Combining Loop and Thiazide Diuretics Across the Left Ventricular Ejection Fraction Spectrum: The CLOROTIC Trial.

BACKGROUND: The addition of hydrochlorothiazide (HCTZ) to furosemide in the CLOROTIC (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure) trial improved the diuretic response in patients with acute heart failure (AHF). OBJECTIVES: This work aimed to evaluate if these results differ across the spectrum of left ventricular ejection fraction (LVEF). METHODS: This post hoc analysis of the randomized, double-blind, placebo-controlled CLOROTIC trial enrolled 230 patients with AHF to receive either HCTZ or a placebo in addition to an intravenous furosemide regimen. The influence of LVEF on primary and secondary outcomes was evaluated. RESULTS: The median LVEF was 55%: 166 (72%) patients had LVEF >40%, and 64 (28%) had LVEF ≤40%. Patients with a lower LVEF were younger, more likely to be male, had a higher prevalence of ischemic heart disease, and had higher natriuretic peptide levels. The addition of HCTZ to furosemide was associated with the greatest weight loss at 72 of 96 hours, better metrics of diuretic response, and greater 24-hour diuresis compared with placebo, with no significant differences according to the LVEF category (using 2 LVEF cutoff points: 40% and 50%) or LVEF as a continuous variable (all P values were insignificant). There were no significant differences observed with the addition of HCTZ in terms of mortality, rehospitalizations, or safety endpoints (impaired renal function, hyponatremia, and hypokalemia) among the 2 LVEF groups (all P values were insignificant). CONCLUSIONS: Adding HCTZ to intravenous furosemide seems to be effective strategy for improving diuretic response in AHF without treatment effect modification according to baseline LVEF. (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure [CLOROTIC], NCT01647932; Randomized, double blinded, multicenter study, to asses Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop diuretics with placebo in Patients With Decompensated, EudraCT Number 2013-001852-36).

Combining loop with thiazide diuretics in patients discharged home after a heart failure decompensation: Association with 30-day outcomes.

OBJECTIVE: To investigate the association of the addition of thiazide diuretic on top of loop diuretic and standard of care with short-term outcomes of patients discharged after surviving an acute heart failure (AHF) episode. METHODS: This is a secondary analysis of 14,403 patients from three independent cohorts representing the main departments involved in AHF treatment for whom treatment at discharge was recorded and included loop diuretics. Patients were divided according to whether treatment included or not thiazide diuretics. Short-term outcomes consisted of 30-day all-cause mortality, hospitalization (with a separate analysis for hospitalization due to AHF or to other causes) and the combination of death and hospitalization. The association between thiazide diuretics on short-term outcomes was explored by Cox regression and expressed as hazard ratios (HR) with 95 % confidence intervals, which were adjusted for 18 patient-related variables and 9 additional drugs (aside from loop and thiazide diuretics) prescribed at discharge. RESULTS: The median age was 81 (interquartile range=73-86) years, 53 % were women, and patients were mainly discharged from the cardiology (42 %), internal medicine or geriatric department (29 %) and emergency department (19 %). There were 1,367 patients (9.5 %) discharged with thiazide and loop diuretics, while the rest (13,036; 90.5 %) were discharged with only loop diuretics on top of the remaining standard of care treatments. The combination of thiazide and loop diuretics showed a neutral effect on all outcomes: death (adjusted HR 1.149, 0.850-1.552), hospitalization (0.898, 0.770-1.048; hospitalization due to AHF 0.799, 0.599-1.065; hospitalization due to other causes 1.136, 0.756-1.708) and combined event (0.934, 0.811-1.076). CONCLUSION: The combination of thiazide and loop diuretics was not associated with changes in risk of death, hospitalization or a combination of both.

Thiazide-associated hyponatremia in arterial hypertension patients: A nationwide population-based cohort study.

