Reduction Of Cardiovascular Events With Icosapent Ethyl-Intervention Trial Research Articles

Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies.

Mineral oil is often used as a clinical trial placebo. Pharmaceutical-grade mineral oil consists of a mixture of saturated hydrocarbons, with a purity and chemical structure that differs substantially from food-grade or technical-/industrial-grade mineral oils. Interest in mineral oil was piqued by suggestions that a portion of the substantially positive results of the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) might be attributable to the theoretical negative effects of mineral oil rather than being due to the clinical benefits of icosapent ethyl. The objective of this review was to explore possible mineral oil safety and efficacy effects and contextualize these findings in light of the REDUCE-IT conclusions. A literature search identified studies employing mineral oil placebos. Eighty studies were identified and relevant data extracted. Adverse events associated with mineral oil were generally gastrointestinal and consistent with use as a lubricant laxative. Changes in triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and other biomarkers were inconsistent and generally not statistically significant, or clinically meaningful with mineral oil, as were changes in blood pressure. There was no consistent evidence that mineral oil in the amounts used in the REDUCE-IT or Effect of Vascepa on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) trials affects absorption of essential nutrients or drugs, including statins. These results were then considered alongside publicly available data from REDUCE-IT. Based on available evidence, mineral oil does not appear to impact medication absorption or efficacy, or related clinical outcomes, and, therefore, does not meaningfully affect study conclusions when used as a placebo at the quantities used in clinical trials.

Impact of expanded FDA indication for icosapent ethyl on enhanced cardiovascular residual risk reduction.

Hypertriglyceridemia is associated with increased cardiovascular disease (CVD) risk. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated that the purified, stable ethyl ester of eicosapentaenoic acid, icosapent ethyl (IPE), added to statins reduced CVD events by 25% (p <0.001), leading to an expanded indication in the USA. IPE is now approved as an adjunct to maximally tolerated statins to reduce CVD event risk in adults with triglyceride (TG) levels ≥150mg/dl and either established CVD or diabetes mellitus plus ≥2 additional CVD risk factors. The new indication allows co-administration of IPE for elevated TG levels with statin treatment, enabling effective residual risk reduction in a broader at-risk population beyond what can be achieved with intensive low-density lipoprotein cholesterol control alone.

REDUCE-IT Eligibility and Preventable Cardiovascular Events in the US Population (from the National Health and Nutrition Examination Survey [NHANES

The reduction of cardiovascular events with icosapent ethyl-intervention (REDUCE-IT) trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl (IPE) reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US adults with available REDUCE-IT inclusion criteria from NHANES Surveys 1999-2016 and estimated primary (CVD death, nonfatal myocardial infarction, stroke, revascularization, or unstable angina) and secondary composite (CVD death, nonfatal MI or stroke) events using REDUCE-IT published event rates in the IPE and placebo groups, the difference being the number of preventable events. From 11,445 adults aged ≥45 years (representing 111.1 million [M]), a total of 319 persons (3.0 M) fit key REDUCE-IT eligibility criteria: triglycerides of 135 to 499 mg/dL, HbA1c <10%, blood pressure <200/100 mm Hg, and on a statin with LDL-C of 40 to 99 mg/dL. 63% had prior CVD and 37% had DM + ≥1 risk factor (primary prevention cohort). If these persons are given IPE for the REDUCE-IT median trial period of 4.9 years, we estimated preventing a total 349,817 (71,391/year) primary CVD outcomes of which 146,011 (29,798/year) were initial events. Most (24,151) preventable events were from the secondary prevention cohort. Using FDA eligibility criteria, an estimated 4.6 million persons would be eligible for IPE, with 60,544 preventable primary CVD outcomes annually from REDUCE-IT USA event rates. In conclusion, many CVD events in US adults with known CVD or DM and well-controlled LDL-C on statin therapy can be prevented with IPE.

