Georgios D. Kitsios

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% confidence interval [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.

Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphic Variant as a Marker of Coronary Artery Disease: A Meta-analysis

BACKGROUND Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphic variant and coronary artery disease (CAD). However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous samples. To shed light on these inconclusive findings, we conducted a meta-analysis of studies relating the ACE I/D polymorphic variant to the risk of CAD. METHODS We searched the PubMed database for English-language articles on CAD in humans. We estimated summary odds ratios and explored potential sources of heterogeneity and bias. RESULTS The 118 studies chosen for the analysis involved 43 733 cases with CAD and 82 606 controls. The heterogeneity between studies was significant. When we compared homozygotes with the D and I alterations, the ACE I/D polymorphic variant was associated with a 25% increased risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.16-1.35). Subgroup analyses for myocardial infarction, diabetes mellitus, male sex, white race, East Asian subjects, and Turkish subjects showed significant associations. No association was found in other racial/ethnic groups, in women, in premature cases, or in cases with low levels of risk factors. The major sources of heterogeneity were due to racial/ethnic diversity, genotyping procedure, and age matching. Cumulative meta-analysis for the allelic contrast showed a trend of association as information accumulated. There was a differential magnitude of effect in large vs small studies. CONCLUSIONS The meta-analysis demonstrated evidence of a modest positive association between ACE I/D polymorphic variant and CAD. The meta-analysis also highlights the heterogeneity of reported results, considerable gaps in research, and the need for future studies focused on certain high-risk patient populations.

Risk prediction models for patients with chronic kidney disease: a systematic review.

BACKGROUND Patients with chronic kidney disease (CKD) are at increased risk for kidney failure, cardiovascular events, and all-cause mortality. Accurate models are needed to predict the individual risk for these outcomes. PURPOSE To systematically review risk prediction models for kidney failure, cardiovascular events, and death in patients with CKD. DATA SOURCES MEDLINE search of English-language articles published from 1966 to November 2012. STUDY SELECTION Cohort studies that examined adults with any stage of CKD who were not receiving dialysis and had not had a transplant; had at least 1 year of follow-up; and reported on a model that predicted the risk for kidney failure, cardiovascular events, or all-cause mortality. DATA EXTRACTION Reviewers extracted data on study design, population characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness. DATA SYNTHESIS Thirteen studies describing 23 models were found. Eight studies (11 models) involved kidney failure, 5 studies (6 models) involved all-cause mortality, and 3 studies (6 models) involved cardiovascular events. Measures of estimated glomerular filtration rate or serum creatinine level were included in 10 studies (17 models), and measures of proteinuria were included in 9 studies (15 models). Only 2 studies (4 models) met the criteria for clinical usefulness, of which 1 study (3 models) presented reclassification indices with clinically useful risk categories. LIMITATION A validated risk-of-bias tool and comparisons of the performance of different models in the same validation population were lacking. CONCLUSION Accurate, externally validated models for predicting risk for kidney failure in patients with CKD are available and ready for clinical testing. Further development of models for cardiovascular events and all-cause mortality is needed. PRIMARY FUNDING SOURCE None.

Management Strategies for Asymptomatic Carotid Stenosis: A Systematic Review and Meta-analysis

BACKGROUND Adults with asymptomatic carotid artery stenosis are at increased risk for ipsilateral carotid territory ischemic stroke. PURPOSE To examine comparative evidence on management strategies for asymptomatic carotid stenosis and the incidence of ipsilateral stroke with medical therapy alone. DATA SOURCES MEDLINE, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration documents, and review of references through 31 December 2012. STUDY SELECTION Randomized, controlled trials (RCTs) and prospective or retrospective nonrandomized, comparative studies of medical therapy alone, carotid endarterectomy (CEA) plus medical therapy, or carotid artery stenting (CAS) plus medical therapy for adults with asymptomatic carotid stenosis, as well as single-group prospective cohort studies of medical therapy, were reviewed. DATA EXTRACTION Two investigators extracted information on study and population characteristics, results, and risk of bias. DATA SYNTHESIS Forty-seven studies in 56 publications were eligible. The RCTs comparing CAS and CEA were clinically heterogeneous; 1 RCT reported more but not statistically significant ipsilateral stroke events (including any periprocedural stroke) in CAS compared with CEA, whereas another RCT, in a population at high surgical risk for CEA, did not. Three RCTs showed that CEA reduced the risk for ipsilateral stroke (including any periprocedural stroke) compared with medical therapy alone, but these results may no longer be applicable to contemporary clinical practice. No RCT compared CAS versus medical therapy alone. The summary incidence of ipsilateral stroke across 26 cohorts receiving medical therapy alone was 1.68% per year. LIMITATIONS Studies defined asymptomatic status heterogeneously. Participants in RCTs did not receive best-available medical therapy. CONCLUSION Future RCTs of asymptomatic carotid artery stenosis should explore whether revascularization interventions provide benefit to patients treated by best-available medical therapy. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Auto-titrating versus fixed continuous positive airway pressure for the treatment of obstructive sleep apnea: a systematic review with meta-analyses

