The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial

Abstract

Background

Apabetalone is a selective bromodomain and extra-terminal (BET) inhibitor which modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated coronary atherosclerotic plaque (AP), a measure of vulnerability, is unknown.

Methods

The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE; NCT01067820) study employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in 281 patients treated with apabetalone or placebo for 26 weeks. AP was measured at baseline and follow-up. Factors associated with changes in AP were investigated.

Results

AP was observed in 31 patients (11%) [27 (13.0%) in the apabetalone group and four (5.5%) in the placebo group]. The apabetalone group demonstrated reductions in AP length by − 1 mm [interquartile range (IQR) − 4, 1] (p = 0.03), AP arc by − 37.0° (IQR − 59.2, 8.2) (p = 0.003) and the AP index by − 34.6 mm° (IQR − 52.6, 10.1) (p = 0.003) from baseline. The change in AP index correlated with on-treatment concentration of high-density lipoprotein (HDL) particles (r = − 0.52, p = 0.006), but not HDL cholesterol (r = − 0.11, p = 0.60) or apolipoprotein A-1 (r = − 0.16, p = 0.43). Multivariable analysis revealed that on-treatment concentrations of HDL particles (p = 0.03) and very low-density lipoprotein particles (p = 0.01) were independently associated with changes in AP index.

Conclusions

Apabetalone favorably modulated ultrasonic measures of plaque vulnerability in the population studied, which may relate to an increase in HDL particle concentrations. The clinical implications are currently being investigated in the phase 3 major adverse cardiac event outcomes trial BETonMACE.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Nicholls SJ, Gordon A, Johansson J, et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol. 2011;57:1111–9.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:2580–9.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Gilham D, Wasiak S, Tsujikawa LM, et al. RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease. Atherosclerosis. 2016;247:48–57.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Pu J, Mintz GS, Biro S, et al. Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2294 human coronary artery segments. J Am Coll Cardiol. 2014;63:2220–33.

    Article  PubMed  Google Scholar 

  5. 5.

    Nicholls SJ, Puri R, Wolski K, et al. Effect of the BET protein inhibitor, RVX-208, on progression of coronary atherosclerosis: results of the phase 2b, randomized, double-blind, multicenter, ASSURE trial. Am J Cardiovasc Drugs. 2016;16:55–65.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Mackey RH, Greenland P, Goff DC Jr, Lloyd-Jones D, Sibley CT, Mora S. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2012;60:508–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation. 2009;119:931–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556–63.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Tanaka A, Kawarabayashi T, Nishibori Y, et al. No-reflow phenomenon and lesion morphology in patients with acute myocardial infarction. Circulation. 2002;105:2148–52.

    Article  PubMed  Google Scholar 

  10. 10.

    Wu X, Mintz GS, Xu K, et al. The relationship between attenuated plaque identified by intravascular ultrasound and no-reflow after stenting in acute myocardial infarction: the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc Interv. 2011;4:495–502.

    Article  PubMed  Google Scholar 

  11. 11.

    Shiono Y, Kubo T, Tanaka A, et al. Impact of attenuated plaque as detected by intravascular ultrasound on the occurrence of microvascular obstruction after percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2013;6:847–53.

    Article  PubMed  Google Scholar 

  12. 12.

    Sutsch G, Kiowski W, Bossard A, et al. Use of an emboli containment and retrieval system during percutaneous coronary angioplasty in native coronary arteries. Schweiz Med Wochenschr. 2000;130:1135–45.

    CAS  PubMed  Google Scholar 

  13. 13.

    Kimura S, Kakuta T, Yonetsu T, et al. Clinical significance of echo signal attenuation on intravascular ultrasound in patients with coronary artery disease. Circ Cardiovasc Interv. 2009;2:444–54.

    Article  PubMed  Google Scholar 

  14. 14.

    Bayturan O, Tuzcu EM, Nicholls SJ, et al. Attenuated plaque at nonculprit lesions in patients enrolled in intravascular ultrasound atherosclerosis progression trials. JACC Cardiovasc Interv. 2009;2:672–8.

    Article  PubMed  Google Scholar 

  15. 15.

    Nicholls SJ, Ray KK, Johansson JO, et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs. 2018;18:109–15.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Wasiak S, Gilham D, Tsujikawa LM, et al. Downregulation of the complement cascade in vitro, in mice and in patients with cardiovascular disease by the BET protein inhibitor apabetalone (RVX-208). J Cardiovasc Transl Res. 2017;10:337–47.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wasiak S, Gilham D, Tsujikawa LM, et al. Data on gene and protein expression changes induced by apabetalone (RVX-208) in ex vivo treated human whole blood and primary hepatocytes. Data Brief. 2016;8:1280–8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Nicholls SJ, Cutri B, Worthley SG, et al. Impact of short-term administration of high-density lipoproteins and atorvastatin on atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 2005;25:2416–21.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Brewer HB Jr. HDL metabolism and the role of HDL in the treatment of high-risk patients with cardiovascular disease. Curr Cardiol Rep. 2007;9:486–92.

    Article  PubMed  Google Scholar 

  20. 20.

    Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95:764–72.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707–14.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    von Birgelen C, Hartmann M, Mintz GS, Baumgart D, Schmermund A, Erbel R. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial long-term (> or = 12 months) follow-up intravascular ultrasound. Circulation. 2003;108:2757–62.

    Article  CAS  Google Scholar 

  23. 23.

    Johnsen SH, Mathiesen EB, Fosse E, et al. Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromso study. Circulation. 2005;112:498–504.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Investigators A-H, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  CAS  Google Scholar 

  26. 26.

    Landray MJ, Haynes R, Group HTC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Monette JS, Hutchins PM, Ronsein GE, et al. Patients with coronary endothelial dysfunction have impaired cholesterol efflux capacity and reduced HDL particle concentration. Circ Res. 2016;119:83–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Jahagirdar R, Zhang H, Azhar S, et al. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis. 2014;236:91–100.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Hodis HN, Mack WJ. Triglyceride-rich lipoproteins and the progression of coronary artery disease. Curr Opin Lipidol. 1995;6:209–14.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS) Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol. 1996;16:697–704.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Peter J. Psaltis is supported by a Future Leader Fellowship from the National Heart Foundation of Australia and project Grant funding from the National Health and Medical Research Council and National Heart Foundation of Australia. Stephen J. Nicholls is supported by a Principal Research Fellowship from the National Health and Medical Research Council of Australia.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stephen J. Nicholls.

Ethics declarations

Conflict of interest

Peter J. Psaltis has received research support from Abbott Vascular and speaker honoraria from AstraZeneca, Merck and Bayer. Stephen J. Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck Schering-Plough and Takeda, consulting fees from AstraZeneca, Abbott, Atheronova, Esperion, Amgen, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, Pfizer, Merck Schering-Plough, Takeda, Roche, NovoNordisk, LipoScience and Anthera and research support from Anthera, AstraZeneca, Cerenis, EliLilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. Jan Johansson, Ewelina Kulikowski, Norman Wong and Michael Sweeney are employees of Resverlogix Corp. Other authors (Daisuke Shishikura, Yu Kataoka, Satoshi Honda, Kohei Takata, Susan W. Kim, and Jordan Andrews) have nothing to disclose.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shishikura, D., Kataoka, Y., Honda, S. et al. The Effect of Bromodomain and Extra-Terminal Inhibitor Apabetalone on Attenuated Coronary Atherosclerotic Plaque: Insights from the ASSURE Trial. Am J Cardiovasc Drugs 19, 49–57 (2019). https://doi.org/10.1007/s40256-018-0298-8

Download citation