Abstract
Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A2 (TXA2) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7–10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA2 stable analogue (7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP 20 μM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings.
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References
Ferroni P, Basili S, Falco A, Davì G (2004) Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2:1282–1291
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229–234
Creager MA, Lüscher TF, Cosentino F, Beckman JA (2003) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 108:1527–1532
Ferreiro JL, Angiolillo DJ (2011) Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 123:798–813
Rollini F, Franchi F, Muñiz-Lozano A, Angiolillo DJ (2013) Platelet function profiles in patients with diabetes mellitus. J Cardiovasc Transl Res 6:329–345
Daví G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, Patrono C (1990) Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 322:1769–1774
Daví G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494
Fontana P, Alberts P, Sakariassen KS, Bounameaux H, Meyer JP, Santana Sorensen A (2011) The dual thromboxane receptor antagonist and thromboxane synthase inhibitor EV-077 is a more potent inhibitor of platelet function than aspirin. J Thromb Haemost 9:2109–2111
Tello-Montoliu A, Rollini F, Desai B, Pasqualino G, Patel R, Sorensen AS, Sakariassen KS, Angiolillo DJ (2012) Pharmacodynamic effects of EV-077: results of an in vitro pilot investigation in healthy volunteers. J Thromb Thrombolysis 34:297–299
Sakariassen KS, Femia EA, Daray FM, Podda GM, Razzari C, Pugliano M, Errasti AE, Armesto AR, Nowak W, Alberts P, Meyer JP, Sorensen AS, Cattaneo M, Rothlin RP (2012) EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin. Thromb Res 130:746–752
Richardson A, Sakariassen KS, Meyer JP, Alberts P, Sorensen AS (2013) Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation. Eur J Clin Pharmacol 69:459–465
Alberti KG, Zimmet PZ, WHO Consultation (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553
Sakariassen KS, Muggli R, Baumgartner HR (1989) Measurements of platelet interaction with components of the vessel wall in flowing blood. Methods Enzymol 169:37–70
Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA (2007) A randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the OPTIMUS (optimizing anti-platelet therapy in diabetes mellitus) study. Circulation 115:708–716
Lancaster GA, Dodd S, Williamson PR (2004) Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 10:307–312
Huang JS, Ramamurthy SK, Lin X, Le Breton GC (2004) Cell signalling through thromboxane A2 receptors. Cell Signal 16:521–533
Daví G, Ciabattoni G, Consoli A et al (1999) In vivo formation of 8-iso-prostaglandinF2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 99:224–229
Santilli F, Daví G, Consoli A et al (2006) Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol 47:391–397
Meade EA, Smith WL, DeWitt DL (1993) Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268:6610–6614
Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R et al (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:1849–1860
Di Chiara J, Bliden KP, Tantry US et al (2007) The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes 56:3014–3019
Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ (2002) Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 90:625–628
Angiolillo DJ, Bernardo E, Sabaté M, Jimenez-Quevedo P, Costa MA, Palazuelos J, Hernández-Antolin R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Guzman LA, Bass TA, Macaya C, Fernandez-Ortiz A (2007) Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 50:1541–1547
Nakahata N (2008) Thromboxane A2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacol Ther 118:18–35
Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, Hennerici MG, Mattle HP, Rothwell PM, de Cordoue A, Fratacci MD (2011) Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. Lancet 377:2013–2022
Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction. The Ridogrel Versus Aspirin Patency Trial (RAPT). (1994) Circulation 89:588–595
Neri Serneri GG, Coccheri S, Marubini E, Violi F (2004) Drug evaluation in atherosclerotic vascular disease in diabetics (DAVID) study group. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur Heart J 25:1845–1852
Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B (2000) Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 101:2823–2828
Acknowledgments
We thank Evolva SA, Reinach, Switzerland, for providing EV-077 and financial support.
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Fabiana Rollini, Antonio Tello-Montoliu, Ronakkumar Patel, Andrew Darlington, Ryan E. Wilson, Francesco Franchi, Ana Muñiz-Lozano, Bhaloo Desai declare that they have no conflict of interest to report. Norbert Bender is previous Chief Medical Officer of Evolva SA. Kjell S. Sakariassen is previous Member of Cardiovascular Board of Evolva SA. Dominick J. Angiolillo received payment as an individual for: (a) Consulting fee or honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and PLx Pharma; (b) Participation in review activities from Johnson & Johnson, St. Jude, and Sunovion. Institutional payments for grants from Bristol Myers Squibb, Sanofi-Aventis, Glaxo Smith Kline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva; and has other financial relationships with Esther and King Biomedical Research Grant.
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Rollini, F., Tello-Montoliu, A., Patel, R. et al. Pharmacodynamic effects of EV-077 in patients with diabetes mellitus and coronary artery disease on aspirin or clopidogrel monotherapy: results of an in vitro pilot investigation. J Thromb Thrombolysis 37, 131–138 (2014). https://doi.org/10.1007/s11239-013-0979-8
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DOI: https://doi.org/10.1007/s11239-013-0979-8