Jennifer S. Lutz

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

Recurrent stroke predictors differ in medically treated patients with pathogenic vs other PFOs

Objective: To examine predictors of stroke recurrence in patients with a high vs a low likelihood of having an incidental patent foramen ovale (PFO) as defined by the Risk of Paradoxical Embolism (RoPE) score. Methods: Patients in the RoPE database with cryptogenic stroke (CS) and PFO were classified as having a probable PFO-related stroke (RoPE score of >6, n = 647) and others (RoPE score of ≤6 points, n = 677). We tested 15 clinical, 5 radiologic, and 3 echocardiographic variables for associations with stroke recurrence using Cox survival models with component database as a stratification factor. An interaction with RoPE score was checked for the variables that were significant. Results: Follow-up was available for 92%, 79%, and 57% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA. For all other predictors, effects were significantly different in the 2 RoPE score categories. For the low RoPE score group, but not the high RoPE score group, older age and antiplatelet (vs warfarin) treatment predicted recurrence. Conversely, echocardiographic features (septal hypermobility and a small shunt) and a prior (clinical) stroke/TIA were significant predictors in the high but not low RoPE score group. Conclusion: Predictors of recurrence differ when PFO relatedness is classified by the RoPE score, suggesting that patients with CS and PFO form a heterogeneous group with different stroke mechanisms. Echocardiographic features were only associated with recurrence in the high RoPE score group.

Transesophageal Echocardiography in Cryptogenic Stroke and Patent Foramen Ovale: Analysis of Putative High-Risk Features From the Risk of Paradoxical Embolism Database

Background—Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), although the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography features such as PFO size, 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 transesophageal echocardiography 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 transesophageal echocardiography features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n=637) compared with 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 (odds ratio [OR], 0.92; P=0.53). The presence of neither a hypermobile septum nor a right-to-left shunt at rest was detected more often in those with a probable PFO-attributable stroke (OR, 0.80; P=0.45; OR, 1.15; P=0.11, respectively). Conclusions—We found no evidence that the proposed transesophageal echocardiography 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.

Clinical Prediction Models for Cardiovascular Disease Tufts Predictive Analytics and Comparative Effectiveness Clinical Prediction Model Database

Background—Clinical prediction models (CPMs) estimate the probability of clinical outcomes and hold the potential to improve decision making and individualize care. For patients with cardiovascular disease, there are numerous CPMs available although the extent of this literature is not well described. Methods and Results—We conducted a systematic review for articles containing CPMs for cardiovascular disease published between January 1990 and May 2012. Cardiovascular disease includes coronary heart disease, heart failure, arrhythmias, stroke, venous thromboembolism, and peripheral vascular disease. We created a novel database and characterized CPMs based on the stage of development, population under study, performance, covariates, and predicted outcomes. There are 796 models included in this database. The number of CPMs published each year is increasing steadily over time. Seven hundred seventeen (90%) are de novo CPMs, 21 (3%) are CPM recalibrations, and 58 (7%) are CPM adaptations. This database contains CPMs for 31 index conditions, including 215 CPMs for patients with coronary artery disease, 168 CPMs for population samples, and 79 models for patients with heart failure. There are 77 distinct index/outcome pairings. Of the de novo models in this database, 450 (63%) report a c-statistic and 259 (36%) report some information on calibration. Conclusions—There is an abundance of CPMs available for a wide assortment of cardiovascular disease conditions, with substantial redundancy in the literature. The comparative performance of these models, the consistency of effects and risk estimates across models and the actual and potential clinical impact of this body of literature is poorly understood.

