Bottom line: In patients with existing ASCVD or diabetes + other CV risk factors, isocapent ethyl (esterified EPA) reduced the risk of CV events (NNT 21) versus placebo over 4.8 years. Conversely, icosapent increased the risk of AF (NNH 72), peripheral edema (NNH 67) and possibly serious bleeding (NNH 167) versus placebo.
It remains unclear how icosapent ethyl works to reduce CV events, or whether it benefits only patients with elevated triglycerides.
Enrolled in 11 countries from November 2011 to August 2016
19,212 screened (10,429 did not meet inclusion criteria) -> 8179 randomized
Secondary prevention: 45+ y/o + established ASCVD, or
Primary prevention: 50+ y/o with diabetes + 1 other CV risk factor (male age 55+ y/o or female 65+ y/o; smoker; HTN; HDL-C <1 for men or <1.2 for women; hsCRP >3 mg/L; CrCl 30-60; retinopathy; albuminuria; ABI <0.9 without intermittent claudication)
Fasting triglyceride 1.5-5.6 mmol/L (amended in 2013 to 2.3-5.6)
LDL-C 1.0-2.6 mmol/L on a stable statin dose for at least 4 weeks
Key exclusion criteria
HF NYHA functional class 4; life-threatening condition other than CVD with expected prognosis <2y
BP >200/100 mm Hg; HbA1c >10.0%; CrCl <30 or need for peritoneal/hemodialysis
Prior pancreatitis; ETOH abuse in past 6 months
Lipid-lowering drugs other than statin +/- ezetimibe (niacin (>200 mg/d), fibrate, omega-3 supplements, bile acid sequestrants, PCSK9 inhibitors
Drugs that affect triglycerides & other lipids (tamoxifen, estrogen, progestins, thyroid replacement, systemic steroids.
Allergy to fish or shellfish
Typical baseline characteristics
64 y/o, male (71%), white (90%)
Secondary prevention (71%), primary prevention (29%)
Type 2 diabetes (58%)
LDL-C 1.9 mmol/L, HDL-C 1.0 mmol/L, trigs 2.4 mmol/L
hsCRP 2.2 mg/L
Statin (100%): High-intensity (32%), moderate (62%), low (6%)
Intervention & control
I: Icosapent ethyl 2 g PO BID
Purified formulation of eicosapentanoic acid (EPA), one of the main omega-3 fatty acids in fish oil;
Far exceeds doses found in over-the-counter (OTC) fish oil products, which are typically labeled to contain ~200 mg of EPA/capsule.
C: Matching “placebo” containing mineral oil
Results @ median 4.9 years
Reduction in primary CV outcome (composite of CV death, MI, stroke, PCI/CABG, or hospitalization for unstable angina [UA]): Icosapent ethyl 17.2% vs placebo 22.0% (NNT 21) & every individual component
Hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68-0.83
Reduction in 3-point MACE (CV death, MI, stroke): 11.2% vs 14.8% (NNT 28), HR 0.74, 95% CI 0.65-0.83
CV death: 4.3% vs 5.2% (HR 0.80, 95%CI 0.66-0.98)
Non-fatal or fatal MI: 6.1% vs 8.7% (HR 0.69, 95%CI 0.58-0.81)
Stroke: 2.4% vs 3.3% (HR 0.72, 95%CI 0.55-0.93)
Urgent/emergent PCI/CABG: 5.3% vs 7.8% (HR 0.65, 95%CI 0.55-0.78)
UA hospitalization: 2.6% vs 3.8% (HR 0.68, 95%CI 0.53-0.87)
Death from any cause: 6.7% vs 7.6% (HR 0.87, 95%CI 0.74-1.02 - inconclusive)
Atrial fibrillation: 5.3% vs 3.9% (NNH 72)
Hospitalization for afib/flutter: 3.1% vs 2.1% (NNH 100)
Peripheral edema: 6.5% vs 5.0% (NNH 67)
Possible increased risk of serious bleeding: 2.7% vs 2.1% (NNH 167; p=0.06)
No difference in GI bleeds (1.5% vs 1.1%) or CNS bleeds (0.3% vs 0.2%)
Effect on surrogate outcomes
Trigs at year 1: -0.4 vs +0.05 mmol/L (-20% [-0.5 mmol/L] from baseline vs placebo
LDL-C at year 1: +0.05 vs 0.18 mmol/L (0.13 mmol/L lower vs placebo)
hsCRP at year 2: -0.2 vs +0.5 mg/L (-38% [0.8 mg/L] lower vs placebo
Low risk of allocation, performance and detection bias
Computer-generated randomization sequence stratified by CV risk group (2o or 1o prevention), use of ezetimibe & geographic region
Allocation concealment maintained by central allocation via interactive voice response system
Blinding of patients, investigators, clinicians maintained by use of mineral oil “placebo” in control group, which is similar in appearance to the intervention
Unclear (potentially high) risk of attrition bias
Low loss to follow-up (0.2%) for death
High loss to follow-up for non-fatal outcomes, with similar frequency between groups (icosapent ethyl 9.3%, placebo 10.0%)
This is not a study of fish oil/omega-3 fatty acid supplements
High-quality evidence is exceptionally clear that fish oil/omega-3 fatty acid supplements, such as those sold at pharmacies, health food stores or over the Internet, do NOT reduce the risk of CV events in patients with or without CVD. This has been shown in a meta-analysis of 20 RCTs including 68,680 patients, as well as 2 other recent RCTs (ASCEND & VITAL).
The mechanism of action for CV event reduction with icosapent ethyl is unclear
Unlikely to be explained by triglyceride reduction
Identical CV relative risk reduction (RRR) regardless of baseline triglyceride concentration (<1.7 vs >1.7 or <2.3 vs >2.3 mmol/L);
Identical CV RRR regardless of whether achieved trigs <1.7 or 1.7+ mmol/L.
Not fully explained by LDL-C increase caused by mineral oil within placebo in comparator group
Identical RRR vs placebo patients who had LDL-C increase, decrease, or no change;
LDL-C difference of 0.13 mmol/L would only explain a ~3% RR difference based on estimates from the Cholesterol Treatment Trialists’ Collaboration meta-analysis of statins (where 1 mmol/L reduction in LDL-C associated with a ~25% RRR in CV events)
Other possible mechanisms include
Anti-inflammatory effect (or pro-inflammatory effect of mineral oil in placebo)?
hsCRP 0.8 mmol/L (38%) lower with icosapent ethyl than with mineral oil, which is similar in magnitude to hsCRP reduction with canakinumab vs placebo in the CANTOS trial
However, subgroup analysis showed benefit regardless of baseline hsCRP (<2 vs >2 mg/L). If anything, greater CV RRR with lower baseline hsCRP.
Antiarrhythmic effect, or stabilization of cellular membranes?
Reduced tertiary outcomes of cardiac arrest (HR 0.52, 95% CI 0.31-0.86) & sudden cardiac death (HR 0.69, 95% CI 0.50-0.96)
Reduced MI, stroke, as well as sudden cardiac events & likely increased risk of bleeding