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1.  Response to Letter Regarding Article, “Potentially Large Yet Uncertain Benefits: A Meta-analysis of Patent Foramen Ovale Closure Trials 
doi:10.1161/STROKEAHA.113.003654
PMCID: PMC3934642  PMID: 24193802
Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
2.  Transesophageal Echocardiography in Cryptogenic Stroke and PFO: The Analysis of Putative High Risk Features from the Risk of Paradoxical Embolism (RoPE) Database 
Background
Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography (TEE) features such as PFO size, an associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these TEE features with other markers of pathogenicity has not been examined.
Methods and Results
We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high risk TEE features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n = 637) compared to those less likely to have a PFO attributable stroke (n = 657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (OR=0.92; p = 0.53). Neither the presence of a hypermobile septum nor a right-to-left shunt at rest were detected more often in those with a probable PFO-attributable stroke (OR=0.80; p = 0.45 and OR=1.15; 0.11 respectively).
Conclusions
We found no evidence that the proposed TEE risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.
doi:10.1161/CIRCIMAGING.113.000807
PMCID: PMC3934652  PMID: 24214884
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
3.  The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database 
Background
Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence.
Aims
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
Methods
We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible.
Results
The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling.
Conclusion
While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure.
doi:10.1111/j.1747-4949.2012.00843.x
PMCID: PMC4060865  PMID: 22883936
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
4.  Potentially Large Yet Uncertain Benefits: A Meta-analysis of PFO Closure Trials 
Stroke; a journal of cerebral circulation  2013;44(9):10.1161/STROKEAHA.113.001773.
Background and Purpose
Despite widespread clinical use, the efficacy of percutaneous closure of patent foramen ovale (PFO) for secondary prevention in patients with cryptogenic stroke has been formally tested only recently by 3 randomized clinical trials (RCTs) with null results in their primary analyses. We aimed to draw more precise conclusions from these RCTs via meta-analysis.
Methods
Meta-analysis of incidence rates (IRs) of stroke in treatment arms and hazard ratios (HRs) for the efficacy of closure with random-effects model. Sensitivity analyses were explored for additional outcomes and types of analyses.
Results
Two different types of closure devices were used (StarFLEX in CLOSURE-I trial and Amplatzer PFO occluder in RESPECT and PC-trial). Summary IRs of stroke were low in both arms: 0.76 (95% confidence interval, 0.30-1.96) per 100 person-years in the device group and 1.30 (95%CI, 0.94-1.81) in the medical group. Meta-analysis for HR of stroke showed a non-significant 45% risk reduction (summary HR=0.55 (0.26-1.18)) and results remained non-significant when the two Amplatzer-device trials were combined. However, statistically significant and stronger results were obtained in sensitivity analyses, when composite outcomes or fixed-effects models were considered. Subgroup meta-analyses failed to show any detectable closure-effect modifiers.
Conclusions
Meta-analysis of 3 RCTs for PFO closure does not remedy the uncertainty of individual RCTs. Different inclusion and analysis criteria can lead to mutually conflicting summary conclusions on the benefits of closure. Our findings underscore the importance of generating more randomized evidence for informed decisionmaking on the risks and benefits of closure versus medical therapy.
doi:10.1161/STROKEAHA.113.001773
PMCID: PMC3821529  PMID: 23868270
Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
5.  Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO 
BACKGROUND
Patent foramen ovale (PFO) and cryptogenic stroke (CS) are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related etiology. We examined whether specific radiological findings are associated with PFO among subjects with CS and known PFO status.
METHODS
We analyzed the Risk of Paradoxical Embolism (RoPE) database of subjects with CS and known PFO status, for associations between PFO and: 1) index stroke seen on imaging, 2) index stroke size, 3) index stroke location, 4) multiple index strokes, and 5) prior stroke on baseline imaging. We also compared imaging with purported “high risk” echocardiographic features.
RESULTS
Subjects (n=2680) were significantly more likely to have a PFO if their index stroke was large (OR 1.36, p=0.0025), seen on index imaging (OR 1.53, p=0.003), and superficially located (OR 1.54, p<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR 0.66, p<0.0001). Finding multiple index strokes was unrelated to PFO status (OR 1.21, p=0.161). No echocardiographic variables were related to PFO status.
CONCLUSIONS
This is the largest study to report the radiological characteristics of patients with CS and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
doi:10.1161/STROKEAHA.112.677039
PMCID: PMC3595100  PMID: 23339957
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
6.  Recurrent stroke on imaging and presumed paradoxical embolism 
Neurology  2012;78(13):993-997.
Objective:
To identify whether factors supporting a diagnosis of paradoxical embolism (i.e., venous thrombosis or Valsalva maneuver) are associated with radiologic markers of recurrent strokes in patients with patent foramen ovale (PFO) and cryptogenic stroke (CS). Such clinical indicators of paradoxical embolism are commonly viewed as risk factors for CS recurrence, but precise risk estimates are lacking.
