Predicting Thromboembolic and Bleeding Event Risk in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review

Ethan D Borre; Adam Goode; Giselle Raitz; Bimal Shah; Angela Lowenstern; Ranee Chatterjee; Lauren Sharan; Nancy M Allen LaPointe; Roshini Yapa; J Kelly Davis; Kathryn Lallinger; Robyn Schmidt; Andrzej Kosinski; Sana M Al-Khatib; Gillian D Sanders

doi:10.1055/s-0038-1675400

. Author manuscript; available in PMC: 2019 Dec 1.

Published in final edited form as: Thromb Haemost. 2018 Oct 30;118(12):2171–2187. doi: 10.1055/s-0038-1675400

Predicting Thromboembolic and Bleeding Event Risk in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review

Ethan D Borre ¹, Adam Goode ^1,⁷, Giselle Raitz ¹, Bimal Shah ^1,⁶, Angela Lowenstern ^2,⁵, Ranee Chatterjee ¹, Lauren Sharan ¹, Nancy M Allen LaPointe ^1,⁹, Roshini Yapa ¹⁰, J Kelly Davis ⁴, Kathryn Lallinger ^1,^2,³, Robyn Schmidt ^1,^2,³, Andrzej Kosinski ⁸, Sana M Al-Khatib ^2,⁵, Gillian D Sanders ^1,^2,^3,⁴

PMCID: PMC6754740 NIHMSID: NIHMS1049951 PMID: 30376678

Abstract

Background:

Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke. Medical therapy for decreasing stroke risk involves anticoagulation, which may increase bleeding risk for certain patients. In determining optimal therapy for stroke prevention for patients with AF, clinicians use tools with various clinical, imaging, and patient characteristics to weigh stroke risk against therapy-associated bleeding risk.

Aim:

Review published literature and summarize available risk stratification tools for stroke and bleeding prediction in patients with AF.

Methods:

We searched for English-language studies in PubMed^®, Embase^®, and the Cochrane Database of Systematic Reviews published between January 1, 2000, and February 14, 2018. Two reviewers screened citations for studies that examined tools for predicting thromboembolic and bleeding risks in patients with AF. Data regarding study design, patient characteristics, interventions, outcomes, quality and applicability were extracted.

Results:

61 studies were relevant to predicting thromboembolic risk and 38 to predicting bleeding risk. Data suggest that CHADS₂, CHA₂DS₂-VASc, and ABC risk scores have the best evidence predicting thromboembolic risk (moderate strength of evidence for limited prediction ability of each score) and that HAS-BLED has the best evidence for predicting bleeding risk (moderate strength of evidence).

Limitations:

Studies were heterogeneous in methodology and populations of interest, setting, interventions, and outcomes analyzed.

Conclusion:

CHADS₂, CHA₂DS₂-VASc, and ABC stroke have the best prediction for stroke events, and HAS-BLED provides the best prediction for bleeding risk. Future studies should define the role of imaging tools and biomarkers in enhancing the accuracy of risk prediction tools.

Primary Funding Source:

Patient-Centered Outcomes Research Institute (PROSPERO #CRD42017069999)

Keywords: nonvalvular atrial fibrillation, stroke risk, bleeding risk

INTRODUCTION

Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, occurring in up to 6.1 million people in the United States and accounting for approximately one-third of hospitalizations for cardiac rhythm disturbances.^1-3 Further, AF is associated with significant morbidity and mortality, including increased risk of embolic stroke, heart failure, and cognitive impairment; reduced quality of life; and higher overall mortality.^4-6

Optimal clinical management of AF is critical to reducing this associated morbidity and mortality, and includes prevention of AF-related thromboembolic events in at risk patients. Vitamin K antagonists or direct oral anticoagulants have been shown to reduce thromboembolic events, but long-term use of these medications puts certain patients at higher risk for serious bleeding events. As such, accurate risk stratification for both thromboembolic and bleeding risk is paramount in identifying patients for whom antithrombotic therapy would achieve maximum treatment benefit with the lowest risk of complications.

Unfortunately, it is challenging to estimate the tradeoff between stroke risk and risk of bleeding complications from long-term anticoagulation therapy because many risk factors for stroke are also associated with increased risk of bleeding. There are several available risk stratification tools used to determine thromboembolic and bleeding risk that incorporate diagnostic imaging as well as patient factors such as age, sex, and history of heart disease to aid in clinical decisionmaking around treatment strategies for AF. Of the many available risk stratification tools, the 2014 AHA/ACC/HRS guideline for patients with AF recommends the use of the CHADS2-VASc score to estimate the stroke risk and the HAS-BLED score for bleeding risk.^7-9 However, these risk scores have been previously categorized as poor to moderate predictors of risk, and are just two of many different published and validated methods for assessing stroke and bleeding risk in patients with AF. Because patients, providers, and policymakers have numerous decision tools that could inform treatment decisions and policy recommendations, there is a need for a compilation and analysis of the currently available data. This systematic review was commissioned by the Patient-Centered Outcomes Research Institute (PCORI) to update a 2013 Agency for Healthcare Research and Quality (AHRQ) review,¹⁰ with a focus on evaluating the comparative diagnostic accuracy and impact on clinical decisionmaking of available clinical and imaging tools and associated risk factors for predicting thromboembolic and bleeding risk in U.S. patients with AF. Our findings related to stroke prevention treatments are discussed in a companion paper.

METHODS

Methods for this updated comparative effectiveness review (CER) follow the AHRQ’s Methods Guide for Effectiveness and Comparative Effectiveness Reviews (hereafter referred to as the Methods Guide)¹¹ and Methods Guide for Medical Test Reviews (hereafter referred to as the Medical Test Guide).¹² This paper is part of the larger updated review; complete details of our methods, including exact search strings, and full results and conclusions can be found in the full report, available at www.efectivehealthcare.ahrq.gov.

Defining the Key Questions

PCORI convened two multi-stakeholder virtual workshops in December 2016 and January 2017 to (1) gather input from end users and clinical, content, and methodological experts on scoping for the updated review; (2) prioritize the key questions; (3) discuss changes in the evidence base since the 2013 review; and (4) explore emerging issues in AF. The protocol for this systematic review was informed by discussion at the January 2017 workshop and builds upon the original report. The final protocol for this review is posted on the Effective Healthcare (EHC) website (www.effectivehealthcare.ahrq.gov) and registered at PROSPERO (CRD42017069999).

In this paper we summarize the evidence and findings related to two key questions (KQs): (1) In patients with nonvalvular AF, what are the comparative diagnostic accuracy and impact on clinical decisionmaking (diagnostic thinking, therapeutic, and patient outcome efficacy) of available clinical and imaging tools and associated risk factors for predicting thromboembolic risk? and (2) In patients with nonvalvular AF, what are the comparative diagnostic accuracy and impact on clinical decisionmaking (diagnostic thinking, therapeutic, and patient outcome efficacy) of clinical tools and associated risk factors for predicting bleeding events?

Data Sources and Study Selection

In consultation with an expert medical librarian, we searched PubMed^®, Embase^®, and the Cochrane Database of Systematic Reviews for relevant literature published from August 1, 2011, to February 14, 2018 (exact search strings in Appendix Table 1). We supplemented electronic searches with a manual search of citations from a set of systematic review articles. Our findings were combined with those from the 2013 review, and so the literature summarized here reflects evidence back through January 1, 2000.¹⁰ Due to updates in inclusion criteria, any studies excluded from the original review were also re-reviewed for eligibility. We used search criteria to identify relevant ongoing clinical trials through ClinicalTrials.gov as well as citations to guide the conclusions (Appendix Table 1).

