João Pedro Ferreira1,2, Brian L Claggett3, Jiankang Liu3, Akshay S Desai3, Marc A Pfeffer3, Inder S Anand4, Dirk J van Veldhuisen5, Lars Kober6, John G F Cleland7, Jean L Rouleau8, Milton Packer9,10, Michael R Zile11, Victor C Shi12, Martin P Lefkowitz12, Sanjiv J Shah13, Orly Vardeny14, Faiez Zannad1, Scott D Solomon3, John J V McMurray2. 1. National Institute of Health and Medical Research, Center for Clinical Multidisciplinary Research, INSERM U1116, University of Lorraine, Regional University Hospital of Nancy, French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France. 2. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. 3. Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 4. Department of Cardiovascular Medicine, University of Minnesota, Minneapolis, MN, USA. 5. Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 6. Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 7. Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, UK. 8. Montreal Institute of Cardiology, University of Montreal, Montreal, Canada. 9. Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA. 10. Imperial College, London, UK. 11. Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA. 12. Novartis, East Hanover, NJ, USA. 13. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 14. Minneapolis VA Center for Care Delivery and Outcomes Research, University of Minnesota, Minneapolis, MN, USA.
Abstract
AIMS: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. METHODS AND RESULTS: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up. CONCLUSIONS: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
RCT Entities:
AIMS: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. METHODS AND RESULTS: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up. CONCLUSIONS: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
Authors: João Pedro Ferreira; Faiez Zannad; Javed Butler; Gerasimos Filipattos; Ivana Ritter; Elke Schüler; Bettina J Kraus; Stuart J Pocock; Stefan D Anker; Milton Packer Journal: Eur Heart J Date: 2022-08-14 Impact factor: 35.855