PFO Tied to Quadruple Stroke Risk in Pulmonary Embolism

May 06, 2019

Patients with acute pulmonary embolism (PE) are at high risk for stroke, and the risk is further raised by about fourfold by the presence of a patent foramen ovale (PFO), a new study suggests.

"This finding supports the hypothesis that paradoxical embolism (the migration of emboli of venous origin to systemic circulation from the right to the left atrium via a PFO) is an important mechanism of ischemic stroke in patients with concomitant PFO and PE," the authors, led by Emmanuelle Le Moigne, MD, Brest University Hospital, France, note.

They believe their findings could have important clinical implications for the management of PE.

"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," they state.

The study was published online May 6 in the Annals of Internal Medicine.

Several studies have reported increased risk for ischemic stroke during the acute phase of PE in association with PFO, they write, but the frequency of the paradoxical embolism mechanism in patients with PE and the strength of the association between stroke and PFO remain uncertain.

They note that studies of this association have been small and have mainly included patients with severe PE. Because of this, results have varied greatly.

The authors point out that this issue is important in clinical practice because PFO has been found in one quarter to one third of PE cases. If the association of PFO and increased risk for ischemic stroke in patients with PE is confirmed, systematic PFO screening at the time of PE diagnosis might be warranted to identify patients with PFO for whom prolonged anticoagulation or other treatment options should be considered.

The current study included 361 consecutive patients with symptomatic acute PE (median age, 66 years) from four French hospitals. The patients underwent systematic contrast transthoracic echocardiography (TTE) to detect PFO and cerebral MRI to detect recent stroke within 7 days of enrollment.

Results showed that contrast TTE was conclusive in 324 of the 361 patients and showed PFO in 43 patients (13%).

Cerebral MRI was conclusive in 315 patients and showed that recent ischemic stroke had occurred in 7.6% of the PE patients overall. However, the risk was almost four times higher in patients with a PFO (21.4%) than in those without a PFO (5.5%).

In total, 51% of patients had associated deep venous thrombosis, 91% had cardiovascular risk factors, and 10% presented with arrhythmia. These comorbidities did not differ between the PFO group and the non-PFO group.

The authors note that to their 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."

They report that 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, recent ischemic stroke diagnoses were objectively confirmed by MRI, and ischemic strokes were adjudicated by a blinded central committee, so "the prevalence we observed is likely to be valid."

They further point out that no difference was observed between the PFO and non-PFO groups in terms of alternative causes of stroke, patient factors (demographic characteristics, personal arterial or venous vascular history, and cardiovascular risk factors), and PE severity. "Thus, the hypothesis that a higher risk for stroke in patients with PFO might have been caused by hypoxia or arrhythmia is unlikely to be true in our cohort," they state.

They also found that 4 of 24 participants who had recently experienced ischemic stroke had both PFO and atrial septal aneurysm (ASA), which increases risk for stroke. "It is hypothesized that ASA allows greater blood flow through the PFO canal, increasing the chance of a thrombus passing from the venous to the arterial system," they state.

In an accompanying editorial, Michael Rahbek Schmidt, MD, and Lars Søndergaard, MD, Rigshospitalet, Copenhagen, Denmark, agree that this is the largest study to date to quantify the presence of ischemic stroke and PFO in consecutively enrolled all-comer patients admitted with acute PE.

They note that that use of standard contrast echocardiography to detect PFO produces highly variable results and that the sensitivity of that modality is suboptimal. Transesophageal echocardiography may be justified as an adjunctive examination to increase sensitivity, they indicate.

"Le Moigne and colleagues have provided strong evidence in support of PFO as an independent risk factor for stroke after PE. The logical next step would be interventional studies aiming to modify risk for stroke through prevention of paradoxical embolization," the editorialists conclude.

They make the point that future management options depend on the timing of the stroke risk.

If the stroke occurs immediately after the PE, clinical benefit may be conferred by early MRI and possibly by thrombolytic treatment. If the stroke risk is permanently increased after PE in patients with PFO, lifelong anticoagulant treatment may be justified; because the risk for recurrent PE is much higher than that for first-time PE, "this assumption is not ungrounded," they say.

If cerebral injury is the result of repetitive embolization during the whole period (usually weeks to months) of increased pulmonary arterial pressure after PE, this could imply that pulmonary antihypertensive treatment, or even subacute PFO closure on admission, would be beneficial, they suggest.

The study was supported by grants from the Programme Hospitalier de Recherche Clinique (French Department of Health). Le Moigne has disclosed no relevant financial relationships.

Ann Intern Med. Published online May 6, 2019. Abstract, Editorial

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