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European Heart Journal Aug 2023To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Humans; Metolazone; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Heart Failure; Diuretics; Sodium
PubMed: 37210742
DOI: 10.1093/eurheartj/ehad341 -
JACC. Heart Failure Mar 2020This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).
BACKGROUND
Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence.
METHODS
This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss.
RESULTS
The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001).
CONCLUSIONS
In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).
Topics: Administration, Oral; Aged; Chlorothiazide; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Male; Metolazone; Middle Aged; Prospective Studies; Retrospective Studies; Tolvaptan; Treatment Outcome
PubMed: 31838029
DOI: 10.1016/j.jchf.2019.09.012 -
BMJ Case Reports Feb 2020A 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...
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.
Topics: Antihypertensive Agents; Atrioventricular Block; Bradycardia; Bumetanide; Carvedilol; Female; Humans; Hyperkalemia; Metolazone; Middle Aged; Renal Insufficiency; Shock; Syndrome; Vasoconstrictor Agents
PubMed: 32094236
DOI: 10.1136/bcr-2019-233825 -
Cureus Sep 2023Heart failure (HF) is a notable public health issue, and intravenous loop diuretics are frequently employed to address acute decompensated heart failure (ADHF) and... (Review)
Review
Heart failure (HF) is a notable public health issue, and intravenous loop diuretics are frequently employed to address acute decompensated heart failure (ADHF) and alleviate symptoms of congestion. However, prolonged use of loop diuretics can lead to drug resistance, and some patients experience refractory volume overload that does not respond to treatment. Sequential nephron blockade, which involves combining loop and thiazide diuretics, has been proposed as a strategy to overcome diuretic resistance and improve fluid overload management. This systematic review aims to critically evaluate the effectiveness and safety of this combination diuretic therapy. Following the directives detailed in the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted. Eligibility criteria were established to select relevant studies, including the requirement for studies to be conducted on human subjects and published as free full-text papers in English within the last 10 years. Several databases were searched using a combination of Medical Subject Heading (MeSH) phrases and keywords related to heart failure, loop diuretics, and thiazide diuretics. The search yielded 948 references, and after screening titles, abstracts, and full-text papers, eight final studies (five observational studies and three randomized control trials) were included in the review. Based on the findings of this systematic review, there is substantial evidence to endorse the efficacy of combination diuretic therapy of loop and thiazide diuretics in augmenting diuresis and enhancing outcomes for patients who exhibit insufficient responses to single-agent diuretics. Additionally, the review provides valuable insights about the timing and type of diuretics to use, helping clinicians make informed therapeutic decisions. However, to ensure patient safety and well-being, it is imperative to take into account the potential for electrolyte disturbances and impacts on renal function, necessitating diligent and vigilant monitoring as well as effective management strategies. In light of these findings, further research is warranted to optimize the dosing regimens and to delve deeper into the long-term safety and efficacy of combination therapy. Such research endeavors will undoubtedly contribute to refining treatment approaches and advancing patient care in the field of HF management.
PubMed: 37720125
DOI: 10.7759/cureus.44624 -
Biochemical Pharmacology Nov 2014Human pregnane X receptor (hPXR) regulates the expression of drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and drug transporters such as multidrug-resistance...
Human pregnane X receptor (hPXR) regulates the expression of drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and drug transporters such as multidrug-resistance protein 1 (MDR1). PXR can be modulated by small molecules, including Federal Drug Administration (FDA)-approved drugs, thus altering drug metabolism and causing drug-drug interactions. To determine the role of FDA-approved drugs in PXR-mediated regulation of drug metabolism and clearance, we screened 1481 FDA-approved small-molecule drugs by using a luciferase reporter assay in HEK293T cells and identified the diuretic drug metolazone as an activator of hPXR. Our data showed that metolazone activated hPXR-mediated expression of CYP3A4 and MDR1 in human hepatocytes and intestine cells and increased CYP3A4 promoter activity in various cell lines. Mammalian two-hybrid assays showed that hPXR recruits its co-activator SRC-1 upon metolazone binding in HepG2 cells, explaining the mechanism of hPXR activation. To understand the role of other commonly-used diuretics in hPXR activation and the structure-activity relationship of metolazone, thiazide and non-thiazide diuretics drugs were also tested but only metolazone activates hPXR. To understand the molecular mechanism, docking studies and mutational analysis were carried out and showed that metolazone binds in the ligand-binding pocket and interacts with mostly hydrophobic amino acid residues. This is the first report showing that metolazone activates hPXR. Because activation of hPXR might cause drug-drug interactions, metolazone should be used with caution for drug treatment in patients undergoing combination therapy.
