Madrid, Spain – 29 August 2025: Targeting high-normal potassium levels reduced the risk of arrhythmias, hospitalisation for heart failure or arrhythmia and death compared with no intervention, according to late-breaking research presented in a Hot Line session today at ESC Congress 2025 and simultaneously published in New England Journal of Medicine.1
Presenter, Doctor Christian Jons from Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark, explained the rationale for the POTCAST trial: “There is some evidence from observational studies to suggest that low plasma potassium levels are associated with increased risk of dangerous alterations in heart rhythms and that potassium levels in the upper normal level have protective effects.2 We conducted the POTCAST trial to assess the benefits and risks of targeting high-normal potassium levels in patients at high risk of ventricular arrhythmias with an implantable cardioverter defibrillator (ICD).”
The open label randomised controlled POTCAST trial was conducted at three sites in Denmark. Eligible participants had an ICD or cardiac resynchronisation therapy defibrillator and had a baseline plasma potassium ≤4.3 mmol/L. Exclusion criteria included renal impairment (estimated glomerular filtration rate <30 mL per minute per 1.73 m2) and pregnancy.
Participants were randomised 1:1 to a treatment regimen aiming at increasing plasma potassium level to 4.5−5.0 mmol/L, using dietary guidance, potassium supplements and/or mineralocorticoid receptor antagonist (MRA) therapy, or to standard care. The primary endpoint was a composite of sustained ventricular tachycardia >125 bpm lasting >30 seconds, any appropriate ICD therapy, unplanned hospitalisation (>24 hours) due to arrhythmia or heart failure, and all-cause mortality.
Among 1,200 participants who had undergone randomisation, median follow-up was 39.6 months. The mean age of the participants was 62.7 years and 19.8% were women. From mean baseline levels of 4.01 mmol/L, plasma potassium levels reached a mean of 4.36 mmol/L in the high-normal potassium group compared with 4.05 mmol/L in the control group after 6 months.
The primary endpoint was significantly lower in the high-normal potassium group (22.7%) than in the control group (29.2%; hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.61 to 0.95; p=0.015). The effect was consistent across prespecified subgroups, including ischaemic heart disease and heart failure.
Any appropriate ICD therapy (shock therapy or anti-tachycardia pacing) was the main driver of the difference, occurring in 15.3% of participants in the high-normal potassium group and 20.3% in the control group (HR 0.75; 95% CI 0.57 to 0.80). Unplanned hospitalisations for cardiac arrhythmias occurred in 6.7% of participants in the high-normal group and 10.7% in the control group (HR 0.63; 95% CI 0.28 to 0.64). Unplanned hospitalisations for heart failure occurred in 3.5% and 5.5% participants, respectively (HR 0.62; 95% CI 0.37 to 1.11). A total of 5.7% in the high-normal potassium group and 6.8% in the control group died (HR 0.85; 95% CI 0.54 to 1.34).
Regarding safety outcomes, hospitalisation due to very high (hyperkalaemia) or very low (hypokalaemia) potassium levels occurred in 1% of participants in both groups. An unplanned hospitalisation lasting more than 24 hours and death from all causes occurred in 29.5% of participants in the high-normal potassium group and 33.2% in the control group (HR 0.88; 95% CI 0.72 to 1.08).
Summing up, Professor Henning Bundgaard, senior author, said: “A treatment-induced increase in plasma potassium level of approximately 0.3 mmol/L significantly reduced the arrhythmia burden without increasing the combined risk of hyper- or hypokalaemia. The benefits occurred across cardiovascular disease types and regardless of the method used to increase potassium levels, e.g. supplementation or MRAs. In several landmark heart failure trials, the improvements in cardiovascular outcomes seen with MRAs were accompanied by increases in potassium levels.3–6 The findings of POTCAST lead us to speculate that increased potassium levels may, at least partially, be responsible for MRAs’ positive outcomes, rather than merely being a side effect. We believe the time is right to consider increasing potassium levels to the mid-to-high normal range as an inexpensive and widely available treatment strategy in patients with a broad spectrum of cardiovascular diseases associated with a high risk of ventricular arrhythmia.”
ENDS
Notes to editor
Funding: The trial received funding from the Independent Research Fund Denmark, the Danish Heart Foundation and the Novo Nordisk Foundation.
Disclosures: Doctor Jons and Professor Bundgaard report no disclosures
References and notes:
1‘POTCAST – a randomized controlled trial of arrhythmia prevention using targeted plasma potassium levels in ICD patients’ presented during HOT LINE 1 on 29 August 2025 at 11:00 to 11:10 in Madrid (Main Auditorium) and simultaneously published in New England Journal of Medicine.
2Ferreira JP, Butler J, Rossignol P, et al. Abnormalities of potassium in heart failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75:2836–2850.
3Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717.
4Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–1321.
5Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.
6Vardeny O, Vaduganathan M, Claggett BL, et al. Finerenone, serum potassium, and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction. JAMA Cardiol. 2025;10:42–48.
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