FF/VI represents the first once-daily ICS/LABA combination to be approved for use in the treatment of asthma; two strengths of FF/VI have been approved in Europe and Japan. We sought to compare the clinical efficacy of FF/VI 92/22 mcg with that of twice-daily FP/SAL 250/50 mcg and BUD/FORM 320/9 mcg, and that of FF/VI 184/22 mcg with FP/SAL 500/50 mcg and BUD/FORM 640/18 mcg. FF/VI 92/22 mcg has previously been shown to be comparable in efficacy in improving lung function and health status with FP/SAL 250/50 mcg in a head-to-head randomised controlled trial [7].
Using an MTC approach, we examined the probability of non-inferiority of once-daily FF/VI compared with corresponding strengths of twice-daily FP/SAL and BUD/FORM by combining data on clinical efficacy outcomes from several RCTs. All three ICS/LABA combination therapies have previously been shown to be associated with improvements in these outcomes relative to placebo.
We chose to use a Bayesian, hierarchical MTC modelling approach to synthesise evidence from RCTs conducted in adolescents and adults with asthma that involved at least one ICS/LABA comparator. Broad-scope searches were used to identify as many studies as possible that were potentially suitable for inclusion in the MTC. Exclusion criteria were subsequently applied on an outcome-by-outcome basis. The Bayesian approach that we used enabled a probabilistic estimate of non-inferiority to be generated directly from the posterior distribution [22].
To output meaningful probabilities of non-inferiority, it was necessary to select suitable margins. The non-inferiority margins used for the PEF analysis in this study, 12Â l/min and 15Â l/min, are well-established margins used in numerous previous studies and based upon European Medicines Agency guidelines [11, 23, 24]. For FEV1, the margins of 75Â ml, 100Â ml and 125Â ml were chosen based upon the minimal clinically important difference (MCID) of 230Â ml [13] and non-inferiority margins used in previous comparative studies involving FF/VI [6] or FF [25]. For exacerbations, the non-inferiority margins of 10Â % and 20Â % rate ratio reductions are consistent with the margin of 1.18 used in a previous non-inferiority study of FP/SAL vs FP [12]. The accepted MCID for the AQLQ is 0.5 [14], hence the use of a margin of 0.25, representing half of the MCID, preserves 50Â % of the active comparator effect. We consider that, as these margins are smaller than the MCID and therefore imply higher thresholds for demonstrating non-inferiority between treatments, they represent conservative margins for the non-inferiority analysis. However, it is important to note that a finding of a low probability of non-inferiority, using such conservative margins, does not imply lack of comparability or inferiority.
Based on these conservative margins, the results of the primary MTC analyses suggest that there is a high probability that FF/VI 92/22 mcg is non-inferior to FP/SAL 250/50 mcg and BUD/FORM 320/9 mcg on lung function (PEF and FEV1) and health status (AQLQ) endpoints, supporting the findings of the previous head-to-head RCT of FF/VI 92/22 mcg compared with FP/SAL 250/50 mcg. The analysis of exacerbation rate was inconclusive owing to the lack of sufficient data and disconnectedness of the network.
The effectiveness of any meta-analytic method can be limited by the amount of clinical trial data available for each of the treatments in the analysis. As a consequence of the limited number of RCTs available to inform comparisons of ICS/LABA therapies in asthma, the CrI for most of the non-inferiority estimates in our study were wide. Moreover, we decided a priori to treat different strengths of the same therapies as different treatments. This represents both a strength–in that the comparisons we have studied are more precise–and a weakness of our approach, as combining dosages may have produced a stronger and more connected network for the lung function and health status outcomes. The CrI were particularly wide for the outcomes of secondary interest (i.e. exacerbations and AQLQ). Exacerbations, in particular, are relatively rare events and are therefore typically only examined in longer-term studies. In addition, the primary endpoints of most RCTs in asthma assess lung function, rather than exacerbations. As such, our study network was weak with respect to exacerbations; this MTC incorporated only six studies, including just one study of FF/VI 92/22 mcg [5] and no studies of FF/VI 184/22 mcg for the primary exacerbations analysis. The small number of studies led to limited information in the network and subsequent disconnections in treatment networks. The full model did not converge because of the weak network. One consequence of this was that we were unable to account for covariates in the exacerbations MTC as was possible for the other three MTC outcomes. The post-hoc assessment of alternative modelling approaches showed that the findings of the lung function and health status MTCs were consistent upon the application of varied methodologies, including a frequentist approach, to the data where the network was sufficiently connected to permit this.
Population and endpoint heterogeneity in the studies included in the MTC analyses was addressed as far as possible by our inclusion criteria to ensure that patient populations were suitable for comparison. To minimise study-to-study variability, studies were only included in the primary PEF analysis if they reported mean change from baseline averaged across the whole trial, rather than from baseline to a specific timepoint. For the same reason, studies were excluded from the exacerbations analysis if the definition of exacerbation differed considerably from that set out in the ATS/ERS Task Force recommendation [8]. The findings of sensitivity analyses of both of these outcomes, conducted using data from enlarged networks derived from relaxed inclusion criteria, suggest that the MTC findings are highly susceptible to the addition of studies to the network.
Despite the measures we took in order to reduce study-to-study variability as far as possible given the nature of the analysis, over-dispersion was observed in the primary analysis model distributions. Through study-level covariate modelling within the MTC, we assessed whether variables including study duration, average patient age and exacerbation history affected the comparisons; we sought to correct for this through the incorporation of heterogeneity factors at the study level. Significant covariate effects of baseline FEV1 and study duration were observed in the PEF analysis only. The observation that greater baseline FEV1 is associated with slightly greater improvement from baseline in PEF is consistent with incompleteness of reversibility in patients with more severe airflow limitation [26].
Still, a limitation of this approach that should be borne in mind in the interpretation of the results is that it is not possible to correct for all confounding factors, particularly as patient-level data were not available. For instance, although the study inclusion criteria specified that patients had to be uncontrolled/symptomatic at baseline, it was not possible to ensure a consistent definition of “uncontrolled†across studies as the required data was often not reported. Furthermore, the fact that we have synthesised evidence from trials conducted at different periods of time and in different regions means that there will inevitably be some degree of underlying variation that could have influenced the findings. For instance, basic standards of care vary across regions and typically improve over time.
Although MTC are established as a useful tool for the synthesis of evidence that is suitable for use in clinical decision-making [27], to our knowledge, this is the first study to apply this methodology to data from clinical trials in asthma to investigate the relative efficacy of specific treatments. In a recently-published network meta-analysis in which data on treatment interventions in asthma were combined across classes [28] and their effectiveness assessed, ICS/LABA combination therapies were found to be the most effective intervention for the prevention of asthma exacerbations. In COPD, findings of meta-analyses of treatment efficacy data [29, 30] have indicated that ICS/LABA combination therapy have a greater positive effect on COPD outcomes than alternative treatment modalities.