David M. Kent

Initial experience using the transconjunctival sutureless vitrectomy system for vitreoretinal surgery

OBJECTIVE To describe the initial experience and to evaluate the safety and feasibility of using the 25-gauge Transconjunctival Sutureless Vitrectomy System (TSV) for a variety of vitreoretinal procedures. DESIGN Retrospective review of a consecutive interventional case series. PARTICIPANTS Thirty-five eyes of 33 patients, including cases of idiopathic epiretinal membrane (12 cases), retinal detachment (6 cases), macular hole (5 cases), branch retinal vein occlusion (4 cases), retinopathy of prematurity (4 cases), persistent diabetic macular edema (1 case), diabetic vitreous hemorrhage (1 case), retained lens material after cataract extraction (1 case), and Norrie disease (1 case). INTERVENTION All patients underwent surgery using the 25-gauge TSV. MAIN OUTCOME MEASURES Intraocular pressure, visual acuity, and postoperative complications. RESULTS The median preoperative intraocular pressure was 16 mmHg (range, 10-21 mmHg), whereas the median intraocular pressure on the first postoperative day was 12 mmHg (range, 6-28 mmHg). The median intraocular pressure at 1 week and 1 month were both 16 mmHg (range, 10-30 mmHg). Overall, the median preoperative visual acuity was 20/100 (range, 20/30 to hand motions), and the median postoperative visual acuity after a mean follow-up of 14 weeks (range, 1-60 weeks) was 20/60 (range, 20/20-20/150). One eye developed a postoperative retinal detachment. CONCLUSIONS The 25-gauge TSV seems to be practical and safe for a variety of vitreoretinal procedures. The concept of transconjunctival surgery has the potential to increase the efficiency of a variety of vitreoretinal surgeries and possibly hasten the postoperative recovery and outcomes in several conditions by simplifying the surgical procedure; minimizing surgically induced trauma; and decreasing the convalescence period, the operating time, and the postoperative inflammatory response.

Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis

BACKGROUND Over the past 20 years, percutaneous transluminal balloon coronary angioplasty (PTCA), bare-metal stents (BMS), and drug-eluting stents (DES) succeeded each other as catheter-based treatments for coronary artery disease. We undertook a systematic overview of randomised trials comparing these interventions with each other and with medical therapy in patients with non-acute coronary artery disease. METHODS We searched Medline for trials contrasting at least two of the four interventions (PTCA, BMS, DES, and medical therapy). Eligible outcomes were death, myocardial infarction, coronary artery bypass grafting, target lesion or vessel revascularisation, and any revascularisation. Random effects meta-analyses summarised head-to-head (direct) comparisons, and network meta-analyses integrated direct and indirect evidence. FINDINGS 61 eligible trials (25 388 patients) investigated four of six possible comparisons between the four interventions; no trials directly compared DES with medical therapy or PTCA. In all direct or indirect comparisons, succeeding advancements in percutaneous coronary intervention did not produce detectable improvements in deaths or myocardial infarction. The risk ratio (RR) for indirect comparisons between DES and medical therapy was 0.96 (95% CI 0.60-1.52) for death and 1.15 (0.73-1.82) for myocardial infarction. By contrast, we recorded sequential significant reductions in target lesion or vessel revascularisation with BMS compared with PTCA (RR 0.68 [0-60.0.77]) and with DES compared with BMS (0.44 [0.35-0.56]). The RR for the indirect comparison between DES and PTCA for target lesion or vessel revascularisation was 0.30 (0.17-0.51). INTERPRETATION Sequential innovations in the catheter-based treatment of non-acute coronary artery disease showed no evidence of an effect on death or myocardial infarction when compared with medical therapy. These results lend support to present recommendations to optimise medical therapy as an initial management strategy in patients with this disease.

Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis

Knee osteoarthritis (OA) is a common and progressive joint disease affecting more than 250 million people worldwide (1). It has significant effects on function (2) and considerable societal costs in terms of work loss (3), early retirement, and joint replacement (4). Osteoarthritis is a leading indication for use of prescription drugs, which costs about

Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke: a pooled analysis of randomized clinical trials.

