Meta-Analysis Comparing the Effect of Combined Omega-3 + Statin Therapy Versus Statin Therapy Alone on Coronary Artery Plaques

Statin therapy plays an important role in stabilizing and regressing coronary artery plaques. Omega-3 supplements also have anti-inflammatory antioxidant effects on However, the effect of omega-3 supplementation basis statin stability composition plaques, is still unclear. We searched for randomized controlled trials published prior to November 2020 PubMed, Embase Cochrane databases. Finally, eight studies using different imaging techniques evaluate atherosclerotic plaque, including optical coherence tomography (OCT), CT angiography (cCTA) intravascular ultrasound (IB-IVUS), met our inclusion criteria. pooled data extracted from included standardized mean difference (SMD) or (MD) random model. Compared with treatment alone, combined further delayed progression total plaque volume [SMD -0.36, 95% confidence interval (CI) -0.64 -0.08, p = 0.01] fiber content (SMD -0.40, CI -0.68 -0.13, 0.004). The plasma high-sensitivity C-reactive protein (hs-CRP) level patients combination group was significantly lower than that alone -0.30, -0.59 -0.01, 0.04). In addition, use increases fibrous cap thickness (FCT) MD 29.45 ?m. There were no significant differences high-density lipoprotein cholesterol (HDL-C), low-density (LDL-C), lipid plaques between two groups. statins superior promoting regression may help reduce occurrence cardiovascular events. Unstable which are characterized by thin caps, large pools, infiltration macrophages,1Narula J Nakano M Virmani R Kolodgie FD Petersen Newcomb Malik S Fuster V Finn AV Histopathologic characteristics disease implications findings invasive noninvasive detection vulnerable plaques.J Am Coll Cardiol. 2013; 61: 1041-1051Crossref PubMed Scopus (329) Google Scholar,2Stone GW Maehara A Lansky AJ de Bruyne B Cristea E Mintz GS Mehran McPherson Farhat N Marso SP Parise H Templin White Zhang Z Serruys PW prospective natural-history study atherosclerosis.N Engl Med. 2011; 364: 226-235Crossref (2062) Scholar main cause major adverse closely related high incidence events.3Nicholls SJ Hsu Wolski K Hu Bayturan O Lavoie Uno Tuzcu EM Nissen SE Intravascular ultrasound-derived measures burden clinical outcome.J 2010; 55: 2399-2407Crossref (317) As lipid-lowering drugs, can stabilize even reverse atherosclerosis.4Nicholls Ballantyne CM Barter PJ Chapman MJ Erbel RM Libby P Raichlen JS Borgman Effect intensive regimens disease.N 365: 2078-2087Crossref (575) Scholar,5Komukai Kubo T Kitabata Matsuo Y Ozaki Takarada Okumoto Shiono Orii Shimamura Ueno Yamano Tanimoto Ino Yamaguchi Kumiko Tanaka Imanishi Akagi Akasaka atorvastatin as assessed tomography: EASY-FIT study.J 2014; 64: 2207-2217Crossref (137) residual risk exists after treatment6Baigent C Keech Kearney PM Blackwell L Buck G Pollicino Kirby Sourjina Peto Collins Simes Efficacy safety cholesterol-lowering treatment: meta-analysis 90,056 participants 14 randomised statins.Lancet. 