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Acetyl-L-carnitine for patients with hepatic encephalopathy.
Martí-Carvajal, AJ, Gluud, C, Arevalo-Rodriguez, I, Martí-Amarista, CE
The Cochrane database of systematic reviews. 2019;(1):CD011451
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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.
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A meta-analysis of phosphate binders lanthanum carbonate versus sevelamer hydrochloride in patients with end-stage renal disease undergoing hemodialysis.
Zhou, T, Li, H, Xie, W, Lin, Z
African health sciences. 2018;(3):689-696
Abstract
BACKGROUND AND OBJECTIVES The purpose of this study was to compare the effects of phosphate binders lanthanum carbonate (LC) versus sevelamer hydrochloride (SH) in end-stage renal disease (ESRD) patients undergoing hemodialysis. METHODS Studies including randomized controlled trials (RCTs) comparing phosphate binders lanthanum carbonate versus sevelamer hydrochloride, in ESRD patients undergoing hemodialysis, were identified using a pre-defined search strategy. Phosphate, calcium, calcium-phosphorus product, intact parathyroid hormone, alkaline phosphatase, total cholesterol, and triglyceride were extracted and compared by RevMan 5.1 (The Cochrane Collaboration, Oxford, UK). RESULTS Six studies were identified. Meta-analysis showed that SH treatment reduced levels of phosphate, intact parathyroid hormone, and total serum alkaline phosphatase (ALP) when compared with LC treatment. Furthermore, patients on SH treatment tended to have reduced calcium levels, calcium-phosphorus product, total cholesterol, and triglyceride when compared to patients treated with LC, but there was no statistical difference. CONCLUSION SH treatment of patients with ESRD is more effective compared to LC treatment. However, more well-designed random control trails are required for confirmation.
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The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis.
Habbous, S, Przech, S, Acedillo, R, Sarma, S, Garg, AX, Martin, J
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(1):111-125
Abstract
BACKGROUND It remains unclear which phosphate binders should be preferred for hyperphosphatemia management in chronic kidney disease (CKD). METHODS We performed a systematic review and meta-analysis of randomized trials comparing sevelamer or lanthanum with other phosphate binders in CKD. RESULTS Fifty-one trials (8829 patients) were reviewed. Compared with calcium-based binders, all-cause mortality was nonsignificantly lower with sevelamer {risk ratio [RR] 0.62 [95% confidence interval (CI) 0.35-1.08]} and lanthanum [RR 0.73 (95% CI 0.18-3.00)], but risk of bias was concerning. Compared with calcium-based binders, sevelamer reduced the risk of hypercalcemia [RR 0.27 (95% CI 0.17-0.42)], as did lanthanum [RR 0.12 (95% CI 0.05-0.32)]. Sevelamer reduced hospitalizations [RR 0.50 (95% CI 0.31-0.81)], but not lanthanum [RR 0.80 (95% CI 0.34-1.93)]. The presence/absence of other clinically relevant outcomes was infrequently reported. Compared with calcium-based binders, sevelamer reduced serum calcium, low-density lipoprotein and coronary artery calcification, but increased intact parathyroid hormone. The clinical relevance of these changes is unknown since corresponding clinical outcomes were not reported. Lanthanum had less favorable impact on biochemical parameters. Sevelamer hydrochloride and sevelamer carbonate were similar in three studies. Sevelamer was similar to lanthanum (three studies) and iron-based binders (three studies). CONCLUSION Sevelamer was associated with a nonsignificant reduction in mortality and significantly lower hospitalization rates and hypercalcemia compared with calcium-based binders. However, differences in important outcomes, such as cardiac events, fractures, calciphylaxis, hyperchloremic acidosis and health-related quality of life remain understudied. Lanthanum and iron-based binders did not show superiority for any clinically relevant outcomes. Future studies that fail to measure clinically important outcomes (the reason why phosphate binders are prescribed in the first place) will be wasteful.
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Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis.
