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.

Understanding intent to treat analyses: An important lesson from the international cooperative study on the timing of aneurysm surgery.

BACKGROUND AND PURPOSE: Intent-to-treat analyses (ITT) are the best way to analyze randomized clinical trials because they preserve the benefits of randomization: to provide an unbiased assessment of relative treatment effects. Yet they play a more fundamental role, which can be demonstrated with observational studies. METHODS: We use a hypothetical RCT to explain why ITT analyses are more appropriate to analyze RCT results. We review the International Cooperative Study on the Timing of Aneurysm Surgery (ICSTAS), a landmark observational study on the management of ruptured aneurysm patients. We discuss the impact of the ICSTAS lesson on the interpretation of future observational studies using Big Data. RESULTS: Per-protocol (or as-treated) analyses can be misleading: The ICSTAS study provided 'as-treated' results clearly in favour of delayed surgery, while overall management or ITT results showed no difference between early and delayed surgery. A contemporary RCT showed that early surgery was best. ICSTAS' lesson is that observational studies can provide misleading results when intent-to-treat categories are not predefined in the first place. CONCLUSION: Intent-to treat analyses are the most appropriate way to analyze data, whether from randomized trials or observational studies. This observation has momentous consequences. A science of medical practice is impossible without predefined questions regarding optimal care.

Understanding the importance of the primary trial hypothesis: The randomized trial on the timing of ruptured aneurysm surgery.

BACKGROUND AND PURPOSE: The primary hypothesis of a trial must be explicitly formulated. The primary hypothesis is essential for the proper interpretation of trial results. METHODS: We review the seminal Finnish randomized trial on the timing of aneurysm surgery, and re-examine how trial results could have been interpreted at the time had a precise primary hypothesis been pre-specified. Finally, we compare the power of this single center randomized trial with the multicenter International Cooperative (observational) Study that examined the same clinical problem. RESULTS: Had the Finnish authors worked under a pragmatic hypothesis in favor of early surgery (within 3days) versus delayed surgery, the trial results could have been interpreted as conclusive. The randomized trial was more appropriate, more ethical, and more efficient than the inconclusive International Cooperative study. CONCLUSION: The randomized trial on the timing of aneurysm surgery was a landmark in neurovascular research. A precise pragmatic primary hypothesis is a crucial step in trial design and interpretation.