Introduction: The National Lipid Association Statin Intolerance (SI) Panel recognized the need for better understanding of the patient SI experience. Objective: The objective of this research was to develop a patient-reported outcome (PRO) questionnaire to assess a patient’s experience with SI. Methods: Questionnaire development was informed via a series of research activities: literature review, concept elicitation, item generation, and content evaluation. Following the literature review and concept elicitation, a draft questionnaire was constructed and subsequently modified based on feedback from therapeutic area experts and patients via cognitive debriefing interviews. Results: Muscle-related symptoms were the most commonly reported symptoms associated with SI in the literature review (35 of 41 articles reviewed [85%]) and in semi-structured interviews with experts (n = 5 [100%]) and patients (n = 17 of 20 [85.0%]). Physical and other impacts of SI symptoms on daily activities were also frequently reported. A 17-item draft questionnaire was created, and cognitive debriefing with experts (n = 5) and patients (n = 15) was conducted. Overall, the items, response options, and instructions were comprehensible and positively reviewed; minor changes resulted in the 15-item Statin Experience Assessment Questionnaire (SEAQ)©. Using a 30-day recall period, the SEAQ© assesses the severity and impact of six SI symptoms (muscle ache, muscle pain, muscle cramps, muscle weakness, tiredness, and joint pain) on an 11-point numeric scale. Statin discontinuation and likelihood of discontinuation due to symptoms are assessed and scored on a yes/no and five-point verbal response scale, respectively. Conclusion: The SEAQ© is a novel content-valid PRO questionnaire that assesses patient SI experience and fosters dialogue about SI between patients and providers.

Background: Coronary heart disease risk increases with advancing age and is further increased in patients with mixed dyslipidemia, characterized by elevated low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and high triglycerides (TG). Combination lipid therapy is an option; however, efficacy and safety data among elderly patients are lacking. Hypothesis The combination of rosuvastatin and fenofibric acid (R + FA) results in more comprehensive lipid improvements than corresponding-dose monotherapies, without additional safety concerns, in elderly patients with mixed dyslipidemia. Methods: This post-hoc analysis evaluated data from patients age ≥ 65 years (n = 401) with mixed dyslipidemia (LDL-C ≥ 130 mg/dL, HDL-C < 40 mg/dL [men] or < 50 mg/dL [women], and TG ≥ 150 mg/dL) in 2 randomized studies. Patients included in this analysis received either monotherapy (as R 5, 10, or 20 mg or FA 135 mg), or combination therapy with R (5, 10, or 20 mg) + FA 135 mg, for 12 weeks. Data were pooled and analyzed, and mean/median percent changes in multiple lipid parameters and biomarkers were compared. Results: Combination therapy decreased LDL-C by 31.8%-47.2% vs 10.6% with FA monotherapy (P < 0.001). Combination therapy also increased HDL-C by 21.9%-27.0% vs 5.9%-9.9% with R monotherapy (P < 0.001), and decreased TG by 48.3%-53.5% vs 20.7%-32.8% with R monotherapy (P < 0.001). In general, safety profiles were consistent between combination therapy and individual monotherapies. Conclusions: In these elderly patients with mixed dyslipidemia, R 5, 10, or 20 mg in combination with FA 135 mg improved the overall lipid profile, without new or unexpected safety issues.

Residual cardiovascular risk persists despite statins, yet outcome studies of lipid-targeted therapies beyond low-density lipoprotein cholesterol (LDL-C) have not demonstrated added benefit. Triglyceride elevation is an independent risk factor for cardiovascular events. High-dose eicosapentaenoic acid (EPA) reduces triglyceride-rich lipoproteins without raising LDL-C. Omega-3s have postulated pleiotropic cardioprotective benefits beyond triglyceride-lowering. To date, no large, multinational, randomized clinical trial has proved that lowering triglycerides on top of statin therapy improves cardiovascular outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT; NCT01492361) is a phase 3b randomized, double-blinded, placebo-controlled trial of icosapent ethyl, a highly purified ethyl ester of EPA, vs placebo. The main objective is to evaluate whether treatment with icosapent ethyl reduces ischemic events in statin-treated patients with high triglycerides at elevated cardiovascular risk. REDUCE-IT enrolled men or women age ≥45 years with established cardiovascular disease or age ≥50 years with diabetes mellitus and 1 additional risk factor. Randomization required fasting triglycerides ≥150 mg/dL and <500 mg/dL and LDL-C >40 mg/dL and ≤100 mg/dL with stable statin (± ezetimibe) ≥4 weeks prior to qualifying measurements. The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Several secondary, tertiary, and exploratory endpoints will be assessed. Approximately 8000 patients have been randomized at approximately 470 centers worldwide. Follow-up will continue in this event-driven trial until approximately 1612 adjudicated primary-efficacy endpoint events have occurred.

Aims: To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results: A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.

