Novel Potassium Binders as Enabling Therapy in Heart Failure

Hyperkalaemia is a common problem in patients with heart failure (HF). For example, in the contemporary PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, patients with hyperkalaemia or estimated glomerular filtration rate of < 30 mL/min/1.73 m2 at screening were excluded, and those who developed hyperkalaemia during the 4–6 weeks run-in phase were also disqualified.1 Despite this, ∼1 in six patients developed serum potassium (K+) levels of > 5.5 mmol/L during the trial duration of 27 months. In PIONEER-HF (Comparison of Sacubitril/Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode) trial, 10% of patients with decompensated HF developed hyperkalaemia within only 8 weeks.2 Concern for hyperkalaemia often results in failure to initiate or maximize dosing of renin–angiotensin–aldosterone system inhibitors (RAASi). Around 30% of the eligible HF patients are not prescribed mineralocorticoid receptor antagonists (MRA) because of the fear of hyperkalaemia.3, 4 Furthermore, most RAASi trials have excluded patients with hyperkalaemia or advanced chronic kidney disease (CKD), leading to a major knowledge gap regarding the role of these agents in high-risk patients. This is concerning as RAASi have established benefits in HF patients who are otherwise at risk of hyperkalaemia, e.g. those with CKD or diabetes mellitus or older age. Secondary analyses of RAASi trials have demonstrated that the benefit of RAASi was independent of the risk for developing hyperkalaemia. However, with safety being a primary concern, the guidelines recommend lowering the dose or discontinuation of RAASi therapy in HF patients who develop hyperkalaemia.5 To maximize the use of RAASi and simultaneously maintaining normokalaemia, several new options have emerged. Novel potassium binders such as patiromer and sodium zirconium cyclosilicate (SZC) effectively normalize hyperkalaemia and maintain normokalaemia with acceptable safety and tolerability profile, as opposed to sodium polystyrene sulfonate.6-8 Considering that long-term options for treatment of hyperkalaemia are limited and restricting dietary potassium intake is often difficult and ineffective, these drugs represent an attractive alternative to RAASi discontinuation or dose reduction due to hyperkalaemia. Table 1 outlines the completed and ongoing trials of patiromer and SZC reporting RAASi use. According to the current HF guidelines,5 initiation of MRA should be avoided in patients with K+ > 5.0 mmol/L. This translates to 20–30% of HF patients not being prescribed MRA. In observational studies, even high-normal K+ levels are associated with an increased mortality risk in HF. Dose reduction is further recommended for K+ > 5.5 mmol/L and discontinuation for > 6.0 mmol/L. However, these actions put the patients at risk for disease progression caused by suboptimal dosing of RAASi.9 Thus, it becomes a clinical conundrum to find a balance between initiation/optimization of RAASi and hyperkalaemia in HF. Despite this, the novel potassium binders are neither recommended in the guidelines nor are widely prescribed in HF patients with hyperkalaemia to maintain RAASi therapy to avert the risk of cardiovascular disease progression. The main argument is that while efficacy and safety profile has been shown with these agents conclusively, there is insufficient evidence to show that novel potassium binder enabled optimization of RAASi would translate into improved HF outcomes. Recommendation for using enabling therapies in the interest of best patient outcomes has been appropriately done many times before. For example, dexrazoxane is converted intracellularly to a chelating agent that interferes with iron-mediated free radical generation thought to be responsible for anthracycline-induced cardiomyopathy. The American Society of Clinical Oncology recommends dexrazoxane for cardio-protection in metastatic breast cancer patients who have received more than 300 mg/m2 of doxorubicin10 to reduce the risk of developing HF and thus permitting longer duration of treatment. However, this recommendation is without definitive trial data showing benefit. The American College of Cardiology/American Heart Association guidelines recommended the use of proton pump inhibitors since 2008 prior to any evidence from a clinical trial in patients who have a history of or who are at increased risk of gastrointestinal bleeding, to enable the use of dual antiplatelet therapy in patients with acute coronary syndrome,11 since the discontinuation of antiplatelet therapy in patients with bleeding may increase the risk of cardiovascular events. The European Society of Cardiology (ESC) guidelines gave similar recommendation.12 While data behind these examples were absent or modest, as conducting large trials is extraordinarily costly, and conversely inaction is also not affordable as patients are left at higher risk, these recommendations were put forward based on clinical reasoning. As the population of HF patients with concomitant CKD continues to rise, lifesaving treatments such as RAASi will be continued to be under-utilized due to the concerns of hyperkalaemia. Novel potassium binders in this respect should serve to extend the use of RAASi to many patients who are otherwise unable to take them due to hyperkalaemia. The only hypothesis that should require first a randomized outcomes trial prior to a recommendation is to propose that patients who develop hyperkalaemia will not respond to RAASi therapy and hence enablement does not matter. This hypothesis is neither supportive by logic nor by secondary analysis on hyperkalaemic patients from previous RAASi trials.13 For example, to propose studying a chemotherapeutic agent with known benefit but is not tolerated due to nausea/vomiting to be studied in a fully powered large outcomes trial randomizing patients to with and without an adjuvant antiemetic drug as opposed to a smaller safety and tolerability study, would be considered irrational. Not giving a strong recommendation in this regard without a large trial is prudent. However, it may be sensible to have a class II recommendation for the use of these agents in select patients who would otherwise benefit from continuation or optimization of RAASi therapy. Any possibility of an adequately powered prospective randomized trial demonstrating the efficacy and safety of novel potassium binders vs. the current strategy of reducing or discontinuing RAASi therapy in patients with HF who develop hyperkalaemia is welcomed, but the current inertia in this regard is putting patients at ongoing risk. Conflict of interest: J.B. has received research support from the NIH, PCORI and the European Union; and serves as consultant for Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmaceuticals, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, StealthPeptide, SC Pharma, Vifor, and ZS Pharma. S.D.A. reports receiving fees for trial and registry related to consultancy work and speaking from Bayer, Boehringer Ingelheim, AstraZeneca, Servier, Novartis, Respicardia, Vifor and V-Wave. He also reports receiving grants for IITs from Vifor and Abbott Vascular. M.S.K. has no disclosures.