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European Journal of Heart Failure Sep 2020It is unclear whether spironolactone reduced heart failure (HF) hospitalizations in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone...
AIMS
It is unclear whether spironolactone reduced heart failure (HF) hospitalizations in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial through potential diuretic or other effects. We examined the effects of spironolactone on weight, diuretic use, and renal function, and their subsequent impact on outcomes.
METHODS AND RESULTS
We analysed data from TOPCAT Americas (1767 patients with HF and preserved ejection fraction; 886 in spironolactone, 881 in placebo arm). We used mixed-effects models for serial data and shared frailty models to identify determinants of recurrent HF hospitalizations among baseline and serial parameters. There were 800 HF hospitalizations after a median of 3.0 years. Despite more weight loss with spironolactone initially, weight trajectories overlapped after 12 months. Daily furosemide dose (time-averaged Δ: -4.8% vs. +11.6%, P < 0.001) and thiazide use (-4.3% vs. +1.7%; P = 0.003) decreased with spironolactone; however, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use decreased also (-13.1% vs. -7.3%; P = 0.004). Serum creatinine increased more with spironolactone (+12.5% vs. +3.5%; P < 0.001). In time-updated models, loop diuretic dose [hazard ratio (HR) per doubling 1.21; 95% confidence interval (CI) 1.10-1.32; P < 0.001], creatinine (HR per doubling 1.28; 95% CI 1.04-1.40; P = 0.019), and ACEI/ARB use (HR 0.82; 95% CI 0.67-1.00; P = 0.048) were associated with HF hospitalizations. However, the effect of spironolactone on HF hospitalizations persisted (HR 0.77; 95% CI 0.62-0.96; P = 0.021) in these models. Results were similar for cardiovascular mortality and time to first HF hospitalization.
CONCLUSIONS
In TOPCAT Americas, the benefit of spironolactone on outcomes could not be solely attributed to potential diuretic effects, suggesting the presence of non-diuretic mechanisms.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone; Stroke Volume; Treatment Outcome
PubMed: 32469156
DOI: 10.1002/ejhf.1917 -
Current Opinion in Nephrology and... Sep 2022Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent... (Review)
Review
PURPOSE OF REVIEW
Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD.
RECENT FINDINGS
Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI.
SUMMARY
Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.
Topics: Acute Kidney Injury; Chlorthalidone; Diuretics; Humans; Hypertension; Renal Insufficiency, Chronic; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Thiazides
PubMed: 35894274
DOI: 10.1097/MNH.0000000000000814 -
JACC. Heart Failure Jun 2022Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.
BACKGROUND
Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.
OBJECTIVES
The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.
METHODS
Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined.
RESULTS
At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P < 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P < 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002).
CONCLUSIONS
Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Diuretics; Heart Failure; Humans; Prospective Studies; Stroke Volume; Tetrazoles; Ventricular Dysfunction, Left
PubMed: 35654526
DOI: 10.1016/j.jchf.2022.01.020 -
American Journal of Physiology. Renal... Mar 2023Sex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning....
Sex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning. Similarly, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. That regulation is sexually dimorphic; as such, sex and time of day are not two independent regulators of kidney function and blood pressure. The objective of the present study was to assess the effect of sex and administration time on the natriuretic and diuretic effects of loop, thiazide, and K-sparing diuretics, which are common treatments for hypertension. Loop diuretics inhibit Na-K-2Cl cotransporters on the apical membrane of the thick ascending limb, thiazide diuretics inhibit Na-Cl cotransporters on the distal convoluted tubule, and K-sparing diuretics inhibit epithelial Na channels on the connecting tubule and collecting duct. We simulated Na transporter inhibition using sex- and time-of-day-specific computational models of mouse kidney function. The simulation results highlighted significant sex and time-of-day differences in the drug response. Loop diuretics induced larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibited sex and time-of-day differences, whereas these effects of K-sparing diuretics exhibited a significant time-of-day difference in females only. The kaliuretic effect depended on the type of diuretics and time of administration. The present computational models can be a useful tool in chronotherapy, to tailor drug administration time to match the body's diurnal rhythms to optimize the drug effect. Sex influences cardiovascular disease, and the timing of onset of acute cardiovascular events exhibits circadian rhythms. Kidney function also exhibits sex differences and circadian rhythms. How do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets the kidneys, differ between the sexes? And how do these effects vary during the day? To answer these questions, we conducted computer simulations to assess the effects of loop, thiazide, and K-sparing diuretics.
Topics: Female; Male; Mice; Animals; Diuretics; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Hypertension; Kidney Tubules, Distal; Sodium; Thiazides
PubMed: 36701479
DOI: 10.1152/ajprenal.00296.2022 -
ESC Heart Failure Dec 2022Given the various effects of sacubitril/valsartan in heart failure, a deeper understanding of atrial natriuretic peptide (ANP) actions is warranted. Natriuresis is a...
