Effects of Rivaroxaban on Vascular FMD in Patients With Stable Atherosclerotic Vascular Diseases

Summary

The specific mechanistic benefit of rivaroxaban versus other FXa inhibitors on atherothrombotic events remain unclear. Therefore plan to initiate a prospective, randomized study to investigate the effect of rivaroxaban and aspirin versus aspirin alone on changes of number circulating endothelial cells and endothelial function, and alteration in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases. The working hypothesis of this trial is that rivaroxaban and aspirin is superior to aspirin alone improvement in the number of circulating endothelial cells and endothelial function, assessed by flow-mediated vasodilatation, and reduction in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases at 3 months follow-up.

Timeline

Start

2021-05-04

Primary completion

2023-08-28

Completion

2024-03-01

Publications

• Results Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011 May 5;364(18):1746-60. doi: 10.1056/NEJMra1011670. No abstract available.
• Results Spronk HM, de Jong AM, Crijns HJ, Schotten U, Van Gelder IC, Ten Cate H. Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants. Cardiovasc Res. 2014 Mar 1;101(3):344-51. doi: 10.1093/cvr/cvt343. Epub 2014 Jan 2.
• Results Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014 Apr 1;111(4):625-33. doi: 10.1160/TH13-09-0730. Epub 2013 Dec 12.
• Results Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41-57. doi: 10.1146/annurev-med-062209-095159.
• Results Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011 Aug 25;365(8):699-708. doi: 10.1056/NEJMoa1105819. Epub 2011 Jul 24.
• Results Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Jan 5;366(1):9-19. doi: 10.1056/NEJMoa1112277. Epub 2011 Nov 13.
• Results Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Stork S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330. doi: 10.1056/NEJMoa1709118. Epub 2017 Aug 27.
• Results Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, Metsarinne K, O'Donnell M, Dans AL, Ha JW, Parkhomenko AN, Avezum AA, Lonn E, Lisheng L, Torp-Pedersen C, Widimsky P, Maggioni AP, Felix C, Keltai K, Hori M, Yusoff K, Guzik TJ, Bhatt DL, Branch KRH, Cook Bruns N, Berkowitz SD, Anand SS, Varigos JD, Fox KAA, Yusuf S; COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Jan 20;391(10117):205-218. doi: 10.1016/S0140-6736(17)32458-3. Epub 2017 Nov 10.
• Results Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, Aboyans V, Alings M, Kakkar AK, Keltai K, Maggioni AP, Lewis BS, Stork S, Zhu J, Lopez-Jaramillo P, O'Donnell M, Commerford PJ, Vinereanu D, Pogosova N, Ryden L, Fox KAA, Bhatt DL, Misselwitz F, Varigos JD, Vanassche T, Avezum AA, Chen E, Branch K, Leong DP, Bangdiwala SI, Hart RG, Yusuf S; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018 Jan 20;391(10117):219-229. doi: 10.1016/S0140-6736(17)32409-1. Epub 2017 Nov 10.
• Results Alvarez E, Paradela-Dobarro B, Raposeiras-Roubin S, Gonzalez-Juanatey JR. Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium. Br J Clin Pharmacol. 2018 Feb;84(2):280-291. doi: 10.1111/bcp.13440. Epub 2017 Oct 25.
• Results Lee IO, Kratz MT, Schirmer SH, Baumhakel M, Bohm M. The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. J Pharmacol Exp Ther. 2012 Nov;343(2):253-7. doi: 10.1124/jpet.112.194837. Epub 2012 Jul 25.
• Results Borissoff JI, Otten JJ, Heeneman S, Leenders P, van Oerle R, Soehnlein O, Loubele ST, Hamulyak K, Hackeng TM, Daemen MJ, Degen JL, Weiler H, Esmon CT, van Ryn J, Biessen EA, Spronk HM, ten Cate H. Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One. 2013;8(2):e55784. doi: 10.1371/journal.pone.0055784. Epub 2013 Feb 7.
• Results Ragosta M, Gimple LW, Gertz SD, Dunwiddie CT, Vlasuk GP, Haber HL, Powers ER, Roberts WC, Sarembock IJ. Specific factor Xa inhibition reduces restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits. Circulation. 1994 Mar;89(3):1262-71. doi: 10.1161/01.cir.89.3.1262.
• Results Borissoff JI, Heeneman S, Kilinc E, Kassak P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyak K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation. 2010 Aug 24;122(8):821-30. doi: 10.1161/CIRCULATIONAHA.109.907121. Epub 2010 Aug 9.

Drugs

Indications