Epidemiology and health outcomes associated with hyperkalemia in a primary care setting in England

Hyperkalemia (HK) is a potentially life-threatening electrolyte abnormality typically characterized by elevated serum potassium (K⁺) levels (> 5.0 mmol/L) [1]. It is often associated with severe adverse clinical outcomes, including cardiac arrhythmias and mortality, with increasing frequency as K⁺ increases [1, 2]. Generally, dietary restrictions are recommended to control K⁺, and while there are a few acute and chronic drug therapies available to help control K⁺, these are not widely prescribed and there may be a need for improved treatments. [3]. Sodium polystyrene sulfonate, the traditional first-line oral therapy, has not been robustly tested in clinical trials for HK, has a variable onset of effect, and is associated with gut necrosis when administered over prolonged periods [4, 5]. Patiromer, a K⁺-binding agent recently approved in the United States and Europe, is a potential option for long-term use but must not be taken within 3 h of other oral medications [6], potentially limiting its use. With few options for long-term control of K⁺ and little consensus on how and when to treat, patients with HK may be undertreated, thereby increasing their risk of HK-related adverse clinical outcomes.

Few studies have evaluated HK incidence or prevalence; those published primarily describe highly selected patient populations. Frequency estimates of HK vary based on study designs, including definition of HK and frequency of K⁺ monitoring, and patient characteristics (including comorbidities and medication use) [7, 8]. For example, the HK prevalence among patients with heart failure (HF) in clinical trials evaluating renin–angiotensin–aldosterone system antagonists ranged from 1.4 to 6.0% depending on the definition of HK used, severity of HF, and medications used [9]. In two studies of patients with chronic kidney disease (CKD), the prevalence of HK, defined as K⁺ ≥ 5.5 mmol/L, ranged from 3.2 to 31.5% [7, 8].

Availability of high-quality electronic health records enables quantification of HK incidence and the clinical conditions, use of medications, and real-world health consequences associated with HK in the general population. Here, we report results from a population-based analysis characterizing the incidence rate of HK and its associated factors, frequency of retesting, clinical consequences, and healthcare resource utilization (HRU) associated with HK among patients receiving healthcare in England.

A total of 195,178 patients with an index HK event during the study period were analyzed (Additional file 1: Figure S1). Patient demographics and baseline characteristics are shown in Table 1. Most patients were female (52.1%), with a mean (standard deviation [SD]) age of 60.6 (16.6) years and mean (SD) eGFR of 80.5 (21.1) mL/min/1.73 m². Common baseline comorbidities included hypertension, hyperlipidemia, ischemic heart disease, CKD, and obstructive lung disease. Patients with an index HK event with K⁺ > 6.0 mmol/L had generally higher frequencies of comorbidities, especially ischemic heart disease, arrhythmia, and atrial fibrillation, compared with patients with an index HK event with K⁺ ≤ 6.0 mmol/L, although eGFR did not appear to be substantially lower.

Concomitant medications were similar across HK severity strata; key exceptions were loop diuretics and mineralocorticoid receptor antagonists (MRAs), which were roughly two-fold more common among patients with an index HK event with K⁺ > 6.0 mmol/L versus K⁺ ≤ 6.0 mmol/L.

Using a large comprehensive medical records database from England, we found most index HK events involved only modest increases in K⁺ levels; however, severe HK occurred more often than might be expected within the general population. Furthermore, HK appeared to be persistent upon retesting and had a graded association with adverse outcomes including hospitalization and death, yet rarely resulted in rapid retesting, even among those with a severe index HK event.

To our knowledge, this is the first population-based study to evaluate the incidence of an index HK event, patterns of retesting K⁺, and subsequent clinical outcomes in a large general primary-care setting. The observed incidence rate of an index HK event in this study (~ 3 per 100 person-years) was generally comparable to that of other studies. A Swedish observational study using a marginally more strict definition of HK (K⁺ > 5.0 mmol/L) found a crude incidence rate of HK of 5 per 100 person-years [14]. This finding could be due to differences in our study populations, frequency of testing, use of concomitant medications, or prevalence of comorbidities.

Several key factors were associated with index HK in our study. The presence of a baseline eGFR value was strongly associated with HK, likely reflecting prescribers’ awareness of its inherent risk associated with kidney dysfunction.

Additionally, use of ACE inhibitors, ARBs, and MRAs, each known to potentially increase K⁺ [14‐16], were found to be strong risk factors for HK. Of note, more than half of individuals who had HK were not users of RAAS inhibitors, which may indicate that providers judged these patients to be at disproportionate risk of developing HK, and so did not prescribe these drugs.

