Patent foramen ovale and cryptogenic stroke: Many unanswered questions

KEY TREATMENT CONSIDERATIONS FOR SECONDARY PREVENTION

Given the complicated relationship between PFO and cryptogenic stroke, there has been much debate over management strategies. The three options are surgical closure, percutaneous closure with a device, and medical therapy. The goal of all three is to prevent the recurrence of stroke or TIA.

Surgical closure has largely been supplanted by percutaneous closure, but is still done in specific situations such as when a PFO is found incidentally on transesophageal echocardiography during surgery for another cardiac condition. The data on such cases²² tend to support the argument that asymptomatic PFOs in the general population have a relatively benign natural history.

Thus, the two key questions about management that warrant discussion are: is anticoagulation superior to antiplatelet therapy? And is percutaneous closure superior to medical management?

Anticoagulant vs antiplatelet therapy

Whether to treat with aspirin or with a vitamin K antagonist has been a subject of debate, although there is no strong evidence to suggest that anticoagulation is superior to antiplatelet therapy.

The concern that aspirin alone is insufficient in some patients stems from a study by Mas et al,²³ who followed 581 patients with cryptogenic stroke who had a PFO alone, a PFO with an atrial septal aneurysm, or neither. The rate of stroke recurrence at 4 years on aspirin therapy was 2.3% in those with a PFO alone, 15.2% in those with a PFO with an atrial septal aneurysm, and 4.2% in those with neither.

Many have concluded that aspirin therapy does not sufficiently protect those with both PFO and atrial septal aneurysm, given the high recurrence rate in this group. This might lead to the suggestion that anticoagulation could be of benefit in these patients.

However, the Patent Foramen Ovale in Cryptogenic Stroke Study (PiCSS)²⁴ and the Spanish Multicenter Study Into Right-to-Left Shunt in Cryptogenic Stroke (CODICIA)²⁵ found similar recurrence rates in patients with PFO and atrial septal aneurysm compared with those with only PFO. In these two studies, recurrence rates were similar regardless of whether patients were taking aspirin or warfarin.

In a study that followed 140 consecutive patients with both stroke and PFO, those treated in a nonrandomized fashion with antiplatelet agents had no difference in the recurrence rate compared with those treated with anticoagulation.²⁶

Although uncertainty remains because no head-to-head randomized controlled trial has been done, some patients with PFO have other indications for anticoagulation, most commonly atrial fibrillation and venous thromboembolic disease.

There are currently no data on the use of novel oral anticoagulants in this setting.

Is percutaneous closure better than medical therapy?

When cryptogenic stroke is treated with antiplatelet therapy or anticoagulation therapy, the recurrence rate is the same whether or not the patient has a PFO.^23–25 The belief that medical therapy offers adequate secondary protection is supported by a meta-analysis of 15 studies that found no increased risk of recurrent ischemic events in those with a PFO on medical therapy (antiplatelet or anticoagulant) vs those without a PFO (relative risk 1.1, 95% CI 0.8–1.5).²⁷

Despite the conflicting evidence, percutaneous closure of PFO is still performed, mostly on a case-by-case basis. This has been supported by an apparent benefit in observational studies.

A systematic review of 52 single-arm studies and 7 comparative nonrandomized studies of patients with PFO and cryptogenic stroke found the rate of recurrent stroke to be 0.36 per 100 person-years with percutaneous closure vs 2.53 per 100 person-years with medical therapy.²⁸ However, three long-awaited randomized controlled trials (CLOSURE 1, the PC trial, and RESPECT) failed to show a significant reduction in primary end points with percutaneous closure vs standard medical therapy.^15–17

These trials had several limitations: event rates were low, medical therapy varied by provider, and enrollment was slowed by out-of-study percutaneous closure in patients perceived to be at high risk (though, as discussed above, high risk is difficult to determine).

Intention-to-treat analysis in RESPECT showed no benefit from percutaneous closure, but a favorable outcome was noted with closure in as-treated analysis (HR 0.27; 95% CI 0.1–0.75; P = .007) and per-protocol analysis (HR 0.37; 95% CI 0.14–0.96; P = .03) of the 980 randomized patients.¹⁷ This suggests some benefit, as does the CLOSURE 1 trial, in which 3 of the 12 recurrent strokes in the percutaneous closure group occurred before the device was implanted.¹⁵

The low event rates in these studies prompted several meta-analyses.^29–35 However, only two suggested a benefit of percutaneous closure over medical therapy. In one recent meta-analysis,²⁹ observational study data suggested benefit from percutaneous closure, whereas three randomized controlled trials failed to show a statistically significant benefit.

The conclusions of the meta-analyses must be interpreted with caution because of inherent differences in the randomized controlled trials, including the closure device used, inclusion criteria, study end points, and variations in medical therapy.

