Oral Metolazone Versus Intravenous Chlorothiazide as an Adjunct to Loop Diuretics for Diuresis in Acute Decompensated Heart Failure With Reduced Ejection Fraction

Abstract

Background: Thiazide diuretics are often utilized to overcome loop diuretic resistance when treating acute decompensated heart failure (ADHF). In addition to a large cost advantage, several pharmacokinetic advantages exist when administering oral metolazone (MTZ) compared with intravenous (IV) chlorothiazide (CTZ), yet many providers are reluctant to utilize an oral formulation to treat ADHF. The purpose of this study was to compare the increase in 24-hour total urine output (UOP) after adding MTZ or CTZ to IV loop diuretics (LD) in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: From September 2013 to August 2016, 1002 patients admitted for ADHF received either MTZ or CTZ in addition to LD. Patients were excluded for heart failure with preserved ejection fraction (HFpEF) (n = 469), <24-hour LD or UOP data prior to drug initiation (n = 129), or low dose MTZ/CTZ (n = 91). A total of 168 patients were included with 64% receiving CTZ. No significant difference was observed between the increase in 24-hour total UOP after MTZ or CTZ initiation (1458 [514, 2401] mL vs 1820 [890, 2750] mL, P = .251). Conclusions: Both MTZ and CTZ similarly increased UOP when utilized as an adjunct to IV LD. These results suggest that while thiazide agents can substantially increase UOP in ADHF patients with HFrEF, MTZ and CTZ have comparable effects.

Introduction

Management of acute decompensated heart failure (ADHF) requires diuresis with high-dose intravenous (IV) loop diuretics to achieve adequate relief of symptoms; however, many patients with ADHF develop loop diuretic resistance after prolonged therapy.¹ Other options of therapy beyond intermittent loop diuretics, such as continuous loop diuretic administration and ultrafiltration, have not been shown to be more efficacious.^2,3 However, the addition of thiazide diuretics to loop diuretics has been shown to overcome loop diuretic resistance.⁴

The distal convoluted tubule (DCT) is thought to be the site of loop diuretic resistance due to hypertrophy of DCT cells and upregulation of NaCl cotransporters. Thiazide diuretics can be added to IV loop diuretics to counteract resistance via their primary site of action in the DCT.^5,6 The sequential nephron blockade results in profound diuresis and relief of congestion in many cases.^5,7,8 The choice of thiazide agent has mainly focused on a debate between oral metolazone (MTZ) and IV chlorothiazide (CTZ). Although MTZ is less invasive, has a significant cost benefit, and pharmacokinetic advantages, many clinicians still prefer CTZ likely due to the faster onset and perceived superior efficacy of IV administration. The onset of diuresis seen with MTZ and CTZ is 1 hour versus 15 minutes, respectively.^9,10

Several studies have sought to end this debate, with a recent retrospective cohort study showing similar efficacy between the agents in net urine output (UOP); however, the study had significant limitations. Due to the small sample size (55 patients), inclusion of patients with heart failure with preserved ejection fraction (HFpEF), inclusion of only patients with creatinine clearance of 15 to 50 mL/min, and use of net UOP as the primary outcome, further investigation is needed to determine whether a difference exists between MTZ and CTZ for this indication.¹¹ Another recent retrospective study by Shulenberger et al compared MTZ and CTZ in 177 patients with ADHF resistant to loop diuretics. No difference in the primary outcome of change in 24-hour net UOP was seen; however, this study was similarly limited by inclusion of HFpEF patients and use of net UOP as the primary outcome which can be drastically affected by oral intake.¹² The purpose of the present study is to determine whether CTZ increases change in 24-hour total UOP more effectively than MTZ in patients with ADHF and reduced ejection fraction (EF) receiving IV loop diuretics.