Applicability of the REDUCE-IT trial to the FAST-MI registry. Are the results of randomized trials relevant in routine clinical practice?

BackgroundThe reduction of cardiovascular events with icosapent ethyl‐intervention trial (REDUCE‐IT) trial revealed robust atherosclerotic cardiovascular risk reduction with a strategy comprising high‐dose omega‐3 icosapent ethyl vs placebo in statin‐treated patients with elevated triglycerides and controlled low‐density lipoprotein cholesterol (LDL‐C).HypothesisAre the results of the REDUCE‐IT trial applicable to the French registry on acute ST‐elevation and non‐ST‐elevation myocardial infarction (FAST‐MI) population?MethodsData were extracted from the FAST‐MI 2010 and 2015 registries. We applied the REDUCE‐IT enrolment criteria (triglycerides 150‐500 mg/dL and LDL‐C 40‐100 mg/dL on statins) to the FAST‐MI population in patients aged ≥45 years who had detailed lipid values postacute hospitalization, focusing on their clinical profile and cardiovascular prognosis.ResultsOf the 3789 FAST‐MI patients with a full lipid profile (median 11.1 [IQR 7.6‐17.4] months after hospitalization for myocardial infarction), 472 (12.5%; 95% CI 11.4‐13.5) met the eligibility criteria for REDUCE‐IT (REDUCE‐IT‐like group). The cardiovascular event rate (all‐cause death, nonfatal myocardial infarction, nonfatal stroke) was 36.7 (95% CI 27.8‐48.6) per 1000 person‐years for the REDUCE‐IT‐like group, which compares with the 36.9 (95% CI 26.1‐51.5) per 1000 person‐years (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) reported in the REDUCE‐IT trial. The residual cardiovascular risk related to elevated triglycerides in the REDUCE‐IT‐like group was similar to the risk in the REDUCE‐IT trial.ConclusionsIf the results of REDUCE‐IT are applied to patients hospitalized for a myocardial infarction in France, 12.5% of these patients could benefit from a strategy of high‐dose omega‐3 icosapent ethyl on top of contemporary therapy including statins to improve their clinical outcomes.

Highlights of Studies in Cardiovascular Disease Prevention Presented at the 2020 American College of Cardiology Annual Scientific Session.

Purpose of ReviewThe review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC).Recent FindingsThe studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). In addition, results from the pooled analysis of phase III trials on inclisiran and secondary analysis examining eicosapentaenoic acid levels and cardiovascular outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) were included. Finally, we discuss studies examining the use of polygenic risk score with low density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on lifetime cardiovascular risk.SummaryThe studies presented at the ACC.20/WCC represent notable contributions in the field of CVD prevention.

Reducing Cardiovascular Disease Risk in Women Beyond Statin Therapy: New Insights 2020.

Management of residual and persistent cardiovascular disease (CVD) risk among statin-treated individuals has emerged as an important preventive strategy. The purpose of this article is to review the unique landscape of CVD in women and relevant prior prevention trials, and to discuss how the recent results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) might apply to the contemporary management of CVD risk among statin-treated women. Women have unique risk factors that may impact CVD and its prevention. Historically, women have been underrepresented in CVD trials, posing a challenge to development of clinical recommendations for women. Low-density lipoprotein cholesterol-targeting treatments have demonstrated CVD risk reduction, with comparable effects in both sexes. In contrast, triglyceride-lowering treatments (niacin, fenofibrate, and omega-3 fatty acids) have reported mixed findings for CVD risk reduction. Recent clinical trials of combination omega-3 fatty acids (docosahexaenoic acid/eicosapentaenoic acid [EPA]) have not found significant CVD risk reduction. The recently published REDUCE-IT study found that icosapent ethyl, an EPA-only omega-3 fatty acid, in combination with statins, significantly reduced CVD events in high-risk patients. The icosapent ethyl group had a significantly lower occurrence of the primary composite CVD endpoint (17.2%) than the placebo group (22.0%; hazard ratio 0.75; 95% confidence interval 0.68-0.83; p < 0.001). CVD risk reduction with icosapent ethyl treatment was comparable between women and men (p for interaction, 0.33). Data from REDUCE-IT suggest women benefit similarly to men with respect to icosapent ethyl, a novel therapy for prevention of CVD.

