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.

A Systematic Review and Meta‐Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure

“…Data evaluating the efficacy and safety of oral metolazone compared to parenteral chlorothiazide are primarily limited to single center, retrospective cohort studies conducted between 2015 and 2019, with only one prospective, randomized trial. [10][11][12][13] Table 1 summarizes study design, duration, treatment arms, baseline characteristics, and efficacy/safety outcomes of individual studies. Table 2 summarizes the results of the GRACE checklist.…”

“…10,11 While the two prior studies included a mix of HFpEF and HFrEF patients with ADHF, in a recent study, the investigators analyzed 168 Study D1 D2 D3 D4 D5 D6 M1 M2 M3 M4 M5 2015 10 Y Y Y Y Y Y N Y N Y N R 2016 11 Y Y Y Y Y Y Y Y Y Y Y a 2019 12 Y Y Y Y Y N Y Y N Y N R 2019 patients admitted with ADHF but limited the cohort to patients with HFrEF (LVEF 40% or less). 12 This is the only study to date that examined patients with HFrEF exclusively. All patients received IV loop diuretic at least 24 hours prior to receiving at least one dose of metolazone or chlorothiazide at doses of at least 5 or 500 mg, respectively.…”

“…The authors concluded that metolazone and chlorothiazide increase UOP to a similar degree when utilized as an adjunct to loop diuretics in patients with ADHF and HFrEF. 12 In the most recent study, researchers analyzed 60 patients admitted with ADHF and treated with either PO metolazone, IV chlorothiazide, or PO tolvaptan. 13 To date, this is the only prospective, randomized trial of its nature.…”

“…Until recently, there was a lack of head-to-head comparisons to support the use of one agent over the other; however, studies published in the last 5 years have sought to end this debate. [10][11][12][13] All studies demonstrated increased net UOP with both agents and found either no difference or non-inferiority of oral metolazone compared to IV chlorothiazide. [10][11][12][13] Combined, these data have demonstrated that both agents augment diuresis to a similar degree in ADHF patients with high-dose loop diuretic resistance with comparable safety profiles.…”

“…11,13 Additionally, pooling and analyzing the combined results further minimizes this possibility. Several studies had significant variations in baseline loop diuretics, with chlorothiazide groups having higher IV furosemide equivalents in studies [10][11][12] and more continuous infusion loop diuretics in the Bohn study. Though metolazone was shown to have similar efficacy despite less aggressive loop diuretic use than in the chlorothiazide groups of these studies, it may be perceived that patients in the chlorothiazide groups had a greater degree of loop diuretic resistance.…”