Methods:
Data from the prospective Tufts PFO Registry collected at the time of the index CS were analyzed. We defined the following radiologic markers of stroke recurrence: 1) strokes of different radiologic ages and 2) silent strokes (detected on MRI but without symptoms preceding the index event). We examined the association between the radiologic endpoints and the clinical indicators of paradoxical embolism with multivariate logistic regression models, adjusting for age and gender.
Results:
Data were available for 224 subjects. Strokes of different radiologic ages were not associated with the thrombosis-predisposing conditions (1.2 [95% confidence interval 0.5–2.7]), the Valsalva maneuver (1.3 [0.6–3.1]), or the presence of either of these factors. No statistically significant association was found in subgroups stratified by anatomic location of the index stroke or for the outcome of silent strokes.
Conclusions:
Our negative findings do not lend support to using the presence of clinical indicators of paradoxical embolism as an indication for percutaneous PFO closure. Factors that support a paradoxical embolism mechanism may be different from those that predict paradoxical embolism recurrence. Further investigations with clinical follow-up and larger sample sizes are needed to reach more precise estimates for the associations examined.
doi:10.1212/WNL.0b013e31824d58bc
PMCID: PMC3310316  PMID: 22422892
7.  Patent Foramen Ovale Closure and Medical Treatments for Secondary Stroke Prevention A Systematic Review of Observational and Randomized Evidence 
Background and Purpose
Patients discovered to have a patent foramen ovale in the setting of a cryptogenic stroke may be treated with percutaneous closure, antiplatelet therapy, or anticoagulants. A recent randomized trial (CLOSURE I) did not detect any benefit of closure over medical treatment alone; the optimal medical therapy is also unknown. We synthesized the available evidence on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke.
Methods
A MEDLINE search was performed for finding longitudinal studies investigating medical treatment or closure, meta-analysis of incidence rates (IR), and IR ratios of recurrent cerebrovascular events.
Results
Fifty-two single-arm studies and 7 comparative nonrandomized studies and the CLOSURE I trial were reviewed. The summary IR of recurrent stroke was 0.36 events (95% CI, 0.24–0.56) per 100 person-years with closure versus 2.53 events (95% CI, 1.91–3.35) per 100 person-years with medical therapy. In comparative observational studies, closure was superior to medical therapy (IR ratio=0.19; 95% CI, 0.07–0.54). The IR for the closure arm of the CLOSURE I trial was higher than the summary estimate from observational studies; there was no significant benefit of closure over medical treatment (P=0.002 comparing efficacy estimates between observational studies and the trial). Observational and randomized data (9 studies) comparing medical therapies were consistent and suggested that anticoagulants are superior to antiplatelets for preventing stroke recurrence (IR ratio=0.42; 95% CI, 0.18–0.98).
Conclusions
Although further randomized trial data are needed to precisely determine the effects of closure on stroke recurrence, the results of CLOSURE I challenge the credibility of a substantial body of observational evidence strongly favoring mechanical closure over medical therapy.
doi:10.1161/STROKEAHA.111.631648
PMCID: PMC3342835  PMID: 22180252
meta-analysis; observational; studies; patent; foramen; ovale; stroke
8.  An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke 
Neurology  2013;81(7):619-625.
Objective:
We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO.
Methods:
Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates.
Results:
Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%–26%) in those with 0 to 3 points to 73% (95% CI: 66%–79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%–28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%–4%) in the highest.
Conclusion:
Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.
doi:10.1212/WNL.0b013e3182a08d59
PMCID: PMC3775694  PMID: 23864310
9.  Princeton Conference: Is PFO a Modifiable Risk Factor for Stroke Recurrence? 
Stroke; a journal of cerebral circulation  2010;41(10 Suppl):S26-S30.
While the prevalence of patent foramena ovale (PFOs) in the general population is around 25%, it is approximately doubled among cryptogenic stroke (CS) patients. This has generally been attributed to paradoxical embolism and many physicians recommend PFO closure to prevent recurrence. However, the benefit of PFO closure in patients with stroke has not been demonstrated. Further, the epidemiology of stroke recurrence in patients with CS with PFO versus without PFO, and in those with large right-to-left shunts versus small right-to-left shunts, has yielded results that appear difficult to reconcile with the hypothesis that paradoxical embolism is an important cause of stroke recurrence. The purpose of this review is to critically examine the epidemiological evidence that PFO is a potentially modifiable risk factor for stroke recurrence in patients with cryptogenic stroke. The evidence suggests that many patients with CS and PFO have strokes that are PFO-attributable, but that many have strokes that are unrelated to their PFO.. We introduce the concept of “PFO-propensity”, defined as the patient-specific probability of finding a PFO in a patient with cryptogenic stroke based on their age and other risk factors. We show that this value is directly related to the probability that a CS is PFO-attributable. Because there is substantial heterogeneity both in PFO-propensity and in recurrence risk among patients with PFO and cryptogenic stroke, stratification for closure by these joint probabilities will likely prove crucial for appropriate patient selection.
doi:10.1161/STROKEAHA.110.595140
PMCID: PMC2954503  PMID: 20876498
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention; Cryptogenic Stroke
10.  The Risk of Paradoxical Embolism (RoPE) Study: Developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke 
Trials  2011;12:185.
