Clinical implication of initial intravenous diuretic dose for acute decompensated heart failure

Although intravenous diuretics is a cornerstone of acute heart failure treatment (AHF), its optimal initial dose is unclear. This is a post-hoc analysis of the REALITY-AHF, a prospective multicentre observational registry of AHF. The initial intravenous diuretic dose used in each patient was categorised into below, standard, or above the recommended dose groups according to guideline-recommended initial intravenous diuretic dose. The recommended dose was individualised based on the oral diuretic dose taken at admission. We compared the study endpoints, including 60-day mortality, diuretics response within six hours, and length of hospital stay (HS). Of 1093 patients, 429, 558, and 106 were assigned to the Below, Standard, and Above groups, respectively. The diuretics response and HS were significantly greater in the Below group than in the Standard group after adjusting for covariates. Kaplan–Meier analysis indicated a significantly higher incidence of 60-day mortality in the Above group than the Standard group. This difference was retained after adjusting for other prognostic factors. Treatment with a lower than guideline-recommended intravenous diuretic dose was associated with longer HS, whereas above the guideline-recommended dose was associated with a higher 60-day mortality rate. Our results reconfirm that the guideline-recommended initial intravenous diuretic dose is feasible for AHF.

Decongestion with intravenous (IV) diuretics is a mainstay of acute heart failure (AHF) treatment since congestion is one of the primary reasons for heart failure admission 1 . Although diuretics are an effective treatment for most patients with AHF, the ideal dose of IV loop diuretics has yet to be established. The Diuretic Optimization Strategies Evaluation (DOSE) trial provided important insights regarding clinical and prognostic implications of high vs. low dose loop diuretics, finding no prognostic differences. However, current guidelines recommend using the smallest amount of diuretics to provide adequate decongestion 2,3 . This reflects the fact that a greater amount of loop diuretics tends to induce a stronger diuresis and greater relief of symptom. However, giving a large amount of diuretics is not always good given the adverse effects reported in patients with heart failure 4,5 . Current guidelines recommend 20 to 40 mg of IV furosemide for patients with AHF not receiving oral diuretics, or an equivalent or higher dose than the oral diuretics for those already taking it. However, these recommendations  2,3 . Therefore, we sought to examine the current recommendations on the initial IV furosemide dose administered to patients with AHF in terms of treatment efficiency and prognostic impact, using the REALITY-AHF (Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure) cohort 6 .

Results
Of the 1,682 patients enrolled in the REALITY-AHF, 1109 remained after excluding those not treated with furosemide within six hours of admission or treated with continuous furosemide infusion. We further excluded 26 patients with missing data on the amount of the first IV furosemide bolus. Consequently, 1093 patients were analysed (Supplemental Figure S1). These patients were assigned to one of three groups according to the guideline-recommended dose: Below (n = 429), Standard (n = 558), and Above (n = 106). Baseline characteristics of the three groups are shown in Table 1. Significant between group differences were observed in blood pressure, presence of orthopnoea and pulmonary oedema, history of heart failure, being treated with loop diuretics, betablockers, and/or aldosterone blocker before admission, and levels of haemoglobin, creatinine, and blood urea nitrogen. Of note, the Below group, but not the Above group, showed patient characteristics associated with poor prognosis such as lower systolic blood pressure, less orthopnoea and pulmonary oedema, more patients with a history of heart failure, being treated with high-dose loop diuretics before admission, and poor renal function in comparison to the Standard group. The total amount of IV furosemide used within the first six hours of admission differed significantly between the Below (20 mg; interquartile range [IQR], 10-30 mg), Standard (20 mg; IQR, 20-37 mg), and Above (40; IQR, 23-50 mg) groups (P < 0.001). Urine output measured during the first six hours of admission and diuretic response (DR) are shown in Fig. 1. The urine output within during the six hours of admission was significantly higher and DR significantly lower in the Above group (P < 0.001 for both). Univariate linear regression analysis showed that the DR in the Above group was significantly lower and in the Below group significantly higher than in the Standard group (Table 2). After adjusting for covariates shown to be related to DR within six hours, the DR in the Below group remained significantly higher than the Standard group, whereas the Above and Standard groups were no longer statistically different.
The median length of hospital stay (HS) differed significantly between the Below (18 days; IQR, 11-26 days), Standard (15 days; IQR, 10-23 days), and Above (12 days; IQR, 7-22 days) groups (P < 0.001; Fig. 2). Multiple linear regression analysis showed that the Below group had a significantly longer HS than in the Standard group (Table 3), while HS in the Above group was marginally but insignificantly shorter than in the Standard group.
Seventy-four deaths were observed during the 60 days of admission. Kaplan-Meier curves showed that the Above group was significantly associated with a higher 60-day mortality rate (Fig. 3). The Cox regression analysis showed that the Above, but not the Below, group was associated with a significantly higher 60-day mortality rate than the Standard group in unadjusted and adjusted models ( Table 4). As we have already demonstrated that the door-to-furosemide time was associated with the 30-day mortality 6 , we added the door-to-furosemide time in the multivariable analysis. Furthermore, additional treatments such as the usage rate of vasodilators, catecholamines, and renin angiotensin aldosterone system inhibitors during the first 48 h were also included; however, the results remained unchanged (Table 4).

