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A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins

Open AccessPublished:August 29, 2017DOI:https://doi.org/10.1016/j.jjcc.2017.07.007

      Abstract

      Background

      There is a residual risk of coronary heart disease (CHD) despite intensive statin therapy for secondary prevention. The aim of this study was to investigate whether coronary plaque regression and stabilization are reinforced by the addition of eicosapentaenoic acid (EPA) to high-dose pitavastatin (PTV).

      Methods

      We enrolled 193 CHD patients who underwent percutaneous coronary intervention (PCI) in six hospitals. Patients were randomly allocated to the PTV group (PTV 4 mg/day, n = 96) or PTV/EPA group (PTV 4 mg/day and EPA 1800 mg/day, n = 97), and prospectively followed for 6–8 months. Coronary plaque volume and composition in nonstenting lesions were analyzed by integrated backscatter intravascular ultrasound (IB-IVUS).

      Results

      The PTV/EPA group showed a greater reduction in total atheroma volume compared to PTV group. IB-IVUS analyses revealed that lipid volume was significantly decreased during follow-up period in only PTV/EPA group. The efficacy of additional EPA therapy on lipid volume reduction was significantly higher in stable angina pectoris (SAP) patients compared to acute coronary syndrome patients. EPA/AA ratio was significantly improved in PTV/EPA group compared to PTV group. There was no significant difference in the incidence of major adverse cardiovascular events and side effects.

      Conclusions

      Combination EPA/PTV therapy significantly reduced coronary plaque volume compared to PTV therapy alone. Plaque stabilization was also reinforced by EPA/PTV therapy in particular SAP patients. The addition of EPA is a promising option to reduce residual CHD risk under intensive statin therapy.

      Keywords

      Introduction

      Many large-scale clinical trials have shown that statin therapy can prevent primary and secondary ischemic cardiovascular events [
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      ]. Intravascular ultrasound (IVUS) studies have revealed that high-intensity statin treatment leads to coronary artery plaque regression and stabilization [
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      • Ballantyne C.M.
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      • Chapman M.J.
      • Erbel R.M.
      • Libby P.
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      • Uno K.
      • Borgman M.
      • Wolski K.
      • Nissen S.E.
      Effect of two intensive statin regimens on progression of coronary disease.
      ,
      • Hiro T.
      • Kimura T.
      • Morimoto T.
      • Miyauchi K.
      • Nakagawa Y.
      • Yamagishi M.
      • Ozaki Y.
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      • Saito S.
      • Yamaguchi T.
      • Daida H.
      • Matsuzaki M.
      Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study).
      ,
      • Nissen S.E.
      • Nicholls S.J.
      • Sipahi I.
      • Libby P.
      • Raichlen J.S.
      • Ballantyne C.M.
      • Davignon J.
      • Erbel R.
      • Fruchart J.C.
      • Tardif J.C.
      • Schoenhagen P.
      • Crowe T.
      • Cain V.
      • Wolski K.
      • Goormastic M.
      • et al.
      Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
      ]. According to recent guidelines [
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • Goldberg A.C.
      • Gordon D.
      • Levy D.
      • Lloyd-Jones D.M.
      • McBride P.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Watson K.
      • 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.
      ], high-intensity statin therapy without a specific low-density lipoprotein cholesterol (LDL-C) goal is recommended in secondary prevention. In fact, despite achieving LDL-C ≤70 mg/dL, >20% of patients demonstrate substantial disease progression [
      • Bayturan O.
      • Kapadia S.
      • Nicholls S.J.
      • Tuzcu E.M.
      • Shao M.
      • Uno K.
      • Shreevatsa A.
      • Lavoie A.J.
      • Wolski K.
      • Schoenhagen P.
      • Nissen S.E.
      Clinical predictors of plaque progression despite very low levels of low-density lipoprotein cholesterol.
      ]. Reducing residual risk is an unmet medical need for secondary prevention with high-intensity statin therapy.
      Low serum long-chain n-3 polyunsaturated fatty acid (PUFA) levels are associated with coronary and carotid atherosclerosis progression [
      • Amano T.
      • Matsubara T.
      • Uetani T.
      • Kato M.
      • Kato B.
      • Yoshida T.
      • Harada K.
      • Kumagai S.
      • Kunimura A.
      • Shinbo Y.
      • Kitagawa K.
      • Ishii H.
      • Murohara T.
      Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study.
      ,
      • Sekikawa A.
      • Curb J.D.
      • Ueshima H.
      • El-Saed A.
      • Kadowaki T.
      • Abbott R.D.
      • Evans R.W.
      • Rodriguez B.L.
      • Okamura T.
      • Sutton-Tyrrell K.
      • Nakamura Y.
      • Masaki K.
      • Edmundowicz D.
      • Kashiwagi A.
      • Willcox B.J.
      • et al.
      Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study.
      ]. Epidemiological and clinical studies showed that long-term intake of long-chain n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can reduce morbidity and mortality due to coronary heart disease (CHD) [
      • Daviglus M.L.
      • Stamler J.
      • Orencia A.J.
      • Dyer A.R.
      • Liu K.
      • Greenland P.
      • Walsh M.K.
      • Morris D.
      • Shekelle R.B.
      Fish consumption and the 30-year risk of fatal myocardial infarction.
      ,
      • Kromhout D.
      • Bosschieter E.B.
      • de Lezenne Coulander C.
      The inverse relation between fish consumption and 20-year mortality from coronary heart disease.
      ]. In the JELIS trial [
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • Matsuzawa Y.
      • Saito Y.
      • Ishikawa Y.
      • Oikawa S.
      • Sasaki J.
      • Hishida H.
      • Itakura H.
      • Kita T.
      • Kitabatake A.
      • Nakaya N.
      • Sakata T.
      • Shimada K.
      • et al.
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      ], the addition of EPA to statin therapy was effective in primary and secondary CHD prevention. However, it remains to be determined whether the addition of EPA therapy can further prevent coronary atherosclerosis in CHD patients receiving high intensity statin therapy.
      IVUS-based evaluation of coronary atherosclerosis progression-regression is reportedly a feasible surrogate endpoint to predict future cardiovascular events [
      • Dohi T.
      • Miyauchi K.
      • Okazaki S.
      • Yokoyama T.
      • Yanagisawa N.
      • Tamura H.
      • Kojima T.
      • Yokoyama K.
      • Kurata T.
      • Daida H.
      Plaque regression determined by intravascular ultrasound predicts long-term outcomes of patients with acute coronary syndrome.
      ,
      • Nicholls S.J.
      • Hsu A.
      • Wolski K.
      • Hu B.
      • Bayturan O.
      • Lavoie A.
      • Uno K.
      • Tuzcu E.M.
      • Nissen S.E.
      Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
      ]. In the present study, we used integrated backscatter IVUS (IB-IVUS) to investigate whether coronary plaque regression and stabilization are reinforced by the addition of EPA to high-dose pitavastatin (PTV) therapy.

