Importance 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.

Observations 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.

重要性 虽然针对急性中风的有益治疗方法（例如中风单位，再灌注，阿司匹林，半颅脑切除术）数量有限，但涉及多种不同作用机制的消极（相对于中性）干预措施却更多。为了减少将来进行阴性研究的风险，至关重要的是要了解为什么以前的干预措施似乎会造成危害。

观察 结果急性缺血性中风的有限有益治疗方法远远多于阴性（非中性）干预措施，这些措施使随机临床试验（RCT）的结果恶化，包括那些假定的神经保护剂，抗凝剂，抗炎药，清除自由基，失血性或血管活性。其他药物降低了溶栓效率或表现出神经精神或心脏毒性。在脑出血中，血小板输注是危险的。尽管应该尽快进行再灌注治疗，但是如物理疗法和血管舒缩剂所见，采用其他策略进行非常早期的干预可能反而很危险。

结论与相关性 从中风RCT中吸取的教训对于设计未来的研究至关重要。多中心临床前研究是必要的，并且必须将死亡的动物包括在分析中。随机临床试验必须评估多种神经，血管，心脏和一般安全性影响，无论这些影响是在靶上还是在靶外。所有临床前试验和RCT必须全部发表。吸取过去的经验将有助于减少将来的中风RCT数量。