Laboratory monitoring of P2Y12 inhibitors: communication from the SSC of the ISTH
2018; Elsevier BV; Volume: 16; Issue: 11 Linguagem: Inglês
10.1111/jth.14282
ISSN1538-7933
AutoresAndrew L. Frelinger, Christian Gachet, Andrew Mumford, Patrizia Noris, Diego Mezzano, Paul Harrison, Paolo Gresele,
Tópico(s)Venous Thromboembolism Diagnosis and Management
ResumoDual antiplatelet therapy (DAPT) with aspirin and a P2Y12 platelet adenosine diphosphate (ADP) receptor antagonist reduces ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) but also increases bleeding 1.Mehta S.R. Yusuf S. Peters R.J. Bertrand M.E. Lewis B.S. Natarajan M.K. Malmberg K. Rupprecht H. Zhao F. Chrolavicius S. Copland I. Fox K.A. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial InvestigatorsEffects of pretreatment with clopidogrel and aspirin followed by long‐term therapy in patients undergoing percutaneous coronary intervention: the PCI‐CURE study.Lancet. 2001; 358: 527-33Abstract Full Text Full Text PDF PubMed Scopus (3041) Google Scholar, 2.Wiviott S.D. Braunwald E. McCabe C.H. Montalescot G. Ruzyllo W. Gottlieb S. Neumann F.J. Ardissino D. De Servi S. Murphy S.A. Riesmeyer J. Weerakkody G. Gibson C.M. Antman E.M. TRITON‐TIMI InvestigatorsPrasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2007; 357: 2001-15Crossref PubMed Scopus (5561) Google Scholar, 3.Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Investigators P. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5544) Google Scholar. Residual high on‐treatment platelet reactivity (HPR) and low on‐treatment platelet reactivity (LPR) in response to P2Y12 receptor stimulation, as measured by different platelet function testing (PFT) methodologies, are associated with increased risk of ischemic and bleeding outcomes, respectively (see 4.Cuisset T. Grosdidier C. Loundou A.D. Quilici J. Loosveld M. Camoin L. Pankert M. Beguin S. Lambert M. Morange P.E. Bonnet J.L. Alessi M.C. Clinical implications of very low on‐treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs).JACC Cardiovasc Interv. 2013; 6: 854-63Crossref PubMed Scopus (65) Google Scholar, 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar and the references contained therein for descriptions of PFT assays and definitions of HPR and LPR), suggesting that altering antiplatelet therapy based on PFT would reduce adverse events. Small randomized and non‐randomized studies demonstrated a reduction in ischemic events when P2Y12 inhibitor therapy was modified if PFT indicated HPR (guided therapy) 6.Bonello L. Camoin‐Jau L. Arques S. Boyer C. Panagides D. Wittenberg O. Simeoni M.C. Barragan P. Dignat‐George F. Paganelli F. Adjusted clopidogrel loading doses according to vasodilator‐stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study.J Am Coll Cardiol. 2008; 51: 1404-11Crossref PubMed Scopus (536) Google Scholar, 7.Siller‐Matula J.M. Francesconi M. Dechant C. Jilma B. Maurer G. Delle‐Karth G. Gouya G. Ruzicka K. Podczeck‐Schweighofer A. Christ G. Personalized antiplatelet treatment after percutaneous coronary intervention: the MADONNA study.Int J Cardiol. 2013; 167: 2018-23Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar. However, larger randomized controlled trials, using different PFT methods and different therapeutic strategies, demonstrated no improved outcome with vs. without guided therapy 8.Price M.J. Berger P.B. Teirstein P.S. Tanguay J.F. Angiolillo D.J. Spriggs D. Puri S. Robbins M. Garratt K.N. Bertrand O.F. Stillabower M.E. Aragon J.R. Kandzari D.E. Stinis C.T. Lee M.S. Manoukian S.V. Cannon C.P. Schork N.J. Topol E.J. Gravitas InvestigatorsStandard‐ vs high‐dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.JAMA. 2011; 305: 1097-105Crossref PubMed Scopus (1184) Google Scholar, 9.Trenk D. Stone G.W. Gawaz M. Kastrati A. Angiolillo D.J. Muller U. Richardt G. Jakubowski J.A. Neumann F.J. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug‐eluting stents: results of the TRIGGER‐PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study.J Am Coll Cardiol. 