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Abstract

Background:

Congestion predominates in exacerbations of heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), but evidence suggests that excess volume may be distributed differently in these 2 subgroups.

Methods and Results:

In this retrospective study, diuretic efficiency (DE, or net urine output per 40-mg of intravenous furosemide equivalent) during the first 72 hours was compared between patients hospitalized with HFrEF (n = 121) versus HFpEF (n = 120). Multivariate analysis was used to compare the 2 groups based on expected baseline differences (e.g., demographics, heart failure etiology, concomitant therapy). During the first 72 hours, mean daily diuretic doses were higher in patients with HFpEF versus HFrEF (172.0 vs. 159.9 mg, respectively, P = 0.026) but urine output was not significantly different (2603.3 mL vs. 2667.5 mL, respectively, adjusted P = 0.100). Similarly, mean cumulative DE did not differ (−673.5 vs. −637.8 mL/40-mg in the HFrEF and HFpEF groups, respectively, adjusted P = 0.884). An exploratory analysis of propensity-matched cohorts yielded similar findings. Correlations between the components of DE varied considerably and only became weak to moderately correlated toward the end of the observation period.

Conclusions:

Although cumulative DE did not differ between patients with HFrEF and HFpEF, variable correlations in the components of DE suggest there may be differences in diuretic response that warrant future analysis.

Keywords

heart failure loop diuretics diuresis furosemide

Introduction

Of the over one million patients admitted with acute decompensated heart failure (ADHF) each year, exacerbations of heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) occur in approximately equal numbers.^1,2 Guideline-directed medical therapy (GDMT) aimed at improving long-term morbidity and mortality in HFrEF, such as angiotensin-converting enzyme (ACE) inhibitors and beta blockers, have not conferred similar benefits in patients with HFpEF. However, since exacerbations of HFrEF and HFpEF are similarly dominated by congestive symptoms, enrollment criteria for most ADHF trials have not distinguished between the 2 groups. Consequently, the number of patients with HFpEF has varied from 20% to 45% in recent landmark trials evaluating therapies for congestion in ADHF.^3

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Although congestion is the most common presentation of ADHF in both HFrEF and HFpEF, recent data suggest that volume may be distributed differently in the 2 subgroups. In a study employing the use of radiolabeled albumin tracers, distinct volume profiles appeared to emerge among patients with HFrEF and HFpEF.⁸ Despite receiving similar diuretic treatment, patients with HFpEF lost more interstitial relative to intravascular volume than those with HFrEF, and experienced greater reductions in body weight and net fluid loss. Differences in the distribution of volume may also explain why wireless invasive hemodynamic monitoring was necessary to demonstrate evidence of vascular congestion in patients with HFpEF, whereas clinical evaluation of signs and symptoms alone was sufficient in those with HFrEF.⁹ Differences in the patterns of remodeling that occur in the 2 subgroups may also explain differences in their response to decongestion. In HFpEF, decreased compliance resulting from stiffening of the left ventricle should confer greater sensitivity to changes in preload compared to the chamber dilatation often observed in HFrEF. Differences in the hemodynamic response to vasodilation were recently demonstrated in a trial comparing patients with HFrEF and HFpEF.¹⁰ Although reductions in end-diastolic pressure were similar in the 2 groups, patients with HFpEF were nearly 4 times more likely to experience a decrease in stroke volume compared to those with HFrEF.

Altogether, these findings suggest that the response to loop diuretics may differ between patients with HFrEF and HFpEF. The purpose of this study was to therefore compare differences in net urine output in response to intravenous (IV) loop diuretics in real-world patients with ADHF and underlying HFrEF versus HFpEF. We chose to use diuretic efficiency (DE) for this aim, defined as the net urine output per 40-mg of IV furosemide equivalents (FE), based on its use as a metric of diuretic responsiveness in prior studies.^11,12 Based on the evidence outlined above that patients with HFpEF may mobilize congestion more readily, we hypothesized that patients with HFpEF would have a more efficient response to loop diuretics (i.e., a higher DE and therefore a lower diuretic requirement) in the first 72 hours of hospitalization for ADHF compared to those with HFrEF.

