Patent Foramen Ovale Closure and Medical Therapy for Cryptogenic Stroke: Evidence from Randomized Controlled Trials and Beyond
Royal Columbian Hospital
*Corresponding Author: Razi Khan, Royal Columbian Hospital, 1028 Barclay St., Apt 3203, Vancouver, BC, Canada, V6E 0B1
Received: 08 May 2020; Accepted: 24 May 2020; Published: 29 May 2020
Citation: Razi Khan. Patent Foramen Ovale Closure and Medical Therapy for Cryptogenic Stroke: Evidence from Randomized Controlled Trials and Beyond. Cardiology and Cardiovascular Medicine 4 (2020): 203-217.View / Download Pdf Share at Facebook
There has been substantial investigation recently into the role of patent foramen ovale (PFO) closure for treatment of patients with cryptogenic stroke (CS). In this review, the background, results and limitations of 6 randomized controlled trials (RCTs) comparing PFO closure with medical therapy (MT) for CS are summarized. Methodologic and treatment-related differences between older and newer trials are outlined and serve as potential sources for discrepancy in results obtained. In particular, the selection of patients with “high-risk” anatomic features of PFO and continued use of antiplatelet therapy were important reasons for the benefit of PFO closure demonstrated in newer RCTs. The review also examines the association of PFO with CS in older patients, as well as discussing the role for PFO closure in these patients who were largely excluded from large RCTs. Thus far, direct comparisons of PFO closure and MT in older patient cohorts are lacking, with results from small, nonrandomized studies demonstrating inconsistent conclusions about differences in recurrent embolic event rates between older and younger patients after device implantation. Finally, this review discusses limitations in the evidence for use of oral anticoagulation compared with antiplatelet therapy in patients with CS and PFO not undergoing PFO closure.
Cryptogenic Stroke; PFO Closure; Oral Anticoagulants; Antiplatelets
Cryptogenic Stroke articles, PFO Closure articles, Oral Anticoagulants articles, Antiplatelets articles
ASA – Atrial Septal Aneurysm
CI - Confidence Interval
CS – Cryptogenic Stroke
ESUS – Embolic Stroke of Unknown Source
HR – Hazard Ratio
OR – Odds Ratio
PFO – Patent Foramen Ovale
MT – Medical Therapy
RCT – Randomized Controlled Trials
TIA – Transient Ischemic Attack
Cryptogenic stroke (CS) is a subset of ischemic stroke where the etiology of disease remains unidentified. CS accounts for 10-40% of all patients with ischemic stroke, and therefore approximately 150,000-250,000 cases of CS are estimated to occur annually in North America [1, 2]. Variation of CS frequency is dependent on patient age, the use of specific diagnostic criteria for evaluation and the extent of peri-stroke investigations performed . In patients<60 years, the frequency of CS noted in studies varies markedly ranging from as little as 10% to up to 60% [4-7]. The term embolic stroke of undetermined source (ESUS) was created recently to lessen the heterogeneity associated with CS by creating strict standardized criteria necessary for diagnosis . However, regardless of the terminology used, annualized rate of stroke amongst patients who have had CS or ESUS has been estimated to be between 1.9-4.5% [8, 9], suggesting the need for additional therapies targeting disease.
Patent foramen ovale (PFO) is thought be involved in the pathophysiology of CS by acting as a channel for passage of paradoxical emboli from the venous to the arterial system, leading to the occlusion of branches of the cerebral artery tree. De novo thrombus formation at the septum and in the right atrium has also been postulated as an alternative source for thromboembolism for CS in patients with PFO, particularly in the presence of atrial septal aneurysm (ASA). Based on both necropsy and imaging-based studies, the prevalence of PFO in the overall population ranges between 20-25% [10, 11]. In contrast, PFOs have been noted in >40% of patients with CS . There have been a number of observational studies that have subsequently noted an association between PFO and CS [13-16]. In contrast, large population-based cohort studies have not consistently found such associations [17, 18], while others have noted that certain anatomical features, such as the presence of ASA or a large degree of interatrial shunting, were required with PFO to increase the risk of recurrent stroke after initial CS . When examining treatment of CS, there has been suggested benefit for PFO closure in preventing recurrent stroke from non-randomized studies and accompanying meta-analysis [19-23]. However, until this last decade, randomized data was lacking.
