Understanding composite primary outcomes: The example of middle meningeal artery embolization for chronic subdural hematoma.

BACKGROUND: Composite primary outcomes are increasingly used. They can inflate the number of control events and render trials more feasible, compared to hard clinical outcomes, but results can be uncertain or biased. METHODS: We critically review the randomized trials on the effects of Middle Meningeal Artery (MMA) embolization on chronic subdural hematomas (CSDH), with special attention to the notion of progression or recurrence, a composite primary outcome variously defined. RESULTS: The components include imaging criteria and clinical symptoms at a certain point in time, in addition to events and retreatments up to that time. Blinding, if it can really be performed, and contribution of an adjudication committee, supposed to decrease the subjectivity of items like retreatments, are often difficult to understand. The details of each component are difficult to extract from most articles. The meaning of an isolated component, such as imaging, may change, from its natural, clinical use (to confirm an event such as CSDH recurrence), to an experimental use as a surrogate at a certain time when it is part of a composite. Three of five trials claimed MMA embolization effective in reducing CSDH progression or recurrence but none of the trials showed any effect on other clinical outcomes such as neurological function. CONCLUSION: The observed effects of MMA embolization on CSDH may be artefactual. Some composite outcomes can be used in screening for promising new therapies in preliminary phase 2 trials, but others cannot be trusted until real clinical effects are demonstrated on hard clinical outcomes.