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Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study

Open AccessPublished:November 08, 2016DOI:https://doi.org/10.1016/j.ijcard.2016.11.105

      Abstract

      Background

      Early initiation of EPA treatment in combination with a statin within 24 h after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (MI) reduces inflammation and ventricular arrhythmia compared with statin monotherapy; however, the impact of early initiation of EPA treatment on cardiovascular events is unclear. We determined whether early eicosapentaenoic acid (EPA) treatment in patients with acute coronary syndrome (ACS) reduces adverse cardiovascular events.

      Methods

      This prospective, open-label, blind end point–randomized trial consisted of 241 patients with ACS. Patients were randomly assigned to receive pitavastatin (2 mg/day) with or without 1800 mg/day of EPA initiated within 24 h after PCI. The primary endpoint was defined as cardiovascular events occurring within 1 year, including death from a cardiovascular cause, nonfatal stroke, nonfatal MI and revascularization.

      Results

      The mean EPA/arachidonic acid ratio at follow-up was 0.40 in the control group and 1.15 in the EPA group. A primary endpoint event occurred in 11 patients (9.2%) in the EPA group and 24 patients (20.2%) in the control group (absolute risk reduction, 11.0%; hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.87; P = 0.02). Notably, death from a cardiovascular cause at 1 year was significantly lower in the EPA group than in the control group (0.8% vs. 4.2%, P = 0.04).

      Conclusions

      Early initiation of treatment with EPA combined with statin after successful primary PCI reduced cardiovascular events after ACS.
      Clinical Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR); Registry Number, UMIN000016723; URL, http://www.umin.ac.jp/ctr/index-j.htm

      Abbreviations:

      18R-HPEPE (18R-hydroperoxyeicosapentaenoic acid), AA (arachidonic acid), ACS (acute coronary syndrome), AMI (acute myocardial infarction), ANOVA (analysis of variance), CABG (coronary artery bypass graft), CAG (coronary angiography), CI (confidence interval), COX2 (cyclooxygenase-2), CRP (C-reactive protein), DHA (docosahexaenoic acid), ECG (electrocardiogram), EPA (eicosapentaenoic acid), LAD (left anterior descending artery), GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico), HDL (high-density lipoprotein), HDL-C (HDL-cholesterol), HR (hazard ratio), IMT (intima-media thickness), JELIS (Japan EPA Lipid Intervention Study), LDL (low-density lipoprotein), LDL-C (LDL-cholesterol), MI (myocardial infarction), MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), PUFA (polyunsaturated fatty acid), PCI (percutaneous coronary intervention), RLP-C (remnant-like lipoparticle cholesterol), TIMI (thrombolysis in MI)