2012; 59: 2159-64Crossref PubMed Scopus (537) Google Scholar, 10.Collet J.P. Cuisset T. Range G. Cayla G. Elhadad S. Pouillot C. Henry P. Motreff P. Carrie D. Boueri Z. Belle L. Van Belle E. Rousseau H. Aubry P. Monsegu J. Sabouret P. O'Connor S.A. Abtan J. Kerneis M. Saint‐Etienne C. et al.ARCTIC InvestigatorsBedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367: 2100-9Crossref PubMed Scopus (759) Google Scholar, 11.Cayla G. Cuisset T. Silvain J. Leclercq F. Manzo‐Silberman S. Saint‐Etienne C. Delarche N. Bellemain‐Appaix A. Range G. El Mahmoud R. Carrie D. Belle L. Souteyrand G. Aubry P. Sabouret P. du Fretay X.H. Beygui F. Bonnet J.L. Lattuca B. Pouillot C. et al.ANTARCTIC InvestigatorsPlatelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open‐label, blinded‐endpoint, randomised controlled superiority trial.Lancet. 2016; 388: 2015-22Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar. PFT has also been proposed as a means to determine when platelet function has recovered sufficiently to enable surgery with minimum risk of bleeding following P2Y12 inhibitor withdrawal 12.Leunissen T.C. Janssen P.W. Ten Berg J.M. Moll F.L. Korporaal S.J. de Borst G.J. Pasterkamp G. Urbanus R.T. The use of platelet reactivity testing in patients on antiplatelet therapy for prediction of bleeding events after cardiac surgery.Vascul Pharmacol. 2016; 77: 19-27Crossref PubMed Scopus (16) Google Scholar and more recently to guide de‐escalation therapy in ACS patients treated with PCI 13.Sibbing D. Aradi D. Jacobshagen C. Gross L. Trenk D. Geisler T. Orban M. Hadamitzky M. Merkely B. Kiss R.G. Komocsi A. Dezsi C.A. Holdt L. Felix S.B. Parma R. Klopotowski M. Schwinger R.H.G. Rieber J. Huber K. Neumann F.J. et al.TROPICAL‐ACS InvestigatorsGuided de‐escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL‐ACS): a randomised, open‐label, multicentre trial.Lancet. 2017; 390: 1747-57Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar. Goals of this position statement are to provide expert opinion on the utility of laboratory monitoring of P2Y12 inhibitors to reduce ischemic and bleeding events in patients on DAPT and to guide timing of surgery if needed in P2Y12 inhibitor‐treated patients. Clopidogrel is a second‐generation (after ticlopidine) thienopyridine oral antiplatelet drug that inhibits ADP‐induced platelet aggregation and decreases major adverse cardiovascular events (MACE) when combined with aspirin, compared to aspirin alone 1.Mehta S.R. Yusuf S. Peters R.J. Bertrand M.E. Lewis B.S. Natarajan M.K. Malmberg K. Rupprecht H. Zhao F. Chrolavicius S. Copland I. Fox K.A. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial InvestigatorsEffects of pretreatment with clopidogrel and aspirin followed by long‐term therapy in patients undergoing percutaneous coronary intervention: the PCI‐CURE study.Lancet. 2001; 358: 527-33Abstract Full Text Full Text PDF PubMed Scopus (3041) Google Scholar. Clopidogrel requires conversion by cytochrome P450 (CYP) enzymes to an active metabolite (CAM), which irreversibly inhibits platelet P2Y12 14.Savi P. Pereillo J.M. Uzabiaga M.F. Combalbert J. Picard C. Maffrand J.P. Pascal M. Herbert J.M. Identification and biological activity of the active metabolite of clopidogrel.Thromb Haemost. 2000; 84: 891-6Crossref PubMed Scopus (703) Google Scholar. CYP gene variants influence production of CAM and the pharmacodynamic response to the drug 15.Mega J.L. Close S.L. Wiviott S.D. Shen L. Hockett R.D. Brandt J.T. Walker J.R. Antman E.M. Macias W. Braunwald E. Sabatine M.S. Cytochrome p‐450 polymorphisms and response to clopidogrel.N Engl J Med. 2009; 360: 354-62Crossref PubMed Scopus (2144) Google Scholar. Loss of function alleles leading to reduced generation of CAM (e.g. CYP2C19*2) have been associated with poor clinical outcomes 16.Collet J.P. Hulot J.S. Pena A. Villard E. Esteve J.B. Silvain J. Payot L. Brugier D. Cayla G. Beygui F. Bensimon G. Funck‐Brentano C. Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.Lancet. 