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.

Cilostazol is a phosphodiesterase III inhibitor with pharmacological effects that include vasodilation, inhibition of platelet activation and aggregation, inhibition of thrombosis, increased blood flow to the limbs, improvement in serum lipids with lowering of triglycerides and elevation of high density lipoprotein cholesterol, and inhibition of vascular smooth muscle cell growth. Cilostazol has been shown in multiple randomized clinical trials to result in decreased claudication and improved ability to walk in patients with peripheral arterial disease. In addition, cilostazol has been shown in multiple randomized clinical trials to decrease restenosis in the setting of coronary stent implantation. The purpose of the present paper was to review the vascular effects of cilostazol and to present results of the major clinical trials of the use of cilostazol in peripheral arterial disease and percutaneous coronary intervention with stent implantation.

BACKGROUND Primary care physicians (PCPs) are often expected to screen for melanomas and refer patients with suspicious pigmented lesions to dermatologists. OBJECTIVE To assess whether there is a difference between dermatologists and PCPs in accurately diagnosing melanoma and appropriately managing (based on decisions to refer/biopsy) suspicious pigmented lesions. DESIGN, PARTICIPANTS A survey based on a random sample of 30 photographs of pigmented lesions with known pathology was administered to 101 dermatologists and 115 PCPs from October 2001 to January 2003. MEASUREMENTS Likelihoods that a photographed lesion was melanoma and that the lesion should be biopsied/referred were scored on a 1 to 10 scale. Accuracy of melanoma diagnosis and appropriateness of pigmented lesion management were compared between dermatologists and PCPs by using the areas under (AUC) the receiver operating characteristic (ROC) curves. RESULTS Dermatologists were superior to PCPs in diagnosing melanomas (AUC 0.89 vs 0.80, P < 0.001) and appropriately managing pigmented lesions (AUC. 84 vs 0.76, P < 0.001). PCPs who tended to biopsy lesions themselves did better at managing pigmented lesions than PCPs who did not perform biopsies. Dermatology training during residency did not significantly improve the diagnostic accuracy of PCPs nor their management of pigmented lesions. CONCLUSIONS Dermatologists have both better diagnostic accuracy and ability to manage pigmented lesions than PCPs. Yet, there is a shortage of dermatologists to meet the demand of accurate melanoma screening. More innovative strategies are needed to better train PCPs and enhance skin cancer screening.

OBJECTIVE Age, BMI, and race/ethnicity are used in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and American Diabetes Association (ADA) guidelines to prompt screening for pre-diabetes and diabetes, but cutoffs have not been evaluated rigorously. RESEARCH DESIGN AND METHODS Random plasma glucose (RPG) was measured and 75-g oral glucose tolerance tests were performed in 1,139 individuals without known diabetes. Screening performance was assessed by logistic regression and area under the receiver operating characteristic curve (AROC). RESULTS NIDDK/ADA indicators age >45 years and BMI >25 kg/m2 provided significant detection of both diabetes and dysglycemia (both AROCs 0.63), but screening was better with continuous-variable models of age, BMI, and race and better still with models of age, BMI, race, sex, and family history (AROC 0.78 and 0.72). However, screening was even better with RPG alone (AROCs 0.81 and 0.72). RPG >125 mg/dl could be used to prompt further evaluation with an OGTT. CONCLUSIONS Use of age, BMI, and race/ethnicity in guidelines for screening to detect diabetes and pre-diabetes may be less important than evaluation of RPG. RPG should be investigated further as a convenient, inexpensive screen with good predictive utility.

Background-In the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, some patients with stable ischemic heart disease randomized to optimal medical therapy (OMT) crossed over to early revascularization. The predictors and outcomes of patients who crossed over from OMT to revascularization are unknown. Methods and Results-We compared characteristics of OMT patients who did and did not undergo revascularization within 12 months and created a Cox regression model to identify predictors of early revascularization. Patients' health status was measured with the Seattle Angina Questionnaire. To quantify the potential consequences of initiating OMT without percutaneous coronary intervention, we compared the outcomes of crossover patients with a matched cohort randomized to immediate percutaneous coronary intervention. Among 1148 patients randomized to OMT, 185 (16.1%) underwent early revascularization. Patient characteristics independently associated with early revascularization were worse baseline Seattle Angina Questionnaire scores and healthcare system. Among 156 OMT patients undergoing early revascularization matched to 156 patients randomized to percutaneous coronary intervention, rates of mortality (hazard ratio=0.51 [0.13-2.1]) and nonfatal myocardial infarction (hazard ratio=1.9 [0.75-4.6]) were similar, as were 1-year Seattle Angina Questionnaire scores. OMT patients, however, experienced worse health status over the initial year of treatment and more unstable angina admissions (hazard ratio=2.8 [1.1-7.5]). Conclusion-Among COURAGE patients assigned to OMT alone, patients' angina, dissatisfaction with their current treatment, and, to a lesser extent, their health system were associated with early revascularization. Because early crossover was not associated with an increase in irreversible ischemic events or impaired 12-month health status, these findings support an initial trial of OMT in stable ischemic heart disease with close follow-up of the most symptomatic patients.

