Extracorporeal liver support in patients with liver failure: a systematic review and meta-analysis of randomized trials
Intensive Care Medicine. 2020;46(1):1-16
This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to examine the efficacy and safety of extracorporeal liver support (ECLS) in liver failure.
The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched from inception through March 13, 2019. Randomized control trials (RCTs) comparing ECLS to usual care in acute liver failure (ALF) or acute chronic liver failure (ACLF) were included. Included studies met the following criteria: (1) the study design was a randomized controlled trial (RCT); (2) the population were adults with ALF or ACLF; (3) the interventions were any form of artificial or bio-artificial ECLS; (4) the control group received supportive care not including ECLS; (5) the outcomes were all-cause mortality or liver-related mortality, bridging to liver transplant, improvement of HE and adverse events such as hypotension, bleeding, thrombocytopenia, line infection, and citrate toxicity.
A total of 25 randomized controlled trials, comprising 1796 patients were identified and used in this study.
The main outcomes explored were mortality, hepatic encephalopathy and adverse effects.
Up to 6 months
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a systematic review and meta-anlaysis of 25 RCTs including a total of 1796 patients randomised to extra-corporeal liver support (ECLS) for acute liver failure or acute on chronic liver failure. Overall the review was conducted with several signs of good quality, by following the PRISMA statement and registering a protocol in advance. Multiple databases were searched and only RCTs were included. Report screening, data extraction and bias assessment were all completed in duplicate by 2 reviewers, another good indicator. Publication bias was assessed by funnel plot with Egger’s test. Among artificial systems, MARS (Teraklin AG, Germany, was the
most commonly used (8 studies) followed by Biologic-DT (HemoCleanse, Inc., USA, 5 studies), FPSA (Prometheus, Fresenius Medical Care, Germany, 2 studies), plasma exchange with hemoperfusion, whole blood exchange, and charcoal hemoperfusion (1 study each). Bio-artifcial modalities included extracorporeal liver assist device (ELAD, Vital Terapies Inc., USA, 3 studies) and HepatAssist (Circe Biomedical Inc., USA, 1 study). Twenty four studies reported mortality and in meta-analysis extra-corporeal liver support was associated with improved mortality, albeit potentially a very small effect (RR=0.84, 95%CI= 0.74-0.96), with low-moderate heterogeneity. The use of ECLS was associated with improved hepatic encephalopathy compared to usual care (RR=0.71; 95% CI= 0.60- 0.84), with low heterogeneity between studies, however some evidence of publication bias was suspected following funnel plot and Egger’s test (P=0.041). There was no significant differences in the risk of bleeding, hypotension or thrombocytopenia. The authors include a number of sensitivity analyses as well to explore the effect of type of liver failure, type of ECLS and study risk of bias, not finding any significant interaction. This is a thorough study overall and if the level of certainty in the conclusions is low, it is not the fault of the authors here. The results suggest that ECLS may reduce mortality and hepatic encephalopathy in acute and acute on chronic liver failure but the degree of benefit for each of the different types of system is not clear. Each of the included studies was small and RCTs using new technology in specific groups of patients are required.
PURPOSE Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure. METHODS We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence. RESULTS We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain. CONCLUSIONS ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.
Comparing preferences of physicians and patients regarding the allocation of donor organs: A systematic review
Transplant Rev (Philadelphia). 2020;[record in progress]:100515
In order to improve the demand-supply-mismatch in transplantation medicine, policy makers have to think about adapting existing legal frameworks for donor organ allocation. This study aims to systematically review preferences of physicians as well as patients in the field of transplantation medicine. PubMed, Web of Science, EBSCO and PsycINFO were searched from January 2000 to December 2018 without language restrictions. Fourteen publications were identified, six aiming at physicians, seven focusing on patients and one on both groups. The criteria used in these studies to elicit preferences can be grouped into six different main categories, all deriving from the general principle of equality: "Effectiveness/Benefit", "Medical urgency", "Own fault", "Social value", "Medical background" and "Socio-demographic status". Whilst patients on the one hand show a high demand for equal access, outcome maximization and punishment for damaging behaviors, they would still allocate organs to people with very low survival chances. Physicians decide against equal access to transplantation in cases where clinical evidence is weighed more heavily, e.g. in the cases of ethnicity and sex. Also, they seem more informed regarding the involvement of medical factors and give less importance to those with uncertain effects on transplantation outcome, such as tissue or blood group match. It is important to continuously monitor preferences of all involved stakeholders in order to achieve fair and accessible transplantation systems.
