Potassium-Increasing Regimens in Patients at High Risk of Ventricular Arrhythmias: A Prespecified Observational Analysis of the Randomized POTCAST Trial
Key result
Potassium-increasing regimens linked to ~31% lower major event risk versus control, with similar efficacy across strategies.
- Adjusted HR 0.69 (combination), HR 0.66 (potassium), HR 0.80 (MRA)
- 95% CI 0.53-0.92
- P=0.8 between regimens
- n=1,172
Why the study?
The POTCAST trial demonstrated that targeting high-normal plasma potassium reduces ventricular arrhythmias in ICD patients, but outcomes across different potassium-increasing regimens were not compared.
Do different plasma potassium-increasing regimens (MRA monotherapy, potassium supplement monotherapy, or combination therapy) differ in their effect on plasma potassium levels, ventricular arrhythmias, and safety outcomes in ICD patients with baseline potassium ≤4.3 mmol/L?
Key Points
- To compare changes in plasma potassium and clinical outcomes across three distinct potassium-increasing regimens in patients with implantable cardioverter-defibrillators.
- Prespecified observational analysis of the randomized POTCAST trial, evaluating 600 control participants and 572 intervention participants who completed potassium up-titration.
- Intervention participants were classified after up-titration into MRA monotherapy (n=73), potassium-supplement monotherapy (n=148), or combination therapy (n=326).
- The primary endpoint was a composite of sustained ventricular arrhythmia, appropriate ICD therapy, hospitalization for arrhythmia or heart failure, or all-cause mortality.
- Plasma potassium increased after 6 months across all groups: from 4.12 to 4.27 mmol/L (p=0.004) with MRA, from 3.99 to 4.24 mmol/L (p<0.001) with potassium supplements, and from 3.98 to 4.34 mmol/L (p<0.001) with combination therapy.
- The primary endpoint occurred in 29% (n=175) of controls, 22% (n=16) with MRA, 21% (n=31) with potassium supplements, and 22% (n=72) with combination therapy (p=0.8 between regimens).
- Hypokalemia occurred in 13% of controls versus 3% with MRA, 9% with potassium supplements, and 5% with combination therapy; hyperkalemia occurred in 0.2% of controls versus 0%, 3%, and 4%, respectively (p>0.1 between regimens).
Study Design
Type
Observational (n=1,172)
Blinding
Open-label with blinded endpoint adjudication
Randomization
Non-randomized subgroup allocation within an open-label RCT
Multicenter
Yes
Structured PICO
Do different plasma potassium-increasing regimens (MRA monotherapy, potassium supplement monotherapy, or combination therapy) differ in their effect on plasma potassium levels, ventricular arrhythmias, and safety outcomes in ICD patients with baseline potassium ≤4.3 mmol/L?
P
Population
1,172 adults in Denmark with heart disease and an ICD (mean age ~62.7 years, 20% female), baseline plasma potassium <=4.3 mmol/L, and eGFR >30 mL/min/1.73 m2, followed for a median of 3.0 to 3.3 years.
E
Exposure
Protocolized potassium-optimization strategy targeting plasma potassium levels between 4.5 and 5.0 mmol/L in addition to standard care and dietary counselling, categorized at the completion of up-titration into three regimens: a) mineralocorticoid receptor antagonist (MRA) monotherapy (spironolactone up to 100 mg daily or eplerenone up to 50 mg daily; n=73), b) potassium supplement monotherapy (up to 4500 mg daily; n=148), or c) combination therapy with both MRA and potassium supplements (n=326).
C
Comparator
Standard care only (control group, n=600), and observational comparisons across the three potassium-increasing regimens.
O
Outcome
Composite of first occurrence of sustained ventricular tachycardia (>125 bpm for >30 s documented on ECG or electrogram), appropriate ICD therapy, unplanned hospitalization >24 h for arrhythmia or heart failure leading to a change in drug or invasive treatment, and all-cause mortality, adjudicated by an independent blinded Endpoint Committee over a median follow-up of 3.0 to 3.3 years.composite
Main Result
Hazard Ratio: 0.69 (95% CI 0.53–0.92)
Absolute Event Rate: 22% vs 29%
p-value: p=0.8 between regimens
Limitations
- Allocation to the specific potassium-increasing regimen within the intervention arm was not randomized, introducing potential confounding and baseline imbalances.
