Tags

Type your tag names separated by a space and hit enter

Acetyl-L-carnitine for patients with hepatic encephalopathy.
Cochrane Database Syst Rev. 2019 01 05; 1:CD011451.CD

Abstract

BACKGROUND

Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy.

OBJECTIVES

To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy.

SEARCH METHODS

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites.

SELECTION CRITERIA

We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms.

DATA COLLECTION AND ANALYSIS

We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach.

MAIN RESULTS

We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated.

AUTHORS' CONCLUSIONS

This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.

Authors+Show Affiliations

Iberoamerican Cochrane Network, Valencia, Venezuela.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

Language

eng

PubMed ID

30610762

Citation

Martí-Carvajal, Arturo J., et al. "Acetyl-L-carnitine for Patients With Hepatic Encephalopathy." The Cochrane Database of Systematic Reviews, vol. 1, 2019, p. CD011451.
Martí-Carvajal AJ, Gluud C, Arevalo-Rodriguez I, et al. Acetyl-L-carnitine for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2019;1:CD011451.
Martí-Carvajal, A. J., Gluud, C., Arevalo-Rodriguez, I., & Martí-Amarista, C. E. (2019). Acetyl-L-carnitine for patients with hepatic encephalopathy. The Cochrane Database of Systematic Reviews, 1, CD011451. https://doi.org/10.1002/14651858.CD011451.pub2
Martí-Carvajal AJ, et al. Acetyl-L-carnitine for Patients With Hepatic Encephalopathy. Cochrane Database Syst Rev. 2019 01 5;1:CD011451. PubMed PMID: 30610762.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acetyl-L-carnitine for patients with hepatic encephalopathy. AU - Martí-Carvajal,Arturo J, AU - Gluud,Christian, AU - Arevalo-Rodriguez,Ingrid, AU - Martí-Amarista,Cristina Elena, Y1 - 2019/01/05/ PY - 2019/1/6/pubmed PY - 2019/4/11/medline PY - 2019/1/6/entrez SP - CD011451 EP - CD011451 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev VL - 1 N2 - BACKGROUND: Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. OBJECTIVES: To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites. SELECTION CRITERIA: We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms. DATA COLLECTION AND ANALYSIS: We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach. MAIN RESULTS: We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/30610762/Acetyl_L_carnitine_for_patients_with_hepatic_encephalopathy_ L2 - https://doi.org/10.1002/14651858.CD011451.pub2 DB - PRIME DP - Unbound Medicine ER -