Sekercioglu, N, Thabane, L, Díaz Martínez, JP, Nesrallah, G, Longo, CJ, Busse, JW, Akhtar-Danesh, N, Agarwal, A, Al-Khalifah, R, Iorio, A, et al
PloS one. 2016;(6):e0156891
Abstract
BACKGROUND Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. This condition is characterized by high phosphate levels and requires phosphate-lowering agents-phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on patient-important outcomes in patients with CKD-MBD. METHODS Data sources included MEDLINE and EMBASE Trials from 1996 to February 2016. We also searched the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD, randomized them to receive calcium (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet, placebo or no treatment, and reported effects on all-cause mortality, cardiovascular mortality or hospitalization at ≥4 weeks follow-up. We performed network meta-analyses (NMA) for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. NCBPBs for all-cause mortality, cardiovascular mortality and hospitalization. In the NMAs, we calculated the effect estimates for direct, indirect and network meta-analysis estimates; for both NMA and conventional meta-analysis, we pooled treatment effects as risk ratios (RR) and calculated 95% confidence intervals (CIs) using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each paired comparison. RESULTS Our search yielded 1190 citations, of which 71 RCTs were retrieved for full review and 15 proved eligible. With 13 eligible studies from a prior review, we included 28 studies with 8335 participants; 25 trials provided data for our quantitative synthesis. Results suggest higher mortality with calcium than either sevelamer (NMA RR, 1.89 [95% CI, 1.02 to 3.50], moderate quality evidence) or NCBPBs (conventional meta-analysis RR, 1.76 [95% CI, 1.21 to 2.56, moderate quality evidence). Conventional meta-analysis suggested no difference in cardiovascular mortality between calcium and NCBPBs (RR, 2.54 [95% CI, 0.67 to 9.62 low quality evidence). Our results suggest higher hospitalization, although non-significant, with calcium than NCBPBs (RR, 1.293 [95% CI, 0.94 to 1.74, moderate quality evidence). DISCUSSION/CONCLUSIONS Use of calcium results in higher mortality than either sevelamer in particular and NCBPBs in general (moderate quality evidence). Our results raise questions about whether administration of calcium as an intervention for CKD- MBD remains ethical. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD-42016032945.
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Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials.
Palmer, SC, Gardner, S, Tonelli, M, Mavridis, D, Johnson, DW, Craig, JC, French, R, Ruospo, M, Strippoli, GF
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016;(5):691-702
Abstract
BACKGROUND Guidelines preferentially recommend noncalcium phosphate binders in adults with chronic kidney disease (CKD). We compare and rank phosphate-binder strategies for CKD. STUDY DESIGN Network meta-analysis. SETTING & POPULATION Adults with CKD. SELECTION CRITERIA FOR STUDIES Randomized trials with allocation to phosphate binders. INTERVENTIONS Sevelamer, lanthanum, iron, calcium, colestilan, bixalomer, nicotinic acid, and magnesium. OUTCOMES The primary outcome was all-cause mortality. Additional outcomes were cardiovascular mortality, myocardial infarction, stroke, adverse events, serum phosphorus and calcium levels, and coronary artery calcification. RESULTS 77 trials (12,562 participants) were included. Most (62 trials in 11,009 patients) studies were performed in a dialysis population. Trials were generally of short duration (median, 6 months) and had high risks of bias. All-cause mortality was ascertained in 20 studies during 86,744 patient-months of follow-up. There was no evidence that any drug class lowered mortality or cardiovascular events when compared to placebo. Compared to calcium, sevelamer reduced all-cause mortality (OR, 0.39; 95% CI, 0.21-0.74), whereas treatment effects of lanthanum, iron, and colestilan were not significant (ORs of 0.78 [95% CI, 0.16-3.72], 0.37 [95% CI, 0.09-1.60], and 0.55 [95% CI, 0.07-4.43], respectively). Lanthanum caused nausea, whereas sevelamer posed the highest risk for constipation and iron caused diarrhea. All phosphate binders lowered serum phosphorus levels to a greater extent than placebo, with iron ranked as the best treatment. Sevelamer and lanthanum posed substantially lower risks for hypercalcemia than calcium. LIMITATIONS Limited testing of consistency; short follow-up. CONCLUSIONS There is currently no evidence that phosphate-binder treatment reduces mortality compared to placebo in adults with CKD. It is not clear whether the higher mortality with calcium versus sevelamer reflects whether there is net harm associated with calcium, net benefit with sevelamer, both, or neither. Iron-based binders show evidence of greater phosphate lowering that warrants further examination in randomized trials.
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Effect of lanthanum carbonate versus calcium-based phosphate binders in dialysis patients: a meta-analysis.