      Keywords

      1. Introduction

      Lowering low-density lipoprotein cholesterol (LDL-C) levels by statins reduces cardiovascular events after acute coronary syndrome (ACS) [
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      ,
      ,
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators.
      ]. In addition, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study demonstrated that early treatment with atorvastatin initiated 24–96 h after ACS reduced recurrent ischemic events [
      • Schwartz G.G.
      • Olsson A.G.
      • Ezekowitz M.D.
      • et al.
      Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
      ]. Thus, early initiation of treatment with statins after ACS is commonly accepted in clinical practice. Although aggressive treatment with statins enables attainment of targeted LDL-C levels, cardiovascular events after ACS is still prevalent [
      • Alagona Jr., P.
      Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy.
      ,
      • Nakamura T.
      • Obata J.E.
      • Hirano M.
      • et al.
      Predictive value of remnant lipoprotein for cardiovascular events in patients with coronary artery disease after achievement of LDL-cholesterol goals.
      ]. Among putative clinical therapies guarding against residual cardiovascular risks, an increased intake of omega-3 polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been reported to protect against mortality after acute myocardial infarction (MI) [,
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      ,
      • Nilsen D.W.
      • Albrektsen G.
      • Landmark K.
      • Moen S.
      • Aarsland T.
      • Woie L.
      Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
      ].
      Ingestion of omega-3 PUFAs including EPA and DHA may attenuate the inflammatory response after MI through multiple mechanisms. Omega-3 PUFAs are readily incorporated into lipid membranes and modify cellular signaling, leading to the disruption of lipid raft–related pro-inflammatory signaling [
      • Borow K.M.
      • Nelson J.R.
      • Mason R.P.
      Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.
      ]. In addition, the conversion of omega-3 PUFAs into oxygenated bioactive derivatives such as resolvins and protectins promotes the resolution of inflammation [
      • Serhan C.N.
      • Clish C.B.
      • Brannon J.
      • Colgan S.P.
      • Chiang N.
      • Gronert K.
      Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.
      ,
      • Serhan C.N.
      Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.
      ,
      • Bannenberg G.L.
      • Chiang N.
      • Ariel A.
      • et al.
      Molecular circuits of resolution: formation and actions of resolvins and protectins.
      ,
      • Arnold C.
      • Markovic M.
      • Blossey K.
      • et al.
      Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids.
      ]. Recent preclinical data have indicated that an acute inflammatory response after MI accelerates systemic atherosclerosis [
      • Takaoka M.
      • Uemura S.
      • Kawata H.
      • et al.
      Inflammatory response to acute myocardial infarction augments neointimal hyperplasia after vascular injury in a remote artery.
      ,
      • Joshi N.V.
      • Toor I.
      • Shah A.S.
      • et al.
      Systemic atherosclerotic inflammation following acute myocardial infarction: myocardial infarction begets myocardial infarction.
      ,
      • Dutta P.
      • Courties G.
      • Wei Y.
      • et al.
      Myocardial infarction accelerates atherosclerosis.
      ]. These results suggest that omega-3 PUFAs could reduce the intensity of the inflammatory response, which then influences clinical outcome after ACS.
      We have reported that early initiation of EPA treatment in patients with acute MI reduced the inflammatory response as assayed by high-sensitivity C-reactive protein (CRP) on days 3 and 4 [
      • Doi M.
      • Nosaka K.
      • Miyoshi T.
      • et al.
      Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study.
      ]. However, the impact of early EPA treatment after ACS on remote-stage clinical outcomes remains unknown. The aim of this study was to investigate whether early initiation of EPA treatment combined with a statin started within 24 h after successful primary percutaneous coronary intervention (PCI) reduced cardiovascular events compared with statin monotherapy in patients after ACS.

      2. Methods

      2.1 Study design

      This study consisted of a prospective, single-center randomized open-labeled trial (Fig. 1). The study protocol was approved by the ethics committee of Kagawa Prefectural Central Hospital, and written informed consent was obtained from all patients.

      2.2 Study population

      Between November 2010 and March 2014, 329 consecutive ACS patients treated with PCI were eligible to participate as part of the study population (Fig. 2). ACS was diagnosed according to the American College of Cardiology/American Heart Association 2007 guideline; recent-onset chest pain, associated with ST segment and/or negative T wave electrocardiogram (ECG) changes and/or positive cardiac enzymes (creatine kinase or troponin T) [
      • King 3rd, S.B.
      • Smith Jr., S.C.
      • Hirshfeld Jr., J.W.
      • et al.
      2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ]. Key exclusion criteria were cardiogenic shock, severe renal insufficiency requiring dialysis, cardiopulmonary arrest, emergent coronary artery bypass, failure of PCI, and expected prognosis less than 1 year because of cancer. Among ACS patients who enrolled in this study, 115 patients with acute myocardial patients were overlapped with our previous study, which evaluated composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month after PCI. [
      • Doi M.
      • Nosaka K.
      • Miyoshi T.
      • et al.
      Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study.
      ]
      Fig. 2.
      Fig. 2Flow diagram of this study. MI, myocardial infarction; CAG, coronary angiography; PCI, percutaneous coronary intervention; EPA, eicosapentaenoic acid.