2009; 373: 309-17Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar, 17.Sibbing D. Stegherr J. Latz W. Koch W. Mehilli J. Dorrler K. Morath T. Schomig A. Kastrati A. von Beckerath N. Cytochrome P450 2C19 loss‐of‐function polymorphism and stent thrombosis following percutaneous coronary intervention.Eur Heart J. 2009; 30: 916-22Crossref PubMed Scopus (378) Google Scholar, leading the Food and Drug Administration to issue a boxed warning advising that clopidogrel's effectiveness may be diminished in CYP2C19*2 carriers. Although CYP2C19 variants account for more than 10% of the variability in response to clopidogrel, other factors may contribute to most of the variation, including non‐adherence, under‐dosing, poor absorption, co‐medications (atorvastatin, proton pump inhibitors and calcium antagonists), accelerated platelet turnover, inflammation and underlying platelet hyperreactivity. Thus, demonstration of HPR, the net effect of all of these factors, potentially offers a better predictive marker than these individual factors in clopidogrel‐treated patients 18.Siller‐Matula J.M. Delle‐Karth G. Lang I.M. Neunteufl T. Kozinski M. Kubica J. Maurer G. Linkowska K. Grzybowski T. Huber K. Jilma B. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS‐PCI study.J Thromb Haemost. 2012; 10: 529-42Crossref PubMed Scopus (83) Google Scholar. Newer P2Y12 inhibitors (e.g. prasugrel and ticagrelor) produce greater inhibition of ADP‐dependent platelet function and decrease MACE to a greater extent than clopidogrel 2.Wiviott S.D. Braunwald E. McCabe C.H. Montalescot G. Ruzyllo W. Gottlieb S. Neumann F.J. Ardissino D. De Servi S. Murphy S.A. Riesmeyer J. Weerakkody G. Gibson C.M. Antman E.M. TRITON‐TIMI InvestigatorsPrasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2007; 357: 2001-15Crossref PubMed Scopus (5561) Google Scholar, 3.Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Investigators P. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5544) Google Scholar. Prasugrel, a third‐generation thienopyridine compound, is, like clopidogrel, a prodrug. However, prasugrel's metabolism to active drug is independent of CYP2C19 and the possibility of mutations in this metabolic pathway that could influence platelet inhibition have been previously addressed 19.Farid N.A. Kurihara A. Wrighton S.A. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans.J Clin Pharmacol. 2010; 50: 126-42Crossref PubMed Scopus (348) Google Scholar. In contrast to clopidogrel and prasugrel, ticagrelor, a direct P2Y12 antagonist, is inherently active and thus is unaffected by CYP polymorphisms 20.Teng R. Oliver S. Hayes M.A. Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects.Drug Metab Dispos. 2010; 38: 1514-21Crossref PubMed Scopus (231) Google Scholar. Clopidogrel‐treated patients with HPR show significantly greater inhibition when switched to prasugrel or ticagrelor 21.Wiviott S.D. Trenk D. Frelinger A.L. O'Donoghue M. Neumann F.J. Michelson A.D. Angiolillo D.J. Hod H. Montalescot G. Miller D.L. Jakubowski J.A. Cairns R. Murphy S.A. McCabe C.H. Antman E.M. Braunwald E. PRINCIPLE‐TIMI InvestigatorsPrasugrel 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: 2923-32Crossref PubMed Scopus (815) Google Scholar, 22.Gurbel P.A. Bliden K.P. Butler K. Antonino M.J. Wei C. Teng R. Rasmussen L. Storey R.F. Nielsen T. Eikelboom J.W. Sabe‐Affaki G. Husted S. Kereiakes D.J. Henderson D. Patel D.V. Tantry U.S. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.Circulation. 2010; 121: 1188-99Crossref PubMed Scopus (411) Google Scholar. Nevertheless, even with these antiplatelet agents on‐treatment platelet reactivity is variable, albeit less than with clopidogrel 21.Wiviott S.D. Trenk D. Frelinger A.L. O'Donoghue M. Neumann F.J. Michelson A.D. Angiolillo D.J. Hod H. Montalescot G. Miller D.L. Jakubowski J.A. Cairns R. Murphy S.A. McCabe C.H. Antman E.M. Braunwald E. PRINCIPLE‐TIMI InvestigatorsPrasugrel 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: 2923-32Crossref PubMed Scopus (815) Google Scholar, 22.Gurbel P.A. Bliden K.P. Butler K. Antonino M.J. Wei C. Teng R. Rasmussen L. Storey R.F. Nielsen T. Eikelboom J.W. Sabe‐Affaki G. Husted S. Kereiakes D.J. Henderson D. Patel D.V. Tantry U.S. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.Circulation. 