PFO Compounds Ischemic Stroke Risk Among Patients With Pulmonary Embolism

Patent foramen ovale (PFO) increase the rate of ischemic stroke among patients with symptomatic pulmonary embolism (PE), according to a new prospective cohort study. Its authors say the findings support the notion that paradoxical embolism plays an important role in the genesis of stroke in PFO patients and that perhaps additional screening is warranted going forward.

“Our findings could have important clinical implications for PE management,” lead author Emmanuelle Le Moigne, MD, PhD (Brest University Hospital, Western Brittany University, France), and colleagues write. “The presence of PFO was associated with increased risk for stroke; hence, systematic screening for PFO could be justified with the aim of identifying patients at risk for ischemic stroke who would be eligible for indefinite anticoagulation to prevent both recurrent PE and stroke. Such an approach seems reasonable, particularly in patients with a first unprovoked PE.”

Commenting to TCTMD, Kenneth Rosenfield, MD (Massachusetts General Hospital, Boston), who was not involved in the study, said that the findings are not surprising but rather confirm what many have already been thinking. “Paradoxical embolization is a common cause of cryptogenic stroke. We've known it for a long time,” he observed. “From the standpoint of somebody who is seeing a patient with a pulmonary embolism, it's a good idea to always look for a PFO or some other connection or potential shunt between the right side and left side of the heart.”

Fourfold Increase in Risk

For the study, published online today in the Annals of Internal Medicine, Le Moigne and colleagues looked at 361 consecutive patients with symptomatic acute PE who presented at four French hospitals between November 2009 and December 2015. All patients prospectively received transthoracic echocardiography and MRI within 7 days of enrollment, and PFO was confirmed in 13%.

From the standpoint of somebody who is seeing a patient with a pulmonary embolism, it's a good idea to always look for a PFO or some other connection or potential shunt between the right side and left side of the heart. Kenneth Rosenfield

Silent or symptomatic recent ischemic stroke (primary endpoint) was diagnosed in 7.6% of 315 patients with available data. Those with PFO were more likely to have ischemic stroke than those without (21.4% vs 5.5%; RR 3.90; 95% CI 1.62-8.67). Cryptogenic stroke was especially more likely in those with PFO (16.7% vs 1.8%; RR 9.10; 95% CI 2.89-39.00).

Lastly, ischemic stroke was found to be more prevalent among patients with atrial septal aneurysm (ASA), regardless of the presence of PFO.

“To our knowledge, our study is the largest prospective trial to assess the frequency of recent ischemic stroke in unselected patients with an acute episode of symptomatic PE,” the investigators write. “Our exclusion criteria were minimal and were not based on PE severity, which led to enrollment of a population close to that in real life. In addition, all cases of PE were documented, and recent ischemic stroke diagnoses were objectively confirmed by MRI. Finally, ischemic strokes were adjudicated by a blinded central committee. Thus, the prevalence we observed is likely to be valid.”

In an accompanying editorial, Michael Rahbek Schmidt, MD, PhD, and Lars Søndergaard, MD (Rigshospitalet, Copenhagen, Denmark), note that this is the “largest study to date” of its kind. It importantly “corroborates that presence of PFO is an independent risk factor because risk for stroke is quadrupled among patients with PFO,” they say. Because the results showed an even higher risk for stroke among patients with ASA, “this contributes to the ongoing discussion about whether certain types of PFO anatomies are particularly prone to paradoxical embolism,” the editorialists point out. “Perhaps more important, no subtypes of PFO have so far been shown to be risk-free in relation to either previous stroke or PE.”

PFO Detection

The study not only “underlines the importance of detecting PFO in patients with acute PE, it also adds to the discussion of how the detection of PFO should influence treatment,” according to Schmidt and Søndergaard.

Rosenfield agreed. “If you in a setting of an acute PE, . . . I think it's pretty important to identify whether the patient has a PFO,” he said. “And so, it raises the question as to whether patients with even low-risk submassive or even small PEs should have some assessment of their cardiac anatomy—ie, should everybody with a pulmonary embolism have an echo?”

Additionally, Rosenfield questioned whether the field “should be more permissive with our ordering of echos to ascertain whether the patients have a PFO.” Only once that is decided upon can we “then talk about what the merits and liabilities of closing that PFO are,” he said. “But it does bring to the front the fact that more information is a good thing and may be important in the long run in terms of prognosticating and maybe even in terms of treating patients who have pulmonary embolism or even [deep vein thrombosis] with a risk of PE, where even small amounts of material breaking off could lead to a stroke.”

Another “big underlying question” in terms of management relates to timing, the editorialists write. If the stroke occurs immediately after PE, then clinical benefit might be achieved by shortening the time from symptom onset to care through promoting early MRI and potentially thrombolytics if indicated, they say. Also, if the stroke risk is permanently upped following PE in PFO patients, “this could justify lifelong anticoagulant treatment,” Schmidt and Søndergaard write. Thirdly, understanding whether cerebral injury happens in the weeks and months of increased pulmonary arterial pressure after PE “could imply benefit from pulmonary antihypertensive treatment or even subacute PFO closure on admission.”

Rosenfield said he would like to see a future study essentially copy this one but in “a broad-based population of real-world patients.” He mentioned that the PERT Consortium, which he spearheads, has a quality assurance database which is “up and running” and could potentially help answer the open questions moving forward.

For the editorialists, “the logical next step would be interventional studies aiming to modify risk for stroke through prevention of paradoxical embolism.”