      2.3 Acute-stage treatment and study protocol

      Before PCI, patients received 200 mg aspirin and 300 mg clopidogrel. PCI was performed with conventional techniques by the femoral or radial approach. Intravenous heparin (10,000 IU) was administered after arterial access was obtained to achieve an activated clotting time of >200 s. Intravenous heparin was continued for 48 h after angioplasty, followed by stent deployment. Post-procedural antithrombotic therapy consisted of 100 mg aspirin daily and 75 mg clopidogrel daily. No patients received glycoprotein inhibitors during the study period.
      After PCI, the patients were randomly assigned at a 1:1 ratio to two groups: patients in one group received pitavastatin at a dose of 2 mg plus EPA, which is highly (>98%) purified EPA ethyl ester (ethyl all-cis-5,8,11,14,17-icosapentaenoate), at a dose of 1800 mg (EPA group); those in the other received pitavastatin alone at a dose of 2 mg (control group). Group placement was determined by a research technician according to a computer-generated randomization plan that included stratification by gender and acute MI or unstable angina pectoris. Drugs were started within 24 h after PCI and were continued for at least 52 weeks. We checked the condition of each patient at 1, 3, 6, 9, and 12 months after the initiation of therapy. Laboratory examinations were performed for each patient at admission and 6–9 months after the initiation of therapy.

      2.4 End points

      The primary composite end point consisted of death from a cardiovascular cause, or nonfatal MI, nonfatal stroke, coronary revascularization for new lesions with either PCI or coronary artery bypass graft (CABG). We assessed the first occurrence of one of these events starting from the time of randomization. The secondary composite end point consisted of either a primary end point or hospitalization for heart failure after starting study drugs. Non-fatal acute MI was defined as having at least two of the following: chest pain of typical intensity and duration; ST segment elevation or depression of ≥1 mm in any limb lead of the ECG, of ≥2 mm in any precordial lead, or both; or at least a doubling of necrosis enzyme levels. Diagnosis of non-fatal stroke required unequivocal signs or symptoms of remaining neurological deficit, with sudden onset and a duration of >24 h.

      2.5 Data collection

      Serum lipids—total cholesterol, HDL-cholesterol (HDL-C), and triglyceride—were measured using an autoanalyzer and routine methods. LDL-C levels were calculated using Friedewald's equation. Concentrations of EPA and DHA were measured on admission (quantification by SRL Company, Tokyo, Japan). Data regarding primary and secondary outcomes were collected from clinical charts, and diagnoses were confirmed by an investigator (M.I.), who was blind to treatment allocation.

      2.6 Statistical analysis

      We assumed that the prevalence of the primary outcomes would be reduced from 15% to 5% by EPA treatment. Regarding incidence of the primary outcomes, the MIRACL study has reported that the incidence of primary outcomes including defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization was 15% in the in the atorvastatin group. In addition, regarding the reduction of outcomes with EPA treatment, our previous study showed that early EPA treatment after PCI in acute myocardial infarction (AMI) patients reduced cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month from 29% to 11%; therefore, to ensure statistical significance in the detection of reduction within this range (power 80%, α = 0.05), 322 patients were recruited into the study. Sample size was based on anticipated event rates at 1 year of 15% in the control arm [
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      ]. Our previous study showed that early EPA treatment after PCI in AMI patients reduced composite events by one-third [
      • Doi M.
      • Nosaka K.
      • Miyoshi T.
      • et al.
      Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study.
      ]. All data were tested for the normal distribution with the Kolmogorov–Smirnov test. Data that conformed to a normal distribution are summarized as the mean ± standard deviation; those that did not are shown as the median and the first and third quartile. Continuous variables were compared using a paired or unpaired Student's t-test or Mann–Whitney U-test, as appropriate. Estimates of the hazard ratios (HRs) and associated 95% confidence intervals (CIs) in comparing control and EPA groups were obtained with the use of the Cox proportional-hazards model. Changes in lipid parameters between the two groups were compared using a repeated analysis of variance (ANOVA). A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL).