Our prespecified inclusion and exclusion criteria are in Appendix Table 2. We included English-language studies of adults with nonvalvular AF (including atrial flutter) that reported the efficacy of clinical or imaging tools, or patient risk factors, on predicting thromboembolic and/or bleeding outcomes. Clinical or imaging tools considered for predicting thromboembolic events were CHADS2 score, CHADS2-VASc score, Framingham risk score, ABC stroke score, transthoracic and transesophageal echocardiography, CT scans, and cardiac MRIs. Clinical or imaging tools considered for predicting bleeding events were HAS-BLED score, HEMORR2HAGES score, ATRIA score, Bleeding Risk Index (BRI), and ABC bleeding risk score. Thromboembolic outcomes included cerebrovascular infarction, transient ischemic attack (TIA), and systemic embolism (excluding pulmonary embolism and deep vein thrombosis). Bleeding outcomes included hemorrhagic stroke, intracranial hemorrhage (ICH), and major and minor bleeds. We excluded studies that evaluated patients exclusively from Asia, Africa, or the Middle East. We also sought to identify studies which used the same patients and linked these as companion papers to an individual study.

Data Extraction and Quality Assessment of Individual Studies

Pairs of investigators screened all citations and abstracts for eligibility, and those considered relevant by either investigator advanced to full-text review. Paired investigators then reviewed all full-text articles and resolved disagreements through discussion or adjudication by a third investigator. Paired investigators independently abstracted data and assessed study quality. Disagreements were resolved by consensus or arbitration by a third investigator. Articles that represented evidence from the same overall study were linked to avoid duplication of patient cohorts.

We assessed methodological quality, or risk of bias, for each individual study using tools specific to the study’s characteristics. For studies assessing diagnostic accuracy, we used the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool.¹³ Our outcome-specific quality assessment classified study outcomes as containing low, medium, or high risk of bias as defined by QUADAS-2.

Data Synthesis and Analysis

We summarized key features of the included studies for each key question, including information on study design; patient characteristics; clinical settings; diagnostic tools; and intermediate, final, and adverse event outcomes. We ordered our findings by diagnostic comparison, and then within these comparisons by outcome, with long-term final outcomes emphasized.

Grouping interventions by prediction tool, we determined the feasibility of completing a quantitative synthesis (i.e., meta-analysis) based on the volume of relevant literature (at least three appropriate studies), conceptual homogeneity of the studies in terms of study population and outcomes, and completeness of the reporting of results. When at least three comparable studies reported the same outcome, we used the R statistical package (version 3.1.2) (The R Foundation) with the “metafor” meta-analysis library (version 1.9-7) to synthesize available c-statistics, which quantify the discrimination ability of studied tools, for each appropriate thromboembolic or bleeding risk prediction tool. We used the random-effects DerSimonian and Laird estimator¹⁴ to generate summary values. In addition, we used the Knapp–Hartung approach to adjust the standard errors of the estimated coefficients. Since the diagnostic tools considered are not binary, it was not possible to consider summary receiver operating characteristic (ROC) curves. When possible, the c-statistics were pooled by considering their estimated values (point estimates) and confidence intervals, and the “generic point estimates” effect specification option in the Comprehensive Meta-Analysis software. For a clinical prediction rule, we assumed that a c-statistic <0.6 had no clinical value, 0.6–0.7 had limited value, 0.7–0.8 had modest value, and >0.8 had discrimination adequate for genuine clinical utility.¹⁵

Strength of Evidence

We assigned strength of evidence scores for each diagnostic tool using the approach described in the AHRQ’s Methods Guide.^11,16 We assessed five domains: study limitations; consistency; directness; precision; and reporting bias, which includes publication bias, outcome reporting, and analysis reporting bias. These domains were considered qualitatively, and a summary rating of high, moderate, or low strength of evidence was assigned for each outcome after independent assessment and discussion by two reviewers. In cases where ratings were impossible or imprudent to make, a grade of “insufficient” was assigned.

Role of the Funding Source

This topic was nominated and funded by PCORI for systematic review by an EPC in partnership with AHRQ. A representative from AHRQ served as a Contracting Officer’s Representative (COR) and provided technical assistance during the conduct of the full evidence report. The AHRQ COR and PCORI program officers provided comments on draft versions of the protocol and full evidence report. PCORI and AHRQ did not directly participate in the literature search; determination of study eligibility criteria; data analysis or interpretation; or preparation, review, or approval of the manuscript for publication.

RESULTS

We screened 11,274 publications and found 45 articles (25 studies) for KQ1 and 34 articles (18 studies) for KQ2 that investigated our included tools for determining stroke or bleeding risk in patients with nonvalvular AF and that met the other inclusion criteria. We combined these newly identified studies with those included in the 2013 review, yielding total of 83 articles (61 studies) for KQ1 and 57 articles (38 studies) for KQ2 included in this updated review (Figure 1). Complete results of the review, including long-term stroke and bleeding risk summaries, are in the full report.

Figure 1. — Abbreviation: KQ=Key QuestionFigure 2A.

Predicting Thromboembolic Risk in Patients with AF

We considered findings from the 61 studies reporting the predictive value of the CHADS₂, CHA₂DS₂-VASc, Framingham, and ABC stroke clinical tools for thromboembolic risk (Table 1). Twenty-nine studies directly compared the predictive ability for thromboembolic events of the CHADS2 risk score with other risk scores,^17-45 24 compared CHA₂DS₂-VASc,^{18-21,23,24,26,37,39-54} 6 compared Framingham,^{18,24,33,34,37,55} and 4 compared ABC stroke.^54,56-58 C-statistics for predicting thromboembolic risk, when available, are reported in Appendix Table 3. Sufficient data existed to permit meta-analysis of studies evaluating c-statistics for the CHADS₂ score using a continuous score (Figure 2A) and categorical score (Figure 2B), the CHA₂DS₂-VASc continuous score (Figure 2C) and categorical score (Figure 2D), the Framingham categorical score (Figure 2E), and the ABC stroke categorical score (Figure 2F). For both the continuous and categorical CHADS₂ scores (continuous: 14 studies with 489,335 patients; categorical: 16 studies, 548,464 patients; Table 2A), there was moderate strength of evidence that the scores provide limited prediction of stroke events (continuous: c-statistic of 0.69; 95% CI 0.66 to 0.73; categorical: c-statistic of 0.66; 95% CI 0.63 to 0.69). There was also moderate strength of evidence (16 studies, 511,481 patients) that the continuous CHA₂DS₂-VASc score provides limited prediction of stroke events (c-statistic of 0.66; 95% CI 0.63 to 0.69). For the categorical CHA₂DS₂-VASc score (13 studies, 496,683 patients), there was low strength evidence of its ability to predict stroke risk (c-statistic of 0.64; 95% CI 0.58 to 0.70. Based on a meta-analysis of 6 studies (282,572 patients), we found moderate strength of evidence that the categorical Framingham score provides limited prediction of stroke events (c-statistic of 0.63; 95% CI 0.62 to 0.65). For the categorical ABC score (4 studies, 25,614 patients), we found a moderate strength of evidence of limited prediction of stroke events (c-statistic of 0.67; 95% CI 0.63 to 0.71) (Table 2A).

Table 1.

Description and Interpretation of Included Risk Scores

Thromboembolic Risk Score	Reference	Risk Factors Included	Interpretation
CHADS₂	Gage, 2001³⁵	Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, prior Stroke/transient ischemic attack [2 points]	Low (0), moderate (1-2), high (3-6)
CHA₂DS₂-VASc	Lip, 2010³⁷	Congestive heart failure/left ventricular ejection fraction ≤ 40%, Hypertension, Age ≥75 [2 points], Diabetes mellitus, prior Stroke/transient ischemic attack/thromboembolism [2 points], Vascular disease, Age 65–74, Sex category female	Low (0), moderate (1), high (2-9)
Framingham		Advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes
ABC	Hijazi, 2016⁹³	Age, Biomarkers (cTnI-hs and NT-proBNP), and Clinical history (prior stroke/TIA)	Low <1%, moderate 1%-2%, high >2%
Bleeding Risk Score	Reference	Risk Factors Included	Interpretation
ABC	Hijazi, 2016⁹³	Age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]	Low <1%, medium 1-2%, high >2%
ATRIA	Fang, 2011⁷⁶	Anemia, renal disease (CrCl <30) (3 points each); age ≥75 (2 points); any prior bleeding, hypertension (1 point each)	Low (0-3), moderate (4), high (5-10)
BRI	Beyth, 1998¹⁰⁹	Age ≥65, GI bleed in past 2 weeks, previous stroke, comorbidities (recent MI, hematocrit <30%,diabetes, creatinine >1.5), with 1 point for presence of each condition and 0 if absent	Low (0), moderate (1-2), high (3-4)
HAS-BLED	Pisters, 2010⁹	Hypertension, abnormal renal (CrCl <50) or liver function (1 point each); stroke, bleeding history or predisposition, labile INR (TTR <60%), age >65, drugs of interest/alcohol (1 point each)	Low (0), moderate (1-2), high (≥3)
HEMORR₂HAGES	Gage, 2006⁷⁹	Liver/renal disease, ethanol abuse, malignancy, age >75, low platelet count or function, re-bleeding risk, uncontrolled hypertension, anemia, genetic factors (CYP2C9), risk of fall or stroke (1 point for each risk factor present with 2 points for previous bleed)	Low (0-1), moderate (2-3), high (≥4)

