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Pharmacotherapy Sep 2020Treatment 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... (Meta-Analysis)
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 24 hours 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.
Topics: Chlorothiazide; Diuretics; Heart Failure; Humans; Metolazone
PubMed: 32639593
DOI: 10.1002/phar.2440 -
Pharmacotherapy Aug 2016To assess the efficacy and safety of intravenous (IV) chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart... (Comparative Study)
Comparative Study
STUDY OBJECTIVE
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.
DESIGN
Retrospective cohort study.
SETTING
Large urban academic medical center.
PATIENTS
Adults admitted with ADHF between 2005 and 2015 who had loop diuretic resistance, defined as administration of IV furosemide at a dose of 160 mg/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.
MEASUREMENTS AND MAIN RESULTS
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 ± 97.6 mg/day in the metolazone group, p=0.004), but net UOP was similar (mean ± SD 877.0 ± 1189.0 ml in the chlorothiazide group vs 710.6 ± 1145.9 ml in the metolazone group, p=0.344). Mean doses of chlorothiazide and metolazone were 491 ± 282 mg and 5.8 ± 3.5 mg, respectively. Following thiazide-type diuretic administration, net UOP improved to a similar degree (2274.6 ± 1443.0 ml vs 2030.2 ± 1725.0 ml 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 ± 1517.4 ml versus 1397.6 ± 1370.7 ml 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.
CONCLUSION
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.
Topics: Acute Disease; Administration, Intravenous; Administration, Oral; Adult; Aged; Chlorothiazide; Cohort Studies; Diuretics; Drug Resistance; Female; Heart Failure; Humans; Male; Metolazone; Middle Aged; Retrospective Studies
PubMed: 27393709
DOI: 10.1002/phar.1798 -
Luminescence : the Journal of... Sep 2019Synchronous spectrofluorimetry is utilized to carry out a rapid, sensitive and reliable method for determination of the binary mixture of metolazone (MTL) and losartan...
Synchronous spectrofluorimetry is utilized to carry out a rapid, sensitive and reliable method for determination of the binary mixture of metolazone (MTL) and losartan potassium (LSP). Under optimized experimental conditions, the synchronized fluorescence spectra of the two drugs were measured at Δλ = 80 nm in acidic methanolic solution and intensities were recorded at 260 nm for MTL and 335 nm for LSP. Linear correlation between fluorescence intensity and concentration were obtained through the ranges 0.02-0.2 μg/mL and 0.2-2.0 μg/mL for MTL and LSP, respectively. Limits of detection were 3.02 and 0.12 ng/mL, whereas limits of quantification were 9.16 and 0.35 ng/mL for MTL and LSP, respectively. The designated procedure was easily and successfully adopted to determine the two compounds in their single, as well as in co-formulated, tablets and the results showed high precision and accuracy without any significant interference from common tablet excipients. A comparison of the obtained results with a published reference method was carried out and both showed good agreement with respect to accuracy and precision.
Topics: Antihypertensive Agents; Fluorescence; Losartan; Metolazone; Spectrometry, Fluorescence; Tablets
PubMed: 31111664
DOI: 10.1002/bio.3646 -
Clinical Pharmacology and Therapeutics Aug 1974
Topics: Administration, Oral; Antihypertensive Agents; Carbon Radioisotopes; Chromatography; Creatinine; Female; Heart Failure; Humans; Injections, Intravenous; Kidney Failure, Chronic; Kinetics; Male; Quinazolines; Time Factors
PubMed: 4853601
DOI: 10.1002/cpt1974162322 -
The Journal of Laboratory and Clinical... Feb 1983Studies with clearance and micropuncture techniques indicate that metolazone inhibits transport of sodium and phosphate in the proximal tubule. The present study is...
Studies with clearance and micropuncture techniques indicate that metolazone inhibits transport of sodium and phosphate in the proximal tubule. The present study is focused on transport across the luminal BBM of the proximal tubule to determine whether metolazone has any direct effect on this initial step in transtubular reabsorption. Addition of metolazone (0.01 to 1.00 mM) to isolated renal BBM vesicles caused dose-dependent inhibition (30% to 70%) of the initial uphill phase of Na+ gradient-dependent phosphate transport but did not inhibit the uptake at equilibrium. There were no significant changes in Na+-independent phosphate transport and phosphate transport under nongradient conditions when metolazone was present at 1.0 mM. The initial Na+ gradient-dependent BBM transport of both D-glucose and L-proline was markedly inhibited by 1.0 mM metolazone, indicating the nonspecific inhibitory action of the drug. Metolazone also inhibited efflux of D-glucose and L-proline from vesicles. Neither acetazolamide nor chlorothiazide at 0.1 to 1.0 mM inhibited BBM transport of phosphate, D-glucose, or L-proline. Metolazone did not change significantly BBM transport of Na+, suggesting that inhibition of Na+-dependent transport was not due to major changes in Na+ flux. These in vitro data indicate that metolazone inhibition of phosphate reabsorption in vivo may be due, in part, to a direct effect of metolazone on transport across the BBM of the proximal tubule.