Background
Despite the diffusion into practice of percutaneous closure of a patent foramen ovale (PFO) in patients with cryptogenic stroke (CS), the benefits have not been demonstrated, and remain unclear. For any individual presenting with a PFO in the setting of CS, it is not clear whether the PFO is pathogenically-related to the index event or an incidental finding. Further, the overall rate of stroke recurrence is low in patients with CS and PFO. How patient-specific factors affect the likelihood that a discovered PFO is related to an index stroke or affect the risk of recurrence is not well understood. These probabilities are likely to be important determinants of the benefits of PFO closure in CS.
Design/Methods
The goal of the Risk of Paradoxical Embolism (RoPE) Study is to develop and test a set of predictive models that can identify those patients most likely to benefit from preventive treatments for PFO-related stroke recurrence, such as PFO closure. To do this, we will construct a database of patients with CS, both with and without PFO, by combining existing cohort studies. We will use this pooled database to identify patient characteristics associated with the presence (versus the absence) of a PFO, and to use this "PFO propensity" to estimate the patient-specific probability that a PFO was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit.
doi:10.1186/1745-6215-12-185
PMCID: PMC3170216  PMID: 21794121
11.  Patent foramen ovale: Rethinking trial strategies and treatment options 
Current opinion in neurology  2010;23(1):73-78.
Purpose of review
The etiology of stroke remains unknown in roughly one third of patients despite extensive investigation. The prevalence of PFOs in the general population is around 25% but the prevalence in cryptogenic stroke patients is doubled. This suggests a causal relationship between PFO and CS. This has generally been attributed to paradoxical embolism. Regardless of mechanism, ~30,000 young patients each year have a cryptogenic stroke and PFO. Optimal management is uncertain.
Recent findings
Many physicians recommend PFO closure, an intuitively attractive mechanical solution for stroke prevention. Unfortunately, the benefit of PFO closure in patients with stroke has not been demonstrated. There are ongoing clinical trials comparing the safety and efficacy of PFO closure to medical therapy. Interpreting these trials will be complicated by two issues: first, it is unclear whether a patient's PFO is causally related to the event (“pathogenic”) or not (“incidental”); and second, recurrent strokes may be due to paradoxical embolism or another stroke mechanism.
Summary
Substantial heterogeneity of patients within trials along these two dimensions of risk may make overall trial results difficult to interpret. With appropriate analyses, the trials may be more informative than the overall data may suggest.
PMCID: PMC2865205  PMID: 20050353
Cryptogenic stroke; patent foramen ovale; risk heterogeneity; endovascular PFO closure; clinical trials
13.  Patent Foramen Ovale in Cryptogenic Stroke: Incidental or Pathogenic? 
BACKGROUND
Patent foramen ovale (PFO) is significantly associated with cryptogenic stroke (CS). However, even in patients with CS, a PFO can be an incidental finding. We sought to estimate the probability that a PFO in a patient with CS is incidental.
METHODS
A systematic search identified 23 case-control studies examining the prevalence of PFO in patients with CS versus controls with stroke of known-cause. Using simple assumptions and Bayes’ theorem we calculated the probability a PFO is incidental in patients with CS. Random effects meta-analyses estimated the odds ratio (OR) of a PFO in CS versus controls in different age populations, with or without atrial septal aneurysms (ASA), and were used to summarize across studies the probability that a PFO in CS is incidental.
RESULTS
The summary OR (95% confidence limits) for PFO in CS versus controls was 2.9 (CI 2.1, 4.0). The corresponding ORs for young and old patients (< or ≥ 55 years) were 5.1 (3.3, 7.8) and 2.0 (1.0, 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28%, 39%) in age-inclusive studies, 20% (16%, 25%) in younger patients, and 48% (34%, 66%) in older patients. These probabilities were much lower when an ASA was present.
CONCLUSIONS
In patients with otherwise CS, approximately a third of discovered PFOs are likely to be incidental, and hence not benefit from closure. This probability is sensitive to patient characteristics such as age and the presence of an ASA, suggesting the importance of patient-selection in therapeutic decision-making.
doi:10.1161/STROKEAHA.109.547828
PMCID: PMC2764355  PMID: 19443800
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention

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