Outcome	Number of Studies (Subjects)	Risk of Bias	Consistency	Directness	Precision	SOE and Effect (95% CI)
CHADS₂ (Categorical)	16 (548,464)	Observational/Moderate	Inconsistent	Direct	Precise	SOE=Moderate Limited risk prediction ability (c-statistics 0.66, 95% CI 0.63 to 0.69)
CHADS₂ (Continuous)	14 (489,335)	Observational/Moderate	Inconsistent	Direct	Precise	SOE=Moderate Limited risk prediction ability (c-statistic=0.69; 95% CI 0.66 to 0.73)
CHA₂DS₂-VASc (Categorical)	13 (496,683)	Observational/Moderate	Inconsistent	Direct	Imprecise	SOE=Low Limited risk prediction ability (c-statistic=0.64; 95% CI 0.58 to 0.70)
CHA₂DS₂-VASc (Continuous)	16 (511,481)	Observational/Moderate	Inconsistent	Direct	Precise	SOE=Moderate Limited risk prediction ability (c-statistic=0.66; 95% CI 0.63 to 0.69)
Framingham (Categorical)	6 (282,572)	Observational/Moderate	Consistent	Direct	Precise	SOE=Moderate Limited risk prediction ability (c-statistic=0.63; 95% CI 0.62 to 0.65)
Framingham (Continuous)	4 (274,538)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Low Limited risk prediction ability (c-statistic ranges between 0.64 and 0.69 across studies)
ABC (Categorical)	4 (25,614)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Moderate Limited risk prediction ability (c-statistic=0.67; 95% CI 0.63 to 0.71)
Imaging Risk Tools	7 (4,962)	Observational/Moderate	Inconsistent	Direct	Imprecise	SOE=Insufficient

Outcome	Number of Studies (Subjects)	Risk of Bias	Consistency	Directness	Precision	SOE and Effect (95% CI)
Summary c-statistic (Patients on Warfarin)
BRI	4 (11,939)	Observational/Moderate	Consistent	Direct	Precise	SOE=Moderate Limited risk discrimination ability (c-statistic ranging from 0.56 to 0.65)
HEMORR₂HAGES	10 (115,348)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Moderate Limited risk discrimination ability (c-statistic ranging from 0.53 to 0.78)
HAS-BLED	11 (194,839)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Moderate Modest risk discrimination ability (c-statistic ranging from 0.50 to 0.80)
ATRIA	7 (76,163)	Observational/Moderate	Inconsistent	Direct	Imprecise	SOE=Insufficient
ABC	1 (22,998)	Observational/Moderate	NA	Direct	Precise	SOE=Low Limited risk discrimination (c-statistic of 0.65 in validation study)
Comparative Risk Discrimination Abilities
Major bleeding events among patients with AF on warfarin	13 (351,985)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Moderate Favors HAS-BLED
Intracranial hemorrhage among patients with AF on warfarin	2 (71,597)	Observational/Moderate	NA	Direct	Precise	SOE=Low No evidence of a difference
Major bleeding events among patients with AF on aspirin alone	3 (177,538)	Observational/Moderate	Inconsistent	Direct	Imprecise	SOE=Low No evidence of a difference
Major bleeding events among patients with AF not on antithrombotic therapy	6 (310,607)	Observational/Moderate	Consistent	Direct	Imprecise	SOE=Low No evidence of a difference

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR "Atrial Flutter"[Mesh] OR "atrial flutter"[tiab]
#2	"Cerebrovascular Disorders"[Majr:NoExp] OR "Stroke"[Mesh] OR "Thromboembolism"[Mesh] OR "Hemorrhage"[Mesh:NoExp] OR "Intracranial Hemorrhages"[Mesh] OR "Brain Ischemia"[Mesh] OR "Prothrombin Time"[Mesh] OR stroke[tiab] OR strokes[tiab] OR thromboembolism[tiab] OR thromboembolisms[tiab] OR thromboembolic[tiab] OR thromboses[tiab] OR hemorrhage[tiab] OR hemorrhages[tiab] OR hemorrhaging[tiab] OR hemorrhagic[tiab] OR haemorrhage[tiab] OR haemorrhages[tiab] OR haemorrhaging[tiab] OR haemorrhagic[tiab] OR (("bleeding"[tiab] OR bleed[tiab] OR bleeds[tiab]) AND (major[tiab] OR risk[tiab] OR event[tiab])) OR ((Systemic[tiab] OR paradoxical[tiab] OR crossed[tiab]) AND (embolism[tiab] OR embolisms[tiab])) OR ((brain[tiab] OR cerebral[tiab] OR brainstem[tiab] OR "brain stem"[tiab]) AND (ischemia[tiab] OR ischaemia[tiab] OR ischemias[tiab] OR ischaemias[tiab] OR infarction[tiab] OR infarctions[tiab])) OR (transient[tiab] AND (ischemic[tiab] OR ischaemic[tiab] OR ischaemia[tiab] OR ischemia[tiab]) AND (attack[tiab] OR attacks[tiab])) OR TIA[tiab] OR TIAs[tiab] OR "cerebrovascular accident"[tiab] OR "cerebrovascular accidents"[tiab] OR CVA[tiab] OR CVAs[tiab] OR "brain vascular accident"[tiab] OR "brain vascular accidents"[tiab]
#3	"Risk"[Mesh] OR risk[tiab] OR risks[tiab] OR "Predictive Value of Tests"[Mesh] OR predict[tiab] OR predicts[tiab] OR predicting[tiab] OR predictor[tiab] OR predictors[tiab] OR predictive[tiab]
#4	#1 AND #2 AND #3
#5	#4 NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])
#6	#5 NOT ("Animals"[MeSH Terms] NOT "Humans"[MeSH Terms])
#7	#6 NOT (("Adolescent"[Mesh] OR "Child"[Mesh] OR "Infant"[Mesh]) NOT "Adult"[Mesh])
#8	"Randomized Controlled Trial"[Publication Type] OR "Controlled Clinical Trial"[Publication Type] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR "Clinical Trial"[Publication Type] OR "clinical trial"[tiab] OR "clinical trials"[tiab] OR "Evaluation Studies"[Publication Type] OR "Evaluation Studies as Topic"[MeSH Terms] OR "evaluation study"[tiab] OR "evaluation studies"[tiab] OR "intervention study"[tiab] OR "intervention studies"[tiab] OR "Case-control Studies"[MeSH Terms] OR "case-control"[tiab] OR "Cohort Studies"[Mesh Terms] OR cohort[tiab] OR "Longitudinal Studies"[MeSH Terms] OR longitudinal[tiab] OR longitudinally[tiab] OR "Prospective Studies"[Mesh Terms] OR "prospective"[tiab] OR prospectively[tiab] OR "Retrospective Studies"[MeSH Terms] OR "retrospective"[tiab] OR "Follow-Up Studies"[Mesh Terms] OR "follow up"[tiab] OR "Comparative Study"[Publication Type] OR "comparative study"[tiab] OR systematic[subset] OR "systematic review"[tiab] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tiab] OR "meta-analyses"[tiab] OR "meta synthesis"[tiab] OR "meta syntheses"[tiab] OR "Multicenter Study"[Publication Type] OR "Multicenter Study"[tiab] OR multicentre[tiab] OR "Registries"[Mesh Terms] OR registry[tiab] OR registries[tiab] OR "Sensitivity and Specificity"[Mesh] OR Sensitivity[tiab] OR specificity[tiab] OR valid[tiab] OR validity[tiab] OR validation[tiab] OR "validation studies"[publication type]
#9	#7 AND #8
#10	#9 AND ("2011/08/01"[Date - Publication] : "3000"[Date - Publication])

