Efficacy and safety of three different potassium increasing regimens in patients at high risk of ventricular arrhythmias: a prespecified analysis of the randomized POTCAST trial

Background The POTCAST trial showed that targeting high-normal plasma potassium levels (4.5-5.0 mmol/L) reduced ventricular arrhythmias in participants with an Implantable Cardioverter-Defibrillator (ICD). Plasma potassium levels were increased using mineralocorticoid receptor antagonists (MRAs), potassium supplements, or both in combination. Purpose The purpose of this prespecified analysis of the POTCAST trial was to compare the efficacy and safety of the three different regiments used to increase plasma potassium levels in the trial. Methods The participants in the intervention group were categorized according to the treatment regimen at completion of the plasma potassium up-titration into a) monotherapy with MRA, b) monotherapy with potassium supplements, or 3) combination therapy with MRA and potassium supplements. The primary endpoint was a composite of sustained ventricular arrhythmia, appropriate ICD-therapy, hospitalization for arrhythmia- or heart failure, or all-cause mortality between groups. Safety outcomes included hypo- and hyperkalaemia. Results A total of 1,200 participants (mean age 62.7 ± 12.0 years, 19.8% female) were randomized to standard of care or to plasma potassium up-titration (600 participants assigned to each group). Plasma potassium up-titration was completed with one of the three regimens in 547 participants from the intervention group. After six months, plasma potassium levels had increased from 4.12 to 4.27 mmol/L (p=0.004) with MRA monotherapy (n=73), from 3.99 to 4.24 mmol/L (p<0.001) with potassium supplement monotherapy (n=148), and from 3.98 to 4.34 mmol/L (p<0.001) with combination therapy (n=326), i.e. the most pronounced increase was observed in participants given combination therapy (p<0.001 for MRA vs. combination therapy; p=0.005 for potassium supplements vs. combination therapy). Plasma potassium levels were highest in the group on combination therapy during the first 18 months of treatment but were similar thereafter (Figure 1). The primary endpoint occurred in 29% of controls, in 22% of the participants in the MRA group, in 23% in the potassium supplement group, and in 23% of the participants given combination therapy (no significant between-regimen interactions) (Figure 2). Hypokalemia (plasma potassium <3.5 mmol/L) occurred in 13% of controls and in 3%, 9%, and 5% of participants receiving MRA, potassium supplements, and combination therapy, respectively (p>0.05 between intervention regimens). Hyperkalaemia (plasma potassium ≥5.5 mmol/L) occurred in 0.2% of controls and in 0%, 3%, and 4% of participants receiving MRA, potassium supplements, and combination therapy, respectively (p>0.05 between intervention regimens). Conclusions Treatment with MRA, potassium supplements or the combination of MRA and potassium supplements increased plasma potassium levels significantly, reduced the risk of the primary endpoint similarly, and had similar safety profiles.