Effect of alirocumab on coronary plaque in patients with coronary artery disease assessed by optical coherence tomography

Fei Gao, Zhi Jian Wang, Xiao Teng Ma, Hua Shen, Li Xia Yang, Yu Jie Zhou, Fei Gao, Zhi Jian Wang, Xiao Teng Ma, Hua Shen, Li Xia Yang, Yu Jie Zhou

Abstract

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited.

Methods: In this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up.

Results: LDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8-29.2] μm vs 13.2 [7.4-18.6] μm; P = 0.029), greater increases in minimum lumen area (0.20[0.10-0.33] mm2 vs 0.13 [0.12-0.24] mm2; P = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8-24.5] vs. 8.4̊ [2.0-10.5]; P = 0.008).

Conclusions: The addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype.

Trial registration: ClinicalTrials.gov Identifier: NCT04851769 . Registered 2 Mar 2019.

Keywords: Coronary artery disease; Coronary plaque; Optical coherence tomography; PCSK9 inhibitors; Statins.

Conflict of interest statement

None.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow
Fig. 2
Fig. 2
Representative OCT imaging. Changes in fibrous cap thickness (white arrows) between baseline and follow-up in a patient with alirocumab

References

    1. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;140(11):e596–e646. doi: 10.1161/CIR.0000000000000678.
    1. Michos ED, McEvoy JW, Blumenthal RS. Lipid management for the prevention of atherosclerotic cardiovascular disease. N Engl J Med. 2019;381(16):1557–1567. doi: 10.1056/NEJMra1806939.
    1. Gao F, Zhou YJ, Hu DY, Zhao YX, Liu YY, Wang ZJ, et al. Contemporary management and attainment of cholesterol targets for patients with Dyslipidemia in China results of a Chinese Society of Cardiology National Survey -- REALITY-CHINA SURVEY. PLoS One. 2013;8(4):e47681. doi: 10.1371/journal.pone.0047681.
    1. Nicholls SJ, Nissen SE, Prati F, Windecker S, Kataoka Y, Puri R, et al. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovasc Diagn Ther. 2021;11(1):120–129. doi: 10.21037/cdt-20-684.
    1. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499. doi: 10.1056/NEJMoa1501031.
    1. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. doi: 10.1056/NEJMoa1615664.
    1. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107. doi: 10.1056/NEJMoa1801174.
    1. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, et al. Effect of Evolocumab on coronary plaque composition. J Am Coll Cardiol. 2018;72:2012–2021. doi: 10.1016/j.jacc.2018.06.078.
    1. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316:2373–2384. doi: 10.1001/jama.2016.16951.
    1. Ako J, Hibi K, Tsujita K, Hiro T, Morino Y, Kozuma K, et al. Effect of Alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndrome - the ODYSSEY J-IVUS trial. Circ J. 2019;83:2025–2033. doi: 10.1253/circj.CJ-19-0412.
    1. Gragnano F, Calabrò P. Role of dual lipid-lowering therapy in coronary atherosclerosis regression: evidence from recent studies. Atherosclerosis. 2018;269:219–228. doi: 10.1016/j.atherosclerosis.2018.01.012.
    1. 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;20:1262–1275. doi: 10.1161/01.atv.20.5.1262.
    1. Kolodgie FD, Burke AP, Farb A, Gold HK, Yuan J, Narula J, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol. 2001;16:285–292. doi: 10.1097/00001573-200109000-00006.
    1. Komukai K, Kubo T, Kitabata H, Matsuo Y, Ozaki Y, Takarada S, et al. 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;64:2207–2217. doi: 10.1016/j.jacc.2014.08.045.
    1. Kini A, Vengrenyuk Y, Shameer K, Maehara A, Purushothaman M, Yoshimura T, et al. Intracoronary imaging, cholesterol efflux, and Transcriptomes after intensive statin treatment: the YELLOW II study. J Am Coll Cardiol. 2017;69(6):628–640. doi: 10.1016/j.jacc.2016.10.029.
    1. Kim Y, Johnson TW, Akasaka T, Jeong MH. The role of optical coherence tomography in the setting of acute myocardial infarction. J Cardiol. 2018;72:186–192. doi: 10.1016/j.jjcc.2018.03.004.
    1. Kume T, Akasaka T, Kawamoto T, Okura H, Watanabe N, Toyota E, et al. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J. 2006;152:755. e1–755. e4. doi: 10.1016/j.ahj.2006.06.030.
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502. doi: 10.1093/clinchem/18.6.499.
    1. Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG, et al. Consensus standards for acquisition, measurement, and reporting of intravas- cular optical coherence tomography studies: a report from the international working Group for Intravascular Optical Coherence Tomography Standardiza- tion and validation. J Am Coll Cardiol. 2012;59:1058–1072. doi: 10.1016/j.jacc.2011.09.079.