Discussion
This study demonstrated that the Standard group, receiving the guideline-recommended initial diuretic IV dose, was associated with a shorter HS than in the Below group, and a higher 60-day survival rate than in the Above group, even after adjusting for various confounders. To the best of our knowledge, this is the first study to validate the guideline-recommended initial IV loop diuretic dose in an AHF cohort.
DR was recently suggested as a metric of diuretic efficiency, and poor DR was reported to be an independent predictor of worse outcomes in patients with AHF 7,8 . It is well known that dose-response curves of loop diuretics have a ceiling effect, suggesting that increasing the doses above a certain point will not increase the diuretic effect 9 . This effect was clearly shown in our study. Our results showed that higher-than-suggested furosemide doses were associated with a significantly poorer DR. The use of a higher diuretic dose is a trade-off between achieving urine output and the subsequent decongestion and risking the downsides of diuretic use. Doses above the ceiling level could be more harmful than beneficial. On the other hand, doses below the diuretic dose recommended by guidelines had significantly greater DR; however, smaller doses were not associated with a better 60-day prognosis than the standard dose and were associated with a longer HS. This finding might suggest that lowering the diuretic dose will not directly lead to a better prognosis, even with a greater DR. Rather, it would result in longer HS, possibly because of the lower urine output achieved. Indeed, the HS after AHF in Japan was reported to be longer than in Western countries. One of the reasons for this difference could be that the diuretic doses given to patients with AHF in Japan are lower than in Western countries 10,11 . As it happens, the guidelinerecommended furosemide dose is the suitable one, neither too high nor too low.
The DOSE trial, a prospective, double-blind, randomised controlled trial focusing on the usage of IV furosemide in patients with AHF, demonstrated conflicting results. That study found no statistical differences between using low and high doses in terms of 60-day composite mortality and rates of re-hospitalisation and emergency visits for AHF 5 . Although the current recommendations on the initial IV diuretic dose were primarily derived from the DOSE study, we could not simply compare the DOSE and our studies because they differ in some crucial elements. First, the DOSE trial enrolled patients with a history of chronic heart failure that took oral loop diuretics equivalent to 80 to 240 mg furosemide, while the present study enrolled consecutive patients with AHF irrespective of whether the presented a de novo disease or were with chronic heart failure, and we did not limit the oral furosemide dose. Given that around half of the patients with AHF are with a newly diagnosed disease,     Table 3. Association between the dose groups and the length of hospital stay. Those who died during the index hospitalisation were excluded. BNP brain natriuretic peptide, CI, confidence interval. *Adjusted for age, sex, history of heart failure, and atrial fibrillation, the New York Heart Association class, systolic blood pressure, haemoglobin, serum creatinine, sodium, albumin, and log-transformed BNP.  www.nature.com/scientificreports/ the patients, i.e., those treated with a higher dose of diuretics were older, with a history of heart failure, and prescribed higher doses. This bias could not be fully adjusted, even if a multivariable model was applied. We found no such association in our study between the Above group and a high-risk profile.

Groups
There are also several limitations that should be acknowledged. This study was not predefined. It was a retrospective analysis of registry data; therefore, the results should be interpreted cautiously. Additionally, a significant number of patients were excluded for a late administration of the first IV furosemide because we focused on the very early phase of AHF treatment. Furthermore, the groups differed in some baseline characteristics. The worse outcome of the higher dose might reflect disease severity rather than the impact of the initial IV furosemide dose. The results consistently demonstrated an association between the initial IV furosemide dose and the outcome, even after adjusting for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) score and catecholamine use to minimize the disease severity effect. However, we should emphasize that there could still be other unmeasured confounders owing to the retrospective nature of our study. Finally, since the dose of the diuretics in our study was relatively lower than previous studies, including the DOSE trial, whether such relatively low dose of the diuretics could have a significant effect on the mid-term mortality has been unclear. Further randomized studies are required to clarify the association between initial IV furosemide dose and prognosis.

Conclusions
Treating patients with AHF with guideline-recommended initial IV furosemide dose was associated with shorter hospital stay than with lower doses and a higher 60-day survival rate than with higher doses. Our study results endorse the current guidelines concerning the first IV furosemide dose in terms of prognosis and diuretic efficiency.

Methods
Study design and patients. The present study utilised data from the REALITY-AHF, a prospective multicentre registry focused on the presentation and treatment during the very early phase of AHF hospitalisation. Details on the study design were published elsewhere 6 . Briefly, consecutive patients with AHF aged ≥ 20 years hospitalised through the emergency department (ED) in 20 hospitals in Japan were enrolled. The AHF diagnosis was determined by an attending physician at each site, using the Framingham criteria 12 . Patients with brain natriuretic peptide (BNP) < 100 ng/L or N-terminal pro b-type natriuretic peptide < 300 ng/L were excluded due to diagnostic uncertainty, following the guidelines 3  We analysed only patients treated with an IV bolus of furosemide within six hours of ED admission. Those treated with continuous furosemide infusion were excluded. We also excluded patients with hypotension (systolic blood pressure < 90 mmHg) at the time of ED admission. To validate the guideline-recommended initial IV furosemide dose, we divided the cohort into three dose groups (Below, Standard, and Above) according to whether the initial IV furosemide dose was lower, equal to, or higher than the guideline-recommended dose of 40 mg IV furosemide for patients with AHF not taking diuretics, or IV furosemide at the same dose as the oral Table 4. Cox proportional hazard analysis for 60-day mortality according to initial furosemide dose groups. *Adjusted for the OPTIME-CHF score and log-transformed brain natriuretic peptide. **Adjusted for Model 1 plus door to furosemide time, dobutamine use within 48 h, dopamine use within 48 h, norepinephrine use within 48 h, phosphodiesterase III inhibitor use within 48 h, vasodilator use within 48 h, total furosemide used within 48 h, and angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use within 48 h. CI confidence interval, D2F door to furosemide, HR hazard ratio.