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Digestive Diseases and Sciences May 2020Type 1 hepatorenal syndrome (HRS) is a fatal complication of cirrhosis. Treatments trend toward HRS reversal, but few show clear mortality benefit. We sought to quantify... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Type 1 hepatorenal syndrome (HRS) is a fatal complication of cirrhosis. Treatments trend toward HRS reversal, but few show clear mortality benefit. We sought to quantify the progress-or lack thereof-in improving outcomes of type 1 HRS over time.
METHODS
We performed a systematic review and meta-analysis for randomized controlled trials (RCTs) comparing type 1 HRS outcomes including (a) overall survival (liver transplant-free survival if reported) and (b) HRS reversal. Each study arm was analyzed separately to look at changes in outcomes over time. RCTs published comparing medical treatments for type 1 HRS were searched using several databases through July 31, 2019.
RESULTS
Fourteen RCTs (28 arms) involving 778 participants enrolled between 2002 and 2018 were included. Twelve RCTs measured HRS reversal. In conjunction with albumin (or plasma expander), the most common medications used were terlipressin (13 arms), antibiotics (7), norepinephrine (6), dopamine (4), and midodrine/octreotide (3). Pooled survival rate was 34.6% (95% CI 26.4-43.8), and pooled HRS reversal rate was 42.8% (95% CI 34.2-51.9). Regression analyzing the incremental effect of the year the RCT was initiated showed that more recent studies were not associated with improved survival (OR 1.02, 95% CI 0.94-1.11, p = 0.66) or HRS reversal rates (OR 1.03, 95% CI 0.96-1.11, p = 0.41). There was no survival improvement when RCTs with endpoints assessed ≤ or > 1 month were analyzed separately with respective OR of 1.07 (95% CI 0.95-1.20, p = 0.26) and 0.97 (95% CI 0.85-1.12, p = 0.70).
CONCLUSION
Outcomes have not improved for patients with type 1 HRS since 2002. There is a need to improve prevention and treatment of type 1 HRS.
Topics: Adult; Albumins; Anti-Bacterial Agents; Dopamine; Drug Therapy, Combination; Female; Hepatorenal Syndrome; Humans; Male; Middle Aged; Midodrine; Norepinephrine; Octreotide; Plasma Substitutes; Randomized Controlled Trials as Topic; Regression Analysis; Survival Rate; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Young Adult
PubMed: 31571102
DOI: 10.1007/s10620-019-05858-2 -
The Cochrane Database of Systematic... Sep 2019Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore...
BACKGROUND
Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome.
OBJECTIVES
To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis.
SELECTION CRITERIA
We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation.
DATA COLLECTION AND ANALYSIS
Two authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
MAIN RESULTS
We included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty-three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow-up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone.There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow-up between the different interventions. None of the trials reported health-related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow-up (four trials; 342 participants), or other features of decompensation at maximal follow-up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta-analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.
FUNDING
two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding.
AUTHORS' CONCLUSIONS
Based on very low-certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all-cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low-certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low- or very low-certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin.Future randomised clinical trials should be adequately powered; employ blinding, avoid post-randomisation dropouts or planned cross-overs (or perform an intention-to-treat analysis); and report clinically important outcomes such as mortality, health-related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials.
Topics: Adult; Bayes Theorem; Female; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Vasoconstrictor Agents
PubMed: 31513287
DOI: 10.1002/14651858.CD013103.pub2 -
The Cochrane Database of Systematic... Sep 2017Hepatorenal syndrome is defined as severe renal failure occurring in people with cirrhosis and ascites. Systematic reviews of randomised clinical trials found that,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hepatorenal syndrome is defined as severe renal failure occurring in people with cirrhosis and ascites. Systematic reviews of randomised clinical trials found that, compared with placebo, terlipressin may reduce mortality and improve renal function in people with hepatorenal syndrome, but we need current evidence from systematic reviews on the benefits and harms of terlipressin versus other vasoactive drugs.
OBJECTIVES
To evaluate the beneficial and harmful effects of terlipressin versus other vasoactive drugs for people with hepatorenal syndrome.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and Science Citation Index Expanded; conducted manual searches of references in relevant literature; and wrote to experts and pharmaceutical companies (date of last search November 2016).
SELECTION CRITERIA
Randomised clinical trials comparing terlipressin versus any other type of vasoactive drugs for hepatorenal syndrome. We allowed albumin and other cointerventions if provided equally in the comparison groups.
