Author + information
- Published online December 31, 2018.
- aInova Heart and Vascular Institute, Falls Church, Virginia
- bDuke University Medical Center, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Lauren B. Cooper, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, Virginia 22042.
Patients with heart failure are at risk for hyperkalemia and hypokalemia because of the heart failure syndrome itself, medications used in the management of heart failure, and common comorbidities. Dyskalemia in this population is known to be associated with morbidity and mortality (Online Refs. 1–3). Most of the work in this area has focused on heart failure with reduced ejection fraction (HFrEF) because guideline-recommended treatments for HFrEF include renin-angiotensin-aldosterone antagonist system inhibitor (RAASi) (angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], angiotensin receptor neprilysin inhibitor, and mineralocorticoid receptor antagonist [MRA] medications) as well as loop diuretics, all of which can contribute to dyskalemia (Online Ref. 4). Patients with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF), however, account for approximately one-half of the prevalence of heart failure and, as with HFrEF, are also associated with significant morbidity and mortality (Online Refs. 5,6). Loop diuretic use is common in these populations as well and MRAs are recommended for patients with HFpEF, and many patients with HFpEF and HFmrEF are on RAASi because of other comorbidities (Online Ref. 4); thus, further study of dyskalemia in these populations is warranted.
In this issue of JACC: Heart Failure, Savarese et al. (1) add to this important literature by exploring dyskalemia in patients with heart failure across the spectrum of ejection fraction in their paper entitled “Incidence, Predictors, and Outcome Associations of Dyskalemia in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction”. In this study, the authors used clinical data from the SwedeHF (Swedish Heart Failure) Registry, a clinical registry of patients with heart failure in the Stockholm region, and laboratory data from the Stockholm Creatinine Measurements project. For 5,848 patients, the authors identified instances of dyskalemia within a year of entering the registry and explored both predictors of dyskalemia and 1-year outcomes after dyskalemia. For hyperkalemia, they found the following: 1) approximately 24% of patients had at least 1 measurement of plasma potassium >5 mmol/l and 10% had potassium >5.5 mmol/l; 2) patients with HFmrEF and HFpEF were at higher risk for severe hyperkalemia than patients with HFrEF; 3) MRA use, as well as comorbidities including low hemoglobin, low estimated glomerular filtration rate, diabetes mellitus, and chronic obstructive pulmonary disease were associated with hyperkalemia, but ACE inhibitor and ARB use were not; and 4) hyperkalemia was associated with a 4-fold risk of death across the EF spectrum but not increased hospitalization risk. For hypokalemia, they found: 1) approximately 20% had at least 1 measurement of plasma potassium <3.5 mmol/l and ∼4% had potassium <3.0 mmol/l; 2) there were similar risks of hypokalemia across EF groups; 3) risk factors for hypokalemia include female sex, low estimated glomerular filtration rate, chronic obstructive pulmonary disease, anemia, history of myocardial infarction, use of diuretics and nonuse of ACE inhibitors/ARBs; and that 4) incidence hypokalemia was associated with a more than 3-fold risk of death across the EF spectrum as well as increased cardiovascular hospitalization.
The strengths of this study are the large sample size, the inclusion of all ranges of ejection fraction, including both hyperkalemia and hypokalemia, and the study population from a clinical practice registry. By using real-world clinical data, the authors have addressed another major limitation of the current literature, which is that much of it originates from clinical trial data that tend to have a more restrictive population. Furthermore, monitoring for dyskalemia, response to dyskalemia, and subsequent outcomes from dyskalemia are markedly different between clinical trials and routine clinical practice. In the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), for example, which studied the use of eplerenone in patients with HFrEF and New York Heart Association functional class II symptoms, 37.9% had serum potassium >5 mmol/l and 11% had serum potassium >5.5 mmol/l, and hospitalization for hyperkalemia was 0.3% (2). In comparison, a registry study from the United States showed the rate of hospitalization for hyperkalemia in the first year after initiation of an MRA was 8.9% (3). Moreover, although there was a 13.8% drug discontinuation rate in the eplerenone arm of EMPHASIS-HF and a 1.1% drug discontinuation rate because of hyperkalemia (4), among new users of MRA therapy in a registry study from Sweden, 47% of patients with a potassium level >5 mmol/l discontinued therapy. Notably, of those, 76% were not reintroduced to therapy during the subsequent year (5). Although hyperkalemia was seen in early RAASi clinical trials, the rates of hospitalization or drug discontinuation because of hyperkalemia were low; whereas in clinical practice, the associated rates of hospitalization and drug discontinuation are much higher. These notable differences highlight the need to study dyskalemia in real-world clinical situations to provide meaningful recommendations to providers caring for these patients.
Despite the clear need to study this problem in a clinical registry environment, there are limitations inherent to registry studies, including this study by Savarese et al. (1). As with all retrospective registry studies, there are likely unmeasured confounders that may have influenced the results. In this study, there was neither documentation of the rationale for laboratory assessment nor the timing and frequency of serial laboratory evaluations. Sicker patients may have had more frequent laboratory monitoring because of more severe heart failure or other comorbidities, making identification of dyskalemia more likely; thus, there may be a degree of ascertainment bias that would be distinct from a clinical trial approach with an algorithmic schedule of assessments. These considerations highlight the utility of complementary information from registry and trial datasets. There was also no information about the clinician response to dyskalemia, including medication changes made in response to dyskalemia. Medication changes, in and of themselves, could account in part for changes in outcomes, because clinicians may adjust life-saving medications (e.g., RAASi discontinuation or dose reduction) in the setting of laboratory abnormalities (4,6). There was also no information on patients who did not have laboratory monitoring because they were excluded. Numerous prior publications have confirmed the lack of appropriate laboratory monitoring in patients with heart failure who are initiating new therapies, and these patients may also be at risk of dyskalemia (Online Refs. 7–10).
The findings of this study have important clinical implications. The authors have shown that dyskalemia is common in heart failure regardless of EF, with an increased risk of hyperkalemia in patients with HFmrEF and HFpEF, and that dyskalemia should be avoided (and/or potentially intervened upon) because it is associated with increased mortality. This study also provides insight into the highest risk patients, including those with impaired renal function who are at highest risk for both hypokalemia and hyperkalemia, those on diuretics who are at an increased risk of hypokalemia, and those on an MRA who are at an increased risk of hyperkalemia. Understanding risk factors can help minimize hypokalemia and hyperkalemia; these conditions can be managed when they do occur.
These considerations related to dyskalemia are particularly important in the setting of heart failure medical therapy. For hyperkalemia, although there were previously limited treatment options, the availability of novel potassium binders may allow for a larger population of patients to be safely initiated and maintained on life-saving medical therapy (Online Refs. 11–14). Additional work is needed to determine best practices regarding the initiation and maintenance use of these novel therapies in patients with heart failure to optimize overall medication regimens. This study by Savarese et al. (1) provides critical information for future studies, including the imperative to design studies investigating strategies to help avoid dyskalemia, and the knowledge of who is at highest risk for dyskalemia. A key next step is to further test and implement effective strategies to avoid dyskalemia in patients with heart failure.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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