2005; 366: 1267-1278Abstract Full Text PDF (5490) Scholar. Previous shown long-term intake long-chain n-3 polyunsaturated fatty acids (PUFAs) events.7Daviglus ML Stamler Orencia Dyer AR Liu Greenland Walsh MK Morris D Shekelle RB Fish consumption 30-year fatal myocardial infarction.N 1997; 336: 1046-1053Crossref (775) Scholar,8Kromhout Bosschieter EB Lezenne Coulander inverse relation fish 20-year mortality heart 1985; 312: 1205-1209Crossref (1799) low serum plaques.9Amano Matsubara Uetani Kato Yoshida Harada Kumagai Kunimura Shinbo Kitagawa Ishii Murohara Impact instability: integrated backscatter study.Atherosclerosis. 218: 110-116Abstract (62) Scholar,10Sekikawa Curb JD Ueshima El-Saed Kadowaki Abbott RD Evans RW Rodriguez BL Okamura Sutton-Tyrrell Nakamura Masaki Edmundowicz Kashiwagi Willcox BJ Takamiya Mitsunami Seto TB Murata RL Kuller LH Marine-derived atherosclerosis Japanese, Japanese-American, white men: a cross-sectional 2008; 52: 417-424Crossref (183) Therefore, adjuvant statins, potential benefits risks statins. it unclear whether better terms progression. we conducted based therapy. accordance Preferred Reporting Items Systematic Reviews Meta-Analyses (PRISMA) statement.11Moher LA Liberati Tetzlaff Altman DG reporting items systematic reviews Meta-Analyses: PRISMA statement.PLoS 2009; 6e1000097Crossref (34710) following databases English-related research 2020: (MEDLINE), Library, Embase. An example search strategy available Table S1. protocol registered PROSPERO (CRD42020222439). articles criteria: (1) must be among adults (?18 years) diagnosis known atherosclerosis; (2) arterial compared therapy; (3) considered relevant outcome, percent absolute change baseline follow-up reported; (4) period ?6 months; (5) full text English. Meanwhile, exclusion criteria follows: subjects who had other parts besides artery; review, meeting abstract, unpublished text; insufficient endpoint data. Two authors selected extraction. extracted: basic information about study, i.e., author, year publication, country where conducted; patient demographics, such age, sex, medication, factors disease, medication target vessel; trial characteristics, number subjects, dose type statin, duration design. outcomes. Any disagreement resolved panel discussion until consensus reached consulting senior author. primary pre-postintervention volume. secondary defined changes follow-up, concentrations (hs-CRP), (HDL-C) (LDL-C). reviewers evaluated quality according Collaboration's tool trials. evaluation each divided into three categories: bias, bias bias. evaluated: sequence generation (selection bias), allocation concealment blinding personnel (performance outcome assessment (detection incomplete (attrition selective (reporting biases. details all presented Figure discrepancy Some reported results form medians interquartile ranges instead standard deviation, so adopted methods Luo et al. Wan X convert data.12Luo Tong Optimally estimating sample size, median, mid-range, and/or mid-quartile range.Stat Methods Med Res. 2018; 27: 1785-1805Crossref (536) Scholar,13Wan Wang W Estimating deviation range range.BMC Res Methodol. 