The leading cause of death among patients receiving maintenance hemodialysis is sudden cardiac death. These patients also experience a high burden of atrial fibrillation (AF), which contributes to higher rates of stroke, cardiomyopathy, and other vascular events.
An important goal of hemodialysis is to remove potassium buildup between treatments while keeping serum potassium (sK+) concentration within a functional range. Most kidney care providers prioritize removal of potassium and use low dialysate (≤2.5 mEq/l) potassium concentrations to help prevent hyperkalemia in patients on hemodialysis.
However, managing blood potassium concentrations in these patients is confounding because both low and high sK+ concentrations may increase the risk of sudden death and heart arrhythmias. In addition, the increased degree and speed of potassium removal with lower dialysate potassium concentrations may increase the risk of peridialytic hypokalemia and associated arrhythmias.
Oral potassium binders may help. When administered regularly, they can limit the accumulation of total body potassium between hemodialysis sessions. This reduces the need for rapid dialytic removal and allows for the use of higher dialysate potassium concentrations, potentially lowering the risk of peridialytic hypokalemia and hypokalemia-induced AF and other arrhythmias.
A study led by David M. Charytan, MD, tested this theory. In the ADAPT trial, they examined whether the use of the potassium binder sodium zirconium cyclosilicate (SZC) in combination with dialysate potassium could reduce the incidence of postdialysis AF and clinically significant cardiac arrhythmias (CSCAs). Their results were published in Kidney International.
ADAPT was a prospective, randomized, open-label, crossover study with a two-week screening period, two eight-week periods of treatment, and a visit at the end of the study. Participants received an implanted cardiac loop recorder and were assigned 1:1 to receive either 2.0 K+/2.5 Ca2+ mEq/l dialysate bath without SZC (2.0K+/noSZC) or 3.0 K+/2.5 Ca2+ mEq/l dialysate bath with oral SZC on nonhemodialysis days (3.0K+/SZC) for eight weeks. This was followed by a second treatment phase during which they switched to the other treatment. During a two-week run-in period before each treatment phase, participants were allowed to equilibrate to both the dialysate and SZC use. The SZC starting dose on nondialysis days (four days per week) was 5 g, which was uptitrated weekly in increments of 5 g up to 15 g to maintain the sK+ concentration within 4.0 to 5.5 mEq/l.
In total, 148 patients from 13 sites including 19 dialysis units were screened for eligibility. Selected participants included 88 adults aged 18 or older with kidney failure and hyperkalemia confirmed by two predialysis sK+ measurements of 5.1 to 6.5 mEq/l. All participants received in-center hemodialysis three days per week for a minimum of three months. Mean age was 57.1 years, 51% were male, 46% were White, and mean predialysis sK+ was 5.5 mmol/l.
The primary outcome was the rate of adjudicated AF episodes lasting two minutes or longer. Secondary outcomes included clinically significant arrhythmias (bradycardia, ventricular tachycardia, and/or asystole) and the percentage of sK+ measurements within an optimal window of 4.0–5.5 mEq/l.
The mean starting dose for SZC during the 3.0 mEq/l K+ dialysate period was 8.1±3.6 g, while the ending dose was 10.2±4.0 g. Twenty-four (28%) participants received the 5 g dose, 30 (35%) received 10 g, and 32 (37%) received 15 g during 3.0K+/SZC treatment. Mean time to titration to first 10 g SZC was 18.1±14.1 days.
Ninety-five percent of expected SZC doses were given during the eight-week treatment periods, totaling 1,114 administrations for sequence A and 1,260 for sequence B. The mean number of administrations per participant was 27.2±9.2 for sequence A and 30.0±5.0 for sequence B. Total treatment days were 1,975 for sequence A and 2,205 for sequence B. The mean number of days of exposure (including the run-in period) was 48.2±15.5 days for sequence A, with a maximum of 83 days, and 52.5±8.4 for sequence B, with a maximum of 56 days.
The follow-up period was 25.5 person-years, during which 296 AF episodes occurred in nine participants. Of these, 123 events occurred in six participants for 3.0K+/SZC and 173 occurred in seven participants for 2.0K+/noSZC. The unadjusted mean incidence rate per year for AF was 9.8 (95% CI, 8.0–11.5) with 3.0K+/SZC and 13.4 (95% CI, 11.4–15.5) with 2.0K+/noSZC. The modeled rate ratio using the quasi-Poisson model was 0.52 (95% CI, 0.41–0.65; P<.001).
The pattern was similar for CSCAs. Eighty-six events were observed in 11 participants with 3.0K+/SZC and 131 events were detected in 13 participants with 2.0K+/noSZC. The unadjusted mean incidence rate per year for CSCA was 6.8 (95% CI, 5.4–8.3) for 3.0K+/SZC and 10.2 (95% CI, 8.4–11.9) for 2.0K+/noSZC. The modeled rate ratio was 0.47 (95% CI, 0.38–0.58; P<.001).
The mean duration of AF events was 1,191 (95% CI, 0–2828) min/yr for 3.0K+/SZC and 2,804 (95% CI, 0–6450) min/yr for 2.0K+/noSZC (mean difference, –1613 min/yr; 95% CI, –5,594 to 2,367 min/yr). The mean proportion of follow-up time spent in AF was 0.22% for 3.0K+/SZC and 0.53% for 2.0K+/noSZC (absolute risk difference, –0.30%; 95% CI, –1.11% to 0.45%). For CSCA events, the mean duration was 3 (95% CI, 0–5) min/yr for 3.0K+/SZC compared to 285 (95% CI, 0–610) min/yr for 2.0K+/noSZC (mean difference, –282 min/yr; 95% CI, –607 to 43 min/yr).
The chances of the sK+ concentration falling outside the optimal window dropped by >70% with 3.0K+/SZC (modeled odds ratio, 0.27; 95% CI, 0.21–0.35). This was mostly due to a reduction in postdialysis hypokalemia. Hyperkalemia (sK+ concentration, >5.5 mEq/l) occurred infrequently with 3.0K+/SZC, appearing in just three patients. The rates of postdialysis hypomagnesemia and hypophosphatemia differed little between the treatment groups.
A higher rate of adverse events (AEs) was observed in participants receiving 3.0K+/SZC (43%) than in those receiving 2.0K+/noSZC (33%). None of the AEs were related to treatment or led to dose interruption.
The study limitations include the small cohort size and short treatment duration. The study population was somewhat young, so generalizations should be made with caution. In addition, the design of the ADAPT trial does not allow for definitive determination of the proportion of the arrhythmia benefits attributable to the change from a dialysate K+ concentration of 2.0 to 3.0 mEq/l and the subsequent reduction in postdialysis hypokalemia versus that attributable to the supplementary use of SZC on nondialysis days to limit the risks of predialysis hyperkalemia.
“In conclusion, in patients with hyperkalemia on maintenance hemodialysis, a combination of 3.0 mEq/l K+ dialysate and SZC on nonhemodialysis days reduced the rates of AF, CSCA, and hypokalemia compared with 2.0K+/noSZC,” the authors wrote. The findings question current dialysis treatment paradigms, they noted, and warrant future prospective trials to determine whether 3.0K+/SZC results in fewer episodes of symptomatic arrhythmia or other major cardiovascular events.
Source: Kidney International.
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