Relationship of Platelet Reactivity With Bleeding Outcomes During Long-Term Treatment With Dual Antiplatelet Therapy for Medically Managed Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Jan H Cornel, E Magnus Ohman, Benjamin Neely, Joseph A Jakubowski, Deepak L Bhatt, Harvey D White, Diego Ardissino, Keith A A Fox, Dorairaj Prabhakaran, Paul W Armstrong, David Erlinge, Udaya S Tantry, Paul A Gurbel, Matthew T Roe, Jan H Cornel, E Magnus Ohman, Benjamin Neely, Joseph A Jakubowski, Deepak L Bhatt, Harvey D White, Diego Ardissino, Keith A A Fox, Dorairaj Prabhakaran, Paul W Armstrong, David Erlinge, Udaya S Tantry, Paul A Gurbel, Matthew T Roe

Abstract

Background: The relationship between "on-treatment" low platelet reactivity and longitudinal risks of major bleeding dual antiplatelet therapy following acute coronary syndromes remains uncertain, especially for patients who do not undergo percutaneous coronary intervention.

Methods and results: We analyzed 2428 medically managed acute coronary syndromes patients from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial who had serial platelet reactivity measurements (P2Y12 reaction units; PRUs) and were randomized to aspirin+prasugrel versus aspirin+clopidogrel for up to 30 months. Contal's method was used to determine whether a cut point for steady-state PRU values could distinguish high versus low bleeding risk using 2-level composites: Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life-threatening or moderate bleeding unrelated to coronary artery bypass grafting (CABG) and non-CABG Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding. Exploratory analyses used 3-level composites that incorporated mild and minimal GUSTO and TIMI events. Continuous measures of PRUs (per 10-unit decrease) were not independently associated with the 2-level GUSTO (adjusted hazard ratio [HR], 1.01; 95% CI, 0.96-1.06) or TIMI composites (1.02; 0.98-1.07). Furthermore, no PRU cut point could significantly distinguish bleeding risk using the 2-level composites. However, the PRU cut point of 75 differentiated bleeding risk with the 3-level composites of GUSTO (26.5% vs 12.6%; adjusted HR, 2.28; 95% CI, 1.77-2.94; P<0.001) and TIMI bleeding events (25.9% vs 12.2%; adjusted HR, 2.30; 95% CI, 1.78-2.97; P<0.001).

Conclusions: Among medically managed non-ST-segment elevation acute coronary syndromes patients receiving prolonged dual antiplatelet therapy, PRU values were not significantly associated with the long-term risk of major bleeding events, suggesting that low on-treatment platelet reactivity does not independently predict serious bleeding risk.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998.

Keywords: DAPT; hemorrhage; platelet.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Cumulative Kaplan–Meier (KM) estimates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life‐threatening (LT) or moderate (A) and Thrombolysis In Myocardial Infarction (TIMI) major or minor (B) bleeding events by P2Y12 reaction unit (PRU) tertiles of distribution.
Figure 2
Figure 2
Cumulative Kaplan–Meier (KM) estimates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life‐threatening (LT), or moderate bleeding (A); Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding (B); GUSTO severe/LT, moderate, or mild bleeding (C); and TIMI major, minor, or minimal bleeding (D) events by the derived low platelet reactivity cut point in P2Y12 reaction units (PRUs).