      Methods

      Study design

      The CHERRY (combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography) study was a prospective, randomized, non-blinded, parallel, multicenter study to investigate the effect of adding EPA to high-dose PTV on coronary plaque analyzed by IB-IVUS. A detailed study protocol was published previously [
      • Watanabe T.
      • Miyamoto T.
      • Miyasita T.
      • Shishido T.
      • Arimoto T.
      • Takahashi H.
      • Nishiyama S.
      • Hirono O.
      • Matsui M.
      • Sugawara S.
      • Ikeno E.
      • Miyawaki H.
      • Akira F.
      • Kubota I.
      Combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography (CHERRY study) – rationale and design.
      ]. All procedures were performed in accordance with the Helsinki declaration. This study was approved by each institutional ethics committee, and written informed consent was obtained from each patient. This study was registered at University Hospital Medical Information Network (UMIN ID: 000002815).
      The primary endpoint was the change in coronary plaque tissue characteristics as evaluated by IB-IVUS. The secondary endpoints included: (1) plaque volume; (2) the changes in total cholesterol (TC), LDL-C, triglyceride, high-density lipoprotein-cholesterol (HDL-C), malonyldialdehyde LDL (MDA-LDL), remnant-like particle-cholesterol (RLP-C), lipoprotein (a), and apolipoproteins; (3) EPA/arachidonic acid (AA) levels; (4) high-sensitivity C-reactive protein (hs-CRP); and (5) the incidence of major adverse cardiovascular events (MACE) defined as cardiac death, nonfatal myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass grafting. Major bleeding was classified according to definition of International Society on Thrombosis and Haemostasis [
      • Schulman S.
      • Kearon C.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      ].

      Patient enrollment and randomization

      Patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) who satisfied the previously described inclusion and exclusion criteria were selected after successful PCI under IVUS guidance [
      • Watanabe T.
      • Miyamoto T.
      • Miyasita T.
      • Shishido T.
      • Arimoto T.
      • Takahashi H.
      • Nishiyama S.
      • Hirono O.
      • Matsui M.
      • Sugawara S.
      • Ikeno E.
      • Miyawaki H.
      • Akira F.
      • Kubota I.
      Combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography (CHERRY study) – rationale and design.
      ]. Briefly, patients who gave written consent after being provided with the details of clinical trial participation were included. Patients with familial hypercholesterolemia, hepatic dysfunction, or renal dysfunction (serum creatinine ≥2.0 mg/dL) were excluded. Patients were randomized for PTV therapy (4 mg/day) and PTV/EPA therapy (PTV 4 mg/day and EPA 1800 mg/day) by controlling for their diagnosis and the presence of diabetes mellitus. All patients received aspirin (100–200 mg/day) and clopidogrel (75 mg/day) for at least 6 months after PCI. The IB-IVUS examination was performed at baseline and the follow-up visit (6–8 months after PCI).

      Laboratory assessment

      Blood examinations were performed at baseline and follow-up at 6–8 months. Serum lipids, RLP-C, apolipoproteins, and hs-CRP were measured using routine laboratory methods. MDA-LDL and fatty acid fractions were measured at SRL Co., Ltd. (Tokyo, Japan).

      IVUS examination

      We performed grayscale and IB-IVUS examinations with a 40-MHz, 5-Fr IVUS imaging catheter (ViewIT™, Terumo, Tokyo, Japan) at baseline and follow-up. IVUS images were captured for as long as possible at a speed of 0.5 mm/s using a motorized pull-back system after intracoronary injection of isosorbide dinitrate.

