Failure to Launch: Targeting Inflammation in Acute Coronary Syndromes

Overview

Journal JACC Basic Transl Sci

Date 2018 Aug 1

PMID 30062164

Citations 24

Authors

Jennifer A Rymer

L Kristin Newby

Affiliations

Soon will be listed here.

Abstract

The importance of inflammation and inflammatory pathways in atherosclerotic disease and acute coronary syndromes (ACS) is well established. The success of statin therapy rests not only on potently reducing levels of low-density lipoprotein cholesterol, but also on the many beneficial, pleiotropic effects statin therapy has on various inflammatory mechanisms in atherosclerotic disease, from reducing endothelial dysfunction to attenuating levels of serum C-reactive protein. Due to the growing awareness of the importance of inflammation in ACS, investigators have attempted to develop novel therapies against known markers of inflammation for several decades. Targeted pathways have ranged from inhibiting C5 cleavage with a high-affinity monoclonal antibody against C5 to inhibiting the activation of the p38 mitogen-activated protein kinase signaling cascades. In each of these instances, despite promising early preclinical and mechanistic studies and phase 2 trials suggesting a potential benefit in reducing post-MI complications or restenosis, these novel therapies have failed to show benefits during large, phase 3 clinical outcomes trials. This review discusses several examples of novel anti-inflammatory therapies that failed to show significant improvement on clinical outcomes when tested in large, randomized trials and highlights potential explanations for why targeted therapies against known markers of inflammation in ACS have failed to launch.

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References

Verrier E, Shernan S, Taylor K, Van de Werf F, Newman M, Chen J . Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA. 2004; 291(19):2319-27. DOI: 10.1001/jama.291.19.2319. View

Kugiyama K, Ota Y, Sugiyama S, Kawano H, Doi H, Soejima H . Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol. 2000; 86(7):718-22. DOI: 10.1016/s0002-9149(00)01069-9. View

Hall R, Smith M, Rocker G . The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg. 1997; 85(4):766-82. DOI: 10.1097/00000539-199710000-00011. View

Seljeflot I, Tonstad S, Hjermann I, Arnesen H . Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis. 2002; 162(1):179-85. DOI: 10.1016/s0021-9150(01)00696-7. View

Fleming T . Surrogate endpoints and FDA's accelerated approval process. Health Aff (Millwood). 2005; 24(1):67-78. DOI: 10.1377/hlthaff.24.1.67. View

Tenaglia A, Buda A, WILKINS R, Barron M, Jeffords P, Vo K . Levels of expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris. Am J Cardiol. 1997; 79(6):742-7. DOI: 10.1016/s0002-9149(96)00861-2. View

Burger P, Wagner D . Platelet P-selectin facilitates atherosclerotic lesion development. Blood. 2002; 101(7):2661-6. DOI: 10.1182/blood-2002-07-2209. View

Fitch J, Rollins S, Matis L, Alford B, Aranki S, Collard C . Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation. 1999; 100(25):2499-506. DOI: 10.1161/01.cir.100.25.2499. View

Zhao Z, Winget M . Economic burden of illness of acute coronary syndromes: medical and productivity costs. BMC Health Serv Res. 2011; 11:35. PMC: 3042911. DOI: 10.1186/1472-6963-11-35. View

10.

Wilensky R, Shi Y, Mohler 3rd E, Hamamdzic D, Burgert M, Li J . Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008; 14(10):1059-66. PMC: 2885134. DOI: 10.1038/nm.1870. View

11.

Armstrong P, Granger C, Adams P, Hamm C, Holmes Jr D, ONeill W . Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA. 2007; 297(1):43-51. DOI: 10.1001/jama.297.1.43. View

12.

Rosenson R, Elliott M, Stasiv Y, Hislop C . Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease. Eur Heart J. 2010; 32(8):999-1005. DOI: 10.1093/eurheartj/ehq374. View

13.

Haverich A, Shernan S, Levy J, Chen J, Carrier M, Taylor K . Pexelizumab reduces death and myocardial infarction in higher risk cardiac surgical patients. Ann Thorac Surg. 2006; 82(2):486-92. DOI: 10.1016/j.athoracsur.2005.12.035. View

14.

Schreiber S, Feagan B, DHaens G, Colombel J, Geboes K, Yurcov M . Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006; 4(3):325-34. DOI: 10.1016/j.cgh.2005.11.013. View

15.

Eichstadt H, Eskotter H, Hoffman I, Amthauer H, Weidinger G . Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease. Am J Cardiol. 1995; 76(2):122A-125A. DOI: 10.1016/s0002-9149(05)80033-5. View

16.

Thomas T, Rollins S, Rother R, Giannoni M, Hartman S, Elliott E . Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996; 33(17-18):1389-401. DOI: 10.1016/s0161-5890(96)00078-8. View

17.

ODonoghue M, Braunwald E, White H, Steen D, Lukas M, Tarka E . Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014; 312(10):1006-15. DOI: 10.1001/jama.2014.11061. View

18.

Rosenson R, Hislop C, McConnell D, Elliott M, Stasiv Y, Wang N . Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet. 2009; 373(9664):649-58. DOI: 10.1016/S0140-6736(09)60403-7. View

19.

Yeh R, Sidney S, Chandra M, Sorel M, Selby J, Go A . Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 2010; 362(23):2155-65. DOI: 10.1056/NEJMoa0908610. View

20.

Vakeva A, Agah A, Rollins S, Matis L, Li L, Stahl G . Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation. 1998; 97(22):2259-67. DOI: 10.1161/01.cir.97.22.2259. View