REDUCE-IT

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Bhatt DL, et al. "Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia". The New England Journal of Medicine. 2018. epub 2018-11-10:1-12.
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Clinical Question

In patients with established atherosclerotic heart disease, or diabetes with an additional risk factor, on pre-existing statin therapy with residual hypertriglyceridemia (fasting triglyceride level 135-499 mg/dL), does icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, reduce cardiovascular events compared to placebo?

Bottom Line

In patients with established atherosclerotic heart disease, or diabetes and an additional risk factor, on pre-existing statin therapy with residual hypertriglyceridemia (fasting triglyceride level 135-499 mg/dL), icosapent ethyl was associated with an absolute 4.8% reduction in cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina), with a 0.9% absolute reduction in cardiovascular death, at 4.9 years.

Major Points

Multiple epidemiologic studies have established elevated triglyceride (TG) levels as an important risk factor for atherosclerotic cardiovascular events.[1][2] However, in randomized trials, medications that reduce TG levels, such as niacin, fibrates, and n-3 fatty acid products, have not reduced cardiovascular events when added to appropriate medical therapy including statins.[3][4] More recently, however, the JELIS trial demonstrated a 19% relative risk reduction in cardiovascular events when 1.8g daily of eicosapentaenoic acid (EPA) was added to low-intensity statin therapy [5] Although promising, the JELIS trial was limited by an open-label design, lack of placebo control, and geographic limitation to patients in Japan.

The 2018 Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) trial randomized 8,179 patients with established atherosclerotic heart disease or diabetes and an additional risk factor, on baseline statin therapy, to icosapent ethyl (a highly purified and stable EPA ethyl ester) or placebo, and assessed for major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina). The majority of enrolled individuals (70%) had established atherosclerotic heart disease. At median 4.9 years, patients randomized to receive icosapent ethyl had an absolute 4.8% lower rate of cardiovascular events compared to the placebo group. There were symmetric reductions in the key components of the primary endpoint, including a 20% relative risk reduction in cardiovascular death with icosapent ethyl. Median TG levels were reduced by 18% in the icosapent ethyl group and rose by 2.2% in the placebo group. LDL levels rose in both groups, although to a lesser degree in the icosapent ethyl group. There was a trend towards increased bleeding (2.7% with eicosapent ethyl versus 2.1% with placebo, p=0.06) with icosapent ethyl, although the absolute rates were low. There was also a modest increase in hospitalizations for atrial fibrillation or flutter with icosapent ethyl (3.1% versus 2.1%).

In summary, the REDUCE-IT trial provides confirmatory evidence that targeting residual elevated TG with icosapent ethyl reduces cardiovascular events, including cardiovascular death, in patients with either established atherosclerotic cardiovascular disease or diabetes and other risk factors. Importantly, patients enrolled in REDUCE-IT were already receiving guideline-based statin therapy and had decent control of LDL cholesterol (median LDL 74 mg/dL in treatment arm), with no reduction in LDL levels over time, suggesting that the effects of icosapent ethyl are additive to the LDL-lowering effect of statins in patients with elevated TG as a marker of residual atherosclerotic risk.

Notably, most enrolled patients (70%) had established atherosclerotic disease, and subgroup analyses suggested a somewhat attenuated benefit in true primary prevention patients, so the degree of benefit in this population is less clear and requires further study. Interestingly, the effect of icosapent ethyl was consistent across baseline TG levels (even among patients with only modest TG elevation 150-200 mg/dL), suggesting the benefit may be mediated through mechanisms outside of TG lowering effects, although whether patients without frank TG elevation would derive this benefit also requires dedicated study.

Guidelines

As of December 2018, no guidelines have been published that reflect the results of this trial.

Design

  • 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
  • Primary Outcome: Cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina

Population

Inclusion Criteria

  • Either of
    • Age ≥ 45 years with established atherosclerotic heart disease defined as ≥ 1 of the following
      • Documented multivessel coronary artery disease (≥ 50% stenosis in at least two major epicardial coronary arteries), prior MI, or hospitalization for NSTEACS
      • Documented cerebrovascular or carotid artery disease
      • Documented peripheral arterial disease
    • Age ≥ 50 years with diabetes and ≥ 1 of the following
      • Age ≥ 55 (men) or ≥ 65 (women)
      • HTN
      • Active smoker or quit within 3 months
      • HDL-C ≤ 40 (men) or ≤ 50 (women)
      • hs-CRP > 3 mg/dL
      • creatinine clearance > 30 and < 60 mL/min
      • Retinopathy
      • Micro- or macro-albuminuria
      • ABI < 0.9 without symptoms of claudication
  • Fasting TG levels ≥ 150 mg/dL and < 500 mg/dL
  • LDL-C > 40 mg/dL and ≤ 100 mg/dL and on stable statin therapy for ≥ 4 weeks prior to measurement
  • Women who are not pregnant, not breastfeeding, not planning on becoming pregnant, and using an acceptable form of birth control during the study
  • Able to provide informed consent and adhere to study schedules
  • Agree to follow and maintain a physician-recommend diet during the study

