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1.  The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database 
Background
Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence.
Aims
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
Methods
We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible.
Results
The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling.
Conclusion
While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure.
doi:10.1111/j.1747-4949.2012.00843.x
PMCID: PMC4060865  PMID: 22883936
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
2.  Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO 
BACKGROUND
Patent foramen ovale (PFO) and cryptogenic stroke (CS) are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related etiology. We examined whether specific radiological findings are associated with PFO among subjects with CS and known PFO status.
METHODS
We analyzed the Risk of Paradoxical Embolism (RoPE) database of subjects with CS and known PFO status, for associations between PFO and: 1) index stroke seen on imaging, 2) index stroke size, 3) index stroke location, 4) multiple index strokes, and 5) prior stroke on baseline imaging. We also compared imaging with purported “high risk” echocardiographic features.
RESULTS
Subjects (n=2680) were significantly more likely to have a PFO if their index stroke was large (OR 1.36, p=0.0025), seen on index imaging (OR 1.53, p=0.003), and superficially located (OR 1.54, p<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR 0.66, p<0.0001). Finding multiple index strokes was unrelated to PFO status (OR 1.21, p=0.161). No echocardiographic variables were related to PFO status.
CONCLUSIONS
This is the largest study to report the radiological characteristics of patients with CS and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
doi:10.1161/STROKEAHA.112.677039
PMCID: PMC3595100  PMID: 23339957
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
4.  Patent Foramen Ovale Closure and Medical Treatments for Secondary Stroke Prevention A Systematic Review of Observational and Randomized Evidence 
Background and Purpose
Patients discovered to have a patent foramen ovale in the setting of a cryptogenic stroke may be treated with percutaneous closure, antiplatelet therapy, or anticoagulants. A recent randomized trial (CLOSURE I) did not detect any benefit of closure over medical treatment alone; the optimal medical therapy is also unknown. We synthesized the available evidence on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke.
Methods
A MEDLINE search was performed for finding longitudinal studies investigating medical treatment or closure, meta-analysis of incidence rates (IR), and IR ratios of recurrent cerebrovascular events.
Results
Fifty-two single-arm studies and 7 comparative nonrandomized studies and the CLOSURE I trial were reviewed. The summary IR of recurrent stroke was 0.36 events (95% CI, 0.24–0.56) per 100 person-years with closure versus 2.53 events (95% CI, 1.91–3.35) per 100 person-years with medical therapy. In comparative observational studies, closure was superior to medical therapy (IR ratio=0.19; 95% CI, 0.07–0.54). The IR for the closure arm of the CLOSURE I trial was higher than the summary estimate from observational studies; there was no significant benefit of closure over medical treatment (P=0.002 comparing efficacy estimates between observational studies and the trial). Observational and randomized data (9 studies) comparing medical therapies were consistent and suggested that anticoagulants are superior to antiplatelets for preventing stroke recurrence (IR ratio=0.42; 95% CI, 0.18–0.98).
Conclusions
Although further randomized trial data are needed to precisely determine the effects of closure on stroke recurrence, the results of CLOSURE I challenge the credibility of a substantial body of observational evidence strongly favoring mechanical closure over medical therapy.
doi:10.1161/STROKEAHA.111.631648
PMCID: PMC3342835  PMID: 22180252
meta-analysis; observational; studies; patent; foramen; ovale; stroke
5.  Personalizing Evidence-based Primary Prevention with Aspirin: Individualized Risks and Patient Preference 
doi:10.1161/CIRCOUTCOMES.111.961136
PMCID: PMC3108244  PMID: 21586722
editorials; antiplatelet; aspirin; medical decision making; patient centered care; primary prevention
6.  Princeton Conference: Is PFO a Modifiable Risk Factor for Stroke Recurrence? 
Stroke; a journal of cerebral circulation  2010;41(10 Suppl):S26-S30.
While the prevalence of patent foramena ovale (PFOs) in the general population is around 25%, it is approximately doubled among cryptogenic stroke (CS) patients. This has generally been attributed to paradoxical embolism and many physicians recommend PFO closure to prevent recurrence. However, the benefit of PFO closure in patients with stroke has not been demonstrated. Further, the epidemiology of stroke recurrence in patients with CS with PFO versus without PFO, and in those with large right-to-left shunts versus small right-to-left shunts, has yielded results that appear difficult to reconcile with the hypothesis that paradoxical embolism is an important cause of stroke recurrence. The purpose of this review is to critically examine the epidemiological evidence that PFO is a potentially modifiable risk factor for stroke recurrence in patients with cryptogenic stroke. The evidence suggests that many patients with CS and PFO have strokes that are PFO-attributable, but that many have strokes that are unrelated to their PFO.. We introduce the concept of “PFO-propensity”, defined as the patient-specific probability of finding a PFO in a patient with cryptogenic stroke based on their age and other risk factors. We show that this value is directly related to the probability that a CS is PFO-attributable. Because there is substantial heterogeneity both in PFO-propensity and in recurrence risk among patients with PFO and cryptogenic stroke, stratification for closure by these joint probabilities will likely prove crucial for appropriate patient selection.
doi:10.1161/STROKEAHA.110.595140
PMCID: PMC2954503  PMID: 20876498
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention; Cryptogenic Stroke
7.  Are “Treatment” Bare Metal Stents Superior to “Control” Bare Metal Stents? A meta-analytic approach 
American heart journal  2008;155(4):624-629.e2.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ahj.2007.11.005
PMCID: PMC3065934  PMID: 18371468
8.  Therapeutic Innovations and Diminishing Returns 
doi:10.1001/jama.2009.1679
PMCID: PMC3063072  PMID: 19934428
9.  Aggregating and Disaggregating Patients in Clinical Trials and their Subgroup Analyses 
Annals of internal medicine  2010;153(1):51-52.
doi:10.1059/0003-4819-153-1-201007060-00012
PMCID: PMC2946839  PMID: 20621903
10.  Predicting Mortality in Incident Dialysis Patients: An Analysis of the United Kingdom Renal Registry 
Background
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.
Study Design
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.
Predictors
Basic patient characteristics, comorbidity and laboratory variables.
Outcomes
All cause mortality censored for kidney transplant, recovery of kidney function, and loss to follow-up.
Results
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).
Limitations
Number of missing comorbidity data and lack of an external validation dataset.
Conclusions
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.
doi:10.1053/j.ajkd.2010.12.023
PMCID: PMC3100445  PMID: 21489668
End stage renal disease; predictive model; mortality; hemodialysis; peritoneal dialysis
11.  Patent Foramen Ovale in Cryptogenic Stroke: Incidental or Pathogenic? 
BACKGROUND
Patent foramen ovale (PFO) is significantly associated with cryptogenic stroke (CS). However, even in patients with CS, a PFO can be an incidental finding. We sought to estimate the probability that a PFO in a patient with CS is incidental.
METHODS
A systematic search identified 23 case-control studies examining the prevalence of PFO in patients with CS versus controls with stroke of known-cause. Using simple assumptions and Bayes’ theorem we calculated the probability a PFO is incidental in patients with CS. Random effects meta-analyses estimated the odds ratio (OR) of a PFO in CS versus controls in different age populations, with or without atrial septal aneurysms (ASA), and were used to summarize across studies the probability that a PFO in CS is incidental.
RESULTS
The summary OR (95% confidence limits) for PFO in CS versus controls was 2.9 (CI 2.1, 4.0). The corresponding ORs for young and old patients (< or ≥ 55 years) were 5.1 (3.3, 7.8) and 2.0 (1.0, 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28%, 39%) in age-inclusive studies, 20% (16%, 25%) in younger patients, and 48% (34%, 66%) in older patients. These probabilities were much lower when an ASA was present.
CONCLUSIONS
In patients with otherwise CS, approximately a third of discovered PFOs are likely to be incidental, and hence not benefit from closure. This probability is sensitive to patient characteristics such as age and the presence of an ASA, suggesting the importance of patient-selection in therapeutic decision-making.
doi:10.1161/STROKEAHA.109.547828
PMCID: PMC2764355  PMID: 19443800
Patent foramen ovale; Risk factors for stroke; Secondary stroke prevention
12.  The Surgical Apgar Score in Hip and Knee Arthroplasty 
Background
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.
Questions/purposes
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.
Results
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.
Conclusions
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.
doi:10.1007/s11999-010-1721-x
PMCID: PMC3048275  PMID: 21132410
15.  Heterogeneity of the Phenotypic Definition of Coronary Artery Disease and Its Impact on Genetic Association Studies 
Background
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.
Conclusions
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.
doi:10.1161/CIRCGENETICS.110.957738
PMCID: PMC3048058  PMID: 21149552
coronary artery disease; myocardial infarction; meta-analysis; genetic association study; phenotype; heterogeneity
16.  Random Treatment Assignment Using Mathematical Equipoise for Comparative Effectiveness Trials 
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.
doi:10.1111/j.1752-8062.2010.00253.x
PMCID: PMC3076795  PMID: 21348950
17.  Association of prolonged QRS duration with ventricular tachyarrhythmias and sudden cardiac death in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) 
OBJECTIVES
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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1016/j.hrthm.2008.02.013
PMCID: PMC2692879  PMID: 18534364
Death; sudden; defibrillation; tachyarrhythmias; risk factors; QRS duration
18.  Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants 
Objective
To determine association of anemia and RBC transfusions with NEC in preterm infants.
