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.

REDUCE-IT was designed as a randomized, placebo-controlled, cardiovascular outcomes trial of patients treated with statins, who had controlled low-density lipoprotein cholesterol, but persistently elevated triglycerides, along with overt presence of or high risk for cardiovascular disease.1 Participants across 11 countries were randomized to receive icosapent ethyl, a highly purified form of eicosapentaenoic acid, 2 g twice daily or placebo and followed for a median of 4.9 years (maximum 6.2 years). The primary endpoint was time from randomization to first occurrence of a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The key secondary endpoint was time from randomization to first occurrence of a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

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.

Importance The Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins. Objective To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment. Design, Setting, and Participants An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021. Interventions Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC). Main Outcomes and Measures Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness. Results A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, –$1788 [95% CI, –$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC. Conclusions and Relevance This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.

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.

BACKGROUND: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. METHODS: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59-0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57-0.88]; P=0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min-1·1.73 m-2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51-0.95]; P=0.02). Although patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86-2.32]; P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90-2.18]; P=0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter=0.92; P-interaction for serious bleeding=0.76). CONCLUSIONS: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Patients with heart failure (HF) are at high risk for atherosclerotic cardiovascular disease. Studies of atherothrombotic treatments in this population have been disappointing to date. Icosapent ethyl reduced the risk of atherosclerotic cardiovascular disease among a broad array of statin‐treated patients at elevated risk for atherosclerotic cardiovascular disease. Whether the treatment benefits of icosapent ethyl are consistent among those with HF is unknown.

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.

BACKGROUND: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations. METHODS: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes. RESULTS: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005). CONCLUSIONS: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial.