Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies


Maciej Banach | Corina Serban | Amirhossein Sahebkar | Dimitri P. Mikhailidis | Sorin Ursoniu | Kausik K. Ray | Jacek Rysz | Peter P. Toth | Paul Muntner | Svetlana Mosteoru | Hector M. García-García | G. Kees Hovingh | John JP Kastelein | Patrick W. Serruys | Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

First published: 2015 Sep 18 |


Virtual histology intravascular ultrasound (VH-IVUS) imaging is an innovative tool for the morphological evaluation of coronary atherosclerosis. Evidence for the effects of statin therapy on VH-IVUS parameters have been inconclusive. Consequently, we performed a systematic review and meta-analysis to investigate the impact of statin therapy on plaque volume and its composition using VH-IVUS.


The search included PubMed, Cochrane Library, Scopus and Embase (through 30 November 2014) to identify prospective studies investigating the effects of statin therapy on plaque volume and its composition using VH-IVUS.


We identified nine studies with 16 statin treatment arms and 830 participants. There was a significant effect of statin therapy in reducing plaque volume (standardized mean difference (SMD): −0.137, 95 % confidence interval (CI): −0.255, −0.019; P = 0.023), external elastic membrane volume (SMD: −0.097, 95 % CI: −0.183, −0.011; P = 0.027) but not lumen volume (SMD: −0.025, 95 % CI: −0.110, +0.061; P = 0.574). There was a significant reduction in fibrous plaque volume (SMD: −0.129, 95 % CI: −0.255, −0.003; P = 0.045) and an increase of dense calcium volume (SMD: +0.229, 95 % CI: +0.008, +0.450; P = 0.043), while changes in fibro-fatty (SMD: −0.247, 95 % CI: −0.592, +0.098; P = 0.16) and necrotic core (SMD: +0.011, 95 % CI: −0.144, +0.165; P = 0.892) tissue volumes were not statistically significant.
ConclusionsThis meta-analysis indicates a significant effect of statin therapy on plaque and external elastic membrane volumes and fibrous and dense calcium volumes. There was no effect on lumen volume, fibro-fatty and necrotic tissue volumes.

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Maciej Banach and Corina Serban contributed equally to this work.

Competing interests
MB reports honoraria for lectures from: Amgen, Sanofi, Abbott, MSD/Merck, he is consultant/member of an international advisory board in Amgen, Sanofi, Daiichi Sankyo, Resverlogix and Abbott Vascular, reports grants from VALLEANT; DPM has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec; KKR reports honoraria for lectures from: Novo Nordisk, Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, Lilly, he is consultant/member of advisory board in: Novo Nordisk, Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, Lilly, Merck; PPT reports honoraria for lectures from: Amgen, Amarin, AstraZeneca, GSK, Kowa, Merck, he is consultant/member of advisory board in: Amgen, AstraZeneca, Kowa, Merck, Novartis; PM reports grants, personal fees and other from Amgen; GKH reports that his institution receives funding from Dezima, Amgen, Pfizer, Sanofi, Regeneron, AstraZeneca, Genzyme, Cerenis, Synageva, Roche, ISIS pharmaceuticals, Kowa, and Merck for undertaking clinical trials related to various forms of lipid-lowering medication and he reports consulting fees from: Amgen, Pfizer, Roche, and Sanofi; JJP reports personal fees from Dezima Pharmaceuticals, Cerenis, The Medicines Company, CSL Behring, Amgen, Sanofi, Regeneron, Eli Lilly, Genzyme, Aegerion, Esperion, AstraZeneca, Omthera, Pronova, Vascular Biogenics, Boehringer Ingelheim, Catabasis, AtheroNova, UniQure, Novartis, Merck, Isis Pharmaceuticals, and Kowa; PWS is a member of the international advisory board of Abbott Vascular; CS, AS, SU, JR, SM and HMGG have nothing to declare.