Zhai, CJ, Yu, XS, Sun, QL, Li, L, Zhang, LT, Zhou, AY, Wang, R
Clinical nephrology. 2014;(6):372-8
Abstract
BACKGROUND The effects of lanthanum carbonate (LC) vs. calciumbased phosphate binders in dialysis patients have been a matter of debate. METHODS We electronically searched PubMed, Embase, CENTRAL, and CBM for all randomized controlled trials comparing LC with calcium-based phosphate binders in adult dialysis patients. Quality assessment was performed using the Cochrane risk of bias tool. Metaanalysis was conducted by RevMan 5.2. RESULTS Nine studies were eligible for our meta-analysis. There was no significant difference in all-cause mortality (RR 0.84, 95% CI 0.25 - 2.83) and cardiovascular events (RR 0.84, 95% CI 0.55 - 1.29) between LC and calcium-based phosphate binders. LC was associated with similar proportions of phosphate-controlled patients (RR 0.63, 95% CI 0.27 - 1.44) and lower incidence of hypercalcemia (RR 0.13, 95% CI 0.05 - 0.35) in comparison to calcium-based phosphate binders. Compared with calcium salts, LC was associated with significantly lower serum calcium, similar serum Ca x P product and higher serum iPTH. CONCLUSION Despite the trends observed, we found no statistically significant differences in all-cause mortality and cardiovascular events between LC and calcium-based phosphate binders in dialysis patients. The conclusion was limited by lack of large sample and long-term trials. LC could reduce the incidence of hypercalcemia while comparable with calcium-based phosphate binders in reducing serum phosphorus level.
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Is lead chelation therapy effective for chronic kidney disease? A meta-analysis.
Yang, SK, Xiao, L, Song, PA, Xu, XX, Liu, FY, Sun, L
Nephrology (Carlton, Vic.). 2014;(1):56-9
Abstract
The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure and the presence of chronic kidney injury. Some studies have suggested that chelation therapy with calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) might help decrease the progression of chronic kidney disease among patients with measurable body lead burdens. However, calcium disodium EDTA chelation in lead exposure is controversial due to the potential for adverse effects such as acute tubular necrosis. Therefore, we investigated the available randomized controlled trials assessing the renoprotective effects of calcium disodium EDTA chelation therapy. Our meta-analysis shows that calcium disodium EDTA chelation therapy can effectively delay the progression of chronic kidney disease in patients with measurable body lead burdens reflected by increasing the levels of estimated glomerular filtration rate (eGFR) and creatinine clearance rate (Ccr). There appears to be no conclusive evidence that calcium disodium EDTA can decrease proteinuria.
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The effects of non-calcium-based phosphate binders versus calcium-based phosphate binders on cardiovascular calcification and bone remodeling among dialysis patients: a meta-analysis of randomized trials.
Liu, L, Wang, Y, Chen, H, Zhu, X, Zhou, L, Yang, Y
Renal failure. 2014;(8):1244-52
Abstract
BACKGROUND Vascular calcification significantly increases the rates of cardiovascular mortality in hemodialysis (HD) patients. Abnormalities in mineral metabolism may play a role in the pathogenesis of arterial calcification. Whether patients treated with non-calcium-based phosphate binders had reduced aortic vascular calcification compared to those treated with calcium-based phosphate binders is still unclear. METHODS We searched multiple databases for studies published through August 2013 that evaluated the effects of non-calcium-based phosphate binders (NCBP) versus calcium-based phosphate binders (CBP) on cardiovascular calcification and bone remodeling among dialysis patients. We summarized test performance characteristics with the use of forest plots, fixed and random effects models, and Egger regression test. RESULTS Eighteen eligible randomized controlled trials totaling 3676 patients were included. Meta-analysis results showed NCBP could significantly attenuate the progression of coronary artery calcification than CBP (WMD: -144.62, 95% CI: -285.62 to -3.63). The serum calcium levels significant lower in NCPB group than in CPB groups (WMD: -0.26, 95% CI: -0.37 to -0.14), but the serum iPTH levels were significantly higher in NCPB groups (WMD: 57.1, 95% CI: 13.42 to 100.78). The osteoid volume and osteoblast numbers were significant higher in NCPB group than in CPB group (WMD: 1.75, 95% CI: 0.78 to 2.73 for osteoid volume; WMD: 4.49, 95% CI: 1.83 to 7.15 for osteoblast numbers). The Egger regression test also showed no potential publication bias (p = 0.725). CONCLUSIONS Based on available data, NCBPs have equally effective with CBPs for serum phosphate control. But there was significantly lower incidence of coronary artery calcification and a significant higher bone formatting rate in NCBP groups than in CBP groups. So we recommend NCBPs as phosphate binders for HD patients.
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Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.
Jamal, SA, Vandermeer, B, Raggi, P, Mendelssohn, DC, Chatterley, T, Dorgan, M, Lok, CE, Fitchett, D, Tsuyuki, RT
Lancet (London, England). 2013;(9900):1268-77
Abstract
BACKGROUND Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. METHODS We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. FINDINGS Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). INTERPRETATION Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. FUNDING None.