Chronic stable angina pectoris, the chest pain associated with reversible myocardial ischemia has detrimental effects on health-related quality of life, particularly in women. The limited research on gender differences in chronic stable angina suggests that angina may be experienced differently in women and that women report greater functional disability related to angina symptoms. No studies have examined gender differences in chronic stable angina from a multidimensional pain perspective or have included reliable and valid measures of pain that would facilitate comparing chronic angina patients with other chronic pain populations. The purpose of this descriptive study was to examine gender differences in characteristics of chronic stable angina using the short-form McGill pain questionnaire (SF-MPQ) and to explore relationships among these pain characteristics and perceived limitation in performing physical activities in patients with coronary artery disease (CAD) (physical limitation subscale of the Seattle angina questionnaire). One hundred and twenty-eight subjects (30.5% women) with stable CAD and angina pectoris documented by a cardiologist completed study questionnaires in an outpatient cardiology clinic. Results of the study suggest that men and women with chronic stable angina had more similarities than differences in chest pain characteristics. No significant gender differences were demonstrated in total sensory or affective intensity scores, the present pain intensity index, or the number of pain words chosen. However, women did report significantly greater pain intensity on the SF-MPQ visual analogue scale. Women were also significantly more likely to describe their chronic angina as 'hot-burning' and 'tender' and to have greater intensity of pain for these two descriptors. Despite the similarities in pain characteristics, women reported greater physical limitation related to anginal pain. The variables of social status and years diagnosed with CAD significantly interacted with gender in predicting physical limitation suggesting that gender-specific models of physical limitation in angina patients need to be explored. To our knowledge, this is one of the first studies that has assessed chronic anginal pain using a reliable and valid generic pain instrument. More research is needed to better understand the nature of gender differences in functional limitation secondary to anginal pain and the physiologic, cognitive-perceptual and psychosocial mechanisms that lead to angina-related functional disability.

OBJECTIVE To determine the proportion of the American population who would merit metformin treatment, according to recent American Diabetes Association (ADA) consensus panel recommendations to prevent or delay the development of diabetes. RESEARCH DESIGN AND METHODS Risk factors were evaluated in 1,581 Screening for Impaired Glucose Tolerance (SIGT), 2,014 Third National Health and Nutrition Examination Survey (NHANES III), and 1,111 National Health and Nutrition Examination Survey 2005–2006 (NHANES 2005–2006) subjects, who were non-Hispanic white and black, without known diabetes. Criteria for consideration of metformin included the presence of both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), with ≥1 additional diabetes risk factor: age <60 years, BMI ≥35 kg/m2, family history of diabetes, elevated triglycerides, reduced HDL cholesterol, hypertension, or A1C >6.0%. RESULTS Isolated IFG, isolated IGT, and IFG and IGT were found in 18.0, 7.2, and 8.2% of SIGT; 22.3, 6.4, and 9.4% of NHANES III; and 21.8, 5.0, and 9.0% of NHANES 2005–2006 subjects, respectively. In SIGT, NHANES III, and NHANES 2005–2006, criteria for metformin consideration were met in 99, 96, and 96% of those with IFG and IGT; 31, 29, and 28% of all those with IFG; and 53, 57, and 62% of all those with IGT (8.1, 9.1, and 8.7% of all subjects), respectively. CONCLUSIONS More than 96% of individuals with both IFG and IGT are likely to meet ADA consensus criteria for consideration of metformin. Because >28% of all those with IFG met the criteria, providers should perform oral glucose tolerance tests to find concomitant IGT in all patients with IFG. To the extent that our findings are representative of the U.S. population, ∼1 in 12 adults has a combination of pre-diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention.

The planning of revascularization strategy for multivessel coronary artery disease (CAD) in nondiabetic patients is optimally made through considering the goals of improving survival and/or relieving symptoms. Existing clinical practice guidelines and appropriate use criteria (1–3) state that in nondiabetic patients with multivessel CAD and stable ischemic heart disease (SIHD), either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) with drug-eluting stents may be used for those with low SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) scores, but CABG is preferred for those with intermediate or high SYNTAX scores. In the overall SYNTAX population (4–6), the rates of death and stroke were similar, but the risk of myocardial infarction (MI) and repeat revascularization were higher in PCI-treated patients. At 5-year follow-up, the rates of death/stroke/MI are 8.0% lower, and the rate of repeat revascularization is 12.8% lower in CABG-treated patients. In the low SYNTAX score tertile, these trends are not significantly different, but they are in the intermediate and high SYNTAX score subsets. When considering only survival in the 3 tertiles, there was a 0.9%, 6.7%, and 9.0% difference over 5 years, an average of 0.2% to 1.8% per year. Yet, PCI is more often performed in multivessel CAD patients, despite the guidelines and clinical evidence. Can this apparent divergence from the evidence base be supported? Drs. Weintraub and Tcheng and colleagues were asked to defend or critique the current guidelines.

Endothelial dysfunction is known to precede the development of atherosclerosis and results primarily from increased oxidative degradation of NO. We hypothesized that assessment of oxidative stress in the bloodstream will reliably predict endothelial function in healthy adults. A total of 124 healthy nonsmokers had endothelial function assessed using ultrasound measurement of brachial artery flow-mediated vasodilation. Plasma oxidative stress was estimated by measuring the levels of the reduced and oxidized forms of thiols, including glutathione (reduced glutathione and oxidized glutathione) and cysteine (cysteine and cystine), respectively, and the mixed disulfide. Among the traditional risk factors, there were significant and independent correlations between flow-mediated vasodilation and high-density lipoprotein level, body mass index, gender, and the Framingham risk score. Among the thiol markers, plasma cystine (r=−0.23; P=0.009) and the mixed disulfide (r=−0.23; P=0.01) levels correlated with endothelium-dependent but not endothelium-independent vasodilation, even after adjusting for the Framingham risk score and high-sensitivity C-reactive protein level. A higher level of oxidized metabolites was associated with worse endothelial function. In conclusion, the oxidative stress markers, cystine, and the mixed disulfide are independent predictors of endothelial function. These markers, in combination with the Framingham risk score, may help in the early identification of asymptomatic subjects with endothelial dysfunction who are at potentially increased risk for future atherosclerotic disease progression.