PDF: REDUCE-IT
(2019)Objective
Assess whether icosapent ethyl reduces major adverse cardiovascular events in statin-treated patients with elevated triglycerides and cardiovascular risk.
Study Summary
• Icosapent ethyl significantly reduced major cardiovascular events in statin-treated patients with elevated triglycerides. The benefit was consistent across subgroups, including those with diabetes and across triglyceride levels, supporting its use in high-risk patients with residual hypertriglyceridemia.
Intervention
Icosapent ethyl 2 g twice daily vs. placebo (mineral oil). All patients were on statin therapy and had triglycerides 135–499 mg/dL and LDL 41–100 mg/dL. Randomized, double-blind, placebo-controlled trial; N=8,179; median follow-up 4.9 years.
Study Design
Arms: Array
Outcome
• Primary endpoint (CV death, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina): 17.2% vs. 22.0%; HR 0.75 (95% CI 0.68–0.83); P<0.001
• Key secondary (CV death, MI, stroke): 11.2% vs. 14.8%; HR 0.74 (95% CI 0.65–0.83); P<0.001
• CV death: 4.3% vs. 5.2%; HR 0.80; P=0.03
• Nonfatal MI: 6.1% vs. 8.7%; HR 0.69; P<0.001
• Stroke: 2.4% vs. 3.3%; HR 0.72; P=0.01
• Sudden cardiac death: 1.5% vs. 2.1%; HR 0.69; P=0.03
• Atrial fibrillation/flutter hospitalization: 3.1% vs. 2.1%; P=0.004
• Serious bleeding: 2.7% vs. 2.1%; P=0.06
• Key secondary (CV death, MI, stroke): 11.2% vs. 14.8%; HR 0.74 (95% CI 0.65–0.83); P<0.001
• CV death: 4.3% vs. 5.2%; HR 0.80; P=0.03
• Nonfatal MI: 6.1% vs. 8.7%; HR 0.69; P<0.001
• Stroke: 2.4% vs. 3.3%; HR 0.72; P=0.01
• Sudden cardiac death: 1.5% vs. 2.1%; HR 0.69; P=0.03
• Atrial fibrillation/flutter hospitalization: 3.1% vs. 2.1%; P=0.004
• Serious bleeding: 2.7% vs. 2.1%; P=0.06
Bottom Line
Among patients at high cardiovascular risk with elevated triglyceride levels despite statin therapy, treatment with 4g of icosapent ethyl daily resulted in a significant 25% relative risk reduction in major adverse ischemic events, including cardiovascular death, compared with placebo.
Major Points
- REDUCE-IT established icosapent ethyl (Vascepa) as the ONLY omega-3 fatty acid preparation with proven cardiovascular benefit — fundamentally distinct from over-the-counter fish oil supplements which contain both EPA and DHA and showed no benefit in STRENGTH and VITAL trials.
- 25% reduction in the 5-point MACE composite (HR 0.75, p<0.001) and 26% reduction in the 3-point MACE (HR 0.74, p<0.001) — the largest cardiovascular risk reduction by a lipid-lowering agent beyond statins since IMPROVE-IT (6% reduction with ezetimibe).
- 8,179 statin-treated patients with triglycerides 135–499 mg/dL across 473 centers in 11 countries. Median follow-up 4.9 years. ~71% secondary prevention, ~58% diabetic — a high-risk population already on optimized statin therapy.
- Stroke specifically reduced by 28% (HR 0.72, 95% CI 0.55–0.93, p=0.01) — one of the most robust stroke prevention signals from any lipid-lowering agent, making it directly relevant to neurologists.
- Cardiovascular death significantly reduced by 20% (HR 0.80, p=0.03) — rare for a lipid-lowering trial to demonstrate mortality benefit, elevating REDUCE-IT above IMPROVE-IT (no mortality benefit) and FOURIER (no mortality benefit).
- The mineral oil placebo controversy: mineral oil may have impaired statin absorption, raised LDL, CRP, and oxidized phospholipids in the placebo group, potentially exaggerating the treatment effect. FDA advisory committee voted 16-0 for approval but noted placebo concern. REDUCE-IT mediation analysis estimated ~57% of benefit was not mediated by TG reduction.
- Mechanism likely beyond triglyceride lowering: EPA reduced TG by 18% but also reduced inflammation (hsCRP), oxidative stress, membrane stabilization, and platelet aggregation. EPA incorporates into cell membranes and atherosclerotic plaques.
- AF/flutter hospitalization increased (3.1% vs 2.1%, p=0.004) — a concerning safety signal. Serious bleeding trended higher (2.7% vs 2.1%, p=0.06). Both effects require consideration when prescribing.
- STRENGTH trial (2020) of EPA+DHA (Epanova, corn oil placebo) was NEGATIVE — supporting the hypothesis that EPA alone (not mixed EPA+DHA) is the active agent, or that the mineral oil placebo inflated REDUCE-IT's results.
- Led to FDA approval of icosapent ethyl (2019) and AHA/ACC guideline recommendation for TG ≥150 mg/dL despite statin therapy. 2019 ESC/EAS guidelines also included it. Price ~$300/month initially limited adoption.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled trial.
- Randomization
- Yes
- Blinding
- Double-blind.
- Sample Size
- 8179
- Follow-up
- Median of 4.9 years.
- Centers
- 473
- Countries
- 11 countries
Primary Outcome
Definition: A composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 22.0% (901/4090) | 17.2% (705/4089) | 0.75 (0.68 to 0.83) | <0.001 |
Limitations & Criticisms
- THE mineral oil placebo controversy: mineral oil raised LDL by ~10%, hsCRP by ~32%, and increased oxidized phospholipids in the placebo group — potentially acting as a harmful comparator that exaggerated the apparent benefit of icosapent ethyl. FDA advisory panel acknowledged this concern.
- STRENGTH trial (2020, corn oil placebo) testing EPA+DHA was NEGATIVE — raising the question of whether REDUCE-IT's results are specific to pure EPA, or whether they were inflated by the mineral oil placebo effect.
- Mediation analysis: only ~43% of the cardiovascular benefit could be attributed to TG reduction — the remaining benefit was unexplained, raising questions about the true mechanism and whether an inert-placebo trial would show the same magnitude of effect.
- Industry-sponsored (Amarin Pharma, the sole manufacturer of icosapent ethyl) — potential for commercial bias. Amarin heavily promoted the results and fought for exclusive patent protection.
- Limited ezetimibe (~6%) and no PCSK9 inhibitor use — whether icosapent ethyl provides incremental benefit on top of maximally intensive modern lipid-lowering therapy remains unknown.
- AF hospitalization increased by 48% (3.1% vs 2.1%, p=0.004) — this signal was not fully explained and is concerning for long-term safety, particularly in stroke patients where AF itself is a major risk factor.
- Serious bleeding trended higher (2.7% vs 2.1%, p=0.06) — while not reaching significance, this is concerning given the anti-platelet effects of EPA and concurrent use with antiplatelet/anticoagulant therapy in many patients.
- 90% White enrollment — limited diversity raises questions about generalizability to non-White populations with different dietary omega-3 intake and genetic variants affecting EPA metabolism.
- 4 g/day is a high dose requiring 4 capsules daily — adherence in real-world practice may be lower than in the trial. The high cost (~$300/month initially) created access barriers.
Citation
N Engl J Med 2019;380:11-22.