Patent foramen ovale and cryptogenic stroke: Many unanswered questions

IS PFO A RISK FACTOR FOR STROKE?

One of the more puzzling aspects of the relationship of PFO to cryptogenic stroke is that despite a clear association, there is little evidence that the relationship is causal.

Di Tullio et al¹¹ followed 1,100 people who had no history of stroke and found that the risk of a first stroke in those with a PFO was not significantly higher than in those without a PFO, regardless of age, sex, or ethnic or racial group. At 80 months, the hazard ratio of stroke in people who had a PFO was 1.64 (95% CI 0.87–3.09).¹¹ The findings were similar at 11 years, with a hazard ratio of 1.10 (95% CI 0.64–1.91).¹²

A prospective study of 585 patients found a similar risk of stroke in those with and without a PFO, with a hazard ratio of 1.46 (95% CI 0.74–2.88; P = .28).¹³

These prospective trials suggest that although previous studies have found a higher prevalence of PFOs in patients with cryptogenic stroke than in patients without stroke, there appears to be very little if any increased risk from baseline for a first stroke or TIA.

The lack of statistical significance in these trials should be interpreted with some caution, as a small increased risk is difficult to show if the event rate is low (approximately 10% of patients had events over 11 years in the study by Di Tullio et al¹²).

HOW DO WE KNOW IF A PFO IS A CULPRIT OR BYSTANDER?

Unfortunately, this is largely unanswered, though experts have suggested that echocardiographic features of the PFO, radiographic characteristics of the stroke, and clinical features of the patient may provide useful information.

‘High-risk’ features on echocardiography

Certain features of PFO may portend a high risk of cerebrovascular events. Both right-to-left shunting at rest and septal hypermobility were found in one study¹⁴ to be more common in patients with a PFO who had a stroke or TIA than in patients with a PFO but no cerebrovascular events. Also, patients who had these features and had a stroke had a higher risk of recurrence than stroke patients without these features (12.5% vs 4.3%, P = .05).¹⁴

Septal hypermobility and shunting at rest are easily diagnosed by echocardiography, and detecting these “high-risk” features would be useful if they could identify patients who would benefit from special therapy, such as percutaneous closure of the PFO.

Unfortunately, when investigators looked at these features in subgroup analysis of the major randomized controlled trials of percutaneous closure vs medical therapy, the results were mixed.

CLOSURE 1 (the Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale)¹⁵ found percutaneous closure to be no better than medical therapy, regardless of shunt size or the presence of atrial septal aneurysm.

Similarly, the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism)¹⁶ found no statistically significant benefit of closure in those with atrial septal aneurysm.

In contrast, the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)¹⁷ showed percutaneous closure to be beneficial in patients with atrial septal aneurysm or large shunt.

Radiographic characteristics of the stroke

Another area of interest in trying to identify culprit PFOs is the radiographic characteristics of the stroke.

In a study comparing patients with stroke related to atrial fibrillation vs patients with cryptogenic stroke and a known PFO, those in the latter group were more likely to have a single cortical infarction (34.2% vs 3.1%; P < .001) or multiple small scattered lesions (23.1% vs 5.9%; P < .01).¹⁸ Similarly, in a large database of patients with cryptogenic stroke and known PFO status, a superficially located stroke was associated with the presence of PFO (OR 1.54; P < .0001).¹⁹

Although these findings do not tell us with certainty that a patient’s PFO was the cause of his or her stroke, they provide guidance when dealing with the uncertainty of how to manage a patient with PFO. They may be useful in clinical practice, for example, when discussing treatment options with a young patient with cryptogenic stroke who has no risk factors and a superficial single infarct and who is found to have a PFO with a right-to-left shunting at rest.

Patient characteristics

Kent et al²⁰ developed a 10-point index (the RoPE score) in an attempt to assign a probability to whether a stroke was PFO-related. Points were assigned for patients who were younger, who had a cortical stroke on neuroimaging, and who did not have diabetes, hypertension, smoking, or prior stroke or TIA. Patients with cryptogenic stroke with a higher RoPE score were more likely to have a PFO and thus had a higher likelihood that the index event was related to PFO. Of note, the patients with the highest likelihood of PFO-related stroke were the least likely to have a recurrence (RoPE score of 9 to 10; PFO-attributable fraction 88%; estimated 2-year recurrence rate 2%; 95% CI 0%–4%), whereas those with a low RoPE score have more traditional risk factors for stroke and thus are more likely to have a recurrence (RoPE 0 to 3; estimated 2-year recurrence rate 20%; 95% CI 12%–28%).²⁰

Again, this sheds light on a difficulty faced by randomized controlled trials: the patients who may benefit from closure of a PFO may very well be those with the lowest recurrence rates without intervention.

The RoPE index was examined in an attempt to validate previously described morphologic criteria of “high-risk” PFO,²¹ though none of the previously described “high-risk” echocardiographic features (large physiologic size, hypermobile septum, shunt at rest) were more common in the group with presumed PFO-attributable stroke (RoPE score > 6). This underscores the difficulty of distinguishing pathologic PFO from incidental PFO.