Authors’ contributions
MB designed the study, made the literature search, drafted the manuscript, prepared the final version and submitted the paper. CS designed the study, made the literature search and drafted the manuscript. AS designed the study, made the statistical analysis and corrected the draft of the paper. SU made the literature search. DPM, KKR, JR, PPT, PM, SM, HMG-G, GKH, JJPK and PWS corrected the draft of the paper and prepared the final version of the manuscript. All authors read and approved the final manuscript.
  1. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics−2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25–146. doi: 10.1161/CIRCULATIONAHA.107.187998. 
  2. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient a call for new definitions and risk assessment strategies: part I. Circulation. 2003;108:1664–72. doi: 10.1161/01.CIR.0000087480.94275.97.
  3. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13–8. doi: 10.1016/j.jacc.2005.10.065. 
  4. Silva Marques J, Pinto FJ. The vulnerable plaque: Current concepts and future perspectives on coronary morphology, composition and wall stress imaging. Rev Port Cardiol. 2014;33:101–10.
  5. Pedrigi RM, de Silva R, Bovens SM, Mehta VV, Petretto E, Krams R. Thin-cap fibroatheroma rupture is associated with a fine interplay of sand wall stress. Arterioscler Thromb Vasc Biol. 2014;34:2224–31. doi: 10.1161/ATVBAHA.114.303426.
  6. Chiocchi M, Chiaravalloti A, Morosetti D, Loreni G, Gandini R, Mancino S, et al. Virtual histology-intravascular ultrasound as a diagnostic alternative for morphological characterization of carotid plaque: comparison with histology and high-resolution magnetic resonance findings. J Cardiovasc Med. 2014; doi: 10.2459/JCM.0b013e328356a5d2
  7. Zamani P, Ganz P, Libby P, Sutradhar SC, Rifai N, Nicholls SJ, et al. Relationship of antihypertensive treatment to plasma markers of vascular inflammation and remodeling in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis study. Am Heart J. 2012;163:735–40. doi: 10.1016/j.ahj.2011.12.008.
  8. Diethrich EB, Margolis MP, Reid DB, Burke A, Ramaiah V, Rodriguez-Lopez JA, et al. Virtual histology intravascular ultrasound assessment of carotid artery disease: the Carotid Artery Plaque Virtual Histology Evaluation (CAPITAL) study. J Endovasc Ther. 2007;14:676–86. doi: 10.1177/152660280701400512
  9. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–35. doi: 10.1056/NEJMoa1002358.
  10. Calvert PA, Obaid DR, O’Sullivan M, Shapiro LM, McNab D, Densem CG, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovasc Imaging. 2011;4:894–901. doi: 10.1016/j.jcmg.2011.05.005.
  11. Cheng JM, Garcia-Garcia HM, de Boer SP, Kardys I, Heo JH, Akkerhuis KM, et al. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J. 2014;35:639–47. doi: 10.1093/eurheartj/eht484.
  12. Nakano M, Ladich E, Virmani R. Multi-modality atherosclerosis imaging and diagnosis. New York, NY: Springer; 2014. Histopathology of atherosclerosis progression: what imagers need to know; pp. 15–24.
  13. Hou J, Jia H, Hu S, Xing L, Yang S, Zhang S, et al. Effect of intensive versus moderate lipid-lowering therapy on the progression of coronary lipid-rich plaque: a prospective, randomized, serial combined optical coherence tomography and intravascular ultrasound study. Circulation. 2014;130:A16064–4.
  14. Lee SW, Hau WK, Kong SL, Chan KK, Chan PH, Lam SC, et al. Virtual histology findings and effects of varying doses of atorvastatin on coronary plaque volume and composition in statin-naive patients: the VENUS study. Circ J. 2012;76:2662–72. doi: 10.1253/circj.CJ-12-0325. 
  15. Tian J, Gu X, Sun Y, Ban X, Xiao Y, Hu S, et al. Effect of statin therapy on the progression of coronary atherosclerosis. BMC Cardiovasc Disord. 2012;12:70. doi: 10.1186/1471-2261-12-70. 
  16. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9. doi: 10.7326/0003-4819-151-4-200908180-00135. 
  17. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive Meta-Analysis. Version 2. Englewood, NJ: Biostat; 2005. pp. 104–4. 
  18. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. doi: 10.1186/1471-2288-5-13. 
  19. Sutton AJ, Abrams KR, Jones DR, Jones DR, Sheldon TA, Song F. Methods for meta-analysis in medical research. Chichester: John Wiley & Sons; 2000. 
  20. Duval S, Tweedie R. Trim and fill: a simple funnel‐plot–based method of testing and adjusting for publication bias in meta‐analysis. Biometrics. 2000;56:455–63. doi: 10.1111/j.0006-341X.2000.00455.x. 
  21. Eshtehardi P, McDaniel MC, Dhawan SS, Binongo J, Krishnan SK, Golub L, et al. Effect of intensive atorvastatin therapy on coronary atherosclerosis progression, composition, arterial remodeling, and microvascular function. J Invasive Cardiol. 2012;24:522–9.
  22. Guo S, Wang R, Yang Z, Li K, Wang Q. Effects of atorvastatin on serum lipids, serum inflammation and plaque morphology in patients with stable atherosclerotic plaques. Exp Ther Med. 2012;4:1069–74. 
  23. Hong MK, Park DW, Lee CW, Lee SW, Kim YH, Kang DH, et al. Effects of statin treatments on coronary plaques assessed by volumetric virtual histology intravascular ultrasound analysis. JACC Cardiovasc Interv. 2009;2:679–88. doi: 10.1016/j.jcin.2009.03.015.