Icosapent ethyl: drug profile and evidence of reduced residual cardiovascular risk in patients with statin-managed LDL-C cholesterol

ABSTRACT Introduction: Icosapent ethyl (IPE) is a highly purified (>96%) form of eicosapentanoic acid, a marine-derived omega-3 fatty acid known to reduce serum triglyceride (TG) levels. In the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), the addition of 4 g IPE daily resulted in a 25% reduction in cardiovascular events beyond statins and other standard of care therapies. IPE is now the only therapy currently approved by the Food and Drug Administration to treat patients with elevated TGs (150–499 mg/dL) with cardiovascular disease (CVD) or Type 2 diabetes mellitus and two or more CVD risk factors. Areas covered IPE is a highly purified form of eicosapentanoic acid for patients with elevated TGs as monotherapy or combined with statins and/or other lipid lowering therapies. The REDUCE-IT Study demonstrated a 25% reduction in the primary outcome measure and 30% reduction in total CVD events in high-risk patients with elevated TGs (135–499 mg/dL) assigned to IPE (4 g daily). Side effects included a statistically significant increased risk of atrial fibrillation and bleeding, although the risk of stroke was reduced and there were no cases of fatal bleeding. The FDA recently approved IPE for treatment of patients with TG levels of 150–499 mg/dL and preexisting CVD or Type 2 diabetes mellitus with two or more risk factors. Expert opinion IPE has proven to be superior to other forms of omega 3 fatty acid in reducing CVD risk in patients with elevated TG. This could be attributed to multiple factors including the use of highly purified eicosapentaenoic acid ethyl esters without docosahexaenoic acid (DHA), thus preventing the increase in low-density lipoprotein cholesterol associated with DHA especially at high TG levels, reduction in atherogenic TG-rich particles, antioxidant and anti-inflammatory properties, improvement in endothelial function, and stabilization of atherosclerotic plaque.

Triglycerides and residual risk.

To review the recent evidence from observational/genetic/interventional studies addressing triglycerides and residual cardiovascular risk (CVRisk). Large population-based and secondary prevention studies consistently show an association of higher triglycerides with increased CVRisk. This is compounded by genetic studies demonstrating an independent relationship between triglyceride raising or lowering genetic variants affecting triglyceride-rich lipoproteins (TRL) metabolism and CVRisk. Mendelian randomization analysis suggests the benefit of genetic lowering of triglycerides and LDL-cholesterol is similar per unit change in apolipoprotein-B. Among cholesterol-lowering trials, more intensive statin therapy produced greater CVRisk reductions in patients with higher TRL-cholesterol or triglycerides; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition led to similar triglycerides reduction but greater non-HDL-C or apolipoprotein-B reductions than fibrates or fish oils. Regarding n-3 fatty acids, A Study of Cardiovascular Events in Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) primary prevention trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid failed to demonstrate cardiovascular benefits, Conversely, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using high-dose icosapent-ethyl (purified EPA) in primary (diabetes) and secondary prevention with hypertriglyceridemia showed significant cardiovascular events reductions (greater than expected by the observed triglycerides or apolipoprotein-B reductions, suggesting potential benefits through non-lipid pathways). Evidence suggests higher triglycerides are a marker of CVRisk and may help identify patients who benefit from intensification of therapy. Moreover, genetic studies support a causal link between TRL/triglycerides and cardiovascular disease. Treatment with high-dose EPA may be of benefit in high-risk patients with hypertriglyceridemia to reduce CVRisk.

Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid.

