Benjamin M Scirica1, Eugene Braunwald2, Itamar Raz2, Matthew A Cavender2, David A Morrow2, Petr Jarolim2, Jacob A Udell2, Ofri Mosenzon2, KyungAh Im2, Amarachi A Umez-Eronini2, Pia S Pollack2, Boaz Hirshberg2, Robert Frederich2, Basil S Lewis2, Darren K McGuire2, Jaime Davidson2, Ph Gabriel Steg2, Deepak L Bhatt2. 1. From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division (B.M.S., E.B., M.A.C., D.A.M., K.I., A.A.U.-E., D.L.B.) and Department of Pathology (P.J.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Diabetes Unit (I.R., O.M.), Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; Cardiovascular Division (J.A.U.), Women's College Hospital and Toronto General Hospital, University of Toronto, Toronto, Canada; AstraZeneca Research and Development (P.S.P., B.H.), Gaithersburg, MD; Bristol-Myers Squibb (R.F.), Princeton, NJ; Cardiovascular Research Institute (B.S.L.), Lady Davis Carmel Medical Center and Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Cardiovascular Medicine (D.K.M.) and Division of Endocrinology, Department of Internal Medicine (J.D.), University of Texas Southwestern Medical Center, Dallas, TX; University Hospital Department (G.S.), Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation, Remodelling), Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1148, Université Paris-Diderot, and Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France (P.G.S.), Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London, UK. bscirica@partners.org. 2. From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division (B.M.S., E.B., M.A.C., D.A.M., K.I., A.A.U.-E., D.L.B.) and Department of Pathology (P.J.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Diabetes Unit (I.R., O.M.), Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel; Cardiovascular Division (J.A.U.), Women's College Hospital and Toronto General Hospital, University of Toronto, Toronto, Canada; AstraZeneca Research and Development (P.S.P., B.H.), Gaithersburg, MD; Bristol-Myers Squibb (R.F.), Princeton, NJ; Cardiovascular Research Institute (B.S.L.), Lady Davis Carmel Medical Center and Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Cardiovascular Medicine (D.K.M.) and Division of Endocrinology, Department of Internal Medicine (J.D.), University of Texas Southwestern Medical Center, Dallas, TX; University Hospital Department (G.S.), Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation, Remodelling), Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1148, Université Paris-Diderot, and Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France (P.G.S.), Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London, UK.
Abstract
BACKGROUND: Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. METHODS AND RESULTS:A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. CONCLUSIONS: In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
RCT Entities:
BACKGROUND:Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. METHODS AND RESULTS: A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. CONCLUSIONS: In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
Authors: Benjamin M Scirica; Ofri Mosenzon; Deepak L Bhatt; Jacob A Udell; Ph Gabriel Steg; Darren K McGuire; KyungAh Im; Estella Kanevsky; Christina Stahre; Mikaela Sjöstrand; Itamar Raz; Eugene Braunwald Journal: JAMA Cardiol Date: 2018-02-01 Impact factor: 14.676