REDUCE-IT - Icosapent ethyl (EPA) to reduce CV events

Bhatt DL, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. NEJM

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.

Patients (n=8179)

  • Enrolled in 11 countries from November 2011 to August 2016

  • 19,212 screened (10,429 did not meet inclusion criteria) -> 8179 randomized

  • Included

    • Either

      • 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

    • Planned PCI/CABG

    • Prior pancreatitis; ETOH abuse in past 6 months

    • Meds:

      • 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%)

    • Labs

      • LDL-C 1.9 mmol/L, HDL-C 1.0 mmol/L, trigs 2.4 mmol/L

      • hsCRP 2.2 mg/L

    • Meds

      • Statin (100%): High-intensity (32%), moderate (62%), low (6%)

      • Ezetimibe 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)

Safety

  • Increased:

    • 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

Internal validity

  • 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%)

    • Intention-to-treat analysis.

Other considerations

  • 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)?

      • 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)

      • Antithrombotic effect?

        • Reduced MI, stroke, as well as sudden cardiac events & likely increased risk of bleeding

  • Ongoing trials with EPA +/- DHA: STRENGTH (International) , RESPECT-EPA (Japan)