In contrast, some characteristics appeared inversely related to index HK development. Interestingly, increased age appeared to reduce the likelihood of an index HK event in this study; the exact reason for this is unknown. Thiazide diuretics, as anticipated, were associated with a lower risk of index HK [17, 18]; loop diuretics, in contrast, were associated with an increased risk of HK. While the nature of our study cannot determine why this is the case, the explanation for this finding may be that the patients with the most complex medical conditions or who were judged by their medical providers as being most at risk of HK were also the ones most likely to receive loop, as opposed to thiazide, diuretics.

Strikingly, retesting of K⁺ within 2 weeks of an index HK event was uncommon. While this may be because most index HK events involved only mildly elevated K⁺, retesting was far less common than might be expected. Retesting was uncommon even in patients with an index HK event with K⁺ > 6.0 mmol/L, with only 55% retested within 2 weeks of an index HK event. In addition, among those with an index HK event with K⁺ > 6.0 mmol/L who were retested, roughly one in five had K⁺ > 6.0 mmol/L when retested within 2 weeks following the event. This is suggestive of both an underappreciation of the importance of K⁺ retesting, especially when K⁺ levels approach or even exceed 6.0 mmol/L, and the likelihood of sustained HK [14]. The lack of prompt K⁺ retesting and the persistence of frank HK could possibly place patients at undue risk of major clinical events. The incidence rate of HK recurrence was particularly high among patients with diabetes, CKD, HF, or hypertension, suggesting that clinicians should pay particular attention to these at-risk groups.

Hospitalization was correlated with the severity of HK. While not all HRU markers were elevated following an HK episode, HK appeared to be associated with hospitalization over short (3 days) and intermediate (30 days) lengths of time. Although the direction of causality is uncertain, HK can be a sign of acute illness (rather than a cause of it), which may portend HK as a particular risk for impending illness and hospitalization, and underscore the need to closely monitor patients with an index HK event. Combined with a comparative lack of HK retesting and high rate of HK recurrence after retesting (especially when the index HK event had K⁺ > 6.0 mmol/L), these findings suggest that prudent HK testing, follow-up, and retesting might identify a patient subgroup at undue risk for adverse events who could benefit from timely interventions in response to HK.

Several study design and database limitations should be considered when interpreting these findings. The CPRD captures data among patients seeking healthcare in a primary care setting and may not fully represent the healthcare status of all patients; this study may not be generalizable to populations outside of England because of inherent differences in populations, treatment strategies, and services. Although the CPRD/HES database is well validated [10, 19], the potential for misclassified or nonspecific ICD-10 codes, diagnosis codes, and/or laboratory data exists and may lead to over- or under-reporting of HK events and other clinical outcomes, especially because clinical diagnoses were not verified by chart review. One study found the sensitivity of ICD-10 codes for diagnosing HK to be low (14.6% at hospital admission), which may contribute to under-reporting of HK events [20]. However, the likely effect of this would be to underestimate the risk associated with HK. As noted earlier, laboratory data are not available in the HES database; therefore, if severe cases were not coded correctly, they would have been excluded from this analysis. Incidence of HK may also be misreported because this analysis primarily relied on laboratory findings of HK in the CPRD which likely included instances of spurious HK due to hemolysis. Further, the data sources could not account for previously unobserved occurrences of HK which might have obfuscated comorbidities at baseline, as it may be unclear if these conditions are a result of untreated HK. In addition, this analysis did not include emergency care data, which may contribute to potential undercapturing of HK diagnoses given that repeat testing may have occurred in an emergency setting. The incidence of repeat testing may have been further affected by mis-diagnoses and inaccurate K⁺ levels due to hemolysis. The analysis may also be limited because of infrequent measurements of K⁺. Finally, this study cannot assess whether there is a causal relationship between HK and outcomes following HK events.

This study is the first to quantify HK incidence, K⁺ testing patterns, and outcomes associated with HK in a primary care setting in England, and findings suggest that current attention to HK in general practice may be suboptimal. Although patients who experienced an index HK event, particularly with K⁺ > 6.0 mmol/L, were more likely to experience a second occurrence of HK as well as adverse clinical outcomes, repeat testing was not common, and it is unclear whether directed treatment for HK was administered. While causality could not be determined in this study, an association between HK and adverse clinical outcomes was identified, suggesting that underdiagnosis and undertreatment of HK may increase the risk of adverse clinical outcomes. As well-tolerated therapies for the long-term management of HK become readily available, the benefits of more frequent testing of K⁺ and restoring normokalemia may become apparent. More research is needed in at-risk patients with frequently monitored K⁺ levels whose K⁺ is controlled to normal levels to fully understand HK and its consequences.