Exclusion Criteria

  • NYHA IV heart failure
  • Any life-threatening illness expected to cause death within 2 years
  • Diagnosis or laboratory evidence of active severe liver disease
  • HbA1c > 10%
  • SBP ≥ 200 mmHg or DBP ≥ 100 mmHg
  • Planned coronary revascularization or any major non-cardiac surgical procedure
  • Known familial lipoprotein lipase deficiency, apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia
  • Intolerance to statin therapy
  • Acute or chronic pancreatitis
  • Malabsorption syndrome and/or chronic diarrhea
  • Use of niacin, fibrates, OM-3 fatty acids, dietary supplements containing OM-3 fatty acids, bile acid sequestrants, or PCSK9 inhibitors unless washout period is provided
  • Use of tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic corticosteroids, HIV-protease inhibitors that have not been stable for ≥ 28 days prior to qualifying lipid measurements, cyclophosphamide, systemic retinoids
  • Known AIDS
  • Requirement for peritoneal dialysis or hemodialysis, or creatinine clearance < 30 mL/min
  • Unexplained CK elevation > 5x ULN or elevation due to known muscle disease
  • Drug or alcohol abuse within 6 months, or significant mental/psychological impairment

Baseline Characteristics

From the placebo group.

  • Demographics: Age 64.0 years, male 70.8%, white 90.2%
  • Comorbidities: BMI 30.8, DM 58.5%
  • Cardiovascular risk: secondary prevention 70.7%, primary prevention 29.3%
  • Statins: low-intensity 6.5%, moderate intensity 63.0%, high intensity 30.0%
  • Medications: ezetimibe 6.4%
  • Biomarkers: hsCRP 2.1, TG 216.0, HDL 40.0, LDL 76.0, eicosapentaenoic acid 26.1

Interventions

  • Patients randomized 1:1 to icosapent ethyl or matching placebo
  • Randomization stratified by cardiovascular risk stratum (primary versus secondary prevention), use of ezetimibe, and geographic region
  • Adjudication of all outcome events performed by an independent clinical endpoints committee unaware of trial group assignments and lipid levels
  • An independent data and safety monitoring committee oversaw the study and performed two prespecified interim efficacy reviews

Outcomes

Comparisons are icosapent ethyl versus placebo

Primary Outcomes

Cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina
705 (17.2%) vs. 901 (22.0%); HR 0.75 (95% CI 0.68-0.83); p < 0.001

Secondary Outcomes

Cardiovascular death, nonfatal MI, nonfatal stroke
459 (11.2%) vs. 606 (14.8%); HR 0.74 (95% CI 0.65-0.83); p < 0.001
Cardiovascular death
174 (4.3%) vs. 213 (5.2%); HR 0.80 (95% CI 0.66-0.98); p < 0.001
Any MI
250 (6.1%) vs. 355 (8.7%); HR 0.69 (95% CI 0.58-0.81); p < 0.001
All death
274 (6.7%) vs. 310 (7.6%); HR 0.87 (95% CI 0.74-1.02); p = NS

Safety Outcomes

Hospitalization for atrial fibrillation or flutter
3.1% vs. 2.1%, p = 0.004
Serious bleeding
2.7% vs. 2.1%, p = 0.06

Subgroup Analyses

  • The effect of icosapent ethyl was fairly consistent across pre-specified subgroups. There was a modest interaction in the effect of icosapent ethyl with age (age ≥ 65 HR 0.87 95% CI 0.76-1.00 versus age < 65 HR 0.65 95% CI 0.56-0.75, interaction p=0.004), with suggestion of greater benefit in younger individuals.

Criticisms

  • Most patients enrolled (70%) had established atherosclerotic disease, and although the subgroup interaction was not significant the benefit was somewhat attenuated in the smaller primary prevention cohort. Thus, whether there is truly substantial benefit with icosapent ethyl in the latter group is somewhat unclear.
  • Ezetimibe and PCSK9 use was very low in the trial. Whether the benefit of icosapent ethyl persists in patients receiving these drugs on 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. Thus, there may be a benefit to icosapent ethyl outside of TG-lowering effects, and potentially in patients without frank TG elevation, but this requires further study.

Funding

  • Study sponsored by Amarin Pharma, who was involved in the development of the protocol, conduct and oversight of the study, interpretation of the data, and collection and management of the data.

Further Reading

  1. Klempfner R et al. Elevated Triglyceride Level Is Independently Associated With Increased All-Cause Mortality in Patients With Established Coronary Heart Disease: Twenty-Two-Year Follow-Up of the Bezafibrate Infarction Prevention Study and Registry. Circ Cardiovasc Qual Outcomes 2016. 9:100-8.
  2. Nichols GA et al. Increased Cardiovascular Risk in Hypertriglyceridemic Patients With Statin-Controlled LDL Cholesterol. J. Clin. Endocrinol. Metab. 2018. 103:3019-3027.
  3. Bosch J et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 2012. 367:309-18.
  4. Ganda OP et al. Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management. J. Am. Coll. Cardiol. 2018. 72:330-343.
  5. Yokoyama M 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.