This review summarizes older and more recent randomized controlled trials (RCTs) comparing PFO closure with medical therapy (MT) for CS. It also outlines the risk and potential benefit for PFO closure in older patients with CS that were not included in large RCTs. Finally, it examines the evidence for use oral anticoagulation compared with antiplatelet therapy for CS patients with PFO that may not be suitable for PFO closure.
PFO Closure RCTs in CS
The CLOSURE trial was the first published RCT comparing PFO closure with MT . The trial examined patients between 18-60 years of age with a history of recent (<6 months) CS or transient ischemic attack (TIA) who were followed for 2 years (Table 1). Transesophageal echocardiography was used to confirm PFO in all patients. The primary end-point, a composite of recurrent stroke/TIA or death at 2-years, occurred in 5.5% and 6.8% of the PFO closure and MT group, respectively (p=0.37) (Table 2). There were no differences in individualized endpoints of TIAs (PFO closure 3.1% vs. MT 4.1%, p=0.44) and recurrent stroke (PFO closure 2.9% vs. MT 3.1%, p=0.79). Rates of atrial fibrillation were almost 20-fold higher in the closure group at 2-year follow-up (PFO closure 5.7% vs. MT 0.3%, p<0.001).
A major criticism of the study pertained to the use of STARFlexâ (NMT, Boston, MA) device for PFO closure. The rate of successful closure, defined by the absence of more than trace residual shunting, was low (86%) at 6-month follow-up with transesophageal echocardiography. A second limitation of the trial related to the fact that alternative identifiable etiologies were noted for recurrent TIA/stroke outcomes in 3/4 patients in the PFO closure and MT groups, respectively. Etiologies for recurrent events included atrial fibrillation, lacunar infarction and left atrial clot, suggesting that the index event for initial patient selection may not have been truly cryptogenic in nature.
The PC trial was the first PFO closure study to start recruitment, with enrollment being initiated 13 years prior to publication in 2000 . Patients included in the RCT were those <60 years of age with PFO and recent TIA, stroke or peripheral thromboembolic event (Table 1). Transesophageal echocardiography was used to diagnose PFO. Mean follow-up was 4.1 and 4.0 years in the PFO closure and MT groups, respectively. Results of the RCT suggested that PFO closure compared with MT was not associated with a statistically significant reduction in the primary outcome composite of death, nonfatal stroke TIA or peripheral embolism (PFO closure 3.4% vs. MT 5.2%, p=0.32) (Table 2). Similarly, no differences were noted between treatment groups when examining the single outcome of non-fatal stroke (PFO closure 0.5% vs. MT 2.4%, p=0.14). Rates of atrial fibrillation were almost 3-times higher in the closure group when compared with MT, although this was not statistically significant (PFO closure 2.9% vs. MT 1%, p=0.16).
ASA – Atrial septal aneurysm, CS- Cryptogenic Stroke DAPT - Dual antiplatelet therapy, M – Months, MI - Myocardial infarction, MT – Medical therapy, PFO - Patent foramen ovale, Refs – References, TEE – Transesophageal echocardiography, TTE - Transthoracic Echocardiography, TIA - Transient ischemic attack
^ 190 patients randomized to oral anticoagulants not included in PFO closure analysis
! Median follow-up 2.8yrs, but outcomes provided for 2yr follow-up
* “High-Risk” PFO - PFO with ASA or Large Shunt
# “High-Risk” PFO - PFO with large size, ASA or hypermobile septum
Table 1: Baseline Data of Randomized Controlled Trials Comparing PFO Closure and Medical Therapy
A major limitation of the PC trial was the very high rate of attrition noted. In the trial, there were a total 55 (13.2%) of patients lost to follow-up across both trials arms. Additionally, antiplatelet therapy was not mandated in the PFO closure group after 6 months. The use of antiplatelet therapy likely serves to reduce the risk of both CS and non-CS ischemic stroke even after PFO closure. Finally, PC trial investigators had expected primary composite outcome rates of 3%/yr in the MT arm rather than the true rate of 1.3%/yr noted at trials end, making benefit with PFO closure difficult to detect.
