Biomedical subjects

L L Gluud

Publications and source records attributed to L L Gluud.

10 recordsLinked to original sources

PubMed2007

Multivariable modelling for meta-epidemiological assessment of the association between trial quality and treatment effects estimated in randomized clinical trials.

Methodological deficiencies are known to affect the results of randomized trials. There are several components of trial quality, which, when inadequately attended to, may bias the treatment effect under study. The extent of this bias, so far only vaguely known, is currently being investigated by 'meta-epidemiological' re-analysis of data collected as part of systematic reviews. As inadequate quality components often co-occur, we maintain that the suspected biases must be evaluated simultaneously. Furthermore, the biases cannot safely be assumed to be homogeneous across systematic reviews. Therefore, a stable multivariable method that allows for heterogeneity is needed for assessing the 'bias coefficients'. We present two general statistical models for analysis of a study of 523 randomized trials from 48 meta-analyses in a random sample of Cochrane reviews: a logistic regression model uses the design of the trials as such to give estimates; a weighted regression model incorporates between-trial variation and thus gives wider confidence intervals, but is computationally lighter and can be used with trials of more general design. In both models, heterogeneity in the bias coefficients can be incorporated in two ways. A stratification approach pools the estimates from models estimated on subgroups of the data. We explore stratification by reviews and by broad trial types, the latter of which gives larger subgroups of the data, circumventing instabilities. A multilevel approach also avoids instabilities and addresses the more fundamental problem of interpretation of the pooled multivariable effect in the presence of heterogeneity.

Clinical Trials as Topic↗

PubMed2006

Cyclosporin versus tacrolimus for liver transplanted patients.

BACKGROUND: Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior. OBJECTIVES: To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently. MAIN RESULTS: We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). AUTHORS' CONCLUSIONS: Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

Cyclosporine↗

PubMed2006

Terlipressin for hepatorenal syndrome.

BACKGROUND: Terlipressin may reverse some of the circulatory changes associated with hepatorenal syndrome. OBJECTIVES: To assess the beneficial and harmful effects of terlipressin for hepatorenal syndrome. SEARCH STRATEGY: Electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Renal Group Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, and EMBASE were combined with scanning of bibliographies and conference proceedings, and correspondence with experts and pharmaceutical companies. Last search update was July 2006. SELECTION CRITERIA: Randomised clinical trials were included irrespective of dose or treatment duration. Included patients had type 1 or type 2 hepatorenal syndrome. Co-interventions were allowed if administered equally to both treatment and control groups. DATA COLLECTION AND ANALYSIS: Data were retrieved from trial reports and correspondence with the authors of included trials. Mortality was the primary outcome. Meta-analyses were performed to calculate risk differences (RD) for binary outcomes and weighted mean differences (WMD) for continuous outcomes. Both were presented with 95% confidence intervals (CI). Due to the limited number of trials, no subgroup analyses were performed. MAIN RESULTS: The initial searches identified 645 potentially relevant references. Six randomised trials were eligible for inclusion. Three trials are still ongoing. Three trials with a total of 51 patients assessed terlipressin 1 mg bid for 2 to 15 days. Co-interventions included albumin, fresh frozen plasma, and cimetidine 800 mg daily. One trial reported adequate bias control assessed by randomisation and blinding. All trials reported mortality. Terlipressin reduced mortality rates by 34% (RD -0.34, 95% CI -0.56 to -0.12). The control group mortality rate was 65%. Terlipressin improved renal function assessed by creatinine clearance (WMD 21 ml/min, 95% CI 17 to 26), serum creatinine (WMD -219 micromol/l, 95% CI -244 to -194), and urine output (WMD 707 ml/day, 95% CI -212 to 1625). Adverse events included headache, abdominal pain, cardiac arrhythmia, and hypertension. AUTHORS' CONCLUSIONS: Additional evidence on terlipressin for hepatorenal syndrome is needed before reliable treatment recommendations can be made. The dose and duration of therapy, and the influence of co-interventions remain to be established.

Hepatorenal Syndrome↗

PubMed2006

Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis.

A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73-0.99; graft loss: RR 0.73, 95% CI 0.61-0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75-0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47-0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01-1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49-0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation.

