By Michael H. Crawford, MD, Editor
Synopsis: A Danish randomized trial of augmenting serum potassium by diet or medications compared to usual care in patients with an implantable cardioverter defibrillator (ICD) has shown that modest increases in potassium resulted in a reduction in the composite endpoint of appropriate ICD therapy or hospitalizations for arrhythmias or heart failure, or death.
Source: Jons C, Zheng C, Winslow UCG, et al. Increasing the potassium level in patients at high risk for ventricular arrhythmias. N Engl J Med. 2025; Aug 29. doi: 10.1056/NEJMoa2509542. [Online ahead of print].
In a trial of patients with cardiovascular disease (CVD) at high risk of sudden cardiac death, it was observed that substituting potassium (K) for sodium (Na) reduced CVD events and all-cause mortality.1 Thus, these investigators from Denmark designed the Targeted Potassium Levels to Decrease Arrhythmia Burden in High-Risk Patients with CVD (POTCAST) trial. The aim of POTCAST was to assess the efficacy of increasing K to high normal levels via diet, K supplementation, or mineralocorticoid receptor antagonists (MRA) administration in patients at high risk of ventricular arrhythmias because they had an implanted cardioversion defibrillator device (ICD) regardless of their heart disease type.
POTCAST was an open-label, event-driven randomized controlled superiority trial conducted in three centers in Denmark that implanted ICDs. The investigators enrolled adults with ICDs and baseline K ≤ 4.3 mmol/L. Excluded were patients with an estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73 m2 or who were pregnant. The patients were randomized to usual care or efforts to increase K by a K-rich diet, K supplementation, or administration of an MRA or both, with a target K of 4.5 mmol/L to 5.0 mmol/L. If possible, diuretic doses were reduced or were eliminated.
The primary endpoint was a composite of sustained ventricular tachycardia (VT) at > 125 beats per minute for > 30 seconds, appropriate ICD therapy, hospitalization for arrhythmia or heart failure (HF), or all-cause mortality. Secondary endpoints included the components of the composite primary endpoint and hospitalization for renal dysfunction or electrolyte abnormalities. Safety endpoints included K out of the normal range and changes in serum creatinine.
Between 2019 and 2024, 1,200 patients were recruited (mean age 63 years, 20% women). The K adjustment period was completed by 95% of the patients. Mean K increased from 4.01 mmol/L to 4.36 mmol/L after a mean of 85 days in the K adjustment group and 44% of the patients reached the target K (4.5 mmol/L to 5.0 mmol/L). In the control group, K was 4.01 mmol/L at entry and 4.05 mmol/L at six-month follow-up. Median follow-up was 40 months and 75% of the patients completed the trial. The primary endpoint occurred in 23% of the high-K group vs. 29% in the control group (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.61 to 0.95; P = 0.01). At five-year follow-up, the difference in K between the two groups was 0.8 mmol/L and the number needed to treat to prevent one event was 12. The methods used to increase K did not affect the results.
Among the secondary endpoints, appropriate ICD therapy or VT was 15% in the high-K group and 20% in controls (HR, 0.75; 95% CI, 0.57 to 0.98) and hospitalization for arrhythmia was 6.7% vs. 10.7% (HR, 0.63; 95% CI, 0.42 to 0.93). The safety endpoint of hospitalizations for K out of the normal range or renal dysfunction occurred in 17 patients in the high-K group and 12 patients in the control group (P = NS). The authors concluded that in patients with ICDs for CVD treatment, increasing K levels within the normal range reduced the risk of appropriate ICD therapy or hospitalizations for arrhythmias or HF, or death.
Commentary
Heart failure drug trials have shown that MRA, beta-blockers, and angiotensin-converting enzyme inhibitors reduce mortality, including sudden death. All three of these classes of drugs raise serum potassium. So, the concept that higher K levels may be cardioprotective certainly is a reasonable hypothesis. POTCAST takes this concept further because 40% of patients enrolled did not have HF. However, the beneficial effects observed in POTCAST were not the result of achieving high normal K levels, since less than half of the patients achieved this goal. Thus, perhaps the benefit was from avoiding low K levels.
Of interest, scientists believe that ancient humans subsisted on a high-K, low-Na diet with a ratio of 10:1, whereas in modern Western humans the ratio is 1:2. Also, a high-K diet has been shown to lower blood pressure, which could reduce CVD events and mortality. Unfortunately, POTCAST did not report on blood pressure. In addition, POTCAST showed that raising K therapeutically was relatively safe and inexpensive.
There are limitations to POTCAST to consider. Only patients with ICDs were included, which certainly is a high risk for the ventricular arrhythmias group. Whether those with lower-risk CVD would see the same benefit is unknown. Also, the study was confined to those with eGFR > 30 mL/min/1.73 m2. In addition, the patient population was Danish citizens and may not apply to other ethnicities or races. Finally, there were no data presented on adherence to diet or medications.
Despite these limitations, I think we all can agree that recommending a high-K diet for CVD patients usually is going to be safe and potentially beneficial and, in selected patients at high risk of ventricular arrhythmias, we should consider adding pharmacologic therapy to keep K in the high-normal range.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
Reference
1. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385(12):1067-1077.