2010; 121: 1188-99Crossref PubMed Scopus (411) Google Scholar, thus their clinical benefit may be reduced in patients with HPR 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar. Moreover, unfortunately a significant fraction of the studies on the clinical efficacy of PFT‐guided antiplatelet therapy have been performed by increasing clopidogrel dose and not by switching to prasugrel or ticagrelor 6.Bonello L. Camoin‐Jau L. Arques S. Boyer C. Panagides D. Wittenberg O. Simeoni M.C. Barragan P. Dignat‐George F. Paganelli F. Adjusted clopidogrel loading doses according to vasodilator‐stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study.J Am Coll Cardiol. 2008; 51: 1404-11Crossref PubMed Scopus (536) Google Scholar, 7.Siller‐Matula J.M. Francesconi M. Dechant C. Jilma B. Maurer G. Delle‐Karth G. Gouya G. Ruzicka K. Podczeck‐Schweighofer A. Christ G. Personalized antiplatelet treatment after percutaneous coronary intervention: the MADONNA study.Int J Cardiol. 2013; 167: 2018-23Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 8.Price M.J. Berger P.B. Teirstein P.S. Tanguay J.F. Angiolillo D.J. Spriggs D. Puri S. Robbins M. Garratt K.N. Bertrand O.F. Stillabower M.E. Aragon J.R. Kandzari D.E. Stinis C.T. Lee M.S. Manoukian S.V. Cannon C.P. Schork N.J. Topol E.J. Gravitas InvestigatorsStandard‐ vs high‐dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.JAMA. 2011; 305: 1097-105Crossref PubMed Scopus (1184) Google Scholar, 10.Collet J.P. Cuisset T. Range G. Cayla G. Elhadad S. Pouillot C. Henry P. Motreff P. Carrie D. Boueri Z. Belle L. Van Belle E. Rousseau H. Aubry P. Monsegu J. Sabouret P. O'Connor S.A. Abtan J. Kerneis M. Saint‐Etienne C. et al.ARCTIC InvestigatorsBedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367: 2100-9Crossref PubMed Scopus (759) Google Scholar. Thus, there is a need for such studies to be undertaken. Arguments against P2Y12 monitoring include cost, variability in individual on‐treatment platelet responsiveness profile, the availability of P2Y12 inhibitors with reduced variability, and the potential use of risk scores 23.Costa F. Tijssen J.G. Ariotti S. Giatti S. Moscarella E. Guastaroba P. De Palma R. Ando G. Oreto G. Zijlstra F. Valgimigli M. Incremental value of the CRUSADE, ACUITY, and HAS‐BLED risk scores for the prediction of hemorrhagic events after coronary stent implantation in patients undergoing long or short duration of dual antiplatelet therapy.J Am Heart Assoc. 2015; 4: e002524Crossref PubMed Scopus (63) Google Scholar to stratify patients. P2Y12 monitoring can be potentially useful in three situations: (i) to assess risk of thrombosis or bleeding in patients treated with P2Y12 inhibitors, (ii) to guide antiplatelet therapy, and (iii) to determine the optimum timing of surgery following P2Y12 inhibitor discontinuation. There is general consensus that HPR has a negative prognostic value for MACE in P2Y12 inhibitor‐treated patients 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar and, although less certain, a predictive value for bleeding 4.Cuisset T. Grosdidier C. Loundou A.D. Quilici J. Loosveld M. Camoin L. Pankert M. Beguin S. Lambert M. Morange P.E. Bonnet J.L. Alessi M.C. Clinical implications of very low on‐treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs).JACC Cardiovasc Interv. 2013; 6: 854-63Crossref PubMed Scopus (65) Google Scholar, 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar. Before 2018, several large randomized clinical trials failed to demonstrate improved clinical outcomes with PFT‐guided antiplatelet therapy 8.Price M.J. Berger P.B. Teirstein P.S. Tanguay J.F. Angiolillo D.J. Spriggs D. Puri S. Robbins M. Garratt K.N. Bertrand O.F. Stillabower M.E. Aragon J.R. Kandzari D.E. Stinis C.T. Lee M.S. Manoukian S.V. Cannon C.P. Schork N.J. Topol E.J. Gravitas InvestigatorsStandard‐ vs high‐dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.JAMA. 2011; 305: 1097-105Crossref PubMed Scopus (1184) Google Scholar, 9.Trenk D. Stone G.W. Gawaz M. Kastrati A. Angiolillo D.J. Muller U. Richardt G. Jakubowski J.A. Neumann F.J. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug‐eluting stents: results of the TRIGGER‐PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study.J Am Coll Cardiol. 