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CLINICAL RESEARCH: ATRIAL ANATOMY AND STROKE

Atrial anatomy in non-cardioembolic stroke patients

Effect of medical therapy

Shunichi Homma, MD, FACC^*,*, Ralph L. Sacco, MD, MS, Marco R. Di Tullio, MD^*, Robert R. Sciacca, EngScD^*, Jay P. Mohr, MD PICSS Investigators

^* Department of Medicine, New York, New York, USA
Neurological Institute, Columbia University, New York, New York, USA

Manuscript received January 9, 2003; revised manuscript received March 14, 2003, accepted March 20, 2003.

^* Reprint requests and correspondence: Dr. Shunichi Homma, Division of Cardiology, Columbia University, College of Physicians & Surgeons, 630 West 168th Street, New York, New York 10032, USA.
sh23{at}columbia.edu

	Abstract

Top Abstract Methods Results Discussion APPENDIX References

 
OBJECTIVES: The purpose of the study was to assess the mechanism responsible for increased stroke risk in patients with atrial septal aneurysm (SA) and patent foramen ovale (PFO), and to determine the efficacy of medical therapy for preventing stroke recurrence or death.

BACKGROUND: Atrial septal aneurysm and PFO are associated with stroke. However, the mechanism for this association is undefined, and the efficacy of medical therapy has not been investigated in a randomized fashion.

METHODS: The Patent foramen ovale In Cryptogenic Stroke Study (PICSS) evaluated transesophageal echocardiography findings in patients enrolled in the Warfarin-Aspirin Recurrent Stroke Study, a randomized double-blind trial to evaluate the efficacy of warfarin compared with aspirin.

RESULTS: Large PFO and prominent eustachian valve (EV) or right atrial (RA) filamentous strands were found more frequently in patients with SA compared with those without SA (37.7% vs. 10.9%, p < 0.001 and 59.4% vs. 43.1%, p = 0.02). Patients with SA and PFO had no significant difference in time to recurrent stroke or death compared with those having neither (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.49 to 2.38, p = 0.84; two-year event rates 15.9% vs. 14.5%). Patients with SA, PFO, and RA anatomy predisposing to paradoxical embolization also had no difference compared with those without these findings (HR 1.22, 95% CI 0.43 to 3.47, p = 0.71; two-year event rates 18.2% vs. 14.2%). There was no significant difference in time to recurrent stroke or death between the patients treated with warfarin or aspirin (HR 1.00, 95% CI 0.22 to 4.47, p = 1.0; two-year event rates 16.0% vs. 15.8%).

CONCLUSIONS: Atrial septal aneurysm is associated with the presence of large PFO and prominent EV or RA filamentous strands. On medical therapy, patients with SA and PFO did not experience increased risk of adverse events, and there was no difference between treatment results for warfarin and for aspirin.

Abbreviations and Acronyms   EV = eustachian valve   INR = international normalized ratio   IVC = inferior vena cava   PFO = patent foramen ovale   PICSS = Patent foramen ovale In Cryptogenic Stroke Study   RA = right atrial   SA = atrial septal aneurysm   TEE = transesophageal echocardiography   TIA = transient ischemic attack   WARSS = Warfarin-Aspirin Recurrent Stroke Study

A recent report indicates a significantly increased recurrent stroke risk in patients with SA and PFO, compared with those having neither (16). We have recently reported that on medical therapy the presence of SA in the overall group of stroke patients with PFO did not increase the adverse event rate beyond that seen with PFO alone (17). However, this group was not compared with the patients with neither SA nor PFO, and cryptogenic stroke patients were not analyzed separately. Furthermore, the effect of RA anatomical variation on the adverse event rates in patients with SA and PFO was not investigated. There is an increasing use of percutaneous or surgical PFO closure to potentially prevent paradoxical embolic events (18–21). In order to define their proper role, it is necessary to rigorously assess the risk of adverse events in conventionally medically treated patients with PFO, particularly in a perceived high-risk group, such as those with SA, PFO, and RA anatomy predisposing to paradoxical embolization. Therefore, in the current study, we investigated whether the presence of SA and PFO, with or without RA anatomical variation, alters the event rates when compared with the patients without these findings.