Methods

Study Design

This study was a retrospective chart review conducted at Barnes-Jewish Hospital, St. Louis, Missouri, from September 1, 2013, to August 15, 2016. The study was approved by the Washington University at St. Louis Institutional Review Board. Hospitalized adult patients (age ⩾18 years old) with a primary diagnosis of ADHF, EF ⩽40%, receiving at least one dose of either MTZ ⩾5 mg or CTZ ⩾500 mg in addition to IV loop diuretics were included in the study. Inclusion criteria required UOP data and IV loop diuretic utilization 24 hours prior to the first dose and 24 hours after the last dose of a thiazide diuretic. Patients were excluded if they were receiving dialysis, ultrafiltration, vasopressin antagonists, only IV medications, had a left ventricular assist device (LVAD), cirrhosis, albumin <2.5 mg/dL, anuria, allergy to study drugs, or received both MTZ and CTZ. An a priori subgroup analysis was also conducted which included all patients in the study who were admitted to an intensive care unit (ICU) and receiving a vasopressor at the time of thiazide diuretic administration. Patients were identified using the medical informatics database at Barnes-Jewish Hospital. Data were collected from the medical informatics database query and by manual chart review.

Endpoints

The primary efficacy endpoint was the change in 24-hour total UOP following the addition of thiazide. The secondary efficacy endpoints were 24-hour total UOP, course of therapy (COT) total UOP, 24-hour net UOP, and COT net UOP. Total UOP is the total UOP without fluid intake subtracted, net UOP is the total UOP with fluid intake subtracted, baseline UOP is the sum of the UOP occurring in the 24 hours prior to the first dose, 24-hour values are the sum of the UOP at 24 hours after initiation, and COT is the sum of UOP at the completion of the consecutive COT. Secondary safety endpoints include hypokalemia (serum potassium <3.3 mEq/L), hyperkalemia (serum potassium >4.9 mEq/L), hyponatremia (serum sodium <135 mEq/L), hypernatremia (serum sodium >145 mEq/L), hypochloremia (serum chloride <97 mEq/L), hyperchloremia (serum chloride >110 mEq/L), hypocalcemia (corrected calcium <8.5 mg/dL), hypercalcemia (corrected calcium >10.3 mg/dL), hypomagnesemia (serum magnesium <1.4 mg/dL), hypermagnesemia (serum magnesium >2.5 mg/dL), and adverse effects such as hypotension (systolic blood pressure [SBP] <90 mm Hg), agranulocytosis (ANC <100 cells/mm³), and pancreatitis (lipase >300 units/L). Laboratory data were assessed from first dose of thiazide diuretic through 48 hours following the final dose. Adverse effects were only recorded if they were not present prior to thiazide administration.

Statistical Analysis

All comparisons of baseline and outcomes data were unpaired, and all tests of significance were two-tailed. Continuous variables were compared using the Student’s t test for normally distributed data and the Mann-Whitney U test for nonnormally distributed data. The chi-squared or Fisher exact test was used to compare categorical variables. A statistical software program (SPSS, version 18.0 for Windows; SPSS, Inc; Chicago, Illinois) was used to perform the analyses. A P value of <.05 was considered significant. The subgroup analysis evaluating clinical outcomes in ICU patients receiving vasopressors was determined a priori.

Results

Patient Groups and Clinical Characteristics

During the study period of 3 years, 1002 patients were admitted to Barnes-Jewish Hospital for ADHF. After patient exclusions, 168 patients were included, 60 receiving MTZ ⩾5 mg, and 108 receiving CTZ ⩾500 mg (Figure 1). The most common exclusion criteria were HFpEF, IV loop diuretic use for <24 hours prior to addition of thiazide, and receiving both MTZ and CTZ during the hospitalization.

Figure 1.

Flow diagram of included and excluded patients.

Note. ADHF = acute decompensated heart failure; IV = intravenous; PO = oral; EF = ejection fraction; MTZ = metolazone; CTZ = chlorothiazide; LVAD = left ventricular assist device; ADH = vasopressin.

Baseline characteristics were similar between the two groups (Table 1). The majority of patients were Caucasian men with an age of 64 years and an EF of 22%. All patients were receiving at least 80 mg IV furosemide (or equivalent) prior to the addition of thiazide diuretics. There were no statistically significant differences in median B-type natriuretic peptide (BNP) (1371 pg/mL CTZ vs 1516.5 pg/mL MTZ,P = .620), Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (12 CTZ vs 10 MTZ, P = .099), and baseline 24-hour total UOP (1692.5 mL CTZ vs 1675 mL MTZ, P = .330). There was also no difference in the 24-hour net UOP at baseline (–350 mL CTZ vs −552 mL MTZ, P = .303). There were statistically significant increases in continuous IV loop diuretic usage (62.0% CTZ vs 41.7% MTZ, P = .011), mechanical ventilation (13.9% CTZ vs 3.3% MTZ, P = .033), and expiration during hospitalization (19.4% CTZ vs 1.7% MTZ, P = .001) in the CTZ arm. Baseline medications, including inotropes and vasopressors, were similar between the groups with the exception of beta-blockers, which were significantly higher in the MTZ group.

