Icosapent Ethyl's CV Mortality Benefit Magnified in Patients With Prior MI

Ted Bosworth

April 26, 2022

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Bhatt said.

Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Boden reports no potential conflicts of interest.

This story originally appeared on MDedge.com, part of the Medscape Professional Network.


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