Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion.

BACKGROUND: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy. METHODS AND RESULTS: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, P<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]). CONCLUSIONS: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.

Association of Elevated Triglycerides With Increased Cardiovascular Risk and Direct Costs in Statin-Treated Patients.

OBJECTIVE: To retrospectively investigate the real-world impact of elevated triglyceride (TG) levels on cardiovascular (CV) outcomes, medical resource utilization, and medical costs using observational administrative claims data from the Optum Research Database. METHODS: Patients with one or more claims for statin therapy between January 1, 2010, and December 31, 2010, and 6 months or more of baseline data prior to the index date were eligible for inclusion in the study. Patients aged 45 years or older with diabetes and/or atherosclerotic CV disease were included and analyzed in an elevated TG cohort (≥150 mg/dL) vs a comparator cohort with TG levels less than 150 mg/dL and high-density lipoprotein cholesterol (HDL-C) levels greater than 40 mg/dL. RESULTS: In the elevated TG vs propensity-matched comparator cohorts (both N=23,181 patients), the mean age was 62.2 vs 62.6 years, mean follow-up was 41.4 vs 42.5 months, 49.7% (11,518) vs 49.5% (11,467) were female, 83.7% (19,392) vs 84.0% (19,478) had diabetes, and 29.8% (6915) vs 29.3% (6800) had atherosclerotic CV disease. In the elevated TG (N=27,471 patients) vs comparator (N=32,506 patients) cohorts, multivariate analysis revealed significantly greater risk of composite major CV events (hazard ratio [HR], 1.26; 95% CI, 1.19-1.34; P<.001), nonfatal myocardial infarction (HR, 1.32; 95% CI, 1.20-1.45; P<.001), nonfatal stroke (HR, 1.14; 95% CI, 1.04-1.24; P=.004), and need for coronary revascularization (HR, 1.46; 95% CI, 1.33-1.61; P<.001) but not unstable angina (P=.53) or CV death (P=.23). Increased CV risk was maintained with the addition of non-HDL-C to the multivariate model and with high and low HDL-C subgroup analysis. Total direct health care costs (cost ratio, 1.12; 95% CI, 1.08-1.16; P<.001) and inpatient hospital stays (HR, 1.13; 95% CI, 1.10-1.17; P<.001) were significantly higher in the elevated TG cohort vs the comparator cohort. CONCLUSION: Statin-treated patients with TG levels of 150 mg/dL or greater had worse CV and health economic outcomes than those with well-managed TG (<150 mg/dL) and HDL-C (>40 mg/dL) levels.

Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia.

OBJECTIVE: Insulin sensitivity affects plasma triglyceride concentration and both differ by race/ethnicity. The purpose of this study was to provide a comprehensive assessment of the variation in insulin sensitivity and its relationship to hypertriglyceridaemia between five race/ethnic groups. RESEARCH DESIGN AND METHODS: In this cross-sectional study, clinical data for 1025 healthy non-Hispanic White, Hispanic White, East Asian, South Asian and African American individuals were analysed. Insulin-mediated glucose disposal (a direct measure of peripheral insulin sensitivity) was measured using the modified insulin suppression test. Statistical analysis was performed using analysis of co-variance. RESULTS: Of the study participants, 63% were non-Hispanic White, 9% were Hispanic White, 11% were East Asian, 11% were South Asian and 6% were African American. Overall, non-Hispanic Whites and African Americans displayed greater insulin sensitivity than East Asians and South Asians. Triglyceride concentration was positively associated with insulin resistance in all groups, including African Americans. Nevertheless, for any given level of insulin sensitivity, African Americans had the lowest triglyceride concentrations. CONCLUSION: Insulin sensitivity, as assessed by a direct measure of insulin-mediated glucose disposal, and its relationship to triglyceride concentration vary across five race/ethnic groups. Understanding these relationships is crucial for accurate cardiovascular risk stratification and prevention.