      IVUS analysis

      IVUS and coronary angiographic images were analyzed at the core laboratory by experienced investigators using an IVUS imaging system (VISIWAVE or VISIATRAS, Terumo). Baseline and follow-up images were reviewed, and target segments were selected. One target segment was determined at a non-PCI site (>5 mm proximal or distal to the stenting site) with a reproducible index side branch on the PCI vessel. Grayscale IVUS analysis was performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement, and Reporting of Intravascular Ultrasound Studies [
      • Mintz G.S.
      • Nissen S.E.
      • Anderson W.D.
      • Bailey S.R.
      • Erbel R.
      • Fitzgerald P.J.
      • Pinto F.J.
      • Rosenfield K.
      • Siegel R.J.
      • Tuzcu E.M.
      • Yock P.G.
      American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.
      ]. Plaque analysis was performed in the target segment at 1-mm axial intervals. The external elastic membrane (EEM) cross-section area (CSA), lumen CSA, and plaque plus media CSA were manually measured in each slice. Plaque volume was calculated as the sum of plaque plus media in each CSA according to Simpson's rule. IB data for each tissue component were calculated as average power levels using a fast Fourier transform, measured in decibels, of the frequency component of backscattered signals from a small volume of tissue. We applied the manufacturer's default setting based on previous data [
      • Kawasaki M.
      • Takatsu H.
      • Noda T.
      • Sano K.
      • Ito Y.
      • Hayakawa K.
      • Tsuchiya K.
      • Arai M.
      • Nishigaki K.
      • Takemura G.
      • Minatoguchi S.
      • Fujiwara T.
      • Fujiwara H.
      In vivo quantitative tissue characterization of human coronary arterial plaques by use of integrated backscatter intravascular ultrasound and comparison with angioscopic findings.
      ]. Plaque components are classified into four color-coded images by IB scores measuring backscattered signals from the tissue: blue (lipid), green (fibrosis), yellow (dense fibrosis), and red (calcification) [
      • Okubo M.
      • Kawasaki M.
      • Ishihara Y.
      • Takeyama U.
      • Yasuda S.
      • Kubota T.
      • Tanaka S.
      • Yamaki T.
      • Ojio S.
      • Nishigaki K.
      • Takemura G.
      • Saio M.
      • Takami T.
      • Fujiwara H.
      • Minatoguchi S.
      Tissue characterization of coronary plaques: comparison of integrated backscatter intravascular ultrasound with virtual histology intravascular ultrasound.
      ]. Volumetric IB-IVUS analysis was performed to calculate lipid volume, fibrosis volume, dense fibrosis volume, and calcification volume from the sum of lipid, fibrosis, dense fibrosis, and calcification in each CSA.
      Percent atheroma volume (PAV) was calculated as follows:
      PAV=(EEM areaLumen area)EEM area×100


      Normalized total atheroma volume (TAV) was calculated as follows:
      NormalizedTAV=(EEM areaLumen area)×median no. of analyzed frames in the populationsno. of analyzed frames in each individual


      Percent change in plaque component volume was calculated as follows:
      Percent change in plaque component volume=Absolute change in plaque component volumePlaque component volume at baseline×100


      Plaque volume regression and lipid volume reduction were defined as decreases in atheroma and lipid volumes from baseline.

      Statistical analysis

      The necessary sample size was estimated based on the previously published effect of EPA or fish oil supplementation on carotid plaque regression [
      • Watanabe T.
      • Miyamoto T.
      • Miyasita T.
      • Shishido T.
      • Arimoto T.
      • Takahashi H.
      • Nishiyama S.
      • Hirono O.
      • Matsui M.
      • Sugawara S.
      • Ikeno E.
      • Miyawaki H.
      • Akira F.
      • Kubota I.
      Combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography (CHERRY study) – rationale and design.
      ], since there is no information about the additive effect of EPA and high-dose PTV on coronary plaques. Continuous variables are presented as means ± standard deviations (SD), except for those data not distributed normally, which are instead presented as medians and interquartile ranges. The unpaired Student's t-test or Mann–Whitney U-test was used to compare continuous variables between two groups according to their distributions. The chi-square test or Fisher exact test was used to compare categorical variables between two groups. The changes in each parameter between baseline and follow-up were compared by the paired Student's t-test or Wilcoxon signed-rank test for normally or not normally distributed data, respectively. Correlations between two continuous variables were analyzed by simple linear regression analysis. Since the Kolmogorov–Smirnov test showed that serum EPA and AA were log-normally distributed, we used common logarithmic-transformed EPA and AA for linear regression analysis. An interaction test was performed to assess the heterogeneity of treatment effects between each subgroup. Both safety and primary analyses were conducted on the intention-to-treat population. A value of p < 0.05 was statistically significant. Statistical analysis was performed using a standard software package (JMP version 9; SAS Institute Inc., Cary, NC, USA).

