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. 2021 Feb 16;77(6):695-708.
doi: 10.1016/j.jacc.2020.12.022.

Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure

Veena S Rao  1 , Juan B Ivey-Miranda  2 , Zachary L Cox  3 , Ralph Riello  4 , Matthew Griffin  1 , James Fleming  1 , Richard Soucier  1 , Prasama Sangkachand  4 , Margaret O'Brien  4 , Francine LoRusso  4 , Julie D'Ambrosi  4 , Keith Churchwell  4 , Devin Mahoney  1 , Lavanya Bellumkonda  1 , Jennifer L Asher  5 , Christopher Maulion  1 , Jeffrey M Turner  6 , F Perry Wilson  7 , Sean P Collins  8 , Jeffrey M Testani  9
Affiliations

Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure

Veena S Rao et al. J Am Coll Cardiol. .

Abstract

Background: Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration.

Objectives: The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy.

Methods: Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor (<50 mmol), suboptimal (<100 mmol), or excellent (>150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol.

Results: Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p < 0.05 for all cutpoints). In the YDP cohort (n = 161) using the NRPE to direct therapy mean daily urine output (1.8 ± 0.9 l vs. 3.0 ± 0.8 l), net fluid output (-1.1 ± 0.9 l vs. -2.1 ± 0.9 l), and weight loss (-0.3 ± 0.3 kg vs. -2.5 ± 0.3 kg) improved substantially following initiation of the YDP (p < 0.001 for all pre-post comparisons).

Conclusions: Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.

Keywords: diuretics; heart failure; natriuretic response; sodium.

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Conflict of interest statement

Funding Support and Author Disclosures This study was supported by National Institutes of Health (NIH) grants K23HL114868, L30HL115790, R01HL139629, R21HL143092, R01HL128973, and R01HL148354 (to Dr. Testani); R01DK113191 and P30DK079210 (to Dr. Wilson); and 5T32HL007950 (to Dr. Griffin). The funding source had no role in study design, data collection, analysis, or interpretation. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of NIH. Dr. Rao has a patent treatment of diuretic resistance (US20200079846A1) issued to Yale and Corvidia Therapeutics Inc. with royalties paid to Yale University; has (with Dr. Testani) a patent method for measuring renalase (WO2019133665A2) issued to Yale; and has received personal fees from Translational Catalyst. Dr. Riello has received consulting fees from Janssen, Johnson & Johnson, Pfizer, and Portola; and has served on advisory boards for AstraZeneca, Janssen, Johnson & Johnson, Medicure, and Portola. Ms. Mahoney has received personal fees from Sequana Medical. Dr. Collins has received grants from the NIH, Patient-Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, and AstraZeneca; and has received personal fees from Ortho Clinical, Boehringer Ingelheim, Roche, and Relypsa Medical. Dr. Testani has (with Dr. Rao) a patent method for measuring renalase (WO2019133665A2) issued to Yale; has received personal fees from Reprieve Medical, AstraZeneca, Novartis, Cardionomic, Bayer, MagentaMed, W.L. Gore, and Windtree Therapeutics; has received grants and personal fees from Bristol Myers Squibb, 3ive Labs, Boehringer Ingelheim, Sanofi, and FIRE1; has received grants from Otsuka, Abbott, and Merck outside of the submitted work; and has patents for treating diuretic resistance filed and issued. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 1.
Figure 1.. Discrimination and calibration of the NRPE with the 2-hour sample to predict poor, suboptimal, and excellent natriuretic response in the 6-hour cumulative sodium output.
The AUC of the NRPE for the prediction of the 6-hour natriuretic response using the 2-hour spot urine sample was A) 0.92 (95% CI 0.89 – 0.95), B) 0.90 (95% CI 0.87 – 0.93), and C) 0.90 (95% CI 0.87 – 0.93) to predict poor, suboptimal, and excellent natriuretic response, respectively. D (poor), E (suboptimal) and F (excellent natriuretic response): The X-axis shows the predicted probability from 0 to 1 at cutoff values of 0.1 (10 groups), and the Y-axis shows the observed proportion. The number of patients included in each category is described underneath each bar.
Figure 2.
Figure 2.. Association between the 6-hour measured sodium output and the NRPE using the 2-hour spot urine sample.
Association between the 6-hour measured sodium output and the NRPE using the 2-hour spot urine sample. The red line shows the predicted association using linear regression, and the blue area shows the 95% confidence interval (P-value for non-linearity = 0.23). The dashed black line is the reference of what would be a perfect association. The dark blue histogram at the bottom show the number of observations. X-axis and Y-axis are in log-scale.
Figure 3.
Figure 3.. Fractional excretion of sodium by dose of loop diuretic administered on the YDP.
An increased peak natriuretic effect was observed by each escalation of loop diuretic dose (p value for trend <.001). *The 4th dose is the highest dose received on day 2 of the YDP.
Figure 4.
Figure 4.. Daily total urine output, Net IO and weight change prior to and after initiation of the YDP.
Total urine output, net fluid output and weight loss improved when patients were on YDP driven by the NRPE compared to before the use of the NRPE (p < 0.001 for all). Mean change (95% CI) in total urine output, net IO, and weight change from pre- to on-YDP was 1208 ml (1015 to 1400 ml), −980 ml (−1181 to −778 ml), and −2.2 kg (−2.8 to −1.6 kg) respectively; all p<0.001. Because not all patients had three days pre-YDP or three days on-YDP, data is presented for the available observations.
Figure 5.
Figure 5.. Reasons for discontinuation of the YDP.
Out of the 161 patients included in the YDP cohort, there were successful reasons for discontinuing YDP in 136 patients (84%): discharge 30%, euvolemia 27%, decision to add a thiazide 14%, transitioned to standing 500mg TID 13%. In 25 patients (16%) YDP was discontinued due to unsuccessful reasons: rise in creatinine 7%; lightheadedness, weakness or myalgia 4.5%; patient refusal or technical difficulty 4.5%. TID: three times a day.
Central Illustration:
Central Illustration:. Use of the Natriuretic Response Prediction Equation in patients with acute heart failure and its implementation to guide diuretic therapy.
After a loop IV diuretic administration, the natriuretic response prediction equation using a 2-hour spot urine sample rapidly and accurately predicted poor natriuretic response. When this equation was incorporated into an automated diuretic titration protocol a rapid and well tolerated decongestion was observed.
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