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Introduction: The Risk of Paradoxical Embolism (RoPE) Score can disaggregate patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) into those who are more likely to have a pathogenic PFO (high RoPE score) than an incidental PFO (low RoPE score). Those with higher RoPE scores have a lower risk of recurrent stroke and different recurrence predictors compared to those with low RoPE scores. Hypotheses: Patients with high RoPE scores benefit more from PFO closure than patients with low RoPE scores. Patients with high RoPE scores and risk factors for recurrence should benefit even more. Methods: The RoPE score was created from a database of CS patients with known PFO status to estimate stratum-specific PFO-attributable fraction and recurrence rates. Variables that predict stroke recurrence in high RoPE score groups (atrial septal aneurysm, history of stroke/TIA prior to index event) were added – the “RoPE Recurrence Score.” Using pooled individual patient data from all 3 RCTs of PFO closure vs. medical therapy (ITT populations; stroke outcome) we tested the ability of the scores to predict the heterogeneity of response to assigned treatment. Results: The mean RoPE score was significantly higher (6.8 vs. 6.3) with smaller variance (Stdev 1.5 vs. 1.9) in the pooled RCT population than in the original RoPE cohort (p Conclusion: As expected, the HR favoring closure trended lower in the high RoPE score group in the RCTs but missed statistical significance. The RoPE Recurrence score did not improve the prediction. This may be due to the narrow distribution of relatively high RoPE scores amongst RCT patients and so a low power to detect heterogeneity of treatment effect. Given that PFO closure can only prevent PFO-related recurrences, the treatment effect may also have been obscured by including recurrent strokes with non-PFO-related mechanisms.

Background and Purpose— Patent foramen ovale (PFO) and cryptogenic stroke are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related cause. We examined whether specific radiological findings are associated with PFO among subjects with cryptogenic stroke and known PFO status. Methods— We analyzed the Risk of Paradoxical Embolism(RoPE) Study database of subjects with cryptogenic stroke 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 (odds ratio [OR], 1.36; P =0.0025), seen on index imaging (OR, 1.53; P =0.003), and superficially located (OR, 1.54; P P 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 cryptogenic stroke 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.

Introduction: The Stroke Thombolytic Predictive Instrument (Stroke TPI), derived on data from the first 5 randomized clinical trials of standard dose rtPA, predicts the probability of good and bad outcomes with and without rtPA. We sought to rebuild and externally validate a simpler Stroke TPI to support implementation in routine clinical care. Methods: Using a derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS 1 and 2; ATLANTIS A and B; ECASS 2), we simplified the Stroke TPI by: 1) removing lower credibility interaction terms; and 2) exploring reduced stroke severity scores, including previously developed 8-item and 3-item measures. Additionally, we included alternative thresholds of a good 90-day functional outcome (i.e. prediction of both modified Rankin Score [mRS] ≤ 1 and mRS ≤ 2). Bootstrapping methods were used for internal validation. External validation was performed on the ECASS 3 trial (n=821). Results: The following 6 variables were included to predict good outcomes: age, systolic blood pressure (SBP), diabetes, stroke severity, symptom onset to treatment time (OTT) and rtPA therapy. Treatment effect modifiers (interaction terms) included OTT and SBP. For the models predicting a bad outcome (mRS ≥ 5), significant variables included: age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. As compared to models using the full NIHSS, models employing the 3-item severity score showed similar discrimination, with c-statistics on bootstrap (internal) validation of: 0.76 (mRS ≤ 1); 0.78 (mRS ≤ 2); and 0.76 (mRS ≥ 5), and with excellent calibration. External validation on ECASS 3 showed similar performance (c-statistics 0.75 [mRS ≤ 1] and 0.80 [mRS ≤ 2]), with good calibration. Conclusion: A simpler prediction model using a 3-item, instead of the 15-item NIHSS stroke severity score, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether the reduced model can improve treatment rates, time to treatment, and outcomes.

