Heart Failure and Hyperkalemia- A Thing of the Past?

Renin-angiotensin-aldosterone inhibitors (RAASi) are fundamental to the treatment of heart failure with reduced ejection fraction (HFrEF). However, RAASi comes with a risk of hyperkalemia, particularly in patients with chronic kidney disease (CKD). Hyperkalemia, while often asymptomatic, can result in muscle weakness, nausea, arrhythmias, chest pain, and even severe cardiovascular collapse. The fear of causing hyperkalemia can lead practitioners to under-dose or discontinue RAASi, especially mineralocorticoid receptor antagonists (MRAs), which have critical symptom and mortality benefit in HFrEF.

Adherence to heart failure guidelines has been a long-standing challenge for many reasons, with medical intolerance being a large contributor. In fact, in the CHAMP-HF registry, fewer than 5% of patients were on guideline recommended doses of RAASi and beta-blockers.1 The 2022 AHA/ACC/HFSA Heart Failure Guidelines indicate that initiation of MRAs is contraindicated in eGFR ≤ 30 mL/min/1.73 m2 or potassium ≥ 5 mEq/L.2 Additionally, MRAs should be discontinued if serum potassium cannot be maintained <5.5 mEq/L. The DIAMOND trial investigators sought a solution to the ubiquitous dilemma of RAASi therapy and hyperkalemia via the study of Patiromer, a potassium-binder that exchanges potassium for calcium in the gastrointestinal tract.3

The DIAMOND trial enrolled 1195 patients in a prospective, multi-center, randomized, double-blind, placebo-controlled trial performed at 389 international sites.3 Patients with HFrEF (ejection fraction ≤40%) and baseline hyperkalemia >5 mmol/L while on RAASi were included. Patients with a history of dose reduction or discontinuation of RAASi for hyperkalemia were also included. Those with CKD with a GFR <30 mL/min/1.73 m2 were excluded. A total of 878 patients completed the run-in-phase of the trial and 439 were randomly assigned to continue patiromer and 439 patients were assigned to switching to placebo. Most patients were men (74.5% in patiromer group, 71.3% in placebo group);42.4% had stage 3 CKD and 40.5% had diabetes. At the time of screening, 40.3% of patients were hyperkalemic and 59.7% were normokalemic but had a history of hyperkalemia.

The study’s primary endpoint was the mean change in serum potassium from baseline. The median duration of follow up was 27 weeks and the median number of potassium assessments for each patient was 5. The mean change in serum potassium in the patiromer group was +0.03 (95% CI -0.01, 0.07) mmol/L and +0.13 (95% CI 0.09, 0.16) mmol/L in the placebo group. The difference between the groups was 0.10 mmol/L (95% CI -0.13, -0.07; p<0.001).

In terms of secondary outcomes, 13.9% of patients in the patiromer group had hyperkalemia events (>5.5 mmol/L) compared to 19.4% in the placebo group (p=0.006). A discontinuation or dose reduction in target MRA dose occurred in 13.9% of the patiromer group compared to 18.9% in the placebo group (p=0.006). Total number of hyperkalemia events/100-person-years were lower with patiromer compared to placebo (77.7 vs 118.2; p<0.001).

The DIAMOND trial results are encouraging for patients with HFrEF and RAASi-related hyperlakemia. Most patients (86.4%) were able to achieve target doses of RAASi therapy while on patiromer during the run-in phase of the trial. The effects of patiromer were also consistent across all sub-groups. However, future studies are necessary to assess the effect of patiromer on clinical outcomes such as hospitalizations and mortality and in patients with eGFR <30 mL/min/1.73 m2. But this is a promising step in the right direction to improving adherence to guideline-directed medical therapy for HFrEF.

 

References:

  1. Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018;72(4):351-366. doi:10.1016/j.jacc.2018.04.070
  2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Journal of the American College of Cardiology. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
  3. Butler J, Anker SD, Lund LH, et al. Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial. Eur Heart J. Published online July 28, 2022:ehac401. doi:10.1093/eurheartj/ehac401