REDUCE-IT: 'A New Era' in CVD Prevention With High-Dose EPA

November 10, 2018

CHICAGO — A high-dose purified form of the omega-3 oil, eicosapentaenoic acid (EPA), in patients with raised triglycerides who had cardiovascular (CV) disease or diabetes and one additional risk factor has shown significant benefit, final results of the REDUCE-IT trial show.

The findings show a "robust benefit that was extremely statistically significant," said lead author Deepak L. Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts.  

Top-line results showing a 25% relative risk reduction in major adverse cardiovascular events were announced a few weeks ago by Amarin, manufacturer of the EPA product, icosapent ethyl (Vascepa), used in the study.

Today Bhatt presented more details from the trial at the American Heart Association (AHA) Scientific Sessions 2018. The study was also simultaneously published online November 10 in the New England Journal of Medicine (NEJM).

"The 25% reduction in the primary endpoint revealed previously is itself very impressive, but now we are reporting detailed results showing large consistent reductions on multiple endpoints and statistics which show that these results are extremely statistically significant and robust," Bhatt told | Medscape Cardiology.

"The primary endpoint had a P value of .00000001 — that is seven zeros. And the key secondary endpoint of hard events CV death/MI [myocardial infarction]/stroke was .0000001 — that is six zeros," Bhatt commented. "I've never seen that degree of statistical significance before in all my years of doing clinical trials, so nobody can say this is the play of chance.

"This is a great outcome for patients and should definitely change clinical practice going forward. It really moves the needle forward in that it has the potential to improve the care of millions of patients around the world," Bhatt said.

"This is the dawn of a new era, as it opens up an entirely new avenue of prevention," he added. "That is very exciting. It feels like a similar situation to that of the early statin trials in which large effects were seen across multiple endpoints and subgroups."

While the results appear to have been very well received in general, some concerns have been voiced over an increase in low-density lipoprotein (LDL) and C-reactive protein (CRP) levels in the control group, which some have suggested may have been caused by the mineral oil used as the placebo, raising the possibility this could account for part of the benefit seen in the active treatment group.

Bhatt says he does not believe the mineral oil is causing adverse effects, and the changes seen in the placebo group would account for only a very small effect on event rate, "nowhere near the 25% relative risk reduction seen with EPA."

Discussant for the study at the AHA's late-breaking clinical trials session, Carl Orringer, MD, University of Miami, Florida, was impressed with the findings.  

"This is a seminal study," he commented to | Medscape Cardiology. "These results have really got us thinking."

The results of REDUCE-IT are "strikingly positive, with a 4.4% absolute reduction in major adverse cardiovascular events and a number needed to treat to prevent one event of just 21. If we just consider the hardest endpoints of CV death, MI, or stroke, the trial showed a 3.6% absolute risk reduction with a number need to treat of 28," Orringer noted. "We rarely see such large risk reductions, and these results are indicative of a highly effective intervention.

"We have grown used to LDL lowering as the yardstick by which cardiovascular benefit is measured, but now we have an exciting new approach to reducing cardiovascular risk in patients with heart disease or diabetes who have raised triglycerides," he added.

Also commenting for | Medscape Cardiology was Jane Armitage, MD, University of Oxford, United Kingdom, coinvestigator of the recent ASCEND trial, which showed no benefit on CV risk of a lower dose (1 g daily) of mixed omega-3 oils.

"This is an interesting and extremely encouraging result in a group of patients at particularly high risk for cardiovascular events," Armitage said. "It seems to have been a well-conducted study, and by targeting people with high triglyceride levels with a treatment that lowered triglycerides and was generally safe, they have shown clear benefit. We have known that high-dose fish oils reduce triglycerides for many years, but this is the first study to show clear clinical benefit and this is important."

The trials of 1 g of fish oils per day have not shown overall cardiovascular benefit, "and typically these low doses have only a trivial impact on triglyceride levels," she added. "It seems that high doses of fish oils are needed to gain benefit at least in this high triglyceride population. How applicable the results are to the approximately two thirds of high-risk patients without raised triglyceride remains to be seen, but experience from the fibrate trials suggest that this is a treatment that needs to targeted at those with high triglycerides."