Background and Purpose— Mismatch between clinical deficits and imaging lesions in acute stroke has been proposed as a method of identifying patients who have hypoperfused but still have viable brain, and may be especially apt to respond to reperfusion therapy. We explored this hypothesis using a combined database including 4 major clinical trials of intravenous (IV) thrombolytic therapy. Methods— To determine what the radiological correlates of a “matched” functional deficit are, we calculated the relationship between the ASPECT score of the 24-hour (follow-up) CT scan and the 24-hour National Institutes of Health Stroke Scale (NIHSS) score on the subsample with ASPECT scores performed at this time (n=820). Based on this empirical relationship, we computed the absolute difference between the observed baseline ASPECT score and the “expected” score (ie, matched) based on baseline NIHSS for all patients (n=2131). We tested whether patients with better than expected baseline ASPECTS were more likely to benefit from IV recombinant tissue plasminogen activation (rtPA). Results— At 24 hours, there was a strong, linear, negative correlation between NIHSS and ASPECTS (r 2 =0.33, P Conclusion— Clinical-CT mismatch using ASPECT scoring does not reliably identify patients more or less likely to benefit from IV rtPA.

Background The “RoPE Score” is a predictive model created to stratify patients by the likelihood that a patent foramen ovale (PFO) is incidental or pathogenic using clinical variables. We hypothesized that the predictors of recurrent stroke differ between patients with pathogenic and incidental PFOs. Methods Patients in the Risk of Paradoxical Embolism (RoPE) database with cryptogenic stroke (CS) and PFO were classified as having a probable pathogenic PFO (RoPE Score of >6, estimated PFO attributable fraction 72-99%, n=646) and others (RoPE Score of Results Follow-up was available for 91%, 80%, and 58% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA, not being on a statin at baseline, and having a prior radiological stroke. For the low RoPE score group, older age, male sex, high cholesterol and antiplatelet (vs warfarin) treatment predicted recurrence. For those with high RoPE scores, predictors were prior (clinical) stroke/TIA and 2 echo features: septal hypermobility and a small shunt ( Conclusions Predictors of recurrence differ when PFO relatedness is classified by the RoPE Score. The hypothesis that patients with CS and PFO form a heterogenous group with different stroke mechanisms is supported. Conventional stroke risk factors were strong predictors among patients with lower RoPE scores. Echocardiographic features - including a counterintuitive association between smaller shunts and increased recurrence risk - were uniquely predictive in the high RoPE score group (likely pathogenic PFO).

Introduction: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be stroke-related or incidental. We have developed a score to stratify CS patients according to the probability that the event is attributable to a PFO (the Risk of Paradoxical Embolism (RoPE) Score), based on easily obtainable clinical and neuroradiological (but not transesophageal echocardiographic (TEE) variables. In this study, we examined whether putative “high risk” TEE features - shunt size, presence of a hypermobile septum, and presence of a right-to-left shunt at rest - vary across RoPE Score strata. Methods and Results: The RoPE Study combined existing cohort studies to create a pooled database of patients with CS and PFO. We dichotomized patients into groups and examined whether putative high risk TEE features are seen more frequently in those with “probable stroke-related” PFOs (RoPE Score of >6, estimated PFO attributable fraction 72-99%, n=637) than in those with lower RoPE Scores ( Conclusion: We found no evidence that proposed TEE markers for “high risk” PFOs correlate with the estimated likelihood that a PFO is related to an index CS. Additional imaging tools or better standardization of imaging techniques are needed to determine whether specific anatomic features are associated with whether a discovered PFO is likely to be related to CS.

