Determining the conclusiveness of a meta-analysis.

The pursuit of conclusive evidence related to an unanswered foreground (decision-making) question has been the driving factor behind multiple ongoing and planned randomized controlled trials as well as meta-analyses. However, a fundamental challenge lies in establishing robust methods for ascertaining whether a collection of synthesized trials has yielded a definitive answer to that foreground question through the process of meta-analysis. This article explores the evolution of methods that attempt to address this challenge. These methods have primarily focused on defining and measuring the sufficiency and stability of evidence within a meta-analytic context. Cumulative meta-analysis and trial sequential analysis are the tools currently used, but they both come with limitations and challenges. We further discuss methods aimed at evaluating the evolution of effects over time more directly, such as the recursive cumulative meta-analysis. The latter method can be considered a better alternative, as it serves to demonstrate whether there is a true underlying treatment effect to which the meta-analysis is converging. However, recursive cumulative meta-analysis falls short of a specific indicator that establishes whether convergence has been reached. We coin the term exit for a meta-analysis where convergence can be demonstrated. Developing methods to determine the exit status of a meta-analysis is the next priority in research synthesis methods, as it will indicate that the research journey has concluded on a particular foreground question with no expectation of a different result with the addition of future trials.

Early warning of potential epidemics: A pilot application of an early warning tool to data from the pulmonary clinic of the university hospital of Thessaly, Greece.

BACKGROUND & METHODS: This paper describes a pilot application of the Epidemic Volatility Index (EVI) to data from the pulmonary clinic of the University Hospital of Thessaly, Greece, for monitoring respiratory infections, COVID-19, and flu cases. EVI, a simple and easily implemented early warning method based on the volatility of newly reported cases, exhibited consistent and stable performance in detecting new waves of epidemics. The study highlights the importance of implementing early warning tools to address the effects of epidemics, including containment of outbreaks, timely intervention strategies, and resource allocation within real-world clinical settings as part of a broader public health strategy. RESULTS: The results presented in the figures demonstrate the association between successive early warnings and the onset of new waves, providing valuable insights for proactive decision-making. A web-based application enabling real-time monitoring and informed decision-making by healthcare professionals, public health officials, and policymakers was developed. CONCLUSIONS: This study emphasizes the significant role of early warning methods in managing epidemics and safeguarding public health. Future research may explore extensions and combinations of multiple warning systems for optimal outbreak interventions and application of the methods in the context of personalized medicine.

Impact of Short-Course Palliative Radiation Therapy on Pancreatic Cancer-Related Pain: Prospective Phase 2 Nonrandomized PAINPANC Trial.

PURPOSE: Clinical evidence is limited regarding palliative radiation therapy for relieving pancreatic cancer-related pain. We prospectively investigated pain response after short-course palliative radiation therapy in patients with moderate-to-severe pancreatic cancer-related pain. METHODS AND MATERIALS: In this prospective phase 2 single center nonrandomized trial, 30 patients with moderate-to-severe pain (5-10, on a 0-10 scale) of pancreatic cancer refractory to pain medication, were treated with a short-course palliative radiation therapy; 24 Gy in 3 weekly fractions (2015-2018). Primary endpoint was defined as a clinically relevant average decrease of ≥2 points in pain severity, compared with baseline, within 7 weeks after the start of treatment. Secondary endpoint was global quality of life (QoL), with a clinically relevant increase of 5 to 10 points (0-100 scale). Pain severity reduction and QoL were assessed 9 times using the Brief Pain Inventory and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-PAL, respectively. Both outcomes were analyzed using joint modeling. In addition, acute toxicity based on clinician reporting and overall survival (OS) were assessed. RESULTS: Overall, 29 of 30 patients (96.7%) received palliative radiation therapy. At baseline, the median oral morphine equivalent daily dose was 129.5 mg (range, 20.0-540.0 mg), which decreased to 75.0 mg (range, 15.0-360.0 mg) after radiation (P = .021). Pain decreased on average 3.15 points from baseline to 7 weeks (one-sided P = .045). Patients reported a clinically relevant mean pain severity reduction from 5.9 to 3.8 points (P = .011) during the first 3 weeks, which further decreased to 3.2 until week 11, ending at 3.4 (P = .006) in week 21 after the first radiation therapy fraction. Global QoL significantly improved from 50.5 to 60.8 during the follow-up period (P = .001). Grade 3 acute toxicity occurred in 3 patients and no grade 4 to 5 toxicity was observed. Median OS was 11.8 weeks, with a 13.3% 1-year actuarial OS rate. CONCLUSIONS: Short-course palliative radiation therapy for pancreatic cancer-related pain was associated with rapid, clinically relevant reduction in pain severity, and clinically relevant improvement in global QoL, with mostly mild toxicity.

