-
1.
Efficacy and safety of pharmacological cachexia interventions: systematic review and network meta-analysis.
Saeteaw, M, Sanguanboonyaphong, P, Yoodee, J, Craft, K, Sawangjit, R, Ngamphaiboon, N, Shantavasinkul, PC, Subongkot, S, Chaiyakunapruk, N
BMJ supportive & palliative care. 2021;(1):75-85
Abstract
AIMS: Randomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia. METHODS PubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI. RESULTS 80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo. CONCLUSIONS Our findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.
-
2.
Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.
Choy, MC, Seah, D, Faleck, DM, Shah, SC, Chao, CY, An, YK, Radford-Smith, G, Bessissow, T, Dubinsky, MC, Ford, AC, et al
Inflammatory bowel diseases. 2019;(7):1169-1186
-
-
Free full text
-
Abstract
BACKGROUND Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. METHODS Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. RESULTS Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. CONCLUSIONS In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.
-
3.
Probiotics for people with hepatic encephalopathy.
Dalal, R, McGee, RG, Riordan, SM, Webster, AC
The Cochrane database of systematic reviews. 2017;(2):CD008716
-
-
Free full text
-
Abstract
BACKGROUND Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient's quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when administered in adequate amounts, may confer a health benefit on the host. OBJECTIVES To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. SELECTION CRITERIA We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random-effects model meta-analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias.We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD -8.29 μmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial.When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD -2.93 μmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. AUTHORS' CONCLUSIONS The majority of included trials suffered from a high risk of systematic error ('bias') and a high risk of random error ('play of chance'). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.
-
4.
Meta-analysis of oro-cecal transit time in fasting subjects.
Kokubo, T, Matsui, S, Ishiguro, M
Pharmaceutical research. 2013;(2):402-11
Abstract
PURPOSE Computer simulations are utilized during pharmaceutical development in order to design appropriate formulation based on the absorption, distribution, metabolism, and excretion (ADME) and physicochemical properties of target compounds, so that adequate prescriptions are offered to patients. Oro-cecal transit time (OCTT) is an important factor affecting these simulations because the absorption of drug that administered orally and the resultant pharmacokinetic profile are expressed as a function of time. Given the large intra- and inter-individual variance in OCTT, it is unsurprising that an accurate model has not yet been proposed. METHODS We conducted a meta-analysis using subject-level data to construct a statistical model that predicted OCTT. Literature that utilized lactulose to measure OCTT was identified and analyzed using a mixed-effects model. RESULTS The OCTTs of fasting healthy subjects were expressed using a linear model, with the amount of lactulose as the single significant explanatory factor. We found that this model could statistically distinguish the OCTTs of subjects with altered physical status from those of healthy people. Specifically, cystic fibrosis and celiac disease most significantly affected OCTT. CONCLUSION The OCTT models developed herein incorporate inter-subject variations and can contribute to providing more accurate predictions of drug pharmacokinetic profiles.
-
5.
Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.
Videlock, EJ, Cheng, V, Cremonini, F
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2013;(9):1084-1092.e3; quiz e68
Abstract
BACKGROUND & AIMS Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 μg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 μg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.
-
6.
Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials.
Ye, Y, Zhao, X, Zhai, G, Guo, L, Tian, Z, Zhang, S
Journal of cardiovascular pharmacology and therapeutics. 2012;(4):357-65
Abstract
BACKGROUND Combining low-dose statin and ezetimibe reduces the low-density lipoprotein cholesterol (LDL-C) similar to high-dose statin. However, whether there is a difference in the effect of these 2 lipid-lowering regimes on endothelial function is still controversial. METHODS We performed a systematic search of databases (MEDLINE [1950 to September 2011], EMBASE [1966 to September 2011]) and references of identified studies. Completely published randomized controlled trials comparing the effect of high-dose statin with low-dose stain plus ezetimibe on endothelial function (flow-mediated dilation [FMD] method) were included in this study. RESULTS Six trials with a total of 213 participants were included in the meta-analysis. The pooled weighted mean difference of FMD did not differ between the 2 lipid-lowering regimes (0.22%; 95% confidence interval [CI]: -0.85%-1.29%, P = .68). Furthermore, no significant reduction in LDL-C and C-reactive protein (CRP) occurred with high-dose statin versus low-dose statin plus ezetimibe (pooled weighted mean differences of LDL-C and CRP were -4.12 mg/dL, 95% CI: -9.54-1.12 mg/dL, P = .12, and -0.02 mg/L, 95% CI: -0.31-0.27 mg/L, P = .89, respectively). CONCLUSIONS Based on the currently available evidence, combining a low-dose statin with ezetimibe may provide similar beneficial effects on endothelial function as high-dose statin.
-
7.
Meta-analysis: long-term therapy with rifaximin in the management of uncomplicated diverticular disease.
