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JAMA May 2023Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9... (Review)
Review
IMPORTANCE
Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people.
OBSERVATIONS
The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.
CONCLUSIONS AND RELEVANCE
Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
Topics: Adult; Humans; Male; Ascites; Carvedilol; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Hepatorenal Syndrome; Lactulose; Liver Cirrhosis; Liver Neoplasms; Muscle Cramp; Propranolol; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors; Terlipressin; United States
PubMed: 37159031
DOI: 10.1001/jama.2023.5997 -
Clinical Journal of the American... Aug 2019
Review
Topics: Diuretics; Edema; Extracellular Fluid; Gastrointestinal Absorption; Humans
PubMed: 30936153
DOI: 10.2215/CJN.09630818 -
JAMA Jan 2023Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide.
OBJECTIVE
To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure.
DESIGN, SETTING, AND PARTICIPANTS
TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022.
INTERVENTIONS
Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage.
MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide.
RESULTS
TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction.
CONCLUSIONS AND RELEVANCE
Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03296813.
Topics: Humans; Female; Middle Aged; Aged; Male; Furosemide; Torsemide; Patient Discharge; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome; Heart Failure; Hospitalization
PubMed: 36648467
DOI: 10.1001/jama.2022.23924 -
Journal of the American College of... Mar 2020Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling... (Review)
Review
Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.
Topics: Diuretics; Gastrointestinal Absorption; Heart Failure; Humans; Kidney; Review Literature as Topic; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 32164892
DOI: 10.1016/j.jacc.2019.12.059 -
European Journal of Heart Failure Feb 2022Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have shown that measuring natriuresis early after hospital admission could reliably identify patients with a poor diuretic response during hospitalization who might require enhanced diuretic treatment. This study will test the hypothesis that natriuresis-guided therapy in patients with acute HF improves natriuresis and clinical outcomes.
METHODS
The Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) is a pragmatic, single-centre, randomized, controlled, open-label study, aiming to recruit 310 acute HF patients requiring treatment with intravenous loop diuretics. Patients will be randomized to natriuresis-guided therapy or standard of care. Natriuresis will be determined at set time points after initiation of intravenous loop diuretics, and treatment will be adjusted based on the urinary sodium levels in the natriuresis-guided group using a pre-specified stepwise approach of increasing doses of loop diuretics and the initiation of combination diuretic therapy. The co-primary endpoint is 24-h urinary sodium excretion after start of loop diuretic therapy and a combined endpoint of all-cause mortality or first HF rehospitalization at 6 months. Secondary endpoints include 48- and 72-h sodium excretion, length of hospital stay, and percentage change in N-terminal pro brain natriuretic peptide at 48 and 72 h.
CONCLUSION
The PUSH-AHF study will investigate whether natriuresis-guided therapy, using a pre-specified stepwise diuretic treatment approach, improves natriuresis and clinical outcomes in patients with acute HF.
Topics: Algorithms; Diuretics; Heart Failure; Humans; Natriuresis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 34791756
DOI: 10.1002/ejhf.2385 -
European Journal of Heart Failure Sep 2022To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF).
METHODS AND RESULTS
ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation.
CONCLUSION
ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.
Topics: Acetazolamide; Aged; Diuretics; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Quality of Life; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Ventricular Function, Left; Water-Electrolyte Imbalance
PubMed: 35733283
DOI: 10.1002/ejhf.2587