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REDUCE-IT

A summary of the trial by Dr Dimitrios Richter



The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) already published and presented during AHA 20181 randomized 8179 patients with established atherosclerosis or diabetes mellitus plus at least one additional risk factor, who had fasting triglyceride levels of 1.52 to 5.63 mmol/L (135–499 mg/dL) while on statin therapy, to either icosapent ethyl or placebo. The median follow-up was 4.9 years.

The primary endpoint was reduced from 22.0% to 17.2% [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68–0.83; P = 0.00000001]. This translates into a number needed to treat of only 21. The key secondary endpoint of cardiovascular death, MI, or stroke was reduced from 14.8% to 11.2% (HR 0.74, 95% CI 0.65–0.83; P = 0.0000006), which translates to a number needed to treat of only 28.

To mention that this is the first study with 4 gr of  ω3  fatty acids in coronary artery disease patients. The combination EPA/DHA which failed in various studies the last years has been used at 1gr per day. The only other study using only EPA (1.8gr/day) was JELIS2 which yielded also positive results for the reduction of cardiovascular events.

In a prespecified analyses, presented at ACC and publishes simultaneously in JACC, when examining not only first events, but also recurrent and total ischaemic events, a 30% reduction was seen using the negative binomial method (P = 0.00000000036).3

Cardiovascular death was significantly reduced in the trial. There was a trend towards lower all-cause mortality (P = 0.091), with no offsetting increase in non-cardiovascular mortality. Interestingly, there were significant reductions in sudden cardiac death (31% reduction; P = 0.026) and cardiac arrest (48% reduction; P = 0.011).

Several prespecified subgroups were examined and revealed consistent benefit in the primary and key secondary endpoints. Of note, 10.3% of REDUCE-IT patients had baseline triglycerides less than 1.69 mmol/L (150 mg/dL), and this subgroup showed a similar degree of benefit as those with higher baseline triglyceride levels.

Elevated triglycerides identify patients at increased cardiovascular risk and additionally appear to be part of the causal pathway of atherosclerosis. Icosapent ethyl is known to lower triglycerides as well as inflammatory markers. As such, this drug is an important addition to the armamentarium of preventive medicine.

Future studies will likely expand the boundaries of efficacy to include patients with even lower levels of triglycerides and even lower levels of cardiovascular risk.

References

  1. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, Jr., Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, for the REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380:11-22.
  2. 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(9567):1090-8.
  3. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT, , Juliano RA, Jiao L, Granowitz C, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM, on Behalf of the REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. 2019. doi: https://doi.org/10.1016/j.jacc.2019.02.032.