2012; 59: 2159-64Crossref PubMed Scopus (537) Google Scholar, 10.Collet J.P. Cuisset T. Range G. Cayla G. Elhadad S. Pouillot C. Henry P. Motreff P. Carrie D. Boueri Z. Belle L. Van Belle E. Rousseau H. Aubry P. Monsegu J. Sabouret P. O'Connor S.A. Abtan J. Kerneis M. Saint‐Etienne C. et al.ARCTIC InvestigatorsBedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367: 2100-9Crossref PubMed Scopus (759) Google Scholar, 11.Cayla G. Cuisset T. Silvain J. Leclercq F. Manzo‐Silberman S. Saint‐Etienne C. Delarche N. Bellemain‐Appaix A. Range G. El Mahmoud R. Carrie D. Belle L. Souteyrand G. Aubry P. Sabouret P. du Fretay X.H. Beygui F. Bonnet J.L. Lattuca B. Pouillot C. et al.ANTARCTIC InvestigatorsPlatelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open‐label, blinded‐endpoint, randomised controlled superiority trial.Lancet. 2016; 388: 2015-22Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar. However, the recent CREATIVE trial 24.Tang Y.D. Wang W. Yang M. Zhang K. Chen J. Qiao S. Yan H. Wu Y. Huang X. Xu B. Gao R. Yang Y. Investigators C. Randomized comparisons of double‐dose clopidogrel or adjunctive cilostazol versus standard dual antiplatelet in patients with high posttreatment platelet reactivity: results of the CREATIVE trial.Circulation. 2018; 137: 2231-45Crossref Scopus (53) Google Scholar, another large randomized study, showed that intensification of antiplatelet therapy (addition of cilostazol) in clopidogrel plus aspirin‐treated PCI patients with HPR, as measured by thromboelastography, significantly improved clinical outcomes (hazard ratio, 0.55; 95% CI, 0.35–0.87) without increasing bleeding. Thus, given these conflicting results, until this recent finding is replicated, consistent with previous guidelines 25.Roffi M. Patrono C. Collet J.P. Mueller C. Valgimigli M. Andreotti F. Bax J.J. Borger M.A. Brotons C. Chew D.P. Gencer B. Hasenfuss G. Kjeldsen K. Lancellotti P. Landmesser U. Mehilli J. Mukherjee D. Storey R.F. Windecker S. Baumgartner H. et al.Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST‐Segment Elevation of the European Society of Cardiology (ESC)2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST‐segment elevation.Eur Heart J. 2016; 37: 267-315Crossref PubMed Scopus (4337) Google Scholar, we believe that this strategy cannot be recommended at this time (Table 1). Given that the newer P2Y12 inhibitors provide greater platelet inhibition and reduce ischemic outcomes compared with clopidogrel, using these agents in patients at high risk of ischemic events without P2Y12 monitoring is reasonable and potentially more cost‐effective than repeated testing. However, improved efficacy is associated with enhanced bleeding and limitations exist to the use of prasugrel 2.Wiviott S.D. Braunwald E. McCabe C.H. Montalescot G. Ruzyllo W. Gottlieb S. Neumann F.J. Ardissino D. De Servi S. Murphy S.A. Riesmeyer J. Weerakkody G. Gibson C.M. Antman E.M. TRITON‐TIMI InvestigatorsPrasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2007; 357: 2001-15Crossref PubMed Scopus (5561) Google Scholar, 3.Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Investigators P. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5544) Google Scholar; moreover, HPR is still observed and is associated with increased risk of ischemic outcomes 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar. Recently, monitoring prasugrel‐treated elderly patients undergoing PCI for ACS was not found to be superior to conventional treatment with respect to both ischemic and bleeding outcomes 11.Cayla G. Cuisset T. Silvain J. Leclercq F. Manzo‐Silberman S. Saint‐Etienne C. Delarche N. Bellemain‐Appaix A. Range G. El Mahmoud R. Carrie D. Belle L. Souteyrand G. Aubry P. Sabouret P. du Fretay X.H. Beygui F. Bonnet J.L. Lattuca B. Pouillot C. et al.ANTARCTIC InvestigatorsPlatelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open‐label, blinded‐endpoint, randomised controlled superiority trial.Lancet. 