Methods and Materials

This retrospective cohort study included adult patients aged 18-89 years who were admitted with a diagnosis of ADHF between December 2015 and 2017 at a large tertiary care medical center. To be included, patients had to have a documented ejection fraction (EF) by transthoracic echocardiogram during or within 6 months of the index hospitalization and receive at least one dose of an IV loop diuretic within the first 24 hours of admission. Patients were excluded if they received spironolactone > 50 mg or eplerenone >100 mg, had a history of cirrhosis or end-stage renal disease (defined as an estimated glomerular filtration rate of <10 mL/min), used renal replacement therapy, or died within the first 72 hours of admission. Patients were then subsequently divided into HFrEF or HFpEF cohorts based on whether their EF was ≤40% or >40%, respectively.²

Data was collected from the electronic medical record (EMR) and included baseline demographics, past medical history and comorbidities, cardiac structure and function, laboratories, and home medications. All home medications were initially documented by a nurse or physician at the time of the patient’s admission and were then verified and reconciled by a pharmacist. Details collected on the treatment of congestion during the first 72 hours included diuretic doses and method of administration (i.e., bolus vs. continuous infusion), concomitant medication use, and changes in weight and fluid balance. Diuretic doses were based on IV FEs according to prior literature (20 mg of IV furosemide was deemed equivalent to 40 mg of oral furosemide, 1 mg of oral/IV bumetanide, or 20 mg of oral torsemide).⁴ The study was approved by the local institutional review board.

End Points

The primary outcome of our study was the mean cumulative DE (net urine output, in mL, per 40-mg of intravenous furosemide) during the first 72 hours of hospitalization. Secondary efficacy endpoints included total urine output, net urine output, and changes in weight at 24, 48, and 72 hours of hospitalization; length of stay; and in-hospital mortality. Safety endpoints included the incidence of hypokalemia (potassium < 4.0 mEq/L), severe hypokalemia (potassium <3.5 mEq/L), hypomagnesemia (magnesium <2.0 mg/dL), severe hypomagnesemia (magnesium <1.6 mg/dL), severe hyponatremia (sodium <125 mEq/L), acute kidney injury (AKI, defined as an increase in serum creatinine of >0.3 mg/dL or 1.5-times baseline during the 72-hour study period), and progression to renal replacement therapy. Thresholds of <4.0 mEq/L for hypokalemia and <2.0 mg/dL for hypomagnesemia were selected because these are the concentrations at which supplementation is typically provided in patients with cardiovascular disease. Finally, we sought to assess the relative performance of DE as a metric in HFrEF versus HFpEF patients during the first 72 hours, which we characterized as the correlation between diuretic dose (in mg) and clinical response (net urine output in mL).

Statistical Analysis

Baseline characteristics and endpoints were compared using chi-square or Fisher’s exact test for categorical variables and t-test/ANOVA for continuous variables as appropriate. Univariate comparison was used to determine significance in unadjusted comparisons. To control for confounding given the expected differences between the HFrEF and HFpEF groups at baseline, a multivariate analysis was performed using a linear regression model, or in the case of skewed outcome variables, a log-linear model. A log-linear model was used for the primary endpoint whereas secondary endpoints were analyzed using linear or log-linear models (for continuous variables) or logistic regression (for categorical variables). Variables added to the models were age, gender, body mass index, heart failure etiology, loop diuretic use prior to admission, baseline use of GDMT, and use of a thiazide-type diuretic, inotrope, or vasodilator during the first 72 hours of hospitalization. We also conducted an exploratory efficacy analysis of propensity score-matched groups based on key differences in baseline characteristics observed after data collection; these were age, gender, heart failure etiology, body mass index, serum sodium concentration, systolic blood pressure, GDMT use, and diuretic use. The relative performance of DE as a metric of diuretic response was assessed using Spearman correlation given the sigmoidal dose-response curve of loop diuretics. No imputations were performed.