Respect (Early) Trial
The RESPECT trial examined PFO closure in patients who had recent CS (≤270 days) between the ages of 18-60 (Table 1) . Median follow-up for the trial was 2.1 years. When compared to the 2 preceeding PFO closure RCTs, the index event for study inclusion was limited to CS rather than TIA or peripheral embolism. PFO was identified by transesophageal echocardiography. At trials end, there was a non-significant trend toward reduced recurrent stroke with PFO closure based on the intention-to-treat analysis (p=0.08) (Table 2). The 2-year recurrent stroke event-rate point was estimated to be 1.6% in the PFO closure group and 3.0% in the MT group. In per-protocol analysis, a significant reduction in primary outcome event rates was evident with PFO closure (p=0.03). Rates of atrial fibrillation were 2-fold greater in the PFO closure arm (3.0% vs 1.5%, p=0.13), but this difference was not statistically significant. A trend toward a higher rate of venous thromboembolism was noted in the PFO closure group.
Table 2: Outcomes in Randomized Controlled Trials Comparing PFO Closure and Optical Medical Therapy
CI – Confidence interval, HR – Hazard ratio, MT – Medical therapy, NS – Not specified, PFO - Patent foramen ovale, Refs – References, TIA - Transient ischemic attack
Respect (Late) Trial
The promising results from the RESPECT study prompted investigators to extended follow-up for a median of 5.9 years (Table 1) . Here, PFO closure was associated with a significant reduction in recurrent stroke, with event rates being noted at 0.58/100 patient-years (3.6%) and 1.07/100 patient-years (5.8%) in the PFO closure and MT groups, respectively (p=0.04) (Table 2). There was also a significant reduction in the secondary outcome of recurrent CS with PFO closure (PFO closure 2.0% vs. MT 4.8%, p=0.007). In long-term follow-up, there was no difference in the rates of atrial fibrillation between both arms of the study (PFO closure 0.2% vs. MT 0.1%, p=0.36).
Much like in the PC trial, a major limitation to the RESPECT trial was the very high dropout rate documented. Over the close to 6-year extended follow-up, the dropout rate was 33.3% in the MT group and 20.8% in the PFO closure group. Disparity between the dropout rates in the MT and PFO closure groups resulted in differences in treatment exposure in the 2 trial arms, potentially affecting the final results of the trial. Finally, again as in the PC trial, antiplatelet therapy was continued for only 6 months after device implantation. Therefore, the secondary prevention stroke benefit provided by aspirin was absent in the PFO closure group after 6 months.
The CLOSE trial was a uniquely designed RCT. In addition to a direct comparison of PFO closure with antiplatelet therapy, a third arm where patients received oral anticoagulation was also included . Patients between the ages of 16-60 years were randomized in 1:1:1 distribution and followed for a mean duration of 5.3 years (Table 1). A total of 663 patients with recent CS (≤6 months) and PFO, diagnosed by transthoracic or transesophageal echocardiography, were enrolled in the study. However, unlike older PFO closure RCTs, only patients with “high-risk” PFO, defined by the presence of an ASA and/or a large right-to-left interatrial shunt, were included. Trial results indicated that PFO closure was associated with a significant reduction in the primary outcome of recurrent stroke when compared with antiplatelet therapy (PFO closure 0% vs. MT 6.0%, p<0.001) (Table 2), with no recurrent strokes being noted in the PFO closure group at study completion. Additionally, there was a >2-fold reduction in the secondary composite outcome of stroke, TIA or systemic embolism with PFO closure (PFO closure 3.4% vs. MT 8.9%, p=0.01). Atrial fibrillation was >5-fold more common in the PFO closure group, with over 90% of episodes resolving within one month of device implantation (PFO closure 4.6% vs. MT 0.9%, p=0.02).
The inclusion of patients with “high-risk” PFO likely selected those with PFO presumably involved in the pathogenesis of CS rather than being incidental in nature. The absence of recurrent stroke noted after >5-year follow-up within the PFO Closure group highlights this careful selection of patients in the trial. Also, in the PFO closure arm, patients received dual antiplatelet therapy for 3 months, followed by single antiplatelet therapy until trial completion, rather than stopping therapy at 6 months as had been practiced in older trials.