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR (atrial[tiab] AND fibrillation[tiab]) OR afib[tiab] OR "atrial flutter"[MeSH Terms] OR "atrial flutter"[tiab]
#2	chads2[tw] OR chads2-vasc[tw] OR "Magnetic Resonance Imaging"[Mesh] OR MRI[tw] OR "Cardiac Imaging Techniques"[Mesh] OR "Tomography, X-Ray Computed"[Mesh] OR "Echocardiography"[Mesh] OR ((transthoracic[tw] OR transesophageal[tw]) AND echo[tw]) OR TTE[tw] OR TEE[tw] OR CT-scan[tw]
#3	"Stroke"[Mesh] OR stroke[tw] OR thromboembolism[tw] OR "Thromboembolism"[Mesh] OR thromboembolic[tw] OR "brain ischemia"[MeSH Terms] OR (brain[tw] AND ischemia[tw]) OR (brain[tw] AND ischaemia[tw]) OR (transient[tw] AND (ischemic[tw] OR ischaemic[tw] OR ischaemia[tw] OR ischemia[tw]) AND attack[tw]) OR TIA[tw]
#4	#1 AND #2 AND #3
#5	(("diagnosis"[Subheading] OR "diagnosis"[tiab] OR "diagnosis"[MeSH Terms]) OR "treatment outcome"[MeSH Terms] OR outcome[tiab] OR outcomes[tiab]) OR (reliability[tw] OR accuracy[tw] OR accurate[tw] OR Sensitivity[tw] OR specificity[tw] OR "Sensitivity and Specificity"[Mesh] OR valid[tw] OR validity[tw] OR validation[tw] OR decision[tw] OR decisions[tw] OR "decision making"[MeSH Terms] OR assessment[tw])
#6	#5 AND #4
#7	#6 NOT (animals[mh] NOT humans[mh]), Limits: English, Publication Date from 2000 to present

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR (atrial[tiab] AND fibrillation[tiab]) OR afib[tiab] OR "atrial flutter"[MeSH Terms] OR "atrial flutter"[tiab]
#2	"Age Factors"[Mesh] OR "Dementia"[Mesh] OR "Accidental Falls"[Mesh] OR "International Normalized Ratio"[Mesh] OR age[tiab] OR dementia[tiab] OR INR[tiab] OR fall[tiab] OR falls[tiab] OR "international normalized ratio"[tiab] OR paroxysmal[tiab] OR persistent[tiab] OR permanent[tiab] OR stratification[tiab] OR classification[tiab] OR schema[tiab] OR has-bled[tiab] OR (cognitive[tw] AND impairment[tw]) OR cognition[tw] OR ((prior[tiab] OR previous[tiab] OR first[tiab]) AND stroke[tiab])
#3	"Intracranial Hemorrhages"[Mesh] OR "Hemorrhage"[Mesh:noexp] OR hemorrhage[tw] OR hemorrhaging[tw] OR bleeding[tw] OR bleed[tw] OR hemorrhagic[tw] OR haemorrhage[tw] OR haemorrhaging[tw] OR haemorrhagic[tw]
#4	#1 AND #2 AND #3
#5	(("diagnosis"[Subheading] OR "diagnosis"[tiab] OR "diagnosis"[MeSH Terms]) OR "treatment outcome"[MeSH Terms] OR outcome[tiab] OR outcomes[tiab]) OR (reliability[tw] OR accuracy[tw] OR accurate[tw] OR Sensitivity[tw] OR specificity[tw] OR "Sensitivity and Specificity"[Mesh] OR valid[tw] OR validity[tw] OR validation[tw] OR decision[tw] OR decisions[tw] OR "decision making"[MeSH Terms] OR assessment[tw])
#6	#5 AND #4
#7	#6 NOT (animals[mh] NOT humans[mh]), Limits: English, Publication Date from 2000 to present

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR (atrial[tiab] AND fibrillation[tiab]) OR afib[tiab] OR "atrial flutter"[MeSH Terms] OR "atrial flutter"[tiab]
#2	"Anticoagulants"[Mesh] OR "Anticoagulants"[Pharmacological Action] OR warfarin[tw] OR "Warfarin"[Mesh] OR coumadin[tw] OR "Vitamin K/antagonists and inhibitors"[Mesh] OR vitamin k[tw] OR "Heparin"[Mesh] OR "Enoxaparin"[Mesh] OR enoxaparin[tw] OR lovenox[tw] OR "rivaroxaban" [Supplementary Concept] OR rivaroxaban[tw] OR xarelto[tw] OR "dabigatran etexilate" [Supplementary Concept] OR dabigatran[tw] OR pradaxa[tw] OR heparin[tw] OR "apixaban" [Supplementary Concept] OR apixaban[tw] OR eliquis[tw] OR "edoxaban" [Supplementary Concept] OR edoxaban[tw] OR lixiana[tw]
#3	"Platelet Aggregation Inhibitors"[Mesh] OR "Platelet Aggregation Inhibitors"[Pharmacological Action] OR "clopidogrel" [Supplementary Concept]OR clopidogrel[tw] OR plavix[tw] OR "Aspirin"[Mesh] OR aspirin[tw] OR "Dipyridamole"[Mesh] OR dipyridamole[tw] OR aggrenox[tw] OR persantine[tw] OR antiplatelet[tw] OR anti-platelet[tw] OR antiplatelets[tw] OR anti-platelets[tw]
#4	Atrial Appendage/surgery[mesh] OR atrial appendage[tw] OR LAA[tw] OR occluder[tw] OR AMPLATZER[tw] OR AtriClip[tw] OR PLAATO[tw] OR Watchman[tw] OR (atrial[tw] AND modification[tw]) OR "atriacure isolator"[tw]
#5	"Stroke"[Mesh] OR stroke[tw] OR thromboembolism[tw] OR "Thromboembolism"[Mesh] OR thromboembolic[tw] OR "brain ischemia"[MeSH Terms] OR (brain[tw] AND ischemia[tw]) OR (brain[tw] AND ischaemia[tw]) OR (transient[tw] AND (ischemic[tw] OR ischaemic[tw] OR ischaemia[tw] OR ischemia[tw]) AND attack[tw]) OR TIA[tw]
#6	#1 AND (#2 OR #3 OR #4) AND #5
#7	"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])
#8	#7 AND #6
#9	#8 NOT (animals[mh] NOT humans[mh]), Limits: English, Publication Date from 2000 to present

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR (atrial[tiab] AND fibrillation[tiab]) OR afib[tiab] OR "atrial flutter"[MeSH Terms] OR "atrial flutter"[tiab]
#2	"Anticoagulants"[Mesh] OR "Anticoagulants"[Pharmacological Action] OR warfarin[tw] OR "Warfarin"[Mesh] OR coumadin[tw] OR "Vitamin K/antagonists and inhibitors"[Mesh] OR vitamin k[tw] OR "Heparin"[Mesh] OR "Enoxaparin"[Mesh] OR enoxaparin[tw] OR lovenox[tw] OR "rivaroxaban" [Supplementary Concept] OR rivaroxaban[tw] OR xarelto[tw] OR "dabigatran etexilate" [Supplementary Concept] OR dabigatran[tw] OR pradaxa[tw] OR heparin[tw] OR "apixaban" [Supplementary Concept] OR apixaban[tw] OR eliquis[tw] OR "edoxaban" [Supplementary Concept] OR edoxaban[tw] OR lixiana[tw]
#3	"Surgical Procedures, Operative"[Mesh] OR /surgery[mesh] OR ((surgical[tw] OR invasive[tw]) AND (procedure[tw] OR procedures[tw])) OR "dental care"[MeSH Terms] OR (dental[tw] AND (procedure[tw] OR procedures[tw])) OR surgery[tw] OR procedures[tiab] OR procedure[tiab]
#4	#1 AND #2 AND #3
#5	"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])
#6	#5 AND #4
#7	#7 NOT (animals[mh] NOT humans[mh]), Limits: English, Publication Date from 2000 to present

