Non-inferiority (NI) trials are essential to evaluate whether new treatments which may offer some collateral benefit (such as less invasiveness, fewer side effects, availability, ease of administration, or lower cost) do so without significant loss of efficacy, as compared to treatments that are already established to be beneficial. NI trials pose specific design challenges, such as selecting appropriate NI margins, as well as unique problems of interpretation.

We examine six NI trials that compared thrombectomy with or without intravenous thrombolysis (IVT). We review fundamental problems with NI trials.

Two of six trials reported that thrombectomy alone was non-inferior compared to thrombectomy combined with IVT. These trials used large NI margins or stopped recruitment prematurely after an interim analysis. The remaining four trials failed to demonstrate non-inferiority. In general, the chosen NI margins were unjustified and clinically unacceptable. A meta-analysis showed NI at a 10% margin, but not at a clinically pertinent 5% level. We examine (i) assay sensitivity, (ii) the constancy assumption and (iii) NI margins, three concepts that are crucial to understand NI trials. We question whether NI trials are appropriate in acute stroke, where there is little room to accept inferiority. Assessing superiority regarding surrogate outcome measures that have shown a causal relationship with clinical outcomes may be an alternative approach.

Thrombectomy alone has not properly been shown non-inferior to thrombectomy with IVT. The NI trial design is poorly adapted for use in acute stroke.