Bianchi, M, Festa, V, Moretti, A, Ciaco, A, Mangone, M, Tornatore, V, Dezi, A, Luchetti, R, De Pascalis, B, Papi, C, et al
Alimentary pharmacology & therapeutics. 2011;(8):902-10
-
-
Free full text
-
Abstract
BACKGROUND Diverticular disease of the colon is a common gastrointestinal disease. Although most patients remain asymptomatic for their whole life, about 20-25% present symptoms related to 'diverticular disease'. Several randomised trials verified efficacy of a poorly absorbed antibiotic, such as rifaximin-α (rifaximin), in soothing symptoms and preventing diverticulitis. AIM: To evaluate the long-term efficacy administration of rifaximin plus fibre supplementation vs. fibre supplementation alone, on symptoms and complications, in patient with symptomatic uncomplicated diverticular disease. METHODS Pertinent studies were selected from the Medline, and the Cochrane Library Databases, references from published articles and reviews. Conventional meta-analysis according to DerSimonian and Laird method was used for the pooling of the results. The outcomes were 1- year complete symptom relief, and 1- year complication incidence. The rate difference (RD, with 95% CI) and the Number Needed to Treat (NNT) were used as measure of the therapeutic effect on each outcome. RESULTS Four prospective randomised trials including 1660 patients were selected. The pooled RD for symptom relief was 29.0% (rifaximin vs. control; 95% CI 24.5-33.6%; P<0.0001; NNT=3). The pooled RD for complication rate was -1.7% in favour of rifaximin (95% CI -3.2 to -0.1%; P=0.03; NNT=59). When considering only acute diverticulitis, the pooled RD in the treatment group was -2% (95% CI -3.4 to -0.6%; P=0.0057; NNT=50). CONCLUSIONS In symptomatic uncomplicated diverticular disease, treatment with rifaximin plus fibre supplementation is effective in obtaining symptom relief and preventing complications at 1 year.
-
8.
Probiotics for patients with hepatic encephalopathy.
McGee, RG, Bakens, A, Wiley, K, Riordan, SM, Webster, AC
The Cochrane database of systematic reviews. 2011;(11):CD008716
Abstract
BACKGROUND Hepatic encephalopathy is a disorder of brain function as a result of liver failure and/or portosystemic shunt. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient's quality of life and daily functioning and represent a significant burden on health care resources. Probiotics are live microorganisms, which when administered in adequate amounts may confer a health benefit on the host. OBJECTIVES To quantify the beneficial and harmful effects of any probiotic in any dosage, compared with placebo or no intervention, or with any other treatment for patients with any grade of acute or chronic hepatic encephalopathy as assessed from randomised trials. SEARCH METHODS We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, conference proceedings, reference lists of included trials and the WHO international clinical trials registry until April 2011 registry platform to identify new and ongoing trials. SELECTION CRITERIA We included randomised trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in patients with hepatic encephalopathy. DATA COLLECTION AND ANALYSIS Three authors independently assessed the risk of bias of the included trials and extracted data on relevant outcomes, with differences resolved by consensus. We conducted random-effects model meta-analysis due to obvious heterogeneity of patients and interventions. A P value of 0.05 or less was defined as significant. Dichotomous outcomes are expressed as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included seven trials of which 550 participants were randomised. Four of the seven trials compared a probiotic with placebo or no treatment in 245 participants, another trial compared a probiotic with lactulose in 40 participants , and the remaining two trials compared a probiotic with both placebo and lactulose in 265 participants. Each trial used different types of probiotics. Duration of administration of the experimental intervention varied from 10 days to 180 days. Two trials were industry funded, and five were unclear about origin of funding. All trials had high risk of bias. When probiotics were compared with no treatment, there was no significant difference in all-cause mortality (2 trials, 105 participants; 1/57 (2%) versus 1/48 (2%): RR 0.72; 95% CI 0.08 to 6.60), lack of recovery (4 trials, 206 participants; 54/107 (50%) versus 68/99 (69%): RR 0.72; 95% CI 0.49 to 1.05), adverse events (3 trials, 145 participants; 2/77 (3%) versus 6/68 (9%): RR 0.34; 95% CI 0.08 to 1.42), quality of life (1 trial, 20 participants contributed to the physical quality of life measurement, 20 participants contributed to the mental quality of life: MD Physical 0.00; 95% CI -5.47 to 5.47; MD Mental 4.00; 95% CI -1.82 to 9.82), or change of/or withdrawal from treatment (3 trials, 175 participants; 11/92 (12%) versus 7/83 (8%): RR 1.28; 95% CI 0.52 to 3.19). No trial reported sepsis or duration of hospital