Use of metolazone as an adjunct therapy to loop diuretics in diuretic resistant acute decompensation of heart failure: A systematic review and meta-analysis

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.

The complexity of diuretic resistance.

Loop diuretics are a fundamental cornerstone in management of hypervolemia encountered in acute decompensated heart failure. There is variation in the literature describing relative potency of loop diuretic agents, and there are very limited available data specific to the heart failure population. In this retrospective cohort study, we aimed to compare the urine output response between intravenous furosemide and bumetanide in patients with acute decompensated heart failure. Patients were eligible for inclusion if they were admitted between July 1, 2021, and June 30, 2022, with acute decompensated heart failure and received intravenous bumetanide or furosemide within 48 hours of admission. Propensity matching was used to determine comparison groups. The primary outcome was total urine output for 24 hours after initiation of the diuretic regimen. A total of 120 patients (60 in each group) were matched after exclusion criteria were applied. The total urine output was similar between groups. The bumetanide group did demonstrate a greater urine output: furosemide-equivalent response (52 ± 46 mL/mg vs. 33 ± 25 mL/mg; P = 0.007). Based on our analysis, similar urine output may be achieved with either intravenous bumetanide or furosemide in acute decompensated heart failure; however, a higher dose of furosemide may be required than what has been previously established as an equivalent dose to bumetanide to achieve a similar diuretic effect. These results should warrant further investigation to better establish dose-response relationships with loop diuretics in acute decompensated heart failure.

BACKGROUND Diuretic resistance is a frequent and clinically important problem in acute decompensated heart failure (ADHF), leading to persistent congestion, prolonged hospitalization, and adverse outcomes. Although loop diuretics remain first-line therapy, many patients show inadequate natriuretic and diuretic responses. Adjunctive pharmacologic therapies targeting different nephron segments or renal sodium handling have been studied to enhance decongestion. However, randomized controlled trial evidence remains heterogeneous, and the relative effectiveness of these strategies in the acute setting is unclear. The study hypothesis is that mechanistically targeted adjunctive therapies improve diuretic response compared with standard therapy alone. AIM To determine the effectiveness and safety of adjunctive pharmacologic therapies for diuretic resistance in ADHF. METHODS Randomized controlled trials enrolling adults hospitalized with ADHF receiving loop diuretics were identified through PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials to February 2025. Adjunctive pharmacologic therapies were compared with placebo or usual care. Outcomes included decongestion, urine output, natriuresis, renal function, safety, and clinical events. Data extraction and risk of bias assessment using the Cochrane Risk of Bias tool were performed independently by two reviewers. Given substantial heterogeneity across study designs, definitions, and endpoints, no meta-analysis or statistical pooling was performed, and all effect estimates reflect study-level values reported in individual trials. A narrative synthesis was conducted. RESULTS Eight randomized controlled trials including 1758 participants were analyzed. Acetazolamide increased successful decongestion compared with placebo (42.2% vs 30.5%; risk ratios 1.46, 95% confidence interval: 1.17-1.82, study-level estimate). Thiazide augmentation produced greater weight loss at 72 hours (2.3 vs 1.5 kg) but increased renal dysfunction (46.5% vs 17.2%, study-level data). Sodium-glucose cotransporter 2 (SGLT2) inhibitors increased urine output and natriuresis and reduced worsening heart failure events in selected studies (10% vs 33%, based on individual trial findings). High-dose spironolactone, low-dose dopamine, and low-dose nesiritide showed no meaningful clinical benefit. Thiazide and thiazide-like diuretics were appropriately classified as distal convoluted tubule agents, whereas acetazolamide and SGLT2 inhibitors act primarily at the proximal nephron. CONCLUSION Adjunctive therapies targeting proximal sodium handling (acetazolamide, SGLT2 inhibitors) or distal sodium reabsorption (thiazide diuretics) improve decongestion and may serve as effective options when loop diuretics alone are insufficient. These findings reflect study-level evidence from individual randomized trials and support a mechanistically guided approach to treating diuretic resistance in ADHF.

Can saline repletion be the true TARGET for achieving fluid balance in acute heart failure?

Renal dysfunction is a common and progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient’s clinical status and treatment. Despite growing recognition of the frequent presentation of combined cardiac and renal dysfunction, or “cardiorenal syndrome,” its underlying pathophysiology is not well understood, and no consensus as to its appropriate management has been achieved. Because patients with heart failure are surviving longer and dying less frequently from primary arrhythmia, we expect that the cardiorenal syndrome will become more common. Against this background, the article by Wang and colleagues1 in the present issue of Circulation is particularly significant because it is the first prospective, controlled therapeutic trial in patients with this condition. To place the findings and implications of this study in context, we first briefly review what is currently known about the cardiorenal syndrome and its treatment options. See p 1620 In ambulatory heart failure patients, the presence of concomitant renal dysfunction consistently has been one of the strongest risk factors for mortality.2–4 This risk becomes evident even at serum creatinine clearance levels >1.3 mg/dL and estimated creatinine clearance values ≤60 to 70 mL/min. Furthermore, renal function is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and New York Heart Association function class. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction.2 In the setting of hospitalization for decompensated heart failure, worsening renal function is even more important than baseline renal function for predicting adverse outcomes.5–8 Although any increase in creatinine is associated with poorer survival rates, longer hospitalization, and more frequent readmission, several studies have used a threshold of a …

Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction. This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities. Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72h in those receiving metolazone (4828mL, interquartile range [IQR] 2800-7209mL) compared to chlorothiazide (3779mL, IQR 1885-6535mL) (P=0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P=NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7days) compared to chlorothiazide (median 15days), suggesting the chlorothiazide cohort was likely sicker. 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.

