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JAMA Neurol. 2019 Dec 2. doi: 10.1001/jamaneurol.2019.4107. [Epub ahead of print]

The Hazard of Negative (Not Neutral) Trials on Treatment of Acute Stroke: A Review.

Author information

Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.
Stroke, Nottingham University Hospitals NHS Trust, Nottingham, England.
Vascular Medicine, Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, England.



While there are a limited number of beneficial treatments for acute stroke (eg, stroke units, reperfusion, aspirin, hemicraniectomy), there are more negative (as opposed to neutral) interventions spanning multiple different mechanisms of action. To reduce the risk of future negative studies, it is vital to understand why previous interventions appeared to cause harm.


The limited number of beneficial treatments for acute ischemic stroke are far outnumbered by negative (not neutral) interventions that worsened outcomes in randomized clinical trials (RCTs), including those with putative neuroprotectant, anticoagulant, anti-inflammatory, free radical-scavenging, hemorrhagic, or vasoactive activity. Other agents reduced thrombolytic efficiency or exhibited neuropsychiatric or cardiac toxicity. In intracerebral hemorrhage, platelet transfusion was hazardous. Although reperfusion treatments should be given as soon as possible, very early intervention with other strategies may instead be hazardous, as has been seen with physical therapy and vasodepressors.

Conclusions and Relevance:

The lessons learned from negative stroke RCTs are vital for designing future studies. Multicenter preclinical studies are necessary, and animals that die must be included in analyses. Randomized clinical trials must assess multiple neurological, vascular, cardiac, and general safety effects, whether these are on target or off target. All preclinical trials and RCTs must be published in full. Learning from the past will help to reduce the number of negative stroke RCTs in the future.

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