Patients with well-controlled LDL (low-density lipoprotein) levels still have residual cardiovascular risk associated with elevated triglycerides. Epidemiological studies have shown that elevated fasting triglyceride levels associate independently with incident cardiovascular events, and abundant recent human genetic data support the causality of TGRLs (triglyceride-rich lipoproteins) in atherothrombosis. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower blood triglyceride concentrations but likely exert additional atheroprotective properties at higher doses. Omega-3 fatty acids modulate T-cell differentiation and give rise to various prostaglandins and specialized proresolving lipid mediators that promote resolution of tissue injury and inflammation. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) with an EPA-only formulation lowered a composite of cardiovascular events by 25% in patients with established cardiovascular disease or diabetes mellitus and other cardiovascular risk factors. This clinical benefit likely arises from multiple molecular mechanisms discussed in this review. Indeed, human plaques readily incorporate EPA, which may render them less likely to trigger clinical events. EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and endothelial function as well as tissue distributions. Trials that have evaluated DHA-containing high-dose omega-3 fatty acids have thus far not shown the benefits of EPA alone demonstrated in REDUCE-IT. This review will consider the mechanistic evidence that helps to understand the potential mechanisms of benefit of EPA.

Translating evidence from clinical trials of omega-3 fatty acids to clinical practice.

The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) study recently demonstrated that administration of high doses of omega-3 fatty acids confers cardiovascular benefit in high-risk patients with the modest hypertriglyceridemia. This provided optimism for a therapeutic area that has challenged the field of cardiovascular prevention for 2decades. However, it raises a number of questions including understanding the mechanism underscoring this benefit, how best to use these therapies and whether similar results will be observed with alternative omega-3 fatty acid preparations. Contemporary clinical trials of omega-3 fatty acids and their attempt to prevent cardiovascular events will be reviewed.

COST-EFFECTIVENESS OF ICOSAPENT ETHYL IN US REDUCE-IT PATIENTS

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that among US patients with elevated triglyceride levels on statin therapy (n=3,146), the risk of cardiovascular disease events was reduced by 31% in those randomized to 4g of icosapent ethyl daily

Cardiovascular Disease Prevention in Focus: Highlights from the 2019 American Heart Association Scientific Sessions.

This review highlights selected cardiovascular disease (CVD) prevention studies presented at the 2019 American Heart Association (AHA) Scientific Sessions. Several important cardiovascular prevention studies were presented at the 2019 AHA Scientific Sessions. Results from the Colchicine Cardiovascular Outcomes Trial (COLCOT) showed that low-dose colchicine reduces the risk of recurrent CVD events among patients with recent myocardial infarction. A prospective analysis from the UK Biobank cohort demonstrated that the increased CVD risk associated with clonal hematopoiesis of indeterminate potential is mitigated by a common disruptive mutation in the IL6R gene that suppresses the pro-inflammatory IL-1β/IL-6 pathway. The Treat Stroke to Target trial demonstrated that reducing low-density lipoprotein cholesterol to <70mg/dL among patients with ischemic stroke or transient ischemic attack reduces the risk of recurrent CVD events as compared with a higher LDL-C target of 90-110mg/dL. A secondary analysis focusing on American participants enrolled in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that these patients receive a similar benefit in terms of cardiovascular risk reduction with icosapent ethyl as compared with the entire trial population. A post hoc analysis of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrated that a genetic risk score comprising 27 single-nucleotide polymorphisms is associated with cardiovascular risk among patients with established atherosclerotic CVD and patients with high genetic risk receive a relatively higher benefit from evolocumab use. Similar results were observed with alirocumab use in a post hoc analysis of the ODYSSEY OUTCOMES trial where a genome-wide polygenic risk score comprising 6.5million DNA variants was used. These studies presented at 2019 AHA Scientific Sessions will help guide our approach to preventing CVD.

REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States.

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. 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. 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. 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. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.

