Risk of Major Bleeding With Potent Antiplatelet Agents After an Acute Coronary Event: A Comparison of Ticagrelor and Clopidogrel in 5116 Consecutive Patients in Clinical Practice

Liam Mullen, Mohammed N Meah, Ahmed Elamin, Suneil Aggarwal, Adeel Shahzad, Matthew Shaw, Jaroslav Hasara, Muhammad Rashid, Michael Fisher, Turab Ali, Billal Patel, Wern Y Ding, Ruth Grainger, Thomas Heseltine, Bilal H Kirmani, Mohammed Obeidat, Yande Kasolo, Jecko Thatchil, Aleem Khand, Liam Mullen, Mohammed N Meah, Ahmed Elamin, Suneil Aggarwal, Adeel Shahzad, Matthew Shaw, Jaroslav Hasara, Muhammad Rashid, Michael Fisher, Turab Ali, Billal Patel, Wern Y Ding, Ruth Grainger, Thomas Heseltine, Bilal H Kirmani, Mohammed Obeidat, Yande Kasolo, Jecko Thatchil, Aleem Khand

Abstract

Background Major bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk. Methods and Results Major bleeding, subsequent myocardial infarction (MI), and all-cause mortality to 1 year were compared in consecutive patients with acute coronary syndrome treated with clopidogrel (n=2491 between 2011 and 2013) and ticagrelor (n=2625 between 2012 and 2015) in 5 English hospitals. Clinical outcomes were identified from national hospital episode statistics. Bleeding and MI events were independently adjudicated by 2 experienced clinicians, blinded to drug, sequence, and year. Bleeding events were categorized using Bleeding Academic Research Consortium 3 to 5 and PLATO (Platelet Inhibition and Patient Outcomes) criteria and MI by the Third Universal Definition. Multivariable regression analysis was used to adjust outcomes for case mix. The median age was 68 years and 34% were women. 39% underwent percutaneous coronary intervention and 13% coronary artery bypass graft surgery. Clinical outcome data were 100% complete for bleeding and 99.7% for MI. No statistically significant difference was seen in crude or adjusted major bleeding for ticagrelor compared with clopidogrel (Bleeding Academic Research Consortium 3-5, hazard ratio [HR], 1.23; 95% CI, 0.90-1.68; P=0.2, PLATO major adjusted HR, 1.30; 95% CI, 0.98-1.74; P=0.07) except in the non-coronary artery bypass graft cohort (n=4464), where bleeding was more frequent with ticagrelor (Bleeding Academic Research Consortium 3-5, adjusted HR, 1.58; 95% CI, 1.09-2.31; P=0.017; and PLATO major HR, 1.67; 95% CI, 1.18-2.37; P=0.004). There was no difference in crude or adjusted subsequent MI (adjusted HR, 1.20; 95% CI, 0.87-1.64; P=0.27). Crude mortality was higher in the clopidogrel group but not after adjustment, using either Cox proportional hazards or propensity matched population (HR, 0.90; 95% CI, 0.76-1.10; P=0.21) as was the case for stroke (HR, 0.82; 95% CI, 0.52-1.32; P=0.42). Conclusions This observational study indicates that the apparent benefit of ticagrelor demonstrated in a clinical trial population may not be observed in the broader population encountered in clinical practice. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02484924.

Keywords: acute coronary syndrome; antiplatelet; bleeding.

