Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
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).
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.
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
Recent proposals suggest that risk-stratified analyses of clinical trials be routinely performed to better enable tailoring of treatment decisions to individuals. Trial data can be stratified using externally developed risk models (e.g. Framingham risk score), but such models are not always available. We sought to determine whether internally developed risk models, developed directly on trial data, introduce bias compared to external models.
Methods and Results
We simulated a large patient population with known risk factors and outcomes. Clinical trials were then simulated by repeatedly drawing from the patient population assuming a specified relative treatment effect in the experimental arm, which either did or did not vary according to a subjects baseline risk. For each simulated trial, two internal risk models were developed on either the control population only (internal controls only, ICO) or on the whole trial population blinded to treatment (internal whole trial, IWT). Bias was estimated for the internal models by comparing treatment effect predictions to predictions from the external model.
Under all treatment assumptions, internal models introduced only modest bias compared to external models. The magnitude of these biases were slightly smaller for IWT models than for ICO models. IWT models were also slightly less sensitive to bias introduced by overfitting and less sensitive to falsely identifying the existence of variability in treatment effect across the risk spectrum than ICO models.
Appropriately developed internal models produce relatively unbiased estimates of treatment effect across the spectrum of risk. When estimating treatment effect, internally developed risk models using both treatment arms should, in general, be preferred to models developed on the control population.
clinical trials; modeling
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.
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.
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.
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.
Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
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.
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.
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.
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.
recurrence risk; collider bias; index event bias
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.
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
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.
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.
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.
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
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.
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.
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.
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.
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
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.
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.
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).
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.
meta-analysis; observational; studies; patent; foramen; ovale; stroke
editorials; antiplatelet; aspirin; medical decision making; patient centered care; primary prevention
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.
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention; Cryptogenic Stroke
It has been suggested that the benefits of drug-eluting stents compared to bare metal stents (BMS) have been over-estimated in part because target lesion/vessel revascularization (TLR/TVR) rates in the BMS control group of these trials were spuriously high.
We used meta-analytic techniques to systematically compare clinical event rates among patients treated with BMS in trials where BMS were the experimental (BMSexperimental) rather than the control (BMScontrol) intervention. MEDLINE searches were performed to identify eligible randomized trials comparing either drug-eluting stents with BMScontrol, or BMSexperimental with balloon angioplasty in patients with non-acute coronary artery disease. Trial characteristics and 6 to 12 month rates for death, myocardial infarction, TLR/TVR and major adverse cardiac events (MACE) were extracted and assessed.
Eligible trials yielded 50 BMS cohorts: 19 in the BMScontrol group (4 046 patients) and 31 in the BMSexperimental group (5 068 patients). Summary death and infarction rates did not differ between groups. The summary TLR/TVR rates were 16.2% (95% confidence interval, CI: 13.5, 19.3) versus 13.8% (95% CI: 12.0, 15.7) in BMScontrol versus BMSexperimental groups, respectively (p=0.15). Among 39 BMS cohorts with ≤250 patients, TLR/TVR rates were significantly higher in BMScontrol versus BMSexperimental groups (18.9% [95% CI: 16.0, 22.2] versus 13.7% [95% CI: 11.5, 16.3], p=0.01). There were no between-group differences among larger BMS cohorts (p=0.98).
While overall clinical event rates did not differ in the BMScontrol and the BMSexperimental groups, a higher rate of TVR/TLR was seen in the BMScontrol group among smaller trials.
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.
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.
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.
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.
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention
We evaluated the prognostic significance of prolonged QRS duration (QRSd) relative to arrhythmic outcomes in medically- and implantable cardioverter-defibrillator (ICD)-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II.
There is conflicting literature on the relationship between prolonged QRSd and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without ICDs.
Using a Cox-proportional hazards model adjusting for ejection fraction (EF), heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd ≥ 140 milliseconds with SCD in the medically-treated arm, and SCD or first ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF, cycle length ≤ 260 ms) in the ICD-treated arm.
In the medically-treated arm, prolonged QRSd was a significant independent predictor of SCD (HR 2.12 [95% CI 1.20–3.76], p = 0.01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (HR 0.77 [95% CI 0.47–1.24], p = 0.28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (p<0.01). These results were not affected by varying the cycle length defining rapid VT/VF or the duration defining QRSd prolongation.