The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study

Background: For patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), it is unknown whether the magnitude of right-to-left shunt (RLSh) measured by contrast transcranial Doppler (c-TCD) is correlated with the likelihood an identified PFO is related to CS as determined by the Risk of Paradoxical Embolism (RoPE) score. Additionally, for patients with CS, it is unknown whether PFO assessment by c-TCD is more sensitive for identifying RLSh compared with transesophageal echocardiography (TEE). Our aim was to determine the significance of RLSh grade by c-TCD in patients with PFO and CS. Methods: We evaluated patients with CS who had RLSh quantified by c-TCD in the Multicenter Study into RLSh in Cryptogenic Stroke (CODICIA) to determine whether there is an association between c-TCD shunt grade and the RoPE Score. For patients who underwent c-TCD and TEE, we determined whether there is agreement in identifying and grading RLSh between these two modalities. Results: The RoPE score predicted the presence versus the absence of RLSh documented by c-TCD (c-statistic = 0.66). For patients with documented RLSh by c-TCD, shunt severity was correlated with increasing RoPE score (rank correlation (r) = 0.15, p = 0.01). Among 293 patients who had both c-TCD and TEE performed, c-TCD was more sensitive (98.7%) for detecting RLSh. Of the 97 patients with no PFO identified on TEE, 28 (29%) had a large amount of RLSh seen on c-TCD. Conclusions: For patients with CS, severity of RLSh by c-TCD is positively correlated with the RoPE score, indicating that this technique for shunt grading identifies patients more likely to have pathogenic rather than incidental PFOs. c-TCD is also more sensitive in detecting RLSh than TEE. These findings suggest an important role for c-TCD in the evaluation of PFO in the setting of CS.

Field Synopsis of the Role of Sex in Stroke Prediction Models

Background Guidelines for stroke prevention recommend development of sex‐specific stroke risk scores. Incorporating sex in Clinical Prediction Models (CPMs) may support sex‐specific clinical decision making. To better understand their potential to guide sex‐specific care, we conducted a field synopsis of the role of sex in stroke‐related CPMs. Methods and Results We identified stroke‐related CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Database, a systematic summary of cardiovascular CPMs published from January 1990 to May 2012. We report the proportion of models including the effect of sex on stroke incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 92 stroke‐related CPMs, 30 (33%) contained a coefficient for sex or presented sex‐stratified models. Only 12/58 (21%) CPMs predicting outcomes in patients included sex, compared to 18/30 (60%) models predicting first stroke (P<0.0001). Sex was most commonly included in models predicting stroke among a general population (69%). Female sex was consistently associated with reduced mortality after ischemic stroke (n=4) and higher risk of stroke from arrhythmias or coronary revascularization (n=5). Models predicting first stroke versus outcomes among patients with stroke (odds ratio=5.75, 95% CI 2.18–15.14, P<0.001) and those developed from larger versus smaller sample sizes (odds ratio=4.58, 95% CI 1.73–12.13, P=0.002) were significantly more likely to include sex. Conclusions Sex is included in a minority of published CPMs, but more frequently in models predicting incidence of first stroke. The importance of sex‐specific care may be especially well established for primary prevention.

Field Synopsis of Sex in Clinical Prediction Models for Cardiovascular Disease

Background—Several widely used risk scores for cardiovascular disease (CVD) incorporate sex effects, yet there has been no systematic summary of the role of sex in clinical prediction models (CPMs). To better understand the potential of these models to support sex-specific care, we conducted a field synopsis of sex effects in CPMs for CVD. Methods and Results—We identified CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Registry, a comprehensive database of CVD CPMs published from January 1990 to May 2012. We report the proportion of models including sex effects on CVD incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 592 CVD-related CPMs, 193 (33%) included sex as a predictor or presented sex-stratified models. Sex effects were included in 78% (53/68) of models predicting incidence of CVD in a general population, versus only 35% (59/171), 21% (12/58), and 17% (12/72) of models predicting outcomes in patients with coronary artery disease, stroke, and heart failure, respectively. Among sex-including CPMs, women with heart failure were at lower mortality risk in 8 of 8 models; women undergoing revascularization for coronary artery disease were at higher mortality risk in 10 of 12 models. Factors associated with the inclusion of sex effects included the number of outcome events and using cohorts at-risk for CVD (rather than with established CVD). Conclusions—Although CPMs hold promise for supporting sex-specific decision making in CVD clinical care, sex effects are included in only one third of published CPMs.

Determinants of antithrombotic choice for patent foramen ovale in cryptogenic stroke

Objective: We examined the influence of clinical, radiologic, and echocardiographic characteristics on antithrombotic choice in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), hypothesizing that features suggestive of paradoxical embolism might lead to greater use of anticoagulation. Methods: The Risk of Paradoxical Embolism Study combined 12 databases to create the largest dataset of patients with CS and known PFO status. We used generalized linear mixed models with a random effect of component study to explore whether anticoagulation was preferentially selected based on the following: (1) younger age and absence of vascular risk factors, (2) “high-risk” echocardiographic features, and (3) neuroradiologic findings. Results: A total of 1,132 patients with CS and PFO treated with anticoagulation or antiplatelets were included. Overall, 438 participants (39%) were treated with anticoagulation with a range (by database) of 22% to 54%. Treatment choice was not influenced by age or vascular risk factors. However, neuroradiologic findings (superficial or multiple infarcts) and high-risk echocardiographic features (large shunts, shunt at rest, and septal hypermobility) were predictors of anticoagulation use. Conclusion: Both antithrombotic regimens are widely used for secondary stroke prevention in patients with CS and PFO. Radiologic and echocardiographic features were strongly associated with treatment choice, whereas conventional vascular risk factors were not. Prior observational studies are likely to be biased by confounding by indication.