BackgroundObstructive sleep apnea is a relatively common disorder that can lead to lost productivity and cardiovascular disease. The form of positive airway treatment that should be offered is unclear.MethodsMEDLINE and the Cochrane Central Trials registry were searched for English language randomized controlled trials comparing auto-titrating positive airway pressure (APAP) with continuous positive airway pressure (CPAP) in adults with obstructive sleep apnea (inception through 9/2010). Six researchers extracted information on study design, potential bias, patient characteristics, interventions and outcomes. Data for each study were extracted by one reviewer and confirmed by another. Random effects model meta-analyses were performed for selected outcomes.ResultsTwenty-four randomized controlled trials met the inclusion criteria. In individual studies, APAP and fixed CPAP resulted in similar changes from baseline in the apnea-hypopnea index, most other sleep study measures and quality of life. By meta-analysis, APAP improved compliance by 11 minutes per night (95% CI, 3 to 19 minutes) and reduced sleepiness as measured by the Epworth Sleepiness Scale by 0.5 points (95% CI, 0.8 to 0.2 point reduction) compared with fixed CPAP. Fixed CPAP improved minimum oxygen saturation by 1.3% more than APAP (95% CI, 0.4 to 2.2%). Studies had relatively short follow-up and generally excluded patients with significant comorbidities. No study reported on objective clinical outcomes.ConclusionsStatistically significant differences were found but clinical importance is unclear. Because the treatment effects are similar between APAP and CPAP, the therapy of choice may depend on other factors such as patient preference, specific reasons for non-compliance and cost.

Randomized trials of dopamine agonists in restless legs syndrome: A systematic review, quality assessment, and meta-analysis

BACKGROUND The use of dopamine agonists (DAs) for the treatment of restless legs syndrome (RLS) has been assessed in numerous randomized clinical trials (RCTs). OBJECTIVES The aims of this study were to assess the reporting quality of published RCTs according to the Consolidated Standards of Reporting Trials (CONSORT) statement and to synthesize the study results in terms of efficacy and tolerability to inform the clinical management of RLS. METHODS PubMed and Cochrane Controlled Trials Register were searched for English-language RCTs that assessed the effects of DAs in RLS. Quality of reporting was measured using the proportion of 17 CONSORT checklist items included in each study. The 2 primary outcomes were pooled mean change from baseline in International RLS (IRLS) Study Group rating scale score (Deltamu) (95% CI) and relative risk (RR) (95% CI) of response based on the Clinical Global Impression-Improvement (CGI-I) scale score. The pooled proportions of adverse events (PAEs) (95% CI) were also estimated. RESULTS Eighteen RCTs (N = 2848 patients) were included. Two of the 17 CONSORT checklist items were reported in 7 studies (39%) and 9 of the 17 items were reported in all 18 studies (100%). The differences in the IRLS scores and RR for CGI-I were significantly greater with pramipexole, ropinirole, rotigotine, and cabergoline compared with placebo. Results for heterogeneity were nonsignificant. The difference in Deltamu (95% CI) was significant with pramipexole (-6.63 [-9.15 to -4.10]) versus ropinirole (-3.64 [-4.76 to 2.51]) (P = 0.04). The difference between pramipexole and rotigotine was nonsignificant. The pooled PAEs (95% CI) for pramipexole, ropinirole, and rotigotine were 4.8% (2.0% to 8.7%), 10.2% (2.6% to 22.1%), and 7.6% (1.3% to 18.5%), respectively. In the trial of sumanirole, the PAE value was 2% (0% to 5.4%). CONCLUSION Based on the findings from the meta-analysis, DAs were significantly more efficacious in the treatment of RLS compared with placebo.

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 nonsynonymous PON1 polymorphisms, rs662 (p.Q192R) and rs854560 (p.L55M) in humans.Methods: We searched multiple electronic databases through June 30, 2009 for eligible studies. In main analyses, we calculated allele-based odds ratios 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 odds ratio of 1.10 per G allele (95% confidence interval, 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 odds ratio of 0.97 per T allele (95% confidence interval, 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.