Publication of the REDUCE trial coincided with that of the CLOSE trial . A total of 664 patients with recent CS and PFO were enrolled in a 2:1 distribution to PFO closure and MT, and subsequently followed for a median of 3.2 years (Table 1). PFO was diagnosed on transesophageal echocardiography. At trial completion, PFO closure was associated with a >3-fold reduction in the rate of recurrent ischemic stroke compared with antiplatelet therapy (PFO closure 1.4% vs. MT 5.4%, p=0.002) (Table 2). There was a similar almost 2-fold reduction in the co-primary endpoint of combined clinical/subclinical stroke with PFO closure (PFO closure 5.7% vs. MT 11.3%, p=0.04). Rates of atrial fibrillation were substantially higher in the PFO group (PFO closure 6.6% vs. MT 0.4%, P<0.001), but the majority of these episodes resolved within 2 weeks of onset.
As in the CLOSE trial, antiplatelet therapy was continued in both treatments arms until trial termination. Although identification of high-risk PFO was not necessary for inclusion in the trial, over 80% of patients had at least moderate-large right-to-left shunting, suggesting again that PFO in patients selected likely contributed to index CS pathology.
The DEFENSE-PFO study was the last RCT published comparing PFO closure and MT for CS, with all centres based solely out of South Korea . After a lengthy enrollment period, only 120 patients with both CS and PFO were randomized equally amongst both treatment groups, and then followed for a median of 2.8 years (Table 1). As with the CLOSE RCT, only those with “high-risk” PFO, as defined by the presence of an ASA, a hypermobile septum (septal excursion in either atria>10mm) or a large-tunnel PFO (≥2mm separation between septum primum and secundum) documented on transesophageal echocardiography, were included. The results of the study suggested that PFO closure was associated with a significant reduction in recurrent stroke (PFO closure 0% vs. MT 10.5%, p=0.023) (Table 2). Atrial fibrillation was noted in 2/60 patients in the PFO closure arm, while rates were not specified in the MT arm.
There were a number of limitations associated with the DEFENSE-PFO RCT. The trial was much smaller than previous PFO closure RCTs. It consisted of only 2 sites which is likely why patient enrollment was difficult and prolonged. Finally, the MT group in the study had a recurrent stroke rate (>5% annually) that was 3-4-fold higher than had been noted in the MT groups of comparable PFO closure RCTs. In contrast, a major strength of the trial was the inclusion of only “high-risk” PFO patients, which is likely a significant reason for the lack of recurrent strokes noted in follow-up after PFO closure.
PFO and CS in Older Patients
Little is known about the potential utility of PFO closure in older patients with CS, as the RCTs discussed have not included patients >60yrs old. However, evidence for the association between CS and PFO is still present in older patients. “High-risk” features of PFO, thought to be involved in increasing risk for CS, have also been noted in older population cohorts. Additionally, both the risk and risk factors for developing deep vein thrombosis, involved in embolic events leading to CS, progressively increase with age. Thus far, few PFO closure studies have attempted to compare outcome benefit between older and younger CS patients.
The association between the increased prevalence of PFO and CS appears to be consistent in both older and younger patient populations. In patients ≥55 years of age, Di Tullio et al noted that PFO was >4-fold more common with CS when compared to those with stroke of known cause . In a landmark paper examining 503 patients with ischemic stroke, the presence of PFO was independently associated with CS . Amongst individuals ≥55yrs of age in this study, the adjusted odds ratio (OR) for the presence PFO was 3.0 in patients with CS when compared to those with stroke of known cause. The frequency of PFO in patients with CS appeared to be similar when comparing those older and younger than 55 years of age . In older patients with CS, risk of recurrent neurological events has been noted to increase with the presence of PFO. In the PICSS trial, CS patients ≥65yrs with PFO had a ≥3-fold risk of adverse events at 2-year follow-up when compared with CS patients without PFO . Of note, amongst patients with PFO in this study, the rate of recurrent neurological event-rate was 31% in older (≥55yrs) CS patients compared with 12.2% noted in younger (<55yrs) CS patients.
