Understanding how the primary endpoint impacts the interpretation of trial results: The Japanese Adult Moyamoya bypass trial.

BACKGROUND: The meaning of a clinical trial depends to a large extent on the choice of the primary outcome measure, which can be explanatory or pragmatic. METHODS: We review the Japanese Adult Moyamoya (JAM) trial, that compared surgical extracranial to intracranial (EC-IC) bypass and medical management of hemorrhagic moyamoya disease. We also review some principles which guide the selection of the primary trial endpoint. DISCUSSION: The main component of the primary outcome measure in JAM was rebleeding, a surrogate outcome that allowed investigators to demonstrate that surgical bypass had causal efficacy. However, the number of patients with a poor outcome, defined as those with a modified Rankin score (mRS)>2, would have been a more pragmatic choice. Unfortunately, the trial was too small to show that patients benefited from surgery. CONCLUSION: The JAM trial showed that EC-IC bypass can decrease rebleeding in moyamoya patients, but whether patients have better outcomes with surgery remains uncertain. Hard pragmatic clinical primary outcome measures are necessary to guide surgical care.

Understanding the difference between theory and practice: The extracranial-intracranial bypass trials in prevention of ischemic stroke.

BACKGROUND: Patients with atherosclerotic carotid or middle cerebral artery occlusions suffer ischemic events that might theoretically be preventable with a surgical extracranial-intracranial bypass, but theory by itself does not justify surgical interventions. METHODS: We review landmark randomized trials on EC-IC bypass surgery for the treatment of ischemic stroke in patients with atherosclerotic stenoses or occlusions. RESULTS: The initial EC-IC bypass trial from 1985 did not show any clinical benefit from surgery. The carotid occlusion surgery study (COSS) performed more than 20 years later included only patients highly selected to potentially benefit from bypass by using modern perfusion studies. While EC-IC bypasses were successfully created and they did improve cerebral perfusion, the COSS study also failed to show any clinical benefit to the participating patients. CONCLUSION: Neurosurgical interventions must not only work in theory; they must improve patient outcomes in real practice.