studies suggest substantial metabolism of flavonoids in the gastrointestinal tract, only a single HPLC procedure has been assembled for monitoring the metabolic products of quercetin in urine of human subjects.

Objective: The purpose of the study was to evaluate the effect of a low carotenoid diet (83 micrograms Beta-carotene) on malondialdehyde-thiobarbituric acid (MDA-TBA) concentrations of nine pre-menopausal women., Methods: Subjects lived on the metabolic research unit of the Western Human Nutrition Research Center (WHNRC), where diet, exercise and other activities were controlled. Five subjects (Group C, control group) consumed a low carotenoid diet and received an additional 0.5 mg/day of Beta-carotene while four subjects (Group P, placebo group) received only the low carotenoid diet during days 1 to 60 (period 1). All subjects received 0.5 mg/day of Beta-carotene during days 60 to 100 (period 2), plus three capsules/day mixed carotenoid supplement (Neo-Life Company) during study days 100 to 120. Changes in MDA-TBA concentrations were analyzed during the study periods and between the groups., Results: At the start of the study (day 1), no significant difference in the MDA-TBA concentration was observed between the control (Group C) and the placebo (Group P) subjects. During period 1 (days 2 to 60), when Group P subjects consumed the low carotenoid diet without supplementation, the MDA-TBA values for Group P rose markedly and were significantly (p < 0.05) higher than the MDA-TBA values for Group C subjects who were receiving carotenoid supplementation. During period 2 (days 60 to 100) when both groups received carotenoid supplementation, the MDA-TBA values of Group P subjects were significantly (p < 0.05) reduced to the point where they were similar to the MDA-TBA values for Group C subjects., Conclusions: These findings provide evidence to support the beneficial effects of carotenoids in preventing lipid peroxidation in the cells. Further studies are needed to identify the exact mechanism by which carotenoids prevent lipid peroxidation and the amount needed for normal activity.

Both the active ester and maleimide moieties of the cross-linking reagent, N-[(gamma-maleimidobutyryl)oxy]succinimide (GMBS), were found to react with the primary amino groups on ribonuclease (RNase). This largely inactivated RNase towards a polymeric (but not monomeric) substrate. Citraconylating the RNase first, so that essentially only a single primary amino group remained to react with GMBS, overcame this problem. The subsequent maleimido-citraconyl-RNase was used to prepare a 1:1.1 M conjugate of anti-T-2 toxin Fab' and RNase (Fab'-RNase) in a 76% yield. The conjugate was used to detect as little as 0.1 microgram of T-2 toxin based on the ability of T-2 toxin to specifically displace Fab'-RNase complexed to a T-2 agarose affinity gel.

An amount of 10 pg of [125I]thyroxine was subjected to DEAE agarose chromatography and then complexed with an antibody. Recycling of the [125I]thyroxine now as a complex with the antibody through a second DEAE agarose column under the same conditions gave a change in the retention of the [125I]thyroxine that potentially constitutes a specific shift away from co-eluting interferences from the first column. The [125I]thyroxine was then dissociated from the antibody and subjected to a third DEAE agarose column for additional shifting of its chromatographic retention. Since the overall recovery of the [125I]thyroxine is 36%, this soluble antibody affinity technique potentially is useful for sample clean-up in labeling analysis of ultratrace solutes such as thyroxine.

A monoclonal antibody for T-2 toxin is converted to a Fab'-fluorescein derivative. The latter is specifically complexed onto a T-2 agarose gel. Fifteen successive doses of T-2 ranging from 1 to 50 ng are then repetitively and linearly detected using a column packed with a small volume (0.2 ml) of this gel without recharging with Fab'-fluorescein. For these assays the effluent from the column is monitored with a spectrofluorometer.

A stable T-2 hydrazide gel is prepared by activating T-2 toxin with tresyl chloride followed by coupling to agarose-adipic acid hydrazide. Utilized as an affinity chromatography column, this T-2 hydrazide gel purifies a monoclonal antibody for T-2 in high yield directly from ascites fluid. Specific antibody trapped on the column is eluted either with excess T-2 or at pH 11.6. Much less successful are two other T-2 affinity columns that were prepared and evaluated: T-2 bovine serum albumin Affi-Gel 15 and T-2 hexylamine Sepharose.