Rethinking trial strategies for stroke and patent foramen ovale.

Objective: The cause of stroke remains unknown in roughly one third of patients, despite extensive investigation. The prevalence of patent foramena ovale (PFOs) in the general population is around 25%, but it is doubled in cryptogenic stroke patients. This suggests a causal relationship between PFO and cryptogenic stroke. This has generally been attributed to paradoxical embolism. Regardless of mechanism, nearly 30,000 young patients each year have a cryptogenic stroke and PFO. Optimal management is uncertain.

Results: Many physicians recommend PFO closure, an intuitively attractive mechanical solution for stroke prevention. Unfortunately, the benefit of PFO closure in patients with stroke has not been demonstrated. There are ongoing clinical trials comparing the safety and efficacy of PFO closure with that of medical therapy. Interpreting these trials will be complicated by two issues: first, it is unclear whether a patient's PFO is causally related to the event ('pathogenic') or not ('incidental'); and second, recurrent strokes may be due to paradoxical embolism or another stroke mechanism.

Conclusions: Substantial heterogeneity of patients within trials along these two dimensions of risk may make overall trial results difficult to interpret. With appropriate analyses, the trials may be more informative than the overall data may suggest.