Long-Term Ticagrelor in Patients With Prior Coronary Stenting in the PEGASUS-TIMI 54 Trial

Abstract

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.

Keywords: P2Y12 inhibitor; PCI; acute coronary syndrome; antiplatelet therapy.

Conflict of interest statement

Brian Bergmark, Yared Gurmu, Julia Kuder, KyungAh Im, Eugene Braunwald, Marc S. Sabatine, and Marc P. Bonaca are members of the TIMI Study Group, which has received institutional grant support through the Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences.

Brian Bergmark: Grant support: Pfizer, AstraZeneca, Abbott Vascular; Consulting fees: Philips, Abbott Vascular, Servier, Daiichi‐Sankyo, Janssen, Quark. Deepak L. Bhatt discloses the following relationships: Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co‐Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. PGS ‐ PG Steg discloses Research grants (to INSERM U1148): Bayer Merck, Servier, Sanofi, and being a speaker or consultant (including steering committee, data monitoring committee, and clinical end point committee memberships): Amarin, Amgen, AstraZeneca, Bayer, Boehringer‐Ingelheim, BristolMyersSquibb, Idorsia, Mylan, NovoNordisk, Novartis, Pfizer, Regeneron, Sanofi, and Servier. Andrzej Budaj reports personal fees and nonfinancial support from Astra Zeneca, related to the study; personal fees and nonfinancial support from Bristol Myers Squibb/Pfizer, personal fees and nonfinancial support from Sanofi Aventis, personal fees from Eisai, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees and non‐financial support from Bayer, personal fees from Amgen, outside the submitted work.

Robert F. Storey reports institutional research grants/support from AstraZeneca, Cytosorbents, GlyCardial Diagnostics and Thromboserin; consultancy fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Cytosorbents, GlyCardial Diagnostics, Haemonetics, Portola, and Thromboserin; and honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Intas Pharmaceuticals, and Medscape. Yared Gurmu: None other than TIMI grant support as listed previously. Julia F. Kuder: None other than TIMI grant support as listed previously. KyungAh Im: None other than TIMI grant support as listed previously. Christian Hamm reports advisory board fees and lecture fees from AstraZeneca. Jindřich Špinar is an investigator in clinical studies sponsored by Boehringer Ingelheim, Astra Zeneca, Bayer, and Novartis. Gilles Montalescot reports research grants to the institution or consulting/lecture fees from Abbott, AIM group, Amgen, Actelion, American College of Cardiology Foundation, Astrazeneca, Axis‐Santé, Bayer, Boston‐Scientific, Bristol‐Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Fréquence Médicale, ICOM, Idorsia, Elsevier, ICAN, Lead‐Up, Menarini, MSD, Novo‐Nordisk, Pfizer, Quantum Genomics, Sanofi‐Aventis, SCOR global life, Servier, and WebMD. Per Johanson is an employee of AstraZeneca. Eugene Braunwald: Research grants (through the Brigham and Women's Hospital) from AstraZeneca, Daiichi‐Sankyo, Merck, and Novartis; Consultancies with Amgen, Cardurion, MyoKardia, NovoNordisk, and Verve. Marc S. Sabatine: Research grant support through Brigham and Women’s Hospital from: Amgen; Anthos Therapeutics; AstraZeneca; Bayer; Daiichi‐Sankyo; Eisai; Intarcia; IONIS; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals; Takeda. Consulting for Althera; Amgen; Anthos Therapeutics; AstraZeneca; Bristol‐Myers Squibb; CVS Caremark; DalCor; Dr. Reddy’s Laboratories; Dyrnamix; Esperion; Fibrogen; IFM Therapeutics; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; and Novo Nordisk. Marc P. Bonaca reports personal fees from Bayer, Bristol Myers Squibb, Daiichi‐Sankyo, and Pfizer. The remaining authors have no disclosures to report.

Figures

Figure 1. Ischemic events at 3 years among patients with prior coronary stenting.

Spontaneous (Type 1) MI was the most frequent event type. CV indicates cardiovascular; HR, hazard ratio; and MI, myocardial infarction.

Figure 2. Kaplan‐Meier rates of MACE by randomized treatment arm in patients with prior coronary stenting.

CV indicates cardiovascular; CVD, cardiovascular death; MACE, major adverse cardiovascular event; HR, hazard ratio; MI, myocardial infarction; and NNT, number needed to treat.

Figure 3. Stent thrombosis with ticagrelor in ITT and on‐treatment cohorts.

The on‐treatment cohort was defined as patients who received at least 1 dose of study drug with events included through 7 days from their last dose or the common study end date. CV indicates cardiovascular; HR, hazard ratio; ITT, intention to treat; and KM, Kaplan‐Meier

Figure 4. Ticagrelor efficacy in patients with DES vs BMS and later generation DES vs first‐generation DES.

A consistent effect of ticagrelor is observed across stent types. BMS indicates bare metal stent; CV, cardiovascular; DES, drug eluting stent; Gen, generation; HR, hazard ratio; and MI, myocardial infarction.