In patients with PFO, risk of recurrent cerebral events after CS is increased with the presence of ASA [9, 15, 34], right-to-left shunting [13, 35], and larger PFO diameter [36, 37]. In patients ≥55 years of age, the combination of PFO and ASA was >3.5 more common in CS patients compared to those with stroke of known cause . Amongst a population of patients ≥55 years of age with ischemic stroke undergoing transesophageal echocardiography, there was no association between the isolated presence of PFO or ASA and CS, but the coexistence of PFO and ASA was >7-fold more common in patients with CS compared with those who had stroke of known cause . Right-to-left shunting noted on bubble transcranial Doppler studies was significantly more common in older patients (>60 years) with CS when compared to those with stroke of known cause (OR 2.06); this association was absent in younger patients (≤60 years) . In this population-based study, the majority (61%) of CS patients with large right-to-left shunting were >60 years of age. Finally, the diameter of PFO has been noted to increase with age, potentially allowing for easier passage of paradoxical emboli from the venous to arterial systems [10, 40].
The risk of deep vein thrombosis, the most common suspected source for paradoxical embolism leading to CS, also increases with age. In particular, the incidence of deep vein thrombosis increases markedly after age ≥55 years . This is likely attributable to a higher co-morbidity burden and/or reduced mobility noted with ageing [42, 43]. Additionally, age-associated alterations in both endothelial and platelet function in older patients may serve as additional cause for increased risk of deep vein thrombosis [44, 45].
Data from RCTs regarding the use of PFO closure in older CS patient populations is lacking. Therefore, evidence for procedural efficacy and safety in older CS patients is derived from a small number of observational studies that have compared outcomes after device implantation in both older and younger patients (Table 3). In the first study published, Kiblawi et al. noted that the risk of neurological events was similar between older (≥55yrs) and younger (<55yrs) patients assessed approximately 18 months after PFO closure . Although the burden of atrial arrhythmias was comparable between both age groups, the risk of atrial fibrillation after PFO closure was higher in older patients. Oddly 5/7 recurrent neurological events occurred within one month of device implantation, while a 6th event arose in a patient with PFO malposition, suggesting that these outcomes may have been in part procedure-related. In a similar but larger comparative study, Spies et al. noted estimated annual recurrent neurological event rates of 1.3% in older (≥55yrs) and 1.8% in younger (≤55yrs) patients after PFO closure for cryptogenic thromboembolism . Examining 475 consecutive patients with cryptogenic thromboembolism and PFO, Wintzer-Wehekind found that there was a trend toward greater risk of recurrent stroke after PFO closure in older patients, but this did not persist after controlling for traditional cardiovascular risk factors . Mortality rates were higher amongst older patients receiving PFO closure, but these differences were predominantly attributable to noncardiovascular causes of death. In fact, older patients undergoing PFO closure had a mortality rate that was similar to the estimated rate for individuals ≥65 years of age in the general population based on provincial (Quebec, Canada) databases. Frequency of atrial fibrillation was similar between older and younger patients in multivariate analysis. In contrast, Scacciatella et al. found that there was an increase in the risk of recurrent neurological events in older (≥55yrs) compared with younger patients . Mean time for recurrent events was >3yrs from the time of procedure suggesting that events were unlikely to be related to device implantation. Age remained the only predictor of recurrent neurological events even after adjusting for other cardiovascular risk factors (hazard ratio (HR) 8.38, 1.5-83.2).
CI – Confidence interval, HR – Hazard ratio, MT – Medical therapy, NS – Not specified, PFO – Patent foramen ovale, Refs – References
Table 3: Studies Comparing Baseline Characteristics and Outcomes in Older and Younger Patients Undergoing PFO Closure
Thus far, there have been no studies directly comparing PFO closure with MT in CS patients older than 60 years of age, despite the fact that contemporary stroke registries have suggested that close to 50% of ischemic strokes may be labelled as CS in this patient population . Although, the presence of PFO and associated “high-risk” PFO features are not uncommon in older patients, evidence for PFO closure remains poor and is derived predominantly from small studies comparing older and younger patients undergoing device implantation. Heterogeneity in the different patient cohorts included in these studies has led to considerable discrepancy in the rates of recurrent neurological events and atrial fibrillation noted after PFO closure in older patients. RCTs examining PFO closure for older CS patients would help offer insights into prognosis and provide direction of care for treatment in these individuals.
