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Challenges remain in management of RAASi therapy in high CV risk cases
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In the United States, there are more than 3 million patients living with hyperkalemia, yet this recurrent condition is often overlooked, even though it can cause abnormal heart rhythms and sudden death.1,2 People at highest risk for hyperkalemia include patients with chronic kidney disease, diabetes and heart failure — three common clinical conditions.
Physicians commonly use a renin-angiotensin-aldosterone system inhibitor (RAASi) to reduce the risk of death and to slow disease progression in patients with heart failure. However, RAASi medications are also linked to an increased risk of hyperkalemia, and in some cases up to 30% of patients on RAASi therapy develop the condition.3,4 Therefore, RAASi therapy is often modified or discontinued once a patient experiences a hyperkalemic event. In turn, this may lead to a greater threat of heart failure and cardiovascular-related death.
Thus, a significant challenge for the optimal management of patients at high cardiovascular risk is that treatment with RAASi therapy may bring significant risk of hyperkalemia.
Benefits and risks
Large clinical trials have shown the critical value of RAASi therapy, demonstrating that risk of death was lowered with RAASi therapy, and discontinuing RAASi therapies or administering them at a suboptimal dose was associated with a higher death rate.4,5 Despite these benefits, RAASi therapies are closely linked to increased potassium concentrations, and ultimately to hyperkalemia, which is common in patients at risk for CKD and/or heart failure.6
Current guidelines advise that heart failure patients who develop hyperkalemia reduce RAASi dosage or discontinue therapy.7 While this strategy addresses the immediate negative effects of hyperkalemia, discontinuing or reducing RAASi therapy exposes the patient to poorer clinical outcomes and to increased health care costs, such as hospitalizations due to cardiovascular issues and cardiovascular mortality.8 Moreover, recent data from the Change the Management of Patients with Heart Failure registry show there is substantial underuse of guideline-directed RAASi therapy.9 As such, there is a significant unmet need for novel therapeutic options for the chronic management of patients at risk for hyperkalemia.
Manage potassium levels
Rather than reduce or eliminate a patient’s RAASi therapy, one clinical alternative is to add a potassium‐binding polymer, such as sodium polystyrene sulfonate (SPS). SPS was first approved by the FDA for the treatment of hyperkalemia in 1958 and has been used in the long-term management of hyperkalemia. However, there have recently been questions regarding its safety and efficacy based on reported cases of bowel necrosis.8
In October 2015, the FDA approved patiromer, the first new potassium binder for the treatment of hyperkalemia in decades.10 Patiromer binds with potassium in exchange for calcium in the colon, thereby decreasing the amount of potassium available for gastrointestinal absorption.11 To date, clinical studies have demonstrated the ability of patiromer to lower serum potassium levels and reduce RAASi discontinuation.11
In the PEARL-HF study of heart failure patients with previously documented hyperkalemia or CKD, patiromer significantly lowered serum potassium levels with a difference between groups of −0.45 mEq/L; a lower incidence of hyperkalemia (7.3% patiromer vs. 24.5% placebo); and a greater proportion of patients on spironolactone 50 mg/day (91% patiromer vs. 74% placebo).
The OPAL-HK study demonstrated that patiromer significantly decreased potassium levels in patients with hyperkalemia and CKD who took RAASi compared to placebo (mean decrease of -1.01 ± 0.03 mEq/L from baseline). During the second part of the study, patients taking patiromer had no change in median potassium from baseline (0.00 mEq/L), whereas potassium levels significantly increased in the placebo group (0.72 mEq/L).12
Data presented at the Kidney Week in 2018 further expand our understanding of the potential role of patiromer in patients on RAASi therapy. Alongside collaborators from COHRDATA, UT-Southwestern and Relypsa, results from a retrospective study were reported that assessed RAASi utilization from a large, de-identified national health insurance claims database.
We identified three cohorts of hyperkalemia diagnoses: those treated with patiromer; those treated with SPS; and those not treated with any potassium binder. Among these cohorts, we evaluated RAASi continuation and dose reductions within 1-, 3- and 6-month time frames. At 6 months post-index, RAASi continuation rates were 87%, 72% and 57% and dose-reduction rates were 11%, 11% and 9% in the patiromer, SPS and non-treatment cohorts, respectively. The highest RAASi continuation rate was observed in the patiromer cohort across all time intervals, and down-titration rates in all three cohorts were low, at about 10%.13
We will need additional studies to clarify these findings, and to further elucidate how clinicians can keep patients on RAASi therapies to maximize the renal and cardiovascular protective effects of the therapies.
Conclusion
The management of hyperkalemia in patients taking RAASi therapies is challenging. RAASi therapies are life-saving medications for patients with heart failure and other chronic conditions. Unfortunately, their use increases the risk for developing hyperkalemia, which can lead to underuse or discontinuation of RAASi therapy. Real-world evidence and clinical trial data suggest that patients with hyperkalemia treated with potassium binders are significantly more likely to stay on RAASi therapy. Novel agents, such as patiromer, have the potential to shift the treatment paradigm in the management of hyperkalemia caused by RAASi and may provide clinicians with a new strategy to improve patient outcomes.
References:
1. Betts KA, et al. Current Medical Research and Opinion. 2018;doi:10.1080/03007995.2018.1433141.
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4. Epstein M et al. Am J Manag Care. 2015; www.ncbi.nlm.nih.gov/pubmed/26619183.
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6. McCullough PA. Nephron 2018;doi:10.1159/000485645.
7. Dunn JD. Am J Manag Care. 2015; www.ajmc.com/journals/supplement/2015/a577_nov15_hyperkalemia/a577_nov15_hyperkalemia.
8. Hagan AE. Clin Nephrol. 2016;doi:10.5414/CN108628.
9. Greene SJ. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.04.070.
10. Lainscak M. Cardiac Failure Review. 2017;doi:10.15420/cfr.2017.2.1.
11. Pitt B, et al. Eur Heart J. 2011;doi:10.1093/eurheartj/ehq502.
12. Weir MR, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410853.
13. Desai NR, et al. Patiromer and maintenance of RAASi therapy in hyperkalemic Medicare patients. Poster presented at: ASN Kidney Week; Oct. 27, 2018.
For more information:
Nihar Desai, MD, MPH, is assistant professor of medicine (cardiology) and in the Institution for Social and Policy Studies, Yale School of Medicine in New Haven, Connecticut.
Disclosure: Desai reports he is a consultant for Relypsa Pharmaceuticals.