Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry

Christoph B. Olivier; Philipp Diehl; Katharina Schnabel; Patrick Weik; Qian Zhou; Christoph Bode; Martin Moser

doi:10.1160/TH13-06-0508

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(02): 266-272
DOI: 10.1160/TH13-06-0508

Platelets and Blood Cells

Schattauer GmbH

Third generation P2Y₁₂ antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry

Authors

Christoph B. Olivier

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Philipp Diehl

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Katharina Schnabel

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Patrick Weik

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Qian Zhou

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Christoph Bode

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany
Martin Moser

¹Heart Center Freiburg University, Cardiology and Angiology I, Freiburg, Germany

Abstract

Summary

The current standard of antiplatelet therapy of patients after myocardial infarction includes the P2Y₁₂ receptor antagonists clopidogrel, prasugrel or ticagrelor. This study aimed to compare the antiplatelet effect of clopidogrel, prasugrel and ticagrelor in patients after myocardial infarction. In a single-centre registry the antiplatelet effect of clopidogrel, prasugrel and ticagrelor was investigated by aggregometry in patients after myocardial infarction. To assess the overall capacity of platelet aggregation whole blood was induced with thrombin receptor activating peptide (TRAP; 32 μM). To specifically quantify the effect of P2Y₁₂ antagonists, whole blood was stimulated with 6.4 μM adenosine diphophosphate (ADP). Relative ADP induced aggregation (r-ADP-agg) was defined as the ADP-TRAP ratio to reflect an individual degree of P2Y₁₂-dependent platelet inhibition. Platelet function of 238 patients was analysed [clopidogrel (n=58), prasugrel (n=65), ticagrelor (n=115)]. The r-ADP-agg was 35 ± 14% for patients receiving clopidogrel, 28 ± 10% for patients receiving prasugrel and 26 ± 11% for patients receiving ticagrelor. The r-ADP-agg was significantly lower in patients treated with prasugrel (p=0.0024) or ticagrelor (p<0.0001) compared to clopidogrel. There was no significant difference between patients receiving prasugrel or ticagrelor (p=0.2559). In conclusion, prasugrel and ticagrelor provide a stronger platelet inhibition compared to clopidogrel in patients after myocardial infarction. No significant difference in platelet inhibition was detected between prasugrel and ticagrelor. (registry for patients after Myocardial Infarction Treated with AntiPlatelet agents; DRKS00003146).