3000 per year per patient (5). In the absence of effective disease-modifying medical treatments, a range of symptomatic treatments is available. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medicines for OA yet have significant toxicity, especially among the demographic groups in which the disorder is most prevalent (6). Intra-articular (IA) treatments are widely used, although their efficacy and safety remain in question. More knowledge about the comparative efficacy and toxicity of these compounds, which would be helpful for patients, physicians, payers, and policymakers, is needed to formulate rational treatment algorithms for OA. The relative effectiveness of OA treatments is difficult to discern from the literature, in part because few head-to-head comparison studies are available and traditional pairwise meta-analysis cannot integrate all of the evidence from several comparators. Therefore, our goal was to comprehensively review the literature and determine the relative efficacy of the primary knee OA treatments using a network meta-analysis design. Methods Data Sources and Searches We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Central Register of Controlled Trials from inception to 15 August 2014 (Supplement Table 1). All searches were limited to randomized, controlled trials in humans. No limits were applied for language, publication date, or publication status, and foreign-language papers were translated. We also hand-searched the reference lists of all retrieved studies and conference proceedings of the American Association of Orthopedic Surgeons, American College of Rheumatology, British Society for Rheumatology, European League Against Rheumatism, International League of Associations of Rheumatology, and Osteoarthritis Research Society International. The conference proceedings were searched from January 1990 to August 2014. We attempted to identify unpublished data by searching the Food and Drug Administration registry, ClinicalTrials.gov, product inserts, and pharmaceutical company Web sites, and by contacting experts, study authors, manufacturers, and primary authors of abstracts with incomplete data. Supplement. Data Supplement Study Selection We included all randomized, controlled trials involving adult human participants with clinical or radiologic diagnosis of symptomatic primary knee OA that compared at least 2 interventions of interest and reported extractable data for at least 1 measure of pain, function, or stiffness. On the basis of the treatment recommendations from the latest clinical practice guidelines for knee OA (7, 8) and the current prescription patterns worldwide (6), we included the following interventions and comparators: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, IA corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo. We did not include nonrandomized studies because they generally lacked the high quality of the randomized evidence; without individual-participant data, we could not properly adjust effect estimates for potential confounders. Two reviewers independently screened all titles and abstracts identified by the searches. Full manuscripts of studies screened as potentially relevant by either reviewer were obtained and assessed by 2 independent reviewers according to the aforementioned criteria. Any discrepancies were resolved by consensus. Data Extraction and Quality Assessment After developing a data extraction form, we tested it on 10 randomly selected, included studies and refined accordingly. After completing an a priori training exercise, 2 reviewers independently extracted data from each study. The data were reviewed for consistency between the 2 extractors, and any disagreements were resolved by consensus. For each study, data extraction details included design, selection criteria, population characteristics, treatments, outcome measures, length of follow-up, and results. The outcome measures of interest were change from baseline in pain, function, and stiffness scores reported at 3-month follow-up. If 3-month data were not available, we used data from 2 to 6 months (the data point closest to 3 months was given preference). Intention-to-treat analysis data were used whenever available. When an article provided data on more than 1 outcome scale or a different outcome from the same construct, we extracted data from the scale that was highest on the hierarchy of suggested outcomes for meta-analysis of knee OA trials (9). Two independent reviewers assessed individual study quality using the Cochrane risk-of-bias tool, with any discrepancies resolved by consensus (10). We investigated the effect of study quality on results in the sensitivity analysis. Data Synthesis and Analysis Because the studies used different outcome measures, the change from baseline Western Ontario and McMaster Universities OA Index (WOMAC), visual analogue scale (VAS), and Likert scale scores in each study was translated into Hedges g effect sizes (11). Hedges g is defined as the difference in change from baseline between 2 interventions divided by the pooled SD of the differences, with corrections for small sample sizes. To assess potential heterogeneity among the studies, we calculated the between-study variance and examined baseline characteristics of participants, interventions, outcomes, and study quality. Network Meta-analysis A network meta-analysis synthesizes all available evidence within a consistent framework, thereby fully preserving the randomization within each trial (12). It accounts for multiple comparisons within a trial when there are more than 2 treatment groups (1315). This method considers all trials simultaneously and enables integration of direct evidence from head-to-head trials (when they exist) with indirect evidence (obtained from comparisons of treatments through their common reference) (16). To account for the expected clinical and methodological heterogeneity, we used Bayesian hierarchical random-effects models for mixed multiple-treatment comparisons with noninformative prior distributions (Supplement [Data Synthesis and Analysis]) (17, 18). The model contained parameters that described the relative treatment effect of each intervention compared with a common comparator (oral placebo). Other treatment comparisons were derived as differences between model parameters. We assumed a normal likelihood distribution for the effect size. The main assumption behind the validity of network meta-analysis is transitivity (13). This assumption requires that a valid synthesis of studies indirectly comparing 2 treatments (for example, A with C) by way of 2 direct comparisons (for example, A with B and B with C) must include studies that are sufficiently similar in important clinical and methodological characteristics (potential effect modifiers) (19). The populations within the included studies were similar and could be eligible for any of the treatments considered here based on the distributions of effect modifiers (mean age, percentage of women, baseline disease severity, baseline pain scores, duration of disease, and study quality) and inclusion and exclusion criteria of the studies. Another key assumption in a network meta-analysis is consistencythe notion that the direct and indirect estimates of the treatment effects are the same (20). Consistency was assessed using the node-splitting method (Supplement [Data Synthesis and Analysis]) (21). The results were presented graphically to visually assess the agreement between direct and indirect estimates. A value near 0 indicated that the comparisons in the network were consistent. Results were presented as median effect sizes for pain, function, and stiffness along with 95% central credible intervals (CrIs). For improving the clinical interpretability, they were converted back to the natural units of the most commonly used scale (WOMAC VAS, 0 to 100) (22). On the basis of the Osteoarthritis Research Society InternationalOutcome Measures in Rheumatology responder criteria, we prespecified an absolute change of 20 points on a scale of 0 to 100 as clinically significant improvement (23). We performed several sensitivity analyses on the primary outcome of pain to explore potential causes for heterogeneity. Multiple-treatment meta-regression analysis and subgroup analyses were done to assess the effect of study quality, sample size, and type of outcome scale used (WOMAC vs. other) (24). To examine the potential effect of reporting bias, we analyzed pain outcomes in trials reporting only pain; those reporting both pain and function; and those reporting pain, function, and stiffness. We also compared the baseline characteristics and study quality measures of these subsets of trials. The Supplement (Data Synthesis and Analysis) provides additional details of the statistical methods used. Role of the Funding Source The Agency for Healthcare Research and Quality had no role in study design, data collection, analysis or interpretation, preparation, review, or approval of the manuscript. The funding agency had no access to the data and did not perform any of the study analyses. Results Of the 4122 citations identified through our literature search, 3625 were excluded through title and abstract screening. Among the 497 full-text reports, 137 studies met inclusion criteria for the network meta-analysis (Appendix Figure). Figure 1 shows the network of all treatment comparisons analyzed for pain; the networks for function and stiffness are shown in the Supplement. Thirteen trials had 3 study group

