CURRICULUM IN CARDIOLOGY - JOURNAL CLUB

Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 44-47

Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia

M Aseem Basha
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. M Aseem Basha
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jpcs.jpcs_16_19

Citation

Background

• Patients with elevated triglyceride (TG) levels are at increased risk for ischemic events.
• Icosapent ethyl, a highly purified eicosapentaenoic acid (EPA) ethyl ester, lowers TG levels, but data are needed to determine its effects on ischemic event.
• Despite adequate statin therapy, there remains a substantial residual cardiovascular risk of cardiovascular events, and in such cases, elevated TG has been found to be an independent indicator of increased risk of ischemic events.^[2]
• Attempts to reduce TGs have provided mixed results, with large chunk of data showing no benefits of additional TG lowering drugs (n-3 fatty acids) in patients receiving statin therapy alone.^[3],[4],[5]
• The basis of this trial was the reassuring results of Japan EPA Lipid Intervention Study (JELIS) trial, an open-label trial that reported that the risk of major adverse cardiovascular events was 19% lower with statin therapy plus 1.8 g of EPA daily than with statin therapy alone.^[6]

• Icosapent ethyl is a highly purified and stable EPA ethyl ester.
• It has been shown to lower TG levels and is used as an adjunct to diet in adult patients who have TG levels of at least 500 mg/deciliter.^[7]
• However, it is not known whether it decreases ischemic events, although it may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties which may be responsible for its beneficial effects.^[8]

• Multicenter, randomized, double-blind, placebo-controlled
• N = 8179



• Icosapent ethyl (n = 4089)
• Placebo (n = 4090).



• Setting: 473 sites in 11 countries
• Enrollment: November 28, 2011–August 4, 2016
• Median follow-up: 4.9 years
• Analysis: Intention-to-treat.

1. Age ≥45 years with established cardiovascular disease (CVD) (secondary prevention cohort) or ≥50 years with diabetes with ≥1 additional risk factor for CVD (primary prevention cohort)
2. Fasting TG levels ≥150 mg/dL and <500 mg/dL
3. Low-density lipoprotein cholesterol LDL-C >40 mg/dL and ≤100 mg/dL and on stable statin therapy (± ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization.

1. Documented coronary artery disease (CAD)



• Multivessel CAD (≥50% stenosis in ≥2 major epicardial coronary arteries – with or without antecedent revascularization
• Prior myocardial infarction (MI)
• Hospitalization for high-risk non-ST-segment elevation acute coronary syndrome with ST-segment deviation or biomarker positivity.



2. Documented cerebrovascular or carotid disease



• Prior ischemic stroke
• Symptomatic carotid artery disease with ≥50% carotid arterial stenosis
• Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis
• History of carotid revascularization.



3. Documented peripheral artery disease



• Ankle–Brachial Index <0.9 with symptoms of intermittent claudication
• History of aortoiliac or peripheral artery intervention.

1. Diabetes mellitus requiring medication AND
2. ≥50 years of age AND
3. ≥1 additional risk factor for CVD



• Men ≥55 years and women ≥65 years
• Cigarette smoker or stopped smoking within 3 months
• Hypertension (≥140 mmHg systolic OR ≥90 mmHg diastolic) or on antihypertensive medication
• High-density lipoprotein (HDL) cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women
• High-sensitivity C-reactive protein >3.0 mg/L
• Renal dysfunction: creatinine clearance >30 and <60 mL/min
• Retinopathy
• Micro- or macroalbuminuria
• Ankle brachial index (ABI) <0.9 without symptoms of intermittent claudication.

1. Severe (New York Heart Association Class IV) heart failure
2. Severe liver disease
3. History of pancreatitis
4. Hypersensitivity to fish and/or shellfish.

• Time from randomization to the first occurrence of the following: which was a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, and unstable angina.

• Composite of cardiovascular death, nonfatal MI, and nonfatal stroke.

• Event-driven trial
• It was estimated that approximately 1612-adjudicated primary endpoint events would be necessary to provide the trial, with 90% power to detect a 15% lower risk of the primary composite endpoint in the icosapent ethyl group than in the placebo group.
• The primary efficacy analysis was based on the time from randomization to the first occurrence of any component of the primary composite endpoint.

Results

• The median duration of follow-up was 4.9 years.
• The median change in TG level from baseline to 1 year was a decrease of 18.3% in the icosapent ethyl group and an increase of 2.2% in the placebo group.
• The median reduction from baseline (as estimated with the use of the Hodges–Lehmann approach) was 19.7% greater in the icosapent ethyl group than in the placebo group (a 44.5 mg/deciliter greater reduction; P < 0.001).
• The median change in LDL-C level from baseline was an increase of 3.1% in the icosapent ethyl group and an increase of 10.2% in the placebo group – a 6.6% (5.0 mg/deciliter lower increase with icosapent ethyl than with placebo (P < 0.001).