OBJECTIVE: Thiazides are the first-line treatment for hypertension, however, they have been associated with hospitalizations for thiazide-associated hyponatremia (TAH). The aim of this study was to evaluate the risk of TAH and other drug-associated hyponatremia in a Korean population. METHODS: The study used big data from the National Health Insurance Sharing Service of 1,943,345 adults treated for hypertension from January 2014 to December 2016. The participants were divided into two groups based on the use of thiazides. Cox proportional hazard models were used to identify independent risk factors for the occurrence of hyponatremia. RESULTS: The study found that hyponatremia-related hospitalizations were significantly higher in the thiazide group than the control group (2.19% vs. 1.45%). The risk increased further with concurrent use of other diuretics or desmopressin, and thiazide+spironolactone+desmopressin and hospitalization risk further increased (4.0 and 6.9 times). Multivariate analysis showed that hyponatremia occurrence increased with age, diabetes mellitus, depression, and thiazide use (hazard ratio = 1.436, p < 0.001). The thiazide group had better 6-year overall survival than the control group but had more fractures and hyponatremia. CONCLUSIONS: Thiazide use is associated with an increased risk of hyponatremia and related complications. However, the mortality rate decreased in those who received thiazides, suggesting that thiazide use itself is not harmful and may help decrease complications and improve prognosis with proper, cautious use in high-risk patients.

Combinational Diuretics in Heart Failure.

PURPOSE OF REVIEW: Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on combinational therapy. RECENT FINDINGS: Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses of loop diuretics with an adequate safety profile. Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy over standard diuretics regimens are warranted.

Diferencias en función del sexo en las características clínicas y resultados del ensayo clínico CLOROTIC (combinación de diuréticos de asa con tiazidas en la insuficiencia cardiaca descompensada) / Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial

ObjetivoEvaluar si existen diferencias en los resultados del ensayo clínico CLOROTIC según el sexo. Métodos Subanálisis del ensayo CLOROTIC, que evaluó la eficacia y la seguridad de añadir hidroclorotiazida (HCTZ) o placebo a furosemida intravenosa en pacientes con insuficiencia cardiaca aguda (ICA). Los resultados primarios y secundarios incluyeron cambios en el peso y la disnea a las 72 y 96horas, medidas de la respuesta diurética y la mortalidad y reingresos a los 30 y 90días. Se evaluó la influencia del sexo en los resultados primarios y secundarios y de seguridad. Resultados De los 230 pacientes incluidos, 111 (48%) eran mujeres, que tenían más edad y valores más elevados de fracción de eyección ventricular izquierda. Los hombres tenían más cardiopatía isquémica, enfermedad pulmonar obstructiva crónica y mayor valor de péptidos natriuréticos. La adición de HCTZ a furosemida se asoció con una mayor pérdida de peso a las 72/96horas y mejor respuesta diurética a las 24horas en comparación con el placebo, sin diferencias significativas según el sexo (ningún valor de p para la interacción fue significativo). El deterioro de la función renal fue más frecuente en mujeres (OR: 8,68; IC95%: 3,41-24,63) que en varones (OR: 2,5; IC95%: 0,99-4,87), p=0,027. No hubo diferencias en la mortalidad ni en los reingresos a los 30/90días. Conclusión La adición de HCTZ a furosemida intravenosa es una estrategia eficaz para mejorar la respuesta diurética en la ICA sin diferencias según el sexo. Sin embargo, el deterioro de la función renal es más frecuente en las mujeres. (AU)

Aims The addition of hydrochlorothiazide (HCTZ) to furosemide improved the diuretic response in patients with acute heart failure (AHF) in the CLOROTIC trial. Our aim was to evaluate if there were differences in clinical characteristics and outcomes according to sex. Methods This is a post hoc analysis of the CLOROTIC trial, including 230 patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The primary and secondary outcomes included changes in weight and patient-reported dyspnoea 72 and 96h after randomization, metrics of diuretic response and mortality/rehospitalizations at 30 and 90days. The influence of sex on primary, secondary and safety outcomes was evaluated. Results One hundred and eleven (48%) women were included in the study. Women were older and had higher values of left ventricular ejection fraction. Men had more ischemic cardiomyopathy and chronic obstructive pulmonary disease and higher values of natriuretic peptides. The addition of HCTZ to furosemide was associated to a greatest weight loss at 72/96h, better metrics of diuretic response and higher 24-h diuresis compared to placebo without significant differences according to sex (all P-values for interaction were not significant). Worsening renal function occurred more frequently in women (OR: 8.68; 95%CI: 3.41-24.63) than men (OR: 2.5; 95%CI: 0.99-4.87), P=.027. There were no differences in mortality or rehospitalizations at 30/90days. Conclusion Adding HCTZ to intravenous furosemide is an effective strategy to improve diuretic response in AHF with no difference according to sex, but worsening renal function was more frequent in women. (AU)

