Author + information
- Received August 30, 2019
- Revision received September 11, 2019
- Accepted September 16, 2019
- Published online December 2, 2019.
- Dipak Kotecha, MD, PhD, MSca,b,∗ (, )@ICVS_UoB,
- Simrat K. Gill, MDa,
- Marcus D. Flather, MDc,
- Jane Holmes, PhDd,
- Milton Packer, MDe,
- Giuseppe Rosano, MD, PhDf,g,
- Michael Böhm, MDh,
- John J.V. McMurray, MDi,
- John Wikstrand, PhDj,
- Stefan D. Anker, MD, PhDk,
- Dirk J. van Veldhuisen, MDl,
- Luis Manzano, MDm,
- Thomas G. von Lueder, MD, PhDb,n,
- Alan S. Rigby, MSco,
- Bert Andersson, MD, PhDp,
- John Kjekshus, MD, PhDq,
- Hans Wedel, PhDr,
- Frank Ruschitzka, MDs,
- John G.F. Cleland, MDt,
- Kevin Damman, MD, PhDl,
- Josep Redon, MDu,
- Andrew J.S. Coats, MD, DScg,
- on behalf of the Beta-Blockers in Heart Failure Collaborative Group
- aInstitute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
- bCentre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, Victoria, Australia
- cNorwich Medical School, Faculty of Medicine and Health Science, University of East Anglia, Norwich, United Kingdom
- dCentre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
- eBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- fCardiovascular and Cell Science Institute, St. George’s University of London, London, United Kingdom
- gDepartment of Medical Sciences, IRCCS San Raffaele Pisana, Roma, Italy
- hKardiologie, Angiologie und Internistische Intensivmedizin, Universitatsklinikum des Saarlandes, Homburg/Saar, Germany
- iRobertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, United Kingdom
- jWallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- kDepartment of Cardiology, Charite Campus Virchow-Klinikum, Berlin, Germany
- lUniversity of Groningen, Department of Cardiology, University Medical Centre Groningen, RB Groningen, the Netherlands
- mInternal Medicine Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá (IRYCIS), Plaza de San Diego, Madrid, Spain
- nDepartment of Cardiology, Oslo University Hospital, Oslo, Norway
- oHull York Medical School, Faculty of Health Sciences, University of Hull, Kingston-upon-Hull, United Kingdom
- pDepartment of Cardiology, Sahlgrenska University Hospital and Gothenburg University, Gothenburg, Sweden
- qRikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway
- rHealth Metrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- sKlinik fur Kardiologie, UniversitätsSpital Zürich, Zürich, Switzerland
- tInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
- uINCLIVA Biomedical Research Institute, Valencia, Spain
- ↵∗Address for correspondence:
Dr. Dipak Kotecha, University of Birmingham Institute of Cardiovascular Sciences, Medical School, Vincent Drive, Birmingham B15 2TT, United Kingdom.
Background Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy.
Objectives This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR).
Methods Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm.
Results Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR.
Conclusions Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.
Menarini Farmaceutica Internazionale provided an unrestricted research grant for administrative costs, GlaxoSmithKline provided data extraction support, IRCCS San Raffaele provided a collaborative research grant, and the British Heart Foundation supports the University of Birmingham Institute of Cardiovascular Sciences with an Accelerator Award (AA/18/2/34218). None of the pharmaceutical groups had any role in data analysis or manuscript preparation. Dr. Kotecha is funded by a National Institute for Health Research (NIHR) Career Development Fellowship (CDF-2015-08-074)—the opinions expressed are those of the authors and do not represent the BHF, NIHR or the U.K. Department of Health; has received personal fees from Bayer and Atricure, outside the submitted work; has been chief investigator for the RAte control Therapy Evaluation in permanent Atrial Fibrillation trial (RATE-AF; NCT02391337); and has received funding through a British Heart Foundation Project Grant (PG/17/55/33087), and EU Innovative Medicines Initiative Collaboration Grant (BigData@Heart; 116074). Dr. Gill has received funding through the BigData@Heart Innovative Medicines Initiative grant no. 116074. Prof. Packer has received personal fees from Abbive, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Gilead, Johnson & Johnson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance, outside the submitted work. Prof. Böhm has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Servier, Medtronic, Vifor, and Novartis, outside the submitted work. Prof. McMurray has received grants from the British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217, during the conduct of the study; and nonfinancial support from Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, Abbvie, DalCor, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Vifor-Fresenius Pharma, and Kidney Research UK, outside the submitted work. Prof. Anker has received grants and personal fees from Vifor Int, and Abbott Vascular; and has received personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, AstraZeneca, and St. Jude Medical, outside the submitted work. Dr. von Lueder has received fees from AstraZeneca, Vifor, Pharmacosmos, Novartis, Pfizer, and Boehringer Ingelheim. Prof. Andersson has received grants from AstraZeneca, and Federal research grants, during the conduct of the study. Prof. Wedel has received personal fees from AstraZeneca, during the conduct of the study. Prof. Ruschitzka has received grants and personal fees from St. Jude Medical/Abbott, Servier, Bayer, and Novartis; has received personal fees from Zoll, AstraZeneca, Sanofi, Amgen, BMS, Pfizer, Fresenius, Vifor, Roche, Cardiorentis, and Boehringer Ingelheim; has received other fees from HeartWare; and has received grants from Mars, all are outside the submitted work. Prof. Cleland has received grants and personal fees from Amgen, Novartis, Vifor, and Stealth Biotherapeutics; has served on Advisory Boards for Abbott and Vifor; and has received nonfinancial support from Medtronic and Boston Scientific, all outside the submitted work. Prof. Coats has received personal fees from AstraZeneca, Menarini, Novartis, Nutricia, Servier, Vifor, Actimed, Enopace, Faraday, WL Gore, Respicardia, Stealth Peptides, and V-Wave, all outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received August 30, 2019.
- Revision received September 11, 2019.
- Accepted September 16, 2019.
- 2019 The Authors