For the primary endpoint, we determined a priori that 500 mL/day (1500 mL over 72 hours) represented a clinically meaningful difference in diuresis. In the DOSE trial, the mean net urine output at 72 hours was 4237 mL in patients who received a cumulative IV furosemide dose of 592 mg (administered as boluses every 12 hours), or a DE of 286.3 mL.⁴ Therefore, a difference in net urine output of 1500 mL at 72 hours would represent a 36% difference. To show an effect size of 36% with a statistical power of 80% and a significance level of 0.05, a minimum of 242 patients were needed (at least 121 patients in the HFrEF and HFpEF groups, respectively). Statistical analyses were performed with SPSS version 23 (IBM Corp; Armonk, NY) and SAS version 9.4 (SAS Institute, Cary, NC).

Results

Sample Characteristics and Treatment

During the selected date range, 121 patients with HFrEF and 120 patients with HFpEF met study criteria. Baseline characteristics for the 2 groups are displayed in Table 1. In brief, patients with HFpEF were more likely to be older and female and less likely to have functional limitations or ischemic disease (all P < 0.05). In patients with HFrEF, the mean ejection fraction was 21.2% (standard deviation [SD] 8.1%). At baseline, patients with HFrEF were more likely to be taking neurohormonal antagonists, the combination of oral long-acting nitrates and hydralazine, and IV inotropes prior to admission. Patients with HFpEF were more likely to be taking diuretics prior to admission but agents and doses (in FEs) were similar between the 2 groups. Renal function was also similar between the 2 groups. Propensity score matching for our exploratory analysis yielded a sample of 118 patients (59 patients in each cohort; detailed reported in Supplemental Table 1).

Table 1.

Baseline Characteristics.

Characteristic	HFrEF (n = 121)	HFpEF (n = 120)	P value
Age	59.6 (14.1)	65.9 (12.5)	<0.001
Male gender	88 (72.7%)	59 (49.2%)	<0.001
Race
White	66 (54.5%)	57 (47.5%)	0.381
Black	52 (43.0%)	55 (45.8%)
Asian	1 (0.8%)	2 (1.7%)
Other	2 (1.7%)	6 (5.0%)
Past medical history
Atrial fibrillation	49 (40.5%)	54 (45.0%)	0.480
Myocardial infarction	49 (40.5%)	32 (26.7%)	0.023
Diabetes mellitus	42 (34.7%)	56 (46.7%)	0.059
Chronic kidney disease	41 (33.9%)	48 (40.0%)	0.325
Ejection fraction	21.2 (8.1)	60.0 (8.7)	<0.001
Ventricular involvement
Right ventricle only	0 (0%)	43 (35.8%)	<0.001
Left ventricle only	55 (45.5%)	26 (21.7%)
Biventricular	66 (54.5%)	51 (64.2%)
Heart failure etiology
Ischemic	42 (34.7%)	11 (9.2%)	<0.001
Non-ischemic	46 (38.0%)	34 (28.3%)
Unknown	33 (27.3%)	75 (62.5%)
NYHA Class
I	3 (2.4%)	1 (0.8%)	0.019
II	2 (1.7%)	1 (0.8%)
III	22 (18.2%)	13 (11.7%)
IV	32 (26.4%)	18 (15.0%)
Unknown	62 (51.2%)	87 (72.5%)
Baseline weight, kg	97.3 (30)	101.5 (32)	0.299
Body mass index, kg/m²	32.5 (9.0)	39.5 (19.8)	<0.001
Baseline laboratories
Sodium, mmol/L	136.2 (4.8)	138.9 (5.2)	<0.001
Serum creatinine, mg/dL	1.7 (1.1)	1.6 (1.0)	0.358
BUN, mg/dL	38.4 (24.7)	38.4 (23.5)	0.982
NT-proBNP, pg/mL	10763 (9673)	9093 (13183)	0.382
Baseline SBP, mm Hg	120.5 (19.6)	126.8 (26.6)	0.039
Home medications
ACE inhibitor, ARB, ARNI	59 (48.8%)	37 (30.8%)	0.004
Beta blocker	77 (63.6%)	58 (48.3%)	0.017
Aldosterone antagonist	39 (32.2%)	23 (19.2%)	0.020
Nitrates/hydralazine	15 (12.4%)	2 (1.7%)	0.001
Thiazide-type diuretic	14 (11.6%)	25 (20.8%)	0.051
IV inotrope	11 (9.1%)	1 (0.8%)	0.003
Home loop diuretic	79 (65.3%)	99 (82.5%)	0.002
Home loop diuretic agent
Furosemide	63 (52.9%)	72 (60.0%)	0.106
Torsemide	16 (13.2%)	15 (12.5%)
Bumetanide	3 (2.5%)	12 (10.0%)
Multiple loop diuretics	0 (0%)	2 (1.7%)
Home loop diuretic dose in furosemide equivalents, mg/day*	79.2 (61.8)	91.5 (78.7)	0.242

