Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions

The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation.

The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed.

We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease ("justification of treatment") or the disadvantages of the drug ("justification of withdrawal"). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case.

We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met.