The convergence epidemic volatility index (cEVI) as an alternative early warning tool for identifying waves in an epidemic.

This manuscript introduces the convergence Epidemic Volatility Index (cEVI), a modification of the recently introduced Epidemic Volatility Index (EVI), as an early warning tool for emerging epidemic waves. cEVI has a similar architectural structure as EVI, but with an optimization process inspired by a Geweke diagnostic-type test. Our approach triggers an early warning based on a comparison of the most recently available window of data samples and a window based on the previous time frame. Application of cEVI to data from the COVID-19 pandemic data revealed steady performance in predicting early, intermediate epidemic waves and retaining a warning during an epidemic wave. Furthermore, we present two basic combinations of EVI and cEVI: (1) their disjunction cEVI + that respectively identifies waves earlier than the original index, (2) their conjunction cEVI- that results in higher accuracy. Combination of multiple warning systems could potentially create a surveillance umbrella that would result in early implementation of optimal outbreak interventions.

Comparison of Demographic, Clinical, Biochemical, and Imaging Findings in Hypertrophic Cardiomyopathy Prognosis: A Network Meta-Analysis.

BACKGROUND: Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death (SCD), risk assessment in HCM patients is still largely unresolved. OBJECTIVES: This study aims to synthesize and compare the prognostic impact of demographic, clinical, biochemical, and imaging findings in patients with HCM. METHODS: The authors searched PubMed, Embase, and Cochrane Library for studies published from 1955 to November 2020, and the endpoints were: 1) all-cause death; 2) an arrhythmic endpoint including SCD, sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and 3) a composite endpoint including (1) or (2) plus hospitalization for HF or cardiac transplantation. The authors performed a pairwise meta-analysis obtaining the pooled estimate separately for the association between baseline variables and study endpoints. A random-effects network meta-analysis was subsequently used to comparatively assess the prognostic value of outcome associates. RESULTS: A total of 112 studies with 58,732 HCM patients were included. Among others, increased brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, late gadolinium enhancement (LGE), positive genotype, impaired global longitudinal strain, and presence of apical aneurysm conferred increased risk for the composite endpoint. At network meta-analysis, LGE showed the highest prognostic value for all endpoints and was superior to all other associates except New York Heart Association functional class >class II. A multiparametric imaging-based model was superior in predicting the composite endpoint compared to a prespecified model based on conventional risk factors. CONCLUSIONS: This network meta-analysis supports the development of multiparametric risk prediction algorithms, including advanced imaging markers additively to conventional risk factors, for refined risk stratification in HCM. (Long-term prognosis of hypertrophic cardiomyopathy according to genetic, clinical, biochemical and imaging findings: a systemic review and meta-analysis; CRD42020185219).

Efficacy and safety of transpancreatic sphincterotomy in endoscopic retrograde cholangiopancreatography: a retrospective cohort study.

