Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long-term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS-TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug-eluting stent and first- versus later-generation drug-eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelorpooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75-96) regardless of stent type (bare metal stent versus drug-eluting stent: pinteraction=0.767; first versus later generation: pinteraction=0.940). The rate of any stent thrombosis was numerically lower with ticagrelorpooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50-1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90-3.68). Conclusions Long-term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

AstraZeneca Mölndal Sweden

Canisius Wilhelmina Hospital Nijmegen the Netherlands

Centre of Postgraduate Medical Education Grochowski Hospital Warsaw Poland

Colorado Prevention Center Clinical Research the Department of Medicine Division of Cardiovascular Medicine University of Colorado Anschutz Medical Campus Aurora CO

Department of Cardiology Military Hospital Budapest Hungary

French Alliance for Cardiovascular TrialsAP HPHôpital BichatUniversité de ParisInstitut National de la Santé et de la Recherche Médicale U 1148 Paris France

Kerckhoff Heart CenterBad NauheimUniversity of Giessen Giessen Germany

National Heart and Lung InstituteRoyal Brompton HospitalImperial College London London UK

Sorbonne Université Paris 6ACTION Study GroupINSERM UMRS 1166Institut de CardiologiePitié Salpêtrière Hospital Paris France

TIMI Study Group Cardiovascular Medicine Department of Medicine Brigham and Women's HospitalHarvard Medical School Boston MA

University Hospital of Parma Parma Italy

University hospital St Ann Pekarska and Medical faculty Brno Czech Republic

University of Leuven Leuven Belgium

University of Sheffield Sheffield UK

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Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49:1982–1988. DOI: 10.1016/j.jacc.2007.03.025. PubMed DOI

Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–1717. DOI: 10.1056/NEJMoa060989. PubMed DOI

Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KAA, Lipka LJ, Liu X, Nicolau JC, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404–1413. DOI: 10.1056/NEJMoa1200933. PubMed DOI

Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377:1319–1330. DOI: 10.1056/NEJMoa1709118. PubMed DOI

Mauri L, Kereiakes DJ, Yeh RW, Driscoll‐Shempp P, Cutlip DE, Steg PG, Normand S‐L, Braunwald E, Wiviott SD, Cohen DJ, et al. Twelve or 30 months of dual antiplatelet therapy after drug‐eluting stents. N Engl J Med. 2014;371:2155–2166. DOI: 10.1056/NEJMoa1409312. PubMed DOI PMC

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. PubMed DOI

Mega JL, Braunwald E, Wiviott SD, Bassand J‐P, Bhatt DL, Bode C, Burton P, Cohen M, Cook‐Bruns N, Fox KAA, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19. DOI: 10.1056/NEJMoa1112277. PubMed DOI

Bainey KR, Welsh RC, Connolly SJ, Marsden T, Bosch J, Fox KAA, Steg PG, Vinereanu D, Connolly DL, Berkowitz SD, et al. Rivaroxaban plus aspirin versus aspirin alone in patients with prior percutaneous coronary intervention (COMPASS‐PCI). Circulation. 2020;141:1141–1151. DOI: 10.1161/CIRCULATIONAHA.119.044598. PubMed DOI

Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. J Am Coll Cardiol. 2016;68:1082. PubMed

Bonaca MP, Bhatt DL, Braunwald E, Cohen M, Steg PG, Storey RF, Held P, Jensen EC, Sabatine MS. Design and rationale for the prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin‐thrombolysis in myocardial infarction 54 (PEGASUS‐TIMI 54) trial. Am Heart J. 2014;167:437–444.e5. DOI: 10.1016/j.ahj.2013.12.020. PubMed DOI

Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es G‐A, Gabriel Steg P, Morel M‐angèle, Mauri L, Vranckx P, et al. Mauri L and Vranckx P. Clinical end points in coronary stent trials a case for standardized definitions. Circulation. 2007;115:2344–2351. DOI: 10.1161/CIRCULATIONAHA.106.685313. PubMed DOI

Furtado RHM, Nicolau JC, Magnani G, Im K, Bhatt DL, Storey RF, Steg PG, Spinar J, Budaj A, Kontny F, et al. Long‐term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS‐TIMI 54. Eur Heart J. 2020;41:1625–1632. DOI: 10.1093/eurheartj/ehz821. PubMed DOI