The REDUCE-IT trial enrolled 8179 patients (70% with established CV disease and 30% with diabetes and other risk factors), who were already taking statin therapy and had raised triglycerides (135 to 499 mg/dL) and LDL levels (41 to 100 mg/dL).

They were randomly assigned to 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo and followed for a median of 4.9 years.

Results showed impressive reductions in the trial's primary endpoint — a composite of CV death, MI, stroke, coronary revascularization, or unstable angina — and the key secondary endpoint of CV death, MI, or stroke.

Table. REDUCE-IT Major Results

Endpoint EPA (%) Placebo (%) Hazard Ratio (95% Confidence Interval) P Value
CV death, MI, stroke, coronary revascularization, or unstable angina (primary endpoint) 17.2 22.0 0.75 (0.68 - 0.83) <.001
CV death, MI, or stroke (key secondary endpoint) 11.2 14.8 0.74 (0.65 - 0.83) <.001
CV death 4.3 5.2 0.80 (0.66 - 0.98) .03


In the NEJM paper, the authors report that the rates of all individual and composite ischemic endpoints were significantly lower in the EPA group, except death from any cause, which just missed significance. In addition, sudden cardiac death and cardiac arrest were both was significantly reduced (hazard ratios of 0.69 and 0.52, respectively).  

In terms of adverse effects, the EPA group showed a slight increase in hospitalizations for atrial fibrillation (AF; 3.2% vs 2.1%; P = .004) and in serious bleeding events (2.7% vs 2.1%; P = .06). 

Orringer described the safety data as "encouraging." He added: "We need to be aware of the slight increase in AF but this is an acceptable risk given the large benefit seen."

Mechanism — More Than Just Lowering Triglycerides?

The high-dose EPA product was chosen for this trial because of its triglyceride-lowering effects, but Bhatt said it is unlikely that this mechanism was responsible for all of the risk reduction seen.

There was a 20% difference in triglyceride levels between the two groups (an 18.3% reduction in the EPA group and a 2.2% increase in the placebo group). Bhatt commented: "This might be expected to produce some reduction in events — maybe a 6% to 7% relative reduction — but not as large as the 25% relative reduction that we saw."

The average triglyceride level at baseline was 216 mg/dL. "That is not actually super high — many patients have levels in this range," Bhatt points out. "It may be that what we think of as being normal triglyceride levels are actually too high — like LDL in the past — and actually they could be do with a being a lot lower."

He noted a very large difference in EPA levels (358%) between the two groups.

"So I think we can say the EPA is doing something beneficial, but it may be that it has multiple mechanisms," he said. "One theory is that it may stabilize the cell membrane as we saw a clear reduction in cardiac arrest and sudden cardiac death. As well as reducing cardiovascular death and MI, which we would have hoped for, we also saw a clear reduction in stroke and in elective revascularization, which we wouldn't have necessarily expected just by lowering triglycerides. So the effect on so many different outcomes suggests it may have many different mechanisms of action."

The REDUCE-IT trial builds on the Japanese JELIS trial, which showed a 19% reduction in major adverse CV events with a 1.8-g daily dose of EPA. "Although the JELIS trial had some weaknesses, including an open-label design and no placebo, the results strongly suggested a benefit," Bhatt said. "Now we've shown a more robust result in a large trial with a strong design in a Western population."

Orringer pointed out that previous trials testing drugs that lower triglycerides, such as niacin and fenofibrate (on top of statins), have not shown a reduction in CV outcomes in the whole population, although there were suggestions of benefit in the subgroup of patients with raised triglycerides at baseline. 

"This is the first time that a major trial has tested a triglyceride-lowering drug as an add-on to statins in a population of patients all with high triglycerides."

He agrees with Bhatt that triglyceride lowering appears unlikely to explain all of the large benefit shown in the trial.

"There was a slightly higher bleeding risk in the EPA arm, so perhaps this agent has some antithrombotic action, and there was a fall in CRP suggesting an anti-inflammatory effect. The reduction in cardiac arrest and sudden death also suggests it may also cause membrane stabilization," he added.