Acute Disease↗

PubMed2005

Ribavirin monotherapy for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades. Ribavirin monotherapy may represent a treatment for some patients. OBJECTIVES: To assess the beneficial and harmful effect of ribavirin monotherapy for patients with chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until May 2005. SELECTION CRITERIA: We included all randomised trials irrespective of blinding, language, or publication status comparing ribavirin versus no intervention, placebo, or interferon for chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the six months sustained loss of hepatitis C virus RNA in blood after end of treatment and liver-related morbidity plus all-cause mortality. Secondary outcome measures were end of treatment virological response, biochemical response, histological response, and adverse events. Random- and fixed-effects meta-analyses with 95% confidence intervals (CI) were performed for all outcomes. We used Peto odds ratios (OR) for analysis of morbidity plus mortality and relative risks (RR) for the remaining outcomes. MAIN RESULTS: We identified 13 randomised trials including 594 patients with chronic hepatitis C. Most trials had low methodological quality. Compared with placebo/no intervention, ribavirin had no significant effect on sustained (RR 1.01, 95% CI 0.96 to 1.07, five trials) or end of treatment virological response (RR 1.00, 95% CI 0.94 to 1.07, ten trials). Ribavirin had no significant effect on liver-related morbidity plus mortality (Peto OR 1.96, 95% CI 0.20 to 19.0, eleven trials). Ribavirin significantly improved end of treatment biochemical and histological response but not sustained biochemical response. Further, ribavirin significantly increased the risk of anaemia. Ribavirin was significantly inferior to interferon regarding virological and biochemical response (four trials). AUTHORS' CONCLUSIONS: We found that ribavirin versus placebo/no intervention had no significant beneficial effect on virological response and liver morbidity, but may improve biochemical and histological response transiently. Ribavirin increased the risk of anaemia. Therefore, we cannot recommend ribavirin monotherapy for patients with chronic hepatitis C outside randomised trials.

Antiviral Agents↗

PubMed2005

Ribavirin plus interferon versus interferon for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.

Antiviral Agents↗

PubMed2004

Dopaminergic agonists for hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopaminergic agonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2004), The Cochrane Central Register of Controlled Trials (Issue 3, 2004), MEDLINE (1966-2004/07), EMBASE (1980-2004/07), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: All randomised trials comparing dopaminergic agonists versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Trial inclusion and data extraction were made independently by two reviewers. Binary outcomes are reported as odds ratios (OR) with 95% confidence intervals (CI) based on a random effects model. The presence of statistical heterogeneity was explored by the chi-squared test with significance set at P < 0.1. Potential sources of heterogeneity were explored through subgroup analyses with regard to the type of hepatic encephalopathy and type of dopaminergic agonist. MAIN RESULTS: Five trials were included. Four trials had low methodological quality. Compared with placebo or no treatment, dopaminergic agonists had no significant effect on the risk of no improvement (OR 0.33, 95% CI 0.01 to 11.25, two trials, 80 patients) or mortality (OR 1.11, 95% CI 0.34 to 3.54, four trials, 139 patients). There was significant heterogeneity (P = 0.09) among trial results on the risk of no improvement, but not on mortality (P = 0.19). The treatment response was not significantly different with regard to the type of hepatic encephalopathy or dopaminergic agonist, but the analyses had very low power to detect potential differences. There was a nonsignificant trend that dopaminergic agonists may be associated with adverse events (OR 8.33, 95% CI 0.37 to 187.74, 2 trials, 13 patients). All adverse events (n = 7) occurred in the experimental group. REVIEWERS' CONCLUSIONS: This review does not provide evidence that dopaminergic agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure. The review is limited by the small number of trials performed within this field, the low number of patients randomised in each trial, and the low methodological quality of included trials. Accordingly, there is also insufficient evidence to exclude a potential beneficial effect. Dopaminergic agonists should not be used for hepatic encephalopathy, but may be assessed in future randomised clinical trials.

Dopamine Agonists↗

PubMed2004

Benzodiazepine receptor antagonists for hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I(2). Potential sources of heterogeneity were explored through subgroup analyses. MAIN RESULTS: Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous. REVIEWERS' CONCLUSIONS: Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.

Acute Disease↗

PubMed2004

Nonabsorbable disaccharides for hepatic encephalopathy.