National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk

Representatives from the National Lipid Association (NLA) participated in the development of the 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol, which reaffirmed that lifestyle changes and statin treatment are therapeutic cornerstones for atherosclerotic cardiovascular disease (ASCVD) risk reduction. It also updated prior recommendations to incorporate newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 inhibitors as adjuncts to statin therapy for patients at high and very-high ASCVD risk. The 2018 Guideline was finalized shortly before full results were available from a randomized, placebo-controlled cardiovascular outcomes trial [Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT)] that examined the effects of icosapent ethyl (IPE) 4 g/d on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. The primary outcome variable of first major adverse cardiovascular event (cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina) was reduced by 25% (95% confidence interval 17%–32%, P < .001). REDUCE-IT served as the primary basis for the NLA's review of evidence for the use of IPE for ASCVD risk reduction. Based on this review, the NLA position is that for patients aged ≥45 years with clinical ASCVD, or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with IPE is recommended for ASCVD risk reduction (evidence rating: class I; evidence level: B-R).

Effect of High-Dose Marine Omega-3 Fatty Acids on Atherosclerosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

A recent randomized controlled trial (RCT), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported that high-dose marine omega-3 fatty acids (OM3) significantly reduce cardiovascular disease (CVD) outcomes, yet the mechanisms responsible for this benefit remain unknown. To test the hypothesis that high-dose OM3 is anti-atherosclerotic, we performed a systematic review and meta-analysis of RCT of high-dose OM3 on atherosclerosis. The protocol of this systematic review was registered with PROSPERO (CRD42019125566). PubMed, Embase, Cochran Central Register for Controlled Trials, and Clinicaltrials.gov databases were searched using the following criteria: adult participants, high-dose OM3 (defined as ≥3.0 g/day, or in Japan 1.8 g/day and purity ≥90%) as the intervention, changes in atherosclerosis as the outcome, and RCTs with an intervention duration of ≥6 months. A random-effects meta-analysis was used to pool estimates across studies. Among the 598 articles retrieved, six articles met our criteria. Four RCTs evaluated atherosclerosis in the coronary and two in the carotid arteries. High-dose OM3 significantly slowed the progression of atherosclerosis (standardized mean difference −1.97, 95% confidence interval −3.01, −0.94, p < 0.001). The results indicate that anti-atherosclerotic effect of high-dose OM3 is one potential mechanism in reducing CVD outcomes demonstrated in the REDUCE-IT trial.

Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants.

BackgroundWhether marine omega‐3 supplementation is associated with reduction in risk of cardiovascular disease (CVD) remains controversial.Methods and ResultsThis meta‐analysis included study‐level data from 13 trials. The outcomes of interest included myocardial infarction, coronary heart disease (CHD) death, total CHD, total stroke, CVD death, total CVD, and major vascular events. The unadjusted rate ratios were calculated using a fixed‐effect meta‐analysis. A meta‐regression was conducted to estimate the dose–response relationship between marine omega‐3 dosage and risk of each prespecified outcome. During a mean treatment duration of 5.0 years, 3838 myocardial infarctions, 3008 CHD deaths, 8435 total CHD events, 2683 strokes, 5017 CVD deaths, 15 759 total CVD events, and 16 478 major vascular events were documented. In the analysis excluding REDUCE‐IT (Reduction of Cardiovascular Events with Icosapent Ethyl‐Intervention Trial), marine omega‐3 supplementation was associated with significantly lower risk of myocardial infarction (rate ratio [RR] [95% CI]: 0.92 [0.86, 0.99]; P=0.020), CHD death (RR [95% CI]: 0.92 [0.86, 0.98]; P=0.014), total CHD (RR [95% CI]: 0.95 [0.91, 0.99]; P=0.008), CVD death (RR [95% CI]: 0.93 [0.88, 0.99]; P=0.013), and total CVD (RR [95% CI]: 0.97 [0.94, 0.99]; P=0.015). Inverse associations for all outcomes were strengthened after including REDUCE‐IT while introducing statistically significant heterogeneity. Statistically significant linear dose–response relationships were found for total CVD and major vascular events in the analyses with and without including REDUCE‐IT.ConclusionsMarine omega‐3 supplementation lowers risk for myocardial infarction, CHD death, total CHD, CVD death, and total CVD, even after exclusion of REDUCE‐IT. Risk reductions appeared to be linearly related to marine omega‐3 dose.