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BUN, blood urea nitrogen; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; NT-proBNP, n-terminal pro-b-type natriuretic peptide; NYHA, New York Heart Association.

Data are depicted as mean (SD) or number (%) of patients.

* Using oral/IV bumetanide 1 mg = oral torsemide 20 mg = IV furosemide 20 mg = oral furosemide 40 mg.

The mean initial dose of loop diuretic selected in the HFrEF and HFpEF groups was a 2.4- and 2.7-fold increase from their home dose, respectively (P = 0.270). Treatment of congestive symptoms during the first 72 hours of hospitalization was similar between the 2 groups (Supplemental Table 2). No differences were observed in terms of dose increases, switches to a continuous infusion, addition of thiazide-type diuretic, or switches to oral therapy. Fewer than 10% of patients had a greater than 24-hour lapse of diuretic administration at any point in this study. Only IV vasodilator and inotrope use differed between the 2 groups. Vasodilators were used in 11.6% versus 4.2% of patients with HFrEF and HFpEF, respectively (P = 0.032), and inotropes were used in 41.3% and 18.3%, respectively (P = 0.049).

Efficacy End Points

The mean cumulative DE did not differ between the HFrEF and HFpEF groups (−673.5 mL/40-mg vs. −637.8 mL/40-mg) in either unadjusted (P = 0.755) or adjusted analyses (P = 0.884), nor did net urine output (Table 2, and illustrated along with other diuresis endpoints in Figure 1). Daily diuretic doses were lower in the HFrEF group (159.9 mg vs. 172.0 mg in the HFpEF group, adjusted P = 0.026) but total daily urine output did not differ (2667.5 mL vs. 2603.3 mL in the HFpEF group, adjusted P = 0.100). Net urine output was also similar in the 2 groups (−1457.8 mL vs. −1635.6 mL in the HFrEF and HFpEF groups, respectively, adjusted P = 0.210). Patients with HFrEF had a shorter length of stay (10.6 days vs. 11.5 days in patients with HFpEF, adjusted P = 0.019) but a difference in mortality was not observed.

Table 2.

Efficacy End Points.

Characteristic	HFrEF (n = 121)	HFpEF (n = 120)	P value (unadjusted)	P value (adjusted)
Diuretic efficiency, mL/40-mg*	−673.5 (954.3)	−637.8 (810.2)	0.755	0.884
Diuretic dose/day, mg	159.9 (155.6)	172.0 (140.5)	0.280	0.026
Urine output/day, mL	2667.5 (1836.5)	2603.3 (1536.9)	0.610	0.100
Net urine output/day, mL	−1457.8 (1639.2)	−1635.6 (1555.6)	0.100	0.210
Weight change from baseline, kg	−2.9 (4.3)	−2.2 (4.0)	0.270	0.330
Length of stay, days	10.6 (10.4)	11.5 (9.9)	0.496	0.019
Mortality	3 (2.5%)	5 (4.2%)	0.499	0.499

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Data are depicted as mean (SD) or number (%) of patients.