Medical Management for CS Patients with PFO
For CS patients with PFO who are not candidates for PFO closure or for those who fall outside the inclusion parameters of PFO closure RCTs, MT has been advocated [50, 51]. However, to date, there remains a question of what ideal or optimal MT entails for patients with CS and PFO. Given the presumptive role of paradoxical embolism in CS pathology, anticoagulation has been suggested as a potential treatment for disease. Comparisons between oral anticoagulation and antiplatelet therapy for treatment of CS in patients with PFO have been restricted to observational studies, subgroup analysis of large CS/ESUS-related RCTs and examination of non-PFO closure groups in the CLOSE trial.
Two meta-analysis published prior to recent PFO closure RCTs have provided conflicting evidence for use of oral anticoagulation in CS patients with PFO. In the first meta-analysis, involving 8 observational studies, there was a suggested reduction in recurrent neurological events by>50% with oral anticoagulation compared with antiplatelet therapy in CS patients with PFO . However, the analysis did not control for confounding factors and bias within these non-randomized studies. A subsequent meta-analysis included patients from observational studies and the MT arms of 3 PFO closure RCTs, with investigators using individual patient data and propensity scoring to help control for confounding. The study noted no significant difference between oral anticoagulation and antiplatelet therapy for the composite outcome of recurrent stroke/TIA/death [adjusted HR 0.76, 95% confidence interval (CI) 0.52–1.12] or for recurrent stroke alone (adjusted HR 0.75, 95% CI 0.44–1.27) . There was also no benefit with oral anticoagulation treatment in patients with high-risk features of PFO, such as the presence of ASA or large shunt on transesophageal echocardiography.
Several subgroup analysis of larger RCTs have assessed the efficacy of oral anticoagulation for treatment of CS in patients with PFO. The first study termed the PICSS trial, a substudy of the WARSS RCT, compared use of warfarin (INR target 1.4-2.8) with aspirin (325mg) in patients with both recent ischemic stroke (≤30 days) and PFO . Only ~40% of stroke patients included had underlying CS. Amongst patients with both CS and PFO, there was no difference in the 2-year rate of recurrent ischemic stroke or death between warfarin and aspirin groups (9.5% vs. 17.9%, p=0.28).
More contemporary data derived from subgroup analysis of the NAVIGATE ESUS trial assessed use of a direct oral anticoagulant, rivaroxaban (15mg daily), with aspirin (100mg daily) for treatment of ESUS patients with PFO . Patients with PFO analysed represented 7.4% (n=534) of all patients from the initial trial. The study found that there was a numerical but not statistical reduction in the risk of recurrent ischemic stroke with rivaroxaban when compared with aspirin (2.6 events/100 patient-years vs. 4.8 events/100 patient-years, HR 0.54 95% CI 0.22-1.36). Due to the relatively few events noted at trial termination, the impact of shunt size or ASA on treatment could not be evaluated. Risk of major bleeding also trended to being higher with rivaroxaban in patients with PFO (HR 2.05; 95% CI 0.51-8.18), which was similar to the findings noted in the overall trial population. Within the same manuscript, the authors performed a meta-analysis comparing oral anticoagulation with antiplatelet therapies for CS patients with PFO, with inclusion of the NAVIGATE ESUS substudy, as well as data from the CLOSE and PICCS trials. The combined data suggested that oral anticoagulation was associated a significant reduction in recurrent stroke when compared to antiplatelet therapy for CS/ESUS patients with PFO (OR 0.48, 95% CI 0.26-0.96). Relatively wide confidence intervals noted were likely due to the small cumulative number of patients analysed (n=838) despite the inclusion of 3 different trial cohorts.
The CLOSE trial was the only RCT examining CS patients with PFO that included separate trial arms comparing oral anticoagulation and antiplatelet treatments amongst those with contraindications to PFO closure . Patients in the oral anticoagulation group were placed on direct oral anticoagulants (7%) or vitamin k antagonists (93%), while those in the antiplatelet therapy group received clopidogrel (10.8%), aspirin (86.7%), aspirin with extended-release dipyramidole (1.3%) or the combination of aspirin and clopidogrel (1.3%). In the intention-to-treat analysis, the 5-year estimate for recurrent stroke was 1.5% and 3.8% in the oral anticoagulation and antiplatelet group, respectively (HR 0.44, 95% CI 0.11-1.48). The study was not powered to assess statistical significance, although there were no marked numerical differences in the frequency of stroke or bleeding events between groups.