PURPOSE: Evolocumab significantly reduces low-density lipoprotein-cholesterol (LDL-C); we investigated its effects on LDL-C lowering in patients with mixed hyperlipidemia. METHODS: We compared the efficacy and safety of evolocumab in hypercholesterolemic patients selected from the phase 2 and 3 trials who had fasting triglyceride levels ≥1.7 mmol/L (150 mg/dL elevated triglycerides) and <1.7 mmol/L (without elevated triglycerides). Fasting triglyceride level ≥ 4.5 mmol/L at screening was an exclusion criterion for these studies, but post-enrollment triglyceride levels may have exceeded 4.5 mmol/L (400 mg/dL). Efficacy was evaluated in four phase 3 randomized studies (n = 1148) and safety from the phase 2 and 3 studies (n = 2246) and their open-label extension studies (n = 1698). Efficacy analyses were based on 12-week studies, while safety analyses included data from all available studies. Treatment differences were calculated vs. placebo and ezetimibe after pooling dose frequencies. RESULTS: Mean treatment difference in percentage change from baseline in LDL-C for participants with elevated triglycerides and those without elevated triglycerides (mean of weeks 10 and 12) with evolocumab was approximately -67 % vs. placebo and -42 % vs. ezetimibe (all P < 0.001) compared to -6 % vs. placebo and -39 % vs. ezetimibe, respectively. Treatment differences for evolocumab vs. placebo and ezetimibe followed a similar pattern for non-high-density lipoprotein (HDL-C) and apolipoprotein B. Evolocumab was well tolerated, with balanced rates of adverse events leading to discontinuation of evolocumab vs. comparator (placebo and/or ezetimibe). CONCLUSION: The significant reductions of atherogenic lipids including LDL-C, non-HDL-C, and apolipoprotein B seen with evolocumab are similar in patients with and without mixed hyperlipidemia.

BACKGROUND: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), icosapent ethyl (IPE) versus placebo) reduced cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization, but was associated with increased atrial fibrillation/atrial flutter (AF) hospitalization (3.1% IPE versus 2.1% placebo; P=0.004). METHODS AND RESULTS: We performed post hoc efficacy and safety analyses of patients with or without prior AF (before randomi-zation) and with or without in-study time-varying AF hospitalization to assess relationships of IPE (versus placebo) and outcomes. In-study AF hospitalization event rates were higher in patients with prior AF (12.5% versus 6.3%, IPE versus placebo; P=0.007) versus without prior AF (2.2% versus 1.6%, IPE versus placebo; P=0.09). Serious bleeding rates trended higher in patients with (7.3% versus 6.0%, IPE versus placebo; P=0.59) versus without prior AF (2.3% versus 1.7%, IPE versus placebo; P=0.08). With IPE, serious bleeding trended higher regardless of prior AF (interaction P value [Pint ]=0.61) or postrandomization AF hospitalization (Pint =0.66). Patients with prior AF (n=751, 9.2%) versus without prior AF (n=7428, 90.8%) had similar relative risk reductions of the primary composite and key secondary composite end points with IPE versus placebo (Pint =0.37 and Pint =0.55, respectively). CONCLUSIONS: In REDUCE-IT, in-study AF hospitalization rates were higher in patients with prior AF especially in those randomized to IPE. Although serious bleeding trended higher in those randomized to IPE versus placebo over the course of the study, serious bleeding was not different regardless of prior AF or in-study AF hospitalization. Patients with prior AF or in-study AF hospitalization had consistent relative risk reductions across primary, key secondary, and stroke end points with IPE. REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01492361; Unique Identifier: NCT01492361.

Despite the established role of low-density lipoprotein cholesterol (LDL-C) as a major risk factor for cardiovascular disease (CVD), and the persistence of CVD as the leading cause of morbidity and mortality in the United States, national quality assurance metrics no longer include LDL-C measurement as a required performance metric. This clinical perspective reviews the history of LDL-C as a quality and performance metric and the events that led to its replacement. It also presents patient, healthcare provider, and health system rationales for re-establishing LDL-C measurement as a performance measure to improve cholesterol control in high-risk groups and to stem the rising tide of CVD morbidity and mortality, cardiovascular care disparities, and related healthcare costs.

Despite multiple patient assessments and interventions, obesity continues to cause significant morbidity and mortality nationwide. This study assesses the prevalence of obesity and weight control practices among middle-aged African-American women. In 1995, 307 women 30 years of age and older were consecutively selected in a non-random fashion from three clinic sites located within a public university hospital that served largely indigent, inner city African-American populations. Interviewers surveyed the respondents using the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System (BRFSS). The prevailing demographic profile of patients in the clinic was middle-aged, indigent, ill, and of low educational attainment. Over 35% of individuals were classified as being overweight (BMI 25 to 29.9 kg/m2) and 45% were classified as being obese (BMI > or = 30 kg/m2). Therefore, more than 80% of individuals in this study were either overweight or obese, with BMI exceeding 25 kg/m2. Of the overweight and obese African-American women in this study, only 40% were attempting current weight loss practices, and weight loss attempts varied directly with body mass index. Although 80% of women attempted weight loss by restricting caloric intake, only 50% were also using physical activity as part of their regime. African-American women in this population have a higher prevalence of obesity and encounter great difficulty losing weight. Counselors should emphasize the value and ease of adopting a moderate regimen of physical activity and not just reducing caloric intake when advising African-American women and their peer network.

Background: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. Methods: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. Results: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. Conclusions: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality.

Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D2–driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events.