Topics: Acetazolamide; Animals; Biological Transport; Chlorothiazide; Diuretics; In Vitro Techniques; Kidney Tubules, Proximal; Male; Metolazone; Microvilli; Phosphates; Rats; Rats, Inbred Strains; Sodium
PubMed: 6822765
DOI: No ID Found -
Clinical Therapeutics 1986Two multicenter, double-blind, randomized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new, shorter-acting... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Two multicenter, double-blind, randomized studies were performed to determine the antihypertensive efficacy and effects on laboratory values of a new, shorter-acting formulation of metolazone in patients with mild to moderate hypertension. After baseline placebo-control periods, 105 patients were randomly assigned to receive single daily doses of either placebo or 0.5, 1.0, or 2.0 mg of the new formulation of metolazone for six weeks in one study, and 164 patients were randomized to receive 0.5, 1.0, or 2.0 mg of the new formulation of metolazone or 2.5 mg of the older, long-acting metolazone in the other. Mean blood pressure reductions in all three metolazone groups were statistically and clinically significant. Blood pressures of 51% to 58% of patients in the 0.5-mg metolazone group were controlled (diastolic blood pressure less than 90 or a fall of greater than or equal to 10 mmHg from baseline). Reductions in mean serum potassium levels were dose-related. We conclude that 0.5 mg of metolazone is safe and effective therapy for hypertension; it will significantly reduce systolic and diastolic blood pressure and minimizes changes in laboratory test values.
Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Diuretics; Double-Blind Method; Female; Humans; Hypertension; Male; Metolazone; Middle Aged; Potassium
PubMed: 3545477
DOI: No ID Found -
Southern Medical Journal Apr 1978In two patients with severe hypertension and moderately severe renal insufficiency, metolazone and furosemide were used in combination with propranolol, methyldopa, and...
In two patients with severe hypertension and moderately severe renal insufficiency, metolazone and furosemide were used in combination with propranolol, methyldopa, and hydralazine to augment control of blood pressure. This combination of diuretics also was used in five patients with refractory congestive heart failure. The patients developed severe electrolyte disturbances with a general pattern of hyponatremia. disproportionate hypochloremia, alkalosis, and phyokalemia. These abnormalities were transient in the patients with severe hypertension and moderately severe renal insufficiency. Effective long-term control of blood pressure was obtained. In the patients with heart failure, edema persisted. Due to the severity of the electrolyte derangements, metolazone and furosemide were discontinued. Because of potential untoward effects, this combination of diuretics should be used with caution.
Topics: Adult; Aged; Diuretics; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Humans; Hypertension; Male; Metolazone; Middle Aged; Water-Electrolyte Imbalance
PubMed: 635611
DOI: 10.1097/00007611-197804000-00011 -
Japanese Journal of Pharmacology Feb 1979Metolazone, the sulfonamide diuretic was investigated to determine the sites of action. We used a radioactive microsphere, clearance and stop-flow method in anesthetized...
Metolazone, the sulfonamide diuretic was investigated to determine the sites of action. We used a radioactive microsphere, clearance and stop-flow method in anesthetized dogs. Urine flow and urinary excretion of sodium and potassium were increased at 5--60 min when metolazone was given intravenously at doses of 0.2--5.0 mg/kg, while total renal blood flow, distribution of cortical renal blood flow and GFR did not change. The urinary excretion rate of sodium to potassium (Na/K) increased from 5.69 +/- 0.82 to 8.07 +/- 0.76 in a dose of 1.0 mg/kg, i.v. Osmolar clearance and free water reabsorption increased almost proportionally, indicating that metolazone has little effect on the medullary portion of the ascending limb of Henle and may have a proximal site of action. In stop-flow experiments, a significantly raised U/PNa/U/Pcreatinine was observed at the dip situated distally to the ascending limb of Henle. These findings indicate that the diuretic action of metolazone may be due to the inhibition of sodium reabsorption in the distal nephron segments, in addition to the absence of modification of the cortical regional blood flow.