stay as an outcome. Plasma ammonia concentration was significantly lower for participants treated with probiotic at one month (3 trials, 226 participants: MD -2.99 μmol/L; 95% CI -5.70 to -0.29) but not at two months (3 trials, 181 participants: MD -1.82 μmol/L; 95% CI -14.04 to 10.41). Plasma ammonia decreased the most in the participants treated with probiotic at three months (1 trial, 73 participants: MD -6.79 μmol/L; 95% CI -10.39 to -3.19). When probiotics were compared with lactulose no trial reported all-cause mortality, quality of life, duration of hospital stay, or septicaemia. There were no significant differences in lack of recovery (3 trials, 173 participants; 47/87 (54%) versus 44/86 (51%): RR 1.05; 95% CI 0.75 to 1.47), adverse events (2 trials, 111 participants; 3/56 (5%) versus 6/55 (11%): RR 0.57; 95% CI 0.06 to 5.74), change of/or withdrawal from treatment at one month (3 trials, 190 participants; 8/95 (8%) versus 7/95 (7%): RR 1.10; 95% CI 0.40 to 3.03), plasma ammonia concentration (2 trials, 93 participants: MD -6.61 μmol/L; 95% CI -30.05 to 16.84), or change in plasma ammonia concentration (1 trial, 77 participants: MD 1.16 μmol/L; 95% CI -1.96 to 4.28). AUTHORS' CONCLUSIONS The trials we located suffered from a high risk of systematic errors ('bias') and high risk of random errors ('play of chance'). While probiotics appear to reduce plasma ammonia concentration when compared with placebo or no intervention, we are unable to conclude that probiotics are efficacious in altering clinically relevant outcomes. Demonstration of unequivocal efficacy is needed before probiotics can be endorsed as effective therapy for hepatic encephalopathy. Further randomised clinical trials are needed.
-
9.
Therapy options in irritable bowel syndrome.
Enck, P, Junne, F, Klosterhalfen, S, Zipfel, S, Martens, U
European journal of gastroenterology & hepatology. 2010;(12):1402-11
Abstract
BACKGROUND Numerous meta-analyses have recently assessed the overall clinical benefit of single therapy options and groups of therapies in the irritable bowel syndrome (IBS). By large, this should enable physicians to select from a number of therapy options available. METHODS We entered dichotomous outcome data from 121 IBS trials published over the last 35 years with different groups and subgroups of drugs (antispasmodics, motility-affecting agents, antidepressants, peppermint oil), dietary interventions (bran, probiotics), and psychotherapy (cognitive behavioral, psychodynamic, hypnotherapy, relaxation techniques) into meta-analytic tools and estimate the overall efficacy (odds ratio, number needed to treat). RESULTS Highest efficacy is currently found for peppermint oil, followed by psychotherapeutic and psychopharmacological interventions and probiotics. Traditional antispasmodic therapy has a moderate efficacy, whereas the list of (partially failed or cancelled) motility affecting drugs yielded weak clinical results, and therapies by bran and fibers are of no value in IBS. CONCLUSION Evidence-based therapy in IBS provides a number of effective treatment options beyond the fact that many novel compounds under development have failed to reach the market. An algorithm for clinical therapy decision is proposed.
-
10.
Meta-analysis: The treatment of irritable bowel syndrome.
Lesbros-Pantoflickova, D, Michetti, P, Fried, M, Beglinger, C, Blum, AL
Alimentary pharmacology & therapeutics. 2004;(11-12):1253-69
-
-
Free full text
-
Abstract
To evaluate therapies available for the treatment of irritable bowel syndrome, and provide consensus recommendations for their use, a total of 51 double-blind clinical trials using bulking agents, prokinetics, antispasmodics, alosetron, tegaserod and antidepressants were selected. The quality of studies was assessed using 5-point scale. Meta-analyses were performed on all studies, and on 'high-quality studies'. The efficacy of fibre in the global irritable bowel syndrome symptoms relief (OR: 1.9; 95% CI:1.5-2.4) was lost after exclusion of low-quality trials (OR: 1.4; 95% CI: 1.0-2.0, P = 0.06). When excluding the low-quality trials, an improvement of global irritable bowel syndrome symptoms with all antispasmodics (OR: 2.1; 95% CI:1.8-2.9) was maintained only for octylonium bromide, but on the basis of only two studies. Antidepressants were effective (OR: 2.6, 95% CI: 1.9-3.5), even after exclusion of low-quality studies (OR: 1.9, 95% CI: 1.3-2.7). Alosetron (OR: 2.2; 95% CI: 1.9-2.6) and tegaserod (OR: 1.4; 95% CI: 1.2-1.5) showed a significant effect in women. We recommend the use of tegaserod for women with irritable bowel syndrome with constipation and alosetron for women with severe irritable bowel syndrome with diarrhoea. Antidepressants can be beneficial for irritable bowel syndrome with diarrhoea patients with severe symptoms. Loperamide can be recommended in painless diarrhoea. Evidence is weak to recommend the use of bulking agents in the treatment of irritable bowel syndrome with constipation.