A comprehensive real-world safety analysis of sodium zirconium cyclosilicate (SZC), AstraZeneca's hyperkalemia treatment, has revealed previously unreported cardiovascular risks and identified 21 distinct adverse drug reaction signals through analysis of the FDA Adverse Event Reporting System (FAERS) database.
The study, which analyzed adverse event reports spanning seven years since SZC's initial approval, employed four pharmacovigilance algorithms to ensure accuracy and identified congestive heart failure as a statistically significant risk across all analytical methods. This finding represents a more severe clinical manifestation than the dose-related edema previously reported in pivotal clinical trials.
Cardiovascular Risks Emerge as Primary Concern
The analysis revealed that cardiovascular adverse reactions constitute a critical area requiring heightened attention. Congestive heart failure emerged as statistically significant across all four pharmacovigilance algorithms (ROR, PRR, IC, EBGM), even after false-discovery-rate correction, with this association appearing stronger for SZC than for the comparator drug patiromer.
Researchers propose two plausible mechanisms for these cardiovascular effects. First, each 5-gram dose of SZC contains approximately 400 mg of sodium, translating to 800-2,400 mg daily depending on treatment phase. For patients already advised to restrict sodium intake to less than 2 grams per day, this may promote volume expansion, elevate cardiac preload, and precipitate heart failure decompensation.
The study also identified potential signals for ventricular fibrillation, which may be related to electrophysiological changes induced by SZC, such as QT interval prolongation. Previous clinical trial data showed that patients in the SZC group demonstrated corrected QT interval prolongation consistent with decreased serum potassium levels, with this prolongation being dose-dependent.
Gastrointestinal and Metabolic Safety Profile
At the system organ class level, disorders related to metabolism and nutrition exhibited the highest signal strength, with a relative odds ratio of 2.45 (95% CI: 2.07-2.9). These effects primarily relate to electrolyte imbalances such as hypokalemia and hypernatremia, attributed to SZC's mechanism of selectively binding potassium ions throughout the gastrointestinal tract while exchanging them for hydrogen and sodium ions.
The analysis identified 21 adverse drug reaction signals spanning various systems, with gastrointestinal adverse reactions such as constipation, nausea, and vomiting being most commonly observed. Notably, the study revealed a unique and severe adverse event signal for SZC: intestinal obstruction. This finding gains credence from recent case reports describing sigmoid colon perforation in patients treated with SZC, particularly those with underlying impaired intestinal transit.
Temporal Patterns and Patient Demographics
The analysis showed a median adverse event onset of 92 days, with 41.9% of events occurring within the first 30 days of SZC initiation. Cumulative incidence curves indicated that early events (≤60 days) predominantly included abdominal discomfort, elevated blood pressure, fluid retention, and fractures, whereas later-onset events (after 200 days) comprised cardiac failure, constipation, hypokalemia, and ileus.
Adverse events associated with SZC showed a notable demographic pattern, with males experiencing an incidence 1.67 times higher than females, and elderly populations being more commonly affected. This distribution aligns with the epidemiological characteristics of conditions that SZC treats, as males generally face higher exposure to risk factors for renal failure, hypertension, and heart failure.
Comparative Safety with Patiromer
The head-to-head comparative safety analysis with patiromer revealed distinct adverse event profiles driven by their different mechanisms of action. While SZC exchanges sodium and hydrogen ions for potassium, patiromer exchanges calcium ions, leading to mechanistically distinct electrolyte disturbances.
SZC was uniquely associated with hypernatremia, while patiromer showed associations with hypo/hypermagnesemia and hypercalcemia. The primary adverse events for SZC were cardiac-related due to its sodium exchange mechanism, whereas patiromer exhibited more pronounced gastrointestinal side effects, with significantly stronger signals for constipation and abdominal discomfort.
Clinical Implications and Monitoring Recommendations
The findings support the need for vigilant monitoring of volume-related complications, especially in elderly patients or those with baseline cardiovascular compromise. The study's identification of cardiovascular risks in real-world settings, particularly among patients who may have been excluded from pivotal trials due to unstable heart failure, highlights the importance of post-marketing surveillance.
The research leveraged the FAERS database to supplement safety data for SZC in real-world contexts, overcoming limitations of clinical trials with stringent inclusion criteria and small sample sizes. This approach allowed identification of rare but serious events such as bowel obstruction and arrhythmias that may not have been adequately captured in controlled clinical settings.
