TY - JOUR
T1 - Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI)
T2 - a phase 3, placebo-controlled, randomised trial
AU - THEMIS Steering Committee and Investigators
AU - Bhatt, Deepak L.
AU - Steg, Philippe Gabriel
AU - Mehta, Shamir R.
AU - Leiter, Lawrence A.
AU - Simon, Tabassome
AU - Fox, Kim
AU - Held, Claes
AU - Andersson, Marielle
AU - Himmelmann, Anders
AU - Ridderstråle, Wilhelm
AU - Chen, Jersey
AU - Song, Yang
AU - Diaz, Rafael
AU - Goto, Shinya
AU - James, Stefan K.
AU - Ray, Kausik K.
AU - Parkhomenko, Alexander N.
AU - Kosiborod, Mikhail N.
AU - McGuire, Darren K.
AU - Harrington, Robert A.
AU - Santos, Vladimir
AU - Jain, Ashit
AU - Lendel, Irina
AU - Russo, Michael
AU - Haught, W. H.
AU - Bouza, Manuel
AU - Gogia, Harinder
AU - Banerjee, Supratim
AU - Kichura, George
AU - Kantaros, Louis
AU - Padron, Francisco
AU - Passi, Rakesh
AU - Stone, Jay
AU - Pursley, Michael
AU - D'Urso, Michael
AU - Gardner, Timothy
AU - Bennett, James
AU - Nour, Khaled
AU - Saini, Satinder
AU - Zhang, Wenwu
AU - Kumbhani, Dharam
AU - Thomas, Dustin
AU - Angiolillo, Dominick
AU - Bertolet, Barry
AU - Roman-Miranda, Amaury
AU - Black, Robert
AU - Manshadi, Ramin
AU - Vaca, Carlos
AU - Blanco, Antonio
AU - Rha, Seung W.
N1 - Funding Information:
The THEMIS study was funded and sponsored by AstraZeneca Research & Development. The statistical analyses were done by AstraZeneca and validated by independent statisticians at the Baim Institute for Clinical Research (Boston, MA, USA), with funding from AstraZeneca. The second and fifth authors were in part supported by the Recherche Hospitalo-Universitaire iVASC [Innovations in Atherothrombosis Science] (grant number ANR-16-RHUS-00010 ) from the French National Research Agency as part of the Investissements d'Avenir programme. The authors had full access to all data. We thank C Michael Gibson and Gheorghe Doros for supervising the statistical analyses, and Jayne Prats for assistance with editing (limited to collation of author comments and formatting for submission) with funding from AstraZeneca. We also thank the trial participants, investigators, and site staff who were involved in the conduct of the trial.
Funding Information:
DLB reports grants from AstraZeneca, during the conduct of the study; grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, Ironwood, Abbott, Regeneron, Idorsia, Synaptic, and Afimmune; other support from FlowCo, PLx Pharma, Takeda, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, VA, St Jude Medical (now Abbott), Biotronik, Cardax, Boston Scientific, Merck, Svelte, Novo Nordisk, Fractyl, and Cereno Scientific; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, TobeSoft, Bayer, Medtelligence/ReachMD, CSL Behring, and Ferring Pharmaceuticals; personal fees, non-financial support, and other support from the American College of Cardiology; personal fees and non-financial support from Society of Cardiovascular Patient Care; non-financial support from American Heart Association; grants and other support from PhaseBio; and personal fees and other support from Boehringer Ingelheim, all outside the submitted work. PGS reports personal fees and non-financial support from AstraZeneca, during the conduct of the study; grants and personal fees from Bayer/Janssen and Servier, Merck, Sanofi, and Amarin, and personal fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron, Lilly, AstraZeneca, Novo Nordisk, and Idorsia, outside the submitted work. SRM reports research grants to Population Health Research Institute from AstraZeneca, Abbott, Boston Scientific, and Sanofi, and is a consultant to AstraZeneca, Bayer, Biosensors, and Sanofi. LAL reports personal fees from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Sanofi, Servier, personal fees from Merck, and grants from Esperion, GlaxoSmithKline, Kowa, and The Medicines Company. TS discloses personal fees from AstraZeneca, during the conduct of the study; grants from AstraZeneca, Daiichi-Sankyo, Eli-Lilly, GlaxoSmithKline, Merck, Sharp & Dohme, Novartis, and Sanofi, and personal fees from BMS, Novartis, and Sanofi. KF reports personal fees from AstraZeneca, during the conduct of the study; personal fees and non-financial support from Servier and Broadview Ventures, and personal fees from Taurx, personal CellAegis, and Celixir outside the submitted study; and is the Director of Vesalius Trials. CH reports grants and personal fees from AstraZeneca, and personal fees from Bayer and Idorsia. MA, AH, WR, and JC are employees of AstraZeneca. YS is an employee of Baim Clinical Research Institute. RD reports grants from The Thrombolysis in Myocardial Infarction study group, Montreal Heart Institute Coordinating Center, Lepetit Pharma, Sanofi, DalCor Phamaceuticals, and Duke Clinical Research Institute. SG reports personal fees from AstraZeneca and The American Heart Association, and grants from Ministry of Education, Culture, Sports, Science and Technology/Japan Society for the Promotion of Science/Grant-in-Aid for Scientific Research (Kakenhi grant number 17K19669, and partly by 18H01726 and 19H03661), The Vehicle Racing Commemorative Foundation, Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering, Bristol-Myers Squibb (from their independent research support project number 33999603), Sanofi, Pfizer, and Ono Pharmaceutical. SKJ discloses grants from AstraZeneca, Jansen, Bayer, PhaseBio, and The Medicines Company. KKR reports personal fees from AstraZeneca, during the conduct of the study; personal fees from AbbVie, AstraZeneca, The Medicines Company, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddy's, Lilly, and Zuellig Pharma, grants and personal fees from Amgen, Sanofi, Regeneron, Merck Sharp & Dohme, Pfizer, and support from the Imperial Biomedical Research Centre, outside the submitted work; and is an editor for Medical Science and Archives of Medical Science-Atherosclerotic Diseases . AP reports grants and personal fees from AstraZeneca, during the conduct of the study; grants from Amgen, Bayer, Bristol-Myers Squibb, and CSL Behring, personal fees from Servier, and grants and personal fees from Sanofi. MNK reports grants, personal fees, and other support from AstraZeneca, during the conduct of the study; grants, personal fees, and other support from AstraZeneca, grants and personal fees from Boehringer Ingelheim, and personal fees from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, and Amarin, outside the submitted work. DKM reports honoraria for clinical trials leadership from AstraZeneca, during the conduct of the study, and from GlaxoSmithKline, Janssen, Lexicon, Sanofi Aventis, Boehringer Ingelheim, Merck, Pfizer, Novo Nordisk, Eisai, Esperion, and Lilly USA, and honoraria for consultancy from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck, Novo Nordisk, Metavant, Applied Therapeutics, and Sanofi Aventis, outside this study. RAH reports grants from AstraZeneca, during the conduct of the study; grants from Sanofi Aventis, Portola, Janssen, Bristol-Myers Squibb, Novartis, The Medicines Company, CSL Behring, outside the submitted work; and consulting (before July 1, 2018) for Amgen, Gilead, and MyoKardia.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/9/28
Y1 - 2019/9/28
N2 - Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk. Funding: AstraZeneca.
AB - Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk. Funding: AstraZeneca.
UR - http://www.scopus.com/inward/record.url?scp=85072571134&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)31887-2
DO - 10.1016/S0140-6736(19)31887-2
M3 - Article
C2 - 31484629
AN - SCOPUS:85072571134
VL - 394
SP - 1169
EP - 1180
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10204
ER -