Rury R Holman1, Ruth L Coleman2, Juliana C N Chan3, Jean-Louis Chiasson4, Huimei Feng2, Junbo Ge5, Hertzel C Gerstein6, Richard Gray7, Yong Huo8, Zhihui Lang9, John J McMurray10, Lars Rydén11, Stefan Schröder12, Yihong Sun13, Michael J Theodorakis2, Michal Tendera14, Lynne Tucker2, Jaakko Tuomilehto15, Yidong Wei16, Wenying Yang13, Duolao Wang17, Dayi Hu18, Changyu Pan19. 1. Diabetes Trials Unit, University of Oxford, Oxford, UK. Electronic address: rury.holman@dtu.ox.ac.uk. 2. Diabetes Trials Unit, University of Oxford, Oxford, UK. 3. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. 4. Department of Medicine, University of Montreal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada. 5. Zhongshan Hospital, Fudan University, Shanghai, China. 6. Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. 7. MRC Population Health Research Unit, University of Oxford, Oxford, UK. 8. Department of Cardiology, Peking University First Hospital, Beijing, China. 9. Bayer Healthcare Company Ltd, Beijing, China. 10. Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. 11. Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. 12. Pharma Division, Bayer AG, Berlin, Germany. 13. China-Japan Friendship Hospital, Beijing, China. 14. Department of Cardiology and Structural Heart Diseases, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. 15. Dasman Diabetes Institute, Dasman, Kuwait; Department of Neurosciences and Preventive Medicine, Danube-University Krems, Krems, Austria; Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; King Abdulaziz University, Jeddah, Saudi Arabia. 16. Shanghai Tenth People's Hospital, School of Medicine of Tongji University, Shanghai, China. 17. Tropical Clinical Trials Unit, Liverpool School of Tropical Medicine, Liverpool, UK. 18. People's Hospital of Peking University, Beijing, China. 19. Department of Endocrinology, People's Liberation Army General Hospital, Beijing, China.
Abstract
BACKGROUND: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. METHODS: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. FINDINGS:Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned toacarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0·08) did not differ between groups. INTERPRETATION: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes. FUNDING: Bayer AG.
RCT Entities:
BACKGROUND: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. METHODS: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. FINDINGS: Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5·0 years (IQR 3·4-6·0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3·33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3·41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0·98; 95% CI 0·86-1·11, p=0·73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3·17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3·84 per 100 person-years; rate ratio 0·82, 95% CI 0·71-0·94, p=0·005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0·0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0·19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0·08) did not differ between groups. INTERPRETATION: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes. FUNDING: Bayer AG.
Authors: Dalton Bertolim Précoma; Gláucia Maria Moraes de Oliveira; Antonio Felipe Simão; Oscar Pereira Dutra; Otávio Rizzi Coelho; Maria Cristina de Oliveira Izar; Rui Manuel Dos Santos Póvoa; Isabela de Carlos Back Giuliano; Aristóteles Comte de Alencar Filho; Carlos Alberto Machado; Carlos Scherr; Francisco Antonio Helfenstein Fonseca; Raul Dias Dos Santos Filho; Tales de Carvalho; Álvaro Avezum; Roberto Esporcatte; Bruno Ramos Nascimento; David de Pádua Brasil; Gabriel Porto Soares; Paolo Blanco Villela; Roberto Muniz Ferreira; Wolney de Andrade Martins; Andrei C Sposito; Bruno Halpern; José Francisco Kerr Saraiva; Luiz Sergio Fernandes Carvalho; Marcos Antônio Tambascia; Otávio Rizzi Coelho-Filho; Adriana Bertolami; Harry Correa Filho; Hermes Toros Xavier; José Rocha Faria-Neto; Marcelo Chiara Bertolami; Viviane Zorzanelli Rocha Giraldez; Andrea Araújo Brandão; Audes Diógenes de Magalhães Feitosa; Celso Amodeo; Dilma do Socorro Moraes de Souza; Eduardo Costa Duarte Barbosa; Marcus Vinícius Bolívar Malachias; Weimar Kunz Sebba Barroso de Souza; Fernando Augusto Alves da Costa; Ivan Romero Rivera; Lucia Campos Pellanda; Maria Alayde Mendonça da Silva; Aloyzio Cechella Achutti; André Ribeiro Langowiski; Carla Janice Baister Lantieri; Jaqueline Ribeiro Scholz; Silvia Maria Cury Ismael; José Carlos Aidar Ayoub; Luiz César Nazário Scala; Mario Fritsch Neves; Paulo Cesar Brandão Veiga Jardim; Sandra Cristina Pereira Costa Fuchs; Thiago de Souza Veiga Jardim; Emilio Hideyuki Moriguchi; Jamil Cherem Schneider; Marcelo Heitor Vieira Assad; Sergio Emanuel Kaiser; Ana Maria Lottenberg; Carlos Daniel Magnoni; Marcio Hiroshi Miname; Roberta Soares Lara; Artur Haddad Herdy; Cláudio Gil Soares de Araújo; Mauricio Milani; Miguel Morita Fernandes da Silva; Ricardo Stein; Fernando Antonio Lucchese; Fernando Nobre; Hermilo Borba Griz; Lucélia Batista Neves Cunha Magalhães; Mario Henrique Elesbão de Borba; Mauro Ricardo Nunes Pontes; Ricardo Mourilhe-Rocha Journal: Arq Bras Cardiol Date: 2019-11-04 Impact factor: 2.000