Conflict of interest statement

Dr Khand has been a speaker or expert member and has received fees from the following companies: Bayer, Daiichi Sankyo, Astra Zeneca, Menarini, St Jude, and Abbot Vascular. Dr Khand has received research funds from the following companies: Bayer medical, Menarini, Dragons Den awards (Liverpool University hospitals). Dr Khand holds research contracts with Abbott Diagnostics. Dr Khand is the director for Northwest Educational Cardiac Group (nwecg), a not‐for‐profit medical educational group and has received sponsorship for educational courses from Bayer, Astra Zeneca, Genzyme (Sanofi), Daiichi Sankyo, Circle Cardiovascular, Menarini, and Circle. Dr Khand works with the Northwest Coast Innovation agency in England, is a clinical champion for high sensitive troponins with funds awarded (both personal payment for work and transformation funding) for dissemination of accelerated diagnostic pathways. Mullen is secretary of NWECG (north West Educational Cardiac Group, a not‐for‐profit medical educational group). NWECG has received sponsorship for educational courses from Bayer, Astra Zeneca, Genzyme (Sanofi), Daiichi Sankyo, Circle Cardiovascular, Menarini, and Circle. Mullen and Khand are guarantors of the data. The remaining authors have no disclosures to report.

Figures

Figure 1. Flowchart of final population.
Figure 1. Flowchart of final population.
ACS indicates acute coronary syndrome.
Figure 2. Flowchart of outcome derivation of…
Figure 2. Flowchart of outcome derivation of subsequent myocardial infarction and bleeding events to 1 year.
^Hospital episode statistics; *Prespecified criteria and duplications. ACS indicates acute coronary syndrome; BARC, Bleeding Academic Research Consortium; HES, hospital episode statistics; MI, myocardial infarction; and PLATO, Platelet Inhibition and Patient Outcomes.
Figure 3. Unadjusted and adjusted Cox proportional…
Figure 3. Unadjusted and adjusted Cox proportional hazard ratios for primary and secondary outcomes at 12 months.
*BARC indicates Bleeding Academic Research Consortium; and **PLATO, Platelet Inhibition and Patient Outcomes.