    1. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Executive group on behalf of the joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/world heart federation (WHF) task force for the universal definition of myocardial infarction. J Am Coll Cardiol. 2018;72(18):2231–2264. doi: 10.1016/j.jacc.2018.08.1038.
    1. Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078–2087. doi: 10.1056/NEJMoa1110874.
    1. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–1080. doi: 10.1001/jama.291.9.1071.
    1. Del Pinto R, Grassi D, Properzi G, Desideri G, Ferri C. Low density lipoprotein (LDL) cholesterol as a causal role for atherosclerotic disease: potential role of PCSK9 inhibitors. High Blood Press Cardiovasc Prev. 2019;26:199–207. doi: 10.1007/s40292-019-00323-7.
    1. Johnson TW, Räber L, di Mario C, Bourantas C, Jia H, Mattesini A, Gonzalo N, et al. Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J. 2019;40(31):2566–2584. doi: 10.1093/eurheartj/ehz332.
    1. Yano H, Horinaka S, Ishimitsu T. Effect of evolocumab therapy on coronary fibrous cap thickness assessed by optical coherence tomography in patients with acute coronary syndrome. J Cardiol. 2020;75(3):289–295. doi: 10.1016/j.jjcc.2019.08.002.
    1. Sugizaki Y, Otake H, Kawamori H, Toba T, Nagano Y, Tsukiyama Y, et al. Adding Alirocumab to Rosuvastatin helps reduce the vulnerability of thin-cap Fibroatheroma: an ALTAIR trial report. JACC Cardiovasc Imaging. 2020;13(6):1452–1454. doi: 10.1016/j.jcmg.2020.01.021.
    1. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29–38. doi: 10.1056/NEJMoa042000.
    1. Puri R, Nissen SE, Libby P, Shao M, Ballantyne CM, Barter PJ, et al. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation. 2013;128:2395–2403. doi: 10.1161/CIRCULATIONAHA.113.004243.
    1. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–28. doi: 10.1056/NEJMoa042378.
    1. Schmidt AF, Hunt NB, Gordillo-Marañón M, Charoen P, Drenos F, et al. Cholesteryl ester transfer protein as a drug target for cardiovascular disease. medRxiv. 2020. 10.1101/2020.09.07.20189571.
    1. Masson W, Lobo M, Siniawski D, Molinero G, Masson G, Huerín M, et al. Role of non-statin lipid-lowering therapy in coronary atherosclerosis regression: a meta-analysis and meta-regression. Lipids Health Dis. 2020;19(1):111. doi: 10.1186/s12944-020-01297-5.
    1. Cesaro A, Gragnano F, Fimiani F, Moscarella E, Diana V, Pariggiano I, et al. Impact of PCSK9 inhibitors on the quality of life of patients at high cardiovascular risk. Eur J Prev Cardiol. 2020;27(5):556–558. doi: 10.1177/2047487319839179.
    1. Gragnano F, Natale F, Concilio C, Fimiani F, Cesaro A, Sperlongano S, et al. Adherence to proprotein convertase subtilisin/kexin 9 inhibitors in high cardiovascular risk patients: an Italian single-center experience. J Cardiovasc Med (Hagerstown) 2018;19(2):75–77. doi: 10.2459/JCM.0000000000000611.
    1. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation. 1994;89:503–505. doi: 10.1161/01.cir.89.1.503.
    1. Sawada T, Shite J, Garcia-Garcia HM, Shinke T, Watanabe S, Otake H, et al. Feasibility of combined use of intravascular ultrasound radiofrequency data analysis and optical coherence tomography for detecting thin-cap fibroatheroma. Eur Heart J. 2008;29:1136–1146. doi: 10.1093/eurheartj/ehn132.
    1. 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;364:226–235. doi: 10.1056/NEJMoa1002358.
    1. Nishiguchi T, Kubo T, Tanimoto T, Ino Y, Matsuo Y, Yamano T, et al. Effect of early pitavastatin therapy on coronary fibrous-cap thickness assessed by optical coherence tomography in patients with acute coronary syndrome: the ESCORT study. JACC Cardiovasc Imaging. 2018;11:829–838. doi: 10.1016/j.jcmg.2017.07.011.
    1. Zanchin C, Koskinas KC, Ueki Y, Losdat S, Häner JD, Bär S, et al. Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study-rationale and design of the PACMAN-AMI trial. Am Heart J. 2021;238:33–44. doi: 10.1016/j.ahj.2021.04.006.
    1. Min JK, Chandrashekhar Y, Narula J. The immediate effects of statins on coronary atherosclerosis. JACC Cardiovasc Imaging. 2018;11:839–841. doi: 10.1016/j.jcmg.2017.08.008.
    1. Otake H, Sugizaki Y, Toba T, Nagano Y, Tsukiyama Y, Yanaka KI, et al. Efficacy of alirocumab for reducing plaque vulnerability: study protocol for ALTAIR, a randomized controlled trial in Japanese patients with coronary artery disease receiving rosuvastatin. J Cardiol. 2019;73(3):228–232. doi: 10.1016/j.jjcc.2018.11.012.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe