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Macrovascular Residual Risk Studies

19 March 2020
More insights from REDUCE-IT: Impact on total cardiovascular events
Icosapent ethyl reduces the burden of first and total primary endpoint events in patients with type 2 diabetes mellitus and elevated triglycerides receiving background statin therapy.
Bhatt DL, Steg PG, Miller M et al. Effects of icosapent ethyl on total ischemic events. From REDUCE-IT. J Am Coll Cardiol 2019;73:2791–802.


Objective: To evaluate the effect of icosapent ethyl on total ischemic events (first and subsequent events) to better characterize the total burden of ischemic events across the overall study population.
Study design: Double-blind, placebo-controlled, randomized study. Patients were randomized 1:1 to icosapent ethyl 4 g/day (2 g twice daily with meals, n=4,089) or placebo (n=4,090).
Study population: 8,179 statin-treated patients with triglycerides (TG) ≥135 and <500 mg/dL (median baseline of 216 mg/dL; low-density lipoprotein (LDL) cholesterol >40 and ≤100 mg/dL (median baseline of 75 mg/dL); and with a history of atherosclerosis (coronary, cerebral, or peripheral) or with diabetes and other cardiovascular risk factors.
Main variables: ·  Primary endpoint: total (i.e. first plus subsequent) ischemic events consisting of the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina
· Key secondary:  total (i.e. first and subsequent) cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. 
Methods: Pre-specified analysis of REDUCE-IT, using multiple statistical models. A binomial regression model to calculate rates and rate ratios for total cardiovascular events was the primary prespecified analysis. The supporting prespecified analyses included the modified Wei-Lin-Weissfeld method (to calculate hazard ratios for the time to the first, second, or third event), and the Andersen-Gill model using a Cox proportional-hazards to model total events.
Main results:

There was a total of 2,909 primary endpoint events, 1,606 (55.2%) first events and 1,303 (44.8%) additional events. Treatment with icosapent ethyl 4 g/day was associated with significant reductions in total events (Table 1).


Table 1. Impact of icosapent on total primary and key secondary events


Rate (per 1,000 patient-years)

Rate ratio (95% confidence interval), P




Icosapent ethyl


0.70 (0.62 to 0.78); p <0.0001




Key secondary



Icosapent ethyl


0.72 (0.63 to 0.82); p < 0.0001




Authors’ conclusion: Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events.


Cardiovascular outcomes trials involving lipid-lowering treatment in patients with atherosclerotic cardiovascular disease (ASCVD) have conventionally chosen the time to first nonfatal or fatal event as the primary endpoint. However, the time to first event may not be the best representation of the total burden of ASCVD in high and very high-risk patients, as it fails to take account of the impact of recurrent cardiovascular events to patients, clinicians, and healthcare resources. Thus, there is growing support for consideration of the effect of treatment on total cardiovascular events in major outcomes studies such as those involving PCSK9 inhibitors.1,2  This in turn will provide a better estimate of the burden of disease, such as measured by patient hospitalization and metrics of the disability of recurrent ASCVCD events.3  These have relevance given that the resources available to healthcare systems are increasingly finite.

 In REDUCE-IT, treatment with icosapent ethyl 4 g/day was associated with a significant 25% relative risk reduction and a 4.8% absolute risk reduction in the primary endpoint.  The impact on the key secondary endpoint was similar (26% relative risk reduction and a 3.6% absolute risk reduction).4 In the current analysis, the REDUCE-IT investigators quantified the effect of treatment on total ischemic events. The results of this analysis showed that icosapent ethyl 4 g/day significantly reduced the burden of total ischemic events. Moreover, evidence of benefit for different endpoints, including coronary, cerebral, fatal and nonfatal events, and revascularization, implies that TG lowering alone is not likely to be responsible, lending support to the involvement of multiple mechanisms of action of icosapent ethyl in REDUCE-IT. 


1. Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER Trial. JAMA Cardiol 2019;4:613-9.

2. Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;73:387-96.

3. Szarek M, Steg PG, DiCenso D, et al. Alirocumab reduces total hospitalizations and increases days alive and out of hospital in the ODYSSEY OUTCOMES Trial. Circ Cardiovasc Qual Outcomes 2019;12(11):e005858.

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

Key words Triglycerides, REDUCE-IT, icosapent ethyl, total cardiovascular events, pre-specified analysis