Background: Difficult cannulation represents a common obstacle during endoscopic retrograde cholangiopancreatography (ERCP). We assessed the efficacy and adverse events of transpancreatic sphincterotomy (TPS), and investigated potential associated confounders. Methods: All patients referred to our department for ERCP during 2015-2020 were eligible if they had intact papilla and visceral anatomy. In addition to standard measures, TPS was combined with pancreatic stent placement. Apart from demographics, we retrieved data related to the indication, periampullary anatomy, necessity for TPS or fistulotomy, their outcomes and complications. Chi-square test was employed to investigate associations between TPS and independent variables. When significance was observed, the respective variables were inserted into a regression model. Results: A total of 1082 individual patients were eligible, with an equal female: male ratio and a mean age of 72.7±15.82 years. Seventy-three patients (6.7%) underwent TPS, with a 95.9% successful cannulation rate. Papilla morphology or regional diverticulum did not affect the decision to perform TPS, though it was significantly associated with malignant common bile duct (CBD) obstruction as the ERCP indication (P=0.001). Considering adverse events, TPS did not increase the incidence of post-ERCP pancreatitis (PEP), though it affected bleeding (P=0.005). Regression analysis revealed a protective role of TPS against PEP (risk ratio [RR] 0.015, 95% confidence interval [CI] 0.23-5.05; P<0.001), while the aforementioned risk of hemorrhage was attributed to previous precut attempts (RR 3.02, 95%CI 1.42-6.43; P=0.004). Conclusion: TPS combined with pancreatic stenting is an effective and safe modality in difficult cannulation cases and could be the first-choice alternative in malignant CBD obstruction.

Hierarchical true prevalence, risk factors and clinical symptoms of tuberculosis among suspects in Bangladesh.

BACKGROUND: The study was aimed to estimate the true prevalence of human tuberculosis (TB); identify risk factors and clinical symptoms of TB; and detect rifampicin (RIF) sensitivity in three study areas of Bangladesh. METHODS: The cross-sectional study was conducted in three Bangladesh districts during 2018. Potential risk factors, clinical symptoms, and comorbidities were collected from 684 TB suspects. Sputum specimens were examined by LED microscopy. TB hierarchical true prevalence, risk factors and clinical symptoms were estimated and identified using a Bayesian analysis framework. Rifampicin sensitivity of M. tuberculosis (MTB) was detected by GeneXpert MTB/RIF assay. RESULTS: The median TB true prevalence was 14.2% (3.8; 34.5). Although overall clustering of prevalence was not found, several DOTS centers were identified with high prevalence (22.3% to 43.7%). Risk factors for TB identified (odds ratio) were age (> 25 to 45 years 2.67 (1.09; 6.99), > 45 to 60 years 3.43 (1.38; 9.19) and individuals in families/neighborhoods where a TB patient(s) has (ve) already been present (12.31 (6.79; 22.60)). Fatigue, night sweat, fever and hemoptysis were identified as important clinical symptoms. Seven of the GeneXpert MTB/RIF positive sputum specimens (65) were resistant to rifampicin. CONCLUSIONS: About one in every seven TB suspects was affected with TB. A number of the TB patients carry multi drug resistant MTB. Hierarchical true prevalence estimation allowed identifying DOTS centers with high TB burden. Insights from this study will enable more efficient use of DOTScenters-based TB surveillance to end the TB epidemic in Bangladesh by 2035.

|tPRiors |: a tool for prior elicitation and obtaining posterior distributions of true disease prevalence.

BACKGROUND: Tests have false positive or false negative results, which, if not properly accounted for, may provide misleading apparent prevalence estimates based on the observed rate of positive tests and not the true disease prevalence estimates. Methods to estimate the true prevalence of disease, adjusting for the sensitivity and the specificity of the diagnostic tests are available and can be applied, though, such procedures can be cumbersome to researchers with or without a solid statistical background. This manuscript introduces a web-based application that integrates statistical methods for Bayesian inference of true disease prevalence based on prior elicitation for the accuracy of the diagnostic tests. This tool allows practitioners to simultaneously analyse and visualize results while using interactive sliders and output prior/posterior plots. METHODS - IMPLEMENTATION: Three methods for prevalence prior elicitation and four core families of Bayesian methods have been combined and incorporated in this web tool. |tPRiors| user interface has been developed with R and Shiny and may be freely accessed on-line. RESULTS: |tPRiors| allows researchers to use preloaded data or upload their own datasets and perform analysis on either single or multiple population groups clusters, allowing, if needed, for excess zero prevalence. The final report is exported in raw parts either as.rdata or.png files and can be further analysed. We utilize a real multiple-population and a toy single-population dataset to demonstrate the robustness and capabilities of |tPRiors|. CONCLUSIONS: We expect |tPRiors| to be helpful for researchers interested in true disease prevalence estimation and who are keen on accounting for prior information. |tPRiors| acts both as a statistical tool and a simplified step-by-step statistical framework that facilitates the use of complex Bayesian methods. The application of |tPRiors| is expected to aid standardization of practices in the field of Bayesian modelling on subject and multiple group-based true prevalence estimation.

