Abstract
Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and real-world database analyses have been conducted. The question of how much information from these two approaches is congruent or discrepant with each other is of great importance for the clinical practice. To answer this question, we focused on data from the antipsychotic (AP) treatment of schizophrenia. Our aim was two-fold: to conduct a meta-analysis of real-world studies (RWS), and to compare the results of RWS meta-analysis with previously published meta-analyses of RCTs. The principal measure of effectiveness was all-cause treatment discontinuation for both RWS and RCTs (when not available, then drop out for RCTs). We included publications for 8 selected APs (oral formulations of amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and long-acting injectable (LAI) risperidone). We identified 11 RWS and 7 RCT meta-analyses for inclusion. Our results indicated that the RWS yielded statistically conclusive and consistent findings across individual investigations. For the overwhelming majority of the comparisons where both RWS and RCT meta-analyses were available, there was good congruency between the RWS and the RCT results. Our results support that RCTs, despite their limitations, provide evidence which is generalizable to real-world settings. This is an important finding for both regulators and clinicians. RWS can provide guidance for situations where no evidence is available from double-blind clinical trials.
Highlights
Antipsychotic drugs (AP) are recommended both for the shortterm treatment of acute episodes as well as for the long-term maintenance treatment in schizophrenia [1]
The list of the eight selected APs we investigated were as reducing the risk of all-cause discontinuation (while it was inferior to follows: amisulpride oral (AMI), aripiprazole oral (ARI), clozapine oral OLA and risperidone oral (RIS) LAI)
With respect to the both statistically conclusive and consistent outcomes we found the following order of superiority in terms of relative risk of all-cause discontinuation for the AP pairs in the individual pair-wise comparisons: OLA > RIS, OLA > QUE, haloperidol oral (HAL) < RIS, risperidone LAI (RIS LAI) > RIS, AMI < OLA, ARI < OLA, ARI < RIS LAI, CLO > HAL, AMI < RIS LAI, CLO < RIS LAI, HAL < QUE, and QUE < RIS LAI
Summary
Antipsychotic drugs (AP) are recommended both for the shortterm treatment of acute episodes as well as for the long-term maintenance treatment in schizophrenia [1]. Even though RCTs are considered to provide the highest grade of evidence, the question of generalizability of their results to real life outcomes arises for several reasons. These are, for example, the inclusion of highly selected non-representative samples in RCTs [6], fix doses, short duration, small sample size, and predominantly placebo control associated with regulatory recommendations [7]. While shorter duration in acute trials has been supported by data, which guides clinical practice [3], the number of long-term follow-up RCT studies is still small [8, 9]. There is still a lack of clinically important real-world endpoints, such as hospitalization in these studies [10]
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