      3. Results

      3.1 Study population

      Fig. 2 shows the trial profile. From the initial 329 patients with ACS, 57 patients were excluded. From the remaining 272 patients undergoing emergent PCI, 29 patients refused consent and 2 had failed PCI. Of the 241 patients who were enrolled and randomly assigned to the EPA and control groups (120 and 121, respectively), 1 patient from the EPA group was excluded because of drug eruption, and 2 patients from the control group were excluded because they did not return for a follow-up, leaving a total of 119 patients in each group. Table 1 shows the baseline characteristics for the patients and the coronary anatomy and angiographic results of the two groups, which were comparable in age, gender, prevalence of diabetes, hypertension, dyslipidemia, and acute MI. In those patients with acute MI (control, n = 77; EPA, n = 80), the two groups were also comparable in Killip class on admission, culprit vessel, onset-to-reperfusion, and final thrombolysis in MI (TIMI) flow grade.
      Table 1Baseline characteristics of patients.
      Control (n = 119)EPA (n = 119)p
      Age, years71 ± 12
      Values are expressed as the mean±SD, as the median (twenty-fifth percentile to seventy-fifth percentile), or as the number of patients followed by the percentage (in parentheses).
      70 ± 110.33
      Males90 (76)92 (77)0.72
      Body mass index, kg/m224.0 ± 3.623.8 ± 3.90.68
      Diabetes mellitus41 (34)51 (43)0.18
      Hypertension82 (69)85 (71)0.68
      Dyslipidemia77 (65)84 (71)0.33
      Current smoking38 (32)33 (28)0.48
      Prior MI7 (6)14 (12)0.11
      Prior PCI15 (13)20 (17)0.36
      Prior CABG2 (2)4 (3)0.68
      History of stroke15 (13)8 (7)0.12
      Index event
       MI without ST-segment elevation14 (12)13 (11)0.84
       MI with ST-segment elevation63 (53)67 (56)0.79
       Unstable angina42 (35)39 (33)0.68
      Lipid values
       Total cholesterol, mg/dl182 ± 41185 ± 350.6
       LDL-C, mg/dl116 (98–134)118 (98–132)0.56
       HDL-C, mg/dl43 ± 1143 ± 110.86
       Triglycerides, mg/dl105 (51–123)117 (52–122)0.59
      Fatty acids
       EPA, μg/ml65 (37–84)63 (37–81)0.85
       AA, μg/ml174 ± 50170 ± 430.57
       EPA/AA0.39 (0.21–0.51)0.38 (0.24–0.45)0.96
      Medications at discharge
       Aspirin119 (100)119 (100)1.0
       Ticlopidine113 (95)116 (97)0.31
       ARB/ACE-I58 (49)61 (51)0.7
       β-blockers70 (60)68 (58)0.79
       Statins119 (100)119 (100)1.0
      MI with or without ST-segment elevationControl (n = 77)EPA (n = 80)p
      Onset-to-reperfusion time, h5.8 (2.6–7.8)6.0 (2.5–7.5)0.96
      Infarct-related artery (LAD/non-LAD)32/4535/450.78
      Killip class (1/2/3)43/24/1045/30/50.31
      TIMI flow grade on admission (0/1 or 2/3)50/21/652/26/20.28
      TIMI flow grade after PCI (2/3)14/6312/680.59
      Peak creatine kinase, IU/l2097 (1032–3228)2104 (1243–3561)0.49
      Abbreviations: AA, arachidonic acid; ARB, angiotensin II receptor blocker; ACE-I, angiotensin conversion enzyme inhibitor; CABG, coronary artery bypass graft; EPA, eicosapentaenoic acid; LAD, left anterior descending artery; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
      a Values are expressed as the mean ± SD, as the median (twenty-fifth percentile to seventy-fifth percentile), or as the number of patients followed by the percentage (in parentheses).
      At the time of randomization, there was no significant difference in the ratio of EPA to arachidonic acid (AA) or the lipid profile before PCI (Table 1). The reduction in LDL-C was comparable between the two groups (p = 0.21 by repeated ANOVA), and the final mean LDL-C levels were 120.8 mg/dl and 117.7 mg/dl in the control and EPA groups, respectively (Fig. 3). Triglyceride did not change during the study period and remained comparable between the two groups (p = 0.61). Final mean triglyceride levels were 138.8 mg/dl and 120.8 mg/dl in the control and EPA groups, respectively. The plasma EPA concentration in the EPA group (162.8 μg/ml) was significantly higher than that of the control group (65.5 μg/ml) during follow-up (p < 0.001). Similarly, the EPA/AA ratio of the EPA group increased more than that of the control group, and this difference was maintained during follow-up (final ratios, 1.15 vs. 0.39, respectively; p < 0.001).
      Fig. 3.
      Fig. 3Serum levels of LDL-C (A) and triglyceride (B), and plasma levels of EPA (C) and EPA/AA (D). Values are the mean; error bars represent the 95% CI. Solid and broken lines indicate the EPA group and the control group, respectively.