The epidemic volatility index, a novel early warning tool for identifying new waves in an epidemic.

Early warning tools are crucial for the timely application of intervention strategies and the mitigation of the adverse health, social and economic effects associated with outbreaks of epidemic potential such as COVID-19. This paper introduces, the Epidemic Volatility Index (EVI), a new, conceptually simple, early warning tool for oncoming epidemic waves. EVI is based on the volatility of newly reported cases per unit of time, ideally per day, and issues an early warning when the volatility change rate exceeds a threshold. Data on the daily confirmed cases of COVID-19 are used to demonstrate the use of EVI. Results from the COVID-19 epidemic in Italy and New York State are presented here, based on the number of confirmed cases of COVID-19, from January 22, 2020, until April 13, 2021. Live daily updated predictions for all world countries and each of the United States of America are publicly available online. For Italy, the overall sensitivity for EVI was 0.82 (95% Confidence Intervals: 0.75; 0.89) and the specificity was 0.91 (0.88; 0.94). For New York, the corresponding values were 0.55 (0.47; 0.64) and 0.88 (0.84; 0.91). Consecutive issuance of early warnings is a strong indicator of main epidemic waves in any country or state. EVI's application to data from the current COVID-19 pandemic revealed a consistent and stable performance in terms of detecting new waves. The application of EVI to other epidemics and syndromic surveillance tasks in combination with existing early warning systems will enhance our ability to act swiftly and thereby enhance containment of outbreaks.

Atrial High-Rate Episode Duration Thresholds and Thromboembolic Risk: A Systematic Review and Meta-Analysis.

Background Available evidence supports an association between atrial high-rate episode (AHRE) burden and thromboembolic risk, but the necessary extent and duration of AHREs to increase the thromboembolic risk remain to be defined. The aim of this systematic review and meta-analysis was to identify the thromboembolic risk associated with various AHRE thresholds. Methods and Results We searched PubMed and Scopus until January 9, 2020, for literature reporting AHRE duration and thromboembolic risk in patients with implantable electronic devices. The outcome assessed was stroke or systemic embolism. Risk estimates were reported as hazard ratio (HR) or relative risk alongside 95% CIs. We used the Paule-Mandel estimator, and heterogeneity was calculated with I2 index. Among 27 studies including 61 919 patients, 23 studies reported rates according to the duration of the longest AHRE and 4 studies reported rates according to the cumulative day-level AHRE duration. In patients with cardiac implantable devices, AHREs lasting ≥30 seconds significantly increased the risk of stroke or systemic embolism (HR, 4.41; 95% CI, 2.32-8.39; I2, 5.5%), which remained consistent for the thresholds of 5 minutes and 6 and 24 hours. Patients with previous stroke or transient ischemic attack and AHREs lasting ≥2 minutes had a marginally increased risk of recurrent stroke or transient ischemic attack. The risk of stroke or systemic embolism was higher in patients with cumulative AHRE ≥24 hours compared with those of shorter duration or no AHRE (HR, 1.25; 95% CI, 1.04-1.52; I2, 0%). Conclusions This systematic review and meta-analysis suggests that single AHRE episodes ≥30 seconds and cumulative AHRE duration ≥24 hours are associated with increased risk of stroke or systemic embolism.

Wenckebach cycle length: A novel predictor for AV block in AVNRT patients treated with ablation.

BACKGROUND: Radiofrequency catheter ablation remains the most effective management option for atrioventricular nodal reentry tachycardia (AVNRT). The risk of atrioventricular (AV) block requiring permanent pacemaker is substantial, but, currently, a reliable method to predict this complication is lacking. METHODS: The electrophysiologic studies (EPS) and baseline characteristics of patients who underwent catheter ablation for the treatment of AVNRT were retrospectively analyzed to investigate predisposing factors for AV block after treatment. Patients were followed for AV block at one month and one year after hospital discharge. RESULTS: Among 784 patients treated with catheter ablation for AVNRT between 1999 to 2019, 15 developed AV block. Patients with AV block were older (p = .001). Among the recorded EPS parameters, patients with AV block had significantly higher Atrial His interval (120 vs. 110 ms, p = .049), Wenckebach cycle length (WCL) (400 vs. 353 ms, p < .001) and tachycardia CL (400 vs. 387 ms, P = .01) during the ablation compared to their peers without AV block. Additionally, only WCL (OR = 1.1, 95% CI 1.02-1.19, p = .017) remained significant after adjustment for age, gender, ERP, AH interval, and HR. This association was confirmed by comparing patients with (n = 15) and without (n = 15) AV block using propensity score-matching. A WCL≥400ms was associated with a 4-fold higher incidence of AV block (4.79% vs. 1.25%). CONCLUSION: Increased pre-procedural WCL was associated with a high risk for AV block after catheter ablation treatment for AVNRT. These findings suggest that this readily available EPS-derived parameter may be a novel marker of risk for severe complications in these patients.

Combined assessment of early and late-phase outcomes in orphan drug development.

In drug development programs, proof-of-concept Phase II clinical trials typically have a biomarker as a primary outcome, or an outcome that can be observed with relatively short follow-up. Subsequently, the Phase III clinical trials aim to demonstrate the treatment effect based on a clinical outcome that often needs a longer follow-up to be assessed. Early-phase outcomes or biomarkers are typically associated with late-phase outcomes and they are often included in Phase III trials. The decision to proceed to Phase III development is based on analysis of the early-Phase II outcome data. In rare diseases, it is likely that only one Phase II trial and one Phase III trial are available. In such cases and before drug marketing authorization requests, positive results of the early-phase outcome of Phase II trials are then likely seen as supporting (or even replicating) positive Phase III results on the late-phase outcome, without a formal retrospective combined assessment and without accounting for between-study differences. We used double-regression modeling applied to the Phase II and Phase III results to numerically mimic this informal retrospective assessment. We provide an analytical solution for the bias and mean square error of the overall effect that leads to a corrected double-regression. We further propose a flexible Bayesian double-regression approach that minimizes the bias by accounting for between-study differences via discounting the Phase II early-phase outcome when they are not in line with the Phase III biomarker outcome results. We illustrate all methods with an orphan drug example for Fabry disease.

A Bayesian meta-analysis on early tobacco exposure and vascular health: From childhood to early adulthood.

BACKGROUND: Smoking has been consistently associated with increased cardiovascular risk in adults. Although exposure to tobacco products often starts in early life, evidence for the possible adverse effects on the cardiovascular system of the young is scarce. We sought to derive pooled estimates of smoking effects on indices of early vascular damage in children and adolescents. DESIGN AND METHODS: We performed a systematic review and meta-analysis of clinical studies involving young individuals up to 21 years old that provided data on smoking exposure (active or passive) and flow-mediated dilatation, carotid to femoral pulse wave velocity and maximum carotid intima-media thickness. We employed three distinct methodologies of random-effects data synthesis, including the Sidik-Jonkman estimator, the Hartung and Knapp correction and a Bayesian method with a well-informed prior on the level of between-study variance. RESULTS: In 12 studies and 5279 individuals in total, smoking exposure was related to deterioration in all three outcomes (mean adjusted flow-mediated dilatation decrease: -0.77%, 95% confidence interval -1.38--0.15, mean adjusted pulse wave velocity increase: 0.1 m/s, 95% confidence interval 0.02-0.17 and mean adjusted carotid intima-media thickness increase: 0.35 mm, 95% confidence interval 0.16-0.55, for the Sidik-Jonkman estimator). No difference was established between active and passive smoking on associations with arterial damage. CONCLUSIONS: Exposure to tobacco products is associated with subclinical vascular damage early in life, even from childhood. Public health initiatives should target these very young age groups to prevent early smoking exposure and associated arterial damage and its sequelae.

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis.

BACKGROUND: Sacubitril/valsartan, vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). METHODS: We compared the treatment arms (sacubitril/valsartan, vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. RESULTS: There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and vericiguat. CONCLUSIONS: Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to vericiguat. REGISTRATION NUMBER: PROSPERO ID 186351.

Prior distributions for variance parameters in a sparse-event meta-analysis of a few small trials.

In rare diseases, typically only a small number of patients are available for a randomized clinical trial. Nevertheless, it is not uncommon that more than one study is performed to evaluate a (new) treatment. Scarcity of available evidence makes it particularly valuable to pool the data in a meta-analysis. When the primary outcome is binary, the small sample sizes increase the chance of observing zero events. The frequentist random-effects model is known to induce bias and to result in improper interval estimation of the overall treatment effect in a meta-analysis with zero events. Bayesian hierarchical modeling could be a promising alternative. Bayesian models are known for being sensitive to the choice of prior distributions for between-study variance (heterogeneity) in sparse settings. In a rare disease setting, only limited data will be available to base the prior on, therefore, robustness of estimation is desirable. We performed an extensive and diverse simulation study, aiming to provide practitioners with advice on the choice of a sufficiently robust prior distribution shape for the heterogeneity parameter. Our results show that priors that place some concentrated mass on small τ values but do not restrict the density for example, the Uniform(-10, 10) heterogeneity prior on the log(τ2 ) scale, show robust 95% coverage combined with less overestimation of the overall treatment effect, across varying degrees of heterogeneity. We illustrate the results with meta-analyzes of a few small trials.

Antithrombotic treatment in patients with stroke and supracardiac atherosclerosis.

OBJECTIVE: To compare the efficacy and safety of oral anticoagulants vs antiplatelets in patients with stroke and atherosclerotic plaques in the aortic arch or cervical or intracranial arteries, collectively described as supracardiac atherosclerosis. METHODS: We searched PubMed and Scopus until August 28, 2019, for randomized trials comparing oral anticoagulants vs antiplatelets in patients with stroke and supracardiac atherosclerosis using the terms "anticoagulant or anticoagulation" and "antiplatelet or aspirin" and "randomized controlled trial or RCT" and "stroke or cerebral ischemia" and "aortic or carotid or vertebrobasilar or intracranial or atherosclerosis or stenosis or arterial." Four outcomes were assessed: recurrent ischemic stroke, major ischemic event or death, major bleeding, and intracranial bleeding. Treatment effects (relative risk [RR] and 95% confidence interval [CI]) were estimated by meta-analysis using random-effects models. RESULTS: Among 1,117 articles identified in the literature search, results from 10 randomized controlled trials involving 6,068 patients with stroke/TIA with supracardiac atherosclerosis were included in the meta-analysis. Recurrent ischemic stroke rates were 2.94 per 100 patient-years in the anticoagulant-assigned patients vs 3.30 per 100 patient-years in the antiplatelet-assigned patients (RR, 0.91; 95% CI, 0.70-1.18 for the SJ estimator, I2 = 26%). Major ischemic event or death rates were 4.39 per 100 patient-years in anticoagulant-assigned patients vs 4.32 in antiplatelet-assigned patients (RR, 1.03; 95% CI, 0.79-1.35; I2 = 54.5%). Major bleeding rates were 2.88 per 100 patient-years in anticoagulant-assigned patients vs 0.82 in antiplatelet-assigned patients (RR, 3.21; 95% CI, 1.96-5.24; I2 = 46%). CONCLUSION: This systematic review and meta-analysis showed that anticoagulant-assigned patients with stroke and supracardiac atherosclerosis were not at different risk of ischemic stroke recurrence and increased risk of major bleeding compared to antiplatelet-assigned patients.