Devices differ

A meta-analysis by Khan et al³⁵ showed a benefit of percutaneous closure when evaluating only studies using the Amplatzer PFO occluder (AGA Medical), as in RESPECT and the PC trial.³⁵ As data accumulate, it is important to remember that there are differences between devices. Ongoing trials continue to investigate the Amplatzer device (NCT01550588) and the GORE HELEX Septal Occluder/GORE Septal Occluder (Gore Medical) (NCT00738894).

In another meta-analysis, Pineda et al³¹ found a benefit with closure in the as-treated analysis using data from all three randomized controlled trials (OR 0.62; 95% CI 0.41–0.94; P = .02).³¹ Although paradoxical embolism through the PFO as the mechanism of stroke has been questioned, this finding suggests that actual closure of a PFO may protect against further events, presumably by preventing paradoxical embolism.

Different closure devices have different side effects. The incidence of atrial fibrillation with the CardioSEAL STARFlex device (NMT Medical) is higher than with medical therapy (used in the CLOSURE trial¹⁵), whereas this risk was not statistically significantly increased in the PC trial¹⁶ and RESPECT,¹⁷ which used the Amplatzer device.

Benefit in those with atrial septal aneurysm?

Percutaneous closure has been shown to be safe and effective in patients with PFO and atrial septal aneurysm.³⁶ There was some benefit of closure over medical therapy in a subgroup analysis from RESPECT in these patients, with a HR of 0.19 (95% CI 0.04–0.87, P = .02),¹⁷ although this was not seen in either CLOSURE 1 or the PC trial.

WHAT ARE THE RISKS OF PERCUTANEOUS CLOSURE?

Minor complications of percutaneous closure include bleeding, atrial arrhythmias, device embolization and fracture, and complications related to vascular access. Major complications include hemorrhage requiring transfusion, need for surgery, cardiac tamponade, pulmonary embolism, and death.

The cumulative rate of major complications in 10 observational studies was 1.5%, and the rate of minor complications was 7.9%.³⁷ The RESPECT investigators reported a serious adverse event in 4.2% of patients (ranging in severity from chest tightness to cardiac tamponade).¹⁷

Another possible consequence of percutaneous closure is the need for chronic anticoagulation because of the increased risk of postprocedural atrial fibrillation seen in meta-analyses,^29,31,32 though this may be device-specific.³²

Percutaneous closure was considered successful—ie, to have nearly or completely eliminated shunting of blood through the defect—at 6 months of follow-up in 95.9% of patients in the PC trial, 93.5% in RESPECT, and 86.1% in CLOSURE 1.^15–17

WHAT SHOULD WE BE DOING IN DAILY PRACTICE?

Give aspirin. Aspirin is effective in secondary stroke prevention, and data suggest that patients with PFO and cryptogenic stroke who receive aspirin therapy alone have a similar risk of recurrent events as patients without PFO.

Give warfarin if indicated. Evidence is insufficient to recommend vitamin K antagonist therapy in all patients with PFO and cryptogenic stroke. However, coexisting conditions that warrant anticoagulation must be taken into account.

Individualize. Given the lack of evidence to definitively guide management of patients with cryptogenic stroke and PFO, we need to individualize our approach, taking into account patient preferences, bleeding risk, ability to tolerate procedures, and the likelihood that the PFO is at fault.

No definitive answer on PFO closure. The most recent data suggest that closure may be beneficial, but key questions remain: Who will benefit? And what is the ideal medical therapy? Optimal management will only be established by the continued enrollment of appropriate patients into ongoing clinical trials.

Another question is whether it is possible to perform a randomized controlled trial with enough patients to definitively prove whether percutaneous closure is superior to medical therapy. Recent experience would suggest not.

In the meantime, we have some guidance from the American Heart Association and the American Stroke Association Council on Stroke³⁸ based on the limited evidence available.

Consider patient preference. The physician should present the options to the patient in a balanced manner to enable him or her to make an informed decision. Patients can also be encouraged to seek additional information at websites such as www.stroke.org and www.nlm.nih.gov.

Referral to an interventional cardiologist for evaluation for closure is reasonable in patients with recurrent stroke, medication failure, complicated atrial septal anatomy such as PFO with aneurysm or large shunt, concurrent thromboembolic disease, or contraindications to anticoagulation.

MORE WORK NEEDED

Areas for further study include further identifying the characteristics of patients with PFO and cryptogenic stroke that might indicate who would benefit from percutaneous closure, elucidating the mechanism of stroke in these patients, and determining whether routine stroke evaluation should include echocardiography with a bubble study if there is no change in management based on the finding of PFO.³⁹