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The New England Journal of Medicine Mar 2023Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited.
METHODS
In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed.
RESULTS
In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo.
CONCLUSIONS
Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).
Topics: Humans; Hydrochlorothiazide; Kidney; Kidney Calculi; Sodium Chloride Symporter Inhibitors; Recurrence; Double-Blind Method; Dose-Response Relationship, Drug; Diuretics
PubMed: 36856614
DOI: 10.1056/NEJMoa2209275 -
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 -
JAMA Internal Medicine Apr 2020Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits. (Comparative Study)
Comparative Study Observational Study
IMPORTANCE
Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits.
OBJECTIVE
To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice.
DESIGN, SETTING, AND PARTICIPANTS
This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018.
EXPOSURES
Chlorthalidone and hydrochlorothiazide.
MAIN OUTCOMES AND MEASURES
The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.
RESULTS
Of 730 225 individuals (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).
CONCLUSIONS AND RELEVANCE
This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.
Topics: Antihypertensive Agents; Chlorthalidone; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Retrospective Studies
PubMed: 32065600
DOI: 10.1001/jamainternmed.2019.7454 -
AMA Journal of Ethics Sep 2017
Topics: Diuretics; Drug Prescriptions; Humans; Hydrochlorothiazide; Hypertension; Medicine in the Arts; Prisons; Restraint, Physical; Urination
PubMed: 28905736
DOI: 10.1001/journalofethics.2017.19.9.imhl1-1709 -
Actas Dermo-sifiliograficas May 2022Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been... (Review)
Review
Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been linked to photosensitivity with heterogeneous clinical manifestations and recovery times. Diagnosis can be aided by phototesting, photopatch testing, and skin biopsy. Long-term use of hydrochlorothiazide has been linked to an increased dose-dependent risk of certain types of skin cancer in recent years. In this review, we also look at other less common or lesser-known adverse effects of thiazide diuretics that have been described in isolated reports.
Topics: Antihypertensive Agents; Dermatologists; Humans; Hydrochlorothiazide; Hypertension; Sodium Chloride Symporter Inhibitors; Thiazides
PubMed: 35697409
DOI: 10.1016/j.ad.2021.12.015 -
British Medical Journal Apr 1958
Topics: Chlorothiazide; Diuretics; Humans
PubMed: 13536400
DOI: No ID Found -
Canadian Family Physician Medecin de... Feb 2020
Review
Topics: Carcinoma, Squamous Cell; Diuretics; Humans; Hydrochlorothiazide; Hypertension
PubMed: 32060193
DOI: No ID Found -
American Journal of Health-system... Dec 2015The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported.
PURPOSE
The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported.
METHODS
Chlorothiazide and furosemide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) system with an electrospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC-MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection.
RESULTS
LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours.
CONCLUSION
Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light.
Topics: Chlorothiazide; Chromatography, Liquid; Diuretics; Drug Stability; Drug Storage; Furosemide; Humans; Pharmaceutical Solutions; Syringes; Tandem Mass Spectrometry
PubMed: 26637518
DOI: 10.2146/ajhp150023 -
Current Opinion in Cardiology Jul 2015To determine usefulness and versatility of hydrochlorothiazide (HCTZ) relative to other thiazide diuretics in the treatment of hypertension. (Review)
Review
PURPOSE OF REVIEW
To determine usefulness and versatility of hydrochlorothiazide (HCTZ) relative to other thiazide diuretics in the treatment of hypertension.
RECENT FINDINGS
HCTZ was found to be less potent in lowering blood pressure (BP) than other thiazide diuretics, including chlorthalidone (CTD) and bendroflumethiazide. A recent meta-analysis also suggested HCTZ (12.5-25 mg daily) to be less potent than antihypertensive agents from several other classes, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and calcium antagonists. The risk of hyponatremia, hypokalemia, and hyperuricemia associated with HCTZ was lower than with CTD, while the risk of gouty arthritis was similar. Despite lower risks of metabolic side-effects, meta-analysis of clinical trials showed that, for any given difference in achieved clinic SBP, HCTZ therapy was associated with 18% higher adverse cardiovascular events when compared with CTD.
SUMMARY
Increasing evidence suggests inferiority of HCTZ in lowering BP and cardiovascular outcomes in hypertensive patients when compared with other drugs in the same class, particularly CTD and indapamide. Thus, HCTZ is neither more useful nor more versatile than other thiazide diuretics. CTD and indapamide should be preferred over HCTZ in most hypertensive patients when diuretics are required for treatment of hypertension.
Topics: Blood Pressure; Diuretics; Humans; Hydrochlorothiazide; Hypertension
PubMed: 26049382
DOI: 10.1097/HCO.0000000000000178 -
Journal of Clinical Hypertension... 2001
Topics: Antihypertensive Agents; Benzimidazoles; Benzoates; Diuretics; Drug Combinations; Humans; Hydrochlorothiazide; Hypertension; Telmisartan
PubMed: 11498659
DOI: 10.1111/j.1524-6175.2001.00471.x