      3.2 Primary and secondary outcomes

      Kaplan–Meier event rates for the primary end point of cardiovascular death, MI, stroke, or coronary revascularization at 1 year were 9.2% in the EPA group and 20.2% in the control group (absolute risk reduction, 11.0%; HR, 0.42; 95% CI, 0.21–087; P = 0.02) (Fig. 4A , Table 2). In terms of non-cardiovascular death, 4 patients in the control group died due to pneumonia, (n = 3) and traffic accident (n = 1) and one patients in the EPA group died due to pneumonia (n = 1). The rate of the secondary end point of cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for heart failure was significantly lower, by 10.9%, in the EPA group than in the control group (HR, 0.90; 95% CI, 0.26–0.98; p = 0.04) (Fig. 4B and Table 2). Notably, death from a cardiovascular cause at 1 year was significantly lower in the EPA group than in the control group (4.2% vs. 0.8%; absolute risk reduction, 5.9%; HR, 0.22; 95% CI, 0.47–0.99; p = 0.04) (Table 2).
      Fig. 4.
      Fig. 4Kaplan–Meier estimates of the incidence of a primary composite end point by 1 year (A) and a secondary composite endpoint of either a primary end point or hospitalization for heart failure (B).
      Table 2Occurrence of primary and secondary outcome events.
      EventControl (n = 119)EPA (n = 119)HR (95% CI)
      Primary outcome
      Death from cardiovascular causes5 (4)
      Values are expressed as the number of patients followed by the percentage (in parentheses). HRs and 95% CIs are based on Cox proportional hazard analysis.
      1 (1)0.22 (0.47–0.99)
       Sudden death2 (2)0 (0)
       MI0 (0)0 (0)
       Heart failure3 (3)1 (1)
       Stroke0 (0)0 (0)
      Nonfatal MI0 (0)1 (1)N/A
      The number of events were too small to evaluate hazard ratio.
      Nonfatal stroke4 (3)0 (0)0.01 (0.00–45.2)
      Coronary revascularization15 (13)9 (8)0.56 (0.24–1.27)
       PCI14 (12)8 (7)
       CABG1 (1)1 (1)
      Total24 (20)11 (9)0.42 (0.21–0.87)
      Secondary outcome
      Hospitalization for heart failure4 (3)3 (3)0.72 (0.16–3.24)
      Total (primary outcome and hospitalization for heart failure)28 (24)14 (12)0.48 (0.25–0.82)
      Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; EPA, eicosapentaenoic acid; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention.
      a Values are expressed as the number of patients followed by the percentage (in parentheses). HRs and 95% CIs are based on Cox proportional hazard analysis.
      b The number of events were too small to evaluate hazard ratio.

