Effect of medical therapy on stroke due to right atrial abnormalities

Patients with atrial septal aneurysm have been shown to have a higher risk of stroke. Those with patent foramen ovale (PFO) also have a higher stroke risk. The combination of the two conditions together increases the risk of stroke significantly.1-5 The eustachian valve is a remnant of the right valve of the sinus venosus, which, during fetal development, directs blood flow from the inferior vena cava to the fossa ovalis region.6 In adults, a marked right-to-left shunt may result when the eustachian valve is prominent in the presence of interatrial communication.7,8 Filamentous strands in the right atrium, which can extend across the eustachian valve to the atrial wall, are also remnants from the right valve of sinus venosus.9 A widespread webbing of strands, or Chiari network, has been shown to be correlated with paradoxical embolization, presumably by also diverting flow from the inferior vena cava to the fossa ovalis region.10

We theorized that a large PFO and a prominent eustachian valve or right atrial filamentous strands were related to septal aneurysm and that the combination of a large PFO and a structure in the right atrium directing flow from the inferior vena cava to the PFO would lead to increased risk of paradoxical embolization. We assessed the characteristics of PFO in patients with septal aneurysm and evaluated whether the presence of septal aneurysm and PFO, with or without the right atrial anatomical abnormalities described above, affected the rate of stroke.

Patients and methods

The Warfarin-Aspirin Recurrent Stroke Study (WARSS) was designed to evaluate the effect of medical treatment on stroke risk factors as shown by transesophageal echocardiography (TEE). The Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) was a substudy of WARSS that included patients undergoing TEE for any clinical purpose, as well as WARSS patients with cryptogenic stroke subtype who were invited to undergo TEE specifically for PICSS entry.11 Participants were 30 to 85 years of age and had had an ischemic stroke within 30 days. Participants with a normal baseline international normalized ratio (INR; < l.4) were included in the study. Patients with plans to have surgery for high-grade carotid stenosis or patients with procedure-related stroke or stroke with a cardioembolic source were excluded. All strokes were categorized according to predefined criteria.12 When no specific cause was found even with an extensive diagnostic examination, patients were considered to have suffered a cryptogenic stroke.13

Patients were randomly assigned to receive aspirin, 325 mg daily, or warfarin, given at a dosage to maintain an INR of 1.4 to 2.8, and an identical placebo. None of the participants received two active treatments or two placebos. A predefined protocol, which used either a biplane or multiplane TEE probe and included extensive characterization of the right atrial anatomy and interatrial septum, was employed. A single investigator, who was blind to treatment assignment, type of stroke, and patient outcome, reviewed the TEE tapes. To identify PFO, saline contrast was injected with and without the use of the Valsalva maneuver or cough. If one or more microbubbles was detected in the left atrium within three cardiac cycles after opacification of the right atrium, a PFO was considered to be present.14 From an image showing the maximum number of microbubbles, the total number of microbubbles was counted on a video frame within three cardiac cycles from the opacification of the right atrium. The size of all PFOs was characterized as small or large based on the size of septal separation, with 2 mm used as the cutoff.11

A patient was considered to have a prominent eustachian valve if there was a protrusion into the right atrium of 10 mm or more of linear membrane-like structure from the junction of the right atrium and the inferior vena cava in the image plane showing the entrance of the inferior vena cava into the right atrium in a vertical plane using a biplane probe or in an equivalent plane using a multiplane probe. A septal aneurysm was defined as a protrusion of 10 mm or more of the atrial septum into the left or right atrium from the midline position.15 A patient was considered to have right atrial filamentous strands if there were freely mobile linear filamentous structures in the right atrium that were attached to the eustachian valve or to any aspect of the right atrial wall. Patients were followed up monthly in person or on the phone for a period of 24 months. At each monthly follow-up, compliance was evaluated and INRs were adjusted.

Death from any cause and recurrent ischemic stroke were the primary end points. A secondary end point was transient ischemic attack (TIA). A patient was determined to have recurrent ischemic stroke if a new lesion was visible on a computed tomography or magnetic resonance imaging scan or, if no new lesions were present, the patient had clinical signs and symptoms of stroke for at least 24 hours. The relative hazard ratio was determined by Cox proportional hazards model. The 95% confidence intervals (CIs) for participants with septal aneurysm and PFO were compared with subjects without septal aneurysm and without PFO. Participants with the combination of PFO, septal aneurysm, and prominent eustachian valve or right atrial filamentous strands were also compared with subjects without these conditions. Analyses were performed for the entire group and for patients with cryptogenic stroke. The effects of warfarin were compared with aspirin for patients with PFO and septal aneurysm. A probability value of .05 or less was accepted as statistical significance.