Study Design
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.
Results
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
Conclusions
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.
doi:10.1038/jp.2010.145
PMCID: PMC3234132  PMID: 21273983
transfusion related gut injury; hematocrit
19.  The Empirical Basis for Determinations of Medical Futility 
Journal of General Internal Medicine  2010;25(10):1083-1089.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1007/s11606-010-1445-3
PMCID: PMC2955478  PMID: 20645019
critically ill; futility; empirical evidence; cardiac arrest
20.  Paraoxonase 1 polymorphisms and ischemic stroke risk: a systematic review and meta-analysis 
Purpose
Paraoxonase 1 (PON1) polymorphisms have been implicated as risk factors for coronary artery disease, but the results of genetic association studies on the related phenotype of ischemic stroke are inconclusive. We performed a meta-analysis of published studies investigating the association between ischemic stroke and two non-synonymous PON1 polymorphisms, rs662 (p.Q192R) and rs854560 (p.L55M) in humans.
Methods
We searched multiple electronic databases through 06/30/2009 for eligible studies. In main analyses we calculated allele-based odds ratios (OR) with random effects models. In secondary analyses we examined dominant and recessive genetic models as well, and performed subgroup and sensitivity analyses.
Results
Regarding rs662, we identified 22 eligible studies (total of 7384 cases/11,074 controls), yielding a summary OR of 1.10 per G allele (95% confidence interval, CI, 1.04–1.17) with no evidence of between-study heterogeneity. For rs854560, 16 eligible studies (total of 5518 cases/8951 controls) yielded a summary OR of 0.97 per T allele (95% CI, 0.90–1.04), again with no evidence of between-study heterogeneity. For both polymorphisms, analyses with dominant and recessive genetic models yielded the same inferences as allele-based comparisons. Subgroup and sensitivity analyses showed similar results.
Conclusion
In agreement with observations in coronary artery disease, PON1 rs662 appears to be associated with a small increase in the risk of ischemic stroke.
doi:10.1097/GIM.0b013e3181ee81c6
PMCID: PMC3081717  PMID: 20856122
paraoxonase 1; PON1; rs662; rs854560; stroke; meta-analysis
21.  The Risk of Paradoxical Embolism (RoPE) Study: Developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke 
Trials  2011;12:185.
Background
Despite the diffusion into practice of percutaneous closure of a patent foramen ovale (PFO) in patients with cryptogenic stroke (CS), the benefits have not been demonstrated, and remain unclear. For any individual presenting with a PFO in the setting of CS, it is not clear whether the PFO is pathogenically-related to the index event or an incidental finding. Further, the overall rate of stroke recurrence is low in patients with CS and PFO. How patient-specific factors affect the likelihood that a discovered PFO is related to an index stroke or affect the risk of recurrence is not well understood. These probabilities are likely to be important determinants of the benefits of PFO closure in CS.
Design/Methods
The goal of the Risk of Paradoxical Embolism (RoPE) Study is to develop and test a set of predictive models that can identify those patients most likely to benefit from preventive treatments for PFO-related stroke recurrence, such as PFO closure. To do this, we will construct a database of patients with CS, both with and without PFO, by combining existing cohort studies. We will use this pooled database to identify patient characteristics associated with the presence (versus the absence) of a PFO, and to use this "PFO propensity" to estimate the patient-specific probability that a PFO was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit.
doi:10.1186/1745-6215-12-185
PMCID: PMC3170216  PMID: 21794121
22.  Patent foramen ovale: Rethinking trial strategies and treatment options 
Current opinion in neurology  2010;23(1):73-78.
Purpose of review
The etiology of stroke remains unknown in roughly one third of patients despite extensive investigation. The prevalence of PFOs in the general population is around 25% but the prevalence in cryptogenic stroke patients is doubled. This suggests a causal relationship between PFO and CS. This has generally been attributed to paradoxical embolism. Regardless of mechanism, ~30,000 young patients each year have a cryptogenic stroke and PFO. Optimal management is uncertain.
Recent findings
Many physicians recommend PFO closure, an intuitively attractive mechanical solution for stroke prevention. Unfortunately, the benefit of PFO closure in patients with stroke has not been demonstrated. There are ongoing clinical trials comparing the safety and efficacy of PFO closure to medical therapy. Interpreting these trials will be complicated by two issues: first, it is unclear whether a patient's PFO is causally related to the event (“pathogenic”) or not (“incidental”); and second, recurrent strokes may be due to paradoxical embolism or another stroke mechanism.