Quantitative Evaluation of Drug or Device Effects on Ventricular Remodeling as Predictors of Therapeutic Effects on Mortality in Patients With Heart Failure and Reduced Ejection Fraction: a Meta-analytic Approach

Background and Purpose— Women experience worse outcomes after stroke compared with men. Prior work has suggested sex-based differences in coagulation and fibrinolysis markers in subjects with acute stroke. We explored whether sex might modify the effect of recombinant tissue plasminogen activator (rtPA) on outcomes in patients with acute ischemic stroke. Methods— Using a combined database including subjects from the National Institute of Neurological Disorders and Stroke (NINDS), Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) A and B, and the Second European Cooperative Acute Stroke Study (ECASS II) trials, we examined 90-day outcomes in patients randomized to rtPA versus placebo by sex. We used logistic regression to control for potential confounders. Results— Among 988 women treated between 0 and 6 hours from symptom onset, patients receiving rtPA were significantly more likely than those receiving placebo to have a modified Rankin Score ≤1 (40.5% versus 30.3%, P<0.0008). Among 1190 men, the trend toward benefit in the overall group did not reach statistical significance (38.5% versus 36.7%, P=0.52). An unadjusted analysis showed that women were significantly more likely to benefit from rtPA compared with men (P=0.04). Controlling for age, baseline National Institutes of Health Stroke Scale, diabetes, symptom onset to treatment time, prior stroke, systolic blood pressure, extent of hypoattenuation on baseline computed tomography scan and several significant interaction terms (including onset to treatment time–by-treatment and systolic blood pressure–by treatment) did not substantially change the strength of the interaction between gender and rtPA treatment (P=0.04). Conclusions— In this pooled analysis of rtPA in acute ischemic stroke, women benefited more than men, and the usual gender difference in outcome favoring men was not observed in the thrombolytic therapy group. For patients presenting at later time intervals, when the risks and benefits of rtPA are more finely balanced, sex may be an important variable to consider for patient selection.

