1,026 Experimental treatments in acute stroke

TLDR

Preclinical neuroprotectant studies had generated high expectations, but uncertainty remains whether poor experimental indicators or lack of translation of the most effective drugs account for limited clinical success, highlighting the need for greater rigor in animal research. The study aimed to compare experimental efficacy and testing scope between clinically used neuroprotectants and those studied only experimentally. Researchers performed a systematic search of neuroprotectants, selected controlled in vivo and in vitro studies with functional or histological endpoints, and statistically examined relationships among outcome, drug mechanism, testing scope, and clinical trial status. Statistical analysis revealed no experimental advantage for clinically used drugs over those only tested in animals, variable testing scope, and no link between mechanism and efficacy, suggesting that the most effective drugs may not be selected for stroke trials and contributing to slow therapeutic progress.

Abstract

Preclinical evaluation of neuroprotectants fostered high expectations of clinical efficacy. When not matched, the question arises whether experiments are poor indicators of clinical outcome or whether the best drugs were not taken forward to clinical trial. Therefore, we endeavored to contrast experimental efficacy and scope of testing of drugs used clinically and those tested only experimentally.We identified neuroprotectants and reports of experimental efficacy via a systematic search. Controlled in vivo and in vitro experiments using functional or histological end points were selected for analysis. Relationships between outcome, drug mechanism, scope of testing, and clinical trial status were assessed statistically.There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for example, improvement in focal models averaged 31.3 +/- 16.7% versus 24.4 +/- 32.9%, p > 0.05, respectively. Scope of testing using Stroke Therapy Academic Industry Roundtable (STAIR) criteria was highly variable, and no relationship was found between mechanism and efficacy.The results question whether the most efficacious drugs are being selected for stroke clinical trials. This may partially explain the slow progress in developing treatments. Greater rigor in the conduct, reporting, and analysis of animal data will improve the transition of scientific advances from bench to bedside.