#1	"Atrial Fibrillation"[Mesh] OR "atrial fibrillation"[tiab] OR (atrial[tiab] AND fibrillation[tiab]) OR afib[tiab] OR "atrial flutter"[MeSH Terms] OR "atrial flutter"[tiab]
#2	"warfarin"[MeSH Terms] OR warfarin[tw] OR coumadin[tw]
#3	"antithrombins"[MeSH Terms] OR "antithrombins"[tiab] OR ("direct"[tiab] AND "thrombin"[tiab] AND "inhibitors"[tiab]) OR "direct thrombin inhibitors"[tiab] OR "antithrombins"[Pharmacological Action]
#4	"Anticoagulants"[Mesh] OR "Anticoagulants" [Pharmacological Action] OR anticoagulant[tiab] OR anticoagulants[tiab]
#5	"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])
#6	#1 AND #2 AND (#3 OR #4) AND #5
#7	#6 NOT (animals[mh] NOT humans[mh]), Limits: English, Publication Date from 2000 to present

#1	'atrial fibrillation'/exp OR 'heart atrium flutter'/exp OR 'atrial fibrillation':ab,ti OR 'atrial flutter':ab,ti
#2	'cerebrovascular disease'/de OR 'cerebrovascular accident'/exp OR 'thromboembolism'/exp OR 'bleeding'/de OR 'brain hemorrhage'/exp OR 'brain ischemia'/exp OR 'prothrombin time'/exp OR stroke:ab,ti OR strokes:ab,ti OR thromboembolism:ab,ti OR thromboembolisms:ab,ti OR thromboembolic:ab,ti OR thromboses:ab,ti OR hemorrhage:ab,ti OR hemorrhages:ab,ti OR hemorrhaging:ab,ti OR hemorrhagic:ab,ti OR haemorrhage:ab,ti OR haemorrhages:ab,ti OR haemorrhaging:ab,ti OR haemorrhagic:ab,ti OR ((bleeding OR bleed OR bleeds) NEAR/2 (major OR risk OR event)):ab,ti OR ((systemic OR paradoxical OR crossed) NEXT/2 (embolism OR embolisms)):ab,ti OR ((brain OR cerebral OR brainstem OR 'brain stem') NEXT/2 (ischemia OR ischaemia OR ischemias OR ischaemias OR infarction OR infarctions)):ab,ti OR (transient NEXT/2 (ischemic OR ischaemic OR ischaemia OR ischemia) NEXT/2 (attack OR attacks)):ab,ti OR tia:ab,ti OR tias:ab,ti OR 'cerebrovascular accident':ab,ti OR 'cerebrovascular accidents':ab,ti OR cva:ab,ti OR cvas:ab,ti OR 'brain vascular accident':ab,ti OR 'brain vascular accidents':ab,ti
#3	'risk'/exp OR risk:ab,ti OR risks:ab,ti OR 'prediction and forecasting'/exp OR predict:ab,ti OR predicts:ab,ti OR predicting:ab,ti OR predictor:ab,ti OR predictors:ab,ti OR predictive:ab,ti
#4	#1 AND #2 AND #3
#5	#4 NOT ('case report'/exp OR 'case study'/exp OR 'a case report':ti OR ': case report':ti OR 'editorial'/exp OR 'letter'/exp OR 'note'/exp OR [conference abstract]/lim)
#6	#5 AND [humans]/lim
#7	#6 NOT (('adolescent'/exp OR 'child'/exp) NOT 'adult'/exp)
#8	'clinical trial'/exp OR 'clinical study'/exp OR 'controlled study'/exp OR randomized:ab,ti OR randomised:ab,ti OR randomization:ab,ti OR randomisation:ab,ti OR randomly:ab,ti OR placebo:ab,ti OR trial:ab,ti OR groups:ab,ti OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR crossover:ab,ti OR (cross NEXT/1 over):ab,ti OR 'clinical trial':ab,ti OR 'clinical trials':ab,ti OR 'clinical study':ab,ti OR 'clinical studies':ab,ti OR 'evaluation study'/exp OR 'evaluation study':ab,ti OR 'evaluation studies':ab,ti OR 'intervention study':ab,ti OR 'intervention studies':ab,ti OR 'case-control':ab,ti OR 'cohort analysis'/exp OR cohort:ab,ti OR longitudinal:ab,ti OR longitudinally:ab,ti OR 'prospective':ab,ti OR prospectively:ab,ti OR 'retrospective':ab,ti OR 'follow up'/exp OR 'follow up':ab,ti OR 'comparative study'/exp OR 'comparative study':ab,ti OR 'comparative studies':ab,ti OR 'systematic review':ab,ti OR 'meta-analysis':ab,ti OR 'meta-analyses':ab,ti OR 'meta synthesis':ab,ti OR 'meta syntheses':ab,ti OR 'survival analysis'/exp OR 'multicenter study'/exp OR 'multicenter study':ab,ti OR multicentre:ab,ti OR 'register'/exp OR registry:ab,ti OR registries:ab,ti OR 'sensitivity and specificity'/exp OR sensitivity:ab,ti OR specificity:ab,ti OR valid:ab,ti OR validity:ab,ti OR validation:ab,ti OR 'validation study'/exp
#9	#7 AND #8
#10	#9 AND [1-8-2011]/sd
#11	#10 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'nuclear magnetic resonance imaging'/exp OR 'cardiac imaging'/exp OR 'computer assisted tomography'/exp OR 'echocardiography'/exp OR chads2:ab,ti OR 'chads2 vasc':ab,ti OR (transthoracic:ab,ti AND echo:ab,ti) OR (transesophageal:ab,ti AND echo:ab,ti) OR tte:ab,ti OR tee:ab,ti OR 'ct scan':ab,ti
#3	'stroke'/exp OR 'thromboembolism'/exp OR 'brain ischemia'/exp OR stroke:ab,ti OR thromboembolism:ab,ti OR thromboembolic:ab,ti OR (brain:ab,ti AND ischemia:ab,ti) OR (brain:ab,ti AND ischaemia:ab,ti) OR (transient:ab,ti AND (ischemic:ab,ti OR ischaemic:ab,ti OR ischaemia:ab,ti OR ischemia:ab,ti) AND attack:ab,ti) OR TIA:ab,ti
#4	#1 AND #2 AND #3
#5	'diagnosis'/exp OR 'treatment outcome'/exp OR 'sensitivity and specificity'/exp OR 'clinical decision making'/exp OR 'decision making'/exp OR diagnosis:ab,ti OR outcome:ab,ti OR outcomes:ab,ti OR reliability:ab,ti OR accuracy:ab,ti OR accurate:ab,ti OR Sensitivity:ab,ti OR specificity:ab,ti OR valid:ab,ti OR validity:ab,ti OR validation:ab,ti OR decision:ab,ti OR decisions:ab,ti OR assessment:ab,ti
#6	#5 AND #4
#7	#6 Limits: Humans, English, 2000 - present
#8	#7 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'anticoagulant agent'/exp OR 'warfarin'/exp OR 'vitamin K group'/exp OR 'heparin'/exp OR 'enoxaparin'/exp OR 'rivaroxaban'/exp OR 'dabigatran etexilate'/exp OR 'apixaban'/exp OR 'edoxaban'/exp
#3	warfarin:ab,ti OR coumadin:ab,ti OR vitamin k:ab,ti OR enoxaparin:ab,ti OR lovenox:ab,ti OR rivaroxaban:ab,ti OR xarelto:ab,ti OR dabigatran:ab,ti OR pradaxa:ab,ti OR heparin:ab,ti OR apixaban:ab,ti OR eliquis:ab,ti OR edoxaban:ab,ti OR lixiana:ab,ti
#4	#2 OR #3
#5	'antithrombocytic agent'/exp OR 'clopidogrel'/exp OR 'acetylsalicylic acid'/exp OR 'dipyridamole'/exp OR clopidogrel:ab,ti OR plavix:ab,ti OR aspirin:ab,ti OR dipyridamole:ab,ti OR aggrenox:ab,ti OR persantine:ab,ti OR antiplatelet:ab,ti OR anti-platelet:ab,ti OR antiplatelets:ab,ti OR anti-platelets:ab,ti
#6	'heart atrium appendage'/exp OR atrial appendage:ab,ti OR LAA:ab,ti OR occluder:ab,ti OR AMPLATZER:ab,ti OR AtriClip:ab,ti OR PLAATO:ab,ti OR Watchman:ab,ti OR (atrial:ab,ti AND modification:ab,ti) OR “atriacure isolator”:ab,ti
#7	'stroke'/exp OR 'thromboembolism'/exp OR 'brain ischemia'/exp OR stroke:ab,ti OR thromboembolism:ab,ti OR thromboembolic:ab,ti OR (brain:ab,ti AND ischemia:ab,ti) OR (brain:ab,ti AND ischaemia:ab,ti) OR (transient:ab,ti AND (ischemic:ab,ti OR ischaemic:ab,ti OR ischaemia:ab,ti OR ischemia:ab,ti) AND attack:ab,ti) OR TIA:ab,ti
#8	#1 AND (#4 OR #5 OR #6) AND #7
