What is the evidence supporting the safe and effective use of intravenous push administration of chlorothiazide (Diuril) in patients with heart failure? How should it be dosed, and over what duration should it be administered?

Comment by InpharmD Researcher

Published evidence suggests that intravenous administration of chlorothiazide (Diuril) in patients with heart failure, particularly in cases of acute decompensated heart failure with loop diuretic resistance, may not significantly differ in safety and efficacy compared to metolazone. Both chlorothiazide and metolazone appear to be effective in augmenting diuretic therapy, with comparable outcomes in terms of weight loss, urine output, and safety parameters. The dosing regimen of chlorothiazide used in literature varied, typically ranging from 500 mg to higher doses depending on the patient’s response. Specific details can be found in Table 1-4 of the respective studies.
Background

Typically, treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is achieved using loop diuretics. However, some patients may develop loop diuretic resistance, thus requiring sequential use of a thiazide-type diuretic. Due to a lack of consensus describing the preferred thiazide-type diuretic, a meta-analysis published in 2020 compared the efficacy and safety of chlorothiazide and metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. A total of 4 studies were included in the analysis, with only one randomized controlled trial meeting the inclusion criteria (3T trial). The 3T trial compared intravenous (IV) chlorothiazide to not only metolazone, but also to tolvaptan. Compared to metolazone, there was no significant difference with IV chlorothiazide or tolvaptan with regard to weight loss at 48 hours or cumulative urine output. At the time of publication, this was the only prospective randomized trial of its nature. [1], [2]

Pooled data within the meta-analysis also revealed no difference in net urine output (standard mean difference [SMD] -0.04; 95% confidence interval [CI] -0.25 to 0.18; p= 0.75) or total urine output (SMD -0.09; 95% CI -0.30 to 0.11; p= 0.36) between chlorothiazide and metolazone. Additionally, no difference in rates of hypokalemia (odds ratio [OR] 0.85; 95% CI 0.51 to 1.41; p= 0.73) or worsening of renal function (OR 1.18; 95% CI 0.58 to 2.39; p= 0.36) were observed with chlorothiazide compared to metolazone. While metolazone was deemed as effective as chlorothiazide to augment loop diuretic therapy in ADHF without an increase in safety concerns, there were notable differences across studies with respect to baseline loop diuretic dosing, ejection fraction, renal function, race, and end-point evaluation timing. [1]

References:

[1] Steuber TD, Janzen KM, Howard ML. A Systematic Review and Meta-Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure. Pharmacotherapy. 2020;40(9):924-935. doi:10.1002/phar.2440
[2] Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020;8(3):157-168. doi:10.1016/j.jchf.2019.09.012

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the evidence supporting the safe and effective use of intravenous push administration of chlorothiazide (Diuril) in patients with heart failure? How should it be dosed, and over what duration should it be administered?

Please see Tables 1-4 for your response.


 

Comparison of Metolazone Versus Chlorothiazide in Acute Decompensated Heart Failure with Diuretic Resistance

Design

Retrospective Cohort Study 

N= 55

Objective

To compare the relative effectiveness of oral metolazone versus IV chlorothiazide as add-on therapy to furosemide in patients hospitalized with acute decompensated heart failure (ADHF) and renal insufficiency

Study Groups

Metolazone (n = 33)

Chlorothiazide (n = 22)

Inclusion Criteria

Adult patient with a diagnosis of ADHF and renal insufficiency (CrCl: 15-50 mL/min)

Exclusion Criteria

Received both metolazone and chlorothiazide, received a thiazide or thiazide-like diuretic prior to the study period, end-stage renal disease requiring dialysis, any form of renal replacement therapy, cirrhosis, malnutrition (albumin <2.5 g/dL)

Methods

Initial diuretic treatment was with IV furosemide monotherapy. Then, metolazone or chlorothiazide therapy was subsequently added to furosemide during the ADHF hospitalization with the maintenance of this combined regimen for at least 72 h in duration.

