Metolazone Versus Chlorothiazide in Acute Heart Failure Patients With Diuretic Resistance and Renal Dysfunction: A Retrospective Cohort Study.

ABSTRACT: Guidelines recommend intravenous loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be used for augmentation, but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction (eGFR <45 mL/min/1.73 m²). We conducted a multicenter, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to intravenous loop diuretics. The primary end point was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety end points included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 221 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. The mean 24-hour UOP increased more among chlorothiazide-treated (from 1668 mL to 3826 mL) versus metolazone-treated patients (from 1672 mL to 2834 mL) ( P < 0.001) after the addition of the second diuretic. Statistically significant reductions in serum creatinine were observed in the chlorothiazide group following 72 hours of treatment ( P = 0.016). More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or changes in weight were observed. Overall, chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.

Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

Metolazone Versus Intravenous Chlorothiazide for Decompensated Heart Failure Sequential Nephron Blockade: A Retrospective Cohort Study.

BACKGROUND: Metolazone and intravenous (IV) chlorothiazide are commonly used diuretics for sequential nephron blockade (SNB) in patients with acute decompensated heart failure (ADHF). Previous studies suggest metolazone may be comparable with chlorothiazide in terms of efficacy and safety. The objective of this study was to determine whether IV chlorothiazide is superior to metolazone in increasing net urine output (UOP) of hospitalized patients with ADHF. METHODS AND RESULTS: This retrospective cohort study included hospitalized patients with ADHF and evidence of loop diuretic resistance in a tertiary academic medical center. The primary end point was the change in net 24-hour UOP in patients treated with IV chlorothiazide compared with metolazone. The relative cost of chlorothiazide doses and metolazone doses administered during SNB was a notable secondary end point. The median change in net 24-hour UOP in the IV chlorothiazide group was -1481.9 mL (interquartile range -2696.0 to -641.0 mL) and -1780.0 mL (interquartile range -3084.5 to -853.5 mL) in the metolazone group (P = .05) across 220 hospital encounters. The median cost of chlorothiazide and metolazone doses used during SNB was $360 and $4, respectively (P < .01). CONCLUSIONS: Chlorothiazide was not superior to metolazone in changing the net 24-hour UOP of patients with ADHF and loop resistance. Preferential metolazone use in SNB is a potential cost-saving measure.

BRASH syndrome.

A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart failure presented to emergency room with weakness. She was hypotensive and had symptomatic bradycardia in the 30 s secondary to hyperkalaemia and beta-blockers, raising concern for BRASH syndrome. Antihypertensives were immediately held. Potassium-lowering agents (with calcium gluconate for cardiac stability) were begun, as were fluids and dopamine for vasopressor support. The patient was admitted to intensive care unit and electrophysiology was consulted. Over the next 2 days, the patient clinically improved: she remained off dopamine for over 24 hours; potassium levels and renal function improved; and heart rate stabilised in 60 s. The patient was eventually discharged and advised to avoid metolazone, bumetanide and carvedilol, with primary care provider and cardiology follow-up.

Comparing the sodium excreting efficacy of furosemide and indapamide combination against furosemide and metolazone combination in congestive heart failure patients: A randomized control trial.

OBJECTIVE: To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients. METHODS: The randomised controlled trial was conducted at Rehman Medical Institute, Peshawar, Pakistan, from January 1 to June 30, 2018, and comprised refractory heart failure patients who were randomised into two groups using lottery method Group 1 received intravenous furosemide 40mg Q12hr with metolazone 5mg Q24hr, while group 2 received intravenous furosemide 40mg Q12hr with indapamide 2.5mg Q24hr. Both groups were assessed for urinary sodium excretion, total urine output and decrease in weight on day one, day three and day five of admission. SPSS 22 was used for data analysis. RESULTS: Of the 150 patients, there were 75(50%) in each of the two groups. Mean age in group 1 was 64.8}11.2 years, while it was 66.3}12.9 years in group 2. Both groups showed increased urinary sodium excretion and total urine output (p>0.05). Hypokalaemia was the most common adverse event 66%. Mean hospital stay was not significantly different between the groups (p>0.05). CONCLUSIONS: There was no significant differences between adverse events and efficacy between patients receiving either indapamide-furosemide combination or metolazone-furosemide combination.

Intravenous Chlorothiazide Versus Enteral Metolazone to Augment Loop Diuretic Therapy in the Intensive Care Unit.

BACKGROUND: In cases of loop diuretic resistance in the intensive care unit (ICU), recommendations for a specific second-line thiazide agent are lacking. OBJECTIVE: To compare the effects of intravenous chlorothiazide (CTZ) and enteral metolazone (MET) on urine output (UOP) when added to furosemide monotherapy therapy in critically ill adults. METHODS: This was a retrospective cohort study conducted in the medical, surgical, and cardiothoracic ICUs of a quaternary medical center. The primary outcome was change in UOP induced by the study interventions compared with furosemide alone. Secondary outcomes included onset of diuresis, eventual need for hemodialysis, and incidence of adverse events. RESULTS: A total of 122 patients (58 in CTZ, 64 in MET) were included. When added to furosemide monotherapy, CTZ induced a greater change in UOP at 24 hours compared with MET (2405 vs 1646 mL, respectively; P = 0.01). CTZ also caused a more rapid dieresis: 1463 mL total UOP in the first 6 hours compared with 796 mL in the MET group ( P < 0.01). There were no differences found regarding ICU length of stay, need for renal replacement therapy, or survival to discharge. The CTZ arm required more potassium supplementation to maintain normokalemia (median 100 vs 57 mEq in MET; P = 0.02) and carried a higher cost (mean $97 vs $8, P < 0.01). CONCLUSION: Both CTZ and MET induced significant increases in UOP. CTZ induced a greater and more rapid change and was associated with higher cost and greater need for potassium replacement. Randomized controlled trials are needed to establish whether a preferable thiazide diuretic exists in this setting.

Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance.

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.

Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance.

AIMS: 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. METHODS: 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 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities. RESULTS: Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (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 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker. CONCLUSION: 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.

Comparison of bumetanide- and metolazone-based diuretic regimens to furosemide in acute heart failure.

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.

[Renal effect of treatment for heart failure]. / Nyrepåvirkning ved behandling af hjertesvigt.

The case of a 66-year-old male with heart failure and cardiorenal syndrome is presented. The patient had normal renal function before intensive treatment with diuretics and ACE inhibitor. Shortly after the ACE inhibitor was stopped and diuretics were either stopped or reduced in dosage, his renal function normalized. Suggestions are presented for follow-up after initiation of ACE inhibitor treatment.

[Pheochromocytoma of the left retroperitoneal paraganglion associated with torsade de pointes: a case report].

A 54-year-old woman developed torsade de pointes with secondary QT prolongation due to hypokalemia and hypomagnesemia. Her serum K and Mg levels were 2.5 mEq/l and 1.5 mg/dl, respectively. This electrolyte imbalance was due to intentional overdosing of metolazone. Attacks of torsade de pointes occurred three times in the intensive care unit and were corrected by intravenous lidocaine administration. Her serum K level was corrected using KCl infusion, restoring the normal QT interval. Routine computed tomography found a left retroperitoneal paraganglioma. Urinary and serum catecholamine examination revealed extremely high values of epinephrine and norepinephrine. The diagnosis was pheochromocytoma in the left retroperitoneal paraganglion. The tumor which was removed measured 70 x 65 x 60 mm in size. Microscopic examination revealed the characteristic patterns of pheochromocytoma.

Efficacy and safety of various combination therapies based on a calcium antagonist in essential hypertension: results of a placebo-controlled randomized trial.

We tested the efficacy and safety of different combination therapies in hypertensive patients with uncontrolled blood pressure (BP) on a monotherapy with a calcium antagonist: 1,647 hypertensive patients were enrolled to receive placebo for 4 weeks followed by isradipine (ISR) 2.5 mg twice daily (b.i.d.) for 4 weeks. Nonresponders [diastolic BP (DBP) > 90 mm Hg] were randomly assigned to receive either the beta-blocker bopindolol 0.5 or 1 mg/day, the diuretic metolazone 1.25 or 2.5 mg/day, the angiotensin-converting enzyme (ACE) inhibitor enalapril 10 or 20 mg/day, ISR 5 mg b.i.d., or placebo. One hundred seventy-five receiving placebo dropped out; 93% (n = 1,376) of the 1,472 patients finished 4-week monotherapy with ISR. Sixty percent (n = 826) reached target BP, and 40% (n = 550) remained uncontrolled and were randomized. Regardless of dosage, all drugs led to a comparable reduction in BP except for the lower dosage of bopindolol and ISR 5 mg b.i.d., which were less effective in lowering systolic BP (SBP). The BP decrease achieved by combination therapy ranged from 10 to 15 mm Hg SBP and from 7 to 11 mm Hg DBP but remained unchanged with placebo. Side effects were minor, and only 2.4% of patients discontinued therapy because of side effects. The side-effect score for edema was lower with ISR plus diuretics than with other combinations, whereas the ACE inhibitor was associated with a higher score for cough. Monotherapy with a calcium antagonist normalizes BP in about two-thirds of patients when used in general practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Case report: metolazone-associated hypercalcemia and acute pancreatitis.

Metolazone-induced acute pancreatitis and hypercalcemia are described in a 58-year-old woman with severe congestive cardiac failure. Her symptoms and laboratory abnormalities rapidly resolved upon discontinuation of metolazone. Both clinical and laboratory findings make other etiologies for the patient's pancreatitis extremely unlikely. The pathophysiology of thiazide-related hypercalcemia and pancreatitis is reviewed. To our knowledge, neither hypercalcemia nor the combination of acute pancreatitis with hypercalcemia has been reported previously in association with metolazone therapy, and the association of pancreatitis and metolazone has been noted previously only once.

Metolazone in treatment of severe refractory congestive cardiac failure.

17 patients with New York Heart Association (NYHA) class IV congestive cardiac failure, refractory to conventional treatment, were additionally treated with oral metolazone (1.25-10 mg daily). 12 improved sufficiently to be discharged from hospital (NYHA class II or III, mean weight loss 8.3 kg), 1 of whom died at home 4 weeks later. The other 5 patients were treated with intravenous dobutamine for 72 h; 2 responded (average weight loss 4.4 kg), and 2 responded to subsequent reintroduction of metolazone. 4 of these 5 patients died, 2 in hospital of acute myocardial infarction. Overall, 15 patients with very severe refractory cardiac failure improved sufficiently to be discharged from hospital. Treatment was associated with mild transient hypokalaemia in 7 patients, and hyponatraemia and renal impairment in 1, for whom metolazone dosage had to be reduced. Failure to respond to the introduction of metolazone may indicate an especially poor prognosis.