Incidence and determinants of hyperkalemia among heart failure patients who used spironolactone

Potassium balance in heart failure is affected by many factors including neurohormonal mechanisms and drugs used in its management. Renin–angiotensin–aldosterone system inhibitor therapies are part of heart failure therapy and have been associated with increase the risk of hyperkalemia. Currently, there are limited data on the prevalence and risk factors of hyperkalemia in heart failure patients who received spironolactone as an add-on to standard therapy which include Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II receptor blockers (ARBs). The objective of this study is to identify Incidence and determine of hyperkalemia risk factors among heart failure patients who have been using spironolactone. Our study showed that half of heart failure patients who used spironolactone developed hyperkalemia. The majority of patients who developed hyperkalemia were either on ACEIs or ARBs. Spironolactone dosing of 50 mg was associated with highest incidence of hyperkalemia. Further study with a larger sample size is required to clarify and conrm our study ndings.


Introduction
Heart failure (HF) is one of the major cardiovascular disease. It is a leading cause of morbidity and mortality worldwide [1,2]. Heart failure is associated with many serious clinical outcomes including atrial brillation, stroke, peripheral embolism, pulmonary embolism, hepatic dysfunction, pulmonary congestion and kidney failure. Disturbances in the potassium homeostasis are common among patients with heart failure (HF) and has been associated with unfavorable clinical outcomes [3,4]. Potassium balance in heart failure is affected by the neurohormonal mechanisms and through the drugs that are used in its treatment [6,7]. Patients with HF have a high prevalence of chronic kidney disease, which increases the risk of hyperkalemia [5,21].
Spironolactone is mineralocorticoid receptor antagonist (MRA) and belongs to a class of medications known as potassium-sparing diuretics. It competitively blocks the binding of aldosterone to its cytoplasmic receptor and so increase the Na and decrease the electrically coupled K secretion [8,9]. The most common side effects for spironolactone are gynecomastia, GI upset and hyperkalemia [10,22,23].
Hyperkalemia is a potentially life-threatening condition and de ned as a serum potassium level more than 5 mmol/L [11,12].
RALES trial is a landmark study supported the use of spironolactone in heart failure patients. This trial included severe heart failure patients with ejection fraction less than 35% and found that adding spironolactone to standard therapy reduced morbidity and mortality in those patients. According to American Heart Association guideline, spironolactone is recommended in patients with NYHA class II-IV with left ventricular ejection fraction (LVEF) of 35% or less and in patients after a myocardial infarction (MI) when they have an LVEF less than 40% with symptoms of HF or an LVEF less than 40% and DM [13,14,15].
A population-based time-series analysis has indicated that the publication of RALES trial was associated with abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality [16]. Among patients with preserved ejection fraction included in TOPCAT trial, the risk of hyperkalemia associated with used of spironolactone and ACE inhibitor/ARB was 4-fold higher than placebo [17]. Furthermore, a cohort study has been done in Brazil to evaluate the risk of hyperkalemia among heart failure patients who used angiotensin converting enzyme inhibitors (ACEIs) with or without spironolactone and they found that spironolactone group has been associated with increase the incidence of hyperkalemia [18]. A retrospective study of 125 congestive heart failure (CHF) patients showed that 30 patients developed hyperkalemia. They identi ed that kidney function, diabetes mellitus (DM) and heart failure medications are independent risk factors for hyperkalemia [19]. Nested case control study in Germany for HF patients who were receiving ACE or ARB in combined with spironolactone were signi cantly associated with increase with risk of hyperkalemia especially with age ≥70 year [20].
Currently, there are limited data on the incidence and risk factors of hyperkalemia in heart failure patients who received spironolactone as an add-on to standard therapy which include ACEIs or Angiotensin II receptor blockers (ARBs). We aimed in this study, to identify Incidence and determine of hyperkalemia risk factors among heart failure patients who have been using spironolactone.

Study design
This retrospective chart review study was carried out in King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia from March 1, 2016 to March 31, 2019. The Medical city contains a Cardiac Center that provide patient care for heart failure. Health electronic system (Bestcare) was used to identify. All known cases of heart failure which required treatment with spironolactone, patients of both sex, and age ≥18 years were included in the study.Patient was excluded if any of the following criteria was found: (i) chronic kidney disease that requires dialysis; (ii) cancer or (iii) history of hyperkalemia (de ned as if the last two readings were > 5 before start on spironolactone).

