Register now to R3i !
Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter

Macrovascular Residual Risk Studies

9 August 2021
News from REDUCE-IT: Icosapent ethyl reduces the risk of ischaemic stroke
A new analysis from REDUCE-IT shows that treatment with icosapent ethyl reduces the risk of a first ischaemic stroke by 36%.
Bhatt DL, Steg PG, Miller M, et al. Reduction in Ischemic Stroke With Icosapent Ethyl - Insights From REDUCE-IT. Stroke 2021; 52 (Suppl_1). INTERNATIONAL STROKE CONFERENCE 2021 ORAL ABSTRACTS
Objective: To investigate the effect of treatment with high-dose icosapent ethyl on the risk of all stroke and ischaemic stroke in statin-treated patients aged ≥45 years with established cardiovascular disease or diabetes and other cardiovascular risk factors such as elevated triglyceride (TG) levels.
Study design: REDUCE-IT was a multinational, double-blind, randomized trial.  Patients were randomized to treatment with icosapent ethyl, a purified, stable ethyl ester of eicosapentaenoic acid (4 grams/day), or placebo. Patients were followed for a median of 4.9 years.
Study population: REDUCE-IT randomized 8179 patients with controlled low-density lipoprotein cholesterol (median 75 mg/dL or 1.94 mmol/L) and elevated TG (median 216 mg/dL or 2.44 mmol/L). Overall, 71% of patients were in secondary prevention and 29% had diabetes mellitus and at least one additional risk factor.
Study outcome: First stroke, first ischaemic stroke and first haemorrhagic stroke
Methods: Prespecified and post hoc analysis
Main results:

Treatment with icosapent ethyl was associated with a significant reduction in the risk of a first stroke and first ischaemic stroke. For every 1,000 patients treated for 5 years with icosapent ethyl, approximately 14 strokes (fatal or nonfatal) were averted (p=0.008). There was no excess risk of haemorrhagic stroke with icosapent ethyl (0.3% vs 0.2%; p=0.55).

Table. Effects of icosapent ethyl on stroke


Icosapent ethyl (N=4089)

Placebo (N=4090)

Hazard ratio   (95% CI)



Event rates




0.72 (0.55-0.93)


Ischaemic stroke



0.64 (0.49-0.85)


Conclusion: In REDUCE-IT, icosapent ethyl significantly reduced the risk of ischaemic stroke, with no excess in haemorrhagic stroke, in statin-treated patients with elevated TG and atherosclerosis or diabetes.


REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) demonstrated that treatment with high-dose icosapent ethyl (4 g/day) significantly reduced cardiovascular events in high-risk primary and secondary prevention patients with elevated TG levels despite the use of statins (1). Despite recognition that effects beyond TG-lowering are likely implicated in this effect (2), the study represents a landmark for the concept that elevated TG (a surrogate for TG-rich lipoproteins and their remnants) are likely contributors to residual cardiovascular risk. These findings were also instrumental in changing guideline recommendations for the management of elevated TG in high-risk patients (3).

This latest analysis from REDUCE-IT adds to the evidence showing that high-dose icosapent ethyl also reduced the risk of stroke in statin-treated patients. In particular, the risk of a first ischaemic stroke was reduced by 36%. These findings are important given the burden that stroke poses on society, healthcare systems, and individuals and their carers (4). Globally, although the age-standardized burden of stroke has decreased, escalating case numbers (nearly doubling between 1990 and 2017) mainly due to population growth and ageing underline the need to identify reversible risk factors (5). These latest findings from REDUCE-IT suggest a role for targeting elevated TG to reduce the residual risk of stroke.

Full reporting of this analysis is awaited.


1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

2. Sharma G, Martin SS, Blumenthal RS. Effects of omega-3 fatty acids on major adverse cardiovascular events: what matters most: the drug, the dose, or the placebo? JAMA 2020;324:2262-4.

3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.

4. Khan SU, Khan MZ, Khan MU, et al. Clinical and economic burden of stroke among young, midlife, and older adults in the United States, 2002-2017. Mayo Clin Proc Innov Qual Outcomes. 2021;5:431-41.

5. Morovatdar N, Avan A, Azarpazhooh MR, et al. Secular trends of ischaemic heart disease, stroke, and dementia in high-income countries from 1990 to 2017: the Global Burden of Disease Study 2017. Neurol Sci 2021; doi: 10.1007/s10072-021-05259-2.

Key words residual cardiovascular risk; stroke; icosapent ethyl; REDUCE-IT