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Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
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| AUTHORS |
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Mitsuhiro Yokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, The JELIS Investigators
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| PUBLICATION INFORMATION |
Journal Name: The Lancet
Volume: 369(9567)
Pages: 1090-8
Date Published: 03/31/2007
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| ABSTRACT/REVIEW |
What were the researchers trying to learn in this study?
They wanted to know if long-term use of an omega-3 supplement called eicosapentaenoic acid (EPA) is effective for preventing major coronary events in Japanese patients with high total cholesterol (hypercholesterolemia) who also take statins and normally consume a large amount of fish.
Eicosapentaenoic Acid (EPA) is a member of the omega-3 fatty acid family. EPA is required for the production of a special group of substances in the body called prostaglandins, which control blood clotting and other arterial functions. It is thought that EPA may provide a natural approach to lower blood cholesterol and triglycerides. EPA is one of the omega-3 fatty acids that is found in fish.
What did they find?
The results showed that EPA treatment reduced the frequency of major heart-related or coronary events. After an average follow-up of 4.6 years, 262 patients (2.8%) in the EPA group and 324 (3.5%) in comparison group not taking EPA experienced a heart-related event. These events included fatal or non-fatal heart attacks, unpredictable chest pain (unstable angina), angioplasty, stenting, bypass surgery or deaths due to heart-related conditions. This represents a 19% reduction in major coronary events in the EPA group as compared to the statin-only group. Unstable angina and non-fatal coronary events were significantly reduced in the EPA group.
The results indicated that blood levels of LDL cholesterol were not a significant predictor of the reduction of risk for major coronary events. Patients in both groups lowered their LDL cholesterol concentrations by an average of 25%.
When they looked at patients with a history of coronary artery disease (secondary prevention group) who were given EPA treatment, major coronary events were reduced by 19% compared to those who did not take EPA. There were 158 such events in the EPA group (8.7%) compared to 197 in the non-EPA group (10.7%).
In patients with no history of coronary artery disease (primary prevention group), EPA treatment reduced major coronary events by 18%, but this finding was not considered statistically significant. There were 104 such events in the EPA group (1.4%) compared to 127 in the non-EPA group (1.7%).
The frequency of fatal or non-fatal heart attack (myocardial infarction) was not significantly reduced in the EPA group; however, that of non-fatal coronary events including non-fatal heart attack (myocardial infarction), unstable angina, and events of angioplasty, stenting, or coronary artery bypass surgery, was significantly lower (19%) in the EPA group compared to non-EPA group.
Strokes occurred in 166 (1.8%) of the EPA patients compared to 162 (1.7%) of the non-EPA group. The frequency of restricted blood flow (ischemic) and bleeding (hemorrhagic) strokes did not differ between the two treatment groups, and neither did deaths from all causes.
Total cholesterol at the last clinic visit decreased significantly by 19% from baseline in both groups and LDL cholesterol decreased from baseline by 25% in both groups. Triglyceride decreased significantly by 9% from baseline in the EPA group and by 4% in non-EPA group. Both treatments produced only small changes in HDL cholesterol.
A quarter of patients in the EPA group had adverse side effects related to treatment, compared with about a fifth of those in the non-EPA group. A total of 1,087 EPA patients (11.7%) discontinued taking EPA because of treatment-related adverse side effects compared to 673 (7.2%) of the non-EPA group. The most common side effects were pain experienced by 1.6%, stomach and intestinal upsets (3.8%), skin rash (1.7%) and bleeding (1.1%).
Who was studied?
18,645 patients with an average total cholesterol of 6.5 mmol/L (253.5 mg/dL) or greater were recruited throughout Japan between 1996 and 1999 and remained eligible throughout the trial.
The participants consisted of 5,859 men (aged 40 to 75 years) and 12,786 postmenopausal women (aged up to 75 years), with or without coronary artery disease, which was defined as previous heart attack (myocardial infarction), procedures for cardiovascular problems (coronary interventions), or confirmed chest pain (angina pectoris).
Eligible patients for this trial had to have hypercholesterolemia (total cholesterol concentration of 6.5 mmol/L, [253.5 mg/dL]) or greater, which corresponded to a LDL cholesterol of 4.4 mmol/L (171.6 mg/dL) or greater.
Patients were excluded if they had a heart attack within the past 6 months, unpredictable chest pain (unstable angina pectoris), a history or complication of serious heart disease (such as severe arrhythmia, heart failure, cardiomyopathy, valvular disease, or congenital disease), cardiovascular reconstruction within the past 6 months, blood vessel disorders in the brain within the past 6 months, complications of serious liver or kidney disease, cancer, uncontrollable diabetes, abnormal cholesterol (hyperlipidemia) due to other disorders, and several other cardiovascular disorders that would have been confounding factors for this study.
How was the study done?
Patients were randomly assigned to receive either EPA daily with a statin (EPA group = 9,326) or statin only (non-EPA = 9,319). They were to be followed for 5-years. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal heart attack, and other nonfatal events including unstable angina, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat, meaning data from patients who did not complete the study was included.
All patients received 10 mg of pravastatin or 5 mg of simvastatin once daily as first-line treatment. These statins were available in Japan at the initiation of this study, and these doses were recommended by the Ministry of Health, Labour, and Welfare. For serious hypercholesterolemia (defined as uncontrolled), this daily dose was increased to 20 mg pravastatin or 10 mg simvastatin.
They sampled blood to measure blood levels of fatty acids (lipids) at 6 and 12 months, and then every year until the final follow-up visits.
The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting.
What did researchers know before starting this study?
Population studies and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids (omega-3 fatty acids) protects against death from coronary artery disease.
Two large-scale prevention trials involving people who had already experienced a coronary event reported that increased consumption of fish or fish-oil supplements afterwards reduced coronary deaths. However, no trials using randomly assigned treatment groups have analyzed the effects of omega-3 fatty acids on major coronary events in high-risk people who have not already experienced a coronary event.
Why did they do it?
They wanted to test the effectiveness of long-term use of eicosapentaenoic acid (EPA) for the prevention of major coronary events in hypercholesterolemic patients in Japan, knowing that their diet is high in fish. No major long-term interventional trial had yet investigated whether the addition of EPA to conventional statin treatment would yield an incremental clinical benefit. The Japan EPA Lipid Intervention Study (JELIS) tested the hypothesis that long-term use of EPA is effective in reduction of major coronary events in Japanese hypercholesterolemic patients given statins.
What did the researchers say their study results mean?
EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese patients with hypercholesterolemia. Because the study population was exclusively Japanese, the researchers noted that the results cannot be interpreted for other population groups. They said the results of this study indicate the need to further investigate whether EPA is effective for prevention of major coronary events in hypercholesterolemic patients without or with coronary artery disease in other countries.
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