Data Collection
The data required for present study was noted down from the patients' charts in a data collection form using Excel sheet. Extracted information included demographic data (age,gender, weight ejection fraction, and baseline potassium levels), patient's comorbidities, dose of spironolactone, hyperkalemia incidence(s) if any, time to the rst event, other medications (ACEI, ARB, digoxin, furosemide, betablockers, and potassium supplements), average potassium level, average creatinine, and average BNP).

Statistical analysis
An Excel-based tool (Microsoft® Excel; Version 2018) was used for systematic data sampling and analysis. Descriptive statistics (i.e., means and frequencies) were generated to present patients' demographic characteristics, clinical variables, study outcomes, and other variables. The study results were summarized using mean and standard deviation (SD), and percentages and proportions were used for categorical variables.

Results
A total of 429 patients records were reviewed. Of these patients, 80 subjects were excluded if at least one of the following criteria was encountered: any form of cancer, a history of hyperkalemia, hemodialysis, or lack of data.
101 patients met the inclusion criteria of this study and were included in the statistical analyses. Table 1 describes the baseline characteristics of included patients. The mean age was 64.87 ± 14.02 years, and 57% were men. The mean of the baseline potassium level before starting spironolactone was 4.34 ± 3.45 mmol/L. 75% of included patients had EF level lower than 40%. 23% of patients have CKD while 69% with DM. 44% of those who developed hyperkalemia were on ACEI, 22% on ARB, and 22% on potassium supplements.

Discussion
Potassium imbalance in heart failure is affected by many factors including neurohormonal mechanisms and medications used in its management and has been associated with unfavorable clinical outcomes [3,4,6,7]. Several studies have been shown that spironolactone utilization in HF patients has been associated with increase the risk of hyperkalemia, speci cally when ACEI/ARB is coadministered or other risk factors are present [16, 17,18]. A limited evidence was found in the literature on assessing the risk of hyperkalemia with concomitant use of ACE inhibitor/ARB and spironolactone therapy in HF patients. Despite the previous studies, much uncertainty still exists about the risk of hyperkalemia associated with spironolactone use in patients with heart failure [23]. Therefore, the objective of this study is to identify the incidence and determine of hyperkalemia risk factors among heart failure patients who have been using spironolactone.
An initial objective of the study was to identify the incidence of hyperkalemia among HF patients who have been using spironolactone. The present study found that 164 patients (53 %) had incidence of hyperkalemia. This result is consistent with data obtained in previous studies that the incidence is increased with using spironolactone [17,18]. Another important nding showed that 60% of the incidence were among senior patients (65 years old or more) which indicate that is advancing in age was associated with increase the risk of hyperkalemia incidence which is consistent with Juurlink study nding [15]. Another important nding that the majority of patients who had hyperkalemia were either on ACEi or ARBs which is consistent with previous study nding [19]. Moreover, the present study was designed to look at different doses of spironolactone and the rate of hyperkalemia incidence. The study showed that the incidence rate of hyperkalemia was increasing with increased the dose of spironolactone. The highest incidence rate was associated with spironolactone 50 mg. however, only 9 patients were receiving this dose.
Several limitations of our study should be noted. First, it's retrospective design and reliance on medical record documentation for data collection, and it was done in single setting. Moreover, the study has a small sample size which may limit the generalizability of the ndings to Saudi patients.

Conclusion
Our study showed that half of heart failure patients who used spironolactone developed hyperkalemia. The majority of patients who developed hyperkalemia were either on ACEIs or ARBs. Spironolactone dosing of 50 mg was associated with highest incidence of hyperkalemia. Further study with a larger sample size is required to clarify and con rm our study ndings.

Declarations Funding
The author(s) received no nancial support for the research, authorship , and/or publication of this article Declaration of con icting interest The author(s) declared no potential con icts of interest with respect to the research, authorship and/or publication of this article

Ethics approval
The study was approved by the Institutional Review Board (IRB) of King Abdullah International Medical Research Canter (KAIMRC), National Guard Health Affairs, Riyadh, Saudi Arabia, in February 2019. The informed consent was waived due to minimal risk associated with design of retrospective studies.

Consent to participate
Not applicable