Background Stroke databanks have consistently found a high ratio of anterior circulation (AC) to posterior circulation (PC) strokes without significant differences when compared for vascular risk factors, stroke etiology, treatments and outcome. One study suggested that there was a deviation from this consistent observation when comparing men and women with cryptogenic stroke (CS) and patent foramen ovale (PFO). We tested these associations using the RoPE database. Methods The Risk of Paradoxical Embolism (RoPE) Study is an international collaboration of 12 merged cohort studies of patients with CS and known PFO status (n=3674). This analysis was restricted to those subjects in the RoPE database with index strokes in the AC or PC (excluding both or unknown) from the 7 databases that had data for CS with, and without, PFO. We compared the effect of sex on infarct location among patients with versus without PFO. We used generalized linear mixed models to examine whether PFO status modified the gender effect on infarct location adjusting for study cohort as a random effect. Results Among cryptogenic stroke patients both with and without PFO, AC strokes were more common (61%) than PC overall (n=1535). Among patients with PFO, PC stroke was higher in men than in women (50% vs. 33%, OR 2.23, 95% CI: 1.58-3.13). This gender effect was attenuated in those without PFO (38% vs. 31%; OR 1.32, 95% CI: 0.98-1.77). The gender-by-PFO-status interaction was significant (p= 0.0224) and was highly consistent across study cohorts. Conclusions These data confirm that males with CS and PFO contravene the otherwise consistent pattern that AC strokes are more commonly observed than PC strokes in stroke populations. The potential mechanisms underlying this interaction between gender and PFO-status remain to be elucidated.

Background: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be incidental or pathogenic. Based on Bayes theorem, the proportion of CS that is PFO-attributable among patients found to have a PFO has been shown to be related to PFO prevalence in CS versus control patients. However, the prevalence of PFO in CS patients is itself dependent on the presence or absence of other risk factors. We exploited this relationship to create an index to stratify CS patients with PFO by their likelihood that the CS is PFO-attributable. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international, multicenter collaboration that has combined data for patients with CS and cryptogenic TIA who have known PFO status from 12 component studies (n=3665). For this study, we included those subjects within the 7 databases enrolling subjects both with and without PFO (n=3023). We used generalized linear mixed models to identify variables associated with the presence of a PFO, accounting for clustering within study. Based on this model, we created a simple index. Bayes theorem was used to estimate the PFO-attributable fraction in each stratum assuming a PFO prevalence in the general population of ∼25%. Results: Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is shown in the table for patients < age 60, i.e. the subset of patients likely to be considered for PFO closure trials. Conclusion: Even among CS patients in the younger age range considered eligible for closure trials, there is considerable heterogeneity in the distribution of risk factors for stroke and other characteristics that identify subgroups of CS patients with variation in PFO prevalence. This reflects substantial and clinically important variation in the probability that a discovered PFO is likely to be pathogenic rather than incidental. This score may be useful in selecting patients for closure trials, or for stratification within trials, particularly if combined with a recurrence risk model.

Introduction We aim to determine whether radiological findings are associated with patent foramen ovale (PFO) among patients with cryptogenic stroke (CS). Radiological findings associated with the presence of a PFO may represent stroke patterns typical of paradoxical embolism which may be distinct from other mechanisms of CS. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international collaboration that has combined individual-level data for subjects with CS and TIA who have known PFO status from 12 component studies (n=3665). For this study 7 databases (n=3023) were used that included subjects with and without PFO, and with radiologic data. Five variables were tested for their relationship with PFO status: 1) protocol-defined large vs. small infarct , 2) Index stroke seen on imaging, 3) superficial vs. deep infarct, 4) multiple index lesions, 5) Prior stroke, i.e. chronic infarct on index imaging. Results are presented in the table . Odds ratios and p-values are adjusted for age, database, sex, diabetes, hypertension, smoking, and history of stroke/TIA. This is the largest study to report the radiological characteristics of patients with CS who are known to have, or not to have, a PFO. Some prior studies had null findings but were limited by small sample size and low statistical power. Because CS unrelated to PFO may also be embolic, the radiological pattern of paradoxical embolism may not be expected to be different from other cryptogenic emboli. Despite this, PFOs were significantly more common in CS patients with large and with superficial infarcts. Conversely, infarcts that were small and deep were associated with PFO absence. This suggests that lacunar disease may account for some non-PFO related CS. Conclusion Participants were significantly more likely to have a PFO if they had 1) an index stroke seen on neuroimaging, 2) a large stroke, 3) a superficial stroke; there was no effect of the variables prior ( i.e. chronic) infarct or multiple vs. single infarcts. Further analyses may help to clarify the ability of neuroimaging to predict the finding of a PFO.