      4. Discussion

      After ACS, early initiation of a combined EPA and statin treatment within 24 h after successful primary PCI resulted in a significantly lower risk of cardiovascular events than that obtained with statin monotherapy. The reduction of primary outcomes was mainly due to a decrease in death from a cardiovascular cause. This is the first study to assess the additive effect of 1800 mg/day of EPA treatment combined with a statin on cardiovascular events after ACS compared with the outcome from therapy with a statin alone.
      Our study is different from those reported previously in several aspects. First, EPA treatment was started within 24 h after primary PCI. Previous randomized clinical trials reported the usefulness of omega-3 PUFAs for the prevention of secondary adverse cardiovascular events in post-MI patients. Results from the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) prevention trial have shown that treatment with EPA + DHA (1 g/day) lowered sudden cardiac death in patients after MI []. In the GISSI prevention trial, omega-3 PUFA was started within 3 months after MI. In the Japan EPA Lipid Intervention Study (JELIS), hypercholesterolemic patients with or without a history of cardiovascular events were administered EPA (1.8 g/day) in combination with a mild statin; the results showed a reduction in cardiovascular events for all participants [
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      ]. In our study, EPA treatment was initiated within 24 h after primary PCI, which is earlier than in the MIRACL Study that reported the benefits of early treatment with atorvastatin initiated 24–96 h after ACS [
      • Schwartz G.G.
      • Olsson A.G.
      • Ezekowitz M.D.
      • et al.
      Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
      ]. In our pilot randomized study, the EPA/AA ratio was increased 1 day after intake of EPA (1800 mg/day) and was significantly higher on the third day in EPA-treated subjects as compared with levels in control subjects (p < 0.05, data not shown). Thus, the early initiation of EPA treatment increased plasma EPA concentration within a few days. Second, all patients included in this study underwent primary PCI successfully. In the GISSI prevention trial, patients treated by thrombolysis were included. Third, pitavastatin was administered to all patients regardless of EPA treatment. A substudy of JELIS showed EPA is effective for prevention of secondary coronary artery disease, especially in individuals with prior MI [
      • Matsuzaki M.
      • Yokoyama M.
      • Saito Y.
      • et al.
      Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.
      ]. However, in JELIS, a mild statin was administered with EPA treatment. Taken together, these differences strengthen our finding that early initiation of EPA treatment is beneficial in patients undergoing primary PCI and receiving a statin after ACS.
      There are several possible mechanisms for the observed relationship between EPA treatment and the reduction of cardiovascular events after ACS. Ventricular arrhythmia after primary PCI in patients with acute MI is reported to be associated with an increased 90-day mortality [
      • Mehta R.H.
      • Harjai K.J.
      • Grines L.
      • et al.
      Sustained ventricular tachycardia or fibrillation in the cardiac catheterization laboratory among patients receiving primary percutaneous coronary intervention: incidence, predictors, and outcomes.
      ]. We have reported that early EPA treatment after primary PCI reduced the incidence of ventricular arrhythmias in the acute stage of MI [
      • Doi M.
      • Nosaka K.
      • Miyoshi T.
      • et al.
      Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study.
      ]. Thus, one explanation is that the anti-arrhythmic effect of EPA treatment early after PCI could contribute to the better prognosis at 1 year after ACS that was noted in this study. Another possibility is the anti-inflammatory effect of EPA. Pietila et al. reported that high serum CRP concentrations in acute MI patients treated with thrombolytic drugs predicted increased mortality up to 6 months [
      • Pietila K.O.
      • Harmoinen A.P.
      • Jokiniitty J.
      • Pasternack A.I.
      Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment.
      ]. Omega-3 PUFAs attenuates the inflammatory response through multiple mechanisms. Omega-3 PUFAs reduce the content of AA in membrane phospholipids, resulting in a competitive decrease in the production of AA-derived pro-inflammatory mediators [
      • Calder P.C.
      N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic.
      ]. In addition, the conversion of omega-3 PUFAs into oxygenated bioactive derivatives such as resolvins and protectins reduces inflammation [
      • Serhan C.N.
      • Clish C.B.
      • Brannon J.
      • Colgan S.P.
      • Chiang N.
      • Gronert K.
      Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.
      ,
      • Serhan C.N.
      Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.
      ,
      • Bannenberg G.L.
      • Chiang N.
      • Ariel A.
      • et al.
      Molecular circuits of resolution: formation and actions of resolvins and protectins.
      ,
      • Arnold C.
      • Markovic M.
      • Blossey K.
      • et al.
      Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of {omega}-3 fatty acids.
      ]. Also, the combination of EPA and aspirin may enhance the production of resolvins. For the generation of resolvin E1, aspirin acetylates cyclooxygenase-2 (COX2) in vascular endothelial cells and generates 18R-hydroperoxyeicosapentaenoic acid (18R-HPEPE), which is further converted via 5-lipoxygenase and additional enzymatic reactions in leukocytes to form resolvin E1 [