14: 135Crossref (2524) models used statistical analysis. Between-study heterogeneity endpoints I2 statistic. According handbook, categorized nonimportant (I2<40%), moderate (30%90%), sensitivity analysis ensure removing first second influential studies. publication funnel meta-analysis. Handbook Interventions Version 5.1.0,14Higgins JPT Green 5.1.0 (update March 2011). Collaboration, 2011http://handbook.cochrane.orgDate accessed: 28, 2020Google when intervention groups, split “shared” control groups smaller size (reasonably independent) comparisons. has several independent comparisons common, regarded coming subjected All analyses Review Manager 5.4. 356 reports retrieved electronic search. read 25 excluding duplicate records screening titles abstracts. Of these studies, 17 excluded various reasons, 8 803 (Figure 1).15Kita Watanabe Kamon Ueda Soeda Okayama Ishigami Kawata Horii Inoue F Doi Okura Uemura Saito Effects Fatty Acid Therapy Addition Strong Coronary Plaques Acute Syndrome: Optical Coherence Tomography Study.J Heart Assoc. 2020; 9e015593Crossref Scholar, 16Sugizaki Otake Kuroda Kawamori Toba Nagasawa Takeshige Matsuoka Tanimura Takahashi Fukuyama Hirata KI Concomitant Rosuvastatin Eicosapentaenoic acid prevents native in-stent neoatherosclerosis.Circ J. 84: 1826-1836Crossref 17Niki Wakatsuki Taketani Oeduka Kusunose Ise Iwase Yamada Soeki Sata addition eicosapentaenoic strong inflammatory cytokines components ultrasound.Circ 2016; 80: 450-460Crossref (51) 18Watanabe Ando Daidoji Otaki Sugawara Matsui Ikeno Hirono Miyawaki Yashiro Nishiyama Arimoto Shishido Miyashita Miyamoto Kubota I statins.J 2017; 70: 537-544Abstract (65) 19Alfaddagh Elajami TK Ashfaque Saleh Bistrian BR Welty FK Docosahexaenoic added Artery disease: Randomized Clinical Trial.J 6e006981Crossref (31) 20Nishio Shinke Nakagawa Nagoshi Kozuki Hariki Osue Taniguchi Iwasaki Hiranuma Konishi Kinutani Shite Stabilizing thin-cap fibroatheroma.Atherosclerosis. 234: 114-119Abstract (76) 21Ahn Park SK TS Kim JH Yun Lee HW Oh Choi Cha KS Hong TJ SY HC Atherosclerosis treated undergoing percutaneous intervention.Korean Circ 46: 481-489Crossref 22Budoff Bhatt DL Kinninger Lakshmanan Muhlestein JB Le VT May HT Shaikh Shekar Roy Tayek Nelson JR icosapent ethyl elevated triglycerides therapy: final EVAPORATE trial.Eur 41: 3925-3932Crossref (86) participants, 421 (52.4%) received omega-3, 382 (47.6%) alone. Details demographics 1. Japan, four RCTs highly purified 1.8 g/d EPA.16Sugizaki Scholar,20Nishio one RCT EPA DHA.15Kita countries, DHA,19Alfaddagh Scholar,21Ahn (IPE), ester acid.22Budoff 2 shows studies.Table 1Patients demographicsStudyStudy armAge(years)MaleDMHTNDLPSmokerKita15Kita (2020)rosuvastatin63(55-73)27(87%)11(35%)22(71%)NR16(52%)rosuvastatin+EPA66(57-70)24(77%)3(10%)18(58%)NR13(42%)rosuvastatin+EPA+DHA67(59-70)28(81%)11(31%)16(46%)NR13(37%)Nishio20Nishio (2014)rosuvastatin63.8±9.513(86.7%)2(13.3%)10(66.7%)NR9(60%)rosuvastatin+EPA61.0±12.613(86.7%)5(33.3%(11(73.3%)NR12(80%)Sugizaki16Sugizaki (2020)rosuvastatin75.3(68.6-80.5)16(76.2%)8(38.1%)16(76.2%)18(85.7%)11(52.4%)rosuvastatin+EPA70.8(68.4-78.8)17(81%)12(57.1%)15(71.4%)19(90.5%)11(52.4%)Niki17Niki (2016)strong statin69.4±10.719(63%)15(50%)30(100%)30(100%)0strong statin+EPA68.1±10.121(72%)15(53%)29(100%)29(100%)0Watanabe18Watanabe (2017)pitavastatin68±1081(84%)34(35%)62(65%)59(61%)50(52%)pitavastatin+EPA67±1078(80%)35(36%)66(68%)64(66%)61(63%)Alfaddagh19Alfaddagh (2017)statin63.5±7.697(85.1%)34(29.8%)101(88.6%)NRNRstatin+EPA+DHA62.5±7.8107(84.9%)34(27.0%)99(78.6%)NRNRBudoff22Budoff (2020)statin+placebo56.5±8.917(58.4%)22(71%)24(77.4%)NR13(41.9%)statin+IPE58.3±8.620(54.1%)25(67.6%)28(75.7%)NR16(43.2%)Ahn21Ahn (2015)statins+placebo60.7±0.826(72.2%)9(23.7%)18(50%)14(48.5%)21(58.3%)statins+EPA+DHA59.6±9.124(63.2%)8(21.1%)19(50%)25(71.4%)14(36.8%)FHxACSBMI(kg/m2)MedicationTarget vesselACEI/ARB?-blockerCCBAspirinstatinsLADLCXRCANR31(100%)24.7(23.3-26.7)10(32%)5(16%)13(42%)4(13%)5(16%)15(48%)7(23%)9(29%)NR31(100%)24.3(23.3-26.7)8(26%)2(6%)7(23%)3(10%)3(9%)11(36%)7(23%)13(42%)NR35(100%)25.0(23.1-26.9)8(23%)1(3%)9(26%)4(11%)9(26%)12(34%)10(29%)13(37%)4(26.7%)8(53.3%)24.6±3.59(60%)3(20%)5(33.3%)15(100%)0NRNRNR5(33.3%)9(60%)26.4±3.610(66.7%)3(20%)2(13.3%)15(100%)0NRNRNR5(23.8%)5(23.8%)NR11(52.4%)9(42.9%)NRNR14(66.7%)9(52.9%)6(66.7%)6(37.5%)6(28.6%)6(28.6%)NR15(71.4%)12(57.1%)NRNR13(61.9%)8(47.1%)3(33.3%)10(62.5%)NRNRNR18(60%)9(30%)13(43%)30(100%)NR11(37%)9(30%)10(33%)NRNRNR16(55%)8(28%)13(45%)29(100%)NR12(41%)7(24%)10(34%)NR34(35%)23.9±2.964(67%)31(32%)NRNR47(49%)45(47%)18(19%)33(34%)NR40(41%)23.7±3.174(76%)38(39%)NRNR41(42%)52(54%)16(17%)28(29%)NRNR30.5±3.588(77.2%)85(74.6%)28(24.6%)110(96.5%)107(93.9%)NRNRNRNRNR30.8±3.789(70.7%)88(69.8%)30(23.8%)121(96.0%)121(96%)NRNRNR13(35.1%)NR34.1±6.5NRNRNR15(48.4%)31(100%)NRNRNR9(29.0%)NR33.3±6.9NRNRNR22(59.5%)37(100%)NRNRNRNR17(47.3%)24.5±2.532(88.9%)26(72.2%)6(16.7%)36(100%)36(100%)18(50%)8(22.2%)10(27.8%)NR19(30%)24.8±2.435(92.1%)22(57.9%)7(18.4%)38(100%)38(100%)19(50%)4(10.5%)15(39.5%)Data given median (interquartile range), mean±SD, n (%). ACS acute syndrome; BMI body mass index; CCB calcium channel blocker; DM diabetes mellitus; DLP dyslipidemia; FHx family history; HTN hypertension; LAD left anterior descending; LCX circumflex; NR RCA right artery. Open table new tab 2Included characteristicStudyCountryClinical PresentationTechniquesubjects(n)Dose Type OM3 statinFollow-up(months)Study designKita15Kita (2020)JapanACSOCT31rosuvastatin8open-label RCT31rosuvastatin+high-dose EPA(1.8g/d)35rosuvastatin+EPA(0.93g/d)+DHA(0.75g/d)Nishio20Nishio (2014)JapanSAP/ACSOCT15rosuvastatin(3.50±3.25mg/d)9open-label RCT15rosuvastatin(3.67±2.08mg/d)+EPA(1.8g/d)Sugizaki16Sugizaki (2020)JapanACS/stable CADOCT21rosuvastatin(2.5mg/d)12open-label RCT21rosuvastatin(10mg/d)+EPA(1.8g/d)Niki17Niki (2016)JapanSAPIB-IVUS30strong statin6open-label RCT29strong statin+EPA(1.8g/d)Watanabe18Watanabe (2017)JapanSAP/ACSIB-IVUS96pitavastatin(4mg/d)6-8non-blinded RCT97pitavastatin(4mg/d)+EPA(1.8g/d)Alfaddagh19Alfaddagh (2017)USAstable CADcCTA53low-intensity statin30open-label RCT61high-intensity satin61low-intensity statin+EPA(1.86g/d)+DHA(1.5g/d)65high-intensity statin+EPA(1.86g/d)+DHA(1.5g/d)Budoff22Budoff (2020)USAcoronary atherosclerosiscCTA37statin+placebo(mineral oil)18double-blind RCT31statin+IPE(4g/d)Ahn21Ahn (2016)KoreaSAP/UAP/NSTEMIIVUS38statins+placebo12RCT36statins+EPA(1.395g/d)+DHA(1.125g/d)Data ± SD n. CAD disease; DHA docosahexaenoic acid; IPE ethyl; NSTEMI non-ST-segment elevation infarction; SAP stable angina pectoris; UAP unstable