Day one of the study period was the date on which add-on therapy with metolazone or chlorothiazide was initiated. All patients received the final dose of metolazone a minimum of 48 hours after its initiation, and for chlorothiazide, the final dose was administered at a minimum of 60 hours after its initiation.

Duration

June 1, 2008 to December 31, 2011

Outcome Measures

Primary efficacy: net urine output (UOP) 72 h after intervention

Secondary efficacy: total UOP at 72 h, net and total UOP at 12-h increments after intervention, achievement of at least 3000 mL of net UOP at 72 h

Safety: worsening renal function, worsening electrolyte imbalances, hypotension

Baseline Characteristics  

Metolazone (n=33)

Chlorothiazide (n=22)

p-value

Age, years

69 (60–78) 70.5 (58–76) 0.84

Female 

22 (67%) 15 (68%) 0.91

Ethnicity

   African American

Caucasian

 

28 (85%)

5 (15%)

 

16 (73%)

6 (27%)

0.26

EF, %

   HFpEF

   HFrEF

35 (17–56)

10 (30%)

23 (70%)

31 (21–38)

7 (32%)

15 (68%)

0.79

0.91

0.91

SCr, mg/dL

2.2 (1.8–2.9)

2.2 (2.0–2.8)

0.88

CrCl - mL/min

   15-30

   31-40

   41-50

27.5 (22.6–36.2)

21 (64%)

7 (21%)

5 (15%)

26.1 (22.1–36.2)

14 (64%)

6 (27%)

2 (9%)

0.71

Baseline UOP, mL 1600 (850–2100) 817.5 (460–2790) 0.31
Furosemide dose equivalent, mg 90 (80–160) 70 (40–80) <0.01
Total IV furosemide dose, mg 500 (240-720) 1015 (775-1300) <0.001

Total metolazone or chlorothiazide  dose - mg

7.5 (7.5-10) 2500 (1750-2500) --
Daily dose of metolazone - mg

2.5 (2.5-2.5)

-- --

Daily dose of chlorothiazide, mg

   Day 1

   Day 2

   Day 3 

 

 

 

500 (500-875)

750 (500-1000)

1000 (625-1000)

 
EF, ejection fraction; HFpEF, heart failure with a preserved ejection fraction; HFrEF, heart failure with a reduced ejection fraction; SCr, serum creatinine; CrCl, creatinine clearance 

Results

Endpoint

Metolazone (n=33)

Chlorothiazide (n=22)

p-value

Net UOP at 72 h, mL

4828 (2800–7209) 3779 (1885–6535)  0.16

Total UOP, mL

9442 (5943–12441) 7500 (5800–10002) 0.47

Net UOP of at least 3000 mL achieved at 72 h

73% 55% 0.17

The metolazone group had numerically greater net UOP at each 12-h increment compared to chlorothiazide, but this did not meet statistical significance with the exception of the first 12 h of therapy (960 mL in Metolazone vs. 340 mL in Chlorothiazide; p = 0.03).

Adverse Events

No significant differences in regard to the defined safety endpoints.

Worsening renal function: metolazone=2, chlorothiazide= 3.

Significant hypokalemia: ~50% from both groups.

Hypotension: occurred rarely in either group.

Study Author Conclusions

Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication.

InpharmD Researcher Critique

This is a retrospective, non-randomized study with the majority of participating patients being African American and having reduced EF, making it difficult to generalize in other ethnicities or patients with a preserved EF.