To assess the efficacy and safety of intravenous (IV) chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance. Retrospective cohort study. Large urban academic medical center. Adults admitted with ADHF between 2005 and 2015 who had loop diuretic resistance, defined as administration of IV furosemide at a dose of 160mg/day or higher (or an equivalent dose of IV bumetanide), during hospitalization, and who then received at least one dose of IV chlorothiazide (88 patients) or oral metolazone (89 patients) to augment diuresis. The primary efficacy end point was a change in 24-hour net urine output (UOP) from before to after thiazide-type diuretic administration, and the study was designed to test for the noninferiority of metolazone. Safety end points included changes in renal function and electrolyte concentrations. The mean dose of IV loop diuretic therapy (in IV furosemide equivalents) at baseline (before thiazide-type diuretic administration) was higher in the chlorothiazide group (mean±SD 318.9±127.7 vs 268.4±97.6mg/day in the metolazone group, p=0.004), but net UOP was similar (mean±SD 877.0±1189.0ml in the chlorothiazide group vs 710.6±1145.9ml in the metolazone group, p=0.344). Mean doses of chlorothiazide and metolazone were 491±282mg and 5.8±3.5mg, respectively. Following thiazide-type diuretic administration, net UOP improved to a similar degree (2274.6±1443.0ml vs 2030.2±1725.0ml in the chlorothiazide and metolazone groups, respectively, p=0.308). For the primary efficacy end point, metolazone met the threshold for noninferiority by producing a net UOP of 1319.6±1517.4ml versus 1397.6±1370.7ml for chlorothiazide (p=0.026 for noninferiority). No significant differences in renal function were observed between the groups. Although hypokalemia was more frequent in the chlorothiazide group (75% with chlorothiazide vs 60.7% with metolazone, p=0.045), no significant differences in the rates of severe hypokalemia or other electrolyte abnormalities were observed between the groups. Oral metolazone was noninferior to IV chlorothiazide for enhancing net UOP in patients with ADHF and loop diuretic resistance and was similarly safe with regard to renal function and electrolyte abnormalities. Given the significant cost disparity between the two agents, these findings suggest that oral metolazone may be considered a first-line option in this patient population.

Acetazolamide and thiazide diuretics have been combined with loop diuretics to overcome diuretic resistance in heart failure patients. However, recent studies have assessed the upfront combination of acetazolamide and hydrochlorothiazide with loop diuretics in hospitalized patients with acute decompensated heart failure without loop diuretic resistance. We reviewed two recent randomized controlled trials on the upfront use of acetazolamide and thiazide diuretics in acute decompensated heart failure, respectively. When the two trials on acetazolamide are considered together, adding oral or intravenous acetazolamide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and natriuresis. However, the effects were significantly higher in patients with serum bicarbonate ≥ 27 mmol/L and those with higher baseline glomerular filtration rate (GFR). Similarly, when the two trials on thiazide diuretics are considered together, adding hydrochlorothiazide to loop diuretics in decompensated heart failure patients resulted in increased diuresis and weight loss. However, it increases the risk of impaired renal function. When all the trials are considered together, the upfront use of acetazolamide may be helpful in carefully selected patients, including patients with underlying elevated bicarbonate levels (≥ 27 mmol/L) and those with good renal function (GFR > 50). Conversely, though the upfront use of thiazide diuretic added to intravenous furosemide improved diuretic response in acute decompensated heart failure, it causes an increased risk of worsening renal function and lack of clear evidence of reducing hospital length of stay.

Loop diuretics continue to be a crucial component of pharmacological treatment, to eliminate extra fluid and enhance symptom control in acute decompensated heart failure (ADHF). Understanding the loop diuretics' more efficient form of administration would be very beneficial in improving the management of people's ADHF, resulting in a quicker resolution of symptoms and a notable decrease inmorbidity. To assess the outcomes of intravenous continuous infusion with bolus injection of loop diuretics for patients with ADHF, this meta-analysis was carried out. The current meta-analysis was conducted as per the Cochrane Collaboration guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension (PRISMA) guidelines. A search was carried out on PubMed and EMBASE databases for studies comparing continuous infusion with intermittent bolus injection of furosemide in patients with congestive heart failure without restriction on the language of publication from 1January 2001 to 31July 2022. The primary outcome of the meta-analysis was all-cause mortality and loss of body weight (kg). Pre-defined secondary outcomes included length of hospital stay (LOS) in days, brain natriuretic peptide(BNP) reduction (pg/ml), number of patients with hypokalemia, and urine output at 24 hours (ml). A total of nine articles were included in this meta-analysis enrolling 713 patients. No significant difference was reported between patients who received intermittent bolus injections and continuous infusion of furosemide in regards to all-cause mortality, LOS, total urine output, the incidence of hypokalemia, and change in BNP. However, the reduction of body weight was greater in the continuous infusion group compared to bolus administration. In conclusion, in the current meta-analysis of nine randomized controlled trials (RCTs), continuous infusion of furosemide seemed to have a greater reduction of body weight. However, no significant difference was there in 24-hrs urine output. However, we cannot conclude that intravenous continuous infusion has a better diuretic effect compared to bolus administration.

