Thromb Haemost 2014; 112(02): 224-242
DOI: 10.1160/TH13-11-0915
Review Article
Schattauer GmbH

Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors

Piotr Adamski
1   Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Marek Koziński
1   Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Małgorzata Ostrowska
1   Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Tomasz Fabiszak
2   Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Eliano Pio Navarese
2   Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Przemysław Paciorek
3   Department of Emergency Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Grzegorz Grześk
2   Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
4   Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
,
Jacek Kubica
2   Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
› Author Affiliations
Further Information

Publication History

Received: 06 November 2013

Accepted after major revision: 21 February 2014

Publication Date:
21 November 2017 (online)

Summary

Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.

 
  • References

  • 1 Gachet C. P2Y12 receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal 2012; 08: 609-619.
  • 2 Bernlochner I, Sibbing D. Thienopyridines and other ADP-receptor antagonists. Handb Exp Pharmacol 2012; 210: 165-198.
  • 3 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
  • 4 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
  • 5 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularisation. N Engl J Med 2012; 367: 1297-1309.
  • 6 Harrington RA, Stone GW, McNulty S. et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318-2329.
  • 7 Bhatt DL, Lincoff AM, Gibson CM. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
  • 8 Bhatt DL, Stone GW, Mahaffey KW. et al. Effect of platelet inhibition with cangrelor during PCI on ischaemic events. N Engl J Med 2013; 368: 1303-1313.
  • 9 Steg PG, Bhatt DL, Hamm CW. et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013; 382: 1981-1992.
  • 10 Welsh RC, Rao SV, Zeymer U. et al. A randomised, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial. Circ Cardiovasc Interv 2012; 05: 336-346.
  • 11 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
  • 12 Högberg C, Svensson H, Gustafsson R. et al. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol 2010; 142: 187-192.
  • 13 Wihlborg AK, Wang L, Braun OO. et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 2004; 24: 1810-1815.
  • 14 Diehl P, Olivier C, Halscheid C. et al. Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes. Basic Res Cardiol 2010; 105: 379-387.
  • 15 Kronlage M, Song J, Sorokin L. et al. Autocrine purinergic receptor signalling is essential for macrophage chemotaxis. Sci Signal 2010; 03: ra55.
  • 16 Haynes SE, Hollopeter G, Yang G. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 2006; 09: 1512-1519.
  • 17 Ben Addi A, Cammarata D, Conley PB. et al. Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. J Immunol 2010; 185: 5900-5906.
  • 18 Warnholtz A, Ostad MA, Velich N. et al. A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomised study. Atherosclerosis 2008; 196: 689-695.
  • 19 André P, DeGuzman F, Haberstock-Debic H. et al. Thienopyridines, but not elinogrel, result in off-target effects at the vessel wall that contribute to bleeding. J Pharmacol Exp Ther 2011; 338: 22-30.
  • 20 Froldi G, Bertin R, Dorigo P. et al. Endothelium-independent vasorelaxation by ticlopidine and clopidogrel in rat caudal artery. J Pharm Pharmacol 2011; 63: 1056-1062.
  • 21 Xiao Z, Théroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 2004; 43: 1982-1988.
  • 22 Quinn MJ, Bhatt DL, Zidar F. et al. Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol 2004; 93: 679-684.
  • 23 Antonino MJ, Mahla E, Bliden KP. et al. Effect of long-term clopidogrel treatment on platelet function and inflammation in patients undergoing coronary arterial stenting. Am J Cardiol 2009; 103: 1546-1550.
  • 24 Donaldson CW, Schneider DJ, Bertges DJ. et al. Increased local cytokine production at culprit superficial femoral artery plaques. J Thromb Thrombolysis 2013; 36: 293-299.
  • 25 Takeda M, Yamashita T, Shinohara M. et al. Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging. Int J Cardiovasc Imaging 2012; 28: 1181-1191.
  • 26 Totani L, Dell’Elba G, Martelli N. et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost 2012; 107: 1130-1140.
  • 27 Bonello L, Laine M, Kipson N. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2013 Epub ahead of print
  • 28 van Giezen JJ, Sidaway J, Glaves P. et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 2012; 17: 164-172.
  • 29 Alexopoulos D, Moulias A, Koutsogiannis N. et al. Differential Effect of Ticagrelor Versus Prasugrel on Coronary Blood Flow Velocity in Patients With Non-ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: An Exploratory Study. Circ Cardiovasc Interv 2013; 06: 277-283.
  • 30 Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G. et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 2013; 61: 723-727.
  • 31 Ohman J, Kudira R, Albinsson S. et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun 2012; 418: 754-758.
  • 32 Torngren K, Ohman J, Salmi H. et al. Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome. Cardiology 2013; 124: 252-258.
  • 33 Grzesk G, Kozinski M, Navarese EP. et al. Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats. Thromb Res 2012; 130: 65-69.
  • 34 Grzesk G, Kozinski M, Tantry US. et al. High-dose, but not low-dose, aspirin impairs anticontractile effect of ticagrelor following ADP stimulation in rat tail artery smooth muscle cells. Biomed Res Int 2013; 2013: 928271.