References:

Moranville MP, Choi S, Hogg J, Anderson AS, Rich JD. Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovasc Ther. 2015;33(2):42-49. doi:10.1111/1755-5922.12109

 

Efficacy of Intravenous Chlorothiazide for Refractory Acute Decompensated Heart Failure Unresponsive to Adjunct Metolazone

Design

Retrospective cohort study with patients serving as their own controls

N= 90 diuretic doses 

Objective

To determine the safety and efficacy of intravenous (IV) chlorothiazide in patients with acute decompensated heart failure (ADHF) who have loop diuretic resistance and refractory to metolazone

Study Groups

Chlorothiazide index doses (n=45)

Metolazone index doses (n=45)

Inclusion Criteria

Diagnosis of chronic heart failure (CHF), if IV chlorothiazide was ordered between Feb 4, 2013 and Feb 28, 2015, at least one oral dose of metolazone 5 mg or greater followed by at least one oral dose of IV chlorothiazide 500 mg or greater, if multiple doses of metolazone were administered, and the last dose before chlorothiazide was considered the index dose

Exclusion Criteria

If not receiving loop diuretics or if diuretics were administered for an indication other than acute exacerbation of chronic CHF, if index dose of metolazone was administered within 2 hours of the index chlorothiazide dose

Methods

The median dose of loop diuretic in IV furosemide equivalents given over the 24-hour period before the metolazone index dose was 400 mg. The average length of stay was 34.7 days, and in-hospital mortality was 35.6% (16/45 patients). 

Duration

Enrollment: February 4, 2013 to February 28, 2015

Outcome Measures

Primary: occurrence of net-negative urine output ≥ 500 ml during 12 hours following administration of index doses of chlorothiazide and metolazone, increase in urine output by at least 500 ml 12 hours following the index dose relative to 12 hours before the index dose

Secondary: total urine output over 6 and 12 hours, change in SCr, body weight, and pulmonary capillary wedge pressure (PCWP) at 24 hours after the index dose compared to baseline

Baseline Characteristics

 

All patients (n=45)

 

 

Age, years

65.1 ± 13.9    

Male 

50 (55.6%)    

Caucasian 

66 (73.3%)    

Ejection fraction, %

38.6 ± 20.2    

Creatinine clearance, ml/min

27.4 ± 19.4    
Home loop diuretic dose in IV furosemide equivalent, mg 226 ± 299    

Home thiazide 

22 (24.4%)    

Dopamine 

58 (64.4%)    

Dobutamine 

34 (37.8%)    

Digoxin 

26 (28.9%)    

ACE inhibitor or ARB

26 (28.9%)    

Spironolactone 

30 (33.3%)    

Nesiritide 

2 (2.22%)    

Milrinone 

34 (37.8%)    

β-blocker

60 (66.7%)    

Hydralazine/nitrate

34 (37.8%)    

Metolazone total dose before chlorothiazide, mg

28.8 ± 21.1    

Chlorothiazide total dose, mg

1689 ± 1543    

Results

Endpoint

Chlorothiazide index doses (n=45)

Metolazone Index Doses (n=45)

All doses (n=90)

Urine output during 12 hrs before index dose 600 (860.5) 600 (676.5)  570 (744)
IV loop diuretic dose given during 24 hrs before index dose in IV furosemide equivalents, mg 480 (553.5) 380 (405) 400 (490)
Serum creatinine concentration, mg/dL 2.3 (1.3) 2.3 (1.3) 2.4 (1.5)
Weight, kg 68.9 (37.1) 67.7 (38.05) 80 (36.2)

PCWP, mm Hg

23.5 (15) 22 (4) 22 (4)

6-hr urine output, ml

500 (566.5) 300 (502.5) p= 0.104
12-hr urine output, ml 1075 (940)  810 (865.5) p= 0.363
SCr change over 24 hrs, mg/dL +0.1 (0.4) +0.2 (0.35) p= 0.487

Data are median (interquartile range) values.

PCWP = pulmonary capillary wedge pressure.

Adverse Events

Hypokalemia or hypomagnesemia occurred in 26.7% (12/45) of patients within 24 hours following the chlorothiazide dose compared with 22.2% (10/45) patients following the metolazone dose (p= 0.688)

Study Author Conclusions

Administration of intravenous chlorothiazide did not improve urine output in ADHF patients considered refractory to high-dose loop diuretics and oral metolazone. However, the addition of a thiazide diuretic enhanced urine output compared with loop diuretics alone in these patients. In terms of safety, there were no differences observed between metolazone and chlorothiazide in either electrolyte abnormalities or changes in serum creatinine. The results of this analysis do not support the use of intravenous thiazide-type diuretics for patients in whom response to oral thiazides in considered inadequate.