References

    1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol Ç, Fitzsimons D, Halle M, Hamm C, Hildick‐Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis Zamorano J. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST‐segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST‐Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:267–315.
    1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry . 2014 AHA/ACC guideline for the management of patients with non‐ST‐elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139–e228.
    1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators . Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST‐segment elevation. N Engl J Med. 2001;345:494–502.
    1. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON‐TIMI 38 Investigators . Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators , Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
    1. Kearney JF Jr. Balancing the risks and benefits of dual platelet inhibition. N Engl J Med. 2015;372:1854–1856.
    1. Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Schömig A, von Beckerath N, Kastrati A. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010;8:250–256.
    1. Patti G, Pasceri V, Vizzi V, Ricottini E, Di Sciascio G. Usefulness of platelet response to clopidogrel by point‐of‐care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty‐Bleeding Study). Am J Cardiol. 2011;107:995–1000.
    1. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, Siller‐Matula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbing D, Gurbel PA; Working Group on On‐Treatment Platelet Reactivity . Consensus and update on the definition of on‐treatment platelet reactivity to ADP associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62:2261–2273.
    1. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva‐Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteză M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRILOGY ACS Investigators . Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367:1297–1309.
    1. Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee . Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non‐ST‐segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J. 2010;160:16–22.e1.
    1. Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M, Goodman SG, Huber K, Chan MY, Cornel JH, Brown E, Zhou C, Jakubowski JA, White HD, Fox KA, Prabhakaran D, Armstrong PW, Tantry US, Roe MT; TRILOGY ACS Platelet Function Substudy Investigators . Platelet function during extended prasugrel and clopidogrel therapy for patients with acs treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA. 2012;308:1785–1794.
    1. Contal C, O'Quigley J. An application of changepoint methods in studying the effect of age on survival in breast cancer. Comput Stat Data Anal. 1999;30:253–270.
    1. Bhatt DL, Paré G, Eikelboom JW, Simonsen KL, Emison ES, Fox KA, Steg PG, Montalescot G, Bhakta N, Hacke W, Flather MD, Mak KH, Cacoub P, Creager MA, Berger PB, Steinhubl SR, Murugesan G, Mehta SR, Kottke‐Marchant K, Lincoff AM, Topol EJ; CHARISMA Investigators . The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study. Eur Heart J. 2012;33:2143–2150.
    1. Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW, Avezum A, Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, Gulba DC, Guneri S, Gurfinkel E, Harrington R, Hochman JS, Kleiman NS, Leon MB, Lopez‐Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, Toro‐Figueroa L, White H; SYNERGY Trial Investigators . Enoxaparin vs unfractionated heparin in high‐risk patients with non‐ST‐segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292:45–54.
    1. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel JH, French J, Held C, Horrow J, Husted S, Lopez‐Sendon J, Lassila R, Mahaffey KW, Storey RF, Harrington RA, Wallentin L. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32:2933–2944.
    1. Giugliano RP, White JA, Bode C, Armstrong PW, Montalescot G, Lewis BS, van‘t Hof A, Berdan LG, Lee KL, Strony JT, Hildemann S, Veltri E, Van de Werf F, Braunwald E, Harrington RA, Califf RM, Newby LK; EARLY ACS Investigators . Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med. 2009;360:2176–2190.
    1. Wiviott SD, White HD, Ohman EM, Fox KA, Armstrong PW, Prabhakaran D, Hafley G, Lokhnygina Y, Boden WE, Hamm C, Clemmensen P, Nicolau JC, Menozzi A, Ruzyllo W, Widimsky P, Oto A, Leiva‐Pons J, Pavlides G, Winters KJ, Roe MT, Bhatt DL. Prasugrel versus clopidogrel for patients with unstable angina or non‐ST‐segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet. 2013;382:605–613.
    1. Moscucci M, Fox KA, Cannon CP, Klein W, López‐Sendón J, Montalescot G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003;24:1815–1823.
    1. Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, Wang TY, Gibler WB, Ohman EM, Roe MT, Pollack CV Jr, Peterson ED, Alexander KP. Baseline risk of major bleeding in non‐ST‐segment‐elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009;119:1873–1882.
    1. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, Parise H, Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumi G, Lansky AJ, Stone GW. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55:2556–2566.
    1. Mathews R, Peterson ED, Chen AY, Wang TY, Chin CT, Fonarow GC, Cannon CP, Rumsfeld JS, Roe MT, Alexander KP. In‐hospital major bleeding during ST‐elevation and non‐ST‐elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®‐GWTG™ . Am J Cardiol. 2011;107:1136–1143.
    1. Genereux P, Giustino G, Witzenbichler B, Weisz G, Stuckey TD, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Yadav M, Francese DP, Palmerini T, Kirtane AJ, Litherland C, Mehran R, Stone GW. Incidence, predictors, and impact of post‐discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol. 2015;66:1036–1145.
    1. Roe MT, Goodman SG, Ohman EM, Stevens SR, Hochman JS, Gottlieb S, Martinez F, Dalby AJ, Boden WE, White HD, Prabhakaran D, Winters KJ, Aylward PE, Bassand JP, McGuire DK, Ardissino D, Fox KA, Armstrong PW. Elderly patients with acute coronary syndromes managed without revascularization: Insights into the safety of long‐term dual antiplatelet therapy with reduced‐dose prasugrel versus standard‐dose clopidogrel. Circulation. 2013;128:823–833.
    1. Cuisset T, Cayla G, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Morange PE, Alessi MC, Bonnet JL. Predictive value of post‐treatment platelet reactivity for occurrence of post‐discharge bleeding after non‐ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention. 2009;5:325–329.
    1. Aradi D, Kirtane A, Bonello L, Gurbel PA, Tantry US, Huber K, Freynhofer MK, ten Berg J, Janssen P, Angiolillo DJ, Siller‐Matula JM, Marcucci R, Patti G, Mangiacapra F, Valgimigli M, Morel O, Palmerini T, Price MJ, Cuisset T, Kastrati A, Stone GW, Sibbing D. 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;36:1762–1771.
    1. Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monségu J, Sabouret P, O'Connor SA, Abtan J, Kerneis M, Saint‐Etienne C, Barthélémy O, Beygui F, Silvain J, Vicaut E, Montalescot G; ARCTIC Investigators . Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100–2109.
    1. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT‐DES Investigators . Platelet reactivity and clinical outcomes after coronary artery implantation of drug‐eluting stents (ADAPT‐DES): a prospective multicentre registry study. Lancet. 2013;382:614–623.
    1. Mangiacapra F, Ricottini E, Barbato E, Demartini C, Peace A, Patti G, Vizzi V, De Bruyne B, Wijns W, Di Sciascio G. Incremental value of platelet reactivity over a risk score of clinical and procedural variables in predicting bleeding after percutaneous coronary intervention via the femoral approach: development and validation of a new bleeding risk score. Circ Cardiovasc Interv. 2015;8:e002106.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera