Network meta-analysis of direct-acting antivirals in combination with peginterferon-ribavirin for previously untreated patients with hepatitis C genotype 1 infection.

AIM: To conduct a network meta-analysis (NMA) to determine the comparative efficacy, as measured by sustained virological response (SVR), between boceprevir (BOC), telaprevir (TEL), faldaprevir (FAL), simeprevir (SIM) and sofosbuvir (SOF) in combination with peginterferon-ribavirin (PR) against a control of PR. DESIGN: A literature search was conducted to identify randomized controlled trials (RCTs) including adult patients with hepatitis C virus genotype 1 who were naive to any prior therapy. RCTs assessing standard duration therapy (SDT) or response-guided therapy (RGT) BOC, TEL, FAL, SIM or SOF in combination with PR against a control of PR were eligible for inclusion. All RCTs must have provided SVR at either 12 or 24 weeks post-therapy cessation. RESULTS: We included nine RCTs. All direct-acting antivirals (DAAs) were found to perform better than PR. Additionally, SDT FAL was found to be better than the 240 mg RGT FAL regimen with the PR lead-in. A sensitivity analysis excluding RCTs with only SVR at 12 weeks was consistent with the results of the primary analysis. A sensitivity analysis removing an RCT assessing SIM that reported SVR of >60% in the PR control group additionally found that RGT SIM was superior to the 240 mg RGT FAL regimen with the PR lead-in. DISCUSSION: Our analyses indicate that SDT and RGT regimens of DAAs plus PR do not differ greatly in terms of SVR among treatment-naive hepatitis C genotype 1 patients. More advanced Bayesian network meta-analyses are likely needed to incorporate a comprehensive evidence base, expanding beyond randomized clinical trials.

Does anaesthesia with nitrous oxide affect mortality or cardiovascular morbidity? A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: The role of nitrous oxide in modern anaesthetic practice is contentious. One concern is that exposure to nitrous oxide may increase the risk of cardiovascular complications. ENIGMA II is a large randomized clinical trial currently underway which is investigating nitrous oxide and cardiovascular complications. Before the completion of this trial, we performed a systematic review and meta-analysis, using Cochrane methodology, on the outcomes that make up the composite primary outcome. METHODS: We used conventional meta-analysis and trial sequential analysis (TSA). We reviewed 8282 abstracts and selected 138 that fulfilled our criteria for study type, population, and intervention. We attempted to contact the authors of all the selected publications to check for unpublished outcome data. RESULTS: Thirteen trials had outcome data eligible for our outcomes. We assessed three of these trials as having a low risk of bias. Using conventional meta-analysis, the relative risk of short-term mortality in the nitrous oxide group was 1.38 [95% confidence interval (CI) 0.22-8.71] and the relative risk of long-term mortality in the nitrous oxide group was 0.94 (95% CI 0.80-1.10). In both cases, TSA demonstrated that the data were far too sparse to make any conclusions. There were insufficient data to perform meta-analysis for stroke, myocardial infarct, pulmonary embolus, or cardiac arrest. CONCLUSION: This systematic review demonstrated that we currently do not have robust evidence for how nitrous oxide used as part of general anaesthesia affects mortality and cardiovascular complications.

Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses.

There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

Longitudinal measurements of oxygen consumption in growing infants during the first weeks after birth: old data revisited.

BACKGROUND: In a study conducted in 1966-1969, longitudinal measurements were made of the metabolic rate in growing infants. Statistical methods for analyzing longitudinal data weren't readily accessible at that time. OBJECTIVES: To measure minimal rates of oxygen consumption (V·O2, ml/min) in growing infants during the first postnatal weeks and to determine the relationships between postnatal increases in V·O2, body size and postnatal age. METHODS: We studied 61 infants of any birth weight or gestational age, including 19 of very low birth weight. The infants, nursed in incubators, were clinically well and without need of oxygen supplementation or respiratory assistance. Serial measures of V·O2 using a closed-circuit method were obtained at approximately weekly intervals. V·O2 was measured under thermoneutral conditions with the infant asleep or resting quietly. Data were analyzed using mixed-effects models. RESULTS: During early postnatal growth, V·O2 rises as surface area (m(2))(1.94) (standard error, SE 0.054) or body weight (kg)(1.24) (SE 0.033). Multivariate analyses show statistically significant effects of both size and age. Reference intervals (RIs) for V·O2 for fixed values of body weight and postnatal age are presented. As V·O2 rises with increasing size and age, there is an increase in the skin-operative environmental temperature gradient (T skin-op) required for heat loss. Required T skin-op can be predicted from surface area and heat loss (heat production minus heat storage). CONCLUSIONS: Generation of RIs for minimal rates of V·O2 in growing infants from the 1960s was enabled by application of mixed-effects statistical models for analyses of longitudinal data. Results apply to the precaffeine era of neonatal care.

Direct-acting antiviral therapies for hepatitis C genotype 1 infection: a multiple treatment comparison meta-analysis.