InpharmD Researcher Critique

The study's retrospective nature limits its ability to control for confounding factors, while its single-center design and reliance on a specific institutional algorithm restrict its external validity. Index dose selection, administered with a minimum time gap despite metolazone's delayed onset and variable duration of effect, may not accurately reflect pharmacokinetics. Variability in drug absorption, particularly in patients with significant edema, further complicates interpretation. Additionally, overlapping dosing schedules hinder clear assessment of treatment effects. 



References:

Cardinale M, Altshuler J, Testani JM. Efficacy of Intravenous Chlorothiazide for Refractory Acute Decompensated Heart Failure Unresponsive to Adjunct Metolazone. Pharmacotherapy. 2016;36(8):843-851. doi:10.1002/phar.1787

 

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

Design

Retrospective chart review

N= 168

Objective

To compare the increase in 24-hour total urine output (UOP) after adding MTZ (metolazone) or CTZ (chlorothiazide) to IV loop diuretics (LD) in patients with heart failure with reduced ejection fraction (HFrEF).

Study Groups

Metolazone (n=60)

Chlorothiazide (n=108)

Inclusion Criteria

Age > 18 years, hospitalized, primary diagnosis of HFrEF with EF < 40%, 

Exclusion Criteria

Receiving dialysis, vasopressin antagonist, only IV medication (no oral), or had cirrhosis.

Methods

Data of patients who received oral metolazone > 5 mg or IV chlorothiazide > 500 mg for at least two days in the chlorothiazide group and 1.5 days in the metolazone group were assessed. Both groups received the agents in addition to loop diuretics. 

Duration

September 2013 to August 2016

Outcome Measures

Primary outcome: change in 24 hours urine output 

Secondary outcome: total urine output in 24 hours

Baseline Characteristics

 

Chlorothiazide (n=108)

Metolazone (n=60)

 

Age, years

64 (54 to 69) 63 (54 to 74)  

Male

74 (68.5%)  41 (68.3%)  

White

68 (63%) 34 (56.6%)  

African American

30 (27.8%) 21 (35%)  

Ejection fraction

22% (15% to 30%) 22.5% (17% to 30%)  

APACHE II score

12 (9 to 15) 10 (7 to 14)  

24 hour total urine output, mL

1692.5 1675   

Creatine clearance, mL/min

46.5 43  

APACHE II = acute physiology and chronic health evaluation II

Results

Endpoint

Chlorothiazide (n=108)

Metolazone (n=60)

p-value

Change in 24 hour urine output, mL 1820 1458 0.251

Total 24 hour urine output, mL

3352 3400 0.697

Adverse Events

There was no statistical difference in adverse effects between the groups. Most common adverse events included hyponatremia (31.7% in the metaolzone group versus 20.4% in the chlorothiazide group), hypochloremia (3.3% versus 3.7%), and hypotension (16.7% versus 24.1%).

Study Author Conclusions

Both metolazone and chlorothiazide similarly increased urine output when utilized as an adjunct to IV loading dose. These results suggest that while thiazide agents can substantially increase urine output in ADHF patients with HFrEF, metolazone and chlorthiazide have comparable effects.

InpharmD Researcher Critique

The retrospective nature of the study presents some challenges such as the measurement in urine output may not have the same rigorous standardization as a prospectively planned study.