AIMS
Given the various effects of sacubitril/valsartan in heart failure, a deeper understanding of atrial natriuretic peptide (ANP) actions is warranted. Natriuresis is a fundamental action of ANP in acute heart failure (AHF), whereas the diuretic effect of ANP is different in each patient according to the diversity of renal response to ANP, which is affected by baseline plasma ANP status and deficiency of circulating ANP. Meanwhile, associations between other neuroendocrine hormones and the diuretic response to ANP are unclear. This study investigated the impact of pivotal neuroendocrine hormones on the diuretic effects of exogenous ANP, carperitide.
METHODS AND RESULTS
Plasma ANP, renin, aldosterone, and vasopressin levels and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 75 patients with AHF. Lower ANP levels were significantly associated with a greater diuretic response to exogenous ANP (r = -0.35, P = 0.002). Additionally, higher vasopressin levels were significantly related to the poor diuretic effects of exogenous ANP (r = -0.54, P < 0.001). Plasma ANP and vasopressin concentrations were not significantly correlated (r = 0.19, P = 0.10). Baseline systolic blood pressure, renal function, and prior use of loop diuretics did not predict the diuretic response to exogenous ANP, whereas vasopressin levels independently predicted a diuretic response to exogenous ANP (P < 0.001), as well as lower plasma ANP levels (P = 0.027).
CONCLUSIONS
Vasopressin status was significantly associated with the diuretic response to exogenous ANP in AHF, independent of plasma ANP status. The results may provide a better understanding of the actions of sacubitril/valsartan.
Topics: Humans; Atrial Natriuretic Factor; Diuretics; Heart Failure; Valsartan; Vasopressins; Neurosecretory Systems
PubMed: 36043451
DOI: 10.1002/ehf2.14083 -
Cardiology Journal 2022Current hypertension guidelines suggest various strategies to reduce blood pressure levels, thereby reducing cardiovascular events: combinations of drugs with different...
Current hypertension guidelines suggest various strategies to reduce blood pressure levels, thereby reducing cardiovascular events: combinations of drugs with different mechanisms of action, such as an angiotensin converting enzyme inhibitors (ACEIs) and a diuretic, are the cornerstone of the modern treatment of hypertension, also as initial therapy. Among ACEIs, zofenopril has been shown to be effective in the management of hypertension both as monotherapy and in combination with a diuretic: zofenopril/hydrochlorothiazide fixed dose combination is particularly useful to improve treatment adherence through simplification of treatment regimen. Moreover, thanks to the sulfhydryl group, zofenopril has some peculiar properties (higher lipophilicity and tissue penetration, lower bradykinin-dependent effect, higher affinity for, and more persistent binding to, tissue ACE, significant antioxidant effect), which may account for the cardioprotective effects of the drug demonstrated in both pre-clinical studies and randomized clinical trials. The positive impact of zofenopril on clinical outcomes has been extensively documented by the SMILE program, including several clinical trials in patients with different conditions of myocardial ischemia treated with zofenopril: the results of the SMILE program, demonstrating the benefits of zofenopril vs. placebo and other ACEIs, emphasize the importance of a differentiated approach to patients with ischemic heart disease, based on a careful choice of the adopted agent, in order to improve the overall impact of pharmacological treatment on clinical outcomes.
Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Diuretics; Humans; Hypertension; Myocardial Ischemia
PubMed: 34622438
DOI: 10.5603/CJ.a2021.0113 -
Journal of the American Heart... Dec 2022Background We hypothesized that stroke outcome is related to multiple baseline hydration-related factors including volume contracted state (VCS) and diuretic use....
Background We hypothesized that stroke outcome is related to multiple baseline hydration-related factors including volume contracted state (VCS) and diuretic use. Methods and Results We analyzed a prospective cohort of subjects with ischemic stroke <24 hours of onset enrolled in acute treatment trials within VISTA (Virtual International Stroke Trials Archive). A VCS was defined based on blood urea nitrogen-to-creatinine ratio. The primary end point was modified Rankin Scale score at 90 days. Primary analysis used generalized ordinal logistic regression over the mRS range, adjusted for Totaled Health Risks in Vascular Events score, onset-to-enrollment time, and thrombolytic use. Of 5971 eligible patients with stroke, 42% were taking diuretics at the time of hospitalization, and 44% were in a VCS. Patients in a VCS were older, had more vascular risk factors, were more likely taking diuretics, and had more severe strokes. Diuretic use was associated with both reduced chance of achieving a good functional outcome (odds ratio [OR], 0.57 [95% CI, 0.52-0.63]) and increased mortality at 90 days (OR, 2.30 [95% CI, 2.04-2.61]). VCS was associated with greater mortality 90 days after stroke (OR, 1.53 [95% CI, 1.33-1.76]). There was no evidence of effect modification among the 3 exposures of VCS, diuretic use, or hypokalemia in relation to outcome. Conclusions A VCS at the time of hospitalization was associated with more severe stroke and odds of death but not associated with worse functional outcome when accounting for relevant characteristics. Diuretic use and low serum potassium at the time of stroke onset were associated with worse outcome and may be worthy of further investigation.