#9	('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR random:ab,ti OR factorial:ab,ti OR crossover:ab,ti OR (cross NEAR/1 over):ab,ti OR placebo:ab,ti OR (doubl NEAR/1 blind):ab,ti OR (singl NEAR/1 blind):ab,ti OR assign:ab,ti OR allocat:ab,ti OR volunteer:ab,ti OR 'clinical study'/exp OR “clinical trial”:ti,ab OR “clinical trials”:ti,ab OR 'controlled study'/exp OR 'evaluation'/exp OR “evaluation study”:ab,ti OR “evaluation studies”:ab,ti OR “intervention study”:ab,ti OR “intervention studies”:ab,ti OR “case control”:ab,ti OR 'cohort analysis'/exp OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR retrospective:ab,ti OR 'follow up'/exp OR “follow up”:ab,ti OR 'comparative effectiveness'/exp OR 'comparative study'/exp OR “comparative study”:ab,ti OR “comparative studies”:ab,ti OR 'evidence based medicine'/exp OR “systematic review”:ab,ti OR “meta-analysis”:ab,ti OR “meta-analyses”:ab,ti) NOT ('editorial'/exp OR 'letter'/exp OR 'case report'/exp)
#10	#8 AND #9
#11	#10 Limits: Humans, English, 2000 - present
#12	#11 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'anticoagulant agent'/exp OR 'warfarin'/exp OR 'vitamin K group'/exp OR 'heparin'/exp OR 'enoxaparin'/exp OR 'rivaroxaban'/exp OR 'dabigatran etexilate'/exp OR 'apixaban'/exp OR 'edoxaban'/exp
#3	warfarin:ab,ti OR coumadin:ab,ti OR vitamin k:ab,ti OR enoxaparin:ab,ti OR lovenox:ab,ti OR rivaroxaban:ab,ti OR xarelto:ab,ti OR dabigatran:ab,ti OR pradaxa:ab,ti OR heparin:ab,ti OR apixaban:ab,ti OR eliquis:ab,ti OR edoxaban:ab,ti OR lixiana:ab,ti
#4	#2 OR #3
#5	'surgery'/exp OR 'dental care'/exp OR ((surgical:ab,ti OR invasive:ab,ti) AND (procedure:ab,ti OR procedures:ab,ti)) OR (dental:ab,ti AND (procedure:ab,ti OR procedures:ab,ti)) OR surgery:ab,ti OR procedures:ab,ti OR procedure:ab,ti
#6	#1 AND #4 AND #5
#7	('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR random:ab,ti OR factorial:ab,ti OR crossover:ab,ti OR (cross NEAR/1 over):ab,ti OR placebo:ab,ti OR (doubl NEAR/1 blind):ab,ti OR (singl NEAR/1 blind):ab,ti OR assign:ab,ti OR allocat:ab,ti OR volunteer:ab,ti OR 'clinical study'/exp OR “clinical trial”:ti,ab OR “clinical trials”:ti,ab OR 'controlled study'/exp OR 'evaluation'/exp OR “evaluation study”:ab,ti OR “evaluation studies”:ab,ti OR “intervention study”:ab,ti OR “intervention studies”:ab,ti OR “case control”:ab,ti OR 'cohort analysis'/exp OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR retrospective:ab,ti OR 'follow up'/exp OR “follow up”:ab,ti OR 'comparative effectiveness'/exp OR 'comparative study'/exp OR “comparative study”:ab,ti OR “comparative studies”:ab,ti OR 'evidence based medicine'/exp OR “systematic review”:ab,ti OR “meta-analysis”:ab,ti OR “meta-analyses”:ab,ti) NOT ('editorial'/exp OR 'letter'/exp OR 'case report'/exp)
#8	#6 AND #7
#9	#8 Limits: Humans, English, 2000 - present
#10	#9 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'warfarin'/exp OR warfarin:ab,ti OR coumadin:ab,ti
#3	antithrombins:ab,ti OR (direct:ab,ti AND thrombin:ab,ti AND inhibitors:ab,ti) OR (direct:ab,ti AND thrombin:ab,ti AND inhibitor:ab,ti) OR "direct thrombin inhibitors":ab,ti OR “Antithrombin III":ab,ti OR “Antithrombin Proteins":ab,ti OR argatroban:ab,ti OR bivalirudin:ab,ti OR “Heparin Cofactor II":ab,ti OR Hirudins:ab,ti OR inogatran:ab,ti OR lepirudin:ab,ti OR melagatran:ab,ti OR “SDZ MTH 958":ab,ti OR ximelagatran:ab,ti
#4	'anticoagulant agent'/exp OR anticoagulant:ab,ti OR anticoagulants:ab,ti
#5	('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR random:ab,ti OR factorial:ab,ti OR crossover:ab,ti OR (cross NEAR/1 over):ab,ti OR placebo:ab,ti OR (doubl NEAR/1 blind):ab,ti OR (singl NEAR/1 blind):ab,ti OR assign:ab,ti OR allocat:ab,ti OR volunteer:ab,ti OR 'clinical study'/exp OR “clinical trial”:ti,ab OR “clinical trials”:ti,ab OR 'controlled study'/exp OR 'evaluation'/exp OR “evaluation study”:ab,ti OR “evaluation studies”:ab,ti OR “intervention study”:ab,ti OR “intervention studies”:ab,ti OR “case control”:ab,ti OR 'cohort analysis'/exp OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR retrospective:ab,ti OR 'follow up'/exp OR “follow up”:ab,ti OR 'comparative effectiveness'/exp OR 'comparative study'/exp OR “comparative study”:ab,ti OR “comparative studies”:ab,ti OR 'evidence based medicine'/exp OR “systematic review”:ab,ti OR “meta-analysis”:ab,ti OR “meta-analyses”:ab,ti) NOT ('editorial'/exp OR 'letter'/exp OR 'case report'/exp)
#6	#1 AND #2 AND (#3 OR #4) AND #5
#7	#6 Limits: Humans, English, 2000 - present
#8	#7 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'anticoagulant agent'/exp OR 'warfarin'/exp OR 'vitamin K group'/exp OR 'heparin'/exp OR 'enoxaparin'/exp OR 'rivaroxaban'/exp OR 'dabigatran etexilate'/exp OR 'apixaban'/exp OR 'edoxaban'/exp
#3	warfarin:ab,ti OR coumadin:ab,ti OR vitamin k:ab,ti OR enoxaparin:ab,ti OR lovenox:ab,ti OR rivaroxaban:ab,ti OR xarelto:ab,ti OR dabigatran:ab,ti OR pradaxa:ab,ti OR heparin:ab,ti OR apixaban:ab,ti OR eliquis:ab,ti OR edoxaban:ab,ti OR lixiana:ab,ti
#4	#2 OR #3
#5	'brain hemorrhage'/exp OR 'bleeding'/exp OR hemorrhage:ab,ti OR hemorrhaging:ab,ti OR bleeding:ab,ti OR bleed:ab,ti OR hemorrhagic:ab,ti OR haemorrhage:ab,ti OR haemorrhaging:ab,ti OR haemorrhagic:ab,ti
#6	'time'/exp OR resume:ab,ti OR resumed:ab,ti OR restart:ab,ti OR restarted:ab,ti OR restarting:ab,ti OR re-initiate:ab,ti OR reinitiate:ab,ti OR continue:ab,ti OR continued:ab,ti OR start:ab,ti OR resumption:ab,ti OR reinitiating:ab,ti OR resuming:ab,ti OR continuing:ab,ti
#7	#1 AND #4 AND #5 AND #6
#8	('randomized controlled trial'/exp OR 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp OR random:ab,ti OR factorial:ab,ti OR crossover:ab,ti OR (cross NEAR/1 over):ab,ti OR placebo:ab,ti OR (doubl NEAR/1 blind):ab,ti OR (singl NEAR/1 blind):ab,ti OR assign:ab,ti OR allocat:ab,ti OR volunteer:ab,ti OR 'clinical study'/exp OR “clinical trial”:ti,ab OR “clinical trials”:ti,ab OR 'controlled study'/exp OR 'evaluation'/exp OR “evaluation study”:ab,ti OR “evaluation studies”:ab,ti OR “intervention study”:ab,ti OR “intervention studies”:ab,ti OR “case control”:ab,ti OR 'cohort analysis'/exp OR cohort:ab,ti OR longitudinal*:ab,ti OR prospective:ab,ti OR prospectively:ab,ti OR retrospective:ab,ti OR 'follow up'/exp OR “follow up”:ab,ti OR 'comparative effectiveness'/exp OR 'comparative study'/exp OR “comparative study”:ab,ti OR “comparative studies”:ab,ti OR 'evidence based medicine'/exp OR “systematic review”:ab,ti OR “meta-analysis”:ab,ti OR “meta-analyses”:ab,ti) NOT ('editorial'/exp OR 'letter'/exp OR 'case report'/exp)
#9	#7 AND #8
#10	#9 Limits: Humans, English, 2000 - present
#11	#10 AND [embase]/lim NOT [medline]/lim