Elevated Serum Triglycerides in the Prognostic Assessment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Hypertriglyceridemia has been positively associated with the risk of acute pancreatitis (AP), but whether increased triglyceride (TG) levels are associated with the severity of AP remains unknown. To this, a meta-analysis was conducted to assess the effect of elevated serum TG on the prognosis of AP. METHODS: We searched PubMed, EMBASE, and the Cochrane library to identify all eligible studies (up to September 2016). We pooled the odds ratios (ORs) or standardized mean difference from individual studies using a random-effects model to investigate associations between levels of TG and the prognosis of AP. RESULTS: A total of 15 studies were included in the meta-analysis, including a total of 1564 patients with triglyceride-related acute pancreatitis (TGAP) and 5721 patients with nontriglyceride-related acute pancreatitis (NTGAP). The occurrence of renal failure [OR=3.18; 95% confidence interval (CI): 1.92, 5.27; P<0.00001], respiratory failure (OR=2.88; 95% CI: 1.61, 5.13; P<0.0001), and shock (OR=3.78; 95% CI: 1.69, 8.44; P<0.0001) was statistically significantly higher in TGAP group than in NTGAP group. Furthermore, mortality (OR=1.90; 95% CI: 1.05, 3.45; P<0.01), systemic inflammatory response syndrome (OR=2.03; 95% CI: 1.49, 2.75; P<0.00001), and Acute Physiology and Chronic Health Evaluation (APACHE-II) scores (standardized mean difference=2.72; 95% CI: 1.00, 4.45; P<0.001) were also statistically significantly higher in TGAP group than in NTGAP group. CONCLUSION: Elevated serum TGs are related to a worse prognosis of AP.

Universal Cholesterol Screening in Childhood: A Systematic Review.

BACKGROUND: In 2011, a US expert panel recommended universal cholesterol screening for children ages 9 to 11 years. Controversy exists over this recommendation, especially because the most recent systematic review on universal childhood screening was inconclusive. OBJECTIVES: To conduct an updated systematic review on universal cholesterol screening in childhood and effect on health outcomes, clinical management, screening acceptability, and healthcare costs. DATA SOURCES: We searched MedLine, EMBASE, Psychinfo, and the Cochrane Registry of Controlled Trials from October 2005 to January 2016. We added new studies identified to those from the previous systematic review (1966-September 2005). STUDY ELIGIBILITY, PARTICIPANTS, AND INTERVENTIONS: We included controlled trials, pre-post, cohort, survey, and qualitative studies of universal cholesterol screening in children ages 0 to 18 years. STUDY APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers assessed abstracts and full-text studies, extracted data, and ranked quality. Cost data were inflation-adjusted to 2015 dollars. RESULTS: Nine new studies met inclusion criteria, taking the total number of relevant studies to 21. Screening was associated with no change in cholesterol in 1 of 1 study on health outcomes. A positive screen for dyslipidemia was associated with diet and/or exercise changes in 29% to 92% of families in 4 of 4 studies. Adherence with new guidelines for universal screening was low (16%-18%) in 3 of 3 studies. Costs per case of familial hypercholesterolemia detected were $12,500 to $20,300. LIMITATIONS: Included studies were heterogeneous in outcomes. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Universal cholesterol screening might have small, positive effects on lifestyle change, but the effect on health remains understudied.

A multicenter study on etiology of acute pancreatitis in Beijing during 5 years.

OBJECTIVES: The aim of this study was to determine the etiology tendency of acute pancreatitis (AP) in the Beijing region and the relationship with influencing factors. METHODS: This retrospective multicenter study enrolled 8 representative general hospitals from January 1, 2006 to December 31, 2010. The etiology tendency was analyzed, and the relationship was defined with sex, aging, severity, mortality, recrudesce rate, length of stay, and hospitalization cost. RESULTS: The study enrolled 2461 patients. The total number was increasing year by year. Causes included biliary (1372, 55.75%), alcoholism (246, 10%), hypertriglyceridemia (255, 10.36%), and the others (588, 23.89%). Biliary AP was the most frequent primary cause. Hypertriglyceridemic AP increased at a faster rate than alcoholic AP. There was higher proportion of alcoholic and hypertriglyceridemic AP in men than in women. There is an increase of AP patients with ages 40 to 49 years and older than 70 years. Alcoholic and hypertriglyceridemic AP were higher in patients younger than the age of 50 years, and biliary pancreatitis was higher in patients older than 70 years. Severe AP was classified among 736 patients (29.9%). Etiology distribution was different between severe AP and mild AP (P < 0.001). Mortality in the hospital was 1.54%, and there was no difference in each group. Recrudesce of hypertriglyceridemic AP was higher (P < 0.01). CONCLUSIONS: Acute pancreatitis patients increased year by year in Beijing. Gallstones were the predominant etiological factor. There were different etiology proportion of AP according age, sex, and severity.