  24. Hwang DS, Shin ES, Kim SJ, Lee JH, Kim JM, Lee SG. Early differential changes in coronary plaque composition according to plaque stability following statin initiation in acute coronary syndrome: classification and analysis by intravascular ultrasound-virtual histology. Yonsei Med J. 2013;54:336–44. doi: 10.3349/ymj.2013.54.2.336. 
  25. Nasu K, Tsuchikane E, Katoh O, Tanaka N, Kimura M, Ehara M, et al. Effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by virtual histology intravascular ultrasound. JACC Cardiovasc Interv. 2009;2:689–96. doi: 10.1016/j.jcin.2009.04.016.
  26. Nozue T, Yamamoto S, Tohyama S, Umezawa S, Kunishima T, Sato A, et al. Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis. Am Heart J. 2012;163:191–9. doi: 10.1016/j.ahj.2011.11.004.
  27. Puri R, Libby P, Nissen SE, Wolski K, Ballantyne CM, Barter PJ, et al. Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN. Eur Heart J Cardiovasc Imaging. 2014;15:380–8. doi: 10.1093/ehjci/jet251.
  28. Taguchi I, Oda K, Yoneda S, Kageyama M, Kanaya T, Toyoda S, et al. Evaluation of serial changes in tissue characteristics during statin-induced plaque regression using virtual histology-intravascular ultrasound studies. Am J Cardiol. 2013;111:1246–52. doi: 10.1016/j.amjcard.2013.01.265. 
  29. Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5.1.0. Oxford: The Cochrane Collaboration; 2011. 
  30. Stone N, Robinson J, Lichtenstein A, Bairey Merz CN, Blum CB, Eckel RH, 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. J Am Coll Cardiol. 2014;129:S1–45. 
  31. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262–75. doi: 10.1161/01.ATV.20.5.1262.
  32. Garcia-Garcia HM, Jang I-K, Serruys PW, Kovacic JC, Narula J, Fayad ZA. Imaging plaques to predict and better manage patients with acute coronary events. Circ Res. 2014;114:1904–17. doi: 10.1161/CIRCRESAHA.114.302745.
  33. Takarada S, Imanishi T, Kubo T, Tanimoto T, Kitabata H, Nakamura N, et al. Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: assessment by optical coherence tomography study. Atherosclerosis. 2009;202:491–7. doi: 10.1016/j.atherosclerosis.2008.05.014.
  34. Garcia-Garcia HM, Mintz GS, Lerman A, Vince DG, Margolis MP, van Es GA, et al. Tissue characterisation using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting. EuroIntervention. 2009;5:177–89. doi: 10.4244/EIJV5I2A29. 
  35. Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses an intravascular ultrasound study. Circulation. 1997;95:1791–8. doi: 10.1161/01.CIR.95.7.1791. 
  36. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation. 2002;105:297–303. doi: 10.1161/hc0302.102610. 
  37. Fujii K, Carlier SG, Mintz GS, Wijns W, Colombo A, Böse D, et al. Association of plaque characterization by intravascular ultrasound virtual histology and arterial remodeling. Am J Cardiol. 2005;96:1476–83. doi: 10.1016/j.amjcard.2005.07.054.
  38. Vancraeynest D, Pasquet A, Roelants V, Gerber BL, Vanoverschelde JLJ. Imaging the vulnerable plaque. J Am Coll Cardiol. 2011;57:1961–79. doi: 10.1016/j.jacc.2011.02.018. 
  39. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–8. doi: 10.1001/jama.285.13.1711.
  40. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504. doi: 10.1056/NEJMoa040583. 
  41. Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, et al. Early statin treatment in patients with acute coronary syndrome demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: The ESTABLISH Study. Circulation. 2004;110:1061–8. doi: 10.1161/01.CIR.0000140261.58966.A4. 
  42. Schartl M, Bocksch W, Koschyk DH, Voelker W, Karsch KR, Kreuzer J, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation. 2001;104:387–92. doi: 10.1161/hc2901.093188. 
  43. Nissen SE, Tuzcu EM, Schoenhagen P, Brown B, Ganz P, Vogel R, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80. doi: 10.1001/jama.291.9.1071
  44. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–65. doi: 10.1001/jama.295.13.jpc60002. 
  45. Ueda T, Uemura S, Watanabe M, Sugawara Y, Soeda T, Okayama S, et al. Colocalization of thin-cap fibroatheroma and spotty calcification is a powerful predictor of procedure-related myocardial injury after elective coronary stent implantation. Coron Artery Dis. 2014;25:384–91. doi: 10.1097/MCA.0000000000000114.
  46. Rodriguez-Granillo GA, Agostoni P, Garcia-Garcia HM, Biondi-Zoccai GG, McFadden E, Amoroso G, et al. Meta-analysis of the studies assessing temporal changes in coronary plaque volume using intravascular ultrasound. Am J Cardiol. 2007;99:5–10. doi: 10.1016/j.amjcard.2006.07.054. 
  47. Nicholls SJ, Hsu A, Wolski K, Hu B, Bayturan O, Lavoie A, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol. 2010;55:2399–407. doi: 10.1016/j.jacc.2010.02.026. 
  48. Puri R, Nissen SE, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, et al. 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. Arterioscler Thromb Vasc Biol. 2014;34:2465–72. doi: 10.1161/ATVBAHA.114.303932.
  49. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002;106:2200–6. doi: 10.1161/01.CIR.0000035654.18341.5E. 
  50. Pundziute G, Schuijf JD, Jukema JW, Decramer I, Sarno G, Vanhoenacker PK, et al. Evaluation of plaque characteristics in acute coronary syndromes: non-invasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J. 2008;29:2373–81. doi: 10.1093/eurheartj/ehn356.