The New England journal of medicine

1533-4406381142019Oct03The New England journal of medicineN Engl J MedTicagrelor in Patients with Stable Coronary Disease and Diabetes.130913201309-132010.1056/NEJMoa1908077Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).Copyright © 2019 Massachusetts Medical Society.StegP GabrielPGFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).BhattDeepak LDL0000-0002-1278-6245From the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).SimonTabassomeTFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).FoxKimKFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).MehtaShamir RSRFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).HarringtonRobert ARAFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).HeldClaesCFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).AnderssonMarielleMFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).HimmelmannAndersAFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).RidderstråleWilhelmWFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).Leonsson-ZachrissonMariaMFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).LiuYuyinY0000-0002-4995-832XFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).OpolskiGrzegorzGFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).ZateyshchikovDmitryDFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).GeJunboJFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).NicolauJosé CJCFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).CorbalánRamónRFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).CornelJan HJHFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).WidimskýPetrPFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).LeiterLawrence ALAFrom the French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université de Paris, INSERM Unité 1148 (P.G.S.), Assistance Publique-Hôpitaux de Paris (P.G.S., T.S.), Hôpital Saint Antoine, Department of Clinical Pharmacology, Unité de Recherche Clinique (T.S.), and Sorbonne Université (T.S.) - all in Paris; the National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London (P.G.S., K.F.); Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) and Baim Institute for Clinical Research (Y.L.) - both in Boston; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON (S.R.M.), and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.) - both in Canada; Stanford University, Stanford, CA (R.A.H.); the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala (C.H.), and AstraZeneca BioPharmaceuticals Research and Development, Mölndal (M.A., A.H., W.R., M.L.-Z.) - both in Sweden; the Department of Cardiology, Medical University of Warsaw, Warsaw, Poland (G.O.); City Clinical Hospital No. 51, State Health Care Agency, Moscow (D.Z.); Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (J.G.); Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (J.C.N.); Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (R.C.); Northwest Clinics, Department of Cardiology, Alkmaar, Dutch Network for Cardiovascular Research, Utrecht, and Department of Cardiology, Radboud University Medical Center, Nijmegen - all in the Netherlands (J.H.C.); and Cardiocenter Charles University, Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic (P.W.).THEMIS Steering Committee and InvestigatorsengClinicalTrials.govNCT01991795Journal ArticleMulticenter StudyRandomized Controlled Trial20190901