2016; 388: 2015-22Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar.Table 1Position statement of the Platelet Physiology Scientific and Standardization Committee on the laboratory monitoring of P2Y12 inhibitorsTopic and RecommendationClass†Class of recommendation: IIa, weight of evidence/opinion is in favor of usefulness/efficacy; IIb, usefulness/efficacy is less well established by evidence/opinion; III, evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. ‡Level of evidence: A, data derived from multiple randomized clinical trials or meta‐analyses; B, data derived from a single randomized clinical trial or large non‐randomized studies; C, consensus of opinion of the experts and/or small studies, retrospective studies and registries.Level‡Class of recommendation: IIa, weight of evidence/opinion is in favor of usefulness/efficacy; IIb, usefulness/efficacy is less well established by evidence/opinion; III, evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. ‡Level of evidence: A, data derived from multiple randomized clinical trials or meta‐analyses; B, data derived from a single randomized clinical trial or large non‐randomized studies; C, consensus of opinion of the experts and/or small studies, retrospective studies and registries.ReferencesP2Y12 inhibitor monitoring to assess risk of bleeding or thrombosis during prolonged DAPTHPR and LPR determined by P2Y12‐monitoring as described in [4,5] are associated with risk of ischemic and hemorrhagic events (respectively) and therefore may be considered in the overall management of patients. Optimal timing and frequency of this monitoring are unclear.IIaA[4,5]P2Y12 inhibitor monitoring to adjust P2Y12 inhibitor dose or adjust P2Y12 inhibitor selectionMonitoring P2Y12 inhibition for the purpose of guiding the intensity of antiplatelet therapy is not recommended.IIbB[8–10,24]Monitoring P2Y12 inhibition for the purpose of guiding the duration of DAPT is not recommended.IIbB[8–10,24]P2Y12 inhibitor monitoring for early de‐escalation from prasugrel to clopidogrel in patients considered not suitable for prolonged prasugrel therapyMonitoring P2Y12 inhibition may be considered for early de‐escalation from prasugrel to clopidogrel in patients considered not suitable for prolonged prasugrel therapy.IIbB[13]P2Y12 inhibitor monitoring to shorten the time window to surgery following P2Y12 inhibitor discontinuationIt is reasonable, in balancing the risk of thrombosis during a delay to surgery with the risk of surgical bleeding, to consider the results of P2Y12 inhibitor monitoring to determine the timing of surgeryIIaB[33,34]• A cut‐off of TEG MAADP > 50 is recommended if this test is available• A cut‐off of PFA‐100_P2Y CT 80% that seen in P2Y12 inhibitor‐free patientsIIbC[33,34]CABG, coronary artery bypass graft; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; HPR, high on‐treatment platelet reactivity; LPR, low on‐treatment platelet reactivity; PFA, platelet function analyzer; TEG, thromboelastograph.† Class of recommendation: IIa, weight of evidence/opinion is in favor of usefulness/efficacy; IIb, usefulness/efficacy is less well established by evidence/opinion; III, evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. ‡Level of evidence: A, data derived from multiple randomized clinical trials or meta‐analyses; B, data derived from a single randomized clinical trial or large non‐randomized studies; C, consensus of opinion of the experts and/or small studies, retrospective studies and registries. Open table in a new tab CABG, coronary artery bypass graft; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; HPR, high on‐treatment platelet reactivity; LPR, low on‐treatment platelet reactivity; PFA, platelet function analyzer; TEG, thromboelastograph. Several explanations have been put forth for the failure of large randomized controlled trials to demonstrate improved clinical outcomes with PFT‐guided antiplatelet therapy. HPR might be a non‐modifiable risk factor and/or PFT may not affect prognostic factors, such as adherence to treatment, procedure‐related technical factors or coexisting conditions influencing platelet reactivity 10.Collet J.P. Cuisset T. Range G. Cayla G. Elhadad S. Pouillot C. Henry P. Motreff P. Carrie D. Boueri Z. Belle L. Van Belle E. Rousseau H. Aubry P. Monsegu J. Sabouret P. O'Connor S.A. Abtan J. Kerneis M. Saint‐Etienne C. et al.ARCTIC InvestigatorsBedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367: 2100-9Crossref PubMed Scopus (759) Google Scholar. Nevertheless, given that platelets contribute to arterial thrombosis, greater inhibition of platelet function is predicted to result in reduction of MACE. Thus, it has been alternatively proposed 26.Gurbel P.A. Tantry U.S. Antiplatelet therapy: What have we learned from the ANTARCTIC trial?.Nat Rev Cardiol. 