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

Abstract

Statin therapy plays an important role in stabilizing and regressing coronary artery plaques. Omega-3 supplements also have anti-inflammatory and antioxidant effects on coronary plaques. However, the effect of omega-3 supplementation on the basis of statin therapy on the stability and composition of plaques, is still unclear. We searched for randomized controlled trials published prior to November 2020 in the PubMed, Embase and Cochrane databases. Finally, eight studies using different imaging techniques to evaluate coronary atherosclerotic plaque, including optical coherence tomography (OCT), coronary CT angiography (cCTA) and intravascular ultrasound (IB-IVUS), met our inclusion criteria. We pooled data extracted from the included studies using the standardized mean difference (SMD) or mean difference (MD) of the random effects model. Compared with statin treatment alone, the combined treatment further delayed the progression of total plaque volume [SMD -0.36, 95% confidence interval (CI) -0.64 to -0.08, p = 0.01] and fiber content (SMD -0.40, 95% CI -0.68 to -0.13, p = 0.004). The plasma high-sensitivity C-reactive protein (hs-CRP) level of patients in the combination treatment group was significantly lower than that of the patients in the statin treatment group alone (SMD -0.30, 95% CI -0.59 to -0.01, p = 0.04). In addition, the combined use of omega-3 further increases the fibrous cap thickness (FCT) of the plaque with an MD of 29.45 μm. There were no significant differences in plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), or lipid content in plaques between the two groups. Omega-3 combined with statins is superior to the statin treatment group in stabilizing and promoting coronary plaque regression and may help to further reduce the occurrence of cardiovascular events. Statin therapy plays an important role in stabilizing and regressing coronary artery plaques. Omega-3 supplements also have anti-inflammatory and antioxidant effects on coronary plaques. However, the effect of omega-3 supplementation on the basis of statin therapy on the stability and composition of plaques, is still unclear. We searched for randomized controlled trials published prior to November 2020 in the PubMed, Embase and Cochrane databases. Finally, eight studies using different imaging techniques to evaluate coronary atherosclerotic plaque, including optical coherence tomography (OCT), coronary CT angiography (cCTA) and intravascular ultrasound (IB-IVUS), met our inclusion criteria. We pooled data extracted from the included studies using the standardized mean difference (SMD) or mean difference (MD) of the random effects model. Compared with statin treatment alone, the combined treatment further delayed the progression of total plaque volume [SMD -0.36, 95% confidence interval (CI) -0.64 to -0.08, p = 0.01] and fiber content (SMD -0.40, 95% CI -0.68 to -0.13, p = 0.004). The plasma high-sensitivity C-reactive protein (hs-CRP) level of patients in the combination treatment group was significantly lower than that of the patients in the statin treatment group alone (SMD -0.30, 95% CI -0.59 to -0.01, p = 0.04). In addition, the combined use of omega-3 further increases the fibrous cap thickness (FCT) of the plaque with an MD of 29.45 μm. There were no significant differences in plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), or lipid content in plaques between the two groups. Omega-3 combined with statins is superior to the statin treatment group in stabilizing and promoting coronary plaque regression and may help to further reduce the occurrence of cardiovascular events. Unstable coronary plaques, which are characterized by thin fibrous caps, large lipid pools, and infiltration of macrophages,1Narula J Nakano M Virmani R Kolodgie FD Petersen R Newcomb R Malik S Fuster V Finn AV Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of 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 R McPherson J Farhat N Marso SP Parise H Templin B White R Zhang Z Serruys PW A prospective natural-history study of coronary atherosclerosis.N Engl J Med. 2011; 364: 226-235Crossref PubMed Scopus (2062) Google Scholar are the main cause of major adverse cardiovascular events. The progression of coronary plaque is also closely related to the high incidence of cardiovascular events.3Nicholls SJ Hsu A Wolski K Hu B Bayturan O Lavoie A Uno K Tuzcu EM Nissen SE Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.J Am Coll Cardiol. 