Table 1.

Baseline Characteristics.

Baseline characteristicsa	CTZ (n = 108)	MTZ (n = 60)	P value
Age (years)	64 (54, 69)	63 (54, 74)	.558
Male, n(%)	74 (68.5%)	41 (68.3%)	.98
Race, n(%)			.621
Caucasian	68 (63%)	34 (56.6%)
African American	30 (27.8%)	21 (35%)
Other	10 (9.3%)	5 (8.3%)
Ejection fraction (%)	22 (15, 30)	22.5 (17, 30)	.293
BNP (pg/mL)	1371 (829.5, 2230)	1516.5 (825, 3313)	.620
APACHE II score	12 (9, 15)	10 (7, 14)	.099
Expiration during visit, n(%)	21 (19.4%)	1 (1.7%)	.001
24-hour total UOP (mL)	1692.5 (862.5, 2387.5)	1675 (1112.5, 2591)	.330
24-hour net UOP (mL)	−350 (1217)	−552 (1205)	.303
Serum creatinine (mg/dL)	1.49 (1.02, 2.12)	1.61 (1.15, 2.13)	.328
Creatinine clearance (mL/min)b	46.5 (30, 68)	43 (30, 61)	.390
Hospital LOS (days)	16 (9, 28)	13 (8, 32)	.502
ICU admission, n(%)	77 (71.3%)	38 (63.3%)	.287
ICU LOS (days)	4 (0, 10)	2 (0, 8)	.088
Mechanical ventilation, n(%)	15 (13.9%)	2 (3.3%)	.033
Baseline medicationsc, n(%)
Continuous IV loop diuretics	67 (62.0%)	25 (41.7%)	.011
Inotropes	53 (49.1%)	24 (40%)	.258
Any vasopressor	34 (31.5%)	16 (26.7%)	.892
Beta blockers	60 (55.6%)	44 (73.3%)	.023
Hydralazine	59 (54.6%)	36 (60%)	.501
Isosorbide	55 (50.9%)	32 (53.3%)	.765
ACE inhibitors	42 (38.9%)	22 (36.7%)	.776
Angiotensin receptor blockers	11 (10.2%)	7 (11.7%)	.766
Aldosterone antagonists	41 (38.0%)	19 (31.7%)	.414
Digoxin	14 (13%)	7 (11.7%)	.808
Acetazolamide	8 (7.4%)	1 (1.7%)	.160
Ethacrynic acid	0	1 (1.7%)	.357
Chlorthalidone	1 (0.9%)	0	1.00

Note. CTZ = chlorothiazide; MTZ = metolazone; BNP = B-type natriuretic peptide; APACHE II = acute physiology and chronic health evaluation II; UOP = urine output; LOS = length of stay; ICU = intensive care unit; IV = intravenous; ACE = angiotensin converting enzyme; IQR = interquartile range.

^aContinuous values expressed as median (IQR) other than baseline net UOP which is expressed as mean (SD).

^bCreatinine clearance was calculated using the Cockcroft-Gault equation.

^cNo patients received amiloride, triamterene, hydrochlorothiazide, or indapamide.

The majority of patients received two doses of MTZ 5 mg or CTZ 500 mg per COT. The median duration of therapy was 2 days for CTZ and 1.5 days for MTZ (P = .450). More patients had nonconsecutive days of therapy in the CTZ arm (25%) as compared with the MTZ arm (10%), P = .019.

Efficacy Outcomes

There was no statistically significant difference in the primary outcome between the two groups with a median increase in 24-hour total UOP post-thiazide of 1820 mL (890, 2750) in the CTZ arm and 1458 mL (514.5, 2401.5) in the MTZ arm (P = .251, Figure 2). There was also no statistically significant difference in the secondary UOP outcomes analyzed (Figure 3) including 24-hour total UOP (3552 mL CTZ vs 3400 mL MTZ, P = .697), total COT UOP (5505 mL CTZ vs 5087.5 mL MTZ, P = .542), 24-hour net UOP (−1870.5 mL CTZ vs −2191.5 mL MTZ, P = .481), and net COT UOP (−2981.5 mL CTZ vs −3134.5 mL MTZ, P = .809).

Figure 2.

Increase in 24 hour total urine output post-thiazide dose.

Note. CTZ = chlorothiazide; MTZ = metolazone; UOP = urine output.

Figure 3.

Secondary urine output outcomes including baseline urine outputs.

Note. UOP = urine output; MTZ = metolazone oral; CTZ = chlorothiazide intravenous; BL = baseline; COT = course of therapy.

Safety Outcomes

There were no statistically significant differences in adverse effects observed between the groups. The three most common adverse events in both arms were hyponatremia, hypochloremia, and hypotension (Table 2).

Table 2.

Adverse Effects.

Adverse effects	CTZ (n = 108), n (%)	MTZ (n = 60), n (%)	P value
Hyponatremia (Na <135 mEq/L)	22 (20.4)	19 (31.7)	.102
Hypernatremia (Na >145 mEq/L)	5 (4.6)	2 (3.3)	.687
Hypokalemia (K <3.3 mEq/L)	17 (15.7)	9 (15)	.899
Hyperkalemia (K >4.9 mEq/L)	9 (8.3)	7 (11.6)	.481
Hypochloremia (Cl <97 mEq/L)	26 (24.1)	17 (28.3)	.544
Hyperchloremia (Cl >110 mEq/L)	4 (3.7)	2 (3.3)	.901
Hypocalcemia (Ca <8.5 mg/dL)	13 (12)	8 (13.3)	.808
Hypercalcemia (Ca >10.3 mg/dL)	11 (10.2)	4 (6.7)	.443
Hypomagnesemia (Mg <1.4 mg/dL)	0	0	—
Hypermagnesemia (Mg >2.5 mg/dL)	6 (5.6)	4 (6.7)	.771
Hypotension (SBP <90 mm Hg)	26 (24.1)	10 (16.7)	.262

Note. CTZ = chlorothiazide; MTZ = metolazone; Na = sodium; K = potassium; Cl = chloride; Ca = calcium; Mg = magnesium; SBP = systolic blood pressure.

Subgroup Analysis

Fifty patients (30%) were receiving a vasopressor agent in an ICU at the time of thiazide administration and included in the subgroup analysis. The baseline total UOP was similar between the two groups. No statistically significant differences were found in change in 24-hour UOP or total 24-hour UOP between CTZ and MTZ in this subgroup of patients (Table 3). No difference was seen between the two groups with respect to adverse effects, including hypokalemia and hypochloremia.

Table 3.

Subgroup Analysis, Patients Receiving Vasopressor in the ICU.

	CTZ (n = 34)	MTZ (n = 16)	P value
BL total UOP (mL)	1810 (169, 3789)	2097.5 (936.5, 3258.5)	.647
Total 24-hour UOP (mL)	3881 (555, 7207)	3962.5 (2072.5, 5852.5)	.852
Change in 24-hour UOP (mL)	1865 (302, 3428)	1622.5 (59.5, 3185.5)	.506
K <3.3 mEq/L	8 (23.5%)	3 (18.8%)	1.00
Cl <97 mEq/L	5 (14.7%)	4 (25%)	.442

Note. ICU = intensive care unit; CTZ = chlorothiazide; MTZ = metolazone; BL = baseline; UOP = urine output; K = potassium; Cl = chloride.