The Complex Relationship Between Serum Uric Acid, Endothelial Function and Small Vessel Remodeling in Humans.

AIMS: The relationship between serum uric acid (SUA) and microvascular remodeling in humans remains largely unexplored. We assessed whether SUA provides additional information on the severity of microvascular remodeling than that obtained from the European Heart Score (HS), the patterns of microvascular remodeling associated with changes in SUA levels and the mediation by endothelial function and nitric oxide (NO) availability on this relationship. METHODS: A total of 162 patients included in the microvascular dataset of the Italian Society of Hypertension with available information on SUA, media-to-lumen (M/L) ratio, media cross-sectional area (MCSA), endothelial function, NO availability and HS were included in the analysis. The top tertile of M/L ratio and MCSA were used to define severe microvascular remodeling. RESULTS: A U-shaped association was observed between SUA and both M/L ratio and MCSA. Adjustment for HS did not affect these associations. SUA was able to reclassify a significant number of subjects without, and with, severe M/L ratio and MCSA remodeling over the HS alone. The microvascular remodeling associated with SUA levels presented a predominant hypertrophic pattern. SUA was inversely associated with endothelial function and NO availability. Structural equation modeling analysis controlling for the HS suggested that the association of SUA with M/L ratio and MCSA was mediated through changes in endothelial function and NO availability. CONCLUSIONS: The addition of SUA to the HS improves the identification of subjects with greater microvascular remodeling. The relationship between SUA and microvascular remodeling is mediated by endothelial function and NO availability.

Antithrombotic Treatment in Cryptogenic Stroke Patients With Patent Foramen Ovale: Systematic Review and Meta-Analysis.

Background and Purpose- It is unclear whether treatment with anticoagulants or antiplatelets is the optimal strategy in patients with stroke or transient ischemic attack of undetermined cause and patent foramen ovale that is not percutaneously closed. We aimed to perform a systematic review and meta-analysis of randomized controlled trials to compare anticoagulant or antiplatelet treatment in this population. Methods- We searched PubMed until July 16, 2019 for trials comparing anticoagulants and antiplatelet treatment in patients with stroke/transient ischemic attack and medically treated patent foramen ovale using the terms: "cryptogenic or embolic stroke of undetermined source" and "stroke or cerebrovascular accident or transient ischemic attack" and "patent foramen ovale or patent foramen ovale or paradoxical embolism" and "trial or study" and "antithrombotic or anticoagulant or antiplatelet." The outcomes assessed were stroke recurrence, major bleeding, and the composite end point of stroke recurrence or major bleeding. We used 3 random-effects models: (1) a reference model based on the inverse variance method with the Sidik and Jonkman heterogeneity estimator; (2) a strict model, implementing the Hartung and Knapp method; and (3) a commonly used Bayesian model with a prior that assumes moderate to large between-study variance. Results- Among 112 articles identified in the literature search, 5 randomized controlled trials were included in the meta-analysis (1720 patients, mean follow-up 2.3±0.5 years). Stroke recurrence occurred at a rate of 1.73 per 100 patient-years in anticoagulant-assigned patients and 2.39 in antiplatelet-assigned patients (hazard ratio, 0.68; 95% CI, 0.32-1.48 for the Sidik and Jonkman estimator). Major bleeding occurred at a rate of 1.16 per 100 patient-years in anticoagulant-assigned patients and 0.68 in antiplatelet-assigned patients (hazard ratio, 1.61; 95% CI, 0.72-3.59 for the Sidik and Jonkman estimator). The composite outcome occurred in 52 anticoagulant-assigned and 54 antiplatelet-assigned patients (odds ratio, 1.05; 95% CI, 0.65-1.70 for the Sidik and Jonkman estimator). Conclusions- We cannot exclude a large reduction of stroke recurrence in anticoagulant-assigned patients compared with antiplatelet-assigned, without significant differences in major bleeding. An adequately powered randomized controlled trial of a non-vitamin K antagonist versus aspirin is warranted.