2010; 55: 2399-2407Crossref PubMed Scopus (317) Google Scholar As the main lipid-lowering drugs, statins can stabilize or even reverse the progression of coronary atherosclerosis.4Nicholls SJ Ballantyne CM Barter PJ Chapman MJ Erbel RM Libby P Raichlen JS Uno K Borgman M Wolski K Nissen SE Effect of two intensive statin regimens on progression of coronary disease.N Engl J Med. 2011; 365: 2078-2087Crossref PubMed Scopus (575) Google Scholar,5Komukai K Kubo T Kitabata H Matsuo Y Ozaki Y Takarada S Okumoto Y Shiono Y Orii M Shimamura K Ueno S Yamano T Tanimoto T Ino Y Yamaguchi T Kumiko H Tanaka A Imanishi T Akagi H Akasaka T Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.J Am Coll Cardiol. 2014; 64: 2207-2217Crossref PubMed Scopus (137) Google Scholar However, residual cardiovascular risk still exists after statin treatment6Baigent C Keech A Kearney PM Blackwell L Buck G Pollicino C Kirby A Sourjina T Peto R Collins R Simes R Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (5490) Google Scholar. Previous studies have shown that long-term intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) can reduce the incidence of cardiovascular events.7Daviglus ML Stamler J Orencia AJ Dyer AR Liu K Greenland P Walsh MK Morris D Shekelle RB Fish consumption and the 30-year risk of fatal myocardial infarction.N Engl J Med. 1997; 336: 1046-1053Crossref PubMed Scopus (775) Google Scholar,8Kromhout D Bosschieter EB de Lezenne Coulander C The inverse relation between fish consumption and 20-year mortality from coronary heart disease.N Engl J Med. 1985; 312: 1205-1209Crossref PubMed Scopus (1799) Google Scholar In addition, the low level of omega-3 in serum is also significantly related to the stability and progression of plaques.9Amano 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.Atherosclerosis. 2011; 218: 110-116Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar,10Sekikawa A Curb JD Ueshima H El-Saed A Kadowaki T Abbott RD Evans RW Rodriguez BL Okamura T Sutton-Tyrrell K Nakamura Y Masaki K Edmundowicz D Kashiwagi A Willcox BJ Takamiya T Mitsunami K Seto TB Murata K White RL Kuller LH Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study.J Am Coll Cardiol. 2008; 52: 417-424Crossref PubMed Scopus (183) Google Scholar Therefore, as an adjuvant treatment of statins, omega-3 may have potential benefits for the residual risks of statins. However, it is still unclear whether combination therapy is better than statin therapy alone in terms of plaque stability and progression. Therefore, we conducted a meta-analysis of the effects of omega-3 on plaque composition and progression based on statin therapy. The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.11Moher D LA Liberati A Tetzlaff J Altman DG Preferred reporting items for systematic reviews and Meta-Analyses: the PRISMA statement.PLoS Med. 2009; 6e1000097Crossref PubMed Scopus (34710) Google Scholar We searched the following databases for English-related research published prior to November 2020: PubMed (MEDLINE), The Cochrane Library, and Embase. An example search strategy for PubMed is available in Table S1. The study protocol was registered with PROSPERO (CRD42020222439). We included articles that met the following criteria: (1) the studies must be conducted among adults (≥18 years) with a diagnosis of coronary artery disease or known coronary atherosclerosis; (2) the effect of statins combined with omega-3 on coronary arterial plaque was compared with statin therapy; (3) atherosclerosis was considered the relevant outcome, and the percent or absolute change in coronary atherosclerosis between baseline and follow-up was reported; (4) randomized controlled research with a follow-up period ≥6 months; and (5) published articles with the full text available in English. Meanwhile, the exclusion criteria were as follows: (1) subjects who had atherosclerosis in other parts besides the coronary artery; (2) review, meeting abstract, meta-analysis or clinical trials with unpublished full text; and (3) insufficient endpoint data. Two authors selected the studies in accordance with the inclusion criteria and conducted the data extraction. The following data were extracted: (1) basic information about the included study, i.e., author, year of publication, and country where the study was conducted; (2) patient demographics, such as age, sex, medication, and risk factors for cardiovascular disease, medication and target vessel; and (3) trial characteristics, such as the number of subjects, dose and type of omega-3 and statin, duration of follow-up and study design. (4) relevant clinical outcomes. Any disagreement was resolved by panel discussion until consensus was reached or by consulting a senior author. 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