      Results

      Patient characteristics

      A total of 241 patients were enrolled between September 2009 and July 2014. All patients underwent successful PCI under IB-IVUS guidance. They were randomly allocated to PTV group (n = 119) or PTV/EPA group (n = 122) and prospectively followed for 6–8 months. After excluding 2 patients in the PTV group and 1 patient in the PTV/EPA group who were lost to follow-up, 117 and 121 in the PTV and PTV/EPA groups, respectively, were included in the safety analysis set. Since 21 in PTV group and 24 in PTV/EPA group did not complete endpoint assessment at follow-up, the remaining 96 and 97 patients in the PTV and PTV/EPA groups, respectively, were included in the primary analysis set. There was no difference in follow-up periods between the PTV and PTV/EPA groups (7.8 ± 1.5 months vs. 8.0 ± 1.5 months, p = 0.357). There were no significant differences in baseline demographics or characteristics between the two groups (Table 1). There were 34 (35%) patients with ACS in the PTV group and 40 (41%) in the PTV/EPA group. Among 74 ACS patients, there were 41 (55%) patients with ST elevation MI. There were 34 (35%) and 35 (36%) patients with diabetes mellitus in the PTV and PTV/EPA groups, respectively. Prior to randomization, 47 (49%) patients in the PTV group and 41 (42%) in PTV/EPA group had already used statins.
      Table 1Comparison of clinical characteristics between PTV group and PTV/EPA group.
      PTV group (n = 96)PTV/EPA group (n = 97)p-Value
      Age, years68 ± 1067 ± 100.853
      Males81 (84)78 (80)0.470
      Body mass index, kg/m223.9 ± 2.923.7 ± 3.10.704
      Smoking
       Current smoker20 (21)31 (32)0.079
       Former smoker30 (31)30 (31)0.961
       Pack-years35.5 (21.4, 47.8)40.0 (23.8, 50)0.726
      ACS34 (35)40 (41)0.406
       STEMI17 (18)24 (25)0.231
       NSTEMI3 (3)1 (1)0.369
      Fisher exact test.
       Unstable angina pectoris14 (15)15 (15)0.864
      Clinical history
       Hypertension62 (65)66 (68)0.611
       Dyslipidemia59 (61)64 (66)0.514
       Diabetes mellitus34 (35)35 (36)0.923
        Insulin use8 (8)6 (6)0.592
      Fisher exact test.
       Prior intervention25 (26)19 (20)0.285
        Atrial fibrillation5 (5)8 (8)0.568
      Fisher exact test.
      Concomitant medications
       Statins47 (49)41 (42)0.351
       Anti-coagulants8 (8)10 (10)0.805
      Fisher exact test.
        ACE-Is37 (39)42 (43)0.502
        ARBs27 (28)32 (33)0.463
       β-Blockers31 (32)38 (39)0.318
      Culprit vessel
       LMT/RCA/LAD/LCx0/33/45/181/28/52/160.491
      Fisher exact test.
      Type of stent
       BMS/DES27/6926/710.837
      Data are expressed as number (percentage) for categorical variables and mean ± standard deviation or median (interquartile range) for continuous variables. Categorical variables with no specification were compared by chi-square test.
      ACS, acute coronary syndrome; STEMI, ST-elevation myocardial infarction; NSTEMI, non ST-elevation myocardial infarction; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LMT, left main trunk; RCA, right coronary artery; LAD, left anterior descending artery; LCx, left circumflex artery; BMS, bare metal stent; DES, drug eluting stent.
      a Fisher exact test.

