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.

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.

Frequency and Severity of Chlorothiazide-Induced Hyponatremia in the Neonatal Intensive Care Unit.

OBJECTIVE: Although thiazide diuretics are commonly used in the neonatal intensive care unit (NICU), the risk of thiazide-induced hyponatremia in infants has not been well documented. The primary objective of this study was to determine the frequency and severity of hyponatremia in neonates and infants receiving enteral chlorothiazide. Secondary objectives included identifying: (1) percent change in serum sodium from before chlorothiazide initiation to nadir, (2) time to reach nadir serum sodium concentration, and (3) percentage of patients on chlorothiazide receiving sodium supplementation. STUDY DESIGN: This was a retrospective cohort study of NICU patients admitted between July 1, 2014, and July 31, 2019, who received ≥1 dose of enteral chlorothiazide. Mild, moderate, and severe hyponatremia were defined as serum sodium of 130 to 134 mEq/L, 120 to 129 mEq/L, and less than 120 mEq/L, respectively. Data including serum electrolytes, chlorothiazide dosing, and sodium supplementation were collected for the first 2 weeks of therapy. Descriptive and inferential statistics were performed in SAS software, Version 9.4. RESULTS: One hundred and seven patients, receiving 127 chlorothiazide courses, were included. The median gestational age at birth and postmenstrual age at initiation were 26.0 and 35.9 weeks, respectively. The overall frequency of hyponatremia was 35.4% (45/127 courses). Mild, moderate, and severe hyponatremia were reported in 27 (21.3%), 16 (12.6%), and 2 (1.6%) courses. The median percent decrease in serum sodium from baseline to nadir was 2.9%, and the median time to nadir sodium was 5 days. Enteral sodium supplements were administered in 52 (40.9%) courses. Sixteen courses (12.6%) were discontinued within the first 14 days of therapy due to hyponatremia. CONCLUSION: Hyponatremia occurred in over 35% of courses of enteral chlorothiazide in neonates and infants. Given the high frequency of hyponatremia, serum sodium should be monitored closely in infants receiving chlorothiazide. Providers should consider early initiation of sodium supplements if warranted. KEY POINTS: · One-third of infants on chlorothiazide develop hyponatremia.. · Nadir serum sodium typically occurs within 5 days.. · Monitor sodium closely after chlorothiazide initiation..

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.

Single-dose and steady-state pharmacokinetics of doxazosin given in combination with chlorothiazide to hypertensive subjects.

The pharmacokinetics of doxazosin were determined in hypertensive subjects after a single dose of 1 mg, and at steady-state while receiving doses of 1, 2, 4 and 8 mg of the drug daily. Chlorothiazide 500 mg once daily was administered as additional therapy throughout the study. After a single dose doxazosin was rapidly absorbed, with peak plasma drug concentrations (Cmax) occurring after 2.1 +/- 0.4 hours. The elimination half-life in plasma was 10.7 +/- 1.2 hours. These parameters remained essentially unchanged during maintenance administration of doxazosin at each of the dose levels. Calculations of Cmax and area under the concentration-time curve (AUC0----infinity) indicated that the pharmacokinetic disposition of the drug remained linear over the dose range 1 to 8 mg.

The evolution of antihypertensive therapy.

Beginning in the early 1950s, when a ganglioplegic agent and a vasodilator were used in combination to provide long-term control of severe hypertension, which neither drug alone could control, much has been learned about the management of hypertension from the use of new antihypertensive agents in man and from clinical trials of antihypertensive regimens. Some of this information includes: the unexpected yet very real hazards as well as benefits associated with the long-term use of powerful drugs, in particular the original description of hydralazine-induced lupus, its relation to genetic markers and its association with control of hypertension; the apparently decreasing need for antihypertensive drugs in subjects with well-controlled severe and moderate hypertension; the identification of risk factors for the complications of hypertension and the quantitation of their effects; the decrease in the incidence of hypertensive complications associated with the pharmacologic treatment of severe, moderate and, at least, the upper ranges of mild hypertension; the possibility of designing a chemical to block a specific reaction and the realization that it would have broader than expected effects; and the primary prevention of myocardial infarction in very high risk subjects.

Potassium loss associated with hydrochlorothiazide versus chlorthalidone.

A retrospective survey using chart review was conducted to determine the incidence of clinically significant hypokalemia resulting from therapy with chlorthalidone (CTLD) or hydrochlorothiazide (HCTZ). The frequency of hypokalemia, potassium less than or equal to 3.0 mEq/liter, was 4/29 patients (13.8%) in the CTLD once-daily group, 0/17 in the HCDL twice-daily group, and 0/31 in the HCTZ once-daily group. Using the Fisher exact probability test, a significant difference in the incidence of hypokalemia was observed between the CTLD once-daily and HCTZ once-daily groups. From the results, it is apparent that a diuretic's duration of actions, as represented by HCTZ (short-acting) and CTLD (long-acting), influences serum potassium concentrations; CTLD produced a greater incidence and degree of hypokalemia.

Comparison of enalapril and hydrochlorothiazide in mild hypertension and changes in plasma lipid concentrations during therapy.

An open, randomized, parallel clinical study comparing the antihypertensive efficacy and tolerability of the angiotensin converting enzyme inhibitor enalapril and the diuretic hydrochlorothiazide was carried out in 40 patients with mild uncomplicated essential hypertension. Changes in plasma lipid profiles were also studied. The results show that the two treatments were equally efficacious in controlling blood pressure and were generally well tolerated. Favorable changes in the plasma lipid profile were observed during the 12-week treatment period with enalapril. However, adverse alterations in the plasma lipid profile were observed during treatment with hydrochlorothiazide. These included a significant increase in the total cholesterol/high density lipoprotein cholesterol ratio and the low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio. Further studies are needed to confirm these plasma lipid findings and to determine their clinical significance.

