Impact of LDL-cholesterol Lowering on Platelet Activation

Summary

The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol. The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.

Timeline

Start

2018-11-16

Primary completion

2020-02-04

Completion

2020-02-04

Publications

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• Background Wada H, Mori Y, Kaneko T, Wakita Y, Nakase T, Minamikawa K, Ohiwa M, Tamaki S, Tanigawa M, Kageyama S, et al. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol. 1993 Oct;44(2):112-6. doi: 10.1002/ajh.2830440208.
• Background Davi G, Romano M, Mezzetti A, Procopio A, Iacobelli S, Antidormi T, Bucciarelli T, Alessandrini P, Cuccurullo F, Bittolo Bon G. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation. 1998 Mar 17;97(10):953-7. doi: 10.1161/01.cir.97.10.953.
• Background Garlichs CD, John S, Schmeisser A, Eskafi S, Stumpf C, Karl M, Goppelt-Struebe M, Schmieder R, Daniel WG. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation. 2001 Nov 13;104(20):2395-400. doi: 10.1161/hc4501.099312.
• Background Puccetti L, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palazzuoli A, Angori P, Auteri A, Bruni F. Time-dependent effect of statins on platelet function in hypercholesterolaemia. Eur J Clin Invest. 2002 Dec;32(12):901-8. doi: 10.1046/j.1365-2362.2002.01086.x.
• Background Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation. 2013 Jan 15;127(2):251-7. doi: 10.1161/CIRCULATIONAHA.112.145334. No abstract available.
• Background Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1405-10. doi: 10.1016/j.jacc.2005.03.077.
• Background Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, Falco A, Cuccurullo F, Davi G. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation. 2002 Jul 23;106(4):399-402. doi: 10.1161/01.cir.0000025419.95769.f0.
• Background Undas A, Brummel-Ziedins KE, Potaczek DP, Stobierska-Dzierzek B, Bryniarski L, Szczeklik A, Mann KG. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost. 2006 Nov;4(11):2397-404. doi: 10.1111/j.1538-7836.2006.02165.x. Epub 2006 Aug 14.
• Background Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015 Mar 16;11(1):115-21. doi: 10.5114/aoms.2015.49216. Epub 2015 Mar 14.
• Background Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21.
• Background Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29.
• Background Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15.
• Background Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1. No abstract available.
• Background Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study. JACC Cardiovasc Interv. 2013 Feb;6(2):169-79. doi: 10.1016/j.jcin.2012.09.013.
• Background Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. Pharmacodynamic effects of adjunctive high dose atorvastatin on double dose clopidogrel in patients with high on-treatment platelet reactivity depending on diabetes mellitus status. J Thromb Thrombolysis. 2014 May;37(4):427-34. doi: 10.1007/s11239-013-0966-0.
• Background Sikora J, Kostka B, Marczyk I, Krajewska U, Chalubinski M, Broncel M. Effect of statins on platelet function in patients with hyperlipidemia. Arch Med Sci. 2013 Aug 30;9(4):622-8. doi: 10.5114/aoms.2013.36905. Epub 2013 Aug 8.

Drugs

Indications