Post-heparin LPL activity measurement using VLDL as a substrate: a new robust method for routine assessment of plasma triglyceride lipolysis defects.

BACKGROUND: Determination of lipoprotein lipase (LPL) activity is important for hyperchylomicronemia diagnosis, but remains both unreliable and cumbersome with current methods. Consequently by using human VLDL as substrate we developed a new LPL assay which does not require sonication, radioactive or fluorescent particles. METHODS: Post-heparin plasma was added to the VLDL substrate prepared by ultracentrifugation of heat inactivated normolipidemic human serums, diluted in buffer, pH 8.15. Following incubation at 37°c, the NEFA (non esterified fatty acids) produced were assayed hourly for 4 hours. LPL activity was expressed as µmol/l/min after subtraction of hepatic lipase (HL) activity, obtained following LPL inhibition with NaCl 1.5 mmol/l. Molecular analysis of LPL, GPIHBP1, APOA5, APOC2, APOE genes was available for 62 patients. RESULTS: Our method was reproducible (coefficient of variation (CV): intra-assay 5.6%, inter-assay 7.1%), and tightly correlated with the conventional radiolabelled triolein emulsion method (n = 26, r = 0.88). Normal values were established at 34.8 ± 12.8 µmol/l/min (mean ± SD) from 20 control subjects. LPL activities obtained from 71 patients with documented history of major hypertriglyceridemia showed a trimodal distribution. Among the 11 patients with a very low LPL activity (< 10 µmol/l/min), 5 were homozygous or compound heterozygous for LPL or GPIHBP1 deleterious mutations, 3 were compound heterozygous for APOA5 deleterious mutations and the p.S19W APOA5 susceptibility variant, and 2 were free of any mutations in the usual candidate genes. No homozygous gene alteration in LPL, GPIHBP1 and APOC2 genes was found in any of the patients with LPL activity > 10 µmol/l/min. CONCLUSION: This new reproducible method is a valuable tool for routine diagnosis and reliably identifies LPL activity defects.

Post-heparin LPL activity measurement using VLDL as a substrate: a new robust method for routine assessment of plasma triglyceride lipolysis defects.

BACKGROUND: Determination of lipoprotein lipase (LPL) activity is important for hyperchylomicronemia diagnosis, but remains both unreliable and cumbersome with current methods. Consequently by using human VLDL as substrate we developed a new LPL assay which does not require sonication, radioactive or fluorescent particles. METHODS: Post-heparin plasma was added to the VLDL substrate prepared by ultracentrifugation of heat inactivated normolipidemic human serums, diluted in buffer, pH 8.15. Following incubation at 37°c, the NEFA (non esterified fatty acids) produced were assayed hourly for 4 hours. LPL activity was expressed as µmol/l/min after subtraction of hepatic lipase (HL) activity, obtained following LPL inhibition with NaCl 1.5 mmol/l. Molecular analysis of LPL, GPIHBP1, APOA5, APOC2, APOE genes was available for 62 patients. RESULTS: Our method was reproducible (coefficient of variation (CV): intra-assay 5.6%, inter-assay 7.1%), and tightly correlated with the conventional radiolabelled triolein emulsion method (n = 26, r = 0.88). Normal values were established at 34.8 ± 12.8 µmol/l/min (mean ± SD) from 20 control subjects. LPL activities obtained from 71 patients with documented history of major hypertriglyceridemia showed a trimodal distribution. Among the 11 patients with a very low LPL activity (<10 µmol/l/min), 5 were homozygous or compound heterozygous for LPL or GPIHBP1 deleterious mutations, 3 were compound heterozygous for APOA5 deleterious mutations and the p.S19W APOA5 susceptibility variant, and 2 were free of any mutations in the usual candidate genes. No homozygous gene alteration in LPL, GPIHBP1 and APOC2 genes was found in any of the patients with LPL activity >10 µmol/l/min. CONCLUSION: This new reproducible method is a valuable tool for routine diagnosis and reliably identifies LPL activity defects.

Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement.

An Expert Panel group of scientists and clinicians met to consider several aspects related to non-fasting and postprandial triglycerides (TGs) and their role as risk factors for cardiovascular disease (CVD). In this context, we review recent epidemiological studies relevant to elevated non-fasting TGs as a risk factor for CVD and provide a suggested classification of non-fasting TG concentration. Secondly, we sought to describe methodologies to evaluate postprandial TG using a fat tolerance test (FTT) in the clinic. Thirdly, we discuss the role of non-fasting lipids in the treatment of postprandial hyperlipemia. Finally, we provide a series of clinical recommendations relating to non-fasting TGs based on the consensus of the Expert Panel: 1). Elevated non-fasting TGs are a risk factor for CVD. 2). The desirable non-fasting TG concentration is <2 mmol/l (<180 mg/dl). 3). For standardized postprandial testing, a single FTT meal should be given after an 8 h fast and should consist of 75 g of fat, 25 g of carbohydrates and 10 g of protein. 4). A single TG measurement 4 h after a FTT meal provides a good evaluation of the postprandial TG response. 5). Preferably, subjects with non-fasting TG levels of 1-2 mmol/l (89-180 mg/dl) should be tested with a FTT. 6). TG concentration ≤ 2.5 mmol/l (220 mg/dl) at any time after a FTT meal should be considered as a desirable postprandial TG response. 7). A higher and undesirable postprandial TG response could be treated by aggressive lifestyle modification (including nutritional supplementation) and/or TG lowering drugs like statins, fibrates and nicotinic acid.

Physical activity energy expenditure predicts progression toward the metabolic syndrome independently of aerobic fitness in middle-aged healthy Caucasians: the Medical Research Council Ely Study.

OBJECTIVE: To examine over a period of 5.6 years the prospective associations between physical activity energy expenditure (PAEE), aerobic fitness (Vo(2max)), obesity, and the progression toward the metabolic syndrome in a population-based cohort of middle-aged men and women (n = 605) who were free of the metabolic syndrome at baseline. RESEARCH DESIGN AND METHODS: PAEE was measured objectively by individually calibrated heart rate against energy expenditure. Vo(2max) was predicted from a submaximal exercise stress test. Fat mass and fat-free mass were assessed by bio-impedance. A metabolic syndrome score was computed by summing the standardized values for obesity, hypertension, hyperglycemia, insulin resistance, hypertriglyceridemia, and the inverse level of HDL cholesterol and expressed as a continuously distributed outcome. Generalized linear models were used to examine the independent prospective associations between PAEE and Vo(2max) and the metabolic syndrome score after adjusting for sex, baseline age, smoking, socioeconomic status, follow-up time, and baseline phenotypes. RESULTS: PAEE predicted progression toward the metabolic syndrome, independent of baseline metabolic syndrome, body fat, Vo(2max), and other confounding factors (standardized beta = -0.00085, P = 0.046). This association was stronger when excluding the adiposity component from the metabolic syndrome (standardized beta = -0.0011, P = 0.035). Vo(2max) was not an independent predictor of the metabolic syndrome after adjusting for physical activity (standardized beta = 0.00011, P = 0.93). CONCLUSIONS: PAEE predicts progression toward the metabolic syndrome independent of aerobic fitness, obesity, and other confounding factors. This finding underscores the importance of physical activity for metabolic disease prevention even when an improvement in aerobic fitness is absent.