#1	'heart atrium fibrillation'/exp OR 'heart atrium flutter'/exp OR “atrial fibrillation”:ab,ti OR (atrial:ab,ti AND fibrillation:ab,ti) OR afib:ab,ti OR “atrial flutter”:ab,ti
#2	'age'/exp OR 'dementia'/exp OR 'falling'/exp OR 'international normalized ratio'/exp OR “age factors”:ab,ti OR “age factor”:ab,ti OR age:ab,ti OR dementia:ab,ti OR INR:ab,ti OR fall:ab,ti OR falls:ab,ti OR "international normalized ratio":ab,ti OR paroxysmal:ab,ti OR persistent:ab,ti OR permanent:ab,ti OR stratification:ab,ti OR classification:ab,ti OR schema:ab,ti OR has-bled:ab,ti OR (cognitive:ab,ti AND impairment:ab,ti) OR cognition:ab,ti OR ((prior:ab,ti OR previous:ab,ti OR first:ab,ti) AND stroke:ab,ti)
#3	'brain hemorrhage'/exp OR 'bleeding'/exp OR hemorrhage:ab,ti OR hemorrhaging:ab,ti OR bleeding:ab,ti OR bleed:ab,ti OR hemorrhagic:ab,ti OR haemorrhage:ab,ti OR haemorrhaging:ab,ti OR haemorrhagic:ab,ti
#4	#1 AND #2 AND #3
#5	'diagnosis'/exp OR 'treatment outcome'/exp OR 'sensitivity and specificity'/exp OR 'clinical decision making'/exp OR 'decision making'/exp OR diagnosis:ab,ti OR outcome:ab,ti OR outcomes:ab,ti OR reliability:ab,ti OR accuracy:ab,ti OR accurate:ab,ti OR Sensitivity:ab,ti OR specificity:ab,ti OR valid:ab,ti OR validity:ab,ti OR validation:ab,ti OR decision:ab,ti OR decisions:ab,ti OR assessment:ab,ti
#6	#5 AND #4
#7	#6 Limits: Humans, English, 2000 - present
#8	#7 AND [embase]/lim NOT [medline]/lim

#1	[mh "Atrial Fibrillation"] OR "atrial fibrillation":ab,ti OR [mh "Atrial Flutter"] OR "atrial flutter":ab,ti
#2	[mh ^"Cerebrovascular Disorders"[mj]] or [mh Stroke] or [mh Thromboembolism] or [mh ^emorrhage] or [mh "Intracranial Hemorrhages"] or [mh "Brain Ischemia"] or [mh "Prothrombin Time"] or stroke:ab,ti or strokes:ab,ti or thromboembolism:ab,ti or thromboembolisms:ab,ti or thromboembolic:ab,ti or thromboses:ab,ti or hemorrhage:ab,ti or hemorrhages:ab,ti or hemorrhaging:ab,ti or hemorrhagic:ab,ti or haemorrhage:ab,ti or haemorrhages:ab,ti or haemorrhaging:ab,ti or haemorrhagic:ab,ti or ((bleeding or bleed or bleeds) near/2 (major or risk or event)):ab,ti or ((systemic or paradoxical or crossed) next/2 (embolism or embolisms)):ab,ti or ((brain or cerebral or brainstem or 'brain stem') next/2 (ischemia or ischaemia or ischemias or ischaemias or infarction or infarctions)):ab,ti or (transient next/2 (ischemic or ischaemic or ischaemia or ischemia) next/2 (attack or attacks)):ab,ti or TIA:ab,ti or TIAs:ab,ti or "cerebrovascular accident":ab,ti or "cerebrovascular accidents":ab,ti or CVA:ab,ti or CVAs:ab,ti or "brain vascular accident":ab,ti or "brain vascular accidents":ab,ti
#3	[mh Risk] or risk:ab,ti or risks:ab,ti or [mh "Predictive Value of Tests"] or predict:ab,ti or predicts:ab,ti or predicting:ab,ti or predictor:ab,ti or predictors:ab,ti or predictive:ab,ti
#4	{and #1-#3}
#5	#4 Publication Year from 2011

#1	(atrial fibrillation OR atrial flutter):ti,ab,kw
#2	Magnetic Resonance Imaging explode all trees OR MeSH descriptor Cardiac Imaging Techniques explode all trees OR MeSH descriptor Tomography, X-Ray Computed explode all trees OR MeSH descriptor Echocardiography explode all trees OR (chads2 OR chads2-vasc OR TEE OR TTE OR ct-scan OR transthoracic echo OR transesophageal echo):ti,ab,kw
#3	MeSH descriptor Stroke explode all trees OR MeSH descriptor Thromboembolism explode all trees OR MeSH descriptor Brain Ischemia explode all trees OR (thromboembolism OR thromboembolic OR brain ischemia OR brain ischaemia OR tia):ti,ab,kw OR (transient ischemic attack):ti,ab,kw or (transient ischaemic attack):ti,ab,kw or (transient ischemia attack):ti,ab,kw or (transient ischaemic attack):ti,ab,kw
#4	#1 AND #2 AND #3
#5	#4, Limits: Cochrane Reviews, 2000 to 2012

