BACKGROUND: Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA. OBJECTIVES: This study sought to evaluate the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia. METHODS: REALIZE-K (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA-induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/day); those with hyperkalemia started SZC. Participants with normokalemia (potassium: 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/day were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/day without rescue therapy for hyperkalemia [months 1-6]). The 5 secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening heart failure (HF) events (hospitalizations and urgent visits). RESULTS: Overall, 203 participants were randomized (SZC: 102; placebo: 101). Higher percentage of SZC- vs placebo-treated participants had optimal response (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; P < 0.001). SZC (vs placebo) improved the first 4 secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR: 4.58; 95% CI: 2.78-7.55; P < 0.001); receiving spironolactone ≥25 mg/day (81% vs 50%; OR: 4.33; 95% CI: 2.50-7.52; P < 0.001); time to hyperkalemia (HR: 0.51; 95% CI: 0.37-0.71; P < 0.001); and time to decrease/discontinuation of spironolactone due to hyperkalemia (HR: 0.37; 95% CI: 0.17-0.73; P = 0.006). There was no between-group difference in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at 6 months (-1.01 points; 95% CI: -6.64 to 4.63; P = 0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of cardiovascular (CV) death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal P = 0.034). CONCLUSIONS: In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalemia and down-titration/discontinuation of spironolactone. Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone; NCT04676646).
- MeSH
- Mineralocorticoid Receptor Antagonists * therapeutic use administration & dosage adverse effects MeSH
- Double-Blind Method MeSH
- Hyperkalemia * drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Prospective Studies MeSH
- Aged MeSH
- Silicates * therapeutic use administration & dosage adverse effects MeSH
- Spironolactone * administration & dosage adverse effects therapeutic use MeSH
- Heart Failure * drug therapy MeSH
- Stroke Volume drug effects physiology MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. OBJECTIVES: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). METHODS: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). RESULTS: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. CONCLUSIONS: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646).
- MeSH
- Mineralocorticoid Receptor Antagonists * therapeutic use administration & dosage adverse effects MeSH
- Double-Blind Method MeSH
- Hyperkalemia * drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Prospective Studies MeSH
- Aged MeSH
- Silicates * therapeutic use administration & dosage MeSH
- Spironolactone * administration & dosage therapeutic use adverse effects MeSH
- Heart Failure * drug therapy physiopathology MeSH
- Stroke Volume * physiology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
U srdečního selhání je hyperkalemie problémem hned z několika důvodů, jimiž jsou například neurohumorální mechanismy v patofyziologii tohoto onemocnění, renální selhání, komorbidity a také léky, které přinášejí prognostický prospěch. Mezi takové léky patří inhibitory renin‑angiotenzin‑aldosteronového systému, které mohou zvyšovat hodnoty kalemie, zejména při kombinaci s jinými léčivy (např. s nesteroidními antirevmatiky). Pokud hyperkalemie není korigovaná, může mít závažné důsledky zejména pro srdce. Proto je velmi důležité respektovat některá pravidla ‒ uvážlivě předepisovat léky, které ovlivňují kalemii, brát v úvahu všechny faktory, které zvyšují riziko hyperkalemie, a pokud hyperkalemie vznikne, zahájit včas její léčbu. V tomto přehledu jsou shrnuty obvyklé postupy v léčbě hyperkalemie a rovněž diskutovány nové molekuly, jež mohou snížit riziko vzniku hyperkalemie (finerenon) nebo mohou účinně zmírňovat kalemii (chelační polymer patiromer či iontové síto zirkonium‑cyklosilikát sodný).
In heart failure, hyperkalaemia is a frequent problem because of several factors, such as neurohumoral mechanisms involved in pathophysiology of the disease, renal failure, comorbidities, and also drugs with prognostic benefit. Among such drugs are inhibitors of the renin‑angiotensin‑aldosterone system, which can increase potassium levels, especially when combined with other drugs, such as nonsteroidal antirheumatics and others. Hyperkalaemia can have severe consequences, if not corrected, mostly cardiac. Therefore, it is important to respect some rules, like prescribing drugs influencing potassium levels prudently, managing all factors increasing the risk of hyperkalaemia, and treating hyperkalaemia immediately if it develops. This overview summarizes all usual treatments of hyperkalaemia. New molecules are also discussed that can decrease the risk of developing hyperkalaemia, like finerenone, or decrease plasma potassium effectively, like chelating polymer patiromer or ion sieve sodium zirkonium cyclosilicate.
- MeSH
- Electrocardiography MeSH
- Hyperkalemia * etiology drug therapy complications MeSH
- Angiotensin-Converting Enzyme Inhibitors administration & dosage adverse effects therapeutic use MeSH
- Ions MeSH
- Investigational New Drug Application * methods MeSH
- Disease Attributes MeSH
- Humans MeSH
- Naphthyridines administration & dosage adverse effects therapeutic use MeSH
- Kidney Diseases complications MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Polymers therapeutic use MeSH
- Randomized Controlled Trials as Topic MeSH
- Renin-Angiotensin System physiology drug effects MeSH
- Risk Factors MeSH
- Silicates MeSH
- Heart Failure * drug therapy complications prevention & control MeSH
- Statistics as Topic MeSH
- Age Factors MeSH
- Zirconium MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
