Most evident in younger patients or those without known stroke risk

Incomplete patent foramen ovale (PFO) closure in patients with cryptogenic stroke was associated with incident stroke and transient ischemic attack (TIA), a prospective longitudinal study found.

Adjusted analysis showed a hazard ratio (HR) for composite stroke or TIA of 3.01 (95% CI 1.59-5.69, P < 0.001) in those with a residual shunt after PFO closure compared to those with complete shunt closure.

Moderate or large residual shunt size was associated with even higher risk (HR 4.50, 95% CI 2.20-9.20, P < 0.001).

“The association of residual shunt with stroke or TIA recurrence was particularly evident in younger patients (≤50 years) (HR 4.78, 95% CI 1.98-11.54; P < 0.001) and those without known stroke risk factors,” wrote MingMing Ning, MD, MMSc, of Massachusetts General Hospital and coauthors in Annals of Internal Medicine.

“This may suggest that residual shunt is associated with risk for stroke or TIA recurrence, regardless of any other traditional or PFO-related high-risk features. However, the association was indeterminate in older patients with comorbid conditions,” they noted.

“That our data are indeterminate regarding the interaction of PFO shunt with noncryptogenic risk factors and older age suggests that shunt stands out more prominently in the absence of other risk factors — but it does not cease to be a risk factor when other risks are present,” they concluded.

In an accompanying editorial, William Kussmaul III, MD, a private cardiologist in Media, Pennsylvania wrote: “At some point, a new technology matures and finds a stable set of indications. Patent foramen ovale closure may be approaching that point, although we are still in an evolutionary phase.”

PFO is an opening between the left and right sides of the heart that can allow some venous blood, which may contain thrombi, to be shunted directly from the right side of the heart to the left side, and from there to arterial circulation as emboli. PFO may also contribute to ischemic events by allowing procoagulable and oxidative factors to pass into arterial circulation without filtering by the lung.

Despite plausible mechanisms for a role in neurologic events, the cost and complication of procedures, the fact that PFO is quite common in people without stroke and the relative lack of outcomes data made closure controversial. Residual shunt due to incomplete PFO closure is seen in up to 25% of patients—roughly the same proportion of people in the general population who have PFO to begin with—but its long-term influence on stroke recurrence is unknown.

A review of more recent data concluded that although the stroke risk of PFO is low compared to other mechanisms, cumulative risk in younger stroke patients argues for overall benefit. Shunts also tend to become smaller due to endothelialization of the closure device. One study found residual shunts in about 20% of PFO closures 4 months post-procedure and 8.4% at 11 months.

To compare recurrent cryptogenic stroke or TIA in those with and without residual shunt, Ning and colleagues analyzed data from 1,078 consecutive patients with PFO and cryptogenic stroke or TIA evaluated between January 1995 and November 2017.

Participants underwent percutaneous PFO with a variety of devices and at 24 hours, transthoracic echocardiogram (TTE) with valsalva maneuver and agitated saline microbubbles to evaluate for shunt. The bubble study was repeated at 1, 6, and 12 months and yearly for average followup of 3.7 years. Shunts were graded as no shunt (0 bubbles in the left atrium within 3 cardiac cycles), small (1 to 10 bubbles), moderate (up to 30 bubbles) and large (more than 30 bubbles).

Incident neurologic events were evaluated and their etiology classified based on TOAST criteria as one of five types: large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, and stroke of undetermined etiology (cryptogenic).

Participants’ average age was about 49. Residual shunt was seen in 22.5% of patients, and about 40% were moderate or large. “Residual shunts diminished over time, especially during the first year, and shunt rates improved over the course of the study,” the authors noted.

Recurrent stroke or TIA incidence was 2.32 events per 100 patient years in those with residual shunt versus 0.75 events per 100 patient-years (unadjusted HR 3.05, 95% CI 1.65-5.62; P < 0.001).

Adjusted analysis for covariates included age, hypertension, hyperlipidemia, and diabetes; high-risk PFO features (atrial septal aneurysm, hypermobile septum, and hypercoagulability), and medication use (aspirin, clopidogrel, and warfarin). It did not substantially change results. Small residual shunts, seen in about 14% of participants overall had a nonsignificant association with stroke or TIA.

The authors offered recommendations based on their clinical practice:

  • Clinical follow-up for at least 5 years with a multidisciplinary team and TTE with bubbles every 3-6 months for one year and 6-12 months thereafter.
  • Medical treatment, such as anticoagulant or dual-antiplatelet therapy, for the entire first year until the shunt stabilizes.
  • Maximal management of PFO-specific risk factors such as hypercoagulable states, deep venous thrombosis prevention, and treatment of stroke risk factors and acquired hypercoagulability, including cancer screening and management of hyperhomocysteinemia.
  • Multidisciplinary assessment in high-risk patients with persistent large or moderate shunt to consider lifelong anticoagulation or a second device closure.

“It would seem reasonable pending longer-term follow-up data to extend oral anticoagulation, as they suggest, hoping that the shunt will eventually diminish along with the attendant risk for further neurologic events,” the editorialist wrote, adding, “Perhaps further along on the learning curve — with newer, simpler techniques and less bulky implants — the risk–benefit equation in this group of patients can be tilted even further toward permanent stroke prevention.”

Limitations include potential patient selection bias and unmeasured confounding. Also, the rate of residual shunt declined over the years of the study (1995 to 2017), “probably because of advances in closure devices and technologies,” the authors noted. Generalizability to non-PFO and non-cryptogenic stroke populations is limited.

  1. Incomplete patent foramen ovale (PFO) closure in patients with cryptogenic stroke was associated with incident stroke and transient ischemic attack (TIA) in a prospective longitudinal study that found an adjusted hazard ratio for composite stroke or TIA of 3.01 in those with a residual shunt after PFO closure compared with those with complete shunt closure.

  2. The association of residual shunt with stroke or TIA recurrence was particularly evident in younger patients and those without known stroke risk factors.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Funding for the study came from the National Institutes of Health.

Ning reported no disclosures.

Kussmaul is an associate editor of Annals of Internal Medicine.

Cat ID: 130

Topic ID: 82,130,730,8,130,38,192,925