Measurement of health-related quality of life in pediatric organ transplantation recipients: a systematic review of the PedsQL transplant module
Quality of Life Research. 2020;[record in progress]
OBJECTIVE To collect and assess the extant empirical literature assessing disease-specific health-related quality of life (HRQOL) in pediatric transplant recipients using the PedsQL 3.0 Transplant Module (PedsQL-TM) assessment. STUDY DESIGN A systematic search and review procedure was conducted of research reporting use and results of the PedsQL-TM with samples of pediatric heart, liver, kidney, and lung transplantation. Searches were conducted in nine scholarly databases and two additional sources to identify unpublished research. Multiple reviewers screened studies meeting inclusion criteria in accordance with PRISMA guidelines. RESULTS A final sample of nine studies reported findings for the PedsQL-TM with pediatric organ transplant recipients. Most studies relied on either kidney or liver transplant recipients from single pediatric transplant centers. Factor validity of the PedsQL-TM and inter-rater reliability (IRR) between patients and parents have not been adequately determined. Internal consistency reliability was found as acceptable or excellent across multiple studies. PedsQL-TM scores were found to vary with other HRQOL issues, yet few studies examined their association with medication adherence or posttransplant health outcomes. CONCLUSIONS With the goal of enhancing and sustaining HRQOL in pediatric organ transplant recipients, the need for a psychometrically valid and reliable measure of transplant-specific HRQOL is apparent. Research on the PedsQL-TM supports the promise of this measure although future efforts should be taken to examine measurement issues such as factor validity and IRR. Assessing transplant-specific HRQOL in these patients is paramount for their care and appropriate decision-making by patients, families, and the transplant team.
Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma
Annals of Surgery. 2020;24:24
OBJECTIVE To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). BACKGROUND Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. METHODS MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. RESULTS Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without. CONCLUSIONS In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.
Photodynamic therapy for the prevention and treatment of Actinic Keratosis/Squamous cell carcinoma in solid organ transplant recipients: A systematic review and meta-analysis
Journal of the European Academy of Dermatology & Venereology. 2020;34(2):251-259
Solid organ transplant recipients (sOTR) are at an increased risk of developing cutaneous cancers, especially squamous cell carcinoma (SCC). Photodynamic therapy (PDT) for the prevention and treatment of actinic keratosis (AK)/SCC in sOTR is increasingly prescribed given the increase in solid organ transplantations performed worldwide. PDT has added advantages of superior cosmetic outcomes and good safety profile compared to conventional surgical methods and other topical therapies. We aim to evaluate the role of PDT in the prevention and treatment of AK/SCC in sOTRs. The Cochrane Library, PubMed and Embase Database were searched. Articles reporting PDT outcomes amongst sOTR with or without AK/SCC at baseline were selected. We classified the studies into two categories: (1)PDT as prevention measure and (2)treatment of AK/SCC in sOTR. Primary outcome for the prevention category was three-year incidence of AK/SCC and complete response (CR) of lesions after PDT exposure in the treatment category. Secondary outcomes were cosmesis and adverse reaction in both categories. Pooled results were expressed as risk difference (RD) with corresponding 95% confidence interval (95% CI). Twelve out of 641 articles met our eligibility criteria, out of which 4 RCTs reported the preventive effect of AK/SCC and another 5 RCTs reported the treatment effect of PDT in sOTR. One RCT did not report absolute number of lesions at baseline/end of study for results to be pooled in the quantitative analysis. The remaining three studies were cohort studies reporting treatment and preventive effect of PDT in sOTR. PDT group had a lower incidence as a preventive measure with pooled RD of 0.14(95% CI 0.08-0.19). The CR in PDT was higher in the treatment group with a pooled RD of 0.77(95% CI 0.6-0.94) and 0.50 (95% CI 0.22-0.79) in pre-divided lesional areas and number of lesions respectively. In conclusion, PDT is efficacious for prevention and treatment of AK/SCC in sOTRs. This article is protected by copyright. All rights reserved.