      IVUS analysis

      The changes in TAV and tissue characteristics were evaluated by IB-IVUS (Table 2 and Supplemental Table 1). As shown in Fig. 1A , the volumetric IVUS analyses showed that normalized TAV was significantly reduced in both groups. PTV/EPA group achieved superior TAV reduction to PTV group (Fig. 1B). Furthermore, the prevalence of TAV regression was significantly higher in the PTV/EPA group than in the PTV group (81% vs. 61%, p = 0.002). To assess which component is reduced by EPA administration, tissue characteristics were evaluated by IB-IVUS. Lipid volume was only significantly decreased during the follow-up period in the PTV/EPA group, while fibrosis volume was significantly decreased in both groups (Fig. 2). Dense fibrosis and calcification volumes did not change in either group.
      Table 2IVUS measurements and changes in each parameter.
      Baselinep-ValueFollow-upp-Value
      PTV group (n = 96)PTV/EPA group (n = 97)PTV group (n = 96)PTV/EPA group (n = 97)
      Lesion length, mm10.0 (7.0, 14.8)10.0 (7.0, 14.5)0.985
      Stent proximal analysis58 (60)57 (59)0.815
      EEM volume, mm3157.9 (107.3, 232.2)145.2 (104.2, 210.7)0.735144.6 (106.1, 232.2)140.8 (102.0, 194.6)0.419
      Lumen volume, mm373.8 (53.5, 106.0)71.0 (52.3, 108.3)0.76877.2 (52.0, 108.1)74.5 (53.2, 106.2)0.798
      Plaque volume, mm370.0 (43.9, 121.2)75.9 (45.6, 102.9)0.91167.4 (44.0, 113.9)63.6 (41.4, 89.3)0.404
      Normalized TAV, mm374.2 (57.5, 96.8)74.2 (55.9, 99.2)0.82568.3 (55.2, 88.1)66.4 (47.9, 88.0)0.357
      PAV, %49.4 (42.2, 56.7)48.8 (42.3, 56.0)0.99747.9 (40.8, 54.3)44.4 (38.7, 51.7)0.143
      IB-IVUS analysis
       Lipid volume, mm342.7 (22.4, 65.0)38.7 (21.6, 59.5)0.49939.3 (22.1, 67.4)36.1 (19.0, 55.7)0.373
       Fibrosis volume, mm326.6 (16.7, 44.5)29.8 (18.4, 40.4)0.53925.0 (15.5, 41.7)23.4 (14.8, 34.9)0.439
       Dense fibrosis volume, mm32.7 (1.3, 5.3)2.5 (1.4, 4.1)0.6812.5 (1.4, 4.6)2.2 (0.9, 4.1)0.162
       Calcification volume, mm30.5 (0.2, 1.3)0.4 (0.2, 1.0)0.3040.6 (0.2, 1.3)0.4 (0.1, 1.2)0.093
      Data are expressed as median (interquartile range) for continuous variables.
      PTV, pitavastatin; EPA, eicosapentaenoic acid; TAV, total atheroma volume; PAV, percent atheroma volume; EEM, external elastic membrane; IB-IVUS, integrated backscatter intravascular ultrasound.
      Figure thumbnail gr1
      Fig. 1(A) Comparisons of total atheroma volume between baseline and follow-up in each group. (B) Comparison of TAV reduction between PTV and PTV/EPA group. PTV, pitavastatin; EPA, eicosapentaenoic acid; TAV, total atheroma volume.
      Figure thumbnail gr2
      Fig. 2Volumetric changes in the plaque components based on integrated backscatter intravascular ultrasound examinations performed at baseline and follow-up at 6–8 months. Data are expressed as median (interquartile range). *p < 0.05 vs. baseline (Wilcoxon signed-rank test). PTV, pitavastatin; EPA, eicosapentaenoic acid.
      Fig. 3 shows the efficacy of additional EPA therapy on lipid volume reduction in each subgroup according to the baseline profile. Additional EPA therapy had a significantly favorable effect on lipid volume reduction in patients with SAP (odds ratio 2.08, 95% confidence interval 1.005–4.39) compared to those with ACS (interaction p = 0.047). There was no heterogeneity in the efficacy of additional EPA therapy on lipid volume reduction in any other subgroup. The prevalence of lipid volume reduction was higher in ACS patients than in SAP patients (67.5% vs. 54%). There were no significant differences in baseline plaque volume, normalized TAV and IB-IVUS data between SAP and ACS patients (Supplemental Table 2). The prevalence of lipid volume reduction was significantly higher in PTV/EPA group than in PTV group in SAP patients (63% vs. 45%, chi-square test, p = 0.048). Although the changes in lipid volume reduction were significantly higher in PTV/EPA group than in PTV group in SAP patients, there was no difference in changes in lipid volume reduction between two groups in ACS patients (Fig. 4A ). TAV regression tended to be larger in ACS patients than in SAP patients (Supplemental Figure 1). While a similar extent of TAV regression was observed between PTV and PTV/EPA groups in ACS patients, TAV regression tended to be larger in PTV/EPA group than in PTV group in SAP patients. There was no statistical significance because of small sample size for each subgroup. Simple linear regression analyses revealed that the on-treatment log EPA/log AA ratio was inversely correlated with the percent change in lipid volume in patients with SAP (r = −0.277, p = 0.006; Fig. 4B). There was no significant correlation between percent change in lipid volume and on-treatment LDL-C level in either ACS or SAP patients. Volumetric changes in the plaque components and representative IVUS images from each group are presented in Supplemental Figure 2.
      Figure thumbnail gr3
      Fig. 3The effect of additional EPA therapy on lipid volume reduction from baseline in each subgroup. Odds ratios (95% confidence intervals) were evaluated by univariate logistic analysis in each subgroup. ACS, acute coronary syndrome; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SAP, stable angina pectoris; PTV, pitavastatin; EPA, eicosapentaenoic acid.
      Figure thumbnail gr4
      Fig. 4(A) Changes in lipid volume between the two groups in both SAP and ACS patients. (B) Simple linear regression analysis for the correlation between percent change in lipid volume and on-treatment log EPA/log AA ratio or LDL-C level. The upper and lower panels show the correlations in patients with SAP. AA, arachidonic acid; ACS, acute coronary syndrome; LDL-C, low-density lipoprotein cholesterol; SAP, stable angina pectoris; PTV, pitavastatin; EPA, eicosapentaenoic acid.
      IVUS analyses were performed by two independent physicians. Intra- and interobserver variabilities in volumetric IB-IVUS analyses were assessed for lipid volume and fibrosis volume in 30 randomly selected plaques that were repeatedly measured by the same analyst and measured once each by two independent analysts. The mean ± SD length of analyzed plaques was 9.7 ± 4.2 mm. Intraobserver correlations and mean ± SD differences in each volume were r = 0.997 and 0.51 ± 2.11 mm3 and r = 0.994 and 0.17 ± 2.41 mm3, respectively. The interobserver correlations and mean ± SD differences in each volume were r = 0.978 and −1.42 ± 5.43 mm3 and r= 0.975 and −1.20 ± 5.64 mm3, respectively.