For vaptans, as for life, balance is better.

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.

Real World Use of Hypertonic Saline in Refractory Acute Decompensated Heart Failure: A U.S. Center’s Experience

Background Congestion is a major determinant of end–organ dysfunction and diuretic resistance in acute decompensated heart failure (ADHF). Vasodilator therapy with nitroglycerin may help treat misdistribution of blood volume, reduce intra–abdominal pressure and improve end–organ function by recruiting capacitance veins. We assessed the role of intravenous nitroglycerin on top of maximal medical therapy to overcome diuretic resistance in ADHF patients. Methods This is a monocentric prospective study including patients with ADHF, systolic dysfunction (left ventricular ejection fraction [LVEF]&amp;lt;35%), persistent moderate–to–severe congestion and oliguria (&amp;lt;0.5 ml/Kg/h) despite high dose intravenous furosemide (&amp;gt;250 mg/die) plus a second diuretic (metolazone and/or acetazolamide). Exclusion criteria were systolic blood pressure &amp;lt; 90mmHg and eGFR &amp;lt; 20 ml/min/1.73m2. Intravenous nitroglycerin was added and uptitrated to the maximum tolerated dose while keeping the other treatments unchanged for at least 24 hours. The primary endpoint was change in urine output at 24 hours (T1) and 72 hours (T3) after nitroglycerin initiation compared to baseline (T0). Secondary endpoints were changes in central venous pressure (CVP), creatinine and total bilirubin. Results We enrolled 17 consecutive patients between March 2020 and October 2021. Mean age was 63±14 years, mean LVEF 31±15%, mean tricuspid annular plane systolic excursion 14.5±4 mm and mean eGFR 41.7±27.3 ml/min/1.73m2. 13 (76%) patients showed a cold profile; among them, 9 (69%) were on dobutamine, 5 (38%) on adrenaline and 3 (23%) on dopamine. At study enrolment all patients were receiving high dose intravenous furosemide (535±395mg/die), 8 (47%) sodium nitroprusside (0.3±0.5y/Kg/min), 9 (53%) metolazone (5mg/die) and 8 (47%) acetazolamide (250 mg/die). Urine output was significantly higher both at T1 and T3 compared to T0 (192±140ml/h vs 50±34ml/h, p &amp;lt; 0.001, and 153±87ml/h vs 50±34ml/h, p &amp;lt; 0.001, respectively; p for overall comparison&amp;lt;0.001). Also, a significant reduction of CVP was found at T1 and T3 compared to T0 (14±6mmHg vs 19±3mmHg, p = 0.025, and 12±5mmHg vs 19±3mmHg, p = 0.022, respectively; p for overall comparison=0.039). No significant changes of creatinine and total bilirubin were reported. Conclusions In this cohort of ADHF patients with diuretic resistance, adding nitroglycerin on top of maximal treatment yielded a potential benefit by significantly increasing hourly urine output whilst reducing CVP.

IntroductionDiuretic resistance is a common complication impairing decongestion during hospitalization for acute decompensated heart failure (ADHF). The current understanding of diuretic resistance mechanisms in ADHF is based upon extrapolations from other disease states and healthy volunteers. However, accumulating evidence suggests that the dominant mechanisms in other populations have limited influence on diuretic response in ADHF. Additionally, the ability to rapidly and reliably diagnose diuretic resistance is inadequate using currently available tools.AimsThe Mechanisms of Diuretic Resistance (MDR) Study is designed to rigorously investigate the mechanisms of diuretic resistance and develop tools to rapidly predict diuretic response in a prospective cohort hospitalized with ADHF.MethodsStudy assessments occur serially during the ADHF hospitalization and after discharge. Each assessment includes a supervised 6‐hour urine collection with baseline blood and timed spot urine collections following loop diuretic administration. Patient characteristics, medications, physical exam findings, and both in‐hospital and post‐discharge HF outcomes are collected. Patients with diuretic resistance are eligible for a randomized sub‐study comparing an increased loop diuretic dose with combination diuretic therapy of loop diuretic plus chlorothiazide.ConclusionsThe Mechanisms of Diuretic Resistance Study will establish a prospective patient cohort and biorepository to investigate the mechanisms of diuretic resistance and urine biomarkers to rapidly predict loop diuretic resistance.