Negative Effect of Mineral Oil Placebo?

On the controversy about the mineral oil placebo being linked to increases in LDL and CRP, Bhatt points out that the difference in LDL between the two groups was 6.6% (5 mg/dL), with LDL rising by 10.2% in the placebo group and by 3.1% in the EPA group.

"This difference would only account for a 2% to 3% relative risk reduction in major adverse cardiovascular events — at the most 4% — and we showed a 25% reduction so it wouldn't account for our results," he said.

He added that a post hoc analysis in which effects of EPA vs placebo in patients who had raised LDL, no change in LDL or a reduction in LDL showed the same degree of benefit in all three groups.  

"If the benefit of EPA was an artefact caused by increased LDL in the placebo arm, then we should have seen most of the benefit in the group who had raised LDL, but this wasn't the case," he said. "The benefit was also clearly seen in patients who had reductions in LDL."

Another point of contention is a large difference (40%) in high-sensitivity CRP (hsCRP) between the two groups. The hsCRP levels in the EPA-treated patients decreased from 2.2 mg/L at baseline to 1.8 mg/L at 2 years (a 14% reduction), whereas the placebo group showed an increase in CRP from 2.1 mg/L at baseline to 2.8 mg/L (a 32% increase) at 2 years.

Again, Bhatt says that this difference would not account for the large relative risk reduction in events shown in the trial. 

"Yes the LDL and CRP are drifting up in the control group, but we've also seen this in other trials," Bhatt said. "Some people are suggesting that mineral oil is having toxic effects. I don't believe that to be the case. It could be due to many other factors, too, and we will obviously look at this in much more detail in future analyses. If people have questions, we want to answer them."

Bhatt also pointed out that a prespecified analysis of "log-transform" hsCRP did not show an increase in the placebo group. He explained that log-transform analyses are conducted to limit the impact of outlier data;  hsCRP is known to have a high degree of variability, and extreme outliers are often seen.

"The REDUCE-IT hsCRP data fit the classic rationale for using a log transformation, with the nontransformed values showing a limited number of extreme outliers that heavily skew from normality," he said. "The log-transform analysis, which was just completed in the last couple of days, showed that the values fit a standard bell curve and show strong agreement with the line of normality. Basically, it shows when appropriately log-transformed, the hsCRP isn't increasing in the placebo arm."

One expert concerned about the LDL and CRP levels in the placebo group is Steve Nissen, MD, Cleveland Clinic, Ohio, who is leading a competing trial (STRENGTH) testing 4 g of omega-3 oil that contains a mixture of EPA and docosahexaenoic acid.

"The REDUCE-IT results are impressive but there are some caveats," he commented to | Medscape Cardiology. The results need to be understood in the context of some unanticipated effects in the placebo group, he noted.

"The main problem is the use of mineral oil as the placebo. A placebo has to be inert, but mineral oil can reduce the absorption of statins and has been shown to have inflammatory effects," he said. "Not many studies show such a large reduction of cardiovascular outcomes, and we have to make sure the results are real and try and understand how the benefit is brought about."

On the log-transform hsCRP analysis, Nissen said, the data in the manuscript that show a large increase of CRP with the mineral oil placebo "is the 'official' result. Mineral oil is probably pro-inflammatory, which is a major problem with the trial."

Icosapent ethyl is already approved in the United States for use in treating patients with very high triglycerides (≥500 mg/dL). Amarin has said it plans to file for the REDUCE-IT indication early in 2019.

"I will use this drug for the many patients that fit the REDUCE-IT criteria, but I will wait for approval for this use by the FDA," Orringer said. "I like to be cautious and wait for all the appropriate questions to be answered."

The REDUCE-IT trial was funded by Amarin. Bhatt reports grants from Amarin during the conduct of the study. Nissen is leading a competing omega-3 oil trial sponsored by Astra Zeneca. Orringer has disclosed no relevant financial relationships. 

American Heart Association (AHA) Scientific Sessions 2018. Session LBS.01. Presented November 10, 2018.

N Engl J Med. Published online November 10. Full text

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