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Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study.

ABSTRACT: Despite reducing progression and promoting regression of coronary atherosclerosis, statin therapy does not fully address residual cardiovascular (CV) risk. High-purity eicosapentaenoic acid (EPA) added to a statin has been shown to reduce CV events and induce regression of coronary atherosclerosis in imaging studies; however, data are from Japanese populations without high triglyceride (TG) levels and baseline EPA serum levels greater than those in North American populations. Icosapent ethyl is a high-purity prescription EPA ethyl ester approved at 4?g/d as an adjunct to diet to reduce TG levels in adults with TG levels >499?mg/dL. The objective of the randomized, double-blind, placebo-controlled EVAPORATE study is to evaluate the effects of icosapent ethyl 4?g/d on atherosclerotic plaque in a North American population of statin-treated patients with coronary atherosclerosis, TG levels of 200 to 499?mg/dL, and low-density lipoprotein cholesterol levels of 40 to 115?mg/dL. The primary endpoint is change in low-attenuation plaque volume measured by multidetector computed tomography angiography. Secondary endpoints include incident plaque rates; quantitative changes in different plaque types and morphology; changes in markers of inflammation, lipids, and lipoproteins; and the relationship between these changes and plaque burden and/or plaque vulnerability. Approximately 80 patients will be followed for 9 to 18?months. The clinical implications of icosapent ethyl 4?g/d treatment added to statin therapy on CV endpoints are being evaluated in the large CV outcomes study REDUCE-IT. EVAPORATE will provide important imaging-derived data that may add relevance to the clinically derived outcomes from REDUCE-IT.

SUBMITTER: Budoff M

PROVIDER: S-EPMC5838559 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study.

Budoff Matthew M Brent Muhlestein J J Le Viet T VT May Heidi T HT Roy Sion S Nelson John R JR

Clinical cardiology 20180124 1

Despite reducing progression and promoting regression of coronary atherosclerosis, statin therapy does not fully address residual cardiovascular (CV) risk. High-purity eicosapentaenoic acid (EPA) added to a statin has been shown to reduce CV events and induce regression of coronary atherosclerosis in imaging studies; however, data are from Japanese populations without high triglyceride (TG) levels and baseline EPA serum levels greater than those in North American populations. Icosapent ethyl is ...[more]

PMID: 29365351

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Project description:BACKGROUND:Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (?500 mg/dL) hypertriglyceridemia. ANCHOR was a 12-week, phase 3 study that evaluated the efficacy and safety of IPE in patients (N?=?702) with residual high fasting TG levels (?200 and <500 mg/dL) despite having optimized low-density lipoprotein cholesterol (LDL-C) levels (?40 and <100 mg/dL) on statin therapy. Among patients randomized to IPE (4 g/day or 2 g/day) or placebo, 514 (73%) had diabetes mellitus. METHODS:A post hoc subgroup analysis of the ANCHOR study was conducted to assess the effects of IPE on median placebo-adjusted percent change from baseline in efficacy end point parameters in 3 subgroups: total (all subjects with diabetes-overall median baseline glycosylated hemoglobin A?c [A?c]?=?6.8%), better-controlled diabetes (below median baseline A1c), and less-controlled diabetes (above median baseline A1c). RESULTS:Baseline efficacy parameters were similar among all groups except high-sensitivity C-reactive protein (hsCRP), which was higher in the total and less-controlled diabetes groups. Compared with placebo, IPE 4 g/day significantly reduced TG, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), lipoprotein-associated phospholipase A2, apolipoprotein B (Apo B), total cholesterol, high-density lipoprotein cholesterol, VLDL-TG, oxidized LDL, and remnant-like particle cholesterol in all 3 diabetes groups, LDL-C in the total diabetes group, and hsCRP in the total and less-controlled diabetes groups. Decreases in hsCRP and Apo B were much greater in patients with less-controlled diabetes. There were no significant increases in fasting plasma glucose, A1c, insulin, or homeostasis model assessment-estimated insulin resistance in any group. CONCLUSION:IPE 4 g/day significantly improved lipid and lipid-related parameters without worsening glycemic control in patients with diabetes and mixed dyslipidemia, with possibly greater effects among those with less-controlled diabetes. TRIAL REGISTRATION:Clinicaltrials.gov Identifier NCT01047501.

Project description:ImportanceThe 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.ObjectiveTo estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment.Design, setting, and participantsAn 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.InterventionsPatients 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 measuresMain outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness.ResultsA 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 relevanceThis 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.

Project description: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.

Project description:Although low-density lipoprotein cholesterol lowering is effective in atherosclerotic cardiovascular disease (ASCVD) prevention, considerable 'lipid-associated' residual risk remains, particularly in patients with mild-to-moderate hypertriglyceridaemia (2-10 mmol/L; 176-880 mg/dL). Triglyceride (TG)-rich lipoproteins carry both TGs and cholesterol (remnant-cholesterol). At TG levels >5 mmol/L (440 mg/dL) vs. <1 mmol/L (88 mg/dL) or remnant-cholesterol >2.3 mmol/L (89 mg/dL) vs. <0.5 mmol/L (19 mg/dL), risk is ∼1.5-fold elevated for aortic stenosis, 2-fold for all-cause mortality, 3-fold for ischaemic stroke, 5-fold for myocardial infarction (MI), and 10-fold for acute pancreatitis. Furthermore, Mendelian randomization studies indicate that elevated TG-rich lipoproteins are causally related to increased risk of ASCVD and even all-cause mortality. While genetic and epidemiological data strongly indicate that TG-rich lipoproteins are causally linked to ASCVD, intervention data are ambiguous. Fibrates, niacin and low-dose omega-3 fatty acids have all been used in outcome trials, but have failed to demonstrate clear benefit in combination with statins. Whether the lack of additional benefit relates to methodological issues or true failure is indeterminate. Importantly, a recent intervention trial evaluating a high dose of eicosapentaenoic-acid showed clear benefit. Thus, REDUCE-IT evaluated the effect of icosapent ethyl (4 g/day) on cardiovascular outcomes in 8179 high-risk patients with moderate TG elevation on statin therapy. Over a median duration of 4.9 years, the relative risk for the primary endpoint (composite of cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina) was reduced by 25% (absolute risk 17.2% vs. 22.0%; P < 0.0001; number needed to treat 21). High-dose icosapent ethyl intervention therefore confers substantial cardiovascular benefit in high-risk patients with moderate hypertriglyceridaemia on statin therapy.

Dataset Information

Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study.

Publications

Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study.

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