Topics: Animals; Binding Sites; Blood Flow Velocity; Diuretics; Dogs; Female; Glomerular Filtration Rate; Hemodynamics; Injections, Intravenous; Kidney; Male; Metolazone; Potassium; Sodium; Urodynamics
PubMed: 459149
DOI: 10.1254/jjp.29.113 -
Schweizerische Medizinische... Nov 1980The natriuretic and diuretic effects of combined treatment with furosemide and metolazone have been studied quantitatively. 15 hospitalized patients with severe fluid...
The natriuretic and diuretic effects of combined treatment with furosemide and metolazone have been studied quantitatively. 15 hospitalized patients with severe fluid retention who showed no reduction of body weight despite treatment with furosemide received metolazone in addition for 3 days. 11 patients had biventricular heart failure with edema, and 4 had cirrhosis of the liver with ascites. Following the addition of metolazone at a starting dose of 2.5 mg/d, a highly significant increase in diuresis and natriuresis, with a corresponding reduction in body weight, was seen in all patients pretreated with a daily dose of 40-370 mg furosemide (mean 122 mg/d). On the first day of this combined treatment the mean sodium excretion increased from 131 to 303 mval/d (2 p less than 0.01) and the mean urine volume increased from 1677 to 2940 ml/d (2 p less than 0.01). The mean reduction in body weight was 6.1 kg (2 p less than 0.001) within 7 days of continuous treatment. Even at low doses metolazone significantly potentiates the diuretic effects of furosemide and therefore simplifies the treatment of fluid retention. High doses of furosemide can be avoided in many cases, a factor of particular advantage in ambulatory long term therapy and in patients with decreased kidney function. It may also lower the cost of the therapy. In 3 patients the furosemide dose had to be lowered after metolazone was started, to avoid an excessive negative fluid balance. These cases clearly demonstrate the importance of daily checks on the patient's body weight after starting combined therapy with furosemide and metolazone.
Topics: Ascites; Body Weight; Diuresis; Diuretics; Drug Combinations; Edema, Cardiac; Female; Furosemide; Heart Arrest; Humans; Male; Metolazone; Middle Aged; Natriuresis
PubMed: 7280609
DOI: No ID Found -
Journal of Cardiovascular Pharmacology... Jul 2013Limited data exist comparing the efficacy and safety of bumetanide- or metolazone-based diuretic regimens to furosemide in acute heart failure (HF). Our purpose was to... (Comparative Study)
Comparative Study
INTRODUCTION
Limited data exist comparing the efficacy and safety of bumetanide- or metolazone-based diuretic regimens to furosemide in acute heart failure (HF). Our purpose was to evaluate the comparative effect on urine output (UO) and renal function between these regimens.
METHODS
A retrospective study of hospitalized HF patients treated with continuous infusion furosemide (CIF), combination furosemide plus metolazone (F + M), or continuous infusion bumetanide (CIB). Primary end points were between regimen comparisons for change in mean hourly UO versus baseline and incidence of worsening renal function.
RESULTS
Data on 242 patients with acute HF (age 58 ± 12 years, 63% male, left ventricular ejection fraction 38% ± 17%) were analyzed (160 CIF, 42 F + M, 40 CIB). The mean duration of diuretic regimens was 41 ± 32 hours. Compared to baseline, all regimens increased mean hourly UO (P < .0001 for all), with greater increases with F + M (109 ± 171 mL) and CIB (90 ± 90 mL) compared to CIF (48 ± 103 mL; P = .009). Incidence of worsening renal function was not different between regimens; however, blood urea nitrogen (BUN) tended to increase more with F + M (4.4 ± 9.8 mg/dL) and CIB (4.3 ± 9.7 mg/dL) than CIF (1.8 ± 10.8 mg/dL), P = .09. The incidence of hyponatremia was higher with F + M and CIB. Differences in UO, BUN, and hyponatremia were retained in the subgroup analysis limited to patients with baseline serum creatinine <1.5 mg/dL, where renal function between the groups was not different.
CONCLUSION
Compared to CIF, F + M or CIB was associated with greater increases in UO. No difference in the incidence of worsening renal function was found; however, electrolyte abnormalities may be more prevalent when furosemide is combined with metolazone or when bumetanide is used. These therapeutic differences warrant prospective study.
Topics: Acute Disease; Adult; Aged; Blood Urea Nitrogen; Bumetanide; Cohort Studies; Diuretics; Drug Therapy, Combination; Female; Furosemide; Heart Failure; Humans; Hyponatremia; Incidence; Male; Metolazone; Middle Aged; Regression Analysis; Retrospective Studies; Treatment Outcome; Urine
PubMed: 23538300
DOI: 10.1177/1074248413482755