Background: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis., Objectives: This study sought to determine the effect of ticagrelor on limb events., Methods: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline., Results: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P interaction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P interaction = 0.40) or TIMI major bleeding (P interaction = 0.3239)., Conclusions: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795)., Competing Interests: Funding Support and Author Disclosures THEMIS was funded and sponsored by AstraZeneca Research & Development. Dr Bonaca is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, Anthos, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cleerly, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has stock in Medtronic and Pfizer; and has received consulting fees from Audentes. Dr Bhatt serves as the co-chair of THEMIS and THEMIS-PCI with research funding from AstraZeneca paid to Brigham and Women’s Hospital. He discloses the following relationships: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), 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; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), 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), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, 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, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, 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), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; and Unfunded Research: FlowCo, Takeda. Dr Leiter has received research funding from, has provided CME on behalf of, and/or has received research funding from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, HLS, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. Dr Himmelmann is an employee of AstraZeneca. Drs Ridderstråle, Andersson, and Chen are employees of AstraZeneca. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on the advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options in Artera Health and Saghmos Therapeutics. Dr McGuire has received honoraria for trial leadership from Boehringer Ingelheim, Sanofi, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring; and has received consulting fees from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, CSL Behring, Bayer, Altimmune, Intercept, and Pfizer. Dr Steg has received grants and nonfinancial support (cochair of the ODYSSEY OUTCOMES trial [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab]; as such, he has received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER [A Study of Rivaroxaban (JNJ-39039039) on the Venous Thromboembolic Risk of Post-Hospital Discharge Patients], grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY OUTCOMES trial; cochair of the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk); has received consulting and speaker fees from Servier (Chair of the CLARIFY registry [Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease]; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (No. 15712241.7), for a method for reducing cardiovascular risk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)