      • Chiang N.
      • Bermudez E.A.
      • Ridker P.M.
      • Hurwitz S.
      • Serhan C.N.
      Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.
      ]. Both the anti-arrhythmic and anti-inflammatory effects of EPA in the early phase after ACS may be beneficial for long-term outcomes.
      Several experimental studies have shown the anti-atherosclerotic effects of EPA [
      • Matsumoto M.
      • Sata M.
      • Fukuda D.
      • et al.
      Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice.
      ,
      • Nakajima K.
      • Yamashita T.
      • Kita T.
      • et al.
      Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor-deficient mice.
      ]. Oral EPA supplementation reduces atherosclerotic lesions in ApoE-deficient mice [
      • Matsumoto M.
      • Sata M.
      • Fukuda D.
      • et al.
      Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice.
      ] by inhibiting endothelial activation. This result was further supported by experimental results showing that oral EPA administration over a 3-month period inhibited monocyte adhesion to endothelial cells in vitro and decreased plasma concentrations of soluble intercellular adhesion molecule 1 [
      • Yamada H.
      • Yoshida M.
      • Nakano Y.
      • et al.
      In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion molecules by eicosapentaenoic acid.
      ]. In a clinical study, EPA treatment decreased carotid intima-media thickness (IMT) in patients with hypertriglyceridemia [
      • Mita T.
      • Watada H.
      • Ogihara T.
      • et al.
      Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes.
      ]. Nishio et al. reported that in patients undergoing PCI for ACS, treatment with EPA plus rosuvastatin for 9 months produced a large increase in fibrous cap thickness as determined with optical coherence tomography [
      • Nishio R.
      • Shinke T.
      • Otake H.
      • et al.
      Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma.
      ]. Thus, EPA treatment prevents or stabilizes coronary atherosclerotic plaques, which reduces the risk of acute plaque rupture and ACS.
      Residual cardiovascular risks remain in many patients despite statin therapy, even at high doses. The residual risks include high levels of triglyceride, very-low-density lipoprotein, and remnant-like lipoparticle cholesterol (RLP-C). Omega-3 PUFAs have beneficial effects through the reduction in the levels of these triglyceride-rich lipoproteins [
      • Pirillo A.
      • Catapano A.L.
      Omega-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia.
      ,
      • Miyoshi T.
      • Noda Y.
      • Ohno Y.
      • et al.
      Omega-3 fatty acids improve postprandial lipemia and associated endothelial dysfunction in healthy individuals - a randomized cross-over trial.
      ,
      • Ito M.K.
      Long-chain omega-3 fatty acids, fibrates and niacin as therapeutic options in the treatment of hypertriglyceridemia: a review of the literature.
      ], suggesting the potential of omega-3 PUFAs as an add-on therapy to statins. In addition, The 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults [
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ] questioned add-on therapy to statins. A recent study showed that combinatorial statin therapy after ACS reduced cardiovascular outcomes and suggested lowering LDL-C to levels below previous targets [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ]. Thus, the concept that lower LDL-C is beneficial is still important. In this respect, omega-3 PUFAs containing DHA may raise LDL-C [
      • Friedberg C.E.
      • Janssen M.J.
      • Heine R.J.
      • Grobbee D.E.
      Fish oil and glycemic control in diabetes. A meta-analysis.
      ,
      • Montori V.M.
      • Farmer A.
      • Wollan P.C.
      • Dinneen S.F.
      Fish oil supplementation in type 2 diabetes: a quantitative systematic review.
      ]. Highly purified EPA reduces atherogenic triglyceride-rich lipoproteins but does not raise LDL-C [
      • Nishio R.
      • Shinke T.
      • Otake H.
      • et al.
      Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma.
      ]. Our study supports the proposition that supplementation with pure EPA may reduce cardiovascular events in statin-treated patients.

      5. Limitations

      There are some limitations in the present study. First, this is a single-center trial and the number of patients was relatively small, although the final number in the study population did reach the predetermined target. Second, this study was not of a double-blind design. Although the investigator in charge of data collection and diagnosis was blind to treatment allocation, patients and physicians were not. Third, as clinical outcomes were followed only up to 1 year, it remains unknown whether this timing of initiation and dose of EPA is optimal to long-term prognosis in patients after ACS. To establish the clinical utility of EPA treatment in patients with ACS, a multicenter randomized trial with a larger population is warranted.

      6. Conclusion

      Early initiation of EPA combined with statin treatment started within 24 h after successful primary PCI resulted in reduced cardiovascular events; thus, EPA treatment constitutes a promising therapy after primary PCI in patients with ACS.

      Disclosures

      HI and MD receive speaker honoraria from Mochida Pharmaceutical Co., Ltd.

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