CV Benefit of Eicosapentaenoic Acid Seen at All eGFR Levels

Daily icosapent ethyl (Vascepa) safely and effectively reduces fatal and nonfatal ischemic events in patients with reduced kidney function, a prespecified analysis of the REDUCE-IT RENAL study shows.

“Some cardiovascular drugs are not as effective in kidney disease patients,” said investigator Deepak Bhatt, MD, MPH, from Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston.

“So we looked at patients according to their eGFR — in particular, patients with an eGFR of less than 60 mL/min per 1.73 m² — because we wanted to make sure the drug was as safe in those patients as it was in others and that they weren’t having any more side effects than others,” he told Medscape Medical News.

Icosapent ethyl, a highly purified prescription formulation of the omega-3 oil eicosapentaenoic acid, has been shown to lower triglycerides and have anti-inflammatory, antioxidative, and plaque-stabilizing properties.

In the original phase 3 Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial (REDUCE-IT), 8179 patients with cardiovascular (CV) disease or diabetes and one additional CV risk factor were randomized to treatment with icosapent ethyl 4 g a day or placebo. Patients had to have a fasting triglyceride level between 150 and 500 mg/dL to be eligible for study enrollment, and a low-density-lipoprotein (LDL) level between 41 and 100 mg/dL.

The primary end point was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina. The key secondary end point was a combination of CV death, MI, and stroke.

At a mean follow-up of 4.9 years, there was a 25% relative risk reduction and a 4.8% absolute risk reduction in the primary composite end point in the REDUCE-IT study, as previously reported by Medscape Medical News,

For the REDUCE-IT RENAL study, REDUCE-IT patients were categorized into three prespecified eGFR categories: less than 60 mL/min per 1.73 m²; 60 to less than 90 mL/min per 1.73 m², and at least 90 mL/min per 1.73 m².

In the cohort of 8179 study participants, the median baseline eGFR was 75 mL/min per 1.73 m² (range, 17 to 123 mL/min per 1.73 m²) and the mean LDL was around 70 mg/dL.

Arjun Majithia

CV event rates were higher in patients in the lowest eGFR category — less than 60 mL/min per 1.73 m² — than in the other categories. With icosapent ethyl, reductions in the primary and secondary end points were greater in the lowest category, although relative risk reductions were similar in the three categories, investigator Arjun Majithia, MD, also from Brigham and Women’s Hospital, reported during his presentation at Kidney Week 2020.

Risk for Events With Icosapent Ethyl by Baseline eGFR Category
eGFR (mL/min per 1.73 m²) Relative Risk, % Absolute Risk, % Number Needed to Treat P Value
Primary end point (composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, unstable angina)
<60 mL –29 –7.1 14 .0002
60 to <90 –20 –3.8 27 .001
≥90 –30 –4.8 21 .003
Secondary end point (combination of CV death, MI, stroke)
<60 mL –29 –5.7 18 .001
60 to <90 –23 –2.9 35 .002
≥90 –30 –3.1 32 .02

The safety profile of icosapent ethyl was comparable with that of placebo and similar in all eGFR subgroups, said Majithia. Although there was an increase in total bleeding events with active therapy, none were serious.

The predominant mode of benefit seen with icosapent ethyl in REDUCE-IT was through its effect on serum levels of eicosapentaenoic acid, as previously reported by Medscape Medical News.

“Reduction in triglycerides did account for a proportion of the benefit, but it was actually a relatively small proportion,” said Bhatt.

Patient Selection

When nephrologists examine their patients, they assess whether they need to reduce LDL cholesterol or blood pressure, whether they need to better control glucose, or whether they require specific renal therapies. From this study, “the most important message for nephrologists” is that they should also look for elevated triglyceride levels, Bhatt explained.

“If patients are already being treated as best as one can with dietary counseling and, if appropriate, a maximally tolerate dose of a statin, icosapent ethyl is something that can be easily prescribed,” he said.

“It appears to be safe and it is also highly effective in terms of reducing CV events, with a risk reduction that is really quite substantial compared with other sorts of therapies, so this really should be in their armamentarium,” he added.

The drug has been approved in a broad population for CV risk reduction by both the US Food and Drug Administration and by Health Canada.

A CV event is the most common cause of death for patients with chronic kidney disease, for patients on dialysis, and for kidney transplant patients — they die from CV complications, not from kidney failure — “so we are acutely aware of how important it is” to reduce the risk for CV disease in these patients, said Jonathan Barratt, MD, PhD, from Leicester General Hospital, United Kingdom.

“And we need to be very cautious about giving them any drug that might make that risk potentially worse,” he said.

The study was funded by Amarin. Majithia has disclosed no relevant financial relationships. Bhatt reports serving as the chair and international principal investigator for REDUCE-IT, and tht Brigham and Women’s Hospital has received research funding from Amarin. Barratt reports receiving research funding from Astellas.

Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstract FR-O18. Presented October 23, 2020.

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