Maximizing Benefits and Mitigating Risks with Mineralocorticoid Receptor Antagonist Therapy

This article refers to ‘Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists’ by M. Trevisan et al., published in this issue on pages 1217–1226. Outcomes with the use of mineralocorticoid receptor antagonist (MRA), spironolactone and eplerenone, therapy in heart failure is a commonly referenced example of the difference between efficacy and effectiveness. Several randomized controlled trials demonstrate efficacy of MRA therapy in heart failure with reduced ejection fraction (HFrEF), showing a significant decrease in mortality and all-cause, cardiovascular, and heart failure hospitalizations with MRA use.1, 2 However, studies from clinical practice registries failed to show the same degree of effectiveness.3, 4 One study from the United States showed no difference in mortality or cardiovascular hospitalization for those on MRA therapy compared to those not on therapy, though it did show a decreased risk of heart failure hospitalization.3 Similarly, a study from Sweden showed that MRA therapy was not independently associated with decreased risk of mortality.4 In part, this could be due to early discontinuation of MRA therapy without considering approaches to maximize benefits and minimize risks. Mitigating risks to allow for maximal benefits could close the gap between clinical trial efficacy and real-world clinical practice effectiveness. In this issue of the Journal, Trevisan and colleagues added some key information to this area of study.5 In their study, they examined real-world clinical practice of MRA initiation in Stockholm, Sweden, and analysed subsequent hyperkalaemia (K+ > 5.0 mmol/L), clinician response to hyperkalaemia, and clinical outcomes. They used laboratory measurements from the Stockholm Creatinine Measurements (SCREAM) database linked to administrative databases to determine medical history, drug dispensation, and outcomes. Briefly, they found that MRA use decreased over the 1-year follow-up period, with only 50% of patients on therapy after 6 months, and only 24% after 12 months. Of all patients, 18.5% experienced K+ > 5 mmol/L, and of those, 47% discontinued the drug, and 10% reduced the dose. Of the patients who discontinued the drug, 76% did not restart during the 1-year follow-up period. For the subset of patients with heart failure, 26.2% experienced hyperkalaemia. In both the overall population and the subset with heart failure, development of hyperkalaemia was associated with a higher risk of mortality. Overall, there are four important conclusions: (i) in new users of MRA therapy, rates of discontinuation in the first year are high, (ii) of patients who experience hyperkalaemia, almost half discontinue the drug, with only a small percentage trying a reduced dose, (iii) of those who discontinue the drug due to hyperkalaemia, few restart, and (iv) patients who experience hyperkalaemia have higher risk of mortality at 1 year. In clinical trials of MRA therapy in heart failure, including the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), there were defined systematic approaches to monitoring potassium levels and managing abnormal values.6, 7 Thus, all patients with abnormal potassium values were treated similarly, with a focus on minimizing risk but maximizing study drug use. Consequently, both trials had very low rates of MRA discontinuation due to hyperkalaemia.1, 2 In comparison, Trevisan's analysis showed high rates of drug discontinuation due to hyperkalaemia. Though different from clinical trial results, Trevisan's study results are similar to prior registry and observational studies from real-world clinical practice, which also had high rates of clinically significant hyperkalaemia and drug discontinuation.3, 8, 9 While prior publications report only rates of hyperkalaemia, adverse events, and outcomes, because of the robust data available in Trevisan's study—including laboratory data, pharmacy data, and administrative data—this study was able to show not only rates of hyperkalaemia, but also response to hyperkalaemia. In this clinical registry, there were high rates of drug discontinuation after even mild hyperkalaemia (K+ 5.0–5.5 mmol/L). Importantly, secondary analyses from clinical trial data suggest that MRA therapy is beneficial in patients with HFrEF despite an increased risk of hyperkalaemia, at least until potassium level reaches 5.5 mmol/L.6, 7 The evidence from clinical trials suggests that hyperkalaemia is permissible with MRA therapy and patients derive a benefit of therapy despite modest hyperkalaemia. Putting those findings in context of Trevisan's results, one can conclude that many patients in the Swedish registry may have been able to safely continue and derive benefit from continued MRA therapy. Hence, the difference between efficacy and effectiveness may be related to clinician response to hyperkalaemia in the real world compared to the tightly regulated clinical trial environment. Furthermore, many prior studies have shown low rates of MRA use among eligible users.10, 11 The current study shows that even when an MRA is started, it is likely to be stopped within the first year, either due to hyperkalaemia or other reasons. In practice, it seems that when providers are weighing the risks and benefits of therapy, they are focusing more on the risks without integrating the benefits into decision making. Almost 20 years after the publication of RALES, appropriate utilization of this life-saving therapy is still low. Perhaps if real-world clinical practice mirrored clinical trial monitoring and management of hyperkalaemia with MRA therapy, real-world outcomes might be more similar to those of clinical trials. Clinical practice guidelines recommend strict monitoring protocols when initiating MRA therapy, but several studies show poor compliance with these guideline recommendations.11-14 Hospitals and clinics should be encouraged to develop strategies to monitor and manage new users of MRA therapy. These strategies should closely align with how MRA initiation was managed in clinical trials with specified drug titration, frequent laboratory monitoring, clear guidance on how to manage hyperkalaemia, when a dose change is appropriate, and when it is truly necessary to discontinue drug therapy. Approaches can include utilization of electronic medical record alerts, engagement of clinical pharmacists, and central monitoring of laboratory values. While this current study adds to the literature in important ways, several limitations must be considered. First and foremost, this analysis includes all patients who were initiated on MRA therapy, but the indication for MRA therapy was not available for analysis. Only 64.4% of patients in this analysis had heart failure, and there was no information on ejection fraction, thus conclusions about response to hyperkalaemia and comparison with prior heart failure studies must be taken in context, with an understanding that the populations may be quite different. Second, the study presented data on hyperkalaemia occurring in the first year after drug initiation, but did not include information on whether clinicians followed guideline recommendations about laboratory monitoring soon after drug initiation. Third, the study only looks at potassium levels and mortality outcomes, not adverse clinical events related to hyperkalaemia such as heart rhythm disturbances, muscle pain or weakness, or need for hospitalization or urgent treatment. Furthermore, this study only includes information about drug discontinuation or dose reduction, but does not include information about dietary counselling, use of potassium binders, or modification of other drug therapies. Whether this is done in the real world or not remains unknown, but clinical management of hyperkalaemia during MRA initiation should include options to try before permanent discontinuation of this therapy. Trevisan and colleagues should be commended for helping to further the understanding of use of MRA therapy in real-world clinical practice. Further studies are needed to determine whether patients who stop MRA therapy, whether for hyperkalaemia or other indications, have different outcomes from patients who continue on the therapy. And furthermore, whether treatment for hyperkalaemia with dietary counselling, traditional or novel potassium binders, or modification of other therapy, impacts outcomes in patients with MRA-induced hyperkalaemia. With further research and the implementation of systems to improve laboratory monitoring and drug management, hopefully we will soon be able to close the gap between efficacy and effectiveness of MRA therapy in heart failure. Conflict of interest: none declared.