- Subgroup sizes were modest, particularly in the MRA monotherapy group (n=73), limiting statistical power and rendering results exploratory.
- Excluded patients with baseline plasma potassium >4.3 mmol/L, eGFR <30 mL/min/1.73 m2, and pediatric patients, limiting generalizability.
- Close protocolized potassium monitoring at repeated study visits represents a controlled best-case scenario that may not reflect routine clinical practice.
- Allocation to the individual treatment regimens was not randomized, and comparisons between regimens were observational.
- Risk of immortal time bias in the primary analysis because control participants entered on the day of randomization whereas intervention participants entered on the day of completed up-titration (addressed via landmark and time-varying sensitivity analyses).
- Analysis was not powered to compare individual endpoint components or exclude clinically meaningful differences in hyperkalemia and safety endpoints across the three regimens.
- Frequent crossovers between treatment regimens during follow-up (41% in MRA monotherapy, 39% in potassium supplement monotherapy, and 31% in combination therapy).
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“It's a positive study, important because it offers a low-cost, easy-to-implement intervention for a very sick and expensive-to-treat patient population, with potential to reduce health care burden.”
“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. 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 ICD.”
Implication
Similar effects on potassium and arrhythmias across regimens; leaves open optimal up-titration strategy in ICD patients.
Abstract
BACKGROUND AND AIMS: The POTCAST trial (n=1,200) showed that targeting high-normal plasma potassium levels reduced ventricular arrhythmias in patients with Implantable Cardioverter-Defibrillators (ICDs). We compared changes in plasma potassium and described outcomes across the three regimens used to increase plasma potassium. METHODS: We studied 600 control participants and 572 intervention participants who completed potassium up-titration in POTCAST. Participants in the intervention arm were categorized according to treatment after plasma-potassium up-titration into: a) mineralocorticoid-receptor antagonists (MRAs) monotherapy, b) potassium-supplement monotherapy, or c) combination-therapy with both. The primary endpoint was a composite of sustained ventricular arrhythmia, appropriate ICD-therapy, hospitalization for arrhythmia or heart-failure or all-cause mortality. Safety outcomes included death and electrolyte/renal disturbances. RESULTS: After six months, plasma potassium increased from 4.12 to 4.27 mmol/L (p=0.004) with MRA, from 3.99 to 4.24 mmol/L (p<0.001) with potassium-supplements, and from 3.98 to 4.34 mmol/L (p<0.001) with combination-therapy. The primary endpoint occurred in 29% (n=175) of controls, 22% (n=16) in the MRA group, 21% (n=31) in the potassium-supplements group and in 22% (n=72) in the combination-therapy group (p=0.8 between regimens). Hypokalemia occurred in 13% of controls and in 3%, 9%, and 5% of participants receiving MRA, potassium-supplements and combination-therapy, respectively. Hyperkalemia occurred in 0.2% of controls and in 0%, 3%, and 4% of participants receiving MRA, potassium-supplements, and combination-therapy (p>0.1 between regimens). CONCLUSIONS: Treatment with MRA, potassium-supplements or both increased potassium levels. All regimens were associated with numerically lower endpoint rates than controls. We detected no statistically significant differences in endpoints or safety between regimens.
Discussion
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Cite This Study
Danielsen et al. (2026) conducted an observational in Heart disease with an Implantable Cardioverter-Defibrillator (ICD) at high risk of ventricular arrhythmias (n=1,172). Potassium-increasing regimens (MRA monotherapy, potassium-supplement monotherapy, or combination therapy) vs. Standard care control group (and comparison across the three active regimens) was evaluated on Composite of sustained ventricular tachycardia (>125 bpm >30 s), appropriate ICD therapy, unplanned hospitalization >24 h for arrhythmia or heart failure, and all-cause mortality (Adjusted HR 0.69 (combination), HR 0.66 (potassium), HR 0.80 (MRA), 95% CI 0.53-0.92, p=0.8 between regimens). MRA monotherapy (22%), potassium supplements (21%), and combination therapy (22%) all raised potassium with similar primary endpoint rates versus control (29%; p=0.8 between regimens).