  • 35 Yang XM, Liu Y, Cui L. et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 2013; 18: 251-262.
  • 36 Yang XM, Liu Y, Cui L. et al. Two classes of anti-platelet drugs reduce anatomical infarct sisatio in monkey hearts. Cardiovasc Drugs Ther 2013; 27: 109-115.
  • 37 Serebruany VL. Mortality benefit in PLATO cannot be explained by antiplatelet properties of ticagrelor. Cardiology 2010; 117: 231-233.
  • 38 Navarese EP, Buffon A, Kozinski M. et al. A critical overview on ticagrelor in acute coronary syndromes. Quart J Med 2013; 106: 105-115.
  • 39 Storey RF, James SK, Siegbahn A. et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets. 2013 Epub ahead of print
  • 40 Storey RF, Bliden KP, Patil SB. et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol 2010; 56: 185-193.
  • 41 Storey RF, Becker RC, Harrington RA. et al. Characterisation of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011; 32: 2945-2953.
  • 42 Scirica BM, Cannon CP, Emanuelsson H. et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy. J Am Coll Cardiol 2011; 57: 1908-1916.
  • 43 Cattaneo M, Faioni EM. Why does ticagrelor induce dyspnea?. Thromb Haemost 2012; 108: 1031-1036.
  • 44 Serebruany VL. Adenosine release: a potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial?. Am Heart J 2011; 161: 1-4.
  • 45 Varenhorst C, Alström U, Scirica BM. et al. Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol 2012; 60: 1623-1630.
  • 46 Navarese EP, Buffon A, Andreotti F. et al. Adenosine improves post-procedural coronary flow but not clinical outcomes in patients with acute coronary syndrome: a meta-analysis of randomised trials. Atherosclerosis 2012; 222: 1-7.
  • 47 Lee CW, Hwang I, Park CS. et al. Comparison of differential expression of P2Y12 receptor in culprit coronary plaques in patients with acute myocardial infarction versus stable angina pectoris. Am J Cardiol 2011; 108: 799-803.
  • 48 Ostad MA, Nick E, Paixao-Gatinho V. et al. Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomised CASSANDRA study. Clin Res Cardiol 2011; 100: 29-36.
  • 49 Angiolillo DJ, Schneider DJ, Bhatt DL. et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012; 34: 44-55.
  • 50 Kubica J, Kozinski M, Navarese EP. et al. Cangrelor: an emerging therapeutic option for patients with coronary artery disease. Curr Med Res Opin. 2014 Epub ahead of print
  • 51 Bhatt DL, Stone GW, Mahaffey KW. et al. Effect of platelet inhibition with cangrelor during PCI on ischaemic events. N Engl J Med 2013; 368: 1303-1313.
  • 52 Muhlestein JB. Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 2010; 103: 71-82.
  • 53 Steinhubl SR, Badimon JJ, Bhatt DL. et al. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007; 12: 113-122.
  • 54 Malek LA, Grabowski M, Spiewak M. et al. Relation between impaired antiplatelet response to clopidogrel and possible pleiotropic effects. J Thromb Thrombolysis 2007; 24: 301-305.
  • 55 Ge H, Zhou Y, Liu X. et al. Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty. Angiology 2012; 63: 62-66.
  • 56 Bernlochner I, Steinhubl S, Braun S. et al. Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. Thromb Haemost 2010; 104: 1193-1200.
  • 57 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006; 55: 780-784.
  • 58 Liverani E, Rico MC, Garcia AE. et al. Prasugrel metabolites inhibit neutrophil functions. J Pharmacol Exp Ther 2013; 344: 231-243.
  • 59 Ridker PM, Rifai N, Pfeffer MA. et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100: 230-235.
  • 60 Musial J, Undas A, Gajewski P. et al. Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia. Int J Cardiol 2001; 77: 247-253.
  • 61 Ridker PM, Rifai N, Clearfield M. et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959-1965.
  • 62 Serebruany VL. Platelet inhibition with prasugrel and increased cancer risks: potential causes and implications. Am J Med 2009; 122: 407-408.
  • 63 Unger EF. Weighing benefits and risks - The FDA’s review of prasugrel. N Engl J Med 2009; 361: 942-945.
  • 64 FDA Briefing Material. Briefing Information for the February 3, 2009 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM181185.pdf Accessed January 11, 2014
  • 65 Chen L, Fredholm BB, Jondal M. Adenosine, through the A1 receptor, inhibits vesicular MHC class I cross-presentation by resting DC. Mol Immunol 2008; 45: 2247-2254.
  • 66 Jacobson KA, Hoffmann C, Cattabeni F. et al. Adenosine-induced cell death: evidence for receptor-mediated signalling. Apoptosis 1999; 04: 197-211.
  • 67 Fishman P, Bar-Yehuda S, Synowitz M. et al. Adenosine receptors and cancer. Handb Exp Pharmacol 2009; 193: 399-441.
  • 68 Jajoo S, Mukherjea D, Watabe K. et al. Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia 2009; 11: 1132-1145.
  • 69 Navarese EP, Verdoia M, Schaffer A. et al. Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomised trials. Quart J Med 2011; 104: 561-569.
  • 70 Mahaffey KW, Wojdyla DM, Carroll K. et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011; 124: 544-554.
  • 71 AstraZeneca, Brilinta REMS Document, NDA 22-433, 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000REMS.pdf Accessed January 11, 2014
  • 72 Gurbel PA, Erlinge D, Ohman EM. et al. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularisation: the TRILOGY ACS platelet function substudy. J Am Med Assoc 2012; 308: 1785-1794.
  • 73 Biondi-Zoccai G, Lotrionte M, Agostoni P. et al. Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. Int J Cardiol 2011; 150: 325-331.