Diferencias en función del sexo en las características clínicas y resultados del ensayo clínico CLOROTIC (combinación de diuréticos de asa con tiazidas en la insuficiencia cardiaca descompensada) / Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial

ObjetivoEvaluar si existen diferencias en los resultados del ensayo clínico CLOROTIC según el sexo. Métodos Subanálisis del ensayo CLOROTIC, que evaluó la eficacia y la seguridad de añadir hidroclorotiazida (HCTZ) o placebo a furosemida intravenosa en pacientes con insuficiencia cardiaca aguda (ICA). Los resultados primarios y secundarios incluyeron cambios en el peso y la disnea a las 72 y 96horas, medidas de la respuesta diurética y la mortalidad y reingresos a los 30 y 90días. Se evaluó la influencia del sexo en los resultados primarios y secundarios y de seguridad. Resultados De los 230 pacientes incluidos, 111 (48%) eran mujeres, que tenían más edad y valores más elevados de fracción de eyección ventricular izquierda. Los hombres tenían más cardiopatía isquémica, enfermedad pulmonar obstructiva crónica y mayor valor de péptidos natriuréticos. La adición de HCTZ a furosemida se asoció con una mayor pérdida de peso a las 72/96horas y mejor respuesta diurética a las 24horas en comparación con el placebo, sin diferencias significativas según el sexo (ningún valor de p para la interacción fue significativo). El deterioro de la función renal fue más frecuente en mujeres (OR: 8,68; IC95%: 3,41-24,63) que en varones (OR: 2,5; IC95%: 0,99-4,87), p=0,027. No hubo diferencias en la mortalidad ni en los reingresos a los 30/90días. Conclusión La adición de HCTZ a furosemida intravenosa es una estrategia eficaz para mejorar la respuesta diurética en la ICA sin diferencias según el sexo. Sin embargo, el deterioro de la función renal es más frecuente en las mujeres. (AU)

Aims The addition of hydrochlorothiazide (HCTZ) to furosemide improved the diuretic response in patients with acute heart failure (AHF) in the CLOROTIC trial. Our aim was to evaluate if there were differences in clinical characteristics and outcomes according to sex. Methods This is a post hoc analysis of the CLOROTIC trial, including 230 patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The primary and secondary outcomes included changes in weight and patient-reported dyspnoea 72 and 96h after randomization, metrics of diuretic response and mortality/rehospitalizations at 30 and 90days. The influence of sex on primary, secondary and safety outcomes was evaluated. Results One hundred and eleven (48%) women were included in the study. Women were older and had higher values of left ventricular ejection fraction. Men had more ischemic cardiomyopathy and chronic obstructive pulmonary disease and higher values of natriuretic peptides. The addition of HCTZ to furosemide was associated to a greatest weight loss at 72/96h, better metrics of diuretic response and higher 24-h diuresis compared to placebo without significant differences according to sex (all P-values for interaction were not significant). Worsening renal function occurred more frequently in women (OR: 8.68; 95%CI: 3.41-24.63) than men (OR: 2.5; 95%CI: 0.99-4.87), P=.027. There were no differences in mortality or rehospitalizations at 30/90days. Conclusion Adding HCTZ to intravenous furosemide is an effective strategy to improve diuretic response in AHF with no difference according to sex, but worsening renal function was more frequent in women. (AU)

Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial.

AIMS: The addition of hydrochlorothiazide (HCTZ) to furosemide improved the diuretic response in patients with acute heart failure (AHF) in the CLOROTIC trial. Our aim was to evaluate if there were differences in clinical characteristics and outcomes according to sex. METHODS: This is a post-hoc analysis of the CLOROTIC trial, including 230 patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The primary and secondary outcomes included changes in weight and patient-reported dyspnoea 72 and 96 h after randomization, metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. The influence of sex on primary, secondary and safety outcomes was evaluated. RESULTS: One hundred and eleven (48%) women were included in the study. Women were older and had higher values of left ventricular ejection fraction. Men had more ischemic cardiomyopathy and chronic obstructive pulmonary disease and higher values of natriuretic peptides. The addition of HCTZ to furosemide was associated to a greatest weight loss at 72/96 h, better metrics of diuretic response and higher 24-h diuresis compared to placebo without significant differences according to sex (all p-values for interaction were not significant). Worsening renal function occurred more frequently in women (OR [95%CI]: 8.68 [3.41-24.63]) than men (OR [95%CI]: 2.5 [0.99-4.87]), p = 0.027. There were no differences in mortality or rehospitalizations at 30/90 days. CONCLUSION: Adding HCTZ to intravenous furosemide is an effective strategy to improve diuretic response in AHF with no difference according to sex, but worsening renal function was more frequent in women. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT01647932; EudraCT Number: 2013-001852-36.

