Chronic Hyponatremia in Acute Heart Failure
Overview
This study aimed to comprehensively assess hyponatremia in patients with acute heart failure (AHF), focusing on its prevalence, associations, hospital course, and post-discharge outcomes. The research analyzed a cohort of 8,298 AHF patients from the European Society of Cardiology Heart Failure Long-Term Registry, regardless of their ejection fraction. Among these patients, 20% presented with hyponatremia (serum sodium <135 mmol/L).
The study identified several independent predictors of hyponatremia, including lower systolic blood pressure, estimated glomerular filtration rate (eGFR), and hemoglobin levels, as well as comorbidities such as diabetes and hepatic disease. Medications like thiazide diuretics, mineralocorticoid receptor antagonists, and digoxin, along with higher doses of loop diuretics and non-use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers, were also associated with hyponatremia.
In-hospital mortality occurred in 3.3% of the patients. The prevalence of hyponatremia and in-hospital mortality were examined based on different combinations: 9% of patients had hyponatremia both at admission and discharge, with an in-hospital mortality rate of 6.9%. Additionally, 11% had hyponatremia at admission but not at discharge (in-hospital mortality 4.9%), while 8% had hyponatremia at discharge but not at admission (in-hospital mortality 4.7%). The majority, 72%, had no hyponatremia both at admission and discharge (in-hospital mortality 2.4%).
Correcting hyponatremia was found to be associated with an improvement in eGFR. In-hospital development of hyponatremia was associated with higher diuretic use and worsening eGFR, but it also resulted in more effective decongestion.
Among hospital survivors, the 12-month mortality rate was 19%, and adjusted hazard ratios (with 95% confidence intervals) for hyponatremia at admission and/or discharge were calculated. Patients with hyponatremia both at admission and discharge had the highest adjusted hazard ratio for mortality (1.60), followed by patients with hyponatremia at admission but not at discharge (1.35). Those with hyponatremia at discharge but not at admission had a slightly elevated hazard ratio (1.18). For death or heart failure hospitalization, similar trends were observed.
In conclusion, 20% of patients with AHF had hyponatremia at admission, which was associated with more advanced heart failure. Half of the patients with hyponatremia at admission experienced a normalization of sodium levels during hospitalization. Persistent hyponatremia at admission, especially if unresolved, was linked to worse in-hospital and post-discharge outcomes. Conversely, hyponatremia developing during hospitalization was associated with a lower risk of adverse outcomes.
Introduction
Hyponatremia, the most common electrolyte imbalance, affects 10-30% of hospitalized heart failure (HF) patients. In acute HF (AHF), hyponatremia is primarily dilutional, resulting from venous congestion, poor perfusion, and increased vasopressin levels leading to water retention. It reflects neurohormonal activation, fluid retention, and congestion, and is associated with worse in-hospital and long-term outcomes. Many HF patients experience frequent thirst due to neurohormonal activation and HF treatment, leading to increased fluid intake.
However, limited reports are present on risk factors and markers for hyponatremia during acute heart failure hospitalization and the associations between sodium concentration changes and post-discharge prognosis in HF. Corrected hyponatremia may be linked to lower risk of death and HF rehospitalization compared to persistent hyponatremia. Despite the effectiveness of the vasopressin receptor blocker tolvaptan in correcting hyponatremia and reducing congestion, it had no impact on long-term mortality or HF-related morbidity in AHF. Aggressive diuresis in acute heart failure may cause depletional hyponatremia due to loss of sodium, yet its impact on long-term patient outcomes are not well understood.
The objective of this analysis was to comprehensively assess hyponatremia and serum sodium changes during AHF hospitalization, regardless of ejection fraction (EF), with respect to prevalence, predictors, in-hospital clinical course and mortality, and post-discharge outcomes.
Method
The European Society of Cardiology-Heart Failure Association (ESC-HFA) EURObservational Research Programme (EORP) HF Long-Term Registry was a comprehensive international study conducted between 2011 and 2018. It involved adult heart failure (HF) patients from 33 ESC member countries, including both outpatients with chronic HF and those hospitalized for acute HF (AHF). AHF was defined as HF symptoms and signs necessitating intravenous HF treatment.
The registry aimed for representation across a diverse range of facilities in proportion to the population size of participating countries. Data were collected at admission and discharge for hospitalized patients, enabling assessment of in-hospital course, mortality, and 1-year follow-up for post-discharge hospitalization and mortality. The study’s methodology and ethical approval were in line with local regulations, and all patients provided written, informed consent.
This retrospective analysis focused on AHF patients with available sodium concentration data on both admission and discharge. Hyponatremia was defined as serum sodium concentration <135 mmol/L. Patients were categorized into four groups based on their natraemia status: (1) hyponatremia at admission and discharge (hyponatremia Yes/Yes), (2) hyponatremia at admission but not at discharge (Yes/No), (3) no hyponatremia at admission but with hyponatremia at discharge (No/Yes), and (4) no hyponatremia at admission or discharge (No/No) – serving as the reference group for statistical comparisons.
The study assessed the baseline characteristics, predictors of hyponatremia at admission, in-hospital clinical course, predictors of natraemia changes during hospitalization, and in-hospital mortality for patients in each natraemia group. For patients who survived to hospital discharge, the association between natraemia groups and post-discharge outcomes was evaluated. The primary outcome was a composite of all-cause death and first HF rehospitalization. Secondary and tertiary endpoints included all-cause death, cardiovascular death, HF death, and rehospitalizations.
Analyses were repeated for important subgroups based on ejection fraction (EF) category and kidney function. The study aimed to provide valuable insights into the impact of natraemia changes during hospitalization on post-discharge outcomes for AHF patients.
Statistical analysis
In this study, baseline characteristics, including categorical data reported as percentages and continuous variables presented as median and interquartile range (IQR) or mean±standard deviation, were analyzed at the time of hospital admission. Multivariable logistic regression analyses were conducted to identify predictors of hyponatremia at admission and predictors of its correction during hospitalization. The cause of HF decompensation was also considered in these analyses. Correction of hyponatremia was defined as a change in natremia status from hyponatremia at admission to normal levels (serum sodium concentration ≥135 mmol/L) at discharge.
To assess the impact of admission hyponatremia on in-hospital endpoints, such as in-hospital death, New York Heart Association (NYHA) class III-IV at discharge, weight reduction >2 kg during hospitalization, and length of intensive cardiac care unit (ICCU) stay >2 days, multivariable logistic regression models were used. Post-discharge, long-term outcomes analyses excluded patients who died in the hospital and those with no follow-up information. Mortality at 12 months was estimated using the Kaplan-Meier method, and cumulative incidence curves were plotted for the primary (death irrespective of cause or first heart failure readmission) and secondary endpoints (death irrespective of the cause) in the groups containing patients with natremia. Multivariable Cox proportional hazards regressions were employed to model the time to the first event. The total incidence of events per 100 patient-years in the tertiary, secondary and primary endpoints were evaluated for the groups consisting of patients with natremia.
Missing data for covariates were imputed using Multiple Imputation by Chained Equations (MICE) with 10 datasets and 10 iterations. The significance level was placed at 0.05 for all tests, and all statistical analyses were conducted using R version 4.2.1.
Result
The ESC-HFA EORP HF Long-Term Registry included 25,621 heart failure (HF) patients, among whom 10,879 were hospitalized for acute HF (AHF). The study aimed to investigate hyponatremia in AHF patients and its impact on in-hospital and long-term outcomes. Out of 10,879 AHF patients, 9,982 (92%) had data on sodium concentration at admission, and 8,298 (76%) had data both at discharge and during admission.
The prevalence of hyponatremia in the AHF cohort was as follows: hyponatremia Yes/Yes (9%), hyponatremia Yes/No (11%), hyponatremia No/Yes (8%), and hyponatremia No/No (72%). The study identified predictors of hyponatremia at admission, such as younger age, lower body mass index, history of diabetes and hepatic disease, higher heart rate, lower systolic blood pressure, estimated glomerular filtration rate (eGFR), hemoglobin, and specific medication use.
Hyponatremia at admission was associated with worse in-hospital outcomes, including higher in-hospital mortality, NYHA class III-IV at discharge, longer intensive cardiac care unit (ICCU) stay, and significant weight reduction during hospitalization. About 54% of patients with admission hyponatremia corrected it during hospitalization, and predictors of correction included higher admission serum sodium level, improvement in NYHA class and eGFR during hospitalization, and beta-blocker therapy.
Post-discharge, long-term outcomes analysis showed that patients with persistent hyponatremia (hyponatremia Yes/Yes) had higher risks of all-cause death or first HF rehospitalization and all-cause death, compared to the reference group (hyponatremia No/No). Patients who corrected hyponatremia during hospitalization (hyponatremia Yes/No) also had higher risks of these outcomes. Interestingly, patients who developed hyponatremia during hospitalization (hyponatremia No/Yes) did not have an increased risk of these endpoints compared to the reference group.
Hyponatremia at admission and at discharge was associated with cardiovascular and HF death but not with all-cause hospitalization, first cardiovascular hospitalization, or first HF hospitalization.
Conclusion
In conclusion, this study provides valuable insights into the prevalence and impact of hyponatremia in AHF patients. It highlights the significance of monitoring sodium levels during hospitalization and its association with both in-hospital and post-discharge outcomes, contributing to a better understanding of managing AHF patients effectively.
The study focused on patients with acute heart failure (AHF) and found that 20% of them had hyponatremia at the time of hospital admission. Interestingly, half of these patients showed improvement and had their hyponatremia resolved during their hospital stay. The presence of hyponatremia at admission was linked to more advanced heart failure, and if it persisted during hospitalization, it was associated with poorer in-hospital and post-discharge outcomes. On the other hand, hyponatremia that developed during hospitalization, likely due to intensive diuretic treatment and effective decongestion, was linked to a lower risk of adverse outcomes.
In summary, the study suggests that addressing hyponatremia in AHF patients is crucial, as it may serve as an indicator of disease severity and impact on patient prognosis. Timely management and resolution of hyponatremia during hospitalization may improve patient outcomes, while the development of hyponatremia during treatment appears to be less detrimental to patient health.
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