In patients with prior myocardial infarction and EF ≤ 30%, prolonged QRSd does not predict SCD/VT/VF in ICD-treated patients, but does predict SCD in medically-treated patients. This underscores the non-equivalence of VT/VF and SCD, and the need for caution in inferring risk of SCD when using non-randomized databases that include only patients with ICDs.
Death; sudden; defibrillation; tachyarrhythmias; risk factors; QRS duration
The risk of death in dialysis patients remains high, but varies significantly among patients. No prediction tool is widely used in current clinical practice. We aimed to predict long-term mortality in incident dialysis patients with easily obtainable variables.
Prospective nationwide multicenter cohort study in the United Kingdom (UK Renal Registry); Models were developed using Cox proportional hazards.
Setting and Participants
Patients initiating hemodialysis or peritoneal dialysis between 2002 and 2004, who survived at least three months on dialysis treatment, were followed for three years. Analyses were restricted to subjects in whom information on comorbid conditions and laboratory measurements were available (n=5447). The dataset was divided into datasets for model development (n=3631, training) and validation (n=1816) by random selection.
Basic patient characteristics, comorbidity and laboratory variables.
All cause mortality censored for kidney transplant, recovery of kidney function, and loss to follow-up.
In the training dataset, 1078 patients (29.7%) died within the observation period. The final model of the training dataset included patient characteristics (age, race, primary kidney disease, treatment modality), comorbidities (diabetes, history of cardiovascular disease, smoking) and laboratory variables (hemoglobin, serum albumin, creatinine, calcium) and reached a C-statistic of 0.75 (95% CI, 0.73–0.77) and could accurately discriminate between patients with low (6%), intermediate (19%), high (33%) and very high (59%) mortality risk. The model was further applied to the validation dataset and achieved a C-statistic of 0.73 (95% CI, 0.71–0.76).
Number of missing comorbidity data and lack of an external validation dataset.
Basic patient characteristics, comorbidity and laboratory variables can predict three-year mortality in incident dialysis patients with sufficient accuracy. Identification of subgroups of patients according to mortality risk can guide future research and subsequently target treatment decisions in individual patients.
End stage renal disease; predictive model; mortality; hemodialysis; peritoneal dialysis
A 10-point Surgical Apgar Score, based on patients’ estimated blood loss, lowest heart rate, and lowest mean arterial pressure during surgery, was developed to rate patients’ outcomes in general and vascular surgery but has not been tested for patients having orthopaedic surgery.
For patients undergoing hip and knee arthroplasties, we asked (1) whether the score provides accurate risk stratification for major postoperative complications, and (2) whether it captures intraoperative variables contributing to postoperative risk based on the three parameters independent of preoperative risk.
Patients and Methods
We retrospectively reviewed the electronic records for all 3511 patients who underwent a hip or knee arthroplasty from March 2003 to August 2006 and extracted data to calculate a Surgical Apgar Score. We evaluated the relationship between scores and likelihood of major postoperative in-hospital complications and assessed its discrimination and calibration.
Complication rates increased monotonically as the score decreased. Even after controlling for preoperative risk, each 1-point decrease in the score was associated with a 34.0% increase (95% confidence interval, 0.66–0.84) in the odds of a complication. The overall discriminatory performance of the score was a c-statistic of 0.61. Seventy-six percent of all major complications occurred in patients classified as low risk with scores of 7 or greater.
For patients undergoing hip and knee arthroplasties, the score captures important intraoperative information regarding risk of complications and contributes additional information to preoperative risk, but on its own is insufficient to provide comprehensive postoperative risk stratification for arthroplasties.
Level of Evidence
Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
Variability in phenotypic characterization of coronary artery disease (CAD) may contribute to the heterogeneity of genetic association studies, and more consistency in phenotype definitions might improve replication of genetic associations. We assessed the extent of phenotypic heterogeneity, and quantified its impact, in a large literature sample of association studies.