Impact of the MELD score on the survival of hepatocellular carcinoma transplantation patients in Brazil: a systematic review
Revista do Colegio Brasileiro de Cirurgioes. 2020;46(6):e20192392
This study aimed to analyse the predictive value of Model For End-Stage Liver Disease (MELD) score on medium- and long-term survival in transplanted hepatocellular carcinoma (HCC) patients in Brazil. The study was registered with International Prospective Register of Systematic Reviews (PROSPERO) under N# 152,363. Inclusion criteria were based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations. The search was performed on the indexed databases of Lilacs, SciELO, PubMed, and Cochrane Library, and used as search strategy the following Medical Subject Headings (MeSH) terms: ((("MELD Score") OR "Model For End-Stage Liver Disease") AND "Hepatocellular Carcinoma") AND ("Brazil"). We included full-text articles published from January 2006 to October 2019. The initial search found 162 articles. After reading the available abstracts and full texts, 156 articles were excluded, totaling six articles for qualitative analysis. Although the small number of eligible articles was a limiting factor of the study, our results partially corroborated those found in the United States, United Kingdom, and Ireland. In these countries, unlike Brazil, MELD prognostic model has shown a strong association with post-liver transplant (LT) survival. However, the low predictive capacity of the model in medium- and long-term has been similar to the one of our study. The urgency of the development and validation of a post-transplant survival model for patients with HCC is set, improving the organ allocation system in Brazil.
Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis
Cochrane Database of Systematic Reviews. 2020;1:CD013203
The aim of study was to compare the benefits and harms of using different immunosuppressive induction regimens among adult liver transplant recipients through a network meta-analysis and to rank the induction immunosuppressive regimens on the basis of their efficacy and safety.
Electronic databases including Cochrane Central Register of Controlled Trials (CENTRAL), Science Citation Index Expanded (Web of Science), Embase Ovid and MEDLINE Ovid were searched for randomised controlled trials comparing two or more pre-specified induction immunosuppressive regimens of interest from inception to July 2019. The World Health Organization International Clinical Trials Registry Platform, the US National Institutes of Health Ongoing Trials Register, existing Cochrane Reviews and the references of the identified trials were also searched to identify additional trials. The study selection and data extraction were carried out by two independent authors. The risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.
25 studies (3271 participants) were included in the review.
The primary outcomes were mortality from all causes at maximal follow-up, time to graft failure (retransplantation or death) at maximal follow up, health-related quality of life and incidence of serious adverse events. The secondary outcomes were incidence of any adverse event, time to liver retransplantation at maximal follow-up and acute rejection at maximal follow-up. The exploratory outcomes included costs at maximal follow-up.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a well conducted Cochrane systematic review of RCTs. Multiple databases were searched and references were screened in duplicate. 25 RCTs were included, with a median 12 months follow up (total 3271 patients). Data extraction was then conducted in duplicate to a pre-designed format. The standard Cochrane risk of bias assessment was used to appraise the included studies. Heterogeneity was assessed both statistically and by examination. As not all included trials made the same comparisons, a network meta-analysis was used to compare immune suppression induction regimens. Despite this approach the key conclusions only draw upon the results of 2
included studies: Basiliximab was associated with reduced all-cause mortality compared to glucocorticoids (131 patients). Only 1 study made the comparison between Basiliximab and glucocorticoids and presented the outcome of graft failure, which was less with Basiliximab (47 patients). This means that there is a low level of certainty with regards to the key outcomes of this systematic review. There is an even lower level of certainty when comparing other induction regimens and glucocorticoids.
BACKGROUND Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) 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 (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life.
Vasomodulators and liver transplantation for portopulmonary hypertension: evidence from a systematic review and meta-analysis
Untreated portopulmonary hypertension (PoPH) carries poor prognosis. Previous reports have described vasomodulator therapy (VM) and liver transplantation (LT) as treatment options. However, no study has systematically summarized the reported effects on pulmonary hemodynamics and survival. We aimed to provide summary estimates on these endpoints in patients with PoPH, treated with different modalities. We performed a systematic review with meta-analysis of mainly observational and case-control studies describing no treatment, VM, LT or VM+LT in patients with PoPH. Twenty-six studies (1019 patients) were included. Both VM and VM+LT improve pulmonary hemodynamics. A substantial proportion of patients treated with VM becomes eligible for LT (44%, 95%CI:31-58). Pooled estimates for 1-, and 3-year post-diagnosis survival in patients treated with VM were 86% (95%CI:81-90) and 69% (95%CI:50-84), versus 82% (95%CI:52-95) and 67% (95%CI:53-78) in patients treated with VM+LT. Of note, studies reporting on the effect of VM mainly included Child-Pugh A/B patients, while studies reporting on VM+LT mainly included Child-Pugh B/C. Seven studies (238 patients) included both patients who received VM only and patients who received VM+LT. The risk of death in VM-only-treated patients was significantly higher than in patients who could be transplanted too (odds ratio 3.5; 95%CI:1.4-8.8), however, importantly, patients who proceeded to transplant had been selected very strictly. In 50% of patients, VM can be discontinued post-LT (95%CI:38-62).