Results

Of the 2,206 patients enrolled in WARSS, 630 took part in the PICSS trial. Among the PICSS participants, there were 265 (42.1%) cryptogenic strokes. There were 601 patients with TEE images suitable for analysis of PFO, 563 for analysis of eustachian valve, 600 for analysis of septal aneurysm, and 563 for analysis of right atrial filamentous strands. Two hundred three patients (33.8%) had PFO; 58.6% of the PFOs were small and 41.4% were large. A total of 69 of 600 patients (11.5%) had an atrial septal aneurysm, 195 of 563 (34.6%) had a prominent eustachian valve, and 106 of 563 (18.8%) had right atrial filamentous strands. Forty-four of 600 patients (7.3%) had a combination of septal aneurysm and PFO, and 252 of 561 patients (44.9%) had right atrial anatomy resulting in inferior vena cava flow to the fossa ovalis region,

a prominent eustachian valve, or right filamentous strands. Septal aneurysms were significantly associated with the presence of a PFO, and the PFOs seen in patients with septal aneurysm were larger than those seen in patients with no septal aneurysm (table 1). A prominent eustachian valve or right atrial filamentous strand was associated with atrial septal aneurysm. A large PFO in the presence of a prominent eustachian valve or right atrial filamentous strands significantly correlated with septal aneurysm. There were 92 end points, including 71 strokes and 21 deaths, among the patients with TEE images suitable for analysis of septal aneurysm and PFO. There were also 34 TIAs, 7 of which took place before the primary event. The minor hemorrhage rate was considerably lower for patients taking aspirin compared with those taking warfarin, although the rate of major hemorrhage was comparable for both groups.11

Risk factors, demographic features, and stroke characteristics of patients with PFO and septal aneurysm were similar to those patients without PFO and septal aneurysm. The time to recurrent stroke or death was the same for both groups (table 2). When TIA was considered as an end point, the groups were also similar. In addition, the subgroup of patients with cryptogenic stroke was also similar with regard to the time to end point, with and without inclusion of TIA (table 2). Comparisons were made between patients with septal aneurysm and PFO as well as with prominent eustachian valves or right atrial filamentous strands and patients without these conditions. The time to end points between the groups with and without TIA as an additional end point was similar for the overall group as well as for the group of patients with cryptogenic stroke. When the effects of aspirin and warfarin were compared in patients with septal aneurysm and PFO, the time to recurrent stroke or death was the same; it was also the same when TIA was included as an end point (table 3).

Discussion

This study showed that large PFOs are often associated with septal aneurysm, and septal aneurysm is associated with the presence of prominent eustachian valves or right atrial filamentous strands. These anatomical features may partly account for the fact that the combination of septal aneurysm and PFO carries an increased risk of stroke compared with either condition alone.

Based on the results of this study, we were able to define for the first time the relationship between septal aneurysm with large PFO and eustachian valves or right atrial filamentous strands. In addition, we showed that aspirin and warfarin were equally effective in preventing stroke in patients with septal aneurysm and PFO, and also in patients with septal aneurysm, PFO, and right atrial anatomy favoring paradoxi-

cal embolization. The results of the

PICSS showed that when patients are receiving medical treatment, the adverse event rate for stroke patients is not higher for patients with a PFO and a septal aneurysm than for patients with only a PFO.11 We also showed that the event rates for patients with septal aneurysm and PFO are no different from those without septal aneurysm and without PFO. In addition, adverse event rates did not increase in the presence of a eustachian valve or right atrial filamentous strands in patients with PFO and septal aneurysm compared with patients without these conditions. Therefore, the event rate does not increase for patients with septal aneurysm and PFO who are receiving medical treatment compared with those without septal aneurysm and PFO. These results suggest that either the presence of a PFO and septal aneurysm impart a measure of risk not identified by our study or that medical therapy is efficacious in stroke prevention among patients with these conditions.

In addition, event rates were similar between the warfarin and aspirin groups for patients with PFO and septal aneurysm, suggesting that either therapy may be considered appropriate for patients with these conditions. Patients who were given warfarin had a mean INR of 2.04.11 This INR was similar in patients with and without events, even though the range was broad.

Conclusions

In our study, septal aneurysm was correlated with large PFO and right atrial anatomy favoring paradoxical embolization. This may be a possible mechanism for the significant correlation of stroke observed with the combination of PFO and septal aneurysm. These patients had outcomes comparable with patients without septal aneurysm and without PFO who were taking aspirin or warfarin. For the entire study sample and for patients with cryptogenic stroke, even when right atrial structures favoring paradoxical embolization existed, there was no difference in event rates. In addition, aspirin and warfarin were equally effective for patients with septal aneurysm and PFO.