TY - JOUR
T1 - Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials
AU - THEMIS Steering Committee and Investigators
AU - Leiter, Lawrence A.
AU - Bhatt, Deepak L.
AU - McGuire, Darren K.
AU - Teoh, Hwee
AU - Fox, Kim
AU - Simon, Tabassome
AU - Mehta, Shamir R.
AU - Lev, Eli I.
AU - Kiss, Róbert G.
AU - Dalby, Anthony J.
AU - Bueno, Héctor
AU - Ridderstråle, Wilhelm
AU - Himmelmann, Anders
AU - Prats, Jayne
AU - Liu, Yuyin
AU - Lee, Jane J.
AU - Amerena, John
AU - Kosiborod, Mikhail N.
AU - Steg, Philippe Gabriel
N1 - Funding Information:
The THEMIS study was funded and sponsored by AstraZeneca Research & Development. The statistical analyses were conducted independently from but with funding from AstraZeneca. Dr. Leiter has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, HLS, Janssen, Novartis, Novo Nordisk, and Sanofi; has received grants from Esperion, GSK, Kowa, Lexicon, Novartis, and The Medicines Company; and has received personal fees from Merck and Servier. Dr. Bhatt served as the co-chair and co–principal investigator of THEMIS and THEMIS-PCI with research funding from AstraZeneca to Brigham and Women’s Hospital; and has served on the advisory board for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado has served on the Biosciences; has served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair of American Heart Association Quality Oversight Committee; has served on the data monitoring committees for 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), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org ; and 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, and 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), 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), and WebMD (CME steering committees); Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry steering committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from 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, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; has been a trustee of American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr. McGuire has received honoraria for clinical trials leadership from AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Lilly USA, Merck, Novo Nordisk, Pfizer, and Sanofi; and has received honoraria for consultancy from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Lilly USA, Merck, Metavant, Novo Nordisk, and Sanofi. Dr. Teoh has received personal fees from Boehringer Ingelheim, Merck, and Servier. Dr. Fox has received fees, honoraria, and travel expenses from AstraZeneca, Broadview Ventures, Celixir, Servier, TaurX, and UCB; and has served as a director of Vesalius Trials. Dr. Simon has received grants to the institution from AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Sanofi; and has received consulting fees or honoraria from AstraZeneca, Bristol Myers Squibb, Novartis, and Sanofi. Dr. Mehta has received research grants to Population Health Research Institute from AstraZeneca, Abbott, Boston Scientific, and Sanofi; and has received honoraria for consultancy from AstraZeneca, Bayer, Biosensors, and Sanofi. Dr. Kiss has received speaker honoraria from Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, and Pfizer. Dr. Dalby has served on South African advisory boards for Aspen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Sanofi, and Servier; has received honoraria from AstraZeneca and Servier; and has received travel sponsorship from Bayer, Boehringer Ingelheim, Novartis, and Sanofi. Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 and PI17/01799), Sociedad Española de Cardiología, AstraZeneca, Bayer, Bristol Myers Squibb, and Novartis; has received honoraria for consultancy from AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, Novartis, and Medscape. Dr. Ridderstråle is an employee of AstraZeneca. Dr. Himmelmann is an employee of AstraZeneca. Dr. Kosiborod has received research support from AstraZeneca and Boehringer Ingelheim; and has received honoraria for clinical trial leadership and consultancy for Amarin, Applied Therapeutics, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Eisai, Glytec, GlaxoSmithKline, Intacia, Janssen, Eli Lilly, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and Vifor Pharma. Dr. Steg has received personal fees and nonfinancial support from AstraZeneca; has received grants and personal fees from Amarin, Bayer/Janssen, Merck, Sanofi, and Servier; and has received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Lilly, Novartis, Novo Nordisk, Pfizer, and Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Publisher Copyright:
© 2021 The Authors
PY - 2021/5/18
Y1 - 2021/5/18
N2 - 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.
AB - 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.
KW - aspirin
KW - bleeding
KW - diabetes mellitus
KW - dual antiplatelet therapy
KW - ticagrelor
UR - http://www.scopus.com/inward/record.url?scp=85105053038&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2021.03.298
DO - 10.1016/j.jacc.2021.03.298
M3 - Article
C2 - 33985681
AN - SCOPUS:85105053038
SN - 0735-1097
VL - 77
SP - 2366
EP - 2377
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 19
ER -