Keywords

Clopidogrel - prasugrel - ticagrelor - platelet - aggregation - P2Y₁₂

Full Text

References

References
1 Lopez AD, Mathers CD, Ezzati M. et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747-1757.
2 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
3 Hamm CW, Bassand JP, Agewall S. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054.
4 Jneid H, Anderson JL, Wright RS. et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elev-ation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2012; 126: 875-910.
5 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619.
6 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
7 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopido-grel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
8 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
9 Montalescot G, Sideris G, Cohen R. et al. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACA-PULCO study. Thromb Haemost 2010; 103: 213-223.
10 Angiolillo DJ, Saucedo JF, Deraad R. et al. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study. J Am Coll Cardiol 2010; 56: 1017-1023.
11 Gurbel PA, Bliden KP, Butler K. et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577-2585.
12 Storey RF, Husted S, Harrington RA. et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopido-grel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852-1856.
13 Storey RF, Angiolillo DJ, Patil SB. et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56: 1456-1462.
14 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.
15 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.
16 Wang WE, Wang H, Wang X. et al. A transition of P2Y antagonists for acute coronary syndrome: benefits, risks and costs. J Thromb Thrombolysis. 2013 Epub ahead of print.
17 Kristensen SD, Grove EL, Hvas AM. P2Y12 inhibitors in acute coronary syndromes: how do we choose the best drug for our patients?. Thromb Haemost 2012; 108: 203-205.
18 Olivier C, Diehl P, Bode C. et al. Thrombin Receptor Antagonism in Antiplatelet Therapy. Cardiol Therapy 2013; 2: 57-68.
19 Badr Eslam R, Lang IM, Koppensteiner R. et al. Residual platelet activation through protease-activated receptors (PAR)-1 and -4 in patients on P2Y12 inhibitors. Int J Cardiol. 2012 Epub ahead of print.
20 Gremmel T, Calatzis A, Steiner S. et al. Is TRAP-6 suitable as a positive control for platelet reactivity when assessing response to clopidogrel?. Platelets 2010; 21: 515-521.
21 Voisin S, Bongard V, Tidjane MA. et al. Are P2Y12 reaction unit (PRU) and% inhibition index equivalent for the expression of P2Y12 inhibition by the Ver-ifyNow assay? Role of haematocrit and haemoglobin levels. Thromb Haemost 2011; 106: 227-229.
22 Montalescot G, Dallongeville J, Van Belle E. et al. STEMI and NSTEMI: are they so different? 1 year outcomes in acute myocardial infarction as defined by the ESC/ACC definition (the OPERA registry). Eur Heart J 2007; 28: 1409-1417.
23 Tardiff BE, Jennings LK, Harrington RA. et al. Pharmacodynamics and pharma-cokinetics of eptifibatide in patients with acute coronary syndromes: prospective analysis from PURSUIT. Circulation 2001; 104: 399-405.
24 Focks JJ, Brouwer MA, van Oijen MG. et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart 2013; 99: 520-527.
25 Gilard M, Arnaud B, Cornily JC. et al. Influence of omeprazole on the antipla-telet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
26 Zhang R, Ran HH, Zhu HL. et al. Differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation. J Intern Med Res 2010; 38: 1617-1625.
27 Ren YH, Zhao M, Chen YD. et al. Omeprazole affects clopidogrel efficacy but not ischaemic events in patients with acute coronary syndrome undergoing elective percutaneous coronary intervention. Chinese Med J 2011; 124: 856-861.
28 Lin CF, Shen LJ, Wu FL. et al. Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan. Br J Clin Pharmacol 2012; 74: 824-834.
29 Fernando H, Bassler N, Habersberger J. et al. Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel. J Thromb Haemost 2011; 9: 1582-1589.
30 Siller-Matula JM, Spiel AO, Lang IM. et al. Effects of pantoprazole and esome-prazole on platelet inhibition by clopidogrel. Am Heart J 2009; 157: 148e141-145.
31 Sibbing D, Morath T, Stegherr J. et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.
32 Gremmel T, Steiner S, Seidinger D. et al. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. J Cardiovasc Pharmacol 2010; 56: 532-539.
33 Mizia-Stec K, Haberka M, Mizia M. et al. Effects of pantoprazole on dual anti-platelet therapy in stable angina pectoris patients after percutaneous coronary intervention. Pharmacol Rep 2012; 64: 360-368.
34 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loading-and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
35 Michelson AD, Frelinger AL, 3rd Braunwald E. et al. Pharmacodynamic assessment of platelet inhibition by prasugrel vs clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-1763.
36 Alexopoulos D, Galati A, Xanthopoulou I. et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012; 60: 193-199.
37 Alexopoulos D, Xanthopoulou I, Gkizas V. et al. Randomized Assessment of Ti-cagrelor Versus Prasugrel Antiplatelet Effects in Patients with ST-Segment-Elev-ation Myocardial Infarction. Circ Cardiovasc Interv 2012; 5: 797-804.
38 Collet JP, Cuisset T, Range G. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
39 Frossard M, Fuchs I, Leitner JM. et al. Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation 2004; 110: 1392-1397.
40 Parodi G, Marcucci R, Valenti R. et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. J Am Med Assoc 2011; 306: 1215-1223.
41 Heestermans AA, van Werkum JW, Taubert D. et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res 2008; 122: 776-781.
42 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.

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