Topics: Cell Survival; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Diuretics; Dose-Response Relationship, Drug; HEK293 Cells; Hep G2 Cells; Humans; Metolazone; Multidrug Resistance-Associated Proteins; Pregnane X Receptor; Protein Binding; Receptors, Steroid; Thiazides
PubMed: 25181459
DOI: 10.1016/j.bcp.2014.08.025 -
Frontiers in Pharmacology 2022A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used... (Review)
Review
A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used PubMed, EMBASE, Cochrane Clinical Trials Register, and Web of Science systems to search studies of randomized controlled trials (RCT) for the treatment of AHF recommended by the guidelines and expert consensus until 1 December 2020. The primary outcome was all-cause mortality within 30 days. The secondary outcomes included 30-days all-cause rehospitalization, rates of HF-related rehospitalization, rates of adverse events, and rates of serious adverse events. A Bayesian NMA based on random effects model was performed. After screening 14,888 citations, 23 RCTs (17,097 patients) were included, focusing on nesiritide, placebo, serelaxin, rhANP, omecamtiv mecarbil, tezosentan, KW-3902, conivaptan, tolvaptan, TRV027, chlorothiazide, metolazone, ularitide, relaxin, and rolofylline. Omecamtiv mecarbil had significantly lower all-cause mortality rates than the placebo (odds ratio 0.04, 0.01-0.22), rhANP (odds ratio 0.03, 0-0.40), serelaxin (odds ratio 0.05, 0.01-0.38), tezosentan (odds ratio 0.04, 0-0.22), tolvaptan (odds ratio 0.04, 0.01-0.30), and TRV027 (odds ratio 0.03, 0-0.36). No drug was superior to the other drugs for the secondary outcomes and safety outcomes. No drug was superior to the other drugs for the secondary outcomes and safety outcomes. Current drugs for AHF show similar efficacy and safety.
PubMed: 36210851
DOI: 10.3389/fphar.2022.677589 -
Clinical Journal of the American... Sep 2017Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their...
BACKGROUND AND OBJECTIVES
Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their association with QT duration.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In total, 3252 Chronic Renal Insufficiency Cohort participants with at least one study electrocardiogram between 2003 and 2011 were included. QT-prolonging medications used in 100 or more visits (=16,451 visits) along with diuretics and proton pump inhibitors, given their potential for electrolyte disturbances, were examined for QT interval prolongation.
RESULTS
Mean QT interval corrected for heart rate was at 414±21 (±SD) milliseconds and prolonged (≥450 milliseconds) in 4.6% of electrocardiograms. QT interval corrected for heart rate was inversely related to serum potassium and calcium. Medications classified as QT prolonging were taken at 76% of visits, with two or more of these taken at 33% of visits. Of 30 medications examined, eight were associated with statistically significant QT interval corrected for heart rate prolongation after adjustment for comorbidities, potassium, and calcium, including amiodarone (+10±2 milliseconds), metolazone (+7±2 milliseconds), fluoxetine (+4±1 milliseconds), citalopram (+4±1 milliseconds), hydroxyzine (+4±1 milliseconds), escitalopram (+3±2 milliseconds), venlafaxine (+3±1 milliseconds), and furosemide (+3±0 milliseconds). Potassium-depleting diuretics were associated with minimal decrements in potassium (between 0.1 and 0.3 mEq/L) and smaller changes in calcium. Diuretics associated with a change in QT interval corrected for heart rate before adjustment for potassium and calcium were metolazone (+8±3 milliseconds), furosemide (+4±1 milliseconds), and spironolactone (-3±3 milliseconds). Most of the QT prolongation associated with metolazone and furosemide, but not spironolactone, remained after adjustment for potassium and calcium. Proton pump inhibitors were not associated with QT prolongation.
CONCLUSIONS
Use of medications associated with QT prolongation is common in CKD; the safety implications of these findings should be considered in these high-risk patients.
PODCAST
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_09_CJASNPodcast_17_09_b.mp3.
Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Antidepressive Agents, Second-Generation; Citalopram; Diabetes Complications; Diuretics; Electrocardiography; Female; Fluoxetine; Furosemide; Heart; Heart Rate; Histamine H1 Antagonists; Humans; Hydroxyzine; Male; Metolazone; Middle Aged; Proton Pump Inhibitors; Renal Insufficiency, Chronic; Venlafaxine Hydrochloride
PubMed: 28793999
DOI: 10.2215/CJN.12991216