REDUCE-IT: Highest risk greatest benefit from icosapent ethyl

July 2024

In this latest analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), icosapent ethyl consistently reduced the risk of major adverse cardiovascular events (MACE) in patients with atherosclerotic cardiovascular disease (ASCVD) and elevated triglycerides across the range of baseline residual risk. However, absolute treatment effects were greater in patients with higher residual risk at baseline.

Burger PM, Bhatt DL, Dorresteijn JAN, et al. Effects of icosapent ethyl according to baseline residual risk in patients with atherosclerotic cardiovascular disease: results from REDUCE-IT. Eur Heart J Cardiovasc Pharmacother 2024; doi: 10.1093/ehjcvp/pvae030.

STUDY SUMMARY

Objective:

To evaluate relative and absolute treatment effects of icosapent ethyl on MACE according to individual baseline cardiovascular risk in patients with ASCVD.

 
Study design: Analysis of REDUCE-IT, a randomized, double-blind, placebo-controlled trial.
Study population: REDUCE-IT included 8,179 patients with cardiovascular disease or aged ≥50 years with diabetes and ≥1 additional risk factor and fasting triglycerides 1.69 to 5.63 mmol/L (150-499 mg/dL) with stable low-density lipoprotein cholesterol (LDL-C) levels. Patients were randomized to treatment with icosapent ethyl 2 g twice daily or matching placebo. This analysis included 5,785 patients (mean age 63.2 years, 78% male) with ASCVD at baseline. Overall, 78% of patients had coronary artery disease, 20% cerebrovascular disease and 12% peripheral artery disease (1% had abdominal aortic aneurysm). Almost all patients (96%) were on moderate to high intensity statin treatment.
Main study variable:

Primary outcome: The primary efficacy outcome of this analysis was 3-point MACE, a composite of first cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Methods:

The European Society of Cardiology guideline recommended SMART2 risk score was used to estimate baseline 5-year risk of MACE. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models including a treatment-by-risk interaction. Treatment effects were assessed stratified by quartiles of baseline risk.

RESULTS

Key risk factors and predicted 5-year risk for 3-point MACE are summarized by quartile in Table 1. Overall, levels of non-lipid cardiovascular risk factors increased across risk quartiles, whereas lipid concentrations and the use of lipid-lowering therapy remained relatively stable.

 

Table 1. Key risk factors and predicted 5-year risk for 3-point MACE

 

Risk quartile 1

(n = 1,452)

Risk quartile 2

(n = 1,442)

Risk quartile 3

(n = 1,445)

Risk quartile 4

(n = 1,446)

SMART2 predicted 5-year risk for 3-point MACE

%, mean (range)

 

9.0 (3.6-11.4)

 

13.7 (11.5-16.0)

 

19.3 (16.1-23.3)

 

33.7 (23.4-83.0)

Risk factors

 

 

 

 

Smokers, n (%)

101 (7%)

239 (17%)

281 (19%)

335 (23%)

Diabetes mellitus,              n (%)

236 (16%)

516 (36%)

703 (49%)

946 (65%)

Non-HDL-C, mmol/L

3.0±0.5

3.1±0.5

3.1±0.5

3.2±0.5

CRP, mg/L

Median (IQR)

1.3 (0.7-2.4)

2.1 (1.0-3.7)

2.4 (1.2-4.6)

3.1 (1.5-6.2)

All data in n (%) or mean±SD, unless otherwise specified.

Abbreviations: CRP C-reactive protein; HDL-C High-density lipoprotein cholesterol; IQR interquartile range

 

Over a median follow-up of 4.8 years, MACE occurred in 361 patients in the icosapent ethyl group versus 489 in the placebo group (Hazard ratio 0.72, 95% confidence interval (CI) 0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%).

 

There was no significant interaction between baseline risk and the relative treatment effects of icosapent ethyl (p = 0.106 for 3-point MACE), although there appeared to be some attenuation of relative benefit at higher baseline risk. However, absolute treatment effects of icosapent ethyl were already substantial at lowest baseline risk (3.9% absolute risk reduction [ARR]) and increased with increasing baseline risk (Table 2).

 

Table 1. Relative and absolute treatment effects of icosapent ethyl per baseline risk quartile

 

Risk quartile 1

(n = 1,452)

Risk quartile 2

(n = 1,442)

Risk quartile 3

(n = 1,445)

Risk quartile 4

(n = 1,446)

Hazard ratio (95% CI)

0.62 (0.43-0.88)

0.66 (0.48-0.92)

0.69 (0.53-0.90)

0.78 (0.63-0.96)

ARR % (95% CI)

3.9% (1.0-6.8)

4.3% (1.2-7.3)

5.1% (1.4-8.7)

5.6% (1.3-10.0)

Number Needed to Treat (NNT)

26 (15-98)

24 (14-84)

20 (11-70)

18 (10-77)
Authors’ conclusion: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE across all quartiles of baseline CVD risk. The absolute treatment effects increase with increasing baseline cardiovascular risk but are already substantial for patients in the lowest risk quartile.

COMMENT

This latest analysis from REDUCE-IT established the benefit of treatment with icosapent ethyl in ASCVD patients with elevated triglycerides across the range of baseline residual risk. Absolute benefits of treatment were comparable with those reported for patients with renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2), prior coronary artery bypass grafting and prior myocardial infarction (1-3). The findings are strengthened by the use of a validated risk model (SMART2) and by evaluating the interaction between the treatment and individual baseline risk as predicted by a multivariable risk model, rather than the use of subgroup analyses with their inherent limitations.

Importantly, the absolute benefit of icosapent ethyl increased (and NNT decreased) with increasing baseline risk, consistent with guideline recommendations for this treatment in high risk patients (4). Despite this, it should be noted that the benefit from icosapent ethyl treatment is already substantial in the lowest risk quartile (3.9% ARR). Given that the remaining life expectancy is generally longer in these lower-risk patients, it is anticipated that treatment with icosapent ethyl over a longer period of time would be expected to provide greater lifetime benefit from reduction in residual cardiovascular risk than that in high-risk patients with ASCVD and elevated triglycerides.

References 1. Majithia A, Bhatt DL, Friedman AN, et al. Benefits of icosapent ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes: REDUCE-IT RENAL. Circulation 2021;144:1750-9.
2. Verma S, Bhatt DL, Steg PG, et al. Icosapent ethyl reduces ischemic events in patients with a history of previous coronary artery bypass grafting: REDUCE-IT CABG. Circulation 2021;144:1845-55.
3. Gaba P, Bhatt DL, Steg PG, et al. Prevention of cardiovascular events and mortality with icosapent ethyl in patients with prior myocardial infarction. J Am Coll Cardiol 2022;79:1660-71.
4. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337.
Key words Key words: Residual cardiovascular risk; REDUCE-IT; absolute risk reduction; icosapent ethyl.