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]). In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Translating plasma eicosapentaenoic acid concentrations into erythrocyte percentages of eicosapentaenoic acid plus docosahexaenoic acid during treatment with icosapent ethyl

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) study demonstrated that 4g/d of eicosapentaenoic acid (EPA) ethyl esters (icosapent ethyl [IPE]) reduced risk for major cardiovascular events by 25% in statin-treated patients with residual hypertriglyceridemia. How this treatment affected red blood cell (RBC) EPA and docosahexaenoic acid (DHA) levels (ie, the Omega-3 Index [O3I]) was not reported, but effects on plasma EPA concentrations were reported. The aim of the study was to estimate baseline and final O3I levels in REDUCE-IT. First, deidentified data from our laboratory on RBC and plasma EPA and DHA from 2311 patients with similar lipid profiles as those in REDUCE-IT were used to generate a regression equation, which was then used to estimate the O3I from plasma FA concentrations. Second, previously published data on the effects of IPE on RBC FA concentrations were also converted to the O3I. Both approaches (from calculations and prior publications) suggested that baseline and follow-up O3I levels were about 5% and 7%, respectively. In addition, plasma EPA levels (but not the O3I) were noted to be influenced by triglyceride levels. For patients using 4 g of IPE, an estimated O3I value of about 7% reflects a cardioprotective state. Plasma EPA concentrations may be ill-suited as treatment targets because they are confounded by triglyceride levels.

Recent Clinical Trials Shed New Light on the Cardiovascular Benefits of Omega-3 Fatty Acids.

Three recent clinical trials have demonstrated the benefits of marine omega-3 fatty acids on cardiovascular disease end points. In the Vitamin D and Omega-3 Trial (VITAL), 840 mg/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) resulted in a 28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events. In the ASCEND trial (A Study of Cardiovascular Events in Diabetes), cardiovascular disease death was significantly reduced by 19% with 840 mg/d of EPA and DHA. However, the primary composite end points were not significantly reduced in either study. In REDUCE-IT (the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), there was a 25% decrease in the primary end point of major cardiovascular events with 4 g/d EPA (icosapent ethyl) in patients with elevated triglycerides (135-499 mg/dL) who also were taking a statin drug. For clinical practice, we now have compelling evidence of the cardiovascular benefits of omega-3 fatty acids. The findings of REDUCE-IT provide a strong rationale for prescribing icosapent ethyl for patients with hypertriglyceridemia who are on a statin. For primary prevention, the goal is to increase the population intake of omega-3 fatty acids to levels currently recommended, which translates to consuming at least one to two servings of fish/seafood per week. For individuals who prefer taking omega-3 fatty acid supplements, recent findings from clinical trials support the benefits for primary prevention.

Icosapent ethyl for dyslipidaemia in patients with diabetes and coronary artery disease: Act now to reduce it.

The risk of atherosclerotic cardiovascular disease (ASCVD) can be significantly reduced in patients with diabetes who are undergoing low-density lipoprotein cholesterol-reducing therapies. However, the elevated triglyceride levels seen in diabetic dyslipidaemia can contribute to residual ASCVD risk. Icosapent ethyl (IPE) has recently been shown to substantially reduce major cardiovascular events in high-risk patients with hypertriglyceridaemia who are undergoing statin therapy. In a real-world study of patients with diabetes and acute coronary syndrome (ACS), 17.1% were found to be eligible for treatment with IPE based on Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) criteria. A significant proportion of patients with diabetes and ACS merit receiving IPE therapy, with important implications for evolving clinical practice guidelines and best standard of care.