Potentially Large yet Uncertain Benefits A Meta-analysis of Patent Foramen Ovale Closure Trials

Until recently, the evidence base for patent foramen ovale (PFO) closure with a device to prevent future cerebrovascular events in patients with cryptogenic stroke and presumed paradoxical embolism consisted of a large body of >50 observational studies that cumulatively showed substantial and unequivocal benefits with this intervention.1 On the basis of this observational data and the compelling pathophysiologic rationale, PFO closure to prevent stroke recurrence had become routine in many centers, and off-label closure of PFOs hampered enrollment in ongoing trials. However, within the past year, the first true clinical experiments on PFO closure were published, and 3 consecutive randomized clinical trials (RCTs) investigating 2 different devices (STARFlex in CLOSURE-I and Amplatzer PFO Occluder in RESPECT and PC trial) failed to show evidence of statistically significant benefit in their primary outcome.2–4 Yet, despite the consistently null overall outcome of these trials, on closer inspection, their results seem well calibrated to sustain the controversy; in particular, the results of the RESPECT and PC trial, published simultaneously, seem highly suggestive of benefit for mechanical closure over medical therapy.5 Thus, we aimed to explore more thoroughly the results from the available randomized evidence via meta-analysis, which can sometimes overcome the uncertainty in individual trials through their pooling.6 We considered the outcome of recurrent stroke as our primary outcome (as opposed to also including transient ischemic attacks), given its more standardized definition and its long-term clinical import. We additionally explored composite outcomes in sensitivity analyses, and apart from the intention-to-treat analysis, we also synthesized the per-protocol results of the trials to appreciate the effects of crossovers and dropouts. For the statistical synthesis, we considered the generally accepted random effects model,7 which accounts for possible between-trial treatment-effect heterogeneity. …

Can We Trust Observational Studies Using Propensity Scores in the Critical Care Literature? A Systematic Comparison With Randomized Clinical Trials.

Objective:To assess the degree of agreement between propensity score studies and randomized clinical trials in critical care research. Data Sources:Propensity score studies published in highly cited critical care or general medicine journals or included in a previous systematic review; corresponding randomized clinical trials included in Cochrane Systematic Reviews or published in PubMed. Study Selection:We identified propensity score studies of the effects of therapeutic interventions on short- or long-term mortality. We systematically matched propensity score studies to randomized clinical trials based on patient selection criteria, interventions, and outcomes. Data Extraction:We appraised the methods of included studies and extracted treatment effect estimates to compare the results of propensity score studies and randomized clinical trials. When multiple studies were identified for the same topic, we performed meta-analyses to obtain summary treatment effect estimates. Data Synthesis:We matched 21 propensity score studies with 58 randomized clinical trials in 18 distinct comparisons (median, one propensity score study and two randomized clinical trials per comparison), for short- and long-term mortality. We found one statistically significant difference between designs (hyperoncotic albumin vs crystalloid fluids) among these 18 comparisons. Propensity score studies did not produce systematically higher (or lower) treatment effect estimates compared with randomized clinical trials, but estimates from the two designs differed by more than 30% in one third of the comparisons examined. Observational studies in critical care met widely accepted methodological standards for propensity score analyses. Conclusions:Across diverse critical care topics, propensity score studies published in high-impact journals produced results that were generally consistent with the findings of randomized clinical trials. However, caution is needed when interpreting propensity score studies because occasionally their results contradict those of randomized clinical trials and there is no reliable way to predict disagreements.

Genomic Convergence of Genome-wide Investigations for Complex Traits

Genome‐wide investigations for identifying the genes for complex traits are considered to be agnostic in terms of prior assumptions for the responsible DNA alterations. The agreement of genome‐wide association studies (GWAS) and genome‐wide linkage scans (GWLS) has not been explored to date. In this study, a genomic convergence approach of GWAS and GWLS was implemented for the first time in order to identify genomic loci supported by both methods. A database with 376 GWLS and 102 GWAS for 19 complex traits was created. Data regarding the location and statistical significance for each genetic marker were extracted from articles or web‐based databases. Convergence was quantified as the proportion of significant GWAS markers located within linked regions. Convergence was variable (0–73.3%) and was found to be significantly higher than expected by chance only for two of the 19 phenotypes. Seventy five loci of interest were identified, which being supported by independent lines of evidence, could merit prioritization in future investigations. Although convergence is supportive of genuine effects, lack of agreement between GWLS and GWAS is also indicative that these studies are designed to answer different questions and are not equally well suited for deciphering the genetics of complex traits.