Currently, optimal MT for CS patients unable or contraindicated to PFO closure remains unclear. Results from studies underpowered for major clinical outcomes make conclusions about the potential risks and benefits of oral anticoagulation treatment in CS patients with PFO difficult to extrapolate into real world practice. There is a need for large RCTs directly comparing anticoagulation and antiplatelet therapies for patients with PFO and CS that cannot undergo PFO closure.
In patients with CS under 60 years of age, PFO closure offers reduction in recurrent stroke risk when compared with antiplatelet therapy. New RCTs have shown the importance of selecting patients with “high-risk” PFO, as well as the need for continued antiplatelet therapy after procedure. For CS patients greater than 60 years of age, data for PFO closure is limited, with smaller, non-randomized studies having suggested variable outcomes when comparing older and younger patient cohorts after device implantation. Amongst CS patients with PFO that are not candidates for PFO closure, there is currently inadequate evidence to recommend use of oral anticoagulation over antiplatelet therapy, with greater study being required to define optimal MT in this patient population.
I would like to thank Natasha Kohli for her patience and thoughtfulness during this manuscript preparation.
- Yaghi S, Bernstein RA, Passman R, et al. Cryptogenic stroke: research and practice. Circulation Research 12 (2017): 527-540.
- Perera KS, Vanassche T, Bosch J, et al. Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. International Journal of Stroke 11 (2016): 526-533.
- Adams HP, Kappelle LJ, Biller J, et al. Ischemic stroke in young adults: experience in 329 patients enrolled in the Iowa Registry of stroke in young adults. Archives of Neurology 52 (1995): 491-495.
- Ji R, Schwamm LH, Pervez MA, et al. Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA Neurology 70 (2013): 51-57.
- Wolf ME, Grittner U, Böttcher T, et al. Phenotypic ASCO characterisation of young patients with ischemic stroke in the prospective multicentre observational sifap1 study. Cerebrovascular Diseases 40 (2015): 129-135.
- Saver JL. Cryptogenic stroke. New England Journal of Medicine 374 (2016): 2065-2074.
- Jacobs BS, Boden-Albala B, Lin IF, et al. Stroke in the young in the northern Manhattan stroke study. Stroke 33 (2002): 2789-2793.
- Hart RG, Diener HC, Coutts SB, et al, Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. The Lancet Neurology 13 (2014): 429-438.
- Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. New England Journal of Medicine 345 (2001): 1740-1746.
- Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. InMayo Clinic Proceedings 59 (1984): 17-20.
- Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. InMayo Clinic Proceedings 74 (1999): 862-869.
- Lechat PH, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. New England Journal of Medicine 318 (1988): 1148-1152.
- De Castro S, Cartoni D, Fiorelli M, et al. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 31 (2000): 2407-2413.
- Mas JL, Zuber M. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. American Heart Journal 130 (1995): 1083-1088.
- Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 24 (1993): 1865-1873.
- Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Annals of Internal Medicine 117 (1992): 461-465.
- Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. Journal of the American College of Cardiology 49 (2007): 797-802.
- Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty?: evidence from a prospective population-based study. Journal of the American College of Cardiology 47 (2006): 440-445.
- Thanopoulos BV, Dardas PD, Karanasios E, et al. Transcatheter closure versus medical therapy of patent foramen ovale and cryptogenic stroke. Catheterization and Cardiovascular Interventions 68 (2006): 741-746.
- van de Wyngaert F, Kefer J, Hermans C, et al. Absence of recurrent stroke after percutaneous closure of patent foramen ovale despite residual right-to-left cardiac shunt assessed by transcranial Doppler. Archives of Cardiovascular Diseases 101 (2008): 435-441.
- Paciaroni M, Agnelli G, Bertolini A, et al. Risk of recurrent cerebrovascular events in patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study. Cerebrovascular Diseases 31 (2011): 109-116.
