The meta-analysis of Palaiodimos et al. [ ] of controlled randomized trials (CRTs) comparing device closure of the patent foramen ovale (PFO) and associated medical therapy to medical therapy alone for the prevention of recurrent ischemic events in patients with suspected cerebral or peripheral paradoxical embolism is a small step into the right direction where a leap is overdue. The report is one of a flurry of meta-analyses concerning the recently published or updated CRTs. In contrast to other currently appearing meta-analyses [ ], it does not yet entail the most recent but smallest CRT (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale (DEFENSE-PFO) [ ]) which corroborates but does not change the results and conclusions.

The laudable distinction of this meta-analysis to others is that it explicitly strives to correct three major misconceptions regarding the topic. First, a patient with a stroke and a PFO never really qualified for the terms cryptogenic stroke or ESUS (embolic stroke of unknown source). PFO is as certified a stroke mediator as atrial fibrillation, albeit in both embolism sources and pathways are hypothetical rather than documented in most cases. Second, a PFO increases its absolute risk of paradoxical embolism with age and disease, only the relative risk decreases due to accruing competitive causes. Third, the guidelines and reimbursement schemes have long overlooked the fact that PFO closure proved at least equivalent in terms of results and costs to lifelong medical treatment, even before the first CRTs. PFO closure should therefore always have been suggested as a valid alternative. Now with the evidence presented here, it must be recommended as the treatment of choice.

The number needed to treat to prevent one stroke by PFO closure may be as low as two over decades of longevity to be expected in many a concerned patient. The absolute risk of a large PFO or a PFO associated with atrial septal aneurysm, Eustachian valve, or Chiari network is significant enough to even evoke PFO closure for primary prevention. Why wait for a stroke or a myocardial infarction in a person with a known dangerous PFO if you can prevent it with a procedure as easy as fixing a tooth (having been referred to as mechanical vaccination [ ]) which can be performed with practically no risk and for less than $10,000?

Paradoxical thrombo-embolism is the prime mechanism of disease inferred by a PFO. Besides cerebral events, this causes other serious problems, such as myocardial infarction and peripheral ischemia, not to mention death [ ]. The frequency of such PFO mediated events is likely underestimated as other causes tend to be preferentially blamed for them (atrial fibrillation, ruptured atherosclerotic plaques, or spontaneous cerebral or coronary dissections) and the PFO is rarely considered or looked for. A Danish field study [ ], for instance, found a high rate of coincidental strokes and myocardial infarctions in patients with acute pulmonary embolism but did not screen for a PFO or even mention it. PFO is the most likely reason for simultaneous embolism in the pulmonary and systemic circulations. This study blatantly ignored a prior German study [ ] showing a markedly increased mortality in people with pulmonary embolism by the mere fact that they had a PFO.

Moreover, there are PFO related diseases not explainable by paradoxical embolism of substrate matter, yet, treatable if not curable by PFO closure. Three migraine CRTs all showed improvement with PFO closure but missed their primary endpoints. Notwithstanding, they met several secondary endpoints of superiority. Neurologists, nonetheless, concluded that PFOs should not be closed for migraine rather than that PFO closure represents a promising alternative to medical treatment for migraine, at the least migraine with aura. Just swopping the primary endpoints of the two recent CRTs, renders them both positive in terms of statistical significance [ ].

There is ample evidence that PFO closure cures problems like platypnea orthodeoxia and exercise desaturation and is helpful in sleep apnea. Furthermore, it renders diving, high altitude climbing, and vocational activities with frequent Valsalva maneuvers safer. All these effects are included in one price as collateral benefits. That is to say that PFO closure for migraine also protects against paradoxical embolism and decreases the professional risk of, e.g., a glass blower, and vice versa. Hence, looking only at stroke prevention, we are seeing but the tip of the iceberg [ ].

Cinderella was finally recognized for her beauty, but even then, her many other virtues remained largely ignored.