DATA COLLECTION AND ANALYSIS
Three authors independently extracted data. The primary outcomes were mortality, hepatorenal syndrome (persistent hepatorenal syndrome despite treatment), and serious adverse events. We conducted meta-analyses and present the results as risk ratios (RR) with 95% confidence intervals (CI). We performed sensitivity, subgroup, and Trial Sequential Analyses and evaluated bias control based on the Cochrane Hepato-Biliary Group domains.
MAIN RESULTS
We included 10 randomised clinical trials with 474 participants. The trials compared terlipressin versus noradrenaline (seven trials), octreotide (one trial), midodrine and octreotide (one trial), or dopamine (one trial). All participants in both groups received albumin as cointervention. We classified two trials at low risk of bias and eight trials at high risk of bias in the assessment of mortality and all trials at high risk of bias for remaining outcomes. In five trials, investigators specifically stated that they did not receive funding from for-profit organisations. We had no information about the funding source from the remaining five trials.Terlipressin was not superior or inferior compared with other vasoactive drugs in regard to mortality when including the two trials with a low risk of bias (RR 0.92, 95% CI 0.63 to 1.36; 94 participants, very low quality evidence) or when including all 10 trials (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). One meta-analysis including nine trials suggested a beneficial effect of terlipressin on hepatorenal syndrome (RR 0.79, 95% CI 0.63 to 0.99; 394 participants; I² = 26%; very low quality evidence). Due to the high mortality of hepatorenal syndrome, the registration of other serious adverse events is uncertain, but comparing terlipressin and other vasoactive drugs we found no significant difference (RR 0.96, 95% CI 0.88 to 1.06; 474 participants; I² = 0%; very low quality evidence). Several trials did not report systematically of adverse events, but terlipressin seemed to increase the risks of diarrhoea or abdominal pain, or both (RR 3.50, 95% CI 1.19 to 10.27; 221 participants; 5 trials, I² = 0%). However, Trial Sequential Analyses found insufficient evidence to support or refute any differences between interventions for all outcomes. Considering reversal of hepatorenal syndrome, subgroup analyses on the type of other vasoactive drugs found that terlipressin was superior compared with midodrine and octreotide (RR 0.47, 95% CI 0.30 to 0.72) or octreotide alone (RR 0.56, 95% CI 0.33 to 0.96), but each subgroup only included one small trial. None of the remaining subgroup or sensitivity analyses found differences between terlipressin and other vasoactive drugs. We downgraded the evidence to very low quality because of the high risk of bias, imprecision, and the results of the Trial Sequential Analyses.
AUTHORS' CONCLUSIONS
This review found insufficient evidence to support or refute beneficial or harmful effects of terlipressin and albumin versus other vasoactive drugs and albumin. Additional research is needed to evaluate if clinically meaningful differences exist between interventions.
Topics: Antihypertensive Agents; Dopamine; Hepatorenal Syndrome; Humans; Lypressin; Midodrine; Norepinephrine; Octreotide; Randomized Controlled Trials as Topic; Terlipressin; Vasoconstrictor Agents
PubMed: 28953318
DOI: 10.1002/14651858.CD011532.pub2 -
Alimentary Pharmacology & Therapeutics Mar 2017Hepatorenal syndrome type 1 (HRS1) is a functional, rapidly progressive, potentially reversible form of acute kidney injury occurring in patients with cirrhosis.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hepatorenal syndrome type 1 (HRS1) is a functional, rapidly progressive, potentially reversible form of acute kidney injury occurring in patients with cirrhosis. Characterised by intense renal arterial vasoconstriction, it carries a very poor prognosis. There is a significant unmet need for a widely approved, safe and effective pharmacological treatment.
AIM
To re-evaluate efficacy and safety of pharmacological treatments for HRS1, in the light of recently published randomised controlled trials (RCTs).
METHODS
MEDLINE (OvidSP), EMBASE, PubMed and Cochrane registers were searched for RCTs reporting efficacy and adverse events related to pharmacological treatment of HRS1. Search terms included: 'hepatorenal syndrome', 'terlipressin', 'noradrenaline', 'octreotide', 'midodrine', 'vasopressin', 'dopamine', 'albumin' and synonyms. Comparison of vasoactive drugs vs. placebo/no treatment, and two active drugs were included. Meta-analysis was performed for HRS1 reversal, creatinine improvement, mortality and adverse events.