	Methods

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Patient recruitment.   The Patent foramen ovale In Cryptogenic Stroke Study (PICSS) was a 42-center study that tested the efficacy of medical therapy for stroke risk factors identified by transesophageal echocardiography (TEE) (17). Patients were drawn from the Warfarin-Aspirin Recurrent Stroke Study (WARSS), a double-blind study to assess the efficacy of warfarin compared with aspirin for prevention of recurrent stroke or death in ischemic stroke patients (22). Patient recruitment started in June 1993 and ended in June 1998. The PICSS patients consisted of WARSS patients undergoing TEE for any clinical purpose, as well as WARSS patients with cryptogenic stroke subtype who were solicited to undergo TEE for PICSS entry (17). Clinical data were collected by the Data Management Center in the Stroke Unit of the Columbia-Presbyterian Medical Center. All protocols for WARSS and PICSS were approved by the institutional review board at each participating center, and informed consent was obtained from each participant.

Eligibility.   Patients age 30 to 85 years were eligible. Eligible patients experienced ischemic stroke within the previous 30 days and rated 3 on the Glasgow Outcome Scale (representing severe disability, moderate disability, no or minimal disability) (23). Ineligible patients had baseline international normalized ratio (INR) above the normal range (>1.4), stroke related to a procedure, stroke attributable to a cardioembolic source, or planned to undergo surgery for high-grade carotid stenosis. Patients with a contraindication to TEE were not considered for PICSS entry.

Stroke subtyping.   All baseline strokes were subtyped by a local neurology principal investigator based on a predefined criteria modeled after the National Institute of Neurological Disorders and Stroke-Stroke Data Bank and Trial of Organon in Acute Stroke Therapy (24). These subtypes were: lacunar, large vessel, cryptogenic, other determined cause, and conflicting mechanisms. Cryptogenic stroke typically has no definite source despite a thorough diagnostic evaluation (25).

Medications and blinding.   Medications used were aspirin 325 mg tablets taken once daily, and warfarin in 2 mg scored tablets taken once daily, adjusted to achieve and maintain INR 1.4 to 2.8. Patients were randomized to active aspirin or warfarin and an identical placebo. No patients received two placebo or two active treatments.

TEE protocol and analysis.   All patients underwent TEE guided by a predefined protocol using either a biplane or multiplane TEE probe and the videotapes were sent to Columbia for central analysis. The TEE protocol emphasized extensive characterization of interatrial septum and RA anatomy. Saline contrast injection with and without Valsalva maneuver or cough was performed for PFO detection. Ongoing quality control was monitored with feedback to the site regarding TEE study quality.

All TEE tapes were analyzed by a single observer (S. H.). All measurements were made blinded to treatment assignment, stroke subtype, or outcome. The PFO was determined to be present if, upon saline contrast injection, there was appearance of at least one microbubble in the left atrium within three cardiac cycles following opacification of the right atrium (26,27). The PFO was distinguished from atrial septal defect by the presence of overlap of septum primum and secundum. The number of microbubbles was counted from an image demonstrating the maximum number on a video frame within three cardiac cycles from the opacification of right atrium (7,28). Measurements were made from resting contrast injection and in conjunction with Valsalva maneuver or cough, whichever demonstrated a larger PFO size or shunt. Each PFO was determined to be large or small, as previously described (17).

The SA was defined as a motion of atrial septum into left or right atrium of at least 10 mm from its midline position (29). Prominent EV was defined as a protrusion into the right atrium of 10 mm or more of linear membrane-like structure from the junction of right atrium with IVC in the image plane demonstrating the entrance of IVC into right atrium in a vertical plane using biplane probe, or an equivalent plane using multiplane probe. Right atrial filamentous strands were defined as freely mobile linear filamentous structures in RA with attachment to EV or to any aspect of RA wall. Inter- and intra-observer variability for determination of the presence of prominent EV or RA filamentous strands was performed by blinded interpretation of 15 studies.

Follow-up.   All patients were followed for two years, operationalized as 24 ± 1 month (maximum 761 days). Follow-up was made on a monthly basis by phone or in-person to assess compliance and to regulate INRs. Quarterly and annual in-person follow-ups for detailed examination were also made.

Assessment of end points.   The primary end point was recurrent ischemic stroke or death from any cause. Transient ischemic attack (TIA) was included for secondary end points. Clinical evidence of a recurrent ischemic stroke was a new lesion on computed tomography or magnetic resonance image, or when new lesions were absent, clinical syndrome consistent with stroke of >24 h duration. All clinical and radiological events were adjudicated independently by a panel blinded to treatment assignment.

Statistical analysis.   The significance of differences in sociodemographic variables, stroke characteristics, and stroke risk factors was assessed by unpaired t test for continuous variables and by Fisher exact test for categorical variables. Kaplan-Meier curves were constructed and a Cox proportional hazards model was used to determine the relative hazard ratio and associated 95% confidence interval (CI) for subjects with SA and PFO compared with subjects with neither SA nor PFO. Similar analyses were performed comparing subjects with the combination of SA, PFO, and prominent EV or RA filamentous strands with subjects having none of these findings. These analyses were performed for the group as a whole, and in the cryptogenic stroke patients. In subjects with SA and PFO, warfarin was compared with aspirin. Reported event rates at two years were derived from the Kaplan-Meier curves, which adjusted for censoring. A value p < 0.05 was considered significant for all analyses.

	Results

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The PICSS enrolled 630 (28.6%) of 2,206 WARSS patients. When the strokes of 630 PICSS patients were subtyped, 265 (42.1%) were cryptogenic, 244 (38.7%) were lacunar, 68 (10.8%) were large vessel, 27 (4.3%) were other determined cause, and 26 (4.1%) were conflicting mechanisms. The mean INR in the warfarin-treated group was 2.04 ± 0.99.

Baseline TEE findings.   Of 630 patients, TEE studies were available for analysis in 627 patients. Of these, 601 (95.9%) patients had TEE images adequate for analysis of PFO, 600 (95.7%) for analysis of SA, 563 (89.8%) for analysis of EV, and 563 (89.8%) for analysis of RA filamentous strands. Lower adequacy for determination of EV or RA filamentous strands derived from the stringent criteria used to determine its presence. The PFO was present in 203 (33.8%) of the patients, of which 58.6% (119/203) were classified as small and 41.4% (84/203) as large. Atrial septal aneurysm was present in 11.5% (69/600), prominent EV was seen in 34.6% (195/563), and RA filamentous strands was present in 18.8% (106/563). A combination of SA and PFO was found in 7.3% (44/600). Right atrial anatomical variation favoring IVC flow towards the fossa ovalis area, a prominent eustachian valve or RA filamentous strands was found in 44.9% (252/561). Blinded interpretation of the studies for determination of the presence of prominent EV or RA filamentous strands showed complete agreement, both within and between observers.

Relationship of SA with PFO, prominent EV, or RA filamentous strands.   As shown in Table 1, SA was strongly associated with the presence of PFO, and these PFOs were larger than those found without SA. Atrial septal aneurysm was associated with the presence of prominent EV or RA filamentous strands, and the combination of a large PFO and prominent EV or RA filamentous strands was strongly associated with the presence of SA. When a more stringent criteria of three or microbubbles for the presence of PFO, and 20 or more microbubbles for large PFO was applied, the findings did not change. Furthermore, when the patients were divided into those <50 years of age and those 50 years of age, in both groups, SA was associated with the presence of PFO and large PFO.

Efficacy of medical therapy.   In the overall patient population the event rate in patients with SA and PFO was compared with that in patients with neither SA nor PFO. Demographics, stroke characteristics, and risk factors were similar between these groups (Table 2). Criteria for clinical variables have been previously defined (22). In the overall group, there was no significant difference in time to recurrent stroke or death in those with SA and PFO compared with the patients with neither of these findings (Table 3). With the addition of TIA as an additional end point, there also was no significant difference. When the cryptogenic subtype was considered separately, there were no significant differences in the time to end point with and without inclusion of TIA (Table 3). We then compared the patients with SA and PFO, along with prominent EV or RA filamentous strands with those without any of these findings. Demographic and stroke characteristics and risk factors were similar between the comparison groups (Table 4). In the overall as well as in the cryptogenic subset, there was no difference in the time to end points between the groups with and without TIA as an additional end point (Table 5). When the efficacy of warfarin and aspirin was compared in the patients with SA and PFO, there was no significant difference in the time to recurrent stroke or death between the two treatment arms. This was also the case when TIA was included as an additional end point (Table 6). When a more stringent criterion of three or more microbubbles was used to define PFO, no significant changes were noted in any of the outcome findings.