* Diuretic efficiency calculated based on IV furosemide equivalent.

Figure 1.

Comparison of diuretic effects between heart failure with reduced versus preserved ejection fraction.

Results of the propensity score-matched analysis are displayed in Table 3. Similar to the overall cohort, no differences in DE were observed between the 2 groups. In contrast with the analysis of the overall cohort described above, differences in daily diuretic doses were numerically but not statistically significant (145.8 mg vs. 186.8 mg in the HFrEF and HFpEF groups, respectively, P = 0.080). Length of stay was also similar in the 2 groups after propensity score matching (P = 0.150). Other findings in the propensity score-matched groups resembled those of the overall cohort.

Table 3.

Efficacy End Points in Propensity Score-Matched Groups.

Characteristics	HFrEF (n = 59)	HFpEF (n = 59)	P value
Diuretic efficiency, mL/40-mg*	−695.2 (886.3)	−675.3 (1037.3)	0.910
Diuretic dose/day, mg	145.8 (117.9)	186.8 (133.4)	0.080
Urine output/day, mL	2819.3 (1565)	2611.7 (1187)	0.420
Net urine output/day, mL	−1555 (1224.9)	−1637.9 (1129.4)	0.700
Weight change from baseline, kg	0.51 (16.4)	−2.0 (3.6)	0.300
Length of stay, days	10.7 (9.0)	13.5 (11.7)	0.150
Mortality	1 (1.7%)	3 (5.1%)	>0.999

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Data are depicted as mean (SD) or number (%) of patients.

* Diuretic efficiency calculated based on IV furosemide equivalent.

Safety End Points

Acute kidney injury was observed at a similar rate in the 2 groups (19.0% vs. 8.3% in the HFpEF group, adjusted P = 0.077) (Table 4), as was the number of patients progressing to renal replacement therapy (3.3% vs. 7.5% in the HFrEF and HFpEF groups, respectively, P = 0.17). Electrolyte abnormalities also occurred at similar rates in the 2 groups.

Table 4.

Adverse Events.

Characteristic	HFrEF (n = 121)	HFpEF (n = 120)	P value (unadjusted)	P value (adjusted)
Acute kidney injury	23 (19.0%)	10 (8.3%)	0.016	0.077
Progression to renal replacement therapy	4 (3.3%)	9 (7.5%)	0.170	0.170
Hypokalemia (K < 4.0 mg/dL)	99 (81.8%)	97 (80.8%)	0.844	0.844
Hypokalemia, severe(K < 3.5 mg/dL)	47 (38.8%)	36 (30.0%)	0.149	0.100
Hypomagnesemia(Mg < 2.0 mg/dL)	66 (54.5%)	70 (58.3%)	0.553	0.800
Hypomagnesemia, severe(Mg < 1.6 mg/dL)	5 (4.1%)	3 (2.5%)	0.446	0.446

Abbreviations: HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Data are depicted as mean (SD) or number (%) of patients.

Evaluating Temporal Changes in DE and Differences Between Groups

Correlations between the 2 components of DE (diuretic dose in FEs and net urine output) for the first 72 hours of hospitalization are displayed in Figure 2. No appreciable correlation was observed between diuretic dose and net urine output in either the HFrEF or HFpEF group during the first 24 hours of hospitalization. At 48 hours, a weak correlation was observed in patients with HFpEF (r_s = −0.244, P = 0.008) but not in patients with HFrEF. By 72 hours of hospitalization, a weak to moderate correlation was observed in both the HFrEF and HFpEF groups (r_s = −0.440, P < 0.001 and r_s = −0.381, P < 0.001, respectively).

Figure 2.

Diuretic dose versus effect by day in heart failure with reduced versus preserved ejection fraction.