BACKGROUND: Nonabsorbable disaccharides (lactulose or lactitol) are considered the treatment of choice for hepatic encephalopathy. OBJECTIVES: To assess the beneficial and harmful effects of nonabsorbable disaccharides for patients with hepatic encephalopathy. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (March 2003), The Cochrane Central Register of Controlled Trials (Issue 1, 2003), MEDLINE (1966 to 2003/03), EMBASE (1980 to 2003/03), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing lactulose or lactitol versus no intervention, placebo, or antibiotics and trials comparing lactulose versus lactitol for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: The primary outcome measures included no improvement of hepatic encephalopathy and all-cause mortality. Binary outcomes are reported as relative risks (RR) based on a random effects model. Subgroup analyses were performed with regard to methodological quality and form of hepatic encephalopathy. MAIN RESULTS: Thirty trials assessed nonabsorbable disaccharides versus placebo, no intervention, or antibiotics or assessed lactulose versus lactitol. We could not extract data from all trials. Compared with placebo or no intervention, nonabsorbable disaccharides had no statistically significant effect on mortality (RR 0.41, 95% CI 0.02 to 8.68, four trials), but appeared to reduce the risk of no improvement of hepatic encephalopathy (RR 0.62, 95% CI 0.46 to 0.84, six trials). However, this result may reflect bias due to low methodological quality of the majority of included trials. Trials of high methodological quality found no significant effect of nonabsorbable disaccharides on the risk of no improvement (RR 0.92, 95% CI 0.42 to 2.04, two trials). We found no statistically significant difference between lactulose and lactitol on mortality (two trials) or risk of no improvement (four trials). However, our meta-analyses were underpowered to establish whether these treatments have comparable effect. Nonabsorbable disaccharides appeared to be inferior to antibiotics on reducing the risk of no improvement (RR 1.24, 95% CI 1.02 to 1.50, 10 trials). REVIEWERS' CONCLUSIONS: This systematic review questions the beneficial effects of nonabsorbable disaccharides and highlights that there is insufficient high-quality evidence to support this treatment. We found that antibiotics appeared to be superior to nonabsorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference in treatment effect is clinically important to patients. Nonabsorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy.

Anti-Bacterial Agents↗

PubMed2004

Artificial and bioartificial support systems for liver failure.

BACKGROUND: Artificial and bioartificial liver support systems may 'bridge' patients with acute or acute-on-chronic liver failure to liver transplantation or recovery. OBJECTIVES: To evaluate beneficial and harmful effects of artificial and bioartificial support systems for acute and acute-on-chronic liver failure. SEARCH STRATEGY: Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2002), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2002), MEDLINE (1966 - September 2002), EMBASE (1985 - September 2002), and The Chinese Biomedical Database (September 2002), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials on artificial or bioartificial support systems for acute or acute on-chronic liver failure were included irrespective of blinding, publication status, or language. Non-randomised studies were included in explorative analyses. DATA COLLECTION AND ANALYSIS: Data were extracted independently by three reviewers. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Sources of heterogeneity were explored through sensitivity analyses and meta-regression. The primary outcome was mortality. MAIN RESULTS: Twelve trials on artificial or bioartificial support systems versus standard medical therapy (483 patients) and two trials comparing different artificial support systems (105 patients) were included. Most trials had unclear methodological quality. Compared to standard medical therapy, support systems had no significant effect on mortality (RR 0.86; 95% CI 0.65-1.12) or bridging to liver transplantation (RR 0.87; 95% CI 0.73-1.05), but a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95% CI 0.52-0.86). Meta-regression indicated that the effect of support systems depended on the type of liver failure (P = 0.03). In subgroup analyses, artificial support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR 0.67; 95% CI 0.51-0.90), but not in acute liver failure (RR 0.95; 95% CI 0.71-1.29). Two trials comparing artificial support systems showed significant mortality reductions with intermittent versus continuous haemofiltration (RR 0.58; 95% CI 0.36-0.94) and no significant difference between five versus ten hours of charcoal haemoperfusion (RR 1.03; 95% CI 0.65-1.62). The incidence of adverse events was inconsistently reported. REVIEWER'S CONCLUSIONS: This Review indicates that artificial support systems may reduce mortality in acute-on-chronic liver failure. Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure. However, considering the strength of the evidence additional randomised clinical trials are needed before any support system can be recommended for routine use.

Chronic Disease↗