Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study

Abstract

In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients ≥50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.

Keywords: antiplatelet therapy; clinical trials; diabetes mellitus; general clinical cardiology/adult; ischemic heart disease.

Conflict of interest statement

Dr. Deepak L. Bhatt discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, 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), 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), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), 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, Amarin, Amgen, AstraZeneca (including for his role as co‐Chair of THEMIS), Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braun wald's Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. Dr Kim Fox receives fees, honoraria and/or travel expenses from Servier, TauRx, CellAegis, Celixir and Broadview Ventures. He is a director of Vesalius Trials Ltd. Dr Harrington discloses research grants/contracts from the National Heart Lung and Blood Institute, Duke, AstraZeneca, CSL‐Behring, Glaxo Smith Kline, Merck, Portola, Regado, Sanofi‐Aventis, and The Medicines Company, and consulting/advisory for Adverse Events, Amgen, Element Science, Gilead, Merck, MyoKardia, The Medicines Company, VidaHealth, and WebMD. Dr. Lawrence Leiter discloses the following relationships: research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, GSK, Kowa, Novo Nordisk, Sanofi, The Medicines Company; speaking or consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi. Dr. Shamir Mehta discloses the following relationships: Institutional research grants from Abbott Vascular, AstraZeneca, Boston Scientific and Sanofi and consulting fees from AstraZeneca and Sanofi. Dr Tabassome Simon discloses the following relationships: research grants from AstraZeneca, Daiichi‐Sankyo, Eli‐Lilly, GSK, MSD, Novartis, Sanofi, speaking or consulting fees from AstraZeneca, BMS, Novartis Sanofi. Dr Claes Held discloses the following relationships: Institutional research grants from AstraZeneca, GlaxoSmith Kline, BristolMyers Squibb, Pfizer and Merck. Advisory board ‐ AstraZeneca, Bayer, Boehringer Ingelheim, Idorsia and Coala Life. Speaking or consulting fees from AstraZeneca, Bayer. Dr. Ph. Gabriel Steg discloses the following relationships: research grants from Amarin, Bayer, Merck, Sanofi, and Servier; speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo‐Nordisk, Pfizer, Regeneron, Sanofi, Servier. Dr Anders Himmelmann, Dr Wilhelm Ridderstråle, and Marielle Andersson report being employees of AstraZeneca.

© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

Figures

Figure 1

THEMIS study design. Data as of Feb 8, 2019

Figure 2

THEMIS study flow diagram. Data as of Feb 8, 2019