MADRID — Among patients with any cardiovascular disease who had an implantable cardioverter-defibrillator (ICD) and were at high risk for ventricular arrhythmias, increasing potassium levels led to a significantly lower risk for arrhythmia events in the randomized POTCAST trial.
The intervention group — treated with dietary and supplement/pharmaceutical approaches to raising potassium levels — showed a mean increase in the concentration of potassium in plasma of approximately 0.3 mmol/L.
This increase was associated with a significant 24% lower risk for a composite endpoint event — sustained ventricular tachycardiaappropriate ICD shocks/pacing therapy, unplanned hospitalization due to arrhythmia or heart failureor death from any cause — than standard care. However, ICD therapy or documented ventricular tachycardia accounted for the majority of events.
The 1200-patient trial was presented today at the 2025 annual congress of the European Society of Cardiology, and results were simultaneously published online in the New England Journal of Medicine.
Henning Bundgaard, MD, a professor of cardiology with the Heart Center at the Rigshospitalet, Copenhagen, Denmark, said the findings add significant evidence in favor of raising potassium levels in certain groups of patients, and may also have implications for the broader population.
“In this trial, we showed clear benefits of raising potassium levels in this high-risk group of patients who already had an ICD,” said Bundgaard, senior author on the study. “But there are many observational trials linking higher levels of potassium to better outcomes in much broader populations, and we know that potassium has an independent beneficial effect on blood pressure. I think it’s a mixture of effects.”
“In this trial, we were only looking at this one group of patients and the results are really only directly applicable to that patient group,” Bundgaard added. “But our perception is that higher potassium intake would also be of benefit in the broader population.”
At an ESC press conference, Bundgaard said the human body evolved on a diet rich in potassium but poor in sodium. Modern diets contain much higher levels of sodium and lower levels of potassium.
“Potassium is crucial for cardiac function, and low potassium is associated with an increased risk of arrhythmias, heart failure, and death,” he said.
The POTCAST trial tested “old and simple drugs,” which most patients tolerate well and which cost pennies per day, Bundgaard added. Among new treatments, this is probably among the most cost effective in cardiology,” he said.
Christian Jøns, MD, also from the Rigshospitalet, presented the results at the meeting.
He pointed out potassium levels outside the normal range are known to increase the risk of cardiac arrhythmias. “Even within the normal range, there’s a marked difference in risk, since low normal levels increase the risk and high normal levels reduce the risk,” Jøns said.
Low normal levels are frequently encountered in well-treated cardiovascular patients. However, it has never been tested whether actively increasing plasma potential levels from low normal to high normal decreases the risk for cardiac events, Jøns reported.
The POTCAST trial aimed to assess efficacy and safety of actively increasing plasma potassium to high normal levels, targeting 4.5 to 5.0 mmol/L in patients at high risk for cardiac arrhythmias.
Baseline plasma potassium had to be less than 4.3 mmol/L and renal function could be no more than moderately reduced. Patients were followed every 6 months, whereupon ICD reports, ECGs, blood samples, and drug status were acquired.
Baseline plasma potassium was equal among the two groups, at 4.0 mmol/L. Before randomization, 25% of the patients were treated with potassium supplements, and 40% were already receiving a mineralocorticoid receptor antagonist (MRA).
The intervention group received advice on potassium-rich diets, and these patients were started on an MRA drug or potassium supplements, or both; if possible, potassium-sparing diuretics were reduced or stopped.
This intervention continued for an average of 85 days and resulted in an increase of plasma potassium of 0.3 mmol/L that was maintained throughout the trial, according to the researchers.
This up-titration of plasma potassium was associated with a reduction of the primary endpoint of 24% (hazard ratio, 0.76; P =.01), with 175 events in the control group and 136 in the group with high-normal potassium. This result was mainly driven by reduction of ventricular tachycardia of 25%, which occurred in 122 patients in the control group and 92 in the intervention group.
The results were consistent across all prespecified subgroups, the researchers said.
Safety endpoints for the trial included hospitalizations for renal failure and for electrolyte disturbances. Plasma creatinine increased on average 4 µmol/L. There were 17 hospitalizations in the intervention group and 12 in the control group, a nonsignificant difference.
“A Very Important Trial”
Experts at the ESC praised the research.
Jens Cosedis Nielsen, MD, of Aarhus University Hospital, Aarhus, Denmark, called the trial “very well conducted.”
“These are the first data from a randomized controlled trial indicating that actively increasing plasma potassium may reduce ventricular arrhythmias in ICD patients,” he said. “The results are credible and valid, and potentially of importance for the treatment of our ICD patients.”
Theresa McDonagh, MD, of King’s College Hospital in London, said, “A very important message here is to get the potassium as high as possible without obviously going into the toxic range. And you can see the beneficial effects of doing so. I think they found a good sweet spot.”
“We know that arrhythmias can be increased with both low and high levels of potassium levels,” said Isabelle Van Gelder, MD, of University Medical Centre in Groningen, the Netherlands. “We have been teaching for years to get the potassium above 4, but not so many people do it. So, this is a very important trial for arrhythmia treatment.”
She added that although the study failed to show a significant reduction in hard endpoints of hospitalization or death, a reduction in ICD shocks is important in terms of quality of life.
Asked if the results could be extended to other groups, Jøns said, “The trial was designed to be as open as possible, and there was a large proportion of patients who had normal ejection fraction who also appeared to benefit. So, with that in mind, I think we can extend these findings to a great proportion of cardiovascular patients.”
On concern about raising potassium levels too much, Bundgaard said moderation is key. “In patients with reasonable kidney function, the risk of adverse effects due to hyperkalemia is very low,” he said. “But in elderly [patients] with other comorbidities or reduced renal function we would have to be more careful.”
Most people consume much less potassium than is recommended, he added.
“The recommendation in the US is to eat 4.7 grams of potassium a day. Less than 5% of the American population gets that much,” he said. “Back in time, when we ate more raw food, we were eating between 5-10 g and even up to 30 grams. But every time we cook, fry, bake food, we gain sodium and lose potassium.”
Caution in US Practice?
Peter Weiss, MD, an electrophysiologist at Banner University Medical Center in Phoenix, Arizona, said the 25% reduction in ICD shocks and arrhythmia admissions was a good result. “That’s as well as we’ve done with antiarrhythmic drugs, and the fact that this can be done without an expensive new medication or device is an optimistic finding,” Weiss told Medscape Medical News.
But Weiss stressed patients with renal dysfunction were excluded from the trial. “As we think about expanding this to broader patient groups, there’s the danger that if we don’t know enough about underlying comorbidities, this type of treatment may be pursed in patients at high risk to develop kidney disease,” he said.
Weiss cautioned about extrapolating the findings to a broader population in US clinical practice. He noted that the trial was conducted in Denmark, which has an organized healthcare system where patients are followed through electronic medical records, making it easier to ensure the laboratory work is done on time. “That is the safest way and the best way to see the most benefit out of this kind of study,” he said.
Patients in the United States who are already being followed in an advanced heart failure clinic could be suitable candidates for this approach, he added: “I would have more caution in thinking that we could broaden the results to the wide population that may not be so closely followed. And I think that is something that would remain to be seen in the US clinical setting.”
The POTCAST trial was funded by the Independent Research Fund Denmark, the Novo Nordisk Foundation, and the Danish Heart Foundation. Bundgaard and Jøns reported no relevant financial relationships.
