The multicenter, double-blind, placebo-controlled trial enrolled 8,179 adults aged 50 years and older on statin therapy who had elevated triglycerides (135-499 mg/dL), and had been diagnosed with cardiovascular disease or diabetes and one additional risk factor for ischemic events. Participants were randomly assigned to treatment with icosapent ethyl (4 grams daily) or placebo.
Participants had a median baseline eGFR of 75 mL/min/1.73m2 (range: 17 to 123 mL/min/1.73m2). Across study visits over a median follow-up period of 4.9 years, there were no significant changes in median eGFR for the intervention or the control group.
However, icosapent ethyl therapy led to a reduced risk of the composite primary endpoint - cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina - across all levels of baseline eGFR.
"Many otherwise effective cardiovascular risk-reducing therapies seem to be less effective in patients with kidney dysfunction," said study co-author and international principal investigator Dr. Deepak Bhatt, executive director of interventional cardiovascular programs at Brigham and Women's Hospital and a professor of medicine at Harvard Medical School in Boston.
"Thus, we were happy to see that the benefits of icosapent ethyl were at least as robust in patients with kidney dysfunction as in those without it," Dr. Bhatt said by email.
Patients with a baseline eGFR of less than 60 mL/min/1.73m2 treated with icosapent ethyl had the largest absolute risk reduction for the composite primary endpoint, which occurred in 21.8% of treated patients versus 28.9% on placebo. Relative risk was significantly lower with the intervention (hazard ratio 0.71) and was similar in other eGFR categories.
Patients with low baseline eGFR also showed the largest risk difference in the secondary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, which occurred in 16.8% of the treated participants versus 22.5% on placebo (HR 0.71).
In addition, deaths among people with low baseline eGFR (7.6%) over the course of the study period were reduced by the greatest amount compared with the deaths in the placebo group (10.6%).
Patients with baseline eGFR below 60 mL/min/1.73m2 treated with icosapent ethyl had the highest number of atrial fibrillation or flutter cases (4.2% vs 3.0% with placebo) and serious bleeding (5.4% vs 3.6%). But the risk of atrial fibrillation or flutter and the risk for serious bleeding was similar across all levels of kidney function, the authors note.
People were excluded from enrollment if they had severe heart failure, planned coronary intervention or surgery, severe liver disease, hemoglobin A1c levels greater than 10%, a history of pancreatitis, or any known allergies that would be a contraindication for the intervention or placebo.
One limitation of the study is that it also excluded patients with a creatinine clearance of less than 30 mL/min or the need for renal replacement therapy. This left a very small number of patients with severe chronic kidney disease in the study population.
Another limitation, the authors note, is that they didn't routinely collect urine samples from participants, which limited the ability to report microalbuminuria or other adverse events that require specimen analysis.
"In patients with known atherosclerosis or with diabetes, physicians should screen them for eligibility for use of icosapent ethyl, including measurement of their triglyceride levels," Dr. Bhatt said. "This is especially true for patients who have kidney disease as reflected by a diminished GFR, as those patients are often at very high cardiovascular risk with relatively few effective therapies."
SOURCE: https://bit.ly/3osDHnK Circulation, online October 28, 2021.
By Lisa Rapaport
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