	Discussion

Top Abstract Methods Results Discussion APPENDIX References

We found that PFO was frequently found in the presence of SA, as was previously noted (30,31). We also found that large PFOs are frequently found in the presence of SA with an increased potential for paradoxical embolization. In the past studies, large PFO has been associated with cryptogenic stroke (7,8). Thus, the higher stroke risk in patients with SA and PFO may in part derive from the frequent presence of large PFO in patients with SA and PFO. Furthermore, we found that SA is associated with the presence of prominent EV or RA filamentous strands, both remnants of right valve of sinus venosus (12,13). In adult life, EV has been associated with cyanosis in patients with atrial septal defect presumably by diverting IVC flow into the left atrium (10,11). Chiari network, an extensive network of RA filamentous strands, has been associated with paradoxical embolization, likely by directing embolic material from IVC into the fossa ovalis (15). We believe these anatomical features in part account for the combination of SA and PFO being strongly associated with stroke.

This study is the first to define the relationship between SA with large PFO and EV or RA filamentous strands. This study is also the first to assess the efficacy of medical therapy in double-blind–treated patients with SA and PFO, as well as in patients with SA, PFO, and RA anatomy favoring paradoxical embolization. The PICSS offered a unique opportunity to assess the adverse event rates in a carefully screened cohort of stroke patients (17). Patients were double-blindly assigned to warfarin or aspirin, and follow-up was conducted using uniform criteria with a very small number of patients lost to follow-up. All TEE studies were centrally and blindly analyzed using uniform criteria.

We have previously reported that on medical therapy the presence of SA in stroke patients with PFO does not increase the adverse event rate beyond that seen with PFO alone (17). In this study, we further demonstrate that patients with SA and PFO have similar event rates even when compared with those with neither SA nor PFO. Moreover, the presence of EV or RA filamentous strands in patients with PFO and SA did not increase the adverse event rates compared with the patients without any of these findings. Thus while on medical therapy, patients with PFO and SA, as a whole, do not experience increased event rate compared with those without such findings. This implies that either the medical therapy is effective or that the presence of PFO and SA confers a degree of risk not detected by our study.

When warfarin was compared with aspirin in patients with PFO and SA, there was no difference in the adverse event rates between the treatment arms. The mean INR of the warfarin-treated patients in PICSS was 2.04 (17). In WARSS, an INR >1.5 proved to be effective in reducing adverse events (22). Thus, we believe adequate INR was achieved in our population. Prior to events, in patients experiencing events, the INR was 1.8 ± 1.0. Although the range of INR was wide, this was not significantly different from the level in those without events. Although the choice of medical therapy did not make a difference, its efficacy will depend on how accurately we can attribute the ischemic event to paradoxical embolization. Indeed, in those with deep venous thrombosis, warfarin is likely to be more effective compared with aspirin in preventing recurrent neurological events in patients with PFO and SA.

In comparing our study with a recent study reporting high adverse event rates in the patients with SA and PFO, our patients were significantly older (16). Adverse event rates and the efficacy of medical therapy for stroke patients with PFO may very well differ according to the age of the subjects. Also, if the follow-up period was significantly longer, differences may have been detected. However, given the similarity in event rates, a considerably longer period would have been necessary.

Conclusions.   We show that large PFO and RA anatomy favoring paradoxical embolization are associated with the presence of SA, providing a plausible mechanism for the strong association of the combination of SA and PFO with stroke. We also demonstrate similar outcome rates in these patients compared with those with neither PFO nor SA while on medical therapy consisting of warfarin or aspirin. Event rates were similar even when the RA structures favoring paradoxical embolization were present. This applied to both the study population as a whole and the cryptogenic stroke patients. Furthermore, when warfarin was compared with aspirin in patients with SA and PFO, no significant differences were noted. It remains to be seen if other therapeutic modalities, such as percutaneous PFO closure, reduces the event rate in these patients.

	APPENDIX

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For a complete list of the PICSS study participants as well as a list of the number of patients that contributed to the PICSS and the names of the institutions, local neurology principal investigators, cardiology investigators, and coordinators, please see the September 17, 2003, issue of JACC at www.cardiosource.com/jacc.html.

	Footnotes

 
This research was supported by NIH-NINDS-RO1-NS-32525 (Dr. Homma), and RO1-NS-28371 (Dr. Mohr).

	References

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