      Laboratory results

      The only differences in baseline lipid profiles between the two groups were for lipoprotein (a) levels and the DHA/AA ratio (Table 3). TC, LDL-C, and apolipoprotein-B levels were significantly decreased, and apolipoprotein-A1 but not HDL-C was significantly increased in both groups. RLP-C was only significantly decreased in the PTV/EPA group (p < 0.001 compared with baseline). However, the percent change in RLP-C in the PTV/EPA group was not statistically different from that of the PTV group (−15% vs. 0%, p = 0.213). The EPA/AA and DHA/AA ratios were significantly decreased in PTV group since the AA level was significantly increased. On the other hand, the EPA and AA levels were significantly increased and decreased in the PTV/EPA group, respectively. Consequently, the EPA/AA ratio was significantly increased in the PTV/EPA group. Serum hs-CRP levels were significantly decreased in both groups.
      Table 3Laboratory parameters at baseline and follow-up in each group.
      Baselinep-ValueFollow-upp-ValuePercent change (%)
      PTV group (n = 96)PTV/EPA group (n = 97)PTV group (n = 96)PTV/EPA group (n = 97)PTV group (n = 96)p-Value compared with baselinePTV/EPA group (n = 97)p-Value compared with baselinep-Value between groups
      TC, mg/dL165.6 ± 37.4174.9 ± 40.50.100142.6 ± 27.5144.1 ± 33.40.730−11.5 ± 18.8<0.001−15.2 ± 21.2<0.0010.202
      LDL-C, mg/dL98.6 ± 32.1107.1 ± 34.30.08076.0 ± 23.676.9 ± 26.20.796−17.6 ± 33.5<0.001−23.6 ± 29.9<0.0010.188
      Triglyceride, mg/dL105.0 (81.0, 140.5)111.0 (76.0, 137.5)0.947101.5 (81.3, 143.3)102.0 (76.0, 136.5)0.352−1.5 (−19.8, 44.7)0.9302.9 (−24.1, 27.8)0.5180.505
      HDL-C, mg/dL47.5 ± 12.249.8 ± 13.00.20448.7 ± 11.350.3 ± 12.10.3474.8 ± 20.70.2143.1 ± 20.20.6710.566
      MDA-LDL, U/l80.5 (57.3, 103.8)81.0 (58.0, 98.3)0.61876.0 (60.5, 102.5)77.0 (57.0, 93.0)0.414−2 (−25.5, 26.7)0.965−6.9 (−24.8, 15.6)0.1250.318
      RLP-C, mg/dL4.2 (2.7, 6.8)4.7 (2.6, 7.7)0.6344.1 (2.6, 6.8)3.7 (2.5, 5.3)0.4000 (−43.8, 49.9)0.496−15 (−40.1, 15.1)<0.0010.213
      Lipoprotein (a), mg/l17.0 (8.6, 23.6)20.0 (11.3, 34.0)0.01216.8 (10.0, 24.0)20.3 (12.3, 37.0)0.0540 (−21.7, 23.3)0.7940 (−16.7, 27.7)0.5750.659
      Apo A1, mg/dL111.6 ± 19.7111.2 ± 20.00.893126.3 ± 23.4122.5 ± 24.50.30514.7 ± 17.7<0.00112.1 ± 22.7<0.0010.433
      Apo B, mg/dL77.1 ± 20.880.8 ± 23.60.26367.6 ± 16.371.5 ± 20.30.169−9.9 ± 25.4<0.001−9.3 ± 23.7<0.0010.880
      DHA, μg/ml113.7 (92.3, 139.9)114.2 (87.2, 143.3)0.533115.7 (93.6, 143.5)98.7 (83.4, 123.0)0.006−5.2 (−18.7, 21.2)0.547−12.6 (−27.3, 7.6)<0.0010.028
      EPA, μg/ml61.2 (43.3, 90.5)62.5 (41.0, 91.7)0.92062.4 (43.5, 86.2)165.6 (133.4, 206.5)<0.0010.1 (−30.2, 31.1)0.800135.5 (78.9, 265.8)<0.001<0.001
      AA, μg/dL137.0 (113.5, 162.3)149.9 (119.3, 180.9)0.052156.2 (120.9, 186.9)134.0 (107.0, 169.8)0.02413.0 (−5.6, 27.0)<0.001−9.9 (−18.3, 4.4)<0.001<0.001
      EPA/AA ratio0.47 (0.29, 0.67)0.43 (0.26, 0.59)0.4730.39 (0.27, 0.63)1.21 (0.90, 1.53)<0.001−0.51 (−34.7, 18.5)0.044181.9 (81.8, 273.3)<0.001<0.001
      DHA/AA ratio0.83 (0.68, 1.05)0.73 (0.57, 1.03)0.0190.72 (0.57, 1.06)0.76 (0.55, 0.93)0.507−13.0 (−28.3, 4.5)<0.001−5.6 (−22.2, 15.4)0.0580.114
      hs-CRP, mg/dL0.13 (0.04, 0.92)0.14 (0.06, 0.53)0.9180.04 (0.02, 0.09)0.04 (0.02, 0.07)0.345−57.4 (−86.6, −1.7)<0.001−69.5 (−89.9, −13.8)<0.0010.644
      Data are expressed as mean ± standard deviation or median.
      PTV, pitavastatin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MDA-LDL, malondialdehyde modified low-density lipoprotein; RLP-C, remnant like particle cholesterol; Apo, apolipoprotein; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; AA, arachidonic acid; hs-CRP, high sensitivity C-reactive protein.
      During the follow-up period for 6–8 months, there was no significant difference in the incidence of MACE, major bleeding, discontinuation of study drug, and adverse drug reaction between PTV group and PTV/EPA group (Table 4). The incidences of side effects from combination therapy of EPA and PTV were in acceptable range compared to PTV therapy alone.
      Table 4Major adverse cardiovascular events and adverse drug side effects.
      PTV group (n = 117)PTV/EPA group (n = 121)p-Value
      Major adverse cardiovascular event21 (17.7)22 (18.0)0.938
       Death from any cause1 (0.9)2 (1.7)1.000
      Fisher exact test.
       Cardiac death02 (1.7)0.498
      Fisher exact test.
       Non-fatal myocardial infarction1 (0.9)3 (2.5)0.622
      Fisher exact test.
       Hospitalization for unstable angina01 (0.8)1.000
      Fisher exact test.
       Coronary revascularization20 (16.8)22 (18.0)0.802
      TLR7 (5.9)14 (11.5)0.170
      Fisher exact test.
      De novo lesion13 (10.9)11 (9.0)0.671
      Non-fatal stroke1 (0.9)00.492
      Fisher exact test.
      Bleeding
       Major bleeding1 (0.9)2 (1.7)1.000
      Fisher exact test.
       Minor bleeding02 (1.7)0.498
      Fisher exact test.
      IVUS-related complication00
      Discontinuation of study drug8 (6.8)12 (9.9)0.486
      Fisher exact test.
      Reason for discontinuation
       Abnormallaboratory value
        CK01 (0.8)1.000
      Fisher exact test.
        AST or ALT1 (0.9)00.492
      Fisher exact test.
       Adverse drug reaction
        Myalgia2 (1.7)00.241
      Fisher exact test.
        Bleeding1 (0.9)3 (2.5)0.622
      Fisher exact test.
        Nausea03 (2.5)0.247
      Fisher exact test.
       Other4 (3.4)6 (5.0)0.749
      Fisher exact test.
      Data were expressed as number (percentage). Variables with no specification were compared by chi-square test. Major bleeding was defined according to definition of International Society on Thrombosis and Haemostasis
      • Schulman S.
      • Kearon C.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      .
      PTV, pitavastatin; EPA, eicosapentaenoic acid; TLR, target lesion revascularization; IVUS, intravascular ultrasound; CK, creatinine kinase; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
      a Fisher exact test.