Bohula EA, Bonaca MP, Braunwald E, Aylward PE, Corbalan R, De Ferrari GM, He P, Lewis BS, Merlini PA, Murphy SA. Atherothrombotic risk stratification and the efficacy and safety of vorapaxar in patients with stable ischemic heart disease and prior myocardial infarction. Circulation. 2016;134:304–313. PubMed

Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J, Farhat N, Marso SP, et al. A prospective natural‐history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–235. DOI: 10.1056/NEJMoa1002358. PubMed DOI

Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–2138. DOI: 10.1016/j.jacc.2009.09.009. PubMed DOI PMC

Bohula EA, Morrow DA, Giugliano RP, Blazing MA, He P, Park J‐G, Murphy SA, White JA, Kesaniemi YA, Pedersen TR, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol. 2017;69:911–921. DOI: 10.1016/j.jacc.2016.11.070. PubMed DOI

Bonaca MP, Scirica BM, Braunwald E, Wiviott SD, O'Donoghue ML, Murphy SA, Morrow DA. Coronary stent thrombosis with vorapaxar versus placebo: results from the TRA 2 degrees P‐TIMI 50 trial. J Am Coll Cardiol. 2014;64:2309–2317. DOI: 10.1016/j.jacc.2014.09.037. PubMed DOI

Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, Held C, Andersson M, Himmelmann A, Ridderstråle W, et al. Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med. 2019;381:1309–1320. DOI: 10.1056/NEJMoa1908077. PubMed DOI

Bhatt DL, Steg PG. THEMIS and THEMIS‐PCI. Eur Heart J. 2019;40:3378–3381. DOI: 10.1093/eurheartj/ehz707. PubMed DOI

Bhatt DL, Steg PG, Mehta SR, Leiter LA, Simon T, Fox K, Held C, Andersson M, Himmelmann A, Ridderstråle W, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS‐PCI): a phase 3, placebo‐controlled, randomised trial. Lancet. 2019;394:1169–1180. DOI: 10.1016/S0140-6736(19)31887-2. PubMed DOI

Storey RF, Angiolillo DJ, Bonaca MP, Thomas MR, Judge HM, Rollini F, Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, et al. Platelet inhibition with ticagrelor 60 mg Versus 90 mg twice daily in the PEGASUS‐TIMI 54 trial. J Am Coll Cardiol. 2016;67:1145–1154. PubMed

Ariotti S, Ortega‐Paz L, van Leeuwen M, Brugaletta S, Leonardi S, Akkerhuis KM, Rimoldi SF, Janssens G, Gianni U, et al. effects of ticagrelor, prasugrel, or clopidogrel on endothelial function and other vascular biomarkers: A randomized crossover study. JACC: Cardiovasc interv. 2018;11:1576–1586. PubMed

Jeong HS, Hong SJ, Cho SA, Kim JH, Cho JY, Lee SH, Joo HJ, Park JH, Yu CW, Lim DS. Comparison of ticagrelor versus prasugrel for inflammation, vascular function, and circulating endothelial progenitor cells in diabetic patients with non‐ST‐segment elevation acute coronary syndrome requiring coronary stenting: a prospective, randomized. Crossover Trial. JACC: Cardiovasc interv. 2017;10:1646–1658. DOI: 10.1016/j.jcin.2017.05.064. PubMed DOI

Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, Ohya M, Suwa S, Takagi K, Nanasato M, et al. Effect of 1‐month dual antiplatelet therapy followed by clopidogrel vs 12‐month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: The STOPDAPT‐2 randomized clinical trial. JAMA. 2019;321:2414–2427. DOI: 10.1001/jama.2019.8145. PubMed DOI PMC

Kim C, Hong SJ, Shin DH, Kim BK, Ahn CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y. Randomized evaluation of ticagrelor monotherapy after 3‐month dual‐antiplatelet therapy in patients with acute coronary syndrome treated with new‐generation sirolimus‐eluting stents: TICO trial rationale and design. Am Heart J. 2019;212:45–52. DOI: 10.1016/j.ahj.2019.02.015. PubMed DOI

Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, Collier T, Dangas G, Dudek D, et al. Ticagrelor with or without aspirin in high‐risk patients after PCI. N Engl J Med. 2019;381:2032–2042. DOI: 10.1056/NEJMoa1908419. PubMed DOI

Franzone A, McFadden E, Leonardi S, Piccolo R, Vranckx P, Serruys PW, Benit E, Liebetrau C, Janssens L, Ferrario M, et al. Ticagrelor alone versus dual antiplatelet therapy from 1 month after drug‐eluting coronary stenting. J Am Coll Cardiol. 2019;74:2223–2234. DOI: 10.1016/j.jacc.2019.08.1038. PubMed DOI

