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

Metolazone (n=33)

Chlorothiazide (n=22)

Age, years

Female 

Ethnicity

   African American

Caucasian

28 (85%)

5 (15%)

16 (73%)

6 (27%)

EF, %

   HFpEF

   HFrEF

10 (30%)

23 (70%)

7 (32%)

15 (68%)

0.91

0.91

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

Total metolazone or chlorothiazide  dose - 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)

Results

Endpoint

Metolazone (n=33)

Chlorothiazide (n=22)

p-value

Net UOP at 72 h, mL

Total UOP, mL

Net UOP of at least 3000 mL achieved at 72 h

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.

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

Male 

Caucasian 

Ejection fraction, %

Creatinine clearance, ml/min

Home thiazide 

Dopamine 

Dobutamine 

Digoxin 

ACE inhibitor or ARB

Spironolactone 

Nesiritide 

Milrinone 

β-blocker

Hydralazine/nitrate

Metolazone total dose before chlorothiazide, mg

Chlorothiazide total dose, mg

Results

Endpoint

Chlorothiazide index doses (n=45)

Metolazone Index Doses (n=45)

All doses (n=90)

PCWP, mm Hg

6-hr urine output, ml

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. 

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

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

Male

White

African American

Ejection fraction

APACHE II score

24 hour total urine output, mL

Creatine clearance, mL/min

APACHE II = acute physiology and chronic health evaluation II

Results

Endpoint

Chlorothiazide (n=108)

Metolazone (n=60)

p-value

Total 24 hour urine output, mL

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.

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)

Age, years

Female

White

African American

22 (78.6%)

5 (17.9%)

41 (75.9%)

10 (18.5%)

Admission weight, kg

Admission Scr, mg/dL

NYHA Class III

NYHA Class IV

17 (60.7%)

11 (39.3%)

35 (4.8%)

19 (35.2%)

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

160 (80 to 320)

120 (40 to 160)

Results

Endpoint

Oral HCTZ (n=28)

IV CTZ (n=54)

p-Value

Change in 24-hour Urine Output, mL

Change in 24-hour Weight Loss, kg

Increase in Scr ≥0.3 mg/dL

Hypokalemia

Hypomagenesemia

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.