Discussion

Despite a number of recent randomized, controlled clinical trials, few strategies conclusively relieve congestive symptoms in patients with ADHF. However, one aspect that confounds the interpretation of these trials is the heterogeneity of the patient populations enrolled, particularly the variable range of patients with HFrEF versus HFpEF.^3

-7 Additionally, with regard to IV diuretic therapy specifically, adjustments are often made on the basis of changes in volume status and weight and not simply the presence or absence of congestive signs or symptoms, which often serve as the primary endpoints in clinical trials. As a result, metrics like DE have been proposed as an alternative strategy for characterizing how patients with ADHF respond to diuretic therapy.^11,12

To our knowledge, this is the first real-world study to compare DE between patients with exacerbations of HFrEF and HFpEF. Contrary to our initial hypothesis, we found no difference in cumulative DE between the 2 groups at 72 hours. Although patients with HFpEF required significantly higher diuretic doses, these differences were not clinically meaningful. More importantly, we did not observe a difference in net urine output or change in weight from baseline, 2 major metrics of interest when evaluating and adjusting diuretic therapy in clinical practice. Although we observed a longer length of stay in the HFpEF group, this was likely unrelated to adjustments made in the first 72 hours given mean lengths of stay of 10.6 and 11.5 days in the HFrEF and HFpEF groups, respectively.

The first important contribution of our study is that it questions whether the physiologic differences observed in patients with HFrEF versus HFpEF in prior studies confer clinically meaningful differences in the management of ADHF. In one study, responses to sodium nitroprusside were compared in a sample comprised of 174 patients with HFrEF and 83 patients with HFpEF undergoing right heart catheterization.¹⁰ Despite similar baseline hemodynamic values and similar reductions in left ventricular filling pressures in response to sodium nitroprusside, patients with HFpEF were more likely to experience decreases in stroke volume (35% vs. 9% of patients with HFrEF, P < 0.0001) and had greater reductions in mean arterial pressure (−30 vs. −18 mmHg, P < 0.0001), suggesting greater preload sensitivity than patients with HFrEF. In a second study, differences in the distribution and mobilization of volume were also observed with the use of a radiolabeled albumin tracer in 35 patients with HFrEF and 20 patients with HFpEF, all of whom presented with ADHF.⁸ Patients in the HFpEF group tended to have greater interstitial relative to intravascular congestion and were more likely to mobilize fluid from the interstitial compartment in response to IV loop diuretics compared to those with HFrEF.

Based on these findings, we expected patients with HFpEF to have a more efficient response to IV loop diuretics (i.e., higher cumulative DE values) and greater risk of hypovolemic complications with over-diuresis (e.g., acute kidney injury) compared to patients with HFrEF. However, neither of these hypotheses were confirmed in our study, although there are several potential reasons for this. For one, day-to-day changes in clinical response and diuretic adjustments may have impacted the cumulative results obtained at 72 hours. However, this explanation is unlikely as we did not observe any clinically meaningful differences in volume status when examining each day individually (Supplemental Table 3). Alternatively, the more prevalent use of inotropes and vasodilators in the HFrEF group (consistent with findings from the ADHERE registry¹³) may have led to improved renal perfusion and thus improved diuretic response compared to patients with HFpEF. Although we attempted to account for this by including a sample of adequate size and representation (albeit one patient short of our goal sample size) and adjusting for differences between groups, we cannot fully exclude selection bias. This is particularly true for the propensity score-matched analysis, as adjusting for potential confounders reduced our sample size considerably.

A second contribution of our study is that it illustrates variability in how the individual components of DE (net urine output and diuretic dose) performed in the 2 groups over time, providing some evidence for our hypothesis that diuretic response may differ between patients with HFrEF and HFpEF (but in ways that could not be captured using cumulative DE). Temporal differences in diuretic response may also reflect a number of other potential etiologies. For example, the response to diuretics may have improved with the relief of renal congestion, or aggressive diuresis may have restored the Frank-Starling relationship in patients with excessive volume overload, thereby improving blood flow and diuretic delivery to the kidney.