Phototoxic reactions to photoactive drugs in patients treated with PUVA.

To determine the potentially adverse effects of photoactive medications taken in conjunction with oral methoxsalen photochemotherapy (PUVA) for psoriasis, we studied the incidence of phototoxic reactions in 1,125 patients treated with PUVA at 15 centers. During the initial (clearing) phase of PUVA therapy, patients using photoactive medications were no more likely to have diffuse delayed erythema than patients who did not use such medications. After clearing, patients 45 years of age or older who used photoactive drugs were 2.3 times as likely to discontinue PUVA therapy for at least one month owing to problems related to UV-induced burns than were those who did not use such drugs. Only 6% of patients older than 45 years who took photoactive medications had problems with phototoxicity sufficiently severe to contribute to permanent discontinuation of PUVA therapy.

Drug-induced pulmonary edema and acute respiratory distress syndrome.

Noncardiogenic pulmonary edema, and, to a lesser extent, acute respiratory distress syndrome (ARDS), are common clinical manifestations of drug-induced lung diseases. Clinical features and radiographic appearances are generally indistinguishable from other causes of pulmonary edema and ARDS. Typical manifestations include dyspnea, chest discomfort, tachypnea, and hypoxemia. Chest radiographs commonly reveal interstitial and alveolar filling infiltrates. Unlike pulmonary edema that is due to congestive heart failure, cardiomegaly and pulmonary vascular redistribution are generally absent in cases that are drug-related. Rare cases of drug-induced myocarditis with heart failure and pulmonary edema have been described. Results from laboratory evaluation and respiratory function tests are nonspecific.

Prolonged therapy by the combination of furosemide and thiazides in refractory heart failure and other fluid retaining conditions.

The efficacy and side effects of the combination therapy of thiazide and furosemide administered to patients with refractory heart failure, for a prolonged period of time, were assessed. Thirty-two patients were hospitalized during the years 1985-1991. Left heart failure (left ventricular ejection fraction (LVEF = 22.4% +/- 6.6%) was present in 26 patients, right heart failure in 3 patients, chronic renal failure, cirrhosis and bilateral pleural effusion were present each in one patient. Chlorothiazide 0.5 g daily was added to conventional therapy. Patients were monitored closely during hospitalization and later as outpatients. During hospitalization, addition of chlorothiazide caused a reduction of 4.8 +/- 4.0 kg in patients' weight, serum potassium decreased from 4.4 +/- 0.6 to 4.0 +/- 0.5 mmol/l (P < 0.005) and serum sodium from 139.0 +/- 4.7 to 136.8 +/- 5.5 mmol/l (P < 0.05). The duration of the combined therapy was 17.2 +/- 19.1 months. Thirteen patients had short treatment (1.6 +/- 0.8 months) and 19 patients had prolonged treatment (26.5 +/- 19.0 months). No specific characteristics distinguished patients in both groups. Thiazides were discontinued in 19 patients, 10 of which had side effects. In only 5 of the 19 patients treated for the prolonged period had thiazides to be discontinued because of side effects. Addition of thiazides to furosemide is efficacious in severe heart failure. The combination should be started during hospitalization. Many patients can be maintained on this combination for a prolonged period of time on an ambulatory basis.

Comparison of the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide in patients receiving intravenous furosemide therapy for the treatment of heart failure.

STUDY OBJECTIVE: To compare the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide added to background intravenous loop diuretic therapy among patients hospitalized with heart failure. DESIGN: Single-center, retrospective review. SETTING: Cardiovascular hospital within a university-affiliated teaching institution. PATIENTS: Eighty-two patients hospitalized for heart failure between September 1, 2009, and August 31, 2011, who were receiving background intravenous furosemide therapy (total daily dose ≥ 160 mg); of those patients, 28 patients also received oral hydrochlorothiazide (median dose 25 mg [interquartile range 25-50 mg]), and 54 patients also received intravenous chlorothiazide (median dose 500 mg [interquartile range 250-750 mg]). MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in 24-hour urine output. Urine output was recorded from the 24 hours before and after the first administration of either oral hydrochlorothiazide or intravenous chlorothiazide. Baseline characteristics, with the exception of female sex (p=0.01) and home loop diuretic dose (p=0.03), were similar between groups. Twenty-four-hour urine output before administration of the thiazide diuretic was not significantly different between groups. After treatment, 24-hour urine output increased in both groups; however, urine output increased to a lesser extent with oral hydrochlorothiazide (from mean ± SD 2104 ± 830 ml to 3038 ± 917 ml) than with intravenous chlorothiazide (from 2342 ± 978 ml to 4128 ± 1755 ml) (p=0.005). Hypokalemia occurred frequently in both groups: 71.4% and 83.3% in the oral hydrochlorothiazide and intravenous chlorothiazide groups, respectively (p=0.21). CONCLUSION: Among hospitalized patients with heart failure receiving intravenous loop diuretics, the addition of either oral hydrochlorothiazide or intravenous chlorothiazide augmented diuresis. Urine output increased to a greater extent with intravenous chlorothiazide compared with oral hydrochlorothiazide. However, given the positive response observed, ease of administration, and lower drug cost, oral hydrochlorothiazide should still be considered as an option for combination diuretic therapy in this patient population.