      Discussion

      There were three major findings of this study. Firstly, IB-IVUS analysis revealed that PTV/EPA combination therapy achieved significant lipid volume reduction, but not PTV therapy alone. Secondly, volumetric IVUS analysis demonstrated that PTV/EPA therapy significantly reduced TAV in the PTV/EPA group compared to PTV group, suggesting that lipid reduction by EPA contributed to significant TAV reduction in CHD patients. Finally, there was no significant difference in the incidence of adverse events between the two groups.
      The recent American College of Cardiology/American Heart Association guidelines for the prevention of atherosclerotic cardiovascular risk recommends high-intensity statin therapy for secondary prevention, whereas nonstatin therapies are not recommended [
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • Goldberg A.C.
      • Gordon D.
      • Levy D.
      • Lloyd-Jones D.M.
      • McBride P.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Watson K.
      • 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.
      ]. The undeniable residual risks gained attention with regard to secondary prevention under high-intensity statin therapy [
      • Chapman M.J.
      • Redfern J.S.
      • McGovern M.E.
      • Giral P.
      Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk.
      ]. The PRECISE-IVUS study recently demonstrated that the addition of ezetimibe to atorvastatin further decreases LDL-C levels and percent coronary atheroma volume more than atorvastatin therapy alone [
      • Tsujita K.
      • Sugiyama S.
      • Sumida H.
      • Shimomura H.
      • Yamashita T.
      • Yamanaga K.
      • Komura N.
      • Sakamoto K.
      • Oka H.
      • Nakao K.
      • Nakamura S.
      • Ishihara M.
      • Matsui K.
      • Sakaino N.
      • Nakamura N.
      • et al.
      Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS Trial.
      ]. The IMPROVE-IT study showed that the combination of simvastatin and ezetimibe successfully reduces morbidity and mortality in ACS patients compared to simvastatin monotherapy [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • McCagg A.
      • White J.A.
      • Theroux P.
      • Darius H.
      • Lewis B.S.
      • Ophuis T.O.
      • Jukema J.W.
      • De Ferrari G.M.
      • Ruzyllo W.
      • De Lucca P.
      • Im K.
      • Bohula E.A.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ]. It was hypothesized that the effect of ezetimibe on coronary atheroma is due to the augmentation of LDL-C reduction achieved by statins.
      The GISSI-Prevenzione study demonstrated that dietary supplementation with n-3 PUFAs significantly decreased cardiovascular events after myocardial infarction [
      Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.
      ]. However, LDL-Cis reportedly increased by n-3 PUFA administration because of their low purity in a number of clinical trials [
      • Bays H.
      Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids.
      ,
      • Harris W.S.
      n-3 fatty acids and serum lipoproteins: human studies.
      ]. We used >99% purity EPA in the present study, a formulation that does not increase serum cholesterol levels. In the JELIS study, high-purity EPA added to mild statins decreased incident CHD, especially in secondary prevention [
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • Matsuzawa Y.
      • Saito Y.
      • Ishikawa Y.
      • Oikawa S.
      • Sasaki J.
      • Hishida H.
      • Itakura H.
      • Kita T.
      • Kitabatake A.
      • Nakaya N.
      • Sakata T.
      • Shimada K.
      • et al.
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      ]. However, it has remained unclear whether additional EPA therapy has an incremental effect for secondary prevention in CHD patients receiving high-intensity statin therapy.
      Consistent with a previous report [
      • Durrington P.N.
      • Bhatnagar D.
      • Mackness M.I.
      • Morgan J.
      • Julier K.
      • Khan M.A.
      • France M.
      An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
      ], we found that EPA therapy did not further decrease LDL-C levels compared to PTV therapy. Since baseline triglyceride levels were not high, it was thought that EPA did not reduce triglyceride levels. These findings imply that lipid volume and plaque volume reductions with EPA therapy are independent of decreases in LDL-C and triglyceride levels. On the other hand, there was significant correlation between on-treatment EPA/AA ratio and % changes in lipid volume in the present study, suggesting the effects of EPA itself as biologically active substance on coronary plaque stabilization.
      Even though EPA therapy does not directly alter serum cholesterol and triglyceride levels, Tanaka et al. reported that EPA is incorporated into the HDL particles where it improves the anti-oxidative and anti-inflammatory functions of HDL-C and promotes cholesterol efflux from macrophages [
      • Tanaka N.
      • Ishida T.
      • Nagao M.
      • Mori T.
      • Monguchi T.
      • Sasaki M.
      • Mori K.
      • Kondo K.
      • Nakajima H.
      • Honjo T.
      • Irino Y.
      • Toh R.
      • Shinohara M.
      • Hirata K.
      Administration of high dose eicosapentaenoic acid enhances anti-inflammatory properties of high-density lipoprotein in Japanese patients with dyslipidemia.
      ]. The experimental studies demonstrated that EPA plays a key role in the resolution of inflammation since it serves as a precursor for bioactive mediators such as 18 hydroxyeicosapentaenoic acid and resolvin [
      • Spite M.
      • Serhan C.N.
      Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins.
      ,
      • Zhang M.J.
      • Spite M.
      Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids.
      ,
      • Arita M.
      Mediator lipidomics in acute inflammation and resolution.
      ]. These metabolites derived from EPA were reported to inhibit inflammation [
      • Isobe Y.
      • Arita M.
      • Matsueda S.
      • Iwamoto R.
      • Fujihara T.
      • Nakanishi H.
      • Taguchi R.
      • Masuda K.
      • Sasaki K.
      • Urabe D.
      • Inoue M.
      • Arai H.
      Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.
      ]. It was reported that low serum EPA levels are associated with lipid-rich plaques [
      • Amano T.
      • Matsubara T.
      • Uetani T.
      • Kato M.
      • Kato B.
      • Yoshida T.
      • Harada K.
      • Kumagai S.
      • Kunimura A.
      • Shinbo Y.
      • Kitagawa K.
      • Ishii H.
      • Murohara T.
      Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study.
      ], and EPA therapy thickens fibrous caps [
      • Nishio R.
      • Shinke T.
      • Otake H.
      • Nakagawa M.
      • Nagoshi R.
      • Inoue T.
      • Kozuki A.
      • Hariki H.
      • Osue T.
      • Taniguchi Y.
      • Iwasaki M.
      • Hiranuma N.
      • Konishi A.
      • Kinutani H.
      • Shite J.
      • et al.
      Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma.
      ,
      • Yamano T.
      • Kubo T.
      • Shiono Y.
      • Shimamura K.
      • Orii M.
      • Tanimoto T.
      • Matsuo Y.
      • Ino Y.
      • Kitabata H.
      • Yamaguchi T.
      • Hirata K.
      • Tanaka A.
      • Imanishi T.
      • Akasaka T.
      Impact of eicosapentaenoic acid treatment on the fibrous cap thickness in patients with coronary atherosclerotic plaque: an optical coherence tomography study.
      ] and reduces the lipid volume of coronary plaques and improving the inflammatory profile [
      • Niki T.
      • Wakatsuki T.
      • Yamaguchi K.
      • Taketani Y.
      • Oeduka H.
      • Kusunose K.
      • Ise T.
      • Iwase T.
      • Yamada H.
      • Soeki T.
      • Sata M.
      Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
      ]. These reports supported our results that additional EPA therapy stabilizes the coronary plaque in patients with CHD through anti-inflammatory function.
      In the present study, EPA and PTV combination therapy achieved superior plaque regression to PTV therapy alone in CHD patients. Considering the significant lipid volume reduction observed in PTV/EPA group, additional EPA therapy facilitated plaque stabilization in CHD patients. Although the prevalence of lipid volume reduction was significantly higher in SAP patients with PTV/EPA therapy than in those with PTV therapy, it was not observed in ACS patients. Since PTV therapy was reported to have greater effect on the lipid volume reduction in ACS patients compared to SAP patients [
      • Puri R.
      • Nissen S.E.
      • Shao M.
      • Ballantyne C.M.
      • Barter P.J.
      • Chapman M.J.
      • Erbel R.
      • Libby P.
      • Raichlen J.S.
      • Uno K.
      • Kataoka Y.
      • Nicholls S.J.
      Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from study of coronary atheroma by intravascular ultrasound: effect of rosuvastatin versus atorvastatin.
      ], contribution of additional EPA therapy to plaque regression might be relatively smaller in ACS patients than in SAP patients in the present study. Furthermore, it may be too short to reinforce the plaque stabilization with additional EPA therapy since most ACS patients had just 6 months follow-up. Longer follow-up period may be needed to reveal the obvious effect of PTV/EPA therapy compared to PTV therapy alone in ACS patients. Finally, the prevalence rates of MACEs and adverse drug side effects were not significantly different between the two groups.