Kogame N, Modolo R, Tomaniak M, Cavalcante R, de Martino F, Tinoco J, Ribeiro EE, Mehran R, Campos CM, Onuma Y, et al. Prasugrel monotherapy after PCI with the SYNERGY stent in patients with chronic stable angina or stabilised acute coronary syndromes: rationale and design of the ASET pilot study. EuroIntervention. 2019;15:e547–e550. DOI: 10.4244/EIJ-D-19-00131. PubMed DOI

Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug‐eluting stent: a multicentre, open‐label, randomised superiority trial. Lancet. 2018;392:940–949. DOI: 10.1016/S0140-6736(18)31858-0. PubMed DOI

O'Donoghue ML, Murphy SA, Sabatine MS. The safety and efficacy of aspirin discontinuation on a background of a P2Y12 inhibitor in patients after percutaneous coronary intervention: a systematic review and meta‐analysis. Circulation. 2020;142:538–545. PubMed

Brilakis ES, Edson R, Bhatt DL, Goldman S, Holmes DR, Rao SV, Shunk K, Rangan BV, Mavromatis K, Ramanathan K, et al. Drug‐eluting stents versus bare‐metal stents in saphenous vein grafts: a double‐blind, randomised trial. Lancet. 2018;391:1997–2007. DOI: 10.1016/S0140-6736(18)30801-8. PubMed DOI PMC

Piccolo R, Bonaa KH, Efthimiou O, Varenne O, Baldo A, Urban P, Kaiser C, Remkes W, Räber L, de Belder A, et al. Drug‐eluting or bare‐metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta‐analysis of randomised clinical trials. Lancet. 2019;393:2503–2510. DOI: 10.1016/S0140-6736(19)30474-X. PubMed DOI

Rymer JA, Harrison RW, Dai D, Roe MT, Messenger JC, Anderson HV, Peterson ED, Wang TY. Trends in bare‐metal stent use in the United States in patients aged ≥65 years (from the CathPCI registry). Am J Cardiol. 2016;118:959–966. DOI: 10.1016/j.amjcard.2016.06.061. PubMed DOI

Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J, Kuder JF, Murphy SA, Wiviott SD, Kurtz CE, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease: analysis from FOURIER. Circulation. 2018;138:756–766. DOI: 10.1161/CIRCULATIONAHA.118.034309. PubMed DOI

Dellborg M, Bonaca MP, Storey RF, Steg PG, Im KA, Cohen M, Bhatt DL, Oude Ophuis T, Budaj A, Hamm C, et al. Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS‐TIMI 54. Eur Heart J Cardiovasc Pharmacother. 2019;5:200–206. DOI: 10.1093/ehjcvp/pvz020. PubMed DOI PMC

European Medicines Agency . Brilique (ticagrelor). 2011. Accessed June 5th, 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/brilique

Neumann F‐J, Sousa‐Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet J‐P, Falk V, Head SJ, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87–165. DOI: 10.1093/eurheartj/ehy394. PubMed DOI

Dangas GD, Serruys PW, Kereiakes DJ, Hermiller J, Rizvi A, Newman W, Sudhir K, Smith RS Jr, Cao S, Theodoropoulos K, et al. Meta‐analysis of everolimus‐eluting versus paclitaxel‐eluting stents in coronary artery disease: final 3‐year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). JACC: Cardiovasc interv. 2013;6:914–922. PubMed

Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schömig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, et al. Outcomes associated with drug‐eluting and bare‐metal stents: a collaborative network meta‐analysis. Lancet. 2007;370:937–948. DOI: 10.1016/S0140-6736(07)61444-5. PubMed DOI

Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Jüni P, 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;35:2541–2619. PubMed

Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel‐coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta‐analysis of randomized controlled trials. J Am Heart Assoc. 2018;7:e011245. DOI: 10.1161/JAHA.118.011245. PubMed DOI PMC

Dan K, Shlofmitz E, Khalid N, Hideo‐Kajita A, Wermers JP, Torguson R, Kolm P, Garcia‐Garcia HM, Waksman R. Paclitaxel‐related balloons and stents for the treatment of peripheral artery disease: Insights from the Food and Drug Administration 2019 Circulatory System Devices Panel Meeting on late mortality. Am Heart J. 2019;222:112–120. DOI: 10.1016/j.ahj.2019.12.012. PubMed DOI

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NCT01225562