Efficacy and safety of ketoconazole combined with calmodulin inhibitor in solid organ transplantation: A systematic review and meta-analysis
Journal of Clinical Pharmacy & Therapeutics. 2020;45(1):29-34
WHAT IS KNOWN AND OBJECTIVE Calcineurin inhibitors (CNIs) can significantly improve the results of solid organ transplantation regarding graft and patient survival. However, the high cost, chronic nephrotoxicity and other side effects are major challenges for the long-term use of these drugs. Ketoconazole can significantly increase the plasma concentration of CNIs by inhibiting the activity of the cytochrome P450 enzyme. The combination of ketoconazole-CNIs can reduce the cost of medication for patients by reducing the dosage of CNIs, but its safety is still controversial. Therefore, this study was designed to assess the safety and efficacy of this combination. METHODS We performed a systematic literature search in PubMed, Embase, Cochrane Library and clinicaltrials.gov for randomized controlled trials on ketoconazole and CNI (cyclosporin or tacrolimus) co-administration in solid organ transplantation. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta-analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019118796. RESULTS AND DISCUSSION Five relevant trials with 326 patients were included. Compared with the controls, ketoconazole combined with CNIs can significantly reduce the dose of CNIs in patients receiving solid organ transplantation (WMD = -203.04 mg/day; 95% CI: -310.51 to -95.57, P = .0002). There was no significant difference in serum creatinine between the experimental group and the control group (WMD = -0.19 mg/mL; 95% CI: -0.52 to 0.14, P = .26). In addition, there was no significant difference in the number of rejections between the two groups (OR = 0.58; 95% CI: 0.27 to 1.22, P = .15). WHAT'S NEW AND CONCLUSION The co-administration of ketoconazole and CNIs can significantly reduce the dose of CNIs. This combination may be safely used as a CNI-sparing agent from the time of solid organ transplantation with low-dose ketoconazole, based on the findings of this review.
Indications and outcomes of combined heart-liver transplant: A systematic review and met-analysis
Transplant Rev (Philadelphia). 2020;34(2):100517
BACKGROUND Combined heart-liver transplantation (CHLT) has become a viable option for treating concomitant heart and liver failure. However, data are lacking with respect to long-term outcomes. METHODS An electronic search was performed to identify all studies on CHLT. Following application of inclusion and exclusion criteria, a total of seven studies consisting of 99 CHLT patients were included from the original 1864 articles. RESULTS CHLT recipient mean age was 53.0years (95% CI 48.0-58.0), 67.5% of which (95% CI 56.5-76.9) were male. 65.5% (95% CI 39.0-85.0) of patients developed heart failure due to amyloidosis whereas 21.6% (95% CI 12.3-35.2) developed heart failure due to congenital causes. The most common indication for liver transplant was amyloidosis [65.5% (95% CI 39.0-85.0)] followed by liver failure due to hepatitis C [13.8% (95% CI 2.1-54.4)]. The mean intensive care unit length of stay was 8days (95% CI 5-11) with a mean length of stay of 24days (95% CI 17-31). Cardiac allograft rejection within the first year was 24.7% (95% CI 9.5-50.7), including antibody mediated [5% (95% CI 1.7-15.2)] and T-cell mediated rejection [22.7% (95% CI 8.8-47.1)]. Overall survival was 87.5% (95% CI 78.6-93.0) at 1year and 84.3% (95% CI 75.4-90.5) at 5years. CONCLUSIONS CHLT in select patients with coexisting end-stage heart and liver failure appears to offer high survival and low rejection rates.