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Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials.

Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Departments of Medicine and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. Electronic address: lawrence.leiter@unityhealth.to. Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School Boston, Boston, Massachusetts, USA. Electronic address: https://twitter.com/dlbhattmd. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom. French Alliance for Cardiovascular Trials, Paris, France; Department of Clinical Pharmacology, Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Sorbonne Université, site St. Antoine, Institut National de la Santé et de la Recherche Médicale U-698, Paris, France. Division of Cardiology, Population Health Institute, Hamilton Health Sciences Corporation, McMaster University, Hamilton, Ontario, Canada. Department of Cardiology, Assuta Ashdod Medical Center, Ashdod, Israel; Faculty of Health Sciences, Ben-Gurion University, Be'er Sheva, Israel. Department of Cardiology, Military Hospital, Budapest, Hungary. Life Fourways Hospital, Randburg, Republic of South Africa. Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Late-Stage Development, Cardiovascular, Renal and Metabolic, Biopharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden. ELYSIS-Med Scientific Solutions, Carlisle, Massachusetts, USA. Baim Institute for Clinical Research, Boston, Massachusetts, USA. Geelong Cardiology Research Unit, University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia; Department of Cardiology, Deakin University, Geelong, Victoria, Australia; Department of Epidemiology and Preventative Medicine, Monash University, Victoria, Australia. Department of Cardiology and Michael & Marlys Haverty Cardio Metabolic Center of Excellence, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; Department of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA; The George Institute for Global Health, Sydney, New South Wales, Australia; University of New South Wales, Sydney, New South Wales, Australia. National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom; French Alliance for Cardiovascular Trials, Paris, France; Université de Paris, Assistance Publique-Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale 1148, Paris, France. Electronic address: https://twitter.com/gabrielsteg.

Journal of the American College of Cardiology. 2021;(19):2366-2377
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Abstract

BACKGROUND THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention. OBJECTIVES In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors. METHODS Outcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications. RESULTS In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications. CONCLUSION Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population.

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