- Khairy P, O'Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Annals of Internal Medicine 139 (2003): 753-760.
- Agarwal S, Bajaj NS, Kumbhani DJ, et al. Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. JACC: Cardiovascular Interventions. 2012 Jul 1;5(7):777-89.
- Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. New England Journal of Medicine 366 (2012): 991-999.
- Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. New England Journal of Medicine 368 (2013): 1083-1091.
- Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. New England Journal of Medicine 368 (2013):1092-1000.
- Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. New England Journal of Medicine 377 (2017): 1022-1032.
- Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. New England Journal of Medicine 377 (2017): 1011-1021.
- Søndergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. New England Journal of Medicine 377 (2017): 1033-1042.
- Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. Journal of the American College of Cardiology 71 (2018): 2335-2342.
- Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. New England Journal of Medicine 357 (2007): 2262-2268.
- Mesa D, Ruiz M, Delgado M, et al. Prevalence of patent foramen ovale determined by transesophageal echocardiography in patients with cryptogenic stroke aged 55 years or older. Same as younger patients?. Revista Española de Cardiología (English Edition) 63 (2010): 315-322.
- Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 105 (2002): 2625-2631.
- Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 55 (2000): 1172-1179.
- Anzola GP, Zavarize P, Morandi E, et al. Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale. European Journal of Neurology 10 (2003): 129-35.
- Steiner MM, Di Tullio MR, Rundek T, et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 29 (1998): 944-948.
- Schuchlenz HW, Saurer G, Weihs W, et al. Persisting eustachian valve in adults: relation to patent foramen ovale and cerebrovascular events. Journal of the American Society of Echocardiography 17 (2004): 231-233.
- Force M, Massabuau P, Larrue V. Prevalence of atrial septal abnormalities in older patients with cryptogenic ischemic stroke or transient ischemic attack. Clinical Neurology and Neurosurgery 110 (2008): 779-783.
- Mazzucco S, Li L, Binney L, et al. Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis. The Lancet Neurology 17 (2018): 609-617.
- Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Archives of Internal Medicine 151 (1991): 933-938.
- Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Archives of Internal Medicine 158 (1998): 585-593.
- Engbers MJ, Blom JW, Cushman M, et al. The contribution of immobility risk factors to the incidence of venous thrombosis in an older population. Journal of Thrombosis and Haemostasis 12 (2014): 290-296.
- Anderson Jr FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 107 (2003): I-9.
- Nurmohamed MT, Büller HR, Jan W. Physiological changes due to age. Drugs & aging 5 (1994): 20-33.
- Schina Jr MJ, Neumyer MM, Healy DA, et al. Influence of age on venous physiologic parameters. Journal of Vascular Surgery 18 (1993): 749-752.
- Kiblawi FM, Sommer RJ, Levchuck SG. Transcatheter closure of patent foramen ovale in older adults. Catheterization and Cardiovascular Interventions 68 (2006): 136-142.
- Spies C, Khandelwal A, Timmemanns I, et al. Recurrent events following patent foramen ovale closure in patients above 55 years of age with presumed paradoxical embolism. Catheterization and Cardiovascular Interventions 72 (2008): 966-970.
- Wintzer-Wehekind J, Alperi A, Houde C, et al. Transcatheter closure of patent foramen ovale in patients older than 60 years of age with cryptogenic embolism. Revista Española de Cardiología (English Edition) 73 (2020): 219-224.
- Scacciatella P, Butera G, Meynet I, et al. Percutaneous closure of patent foramen ovale in patients with anatomical and clinical high-risk characteristics: Long-term efficacy and safety. Journal of Interventional Cardiology 24 (2011): 477-484.
- Messé SR, Gronseth G, Kent DM, et al. Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 87 (2016): 815-821.
- Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 45 (2014): 2160-2236.
- Kitsios GD, Dahabreh IJ, Abu Dabrh AM, et al. Patent foramen ovale closure and medical treatments for secondary stroke prevention: a systematic review of observational and randomized evidence. Stroke 43 (2012): 422-431.
- Kent DM, Dahabreh IJ, Ruthazer R, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. European Heart Journal 36 (2015): 2381-2389.
- Kasner SE, Swaminathan B, Lavados P, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. The Lancet Neurology 17 (2018): 1053-1060.