BACKGROUND: New direct-acting antiviral agents for hepatitis C genotype 1 infection, boceprevir and telaprevir, offer enhanced sustained virologic response (SVR) among both treatment-naïve and treatment-experienced patients. AIM: To determine the relative efficacy of the new direct-acting antiviral agents by applying a multiple treatment comparison meta-analysis. DESIGN: We included published Phase II and III randomized controlled trials evaluating head-to-head comparisons between boceprevir, telaprevir, peg-interferon alpha-2a with ribavirin and peg-interferon alpha-2b with ribavirin in hepatitis C genotype 1 patients. We applied Bayesian multiple treatment comparison meta-analysis. RESULTS: We included data from four boceprevir, three telaprevir and six peg-interferon alpha-2a plus ribavirin vs. peg-interferon alpha-2b plus ribavirin randomized controlled trials. Both boceprevir and telaprevir offer statistically superior outcomes for SVR, relapse and discontinuation due to adverse events than either peg-interferons among both treatment-naïve and treatment-experienced patients. Among treatment-naïve patients, clinical outcomes were similar for boceprevir and telaprevir, for SVR [odds ratio (OR) 0.90, 95% credible interval (95% CrI) 0.41-1.91] and for relapse (OR 1.09, 95% CrI 0.19-4.84). Similarly, among treatment-experienced patients, clinical outcomes were similar for boceprevir and telaprevir and for SVR (OR 1.45, 95% CrI 0.70-3.08) and for relapse (OR 0.35, 95% CrI 0.13-1.02). For treatment-naïve patients receiving standard-duration therapy, telaprevir yielded lower rates of anemia and neutropenia, but higher rates of rash and pruritus. For treatment-experience patients, all adverse event rates were higher with telaprevir. DISCUSSION: Boceprevir and telaprevir exhibit similar effects among hepatitis C genotype 1 treatment-naïve and treatment-experienced patients.

The use of transcutaneous oximetry to predict healing complications of lower limb amputations: a systematic review and meta-analysis.

OBJECTIVE: To determine the validity of transcutaneous oximetry (TcPO(2)) as a predictor of lower limb amputation healing complications. DESIGN: A systematic review and meta-analysis. METHODS: We searched five major medical databases, relevant review articles and reference lists and included all studies that evaluated TcPO(2) for its ability to predict lower limb amputation healing failure. We selected eligible articles and conducted data abstraction independently and in duplicate. RESULTS: Thirty-one studies, enrolling 1824 patients with 1960 amputations, met our inclusion criteria. Only one study reported undertaking a multivariable analysis, which demonstrated that a TcPO(2) level below 20 mmHg was an independent predictor of re-amputation occurrence (adjusted odds ratio (OR) 3.08, 95% confidence interval (CI) 1.19-7.98). Fourteen prospective cohort studies reported data that allowed for the calculation of an unadjusted relative risk of lower limb amputation healing complications leading to amputation revision associated with a TcPO(2) level below cut-offs of 10 mmHg (1.80; 95% CI 1.19-2.72), 20 mmHg (1.75; 95% CI 1.27-2.40) 30 mmHg (1.41; 95% CI 1.22-1.62) and 40 mmHg (1.24; 95% CI 1.13-1.39). CONCLUSIONS: This review suggests that TcPO(2) predicts healing complications of lower limb amputations. A value of less than 40 mmHg results in a 24% increased risk of healing complication compared to over 40 mmHg and the risk further increases as the TcPO(2) decreases. There is, however, insufficient evidence to judge whether this tool adds important information beyond clinical data or to suggest an optimal threshold value. There is a need for a large, sufficiently powered study that adjusts for appropriate clinical variables.

Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials.

BACKGROUND: Glucocorticosteroids versus placebo or no intervention for patients with alcoholic hepatitis have been evaluated for more than 35 years. However, the results of randomized trials and meta-analyses differ substantially. AIM: To review all randomized clinical trials of glucocorticosteroids vs. placebo or no intervention for patients with alcoholic hepatitis. METHODS: We searched for randomized trials published before July 2007. The trials were assessed for risk of bias. RESULTS: We included 15 trials with a total of 721 randomized patients. The overall mortality rate was 39.5%. Twelve of the fifteen trials were at risk of bias. Glucocorticosteroids did not statistically reduce mortality compared with placebo or no intervention (relative risk 0.83, 95% CI 0.63-1.11). Glucocorticosteroids significantly reduced mortality in the subgroup of trials with patients with Maddrey's score of at least 32 or hepatic encephalopathy and with low-bias risk. In all analyses, heterogeneity was significant and substantial. Trial sequential analyses using heterogeneity-adjusted information size demonstrated no significant effect of glucocorticosteroids on mortality. Weighted logistic regression analyses taking prognostic factors at randomization into consideration found no significant effect of glucocorticosteroids on mortality. CONCLUSIONS: The current evidence base of mainly heterogeneous with high bias risk trials does not support the use of glucocorticosteroids in alcoholic hepatitis. Large, low-bias risk placebo-controlled randomized trials are needed.