How to optimize the use of diuretics in patients with heart failure?

Considering the pathophysiology and clinical presentation of heart failure, using diuretics or drugs with diuretic properties is indispensable for adequate management of heart failure patients. However, in clinical practice, fluid expansion is often undiagnosed, and diuretic therapy is not always adequately titrated. Today, several drug classes with diuretic properties are available in addition to classical thiazides, thiazide-like, and loop diuretics. The purpose of this short review is to discuss different ways to optimize diuretic therapy using currently available drugs. Several approaches are considered, including a combination of diuretics to obtain a sequential nephron blockade, use of a drug combining a blocker of the renin-angiotensin system (RAS) and an inhibitor of the metabolism of natriuretic peptides (ARNI), prescription of potassium binders to maintain and up-titrate RAS blockers and mineralocorticoid antagonists, and finally use of inhibitors of renal reabsorption of glucose through the sodium-glucose cotransporter 2 system. Optimal use of these various drug classes should improve the quality of life and reduce the need for hospital admissions and mortality in heart failure patients.

Combining loop and thiazide diuretics for acute heart failure across the estimated glomerular filtration rate spectrum: A post-hoc analysis of the CLOROTIC trial.

AIMS: In patients with acute heart failure (AHF), the addition of hydrochlorothiazide (HCTZ) to furosemide improved diuretic response in the CLOROTIC trial. This work aimed to evaluate if these effects differ across the estimated glomerular filtration rate (eGFR) spectrum. METHODS AND RESULTS: This post-hoc analysis of the CLOROTIC trial analysed 230 patients with AHF and explored the influence of eGFR on primary and secondary endpoints. The median eGFR was 43 ml/min/1.73 m2 (range 14-109) and 23% had eGFR ≥60 ml/min/1.73 m2 (group 1), 24% from 45 to 59 ml/min/1.73 m2 (group 2), and 53% <45 ml/min/1.73 m2 (group 3). Patients treated with HCTZ had greatest weight loss at 72 h in all three groups, but patients in group 1 had a significantly greater response (-2.1 kg [-3.0 to 0.5]), compared to patients in groups 2 (-1.3 kg [-2.3 to 0.2]) and 3 (-0.1 kg [-1.3 to 0.4]) (p-value for interaction = 0.246). At 96 h, the differences in weight were -1.8 kg (-3.0 to -0.3), -1.4 kg (-2.6 to 0.3), and -0.5 kg (-1.3 to -0.1) in groups 1, 2, and 3, respectively (p-value for interaction = 0.256). There were no significant differences observed with the addition of HCTZ in terms of diuretic response, mortality or rehospitalizations, or safety endpoints (impaired renal function, hyponatraemia, and hypokalaemia) among the three eGFR groups (all p-values for interaction were no significant). CONCLUSION: The addition of eGFR-adjusted doses of oral HCTZ to loop diuretics in patients with AHF improved diuretic response across the eGFR spectrum. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01647932; EudraCT number: 2013-001852-36.

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins.

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6 months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6 months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

Thiazides in chronic kidney disease: "back to the future".

The thiazide class diuretics are first-line agents for managing hypertension either as monotherapy or as a fixed-dose combination with other antihypertensive drugs. However, despite the extensive experience with these drugs for >60 years, there is general reluctance to use these agents in patients with advanced chronic kidney disease (CKD) because of concerns about their efficacy and safety as kidney function declines. In this issue of Clinical Kidney Journal, Minutolo et al. performed an updated review of the pharmacological properties, efficacy and side effects and randomized controlled trials that tested these drugs in patients with CKD.

Thiazide diuretics are back in CKD: the case of chlorthalidone.