 

References:

Bohn BC, Hadgu RM, Pope HE, Shuster JE. Oral Metolazone Versus Intravenous Chlorothiazide as an Adjunct to Loop Diuretics for Diuresis in Acute Decompensated Heart Failure With Reduced Ejection Fraction. Hosp Pharm. 2019;54(6):351-357. doi:10.1177/0018578718795855

 

Comparison of the Effects of Combination Diuretic Therapy with Oral Hydrochlorothiazide or Intravenous Chlorothiazide in Patients Receiving Intravenous Furosemide Therapy for the Treatment of Heart Failure

Design

Single-center, retrospective study

N= 82

Objective

To compare the effects of combination diuretic therapy with oral hydrochlorothiazide (HCTZ) or IV chlorothiazide (CTZ) added to background intravenous loop diuretic therapy among patients hospitalized with heart failure

Study Groups

Oral HCTZ (n= 28)

IV CTZ (n= 54)

Inclusion Criteria

Age 18 to 89 years, treated with IV furosemide and either oral HCTZ or IV CTZ, received IV furosemide by continuous infusion or intermittent bolus at a consistent dose ≥160 mg/day for 24 hours before and after thiazide diuretics

Exclusion Criteria

Thiazide or thiazide-type diuretic used prior to admission, patients with incomplete urine output data

Methods

This retrospective review identified patients with simultaneous active orders for IV furosemide and either oral HCTZ or IV CTZ using historical dispensing data. These patients also had to have a diagnosis of heart failure, and had their change in urine output monitored once the second diuretic agent had been initiated.

Duration

September 2009 to August 2011

Outcome Measures

Primary: Change in 24-hour urine output

Secondary: Change in 24-hour weight loss, increase in Scr ≥0.3 mg/dL, hypokalemia, hypomagnesemia

Baseline Characteristics

 

Oral HCTZ (n=28)

IV CTZ (n=54)

p-value

Age, years

64 (47to 73)  63.5 (51 to 71) NS 

Female

14 (50%)  12 (22.2%) 0.01 

White

African American

22 (78.6%)

5 (17.9%)

41 (75.9%)

10 (18.5%)

NS 

Admission weight, kg

96 (81 to 105)  97 (76 to 117) NS 

Admission Scr, mg/dL

1.6 (1.0 to 2.3) 1.7 (1.2 to 2.7) NS 

NYHA Class III

NYHA Class IV

17 (60.7%)

11 (39.3%)

35 (4.8%)

19 (35.2%)

NS 

Oral daily loop diuretic prior to admission in furosemide equivalent, mg/day

160 (80 to 320)

120 (40 to 160)

0.03

Results

Endpoint

Oral HCTZ (n=28)

IV CTZ (n=54)

p-Value

Change in 24-hour Urine Output, mL

934 ± 943 1786 ± 1737 0.005

Change in 24-hour Weight Loss, kg

0.15 (-0.4 to 1.4) 0.8 (-0.4 to 2.9)  0.14

Increase in Scr ≥0.3 mg/dL

1 (3.6%) 5 (9.3%) 0.66

Hypokalemia

20 (71.4%) 45 (83.3%) 0.21

Hypomagenesemia

5 (17.9%) 9 (16.7%) 0.84

Study Author Conclusions

Among patients hospitalized with heart failure, the addition of either oral HCTZ or intravenous CTZ to IV furosemide therapy resulted in enhanced diuresis. The use of CTZ was associated with a more robust initial diuresis compared with HCTZ within the first 24 hours. Given the positive response observed, ease of administration, and lower drug cost, however, oral HCTZ should still be considered as another option for combination diuretic therapy in this patient population. 

InpharmD Researcher Critique

The study was limited by its retrospective design, which could introduce confounders. The study only included patients with NYHA Class III and IV and the oral daily loop diuretic doses prior to admission were higher in the oral group. The follow-up period of 24 hours does not establish sustaining effects of the medication but was justified by the authors to reduce potential confounding factors.

 

References:

Kissling KT, Pickworth KK. Comparison of the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide in patients receiving intravenous furosemide therapy for the treatment of heart failure. Pharmacotherapy. 2014;34(8):882-887. doi:10.1002/phar.1456