Dexmedetomidine vs propofol in intensive care unit patients

Dexmedetomidine is indicated as a sedative agent in intensive care units(ICUs). While several clinical trials and two meta-analyses have compared this agent with propofol or midazolam, the results were variable depending on the specific end-point(e.g., duration of mechanical ventilation, ICU mortality, maintaining a target depth of sedation, incidence of delirium episodes, length of hospital stay). Hence, the effectiveness of this new agent vs the comparators seems to be controversial. Trial sequential analysis(TSA) is a statistical technique that can estimate the optimal, cumulative number of patients that would be needed to generate a conclusive result. We therefore applied a TSA model to the most recent meta-analysis evaluating dexmedetomidine. A total of 10 randomized controlled trials were included in our analysis. According to our results, the comparison of dexmedetomidine vs propofol showed no proof of incremental effectiveness for the end-points of length of ICUs stay and incidence of delirium episodes. In contrast, futility(i.e., proof of no incremental effectiveness) was demonstrated for the end-point of mechanical ventilation. Hence, the results for the comparison of dexmedetomidine vs propofol were inconclusive for the first two end-points; on the other hand, conclusiveness was reached for the third end-point. We conclude that the place of dexmedetomidine in therapy of critically ill patients is very uncertain and further controlled trials are still needed.

Effect of discounting on estimation of benefits determined by hepatitis C treatment

The combination of either boceprevir or telaprevir with ribavirin and interferon (triple therapy) has been shown to be more effective than ribavirin+interferon (dual therapy) for the treatment of genotype 1 hepatitis C. Since the benefit of these treatments takes place after years, simulation models are needed to predict long-term outcomes. In simulation models, the choice of different values of yearly discount rates (e.g., 6%, 3.5%, 2%, 1.5% or 0%) influences the results, but no studies have specifically addressed this issue. We examined this point by determining the long-term benefits under different conditions on the basis of standard modelling and using quality-adjusted life years (QALYs) to quantify the benefits. In our base case scenario, we compared the long-term benefit between patients given a treatment with a 40% sustained virologic response (SVR) (dual therapy) and patients given a treatment with a 70% SVR (triple therapy), and we then examined how these specific yearly discount rates influenced the incremental benefit. The gain between a 70% SVR and a 40% SVR decreased from 0.45 QA-LYs with a 0% discount rate to 0.22 QALYs with a 6% discount rate (ratio between the two values = 2.04).Testing the other discounting assumptions confirmed that the discount rate has a marked impact on the magnitude of the model-estimated incremental benefit. In conclusion, the results of our analysis can be helpful to better interpret cost-effectiveness studies evaluating new treatment for hepatitis C.

Meta-regression of treatments for metastatic colorectal cancer:Quantifying incremental benefit from 2000 to 2012

To evaluate the overall effectiveness of treatments for metastatic colorectal cancer, a meta-regression was undertaken in which randomized studies from 2000 to 2012 were evaluated and the temporal trend for both overall survival(OS) and progression-free survival(PFS) was determined. Our literature search was essentially based on Pub Med but information sources were scanned. Trials were included if a fluoropyrimidine regimen was given to at least one arm and information on PFS and OS was available. Medians for OS and PFS were our end-points. Covariates included temporal trend, arm allocation and Kirsten rat sarcoma status. In analyzing 130 treatment arms identified through our literature search, meta-regression showed an improvement with time for both OS(P < 0.001) and PFS(P < 0.001). The increase in median OS was from 14.9 mo in 2000 to 18.8 mo in 2012. Likewise, the improvement in PFS was from 5.7 to 8.1 mo. Multivariate analysis confirmed these findings. A post-hoc multivariate analysis was focused on patient arms treated with bevacizumab(n = 17) or without bevacizumab(n = 113); the multivariate-adjusted improvement attributable to bevacizumab was 1.66 mo for OS(P = 0.071) and 1.59 mo for PFS(P = 0.002). Overall, our results indicatethat OS and PFS have improved from 2000 to 2012 but the extent of this improvement is small and seems to have quite a questionable clinical relevance.

Maintenance Chemotherapy in Ovarian Cancer: A Trial-Sequential Analysis

In patients with epithelian ovarian cancer who have achieved remission after initial surgery and induction chemotherapy, the role of maintenance chemotherapy is controversial. We carried out a trial-sequential analysis that included 4 randomised controlled trials. The end-point was progression at 3 years while the boundary for non-inferiority was set at ±20% in risk ratio. The results of our trial-sequential analysis indicated the futility of maintenance chemotherapy, i.e. proof of no effectiveness. Consequently, no further trials of this type should be performed to assess the effectiveness of this intervention in this clinical condition.

Are Newer-Generation Drug-Eluting Stents More Effective in Women than Early-Generation Ones?

Evidence-based research is increasingly aimed at differentiating between no proof of difference (failed demonstration of superiority) and proof of no difference (demonstration of equivalence). The latter requires that equivalence margins are incorporated in the analysis of outcomes. We applied an analysis of equivalence to study the incremental benefit of newer-generation vs early-generation drug-eluting stents (DES) in women receiving percutaneous coronary intervention. The clinical material was derived from published data. Our equivalence testing was focused on the end-point of target-lesion revascularisation (TLR). Results were expressed as rate differences (RDs), while the equivalence margins (±2.9%) were derived from the statistical power calculations of a recent trial. Our results clearly indicated that, in women, there was an equivalent effectiveness between newer-generation and early-generation of DES.

Simplified figure to present direct and indirect comparisons:Revisiting the graph 10 years later

A“simplified”figure was proposed in 2011 to summarize the results of controlled trials that evaluate different treatments aimed at the same disease condition.The original criteria for classifying individual binary comparisons included superiority,inferiority and no significance difference;hence,they did not differentiate between no proof of difference vs proof of no difference.We updated the criteria employed in the original“simplified”figure in order to include this differentiation.A revised version of the simplified figure is proposed and described herein.An example of application is also presented.The example is focused on first-line treatments for paroxysmal atrial fibrillation.Three treatments(medical therapy,cryoballoon ablation,radiofrequency ablation)are compared with one another through direct and indirect comparisons.