The wide variability we observed in our analysis of DE also suggests that it may be valuable to assess DE as a continuous rather than categorical measure. Although categorizing patients according to DE may facilitate statistical comparisons, potentially valuable information can be lost when continuous data are converted into categorical measures.¹⁴ For example, there may be thresholds within DE cohorts where differences may become clinically meaningful. At the same time, categorization may also divide clinically meaningless differences, such as patients whose furosemide doses may only differ by 20-40 mg yet their location within the distribution results in them being separated into opposite categories. Although some studies have sorted patients into 3 to 5 categories of DE,^15
-17 characterizing diuretic response as a continuous measure should be considered in future studies.

Although we alluded to some of the limitations of our study above (e.g., baseline differences between patients with HFrEF and HFpEF), others warrant further discussion. First, our population was quite heterogeneous, particularly among patients with HFpEF. We described this as a limitation of major landmark trials in ADHF but were also unable to control for it in this retrospective cohort. Second, although our definition of HFrEF (ejection fraction ≤40%) was consistent with practice guidelines, we did not differentiate between patients with HFpEF (≥50%) and those with borderline HFpEF (41-49%), who may represent a distinct clinical entity.² The remaining limitations of our study are a consequence of its retrospective, single-center design. Although we attempted to account for this by including a sample of adequate size and representation, we cannot fully exclude selection bias. Indeed, there were significant differences in the baseline characteristics between patients with HFrEF and HFpEF, although these did not significantly impact our results. Similarly, the demographics of our population are representative of large tertiary academic medical centers and may not be generalizable to other centers. Finally, the data used for this analysis were extracted from the EMR and are therefore subject to errors in documentation (e.g., collection of urine output). The limitations of the EMR were most notable with regard to heart failure etiology and severity, as these values were unknown in a considerable percentage of our population.

Conclusion

In conclusion, we did not observe any significant differences in overall diuretic response, defined as DE, among patients with ADHF and underlying HFrEF versus HFpEF. Although some differences in diuretic dose were observed, these were minor and of little clinical consequence. On further analysis, we observed variable correlations between diuretic dose and net urine output (the individual components of DE) between patients with HFrEF and HFpEF, as well as differences in the correlations over time. These latter findings suggest that cumulative DE may not capture meaningful differences in day-to-day diuretic response and that alternative measures (e.g., pulmonary artery diastolic pressures obtained via wireless hemodynamic monitoring) be considered in future studies.

Supplemental Material

Supplemental Material, JCPT_Contributor_Agreement_-_Signed - Comparing Diuresis Patterns in Hospitalized Patients With Heart Failure With Reduced Versus Preserved Ejection Fraction: A Retrospective Analysis

Supplemental Material, JCPT_Contributor_Agreement_-_Signed for Comparing Diuresis Patterns in Hospitalized Patients With Heart Failure With Reduced Versus Preserved Ejection Fraction: A Retrospective Analysis by Rachael Broscious, Alina Kukin, Zachary R. Noel, Sandeep Devabhakthuni, Hyunuk Seung, Gautam V. Ramani and Brent N. Reed in Journal of Cardiovascular Pharmacology and Therapeutics

Supplemental Material

Supplemental Material, Supplemental_Tables_-_2020-08-17_Tracked - Comparing Diuresis Patterns in Hospitalized Patients With Heart Failure With Reduced Versus Preserved Ejection Fraction: A Retrospective Analysis

Supplemental Material, Supplemental_Tables_-_2020-08-17_Tracked for Comparing Diuresis Patterns in Hospitalized Patients With Heart Failure With Reduced Versus Preserved Ejection Fraction: A Retrospective Analysis by Rachael Broscious, Alina Kukin, Zachary R. Noel, Sandeep Devabhakthuni, Hyunuk Seung, Gautam V. Ramani and Brent N. Reed in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

Institution work reported was done: University of Maryland Medical Center.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Alina Kukin

Zachary R. Noel

Brent N. Reed

Supplemental Material

Supplemental material for this article is available online.

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