Discussion

The purpose of this study was to determine whether there was a difference in efficacy or safety when administering CTZ or MTZ as an adjunct to IV loop diuretic therapy in patients with ADHF and reduced EF. No differences were seen in the primary endpoint or any secondary UOP outcomes or adverse effects measured in this specific patient population. When IV loop diuretic therapy is insufficient to resolve ADHF, the 2010 heart failure treatment guidelines recommend the addition of spironolactone, MTZ, or CTZ¹; however, few studies compare MTZ and CTZ for efficacy. A recent retrospective cohort study, conducted by Shulenberger et al, compared the addition of CTZ and MTZ in patients with ADHF and identified as resistant to loop diuretics.¹² A total of 177 patients were included and the primary outcome analyzed was 24-hour net UOP. Although the conclusions of Shulenberger et al were similar to the findings of this study, there are several notable differences between the two cohorts. The baseline total UOP found in the current study was less than the sample from Shulenberger et al (1692.5 mL for CTZ and 1675 mL for MTZ vs 2437.9 mL and 2338.5 mL, respectively), as was the baseline net UOP (−350.0 mL for CTZ and −552.0 mL for MTZ vs −877.0 mL and −710.6 mL, respectively). These differences possibly indicate an ADHF patient population more likely to require and benefit from the addition of a thiazide diuretic. In addition, the primary outcome of the current study, change in 24-hour total UOP, may provide more insight to efficacy than net UOP as it is not influenced by the patients’ baseline UOP differences or fluid intake. The same limitation was seen in the retrospective study published in 2013 by Moranville et al, which similarly utilized the primary outcome of 72-hour net UOP. Furthermore, both previous studies included patients with HFpEF which may affect outcomes, specifically increasing the possibility of type II error, as patients with HFpEF often have differing UOP goals than HFrEF patients. In addition, both studies did not exclude patients receiving dialysis or ultrafiltration, which would likely have an effect on the patients’ UOP.^11,12

Another strength of the current study is the subgroup analysis evaluating the efficacy of the two agents in patients receiving vasopressor therapy. MTZ is often avoided in patients in the ICU receiving vasopressors due to the belief that decreased perfusion to the gastrointestinal (GI) tract limits the absorption of enteral medications. Given the lack of data regarding the use of MTZ in patients receiving vasopressors, this subgroup analysis was conducted. The lack of statistically significant differences between the MTZ and CTZ groups analyzed and similar response to thiazide therapy in the subgroup suggest that MTZ remains a viable option for patients in the ICU receiving vasopressors. To our knowledge, this data set was the first to investigate the differences between CTZ and MTZ in patients receiving vasopressors in the ICU.

In addition, this cohort had a larger proportion of patients receiving inotrope therapy (>40%), continuous loop diuretic therapy (>41%) and ICU admission (>63%) than the previous studies, suggesting the patients included had a higher severity of illness. This more severe heart failure (HF) population, in particular, is lacking data comparing efficacy and safety of these two agents, and therefore, these results could provide insights to thiazide choice in this more controversial patient population underrepresented in previous studies.

Pharmacokinetic differences have also raised questions regarding whether MTZ or CTZ is the better option. The erratic bioavailability of MTZ is a significant concern that is overcome by the use of CTZ as this bypasses the oral route.¹³ MTZ does, however, have the benefit of a significantly longer duration of action (24 hours) than that of CTZ (6 hours).^9,10 The lack of statistically significant differences between the change in total and net UOP outcomes observed suggests there is no difference between the efficacy of CTZ and MTZ when added to IV loop diuretics in patients with ADHF. The results of this study are particularly noteworthy for patients with HFrEF experiencing volume overload as this is the only study, to our knowledge, that has compared CTZ and MTZ in a population comprised of entirely HFrEF patients. The lack of significant differences in all adverse events also suggests there is no difference in safety between MTZ and CTZ.

This study has several limitations worth noting. The retrospective nature of the study is a limitation. Due to inconsistencies in the entering of daily weights into the electronic health record, the change in weight during the COT was unable to be accurately evaluated. COT serum creatinine values provided in our data request were inconsistent and could not be evaluated. There was a statistically significant increase in the amount of patients in the CTZ arm that were mechanically ventilated, expired during the hospitalization, and received continuous IV loop diuretics which could potentially indicate that the patients receiving CTZ had a higher severity of illness at baseline. However, the lack of difference between baseline UOP, SCr, BNP, EF, ICU admission, APACHE II score, and vasopressor and inotrope use suggests that the two groups were similar. The subgroup analysis of patients receiving vasopressors in the ICU was significantly limited by a small sample size. Given the small sample size, these results should be viewed as hypothesis generating.

Conclusion

This study found no statistically significant difference between MTZ and CTZ in the primary outcome, change in 24-hour total UOP as well as adverse effects, such as hyponatremia and hypokalemia. These results support the findings of Shulenberger et al and Moranville et al, although a prospective, randomized, controlled trial is ideal to determine whether an efficacy difference exists. Due to the extreme cost difference, clinicians may consider PO MTZ as a first-line therapy for patients with ADHF resistant to IV loop diuretics that are able to take oral or per tube medications.