Sodium and volume excess is the fundamental risk factor underlying hypertension in chronic kidney disease (CKD) patients, who represent the prototypical population characterized by salt-sensitive hypertension. Low salt diets and diuretics constitute the centrepiece for blood pressure control in CKD. In patients with CKD stage 4, loop diuretics are generally preferred to thiazides. Furthermore, thiazide diuretics have long been held as being of limited efficacy in this population. In this review, by systematically appraising published randomized trials of thiazides in CKD, we show that this class of drugs may be useful even among people with advanced CKD. Thiazides cause a negative sodium balance and reduce body fluids by 1-2 l within the first 2-4 weeks and these effects go along with improvement in hypertension control. The recent CLICK trial has documented the antihypertensive efficacy of chlorthalidone, a long-acting thiazide-like diuretic, in stage 4 CKD patients with poorly controlled hypertension. Overall, chlorthalidone use could be considered in patients with treatment-resistant hypertension when spironolactone cannot be administered or must be withdrawn due to side effects. Hyponatremia, hypokalaemia, volume depletion and acute kidney injury are side effects that demand a vigilant attitude by physicians prescribing these drugs. Well-powered randomized trials assessing hard outcomes are still necessary to more confidently recommend the use of these drugs in advanced CKD.

The Urine Calcium/Creatinine Ratio and Uricemia during Hyponatremia of Different Origins: Clinical Implications.

Background: Chronic hyponatremia is known to be associated with osteoporosis. It has been shown that chronic hyponatremia increases bone resorption in an attempt to release body stores of exchangeable sodium by different mechanisms. We wanted to know the calciuria of patients with hyponatremia of different origins. Material and Methods: We made a retrospective study of 114 consecutive patients with asymptomatic hyponatremia of different origins with the usual serum and urine chemistry. Result: In hyponatremia due to SIADH, we had a high urine calcium/creatinine ratio of 0.23 ± 0.096 while in patients with salt depletion the UCa/UCr ratio was low (0.056 ± 0.038), in patients with hyponatremia secondary to thiazide intake the value was also low (0.075 ± 0.047) as in hypervolemic patients (0.034 ± 0.01). In hyponatremia due to polydipsia, the value was high (0.205 ± 0.10). Correction of hyponatremia in the euvolemic patients was associated with a significant decrease in the UCa/UCr ratio. In patients with hyponatremia secondary to thiazide intake, we noted that in the patients with low uric acid levels (<4 mg/dL, suggesting euvolemia) we also observed a low UCa/UCr (<0.10). In nine patients with chronic SIADH (SNa 125.1 ± 3.6 mEq/L), the 24 h urine calcium excretion was 275 ± 112 mg and decreased to 122 ± 77 mg (p < 0.01) after at least 2 weeks of treatment. Conclusions: Patients with chronic hyponatremia due to SIADH usually have a high UCa/UCr ratio (>0.15). This is also observed in hyponatremia secondary to polydipsia. Patients with thiazide-induced hyponatremia usually have low UCa/UCr levels and this is the case even among those with a biochemistry similar to that in SIADH (uric acid < 4 mg/dL).

Effectiveness of thiazide and thiazide-like diuretics in advanced chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Thiazide diuretics are first-line drugs for the treatment of hypertension, but hypertension treatment guidelines have systematically discouraged their use in patients with advanced chronic kidney disease (CKD). For the first time, a systematic review and random-effects meta-analysis were performed to assess the effectiveness of thiazides and thiazide-like diuretics to treat hypertension in patients with stages 3b, 4, and 5 CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review and random-effects meta-analysis that included a literature search using the following databases were performed: MEDLINE through PubMed, Cochrane Database of Systematic Reviews (CDSR) and Cochrane Central Register of Controlled Trials (CENTRAL) through the Cochrane Library, Embase, and ISI - Web of Science (all databases). Prospective studies that evaluated the effectiveness of thiazide and thiazide-like diuretics in individuals with a GFR < 45 mL/min/1.73 m2 were included. RESULTS: Five clinical trials, totaling 214 participants, were included, and the mean GFR ranged from 13.0 ± 5.9 mL/min/1.73 m2 to 26.8 ± 8.8 mL/min/1.73 m2. There was evidence of a reduction in mean blood pressure and in GFR, as well as in fractional sodium excretion and fractional chloride excretion. CONCLUSION: Thiazide and thiazide-like diuretics seem to maintain their effectiveness in lowering blood pressure in patients with advanced chronic kidney disease. These findings should spur new prospective randomized trials and spark discussions, particularly about upcoming hypertension guidelines.

Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial.

AIMS: To evaluate whether the addition of hydrochlorothiazide (HCTZ) to intravenous furosemide is a safe and effective strategy for improving diuretic response in acute heart failure (AHF). METHODS AND RESULTS: A prospective, double-blind, placebo-controlled trial, including patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The coprimary endpoints were changes in body weight and patient-reported dyspnoea 72 h after randomization. Secondary outcomes included metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. Safety outcomes (changes in renal function and/or electrolytes) were also assessed. Two hundred and thirty patients (48 women, 83 years) were randomized. Patients assigned to HCTZ were more likely to lose weight at 72 h than those assigned to placebo [2.3 vs. 1.5 kg; adjusted estimated difference (notionally 95 confidence interval) 1.14 (1.84 to 0.42); P 0.002], but there were no significant differences in patient-reported dyspnoea (area under the curve for visual analogue scale: 960 vs. 720; P 0.497). These results were similar 96 h after randomization. Patients allocated to HCTZ showed greater 24 h diuresis (1775 vs. 1400 mL; P 0.05) and weight loss for each 40 mg of furosemide (at 72 and at 96 h) (P 0.001). Patients assigned to HCTZ more frequently presented impaired renal function (increase in creatinine 26.5 moL/L or decrease in eGFR 50; 46.5 vs. 17.2; P 0.001), but hypokalaemia and hypokalaemia were similar between groups. There were no differences in mortality or rehospitalizations. CONCLUSION: The addition of HCTZ to loop diuretic therapy improved diuretic response in patients with AHF.

Machine Learning Insights Into Uric Acid Elevation With Thiazide Therapy Commencement and Intensification.

Background Elevated serum uric acid, associated with cardiovascular conditions such as atherosclerotic heart disease, hypertension, and heart failure, can be elevated by thiazide or thiazide-like drugs (THZ), essential in hypertension management. Identifying clinical determinants affecting THZ-related uric acid elevation is critical. Methods In this retrospective cross-sectional study, we explored the clinical determinants influencing uric acid elevation related to THZ, focusing on patients where THZ was initiated or the dose escalated. A cohort of 143 patients was analyzed, collecting baseline and control uric acid levels, alongside basic biochemical studies and clinical data. Feature selection was conducted utilizing criteria based on mean squared error increase and enhancement in node purity. Four machine learning algorithms - Random Forest, Neural Network, Support Vector Machine, and Gradient Boosting regressions - were applied to pinpoint clinical influencers. Results Significant features include uncontrolled diabetes, index estimated Glomerular Filtration Rate (eGFR) level, absence of insulin, action of indapamide, and absence of statin treatment, with absence of Sodium-glucose cotransporter 2 inhibitors (SGLT2i), low dose aspirin exposure, and older age also being noteworthy. Among the applied models, the Gradient Boosting regression model outperformed the others, exhibiting the lowest Mean Absolute Error (MAE), Mean Squared Error (MSE), Root Mean Squared Error (RMSE) values, and the highest R2 value (0.779). While Random Forest and Neural Network regression models were able to fit the data adequately, the Support Vector Machine demonstrated inferior metrics. Conclusions Machine learning algorithms are adept at accurately identifying the factors linked to uric acid fluctuations caused by THZ. This proficiency aids in customizing treatments more effectively, reducing the need to unnecessarily avoid THZ, and providing guidance on its use to prevent instances where uric acid levels could become problematic.

Diuretics in the management of chronic heart failure: when and how.

Heart failure is an increasingly prevalent condition resulting in recurrent hospitalisations and significant mortality and morbidity. The management of heart failure has evolved, and multiple drugs have an established mortality benefit in heart failure with reduced ejection fraction. Although the focus should be on ensuring that patients are treated with the maximum tolerated doses of these guideline-directed therapies, diuretics continue to play a key role in the management of clinical congestion in all forms of heart failure. Clinicians play a key role in heart failure management. Familiarity with the role of diuretics and their dosing and monitoring is critical.

Associations of thiazide use with skin cancers: a systematic review and meta-analysis.

BACKGROUND: Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides. METHODS: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use. RESULTS: We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide. CONCLUSIONS: Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions. TRIAL REGISTRATION: PROSPERO CRD42021234317 .