Tufts PACE Clinical Predictive Model Registry: update 1990 through 2015

BackgroundClinical predictive models (CPMs) estimate the probability of clinical outcomes and hold the potential to improve decision-making and individualize care. The Tufts Predictive Analytics and Comparative Effectiveness (PACE) CPM Registry is a comprehensive database of cardiovascular disease (CVD) CPMs. The Registry was last updated in 2012, and there continues to be substantial growth in the number of available CPMs.MethodsWe updated a systematic review of CPMs for CVD to include articles published from January 1990 to March 2015. CVD includes coronary artery disease (CAD), congestive heart failure (CHF), arrhythmias, stroke, venous thromboembolism (VTE), and peripheral vascular disease (PVD). The updated Registry characterizes CPMs based on population under study, model performance, covariates, and predicted outcomes.ResultsThe Registry includes 747 articles presenting 1083 models, including both prognostic (n = 1060) and diagnostic (n = 23) CPMs representing 183 distinct index condition/outcome pairs. There was a threefold increase in the number of CPMs published between 2005 and 2014, compared to the prior 10-year interval from 1995 to 2004. The majority of CPMs were derived from either North American (n = 455, 42%) or European (n = 344, 32%) populations. The database contains 265 CPMs predicting outcomes for patients with coronary artery disease, 196 CPMs for population samples at risk for incident CVD, and 158 models for patients with stroke. Approximately two thirds (n = 701, 65%) of CPMs report a c-statistic, with a median reported c-statistic of 0.77 (IQR, 0.05). Of the CPMs reporting validations, only 333 (57%) report some measure of model calibration. Reporting of discrimination but not calibration is improving over time (p for trend < 0.0001 and 0.39 respectively).ConclusionsThere is substantial redundancy of CPMs for a wide spectrum of CVD conditions. While the number of CPMs continues to increase, model performance is often inadequately reported and calibration is infrequently assessed. More work is needed to understand the potential impact of this literature.

Response to Letter Regarding Article, “Transesophageal Echocardiography in Cryptogenic Stroke and Patent Foramen Ovale Analysis of Putative High-Risk Features From the Risk of Paradoxical Embolism Database”

I read with a great interest the Risk of Paradoxical Embolism (RoPE) Study of Wessler et al,1 who demonstrated that previously proposed high-risk transesophageal echocardiography (TEE) findings of septal hypermobility, shunt at rest, and a physiologically large shunt do not seem to be found more frequently in patients whose clinical and neuroimaging features (ie, superficially located lesions) are highly suggestive of a patent foramen ovale (PFO)-attributable index stroke. They concluded that, “Due to numerous technical limitations, TEE may be unreliable in risk stratifying PFO on the basis of physiological and anatomic features.” In my …Response: Schuchlenz makes important observations that help frame the conclusions we reached through analysis of the transesophageal echocardiography data from the Risk of Paradoxical Embolism (RoPE) database and appropriately highlights some of the limitations of this data set. Specifically, important anatomic features (presence or absence of a prominent eustachian valve) were not routinely reported across the component databases. Additionally, microbubbles were routinely injected via the antecubital vein, a site that Schuchlenz correctly identifies as correlating less well with anatomic size. To create our RoPE database, component studies were combined and data were harmonized with the goals of improving on the methodological and statistical limitations of small individual studies. Yet harmonization across databases creates its own challenges and necessarily excludes details that might not be uniformly collected across component studies, including some transesophageal echocardiography variables. Our observation that proposed that high-risk transesophageal echocardiography features do not correlate with the significance of an observed patent foramen ovale for patients with cryptogenic stroke should be viewed not as a failure of the imaging modality as ideally applied. Instead, we view it as a call for further refining the technique, improving standardization and conducting further research, and as a call too for development of complimentary techniques to better assess risk.