      Limitations

      The results of the present study should be considered in the context of several important limitations. First, patients with ACS and SAP were both included in the present study. Second, the analyzed plaques were short. Expert consensus recommends that volumetric plaque analysis should be performed in longer segments to precisely measure plaque volume since the IVUS catheter can move as much as 5 mm between diastole and systole; therefore, low back-up support of the guiding catheter can result in motion artifacts. Third, we could not investigate whether tissue characteristics estimated by IB-IVUS corresponded with the actual pathohistologic characteristics of coronary plaques. Despite the reported high accuracy for IB-IVUS-based classification of plaque characteristics compared to histological finding (Cohen's kappa = 0.81), it actually overestimates the lipid pool because of an acoustic shadow derived from calcification. However, identifying a lipid pool by IB-IVUS is not necessarily consistent with pathohistologic characteristics since the lipid pool is largely in the tissue behind the severe calcification. Finally, which plaque was selected in patients with multiple plaques in target vessel affects the outcome since vulnerable plaques are mainly in proximal segments of coronary arteries. However, the percentages of proximal plaques were eventually similar between the PTV and PTV/EPA groups (60% and 59%, respectively).

      Conclusion

      EPA and PTV combination therapy elicited greater reduction in coronary plaques compared to PTV therapy alone. Notably, lipid plaque volume was reduced by addition of EPA therapy especially in SAP patients. The addition of EPA is a promising option to reduce the residual risk of CHD under intensive statin therapy.

      Funding

      None.

      Disclosures

      Dr Kubota has received remuneration for lectures from Daiichi-Sankyo and has received scholarship funds from Daiichi-Sankyo, Novartis Pharma, and Boston Scientific. Dr Watanabe has received remuneration for lectures from AstraZeneca, Daiichi-Sankyo, MSD, and Boehringer-Ingelheim. All other authors have no relationships relevant to the contents of this paper to disclose.

      Appendix A. Supplementary data

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