The efficacy and safety of new potassium binders on renin-angiotensin-aldosterone system inhibitor optimization in heart failure patients: a systematic review and meta-analysis

Abstract

Guideline-directed medical therapy (GDMT) has improved outcomes in patients with heart failure, including the use of renin-angiotensin-aldosterone system inhibitors, which can hinder the excretion of potassium, resulting in hyperkalaemia. New potassium binders (NPBs) can prevent this adverse effect; however, the efficacy and safety of NPB for this indication have not been fully established. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, Scopus, and Cochrane through 26 April 2023. The risk of bias assessment was conducted, following Cochrane's updated Risk of Bias 2 assessment tool. We used the fixed-effects model to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), with a 95% confidence interval (CI) (PROSPERO ID: CRD42023426113). We included six RCTs with a total of 1432 patients. NPB was significantly associated with successful mineralocorticoid receptor antagonist (MRA) optimization [RR: 1.13 with 95% CI (1.02-1.25), P = 0.02], decreased patients with MRA at less than the target dose [RR: 0.72 with 95% CI (0.57-0.90), P = 0.004], and decreased hyperkalaemic episodes [RR: 0.42 with 95% CI (0.24-0.72), P = 0.002]. However, there was no difference between NPB and placebo regarding angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/angiotensin receptor/neprilysin inhibitor (ANRi) optimization [RR: 1.02 with 95% CI (0.89-1.17), P = 0.76] and serum potassium change [MD: -0.31 with 95% CI (-0.61 to 0.00), P = 0.05], with an acceptable safety profile except for the increased incidence of hypokalaemia with NPB [RR: 1.57 with 95% CI (1.12-2.21), P = 0.009]. NPB has been shown to improve GDMT outcomes by enhancing MRA optimization and reducing hyperkalaemic episodes. However, there are limited data on the effects of NPB on ACEi/ARB/ANRi optimization. Future RCTs should investigate ACEi/ARB/ANRi optimization and conduct head-to-head comparisons of NPB (patiromer and sodium zirconium cyclosilicate).

Keywords: Heart failure; Hyperkalaemia; Meta-analysis; New potassium binders; Patiromer; Review.

Figure 1

PRISMA flow chart of the screening process.

Figure 2

Quality assessment of the risk of bias in the included trials. The upper panel presents a schematic representation of risks (low = green, unclear = yellow, and high = red) for specific types of biases of each of the studies in the review. The lower panel presents risks (low = red, unclear = yellow, and high = red) for the subtypes of biases of the combination of studies included in this review.

Figure 3

Forest plots of the efficacy outcomes. (A) Mineralocorticoid receptor antagonist (MRA) optimization, (B) MRA at less than the target dose, (C) hyperkalaemia (potassium >5.5 mEq/L), (D) angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor/neprilysin inhibitor optimization, and (E) serum potassium change. CI, confidence interval; M‐H, Mantel–Haenszel; NPB, new potassium binder.

Figure 4

Forest plots of the safety outcomes. AE, adverse event; CI, confidence interval; M‐H, Mantel–Haenszel; NPB, new potassium binder.

Figure 5

Trial sequential analysis (TSA). (A) Mineralocorticoid receptor antagonist optimization and (B) hyperkalaemia (potassium >5.5 mEq/L). NPB, new potassium binder.