• A primary endpoint event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group, an absolute between-group difference of 4.8% points (95% confidence interval [CI], 3.1–6.5).
• The number needed to treat to avoid one primary endpoint event was 21 (95% CI, 15–33) over a median follow-up of 4.9 years.

• A key secondary efficacy endpoint event occurred in 11.2% of the patients in the icosapent ethyl group, as compared with 14.8% of the patients in the placebo group.
• The number needed to treat to avoid one secondary endpoint event was 28 over a median follow-up of 4.9 years.

• The overall rates of adverse events that occurred did not differ significantly between the trial groups.
• The rate of atrial fibrillation was significantly higher in the icosapent ethyl group than in the placebo group (5.3% vs. 3.9%), as was the rate of peripheral edema (6.5% vs. 5.0%), but the rate of anemia was significantly lower in the icosapent ethyl group than in the placebo group (4.7% vs. 5.8%), as were the rates of diarrhea (9.0% vs. 11.1%) and gastrointestinal adverse events (33.0% vs. 35.1%).

Discussion

• The risk of primary composite endpoint was significantly lower, by 25% among icosapent group when compared to placebo.
• The number needed to treat to avoid one primary endpoint event was 21 (95% CI, 15–33) over a median follow-up of 4.9 years.
• The risk of the key secondary composite endpoint was also significantly lower, by 26%, in the icosapent ethyl group than in the placebo group.
• The number needed to treat to avoid one secondary endpoint event was 28 over a median follow-up of 4.9 years.
• These benefits were observed against a background of appropriate statin use among patients who had a median LDL-C level of 75.0 mg/deciliter at baseline.

• JELIS, which compared a combination of statin therapy and pure EPA with statin therapy alone.
• The dose of EPA administered in JELIS (1.8 g daily) was lower than the EPA-equivalent dose used in REDUCE-IT (4 g daily).
• JELIS included an open-label design without a placebo group, used a low-intensity statin, and was conducted in a single country; patients also had higher levels of LDL-C at baseline (182 mg per deciliter before initiation of statin therapy) and lower baseline TG values (151 mg/deciliter) than the patients in REDUCE-IT.

• Results reported by reduce-it trial are similar to those of the JELIS which also reported beneficial effects.
• Based on the results, it can be stated that EPA rises from a dead sea of TG-lowering agents such as n-3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors.
• Cardiovascular benefits of icosapent ethyl were greater than would be predicted on the basis of the changes in TG levels.
• The results were similar regardless of whether a normal TG level was attained.

• Epidemiological studies suggest TG lowering is not associated with reduction of major cardiovascular events With previous meta-analysis not showing benefit, the results of this trial have bought along with it an element of surprise, speculation, and hope.
• Ezetimibe and PCSK9 use were very low in the trial. Whether the benefit of icosapent ethyl persists in patients receiving these drugs on the top of baseline statin therapy is unclear.
• The benefit observed with icosapent ethyl persisted even in patients with very modest TG elevation (150–200 mg/dL), and did not closely correlate with the degree of TG reduction observed, suggesting beneficial effects of icosapent ethyl which are independent of its TG-lowering effects.
• The use of mineral oil as placebo may reduce the absorption of drugs and raise levels of atherogenic lipoproteins and C-reactive protein confounding the results of placebo group suggesting the true cardiovascular effects of icosapent ethyl might be less than that of observed in this trial.
• The mechanism by which icosapent brings these beneficial effects remains a hot topic of debate. Speculated mechanisms are its anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties.

Conclusion

• After a series of trials failing to show beneficial effects with fish oils, reduce-it brings a ray of hope with respect to reduction in major adverse cardiovascular events.
• STRENGTH (Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial of Epanova (AstraZeneca), another n-3 fatty acid might provide the answers for the speculations which exist as of now.
• Based on the results, the trial makes us hopeful that the use of icosapent ethyl can significantly improve cardiovascular health in patients with statin-controlled LDL-C levels who have elevated TG levels.

References

1.	Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
2.	Libby P. Triglycerides on the rise: Should we swap seats on the seesaw? Eur Heart J 2015;36:774-6.
3.	ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.
4.	ASCEND Study Collaborative Group, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
5.	Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol 2018;3:225-34.
6.	Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
7.	Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol 2012;110:984-92.
8.	Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: Effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs 2013;13:37-46.

This article has been cited by 1 Cardiovascular Risk Reduction With Icosapent Ethyl: A Systematic Literature Review Mala Thakur,Pritpal S Sangha,Areesha Satti,Pooja N Shah Cureus. 2020; [Pubmed] | [DOI]