Methods and Results
We searched for large (≥15 studies) meta-analyses of genetic associations and reviewed all studies included therein. From each primary study, we extracted phenotypic definitions, demographics, study design characteristics and genotypic data. For each association, we assessed the magnitude and heterogeneity of genetic effects within and across CAD phenotypes using meta-analytic methodologies. 965 individual studies investigating 32 distinct variants in 22 genes were included, from which we grouped CAD phenotypes into 3 categories: acute coronary syndromes (ACS) (426 studies, 44%), angiographically-documented disease (323 studies, 34%) and “broad, not otherwise specified CAD” (216 studies, 22%). These clinical phenotypes were overlapping. Subgroup meta-analyses by phenotype showed discordant results but phenotypic classification generally explained small proportions of between-study heterogeneity. Differences between phenotypic groups were minimized for associations with robust statistical support. No CAD phenotype was consistently associated with larger or more homogeneous genetic effects in meta-analyses.
Substantial phenotypic heterogeneity exists in CAD genetic associations, but differences in phenotype definition have a small contribution to between-study heterogeneity. We did not find a consistent effect in terms of the magnitude or homogeneity of summary effects for a specific phenotype to support its preferential use in genetic studies or meta-analyses for CAD.
coronary artery disease; myocardial infarction; meta-analysis; genetic association study; phenotype; heterogeneity
In controlled clinical trials, random assignment of treatment is appropriate only when there is equipoise, i.e., no clear preference among treatment options. However, even when equipoise appears absent because prior trials show, on average, one treatment yields superior outcomes, random assignment still may be appropriate for some patients and circumstances. In such cases, enrollment into trials may be assisted by real-time patient-specific predictions of treatment outcomes, to determine whether there is equipoise to justify randomization.
The Percutaneous Coronary Intervention Thrombolytic Predictive Instrument (PCI-TPI) computes probabilities of 30-day mortality for patients having ST elevation myocardial infarction (STEMI), if treated with thrombolytic therapy, and if treated with PCI. We estimated uncertainty around differences in their respective predicted benefits using the estimated uncertainty of the model coefficients. Using the 2,781-patient PCI-TPI development dataset, we evaluated the distribution of predicted benefits for each patient. For three typical clinical situations, randomization was potentially warranted for 70%, 93%, and 80% of patients.
Predictive models may allow real-time patient-specific determination of whether there is equipoise that justifies trial enrollment for a given patient. This approach may have utility for comparative effectiveness trials and for application of trial results to clinical practice.
To determine association of anemia and RBC transfusions with NEC in preterm infants.
111 preterm infants with NEC ≥ Stage 2a were compared with 222 matched controls. 28 clinical variables, including hematocrit and RBC transfusions were recorded. Propensity scores and multivariate logistic regression models were created to examine effects on the risk of NEC.
Controlling for other factors, lower hematocrit was associated with increased odds of NEC [OR 1.10, p =0.01]. RBC transfusion has a temporal relationship with NEC onset. Transfusion within 24h (OR=7.60, p=0.001) and 48h (OR=5.55, p=0.001) has a higher odds of developing NEC but this association is not significant by 96h (OR= 2.13, p =0.07), post transfusion
Anemia may increase the risk of developing NEC in preterm infants. RBC transfusions are temporally related to NEC. Prospective studies are needed to better evaluate the potential influence of transfusions on the development of NEC.
transfusion related gut injury; hematocrit
Decisions to limit treatment in critically ill patients often rely on publications that make claims of futility based on outcome data. Our objective was to systematically review the criteria for futility and the strength of empirical evidence across clinical studies that purport to support or refute claims of futility.
The MEDLINE database was searched for relevant articles published between1980 and 2008. Selected studies reported original outcome data in critically ill or cardiac arrest patients and claimed that these data can support or refute decisions to limit treatment in comparable patients. Two authors independently abstracted data on patient characteristics, intervention, outcomes, cost, and design.
Forty seven studies supporting a claim of futility and 45 refuting it were reviewed. Median point estimate for adverse outcome in studies supporting claims of futility was 100% (range 75% to 100%); median lower 95% confidence limit was 91% (range 48% to 99%). Explicit thresholds for futility were missing in 88% of articles. The original criteria for quantitative futility were fulfilled by only 28% of data, and almost exclusively in studies of cardiopulmonary resuscitation (CPR) for cardiac arrest. Substantial statistical overlap was observed between data brought in support of futility claims and data brought to refute them.
Most studies that purport to guide determinations of futility are based on insufficient data to provide statistical confidence for clinical decision-making. They usually lack explicit a priori thresholds for determination of futility. Many studies draw disparate conclusions based on statistically similar data. In most circumstances these problems preclude confident determinations of futility.
critically ill; futility; empirical evidence; cardiac arrest