Topics: Humans; Prospective Studies; Diuretics; Stroke; Fibrinolytic Agents; Logistic Models; Treatment Outcome; Thrombolytic Therapy
PubMed: 36515241
DOI: 10.1161/JAHA.122.026903 -
Current Heart Failure Reports Apr 2024Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in... (Review)
Review
PURPOSE OF REVIEW
Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.
RECENT FINDINGS
We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
Topics: Humans; Heart Failure; Sodium Potassium Chloride Symporter Inhibitors; Quality of Life; Diuretics; Hospitalization
PubMed: 38300391
DOI: 10.1007/s11897-024-00644-2 -
Journal of the American College of... Feb 2015Hyponatremia frequently poses a therapeutic challenge in acute decompensated heart failure (ADHF). Treating physicians should differentiate between depletional versus... (Comparative Study)
Comparative Study Review
Hyponatremia frequently poses a therapeutic challenge in acute decompensated heart failure (ADHF). Treating physicians should differentiate between depletional versus dilutional hyponatremia. The former is caused by diuretic agents, which enhance sodium excretion, often with concomitant potassium/magnesium losses. This can be treated with isotonic saline, whereas potassium/magnesium administration may be helpful if plasma concentrations are low. In contrast, as impaired water excretion, rather than sodium deficiency, is the culprit in dilutional hyponatremia, isotonic saline administration may further depress the serum sodium concentration. Because free water excretion is achieved by continuous sodium reabsorption in distal nephron segments with low water permeability, diuretic agents that impair this mechanism (e.g., thiazide-type diuretic agents and mineralocorticoid receptor antagonists) should be avoided, and proximally acting agents (e.g., acetazolamide and loop diuretic agents) are preferred. Vasopressin antagonists, which promote low water permeability in the collecting ducts and, hence, free water excretion, remain under investigation for dilutional hyponatremia in ADHF.
Topics: Acute Disease; Animals; Arginine Vasopressin; Diuretics; Heart Failure; Humans; Hyponatremia; Mineralocorticoid Receptor Antagonists; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 25660927
DOI: 10.1016/j.jacc.2014.12.010 -
BioMed Research International 2019is a well-known traditional Chinese medicine and used as an agent for diuresis in China for centuries. This is the first time to evaluate the diuretic activity of the...
is a well-known traditional Chinese medicine and used as an agent for diuresis in China for centuries. This is the first time to evaluate the diuretic activity of the ethanol extract of (LS) and its four fractions (LSA, LSB, LSC, and LSD) in normal rats. After the administration of LS-H, LS-M, LSB-H, and LSC-L, the urine output of the rats was significantly increased, while the urine excretion was significantly reduced after treatment with LSB-L. The urine Na excretion was remarkably increased with LS-H, LS-M, LSA-H, LSA-L, LSB-H, LSC-L, and LSD-L, and the urine K excretion was significantly increased after administration of LS-H and LSB-H. Moreover, the urine Na and K excretion was significantly reduced after treatment with LSC-H and LSD-H. However, the urine pH values and urine and serum Na-K-ATPase levels did not show remarkable change after administration of LS or its four fractions in comparison with the control group. On the contrary, LS and its four fractions can suppress the renin-angiotensin-aldosterone system (RAAS), including ADH arrest by LSB-H, LSB-L, LSC-L, LSD-L, and LSD-H and ALD arrest by LSD-L, as well as promote ANP release by LS-M, LSB-H, LSC-H, and LSD-H, while furosemide can suppress only arrest of ADH within 24 h compared with the control group. In addition, LS and its four fractions did not change the urine and serum TNF- and IL-6 levels in normal rats within 24 h. This study will provide a quantitative basis for explaining the natural medicinal use of LS as a diuretic agent for edema and promoting the diuretic process.
Topics: Animals; Antidiuretic Agents; Diuretics; Lamiaceae; Male; Plant Extracts; Rats; Rats, Sprague-Dawley; Sodium; Urinalysis; Urination
PubMed: 31886241
DOI: 10.1155/2019/6927374