2016; 13: 639-40Crossref Scopus (4) Google Scholar that some previous studies may have been flawed with respect to one or more of the following: (i) study design (e.g. sample size or definition of clinical endpoints), (ii) patient selection (low vs. high risk), (iii) PFT issues (poor predictive value, incorrect cut‐off or improper timing), and (iv) inability of alternative therapy to overcome HPR. The CREATIVE trial may be an example of an appropriate combination of PFT and choice of intensified antiplatelet therapy leading to improved outcomes 24.Tang Y.D. Wang W. Yang M. Zhang K. Chen J. Qiao S. Yan H. Wu Y. Huang X. Xu B. Gao R. Yang Y. Investigators C. Randomized comparisons of double‐dose clopidogrel or adjunctive cilostazol versus standard dual antiplatelet in patients with high posttreatment platelet reactivity: results of the CREATIVE trial.Circulation. 2018; 137: 2231-45Crossref Scopus (53) Google Scholar. Whether optimizing additional parameters would result in improved clinical outcomes with P2Y12 monitoring is unknown, but the results of the CREATIVE trial, registry studies 27.Aradi D. Tornyos A. Pinter T. Vorobcsuk A. Konyi A. Falukozy J. Veress G. Magyari B. Horvath I.G. Komocsi A. Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high‐dose clopidogrel.J Am Coll Cardiol. 2014; 63: 1061-70Crossref PubMed Scopus (77) Google Scholar and model‐based analyses 28.Straub N. Beivers A. Lenk E. Aradi D. Sibbing D. A model‐based analysis of the clinical and economic impact of personalising P2Y12‐receptor inhibition with platelet function testing in acute coronary syndrome patients.Thromb Haemost. 2014; 111: 290-9Crossref PubMed Google Scholar suggest this approach deserves additional testing. Whether P2Y12 monitoring can be of assistance in deciding on DAPT duration has not been assessed. The treatment algorithm for duration of P2Y12 inhibitor therapy suggests that in acute coronary syndromes without ST‐segment elevation or non‐ST‐segment elevation myocardial infarction patients treated with medical therapy or PCI, P2Y12 inhibitor should be maintained for up to 12 months, and thereafter it may be reasonable to continue it if the risk of bleeding is not high 29.Levine G.N. Bates E.R. Bittl J.A. Brindis R.G. Fihn S.D. Fleisher L.A. Granger C.B. Lange R.A. Mack M.J. Mauri L. Mehran R. Mukherjee D. Newby L.K. O'Gara P.T. Sabatine M.S. Smith P.K. Smith Jr, S.C. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST‐elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non‐ST‐elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery.Circulation. 2016; 134: e123-55Crossref PubMed Scopus (887) Google Scholar. Likewise, in patients with stable ischemic heart disease treated with stenting it is reasonable to continue P2Y12 inhibitor beyond 1 or 6 months (for bare metal stent or drug‐eluting stent, respectively) if the risk of bleeding is not high. Long duration of ticagrelor 60 or 90 mg twice daily significantly reduced ischemic outcomes 30.Bonaca M.P. Bhatt D.L. Cohen M. Steg P.G. Storey R.F. Jensen E.C. Magnani G. Bansilal S. Fish M.P. Im K. Bengtsson O. Ophuis T.O. Budaj A. Theroux P. Ruda M. Hamm C. Goto S. Spinar J. Nicolau J.C. Kiss R.G. et al.PEGASUS‐TIMI 54 Steering Committee and InvestigatorsLong‐term use of ticagrelor in patients with prior myocardial infarction.N Engl J Med. 2015; 372: 1791-800Crossref PubMed Scopus (1432) Google Scholar and virtually eliminated HPR 31.Storey R.F. Angiolillo D.J. Bonaca M.P. Thomas M.R. Judge H.M. Rollini F. Franchi F. Ahsan A.J. Bhatt D.L. Kuder J.F. Steg P.G. Cohen M. Muthusamy R. Braunwald E. Sabatine M.S. Platelet inhibition with ticagrelor 60 mg versus 90 mg twice daily in the PEGASUS‐TIMI 54 trial.J Am Coll Cardiol. 