Background and Purpose— The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) uses multivariate equations to predict outcomes with and without thrombolysis. We sought to examine whether such a multivariate predictive instrument might be useful in selecting patients with a favorable risk-benefit treatment profile for therapy after 3 hours. Methods— We explored outcomes in patients from 5 major randomized clinical trials testing intravenous recombinant tissue plasminogen activator (rt-PA) classified by the Stroke-TPI as “treatment-favorable” or “treatment-unfavorable.” We used iterative bootstrap re-sampling to estimate how such a model would perform on independent test data. Results— Among patients treated within the 3- to 6-hour window, 67% of patients were classified by Stroke-TPI predicted outcomes as “treatment-favorable” and 33% were classified as “treatment-unfavorable.” Outcomes in the treatment-favorable group demonstrated benefit for thrombolysis (modified Rankin Scale score ≤1: 44.0% with rt-PA versus 34.2 with placebo, P =0.005), whereas harm was demonstrated in the treatment-unfavorable group (modified Rankin Scale score ≤1: 31.3% with rt-PA versus 38.3% with placebo; P =0.004). Bootstrap resampling with complete cross-validation showed that the absolute margin of benefit in the treatment-favorable group diminished on average by 36% between derivation and independent validation sets, but still represented a significant tripling of improvement in benefit compared with conventional inclusion criteria (5.2% [interquartile range, 1.7% to 8.6%] versus 1.8% [interquartile range, −0.5 to 4.1], P Conclusions— Such multivariable risk-benefit profiling may be useful in the selection of acute stroke patients for rt-PA therapy even more than 3 hours after symptom onset. Prospective testing is indicated.

Background and Purpose— Recombinant tissue plasminogen activator (rtPA) has been demonstrated to improve outcomes in acute ischemic stroke when delivered within 3 hours of symptom onset. However, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS B) trial, in which patients were treated mostly between 3 and 5 hours after symptom onset, found no overall benefit from rtPA. We hypothesized that a subgroup of patients at low risk for thrombolysis-related intracranial hemorrhage, identifiable on the basis of pretreatment clinical variables, may benefit even when treated after 3 hours, despite the overall results of the trial. Methods— Using an independently derived multivariate model that predicts the risk of thrombolysis-related intracranial hemorrhage in patients receiving tPA for acute myocardial infarction (based on 6 easily obtainable clinical characteristics), we stratified patients in the ATLANTIS B trial into low-, intermediate-, and high-risk tertiles. We examined outcomes in the prespecified low-risk subgroup using a global test of significance across 4 outcome scales. Results— Despite having a similar average baseline stroke severity and median time to treatment (270 minutes), patients in the prespecified low-risk group (n=194) were significantly less likely to have a symptomatic intracranial hemorrhage than other patients in the trial (2.2% versus 9.2%, P =0.03). Although there was no treatment effect for rtPA in the overall trial, a consistent trend favoring rtPA therapy (a 5% to 12% absolute treatment benefit) was found across 4 different stroke scales in the prespecified low-risk group ( P =0.10). The treatment-benefit-by-risk interaction was significant ( P =0.03). Conclusions— Use of a multivariate index based on clinical variables is a promising approach to assist in the selection of patients with a favorable risk-benefit profile for thrombolytic therapy beyond 3 hours.

Background and Purpose— Develop achievable benchmarks for 9 stroke performance measures (PM) and to identify organizational factors associated with adherence. Methods— Adherence rates and achievable benchmarks were determined for 9 PM within a study of patients (n=2294) admitted with acute ischemic stroke at 17 hospitals. Baseline information regarding hospital characteristics and stroke-specific processes of care were collected, and multi-level models were used to test the association of these factors with adherence. Results— Benchmarks were ≥90% for 8 of the 9 PM. After controlling for clustering, only use of standing orders was associated with adherence to PM, including: dysphagia screening, venous thrombosis prophylaxis, consideration of tPA, and provision of educational material. Conclusion— High levels of adherence are achievable for several acute stroke PM. Use of standing orders is associated with adherence to PM requiring immediate action on admission.