Summary
Substantial heterogeneity of patients within trials along these two dimensions of risk may make overall trial results difficult to interpret. With appropriate analyses, the trials may be more informative than the overall data may suggest.
PMCID: PMC2865205  PMID: 20050353
Cryptogenic stroke; patent foramen ovale; risk heterogeneity; endovascular PFO closure; clinical trials
23.  Subgroup Analyses in Randomized Controlled Trials: the Need for Risk Stratification in Kidney Transplantation 
Although randomized controlled trials are the gold standard for establishing causation in clinical research, their aggregated results can be misleading when applied to individual patients. A treatment may be beneficial in some patients, but its harms may outweigh benefits in others. While conventional one-variable-at-a-time subgroup analyses have well-known limitations, multivariable risk-based analyses can help uncover clinically significant heterogeneity in treatment effects that may be otherwise obscured. Trials in kidney transplantation have yielded the finding that a reduction in acute rejection does not translate into a similar benefit in prolonging graft survival and improving graft function. This paradox might be explained by the variation in risk for acute rejection among included kidney transplant recipients varying the likelihood of benefit or harm from intense immunosuppressive regimens. Analyses that stratify patients by their immunological risk may resolve these otherwise puzzling results. Reliable risk models should be developed to investigate benefits and harms in rationally designed risk-based subgroups of patients in existing RCT datasets. These risk strata would need to be validated in future prospective clinical trials examining long term effects on patient and graft survival. This approach may allow better individualized treatment choices for kidney transplant recipients.
doi:10.1111/j.1600-6143.2009.02802.x
PMCID: PMC2997518  PMID: 19764948
24.  Percutaneous Coronary Interventions for Nonacute Coronary Artery Disease: A Quantitative Twenty-Year Synopsis 
Lancet  2009;373(9667):911-918.
Summary
Background
Over the last 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 (CAD). We present an overview of randomised trials comparing these interventions with each other and with medical therapy in patients with nonacute CAD.
Methods
We searched Medline for trials contrasting at least two of the aforementioned interventions. Outcomes of interest were death, myocardial infarction (MI), coronary artery bypass grafting (CABG), target lesion or vessel revascularisation (TLR/TVR), 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 4 of 6 possible comparisons between the 4 interventions. No trials directly compared DES with medical therapy or PTCA. In all direct or indirect comparisons, succeeding advancements in PCI did not yield detectable improvements in deaths and MI. The risk ratio for indirect comparisons between DES and medical therapy was 0·96 (95% confidence interval: 0·60, 1·52) for death and 1·15 (0·73, 1·82) for MI. In contrast, there were sequential significant reductions in TLR/TVR with BMS compared to PTCA and with DES compared to BMS. The risk ratio for the indirect comparison between DES and PTCA for TLR/TVR was 0·30 (0·17, 0·51).
Interpretation
Sequential innovations in the catheter-based treatment of nonacute CAD showed no evidence of an impact on death or MI when compared with medical therapy.
doi:10.1016/S0140-6736(09)60319-6
PMCID: PMC2967219  PMID: 19286090
25.  Comparative Effectiveness of STEMI Regionalization Strategies 
BACKGROUND
Primary percutaneous coronary intervention (PCI) is more effective on average than fibrinolytic therapy (FT) in the treatment of ST-segment elevation myocardial infarction (STEMI). Yet most U.S. hospitals are not equipped for PCI and FT is still widely used. This study evaluated the comparative effectiveness of STEMI regionalization strategies to increase the use of PCI against standard emergency transport and care.
METHODS AND RESULTS
We estimated incremental treatment costs and quality-adjusted life expectancies of 2,000 patients with STEMI who received PCI or FT in simulations of emergency care in a regional hospital system. To increase access to PCI across the system, we compared a base case strategy to 12 hospital-based strategies of building new PCI labs or extending the hours of existing labs, and one emergency medical services (EMS)-based strategy of transporting all patients with STEMI to existing PCI-capable hospitals. The base case resulted in 609 (569, 647) patients getting PCI. Hospital-based strategies increased the number of patients receiving PCI, the costs of care, and quality-adjusted life years (QALYs) saved, and were cost effective under a variety of conditions. An EMS-based strategy of transporting every patient to an existing PCI facility was less costly and more effective than all hospital expansion options.
CONCLUSION
Our results suggest that new construction and staffing of PCI labs may not be warranted if an EMS strategy is both available and feasible.
doi:10.1161/CIRCOUTCOMES.109.908541
PMCID: PMC2967250  PMID: 20664025
cost-benefit analysis; fibrinolysis; Percutaneous coronary intervention; ST-segment elevation myocardial infarction; thrombolysis

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