Heart failure (HF) is a growing public health concern that affects 26 million people worldwide.1 Its prevalence is predicted to increase by 25% in the next decade.2 HF is the main cause of hospitalizations >65 years of age in Europe and in the United States of America (USA).3 HF hospitalizations have high associated morbidity and mortality4 and are the main driver of HF-associated costs.5,6 In the USA and Europe, HF has the greatest economic impact of all diseases.1 In Portugal, HF is estimated to represent 2.6% of the total health budget,7 and the loss of disability-adjusted life years is predicted to increase 27.9% by 2036.8 HF mortality is higher than that associated with the most common forms of cancer.9

Heart failure with reduced ejection fraction (HFrEF) guidelines recommend timely institution of triple neurohormonal blockade/modulation. This is the combination of two renin-angiotensin-aldosterone system inhibitors (RAASi) with a beta blocker (BB): an angiotensin-converting enzyme inhibitor (ACEi), or an angiotensin receptor blocker (ARB), or an angiotensin receptor-neprilysin inhibitor (ARNI), associated with a mineralocorticoid receptor antagonist (MRA) and a BB.10

The use of maximal doses of all these drugs is strongly recommended, as studies have shown increased mortality and morbidity among patients who do not reach target doses.11–14 However, this is often hampered by adverse pharmacological effects, such as hyperkalemia, which can occur with all RAASi. According to Juurlink et al.,15 after the publication of the RALES study,16 an increase in spirolactone prescription and hyperkalemia-associated morbidity and mortality was observed. While mild hyperkalemia (serum K+ 5.1–5.5 mEq/L) is generally well tolerated, higher levels of serum potassium are associated with an increased risk of potentially lethal arrhythmias.17,18 The European Society of Cardiology (ESC) HFrEF guidelines recommend halving the dose or discontinuation of RAASi in the presence of moderate (serum K+ 5.6–6.0 mEq/L) or severe hyperkalemia (serum K+ >6.0 mEq/L), respectively.10 However, sub-optimal RAASi doses or RAASi discontinuation is, in turn, linked to worse long term HF prognosis. Hence, new potassium-binders, which lower serum potassium concentration, have been developed, to enable RAASi utilization.19–22 Nevertheless, evidence from clinical practice is still limited.

The present study aims to identify the proportion of HFrEF patients, in real life clinical practice, who cannot reach the neurohormonal blockade/modulation strategy target doses due to hyperkalemia. The recognition of this treatment gap clarifies the magnitude of the unmet need of enabling RAASi with potassium-binders in the optimization of HFrEF patients’ daily care.

Of all the patients with an appointment at the outpatient HF Clinic during 2018, 240 met our inclusion criteria. Median LVEF was 29% (interquartile range (IQR): 24–35).

Patients’ characteristics at index visit are listed in Table 1. Mean age was 61±11 years and 173 (72%) were men.

In 95 (40%) patients, HF etiology was ischemic heart disease. Regarding cardiovascular risk factors, 174 (73%) of patients had dyslipidemia, 118 (49%) a history of smoking, 117 (49%) hypertension, 81 (34%) diabetes and 79 (36%) were obese. In 73 (36%) patients, estimated glomerular filtration rate was <60 ml/min/1.73 m2.

Patients were followed for a median of 160 (IQR: 107–182) weeks. Each patient attended a median of 3.1 appointments per year (IQR: 2.4–4.1). All patients had information regarding the prescribed medication.

Only six patients (3%) reached maximal doses of NH blockade/modulation. Forty-eight (20%) patients were under suboptimal RAASi doses or discontinued one or more RAASi specifically due to hyperkalemia: in 12 (5%) patients one or more RAASi was not prescribed and in 36 (15%) RAASi target doses were not reached. Other reasons include hypotension, bradycardia renal failure and a group of unlisted reasons. Tables 2 and 3 show the tolerated doses of RAASi for the entire sample, and for those patients whose therapy was hampered by hyperkalemia, respectively.

Overall, 100 patients (42%) presented at least one episode of hyperkalemia during the follow-up. A total of 185 hyperkalemia episodes across these patients were registered: 140 (76%) mild, 40 (22%) moderate and 5 (3%) severe.

Patients presenting one or more episodes of hyperkalemia during the follow-up were older (mean age 63±10 vs. 60±11, p=0.027), and had higher prevalence of renal failure (44% vs. 29%, p=0.037), hypertension (61% vs. 41%, p=0.004) and diabetes (46% vs. 26%, p=0.003). These results are summarized in Table 4.

In HFrEF, maximal RAASi doses are associated with better prognosis compared with submaximal doses.11–14 However, in everyday clinical practice RAASi up-titration to maximal doses encounters several obstacles. Among them are hypotension, renal failure and hyperkalemia.15,17,18 In our study, we found that hyperkalemia was the cause of RAASi under-titration in 20% of our HFrEF patients.

The percentage of our patients not reaching RAASi maximal doses due to hyperkalemia aligns with that described in previous real life studies, in which hyperkalemia was present in 4–21% of cases.23

Our study showed that hyperkalemia is frequent in real life clinical practice. The prevalence of hyperkalemia episodes in 42% of our patients is in line with previous reports.23,24 The fact that 24% of hyperkalemia episodes were moderate or severe is a striking result since they are associated with an increased risk of sudden arrhythmic death.25,26 The association of hyperkalemia with older age, diabetes, chronic kidney disease and hypertension has also been previously described.23,27

Hyperkalemia leads to the downgrade of RAASi therapy, which is associated with worse prognosis and increased hospitalizations11 and costs.28 Thus, an approach that simultaneously prevents hyperkalemia and enables RAASi therapy at full dose is a clear and present unmet need. Our study is a contribution to establishing the dimension of this unmet need in daily practice.

Two new potassium-binding drugs, patiromer and sodium zirconium cyclosilicate, have been studied in the OPAL-HK,19 PEARL-HF,20 HARMONIZE,21 and AMETHYST-DN22 trials. They have recently been approved and shown to be able to normalize elevated K+ levels and prevent recurrent hyperkalemia in patients with diabetes, chronic renal disease, and heart failure. Additionally, data on patiromer demonstrated the RAASi-enabling capacity of this drug in the setting of chronic renal disease, diabetes, and congestive heart failure.19–22 Patiromer maintained normokalemia during one year follow-up.22 Currently, the DIAMOND trial is assessing the effective potential of patiromer in reducing cardiovascular death and hospitalizations by enabling optimal RAASi therapy in patients with HFrEF.29 In daily clinical practice, hyperkalemia is frequent and limits NH blockade/modulation by hampering RAASi therapy. Addressing hyperkalemia and enabling RAASi is an important issue in HFrEF treatment with the potential of reducing morbidity, mortality, and costs.

This study has limitations concerning data collection, as they were retrospectively gathered from medical records which were not designed for clinical research. A more granular registry may allow for a more powerful exploration of hyperkalemia and associated factors in future research.

Hyperkalemia is a common side effect of RAASi therapy. It is associated with an increased risk of potentially lethal arrhythmias in patients with HF. This study, conducted under real clinical practice conditions in a Portuguese center, identified the proportion of HFrEF patients who cannot reach RAASi target doses due to hyperkalemia. Our results underline the need for hyperkalemia-controlling strategies to optimize HFrEF patient care.

This work was supported by Vifor Pharma, Portugal, via an educational grant. Support for third-party medical writing assistance for this manuscript, furnished by Ana Macedo, MD, PhD of Keypoint, was provided by Vifor Pharma.

The authors have no conflicts of interest to declare.