2016; 67: 1145-54Crossref PubMed Scopus (96) Google Scholar. However, major bleeding was also increased in these patients, highlighting the need to consider the balance between increased risk of non‐fatal bleeding associated with LPR and the reduced risk of fatal and non‐fatal ischemic events. Although studies have shown a connection between risk of bleeding and LPR 4.Cuisset T. Grosdidier C. Loundou A.D. Quilici J. Loosveld M. Camoin L. Pankert M. Beguin S. Lambert M. Morange P.E. Bonnet J.L. Alessi M.C. Clinical implications of very low on‐treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs).JACC Cardiovasc Interv. 2013; 6: 854-63Crossref PubMed Scopus (65) Google Scholar, 5.Aradi D. Kirtane A. Bonello L. Gurbel P.A. Tantry U.S. Huber K. Freynhofer M.K. ten Berg J. Janssen P. Angiolillo D.J. Siller‐Matula J.M. Marcucci R. Patti G. Mangiacapra F. Valgimigli M. Morel O. Palmerini T. Price M.J. Cuisset T. Kastrati A. et al.Bleeding and stent thrombosis on P2Y12‐inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention.Eur Heart J. 2015; 36: 1762-71Crossref PubMed Scopus (268) Google Scholar, prospective evaluation in clinical trials is required to establish whether PFT may guide duration of DAPT. Most recently, a large randomized trial has shown that a strategy of early PFT‐guided de‐escalation to clopidogrel is non‐inferior to standard treatment with prasugrel in patients with ACS managed with PCI 13.Sibbing D. Aradi D. Jacobshagen C. Gross L. Trenk D. Geisler T. Orban M. Hadamitzky M. Merkely B. Kiss R.G. Komocsi A. Dezsi C.A. Holdt L. Felix S.B. Parma R. Klopotowski M. Schwinger R.H.G. Rieber J. Huber K. Neumann F.J. et al.TROPICAL‐ACS InvestigatorsGuided de‐escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL‐ACS): a randomised, open‐label, multicentre trial.Lancet. 2017; 390: 1747-57Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, suggesting that PFT may be useful in patients not suitable for prolonged therapy with potent P2Y12 inhibitors. Worldwide over three million patients undergo PCI each year, > 90% with stenting, and it is estimated that ≥ 5% will need non‐cardiac surgery within the first year. Current guidelines state that in patients who require non‐emergency major non‐cardiac surgery, postponing surgery for at least 5 days after cessation of ticagrelor or clopidogrel, and 7 days for prasugrel, should be considered unless the patient is at high risk of ischemic events 32.Windecker S. Kolh P. Alfonso F. Collet J.P. Cremer J. Falk V. Filippatos G. Hamm C. Head S.J. Juni P. Kappetein A.P. Kastrati A. Knuuti J. Landmesser U. Laufer G. Neumann F.J. Richter D.J. Schauerte P. Sousa Uva M. Stefanini G.G. et al.2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio‐Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI).Eur Heart J. 2014; 35: 2541-619Crossref PubMed Scopus (3903) Google Scholar. Nevertheless, shortening the delay before surgery is often highly desirable. PFT demonstrated variation between individuals in the time required to recover platelet function following P2Y12 inhibitor discontinuation, and prospective studies showed that a strategy based on preoperative PFT reduced postoperative bleeding and blood consumption and/or shortened waiting time 33.Ranucci M. Baryshnikova E. Soro G. Ballotta A. De Benedetti D. Conti D. for the Surgical and Clinical Outcome Research (SCORE) GroupMultiple electrode whole‐blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines.Ann Thorac Surg. 2011; 91: 123-9Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 34.Mahla E. Suarez T.A. Bliden K.P. Rehak P. Metzler H. Sequeira A.J. Cho P. Sell J. Fan J. Antonino M.J. Tantry U.S. Gurbel P.A. Platelet function measurement‐based strategy to reduce bleeding and waiting time in clopidogrel‐treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel‐associated bleeding related to CABG (TARGET‐CABG) study.Circ Cardiovasc Interv. 2012; 5: 261-9Crossref PubMed Scopus (226) Google Scholar. These results suggest it may be reasonable to decide on surgical timing based on PFT. Recommendations were based on a multistep consensus process (Fig. 1).
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