title: Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.
abstract: BACKGROUND
  Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.
  
  
  METHODS
  After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.
  
  
  RESULTS
  After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).
  
  
  CONCLUSIONS
  In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dickstein
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Lars V
authors.initials: LV
authors.lastname: Køber
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Greenlaw
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: M Atif
authors.initials: MA
authors.lastname: Ali
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Yanntong
authors.initials: Y
authors.lastname: Chiang
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Georgia
authors.initials: G
authors.lastname: Tarnesby
authors.affiliation: From the British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and the Robertson Centre for Biostatistics (N.G.), University of Glasgow, Glasgow, United Kingdom; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (H.K.); the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Ohio State University, Columbus (W.T.A.); Stavanger University Hospital, Stavanger, and the Institute of Internal Medicine, University of Bergen, Bergen - both in Norway (K.D.); Rigshospitalet Copenhagen University Hospital, Copenhagen (L.V.K.); the Cardiovascular Division, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharma, Basel, Switzerland (M.A.A., Y.C., Q.S., G.T.); and the University of California, San Francisco, San Francisco (B.M.M.).
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
mesh_terms: D000368:Aged; D000577:Amides / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005650:Fumarates / Q000009:adverse effects / Q000627:therapeutic use*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D013318:Stroke Volume; D017211:Treatment Failure; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren