External validation of the natriuretic response prediction equation to discriminate diuretic response in heart failure

Abstract

Aims

Incomplete decongestion due to lack of titration of diuretics to effective doses is a common reason for readmission in patients with acute decompensated heart failure (ADHF). The natriuretic response prediction equation (NRPE) is a novel tool that proved to be rapid and accurate to predict natriuretic response and does not need urine collection. However, the NRPE has not been externally validated. The goal of this study was to externally validate the discrimination capacity of the NRPE in patients with ADHF and fluid overload.

Methods and results

Patients admitted with ADHF who required intravenous loop diuretics were included. A spot urine sample was obtained ~2 h following diuretic administration, and a timed 6‐h urine collection by study staff was carried out. Urine sodium and urine creatinine from the spot urine sample were used to predict the 6‐h natriuretic response using the NRPE. The primary goal was to validate the NRPE to discriminate poor loop diuretic natriuretic response (sodium output <50 mmol in the 6 h following diuretic administration). The NRPE was compared with urine sodium and measured urine output which are the methods currently recommended by international guidelines to assess diuretic response. Eighty‐seven diuretic administrations from 49 patients were analysed. Mean age of patients was 57 ± 17 years and 67% were male. Mean estimated glomerular filtration rate was 65 ± 28 mL/min/1.73 m², and ejection fraction was 35 ± 15%. Median dose of intravenous furosemide equivalents administered the day of the study was 80 mg (IQR 40 ‐ 160). Poor natriuretic response occurred in 39% of the visits. The AUC of the NRPE to predict poor natriuretic response during the 6‐h urine collection was 0.91 (95% CI 0.85‐0.98). Compared with the NRPE, spot urine sodium concentration (AUC 0.75) and urine output during the corresponding nursing shift (AUC 0.74) showed lower discrimination capacity.

Conclusions

In this cohort of patients with ADHF, the NRPE outperformed spot urine sodium concentration and all other metrics related to diuretic response to predict poor natriuretic response. Our findings support the use of this equation at other settings to allow rapid and accurate prediction of natriuretic response.

Introduction

Congestion is the most frequent reason for readmission in patients with ADHF (acute decompensated heart failure).¹ Unfortunately, incomplete decongestion often occurs and is strongly associated with poor prognosis. Although there are many reasons for incomplete decongestion, the lack of titration of diuretics to effective doses is a critical one and frequently occurs due to the absence of reliable tools to guide diuresis and decongestion.

Since a central driving pathophysiology of congestion is sodium retention, monitoring sodium excretion should be the preferred tool to guide decongestion.² However, quantification of sodium excretion requires accurate urine collection, which is unreliable in clinical practice. Based on this necessity, the natriuretic response prediction equation (NRPE) was developed and proved to be a rapid and accurate tool that does not require urine volume measurement.³ Following its development, the NRPE was shown to be useful in guiding decongestion in ADHF.⁴ However, the performance of the NRPE has not been validated outside the institution it was developed, which is a critical step to adopt this tool. The goal of this investigation was to externally validate the NRPE in patients with ADHF.

Methods

We included patients admitted with ADHF who required intravenous (IV) loop diuretics. Key inclusion criteria were age ≥18 years, use of IV loop diuretics, and at least one objective sign of volume overload. Patients on dialysis or with inability to comply with urine collection procedures were excluded. Patients could be enrolled more than once if volume overload was present. IV diuretic dosing was determined by the treating physician. The protocol was approved by the local IRB and all patients provided written informed consent.

Urine collection protocol: prior to the administration of the morning diuretic dose, patients were asked to empty their bladder. Following administration of the loop diuretic, a timed 6-h urine collection by study staff was carried out. A spot urine sample was obtained ~2 h following diuretic administration. After 6 h, patients were asked to empty their bladder to complete the urine collection. Total 6 h cumulative natriuresis was then predicted from the 2-h spot urine sample and the NRPE³: $$\begin{gathered} \mathrm{Na}\text{output}\left(\text{mmol}\right)=\text{eGFR}\times \left(\frac{\mathrm{BSA}}{1.73}\right)\times \left(\frac{\text{Serum}\mathrm{Cr}}{\text{Urine}\mathrm{Cr}}\right) \\ \times 60\min \times 3.25\mathrm{h}\times \left(\frac{\text{UrineNa}}{1000\mathrm{ml}}\right) \end{gathered}$$

The primary goal was to externally validate the NRPE to discriminate poor loop diuretic natriuretic response (sodium output <50 mmol in the 6 h following diuretic administration); 50 mmol was used because twice daily dosing would result in a positive sodium balance on a 3 g (130 mmol) sodium diet, assuming limited sodium excretion in the diuretic-free period. Secondary endpoint was to discriminate suboptimal natriuretic response (sodium output <100 mmol).

Continuous data is shown as mean ± standard deviation or median (quartile 1 – quartile 3). Categorical data are shown as percentage. Receiver operating characteristic curves with AUC for the primary and secondary endpoints were performed.

Results

A total of 87 diuretic administrations from 49 patients were included. Mean age was 57 ± 17 years and 67% were male. Medication previous to admission included: loop diuretics 68%; ACEi/ARB/ARNI 60%; beta blocker 57%; aldosterone antagonist 60%; SGLT2i 15%. Mean sodium, eGFR, and ejection fraction were 138 ± 4 mmol/L, 65 ± 28 mL/min/1.73 m², and 35 ± 15%, respectively. Median dose of intravenous furosemide equivalents administered the day of the study was 80 mg (IQR 40–160). Median measured cumulative sodium output was 61 mmol (IQR 32–125) and median urine output was 950 mL (IQR 518–1,300) over the 6-h urine collection period. Poor and suboptimal natriuretic response occurred in 39% and 64% of the visits, respectively.

The AUC of the NRPE for the prediction of the 6-h natriuretic response was 0.91 (95% CI 0.85–0.98), and 0.90 (95% CI 0.84–0.97) to predict poor and suboptimal natriuretic response, respectively. Using the Youden index, the best cutoff value of the NRPE was 36.4 mmol, which yielded a sensitivity of 82%, specificity of 91%, positive predictive value 85%, and negative predictive value of 89%. Compared with NRPE, spot urine sodium concentration, urine output during the corresponding nursing shift, and eGFR showed lower AUC to predict both poor and suboptimal natriuretic response in the 6-h cumulative sodium output (Figure 1). NRPE also outperformed IV furosemide equivalent administered (AUC 0.73, 0.67), spot urine creatinine (AUC 0.85, 0.82) net fluid output during the corresponding nursing shift (AUC 0.75, 0.81), and systolic blood pressure (AUC 0.55, 0.55) to discriminate poor and suboptimal natriuretic response, respectively.

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Discussion

In the present study we externally validated the NRPE as an accurate tool to predict poor natriuretic response using a spot urine sample collected after loop diuretic administration. The NRPE outperformed spot urine sodium, urine output and net fluid output from the corresponding nursing shift, eGFR, diuretic dose, and blood pressure.

External validation is a critical component because it examines whether the findings of a study can be generalized to other contexts. Findings might not be generalizable when conditions are different. In the NRPE, biology is not expected to differ between ADHF patients; however, this tool is not exempt from differences during its execution. For example, modifications on instructions to patients, as well as variations in obtaining, managing, transporting, and processing the urine samples are sources of potential bias. Fortunately, we observed that the discrimination capacity of the NRPE was consistent with previous reports, which is important for future studies using the NRPE such as ESCALATE (NCT04481919).

Urine sodium is currently recommended by international guidelines to monitor response to loop diuretics; however, urine concentration may affect its utility. For example, a urine sample that is highly concentrated (high urine creatinine) might show high urine sodium concentration that does not necessarily imply a good diuretic response. Conversely, the NRPE incorporates urine creatinine to account for urine concentration. In addition, the NRPE incorporates eGFR to predict the rate of urine formation from the product of eGFR and the ratio of serum to urine creatinine. Multiplication of this product by urine sodium concentration allows conversion from the instantaneous rate of urine formation to sodium excretion (mmol/min). As such, it is expected that the NRPE will outperform other metrics to evaluate loop diuretic response.

Key limitations of the study are the single center design with a limited number of patients. Urine catheterization was present only in 5% of urine collections, and we did not perform bladder scans to rule out incomplete bladder emptying. We included only patients hypervolemic ADHF and thus, these results cannot be extrapolated to populations with hypervolemia due to other conditions. Only IV loop diuretics were administered in this study, so the performance of the NRPE on oral loop diuretic administration or other types of diuretics is not known. Finally, we did not assess if the NRPE improved hospital readmission or survival. However, improving such outcomes is related to aspects like achieving complete decongestion before discharge, rapid implementation of guideline directed medical therapy during follow-up, among others. The NRPE is a reliable tool to assess diuretic response, which is key to reduce the risk of incomplete decongestion in ADHF, but all other factors need to be addressed to improve clinical outcomes.

In conclusion, the NRPE was validated at an external institution from where it was developed. The NRPE is an accurate tool and outperformed spot urine sodium concentration and other metrics commonly used to assess diuretic response.

Acknowledgements

We would like to thank Hector Perez and the laboratory department at Hospital de Cardiología Centro Médico Nacional Siglo XXI.

Conflict of interest

None declared.

References

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