Extent of Early Ischemic Changes on Computed Tomography (CT) Before Thrombolysis, Prognostic Value of the Alberta Stroke Program Early CT Score in ECASS II

OBJECTIVES The purpose of this study was to quantitatively assess the relationship between therapy-induced changes in left ventricular (LV) remodeling and longer-term outcomes in patients with left ventricular dysfunction (LVD). BACKGROUND Whether therapy-induced changes in left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) are predictors of mortality in patients with LVD is not established. METHODS Searches for randomized controlled trials (RCTs) were conducted to identify drug or device therapies for which an effect on mortality in patients with LVD was studied in at least 1 RCT of > or = 500 patients (mortality trials). Then, all RCTs involving those therapies were identified in patients with LVD that described changes in LVEF and/or volumes over time (remodeling trials). We examined whether the magnitude of remodeling effects is associated with the odds ratios for death across all therapies or associated with whether the odds ratio for mortality was favorable, neutral, or adverse (i.e., statistically significantly decreased, nonsignificant, or statistically significantly increased odds for mortality, respectively). RESULTS Included were 30 mortality trials of 25 drug/device therapies (n = 69,766 patients; median follow-up 17 months) and 88 remodeling trials of the same therapies (n = 19,921 patients; median follow-up 6 months). The odds ratio for death in the mortality trials was correlated with drug/device effects on LVEF (r = -0.51, p < 0.001), EDV (r = 0.44, p = 0.002), and ESV (r = 0.48, p = 0.002). In (ordinal) logistic regressions, the odds for neutral or favorable effects in the mortality RCTs increased with mean increases in LVEF and with mean decreases in EDV and ESV in the remodeling trials. CONCLUSIONS In patients with LVD, short-term trial-level therapeutic effects of a drug or device on LV remodeling are associated with longer-term trial-level effects on mortality.

Patent Foramen Ovale in Cryptogenic Stroke: Incidental or Pathogenic?

Background and Purpose— The significance of early ischemic changes (EICs) on computed tomography (CT) to triage patients for thrombolysis has been controversial. The Alberta Stroke Program Early CT Score (ASPECTS) semiquantitatively assesses EICs within the middle cerebral artery territory using a10-point grading system. We hypothesized that dichotomized ASPECTS predicts response to intravenous thrombolysis and incidence of secondary hemorrhage within 6 hours of stroke onset. Methods— Data from the European-Australian Acute Stroke Study (ECASS) II study were used in which 800 patients were randomized to recombinant tissue plasminogen activator (rt-PA) or placebo within 6 hours of symptom onset. We retrospectively assessed all baseline CT scans, dichotomized ASPECTS at ≤7 and >7, defined favorable outcome as modified Rankin Scale score 0 to 2 after 90 days, and secondary hemorrhage as parenchymal hematoma 1 (PH1) or PH2. We performed a multivariable logistic regression analysis and assessed for an interaction between rt-PA treatment and baseline ASPECTS score. Results— We scored ASPECTS >7 in 557 and ≤7 in 231 patients. There was no treatment-by-ASPECTS interaction with dichotomized ASPECTS (P=0.3). This also applied for the 0- to 3-hour and 3- to 6-hour cohorts. However, a treatment-by-ASPECTS effect modification was seen in predicting PH (0.043 for the interaction term), indicating a much higher likelihood of thrombolytic-related parenchymal hemorrhage in those with ASPECTS ≤7. Conclusion— In ECASS II, the effect of rt-PA on functional outcome is not influenced by baseline ASPECTS. Patients with low ASPECTS have a substantially increased risk of thrombolytic-related PH.

Index Event Bias as an Explanation for the Paradoxes of Recurrence Risk Research

Background and Purpose— 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 control subjects 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 control subjects in different age populations, with or without atrial septal aneurysms, and were used to summarize across studies the probability that a PFO in CS is incidental. Results— The summary OR (95% CIs) for PFO in CS versus control subjects was 2.9 (CI, 2.1 to 4.0). The corresponding ORs for young and old patients (< or ≥55 years) were 5.1 (3.3 to 7.8) and 2.0 (>1.0 to 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28% to 39%) in age-inclusive studies, 20% (16% to 25%) in younger patients, and 48% (34% to 66%) in older patients. These probabilities were much lower when an atrial septal aneurysm was present. Conclusions— In patients with otherwise CS, approximately one 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 atrial septal aneurysm, suggesting the importance of patient selection in therapeutic decision-making.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke

A review of the recurrence risk literature uncovers several paradoxical observations: thrombolphilias predispose for a first episode of deep venous thrombosis (DVT) but not for recurrence (the thrombophilia paradox1); aspirin takers are at lower risk for cardiac events, but higher risk of recurrence (the aspirin paradox2); and while obesity is an established risk factor for coronary artery disease, it appears to protect against recurrent coronary events (the obesity paradox3). While several hypotheses have been proposed to explain these paradoxes, it is not generally appreciated that all recurrent risk analyses are prone to a particular bias that may induce such paradoxical results. We call it “index event bias” because it arises in studies that select patients based on the occurrence of an index event. We demonstrate how “index event bias” emerges and that – because of the general congruence between risk factors for the index and recurrent events – it will generally tend to bias studies toward the null, causing their contribution to be substantially underestimated or even reversed. We use the association between patent foramen ovale (PFO) and cryptogenic stroke as a prototypical example, and describe several other instances where it may have affected study results. PFO and the risk of stroke Although the prevalence of PFO in the general population is 25%, it is approximately double among cryptogenic stroke patients.4 This association is attributed to paradoxical embolism, i.e. a thromboembolus from the venous system gaining access to the arterial circulation via a right-to-left shunt in the heart. The consistent association of PFO with cryptogenic stroke (suggesting a pathogenic role for this otherwise benign congenital anomaly) has been accompanied by a surprising yet equally consistent finding: PFO is not a risk factor for recurrent stroke.4 The discrepancy can be reconciled by the following observation: among patients with a cryptogenic stroke, those with a PFO tend to be younger, have approximately half the rate of diabetes and hypertension and are less likely to have hypercholesterolemia or smoke.4 Thus, the similarity in recurrence rates in patients with cryptogenic stroke with or without PFO suggests that PFO is an important risk factor for stroke recurrence, since it “compensates” for a profound shortfall in conventional stroke risk factors. Index event bias When multiple risk factors contribute to the risk of an outcome, conditioning on the outcome induces dependence between the risk factors, even when they are independently distributed in the general population (e.g. there is no association between PFO and diabetes, hypertension, hypercholesterolemia in the general population, but there is a negative association in the cryptogenic stroke population). Heuristically, the association may be thought to arise because patients with PFOs do not require the same burden of stroke risk factors to have the index event; thus the presence of a PFO “protects” cryptogenic stroke patients from other risk factors (both known and unknown), see Table.5-6 Because risk factors often have congruent effects on the index and recurrent events, this negative association will tend to bias any estimation of the PFO effect on recurrence risk towards the null, unless there is a thorough accounting for all shared risk factors7 (for example, in a recent study propensity score matched analysis eliminated the obesity paradox8). Obviously, bias will always be a concern since unknown risk factors are often operating to cause a disease. More generally, the biases we describe are special cases of “collider bias”, which is well described in the epidemiologic literature.9 Table Distribution of selected established stroke risk factors in “unselected” individuals and individuals who have had an index stroke event, stratified by PFO status. It is apparent that conditioning on the index stroke radically changes the ... A threat for causal inference in recurrence risk research “Index event bias” is often underappreciated and should be considered as a possible contributing factor to many of the paradoxes enumerated in the introduction. As with PFO, thrombophilias presumably contribute to the risk of a second DVT, but they also “protect” against other DVT risk factors among patients with a first event. Similarly, not taking aspirin will “protect” against other heart attack risk factors among patients with a first heart attack. While the assumptions required to be mathematically certain that one risk factor will consistently “protect” against the presence of others are very stringent and not typically met in the real world,7 dependence between risk factors will occur in all studies that select participants based on the occurrence of a first event because the selection influences the distribution of risk factors in the patients that are included in the study and affects the association of these risk factors with the outcome of interest (the recurrent event).9 However, in such cases, the distribution of the risk factors and the behavior of the bias in estimating causal effects are unpredictable. In addition to being a ubiquitous issue with studies examining risk factors of recurrence, index event bias may affect research that examines disease progression and severity, when there are multiple risk factors for progression or for severity that are also risk factors for having the disease in the first place. For example, the so-called “smokers paradox” describes the better prognosis of smokers compared to non-smokers among patients with myocardial infarction.10 Also, among patients with heart failure, better survival has been associated not only with obesity, but with higher blood pressure and higher levels of low-density lipoprotein and higher total cholesterol – both established risk factors for the development of heart failure. Readers should keep in mind that the true causal models underlying the associations discussed in this commentary are unknown. For many of the above examples, other factors no doubt also contribute. Presumably “confounding by indication” also plays a role in the emergence of the aspirin paradox (since those with more risk factors may have preferentially been prescribed aspirin) and some of the “reverse epidemiology” seen in the context of heart failure and other diseases may actually reflect unknown causal pathways. Our purpose is to underscore how the tenuous relationship between association and causation becomes even more so in the context of recurrence risk research employing simple regression models. In this context – because the index and recurrent events have common risk factors – many so-called paradoxes should actually be expected, since they are induced by conditioning the analyses on the occurrence of the index event.

The Stroke–Thrombolytic Predictive Instrument A Predictive Instrument for Intravenous Thrombolysis in Acute Ischemic Stroke

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.