Effect of Icosapent-ethyl Ester (IPE) to Reduce the Residual Risk Cardiovascular Disease.

A Randomized, Double-blind, Parallel, Placebo-controlled Clinical trial will be carried out. Initially, subjects will be randomly assigned to receive the supplementation or placebo treatment for 6 months. Daily supplemental treatment (IPE) will consist of Icosapent Ethy capsules (4.0 g of EPA) taken twice a day (2.0 g/day x 2). Placebo treatment (PLACEBO) will consist of similar capsules containing corn oil instead of IPE. It has been argued that the CV benefit with IPE in certain trials (most notably REDUCEIT) related to the use of pharmaceutical grade mineral oil as comparator (Sherratt et al., 2023). Although a comprehensive review of mineral oil use in CV trials found no reproducible, consistently statistically significant effect of mineral oil on inflammatory markers, including hsCRP (Olshansky et al., 2020), the investigators opted for use of corn oil as placebo, while there is no consensus about this subject. Participants will be instructed to consume half capsules after lunch and half after dinner. During the trial, the subjects will maintain their habitual routine and diet. Prescribed drugs will be kept without any change throughout the study. The Icosapent-ethyl (IPE) will be purchased from BASF S.A., Avenida Nacoes Unidas, 14171, 04794-000 Sao Paulo, Brazil, and the oil will be encapsulated in a Brazilian company still not defined.

Inclusion criteria

individuals from both sexes, aging 45 years or older having established CVD, without contraindications to the use of IPE, receiving a stable dose of a statin (± ezetimibe) for ≥4 weeks. Women should be not pregnant, not breastfeeding, not planning on becoming pregnant, and using an acceptable form of birth control during the study (if of child-bearing potential). Biomarkers should be:

hsCRP level - mg/liter: from 1 to 4.5; Triglyceride level - mg/dl: from 150 - 500; HDL cholesterol level - mg/dl: from 30 - 50 and LDL cholesterol level - mg/dl: from 40 - 100.

Exclusion criteria

Patients with severe heart failure, active severe liver disease, a glycated hemoglobin level greater than 10.0%, a planned coronary intervention or surgery, a history of acute or chronic pancreatitis, or known hypersensitivity to fish, shellfish, or ingredients of icosapent ethyl or placebo. Autoimmune disease requiring the use of immunosuppressive therapy or current use of systemic corticosteroid therapy; Active neoplasm with indication for surgery, chemotherapy or radiation in the last 12 months (patients with a history of neoplasia and who have undergone curative surgery without the need for treatment in the last 12 months will be allowed); Inflammatory bowel disease or chronic diarrhea; Clinically significant non-transient hematological abnormalities; Renal dysfunction (GFR < 30 mL/min/1.73 m² and/or serum creatinine > 2.5 mg/dL or < 220 μmol/l); Severe liver disease (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 3x ULN in the last 6 months); Inability to sign the free and informed consent form; Participation in another clinical trial involving an investigational agent within 90 days prior to screening; Intolerance or hypersensitivity to statin therapy; History of acute or chronic pancreatitis; Malabsorption syndrome and/or chronic diarrhea; Use of non-study drug-related, non-statin, lipid-altering medications, dietary supplements, Niacin (>200 mg/d) or fibrates (unless ≥28-day washout). Any n-3 fatty acid medications (unless ≥28-day washout). Bile acid sequestrants (unless ≥7-day washout), PCSK9 inhibitors (unless ≥90-day washout); Other medications (not indicated for lipid alteration): Tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid measurements (TG and LDL-C) during screening. Cyclophosphamide or systemic retinoids during the screening period (unless ≥28- day washout) and/or plans for use during the treatment/follow-up period ; HIV-positive patients even without AIDS; Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or creatinine clearance 5 × ULN or elevation due to known muscle disease; Drug or alcohol abuse within the past 6 months, and inability/unwillingness to abstain from drug abuse and excessive alcohol consumption during the study; 16 Mental/psychological impairment or any other reason to expect patient difficulty in complying with the requirements of the study or understanding the goal and potential risks of participating in the study.

Patients with Atrial fibrillation and Bleeding related disorders.

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