References

    1. Investigators TC in UA to PRET . 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. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann F‐J, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, et al. 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. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
    1. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Mahaffey KW, Moliterno DJ, Lincoff AM, Armstrong PW, Van De Werf F, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol. 2006;47:809–816.
    1. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Jonasson J, Minematsu K, Molina CA, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:35–43.
    1. Baigent C, Sudlow C, Collins R, Peto R. Collaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J. 2002;324:71.
    1. Li L, Geraghty OC, Mehta Z, Rothwell PM. Age‐specific risks, severity, time course, and outcome of bleeding on long‐term antiplatelet treatment after vascular events: a population‐based cohort study. Lancet. 2017;390:490–499.
    1. Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C, Madsen JK, Hansen PR, Køber L, Torp‐Pedersen C, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009;374:1967–1974.
    1. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
    1. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381:1524–1534.
    1. Herrett E, Smeeth L, Walker L, Weston C. The myocardial ischaemia national audit project (MINAP). Heart. 2010;96:1264–1267. DOI: 10.1136/hrt.2009.192328.
    1. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, et al. Standardized bleeding definitions for cardiovascular clinical trials. Circulation. 2011;123:2736–2747. DOI: 10.1161/CIRCULATIONAHA.110.009449.
    1. Cohen J. Weighted kappa: nominal scale agreement provision for scaled disagreement or partial credit. Psychol Bull. 1968;70:213–220. DOI: 10.1037/h0026256.
    1. Udell JA, Bonaca MP, Collet JP, Lincoff AM, Kereiakes DJ, Costa F, Lee CW, Mauri L, Valgimigli M, Park SJ, et al. Long‐term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta‐analysis of randomized trials. Eur Heart J. 2016;37:390–399.
    1. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J, Husted S, Steg PG, Cornel JH, Storey RF, et al. Ticagrelor vs. clopidogrel in patients with non‐ST‐elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014;35:2083–2093. DOI: 10.1093/eurheartj/ehu160.
    1. Burns EM, Rigby E, Mamidanna R, Bottle A, Aylin P, Ziprin P, Faiz OD. Systematic review of discharge coding accuracy. J Public Health. 2012;34:138–148. DOI: 10.1093/pubmed/fdr054.
    1. Kivimäki M, Batty GD, Singh‐Manoux A, Britton A, Brunner EJ, Shipley MJ. Validity of cardiovascular disease event ascertainment using linkage to UK hospital records. Epidemiology. 2017;28:735–739. DOI: 10.1097/EDE.0000000000000688.
    1. Rush CJ, Campbell RT, Jhund PS, Petrie MC, McMurray JJV. Association is not causation: treatment effects cannot be estimated from observational data in heart failure. Eur Heart J. 2018;39:3417–3438. DOI: 10.1093/eurheartj/ehy407.
    1. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, et al. Long‐term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791–1800. DOI: 10.1056/NEJMoa1500857.
    1. Sahlén A, Varenhorst C, Lagerqvist B, Renlund H, Omerovic E, Erlinge D, Wallentin L, James SK, Jernberg T. Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry. Eur Heart J. 2016;37:3335–3342. DOI: 10.1093/eurheartj/ehw284.
    1. Olier I, Sirker A, Hildick‐Smith DJR, Kinnaird T, Ludman P, De Belder MA, Baumbach A, Byrne J, Rashid M, Curzen N, et al. Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention. Heart. 2018;104:20.
    1. Zocca P, Van Der Heijden LC, Kok MM, Löwik MM, Hartmann M, Stoel MG, Louwerenburg JW, De Man FHAF, Linssen GCM, Knottnerus IL, et al. Clopidogrel or ticagrelor in acute coronary syndrome patients treated with newer‐generation drug‐eluting stents: CHANGE DAPT. EuroIntervention. 2017;13:1168–1176.
    1. Turgeon RD, Koshman SL, Youngson E, Har B, Wilton SB, James MT, Graham MM. Association of ticagrelor vs clopidogrel with major adverse coronary events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. JAMA Intern Med. 2020;180:420–428.
    1. Von Birgelen C, Sen H, Lam MK, Danse PW, Jessurun GAJ, Hautvast RWM, Van Houwelingen GK, Schramm AR, Gin RMTJ, Louwerenburg JW, et al. Third‐generation zotarolimus‐eluting and everolimus‐eluting stents in all‐comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single‐blind, multicentre, non‐inferiority trial. Lancet. 2014;383:P413–P423.
    1. Costa F, van Klaveren D, James S, Heg D, Räber L, Feres F, Pilgrim T, Hong M‐K, Kim H‐S, Colombo A, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE‐DAPT) score: a pooled analysis of individual‐patient datasets from clinical trials. Lancet. 2017;389:1025–1034.
    1. Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo‐Silberman S, Saint‐Etienne C, Delarche N, Bellemain‐Appaix A, Range G, El Mahmoud R, et al. Platelet 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:P2015–P2022.
    1. Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, Van’t Hof AWJ, Van Der Harst P, Barbato E, Morisco C, Tjon Joe Gin RM, Asselbergs FW, et al. A genotype‐guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019;381:1621–1631.
    1. Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, Orban M, Hadamitzky M, Merkely B, Kiss RG, et al. Guided 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;390:1747–1757.
    1. Pereira NL, Farkouh ME, So D, Lennon R, Geller N, Mathew V, Bell M, Bae J‐H, Jeong MH, Chavez I, et al. Effect of genotype‐guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention. JAMA. 2020;324:761. DOI: 10.1001/jama.2020.12443.
    1. Parodi G, Storey RF. Dyspnoea management in acute coronary syndrome patients treated with ticagrelor. Eur Heart J Acute Cardiovasc Care. 2015;4:555–560.
    1. Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12‐receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol. 2016;13:11–27.
    1. Herbert A, Wijlaars L, Zylbersztejn A, Cromwell D, Hardelid P. Data resource profile: hospital episode statistics admitted patient care (HES APC). Int J Epidemiol. 2017;46:1093–1093i. DOI: 10.1093/ije/dyx015.
    1. World Health Organisation . International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Volume 2. Geneva, Switzerland: World Heath Organisation; 2004.
    1. NHS . OPCS Classification of Interventions and Procedures. NHS Digit 2016. Available at: . Accessed October 19, 2016.

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