RESULTS
Twelve RCTs enrolling 700 HRS1 patients were included. Treatment with terlipressin and albumin led to HRS1 reversal more frequently than albumin alone or placebo (RR: 2.54, 95% CI: 1.51-4.26). Noradrenaline was effective in reversing HRS1, but trials were small and nonblinded. Overall, there was mortality benefit with terlipressin (RR: 0.79, 95% CI: 0.63-1.01), but sensitivity analysis including only trials with low risk of selection bias weakened this relationship (RR: 0.87, 95% CI: 0.71-1.06). Notably, there was a significant risk of adverse events with terlipressin therapy (RR: 4.32, 95% CI: 0.75-24.86).
CONCLUSIONS
Terlipressin treatment is superior to placebo for achieving HRS1 reversal, but mortality benefit is less clear. Terlipressin is associated with significant adverse events, but infusion regimens may be better tolerated. There is continued need for safe and effective treatment options for hepatorenal syndrome.
Topics: Albumins; Creatinine; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Lypressin; Prognosis; Randomized Controlled Trials as Topic; Terlipressin; Treatment Outcome; Vasoconstrictor Agents
PubMed: 28052382
DOI: 10.1111/apt.13912 -
Journal of General Internal Medicine Nov 2013To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH).
METHODS
We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies.
RESULTS
Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p = 0.65) and the mean change in mean arterial pressure from supine to standing was -1.7 mmHg (p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p < 0.001). A significant improvement was seen in patients' and investigators' global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30-1.09; p < 0.001] and 0.80 [95 % CI 0.76-0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias.
CONCLUSION
There is insufficient and low quality evidence to support the use of midodrine for OH.
Topics: Blood Pressure; Clinical Trials as Topic; Humans; Hypotension, Orthostatic; Midodrine; Vasoconstrictor Agents
PubMed: 23775146
DOI: 10.1007/s11606-013-2520-3 -
Clinical Cardiology Jun 2010The association of clinostatic hypertension (CH) and orthostatic hypotension (OH) is described as the "Hyp-Hyp phenomenon," and it has been found in about 5.5% of... (Review)
Review
BACKGROUND
The association of clinostatic hypertension (CH) and orthostatic hypotension (OH) is described as the "Hyp-Hyp phenomenon," and it has been found in about 5.5% of hypertensive patients and in up to 50% of patients with OH. The importance of CH/OH in clinical practice is mainly due to the presence of troublesome symptoms, end-organ damage, and difficulties in its clinical management.
HYPOTHESIS
The review focuses on the clinical problem of CH and review the international literature for the best management, including the diagnostic work-up and the taylored treatment for this kind of patients.
METHODS
A systematic review of the literature was conducted through MEDLINE research to focus the main controversial issues about CH/OH. Included topics: (1) the diagnostic work-up, (2) the association with dysautonomic failure and syncope, and (3) the treatment options and prevention of end-organ damage.
RESULTS
Current standard reference for OH diagnosis includes functional assessment of the cardiac vagal nervous system and the sympathetic adrenergic system. The association with dysautonomic failure and with syncope needs further investigation. Pharmacologic treatment of OH is aimed at controlling symptoms rather than restoring normotension. Midodrine is the only medication that has been put to multicenter placebo-controlled trial and subsequently approved by the U.S. Food and Drug Administration (FDA) for OH treatment. Short-acting oral antihypertensive agents at bedtime should be considered in patients with severe, sustained CH.
CONCLUSIONS
Data obtained from the literature review showed that clinical diagnosis of the Hyp-Hyp phenomenon is relatively simple, but it remains more difficult to establish the causal disease. In our opinion, it is advisable to define simple diagnostic standards for the selection of patients at risk of dysautonomic impairment so that a subsequent highly specific diagnostic work-up could be initiated.
Topics: Antihypertensive Agents; Autonomic Nervous System; Blood Pressure; Humans; Hypertension; Hypotension, Orthostatic; Midodrine; Predictive Value of Tests; Treatment Outcome; Vasoconstrictor Agents
PubMed: 20552588
DOI: 10.1002/clc.20722 -
Archives of Physical Medicine and... May 2009To review systematically the evidence for the management of orthostatic hypotension (OH) in patients with spinal cord injuries (SCIs). (Review)
Review
OBJECTIVE
To review systematically the evidence for the management of orthostatic hypotension (OH) in patients with spinal cord injuries (SCIs).
DATA SOURCES
A key word literature search was conducted of original and review articles as well as practice guidelines using Medline, CINAHL, EMBASE, and PsycInfo, and manual searches of retrieved articles from 1950 to July 2008, to identify literature evaluating the effectiveness of currently used treatments for OH.
STUDY SELECTION
Included randomized controlled trials (RCTs), prospective cohort studies, case-control studies, pre-post studies, and case reports that assessed pharmacologic and nonpharmacologic intervention for the management of OH in patients with SCI.
DATA EXTRACTION
Two independent reviewers evaluated the quality of each study, using the Physiotherapy Evidence Database score for RCTs and the Downs and Black scale for all other studies. Study results were tabulated and levels of evidence assigned.
DATA SYNTHESIS
A total of 8 pharmacologic and 21 nonpharmacologic studies were identified that met the criteria. Of these 26 studies (some include both pharmacologic and nonpharmacologic interventions), only 1 pharmacologic RCT was identified (low-quality RCT producing level 2 evidence), in which midodrine was found to be effective in the management of OH after SCI. Functional electrical stimulation was one of the only nonpharmacologic interventions with some evidence (level 2) to support its utility.
CONCLUSIONS
Although a wide array of physical and pharmacologic measures are recommended for the management of OH in the general population, very few have been evaluated for use in SCI. Further research needs to quantify the efficacy of treatment for OH in subjects with SCI, especially of the many other pharmacologic interventions that have been shown to be effective in non-SCI conditions.
Topics: Combined Modality Therapy; Female; Follow-Up Studies; Humans; Hypotension, Orthostatic; Injury Severity Score; Male; Midodrine; Paraplegia; Physical Therapy Modalities; Quadriplegia; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Spinal Cord Injuries; Treatment Outcome; Vasoconstrictor Agents
PubMed: 19406310
DOI: 10.1016/j.apmr.2009.01.009 -
The Cochrane Database of Systematic... Jul 2005Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Adrenergic drugs have been used for the treatment of urinary incontinence. However, they have generally been considered to be ineffective or to have side effects which may limit their clinical use.
OBJECTIVES
To determine the effectiveness of adrenergic agonists in the treatment of urinary incontinence in adults.
SEARCH STRATEGY
We searched the Cochrane Incontinence Group specialised trials register (searched 9 March 2005) and the reference lists of relevant articles.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials in adults with urinary incontinence which included an adrenergic agonist drug in at least one arm of the trial.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed eligibility, trial quality and extracted data. Data were processed as described in the Cochrane Reviewers' Handbook.
MAIN RESULTS
Twenty-two eligible randomised trials were identified, of which 11 were crossover trials. The trials included 1099 women with 673 receiving an adrenergic drug (phenylpropanolamine in 11 trials, midodrine in two, norepinephrine in three, clenbuterol in another three, terbutaline in one, eskornade in one and Ro-115-1240 in one). No trials included men. The limited evidence suggested that an adrenergic agonist drug is better than placebo in reducing the number of pad changes and incontinence episodes, as well as improving subjective symptoms. In two small trials, the drugs also appeared to be better than pelvic floor muscle training, possibly reflecting relative acceptability of the treatments to women but perhaps due to differential withdrawal of women from the trial groups. There was not enough evidence to evaluate the use of higher compared to lower doses of adrenergic agonists nor the relative merits of an adrenergic agonist drug compared with oestrogen, whether used alone or in combination. Over a quarter of women reported adverse effects. There were similar numbers of adverse effects with adrenergics, placebo or alternative drug treatment. However, when these were due to recognised adrenergic stimulation (insomnia, restlessness and vasomotor stimulation) they were only severe enough to stop treatment in 4% of women.
AUTHORS' CONCLUSIONS
There was weak evidence to suggest that use of an adrenergic agonist was better than placebo treatment. There was not enough evidence to assess the effects of adrenergic agonists when compared to or combined with other treatments. Further larger trials are needed to identify when adrenergics may be useful. Patients using adrenergic agonists may suffer from minor side effects, which sometimes cause them to stop treatment. Rare but serious side effects, such as cardiac arrhythmias and hypertension, have been reported.
Topics: Adrenergic Agonists; Adult; Clenbuterol; Female; Humans; Midodrine; Phenylpropanolamine; Randomized Controlled Trials as Topic; Urinary Incontinence; Urinary Incontinence, Stress
PubMed: 16034867
DOI: 10.1002/14651858.CD001842.pub2