#1	(atrial fibrillation OR atrial flutter):ti,ab,kw
#2	MeSH descriptor Age Factors explode all trees OR MeSH descriptor Dementia explode all trees OR MeSH descriptor Accidental Falls explode all trees OR MeSH descriptor International Normalized Ratio explode all trees OR age:ti,ab,kw OR dementia:ti,ab,kw OR INR:ti,ab,kw OR fall:ti,ab,kw OR falls:ti,ab,kw OR "international normalized ratio":ti,ab,kw OR paroxysmal:ti,ab,kw OR persistent:ti,ab,kw OR permanent:ti,ab,kw OR stratification:ti,ab,kw OR classification:ti,ab,kw OR schema:ti,ab,kw OR has-bled:ti,ab,kw OR cognitive impairment:ti,ab,kw OR cognition:ti,ab,kw OR ((prior:ti,ab,kw OR previous:ti,ab,kw OR first:ti,ab,kw) AND stroke:ti,ab,kw)
#3	MeSH descriptor Intracranial Hemorrhages explode all trees OR MeSH descriptor Hemorrhage explode all trees OR hemorrhage:ti,ab,kw OR hemorrhaging:ti,ab,kw OR bleeding:ti,ab,kw OR bleed:ti,ab,kw OR hemorrhagic:ti,ab,kw OR haemorrhage:ti,ab,kw OR haemorrhaging:ti,ab,kw OR haemorrhagic:ti,ab,kw
#4	#1 AND #2 AND #3
#5	MeSH descriptor Diagnosis explode all trees OR MeSH descriptor Treatment Outcome explode all trees OR MeSH descriptor Sensitivity and Specificity explode all trees OR MeSH descriptor Decision Making explode all trees OR diagnosis:ti,ab,kw OR outcome:ti,ab,kw OR outcomes:ti,ab,kw OR reliability:ti,ab,kw OR accuracy:ti,ab,kw OR accurate:ti,ab,kw OR Sensitivity:ti,ab,kw OR specificity:ti,ab,kw OR valid:ti,ab,kw OR validity:ti,ab,kw OR validation:ti,ab,kw OR decision:ti,ab,kw OR decisions:ti,ab,kw OR assessment:ti,ab,kw
#6	#4 AND #5
#7	#6, Limits: Cochrane Reviews, 2000 to 2012

#1	(atrial fibrillation OR atrial flutter):ti,ab,kw
#2	MeSH descriptor Anticoagulants explode all trees OR warfarin:ti,ab,kw OR coumadin:ti,ab,kw OR vitamin k:ti,ab,kw OR enoxaparin:ti,ab,kw OR lovenox:ti,ab,kw OR rivaroxaban:ti,ab,kw OR xarelto:ti,ab,kw OR dabigatran:ti,ab,kw OR pradaxa:ti,ab,kw OR heparin:ti,ab,kw OR apixaban:ti,ab,kw OR eliquis:ti,ab,kw OR edoxaban:ti,ab,kw OR lixiana:ti,ab,kw OR anticoagulants:ti,ab,kw OR OR anticoagulant:ti,ab,kw
#3	MeSH descriptor Platelet Aggregation Inhibitors explode all trees OR clopidogrel:ti,ab,kw OR plavix:ti,ab,kw OR aspirin:ti,ab,kw OR dipyridamole:ti,ab,kw OR aggrenox:ti,ab,kw OR persantine:ti,ab,kw OR antiplatelet:ti,ab,kw OR anti-platelet:ti,ab,kw OR antiplatelets:ti,ab,kw OR anti-platelets:ti,ab,kw
#4	MeSH descriptor Atrial Appendage explode all trees OR atrial appendage:ti,ab,kw OR LAA:ti,ab,kw OR occluder:ti,ab,kw OR AMPLATZER:ti,ab,kw OR AtriClip:ti,ab,kw OR PLAATO:ti,ab,kw OR Watchman:ti,ab,kw OR (atrial:ti,ab,kw AND modification:ti,ab,kw) OR "atriacure isolator":ti,ab,kw
#5	MeSH descriptor Stroke explode all trees OR MeSH descriptor Thromboembolism explode all trees OR MeSH descriptor Brain Ischemia explode all trees OR (thromboembolism OR thromboembolic OR brain ischemia OR brain ischaemia OR tia):ti,ab,kw OR (transient ischemic attack):ti,ab,kw or (transient ischaemic attack):ti,ab,kw or (transient ischemia attack):ti,ab,kw or (transient ischaemic attack):ti,ab,kw
#6	#1 AND (#2 OR #3 OR #4) AND #5
#7	#6, Limits: Cochrane Reviews, 2000 to 2012

#1	(atrial fibrillation OR atrial flutter):ti,ab,kw
#2	MeSH descriptor Anticoagulants explode all trees OR warfarin:ti,ab,kw OR coumadin:ti,ab,kw OR vitamin k:ti,ab,kw OR enoxaparin:ti,ab,kw OR lovenox:ti,ab,kw OR rivaroxaban:ti,ab,kw OR xarelto:ti,ab,kw OR dabigatran:ti,ab,kw OR pradaxa:ti,ab,kw OR heparin:ti,ab,kw OR apixaban:ti,ab,kw OR eliquis:ti,ab,kw OR edoxaban:ti,ab,kw OR lixiana:ti,ab,kw OR anticoagulants:ti,ab,kw OR OR anticoagulant:ti,ab,kw
#3	MeSH descriptor Surgical Procedures, Operative explode all trees OR MeSH descriptor Dental Care explode all trees OR surgical:ti,ab,kw OR invasive:ti,ab,kw OR procedures:ti,ab,kw OR surgery:ti,ab,kw OR procedure:ti,ab,kw
#4	#1 AND #2 AND #3
#5	#4, Limits: Cochrane Reviews, 2000 to 2012

#1	(atrial fibrillation OR atrial flutter):ti,ab,kw
#2	warfarin:ti,ab,kw OR coumadin:ti,ab,kw
#3	MeSH descriptor Antithrombins explode all trees OR antithrombins:ti,ab,kw OR (direct:ti,ab,kw AND thrombin:ti,ab,kw AND inhibitors:ti,ab,kw) OR "direct thrombin inhibitors":ti,ab,kw OR "direct thrombin inhibitor":ti,ab,kw
#4	MeSH descriptor Anticoagulants explode all trees OR anticoagulant:ti,ab,kw OR anticoagulants:ti,ab,kw OR vitamin k:ti,ab,kw OR enoxaparin:ti,ab,kw OR lovenox:ti,ab,kw OR rivaroxaban:ti,ab,kw OR xarelto:ti,ab,kw OR dabigatran:ti,ab,kw OR pradaxa:ti,ab,kw OR heparin:ti,ab,kw OR apixaban:ti,ab,kw OR eliquis:ti,ab,kw OR edoxaban:ti,ab,kw OR lixiana:ti,ab,kw
#5	#1 AND #2 AND (#3 OR #4)
#6	#5, Limits: Cochrane Reviews, 2000 to 2012

KQ1, KQ2, KQ3
Condition	atrial fibrillation OR afib OR atrial flutter
Outcome	stroke OR thromboembolism OR thromboembolic OR "brain ischemia" OR “brain ischaemia” OR (transient AND ischemic AND attack) OR TIA OR hemorrhage OR hemorrhaging OR bleeding OR bleed OR hemorrhagic OR haemorrhage OR haemorrhaging OR haemorrhagic

KQ1, KQ2, KQ3, KQ6
Condition	atrial fibrillation OR afib OR atrial flutter
Outcome	stroke OR thromboembolism OR thromboembolic OR "brain ischemia" OR “brain ischaemia” OR (transient AND ischemic AND attack) OR TIA OR hemorrhage OR hemorrhaging OR bleeding OR bleed OR hemorrhagic OR haemorrhage OR haemorrhaging OR haemorrhagic

KQ4
Condition	atrial fibrillation OR afib OR atrial flutter
Intervention	Anticoagulants OR anticoagulation OR warfarin OR coumadin OR vitamin k OR Heparin OR enoxaparin OR lovenox OR rivaroxaban OR xarelto OR dabigatran OR pradaxa OR apixaban OR eliquis OR edoxaban OR lixiana
Search Terms	Surgery OR procedures OR procedure

PERMALINK

Predicting Thromboembolic and Bleeding Event Risk in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review

Ethan D Borre, B.A.

Adam Goode, D.P.T., Ph.D.

Giselle Raitz, M.D.

Bimal Shah, M.D., M.B.A.

Angela Lowenstern, M.D.

Ranee Chatterjee, M.D., M.P.H.

Lauren Sharan, M.D.

Nancy M Allen LaPointe, Pharm.D., M.H.S.

Roshini Yapa, M.B.B.S.

J Kelly Davis, B.A.

Kathryn Lallinger, M.S.L.S.

Robyn Schmidt, B.A.

Andrzej Kosinski, Ph.D.

Sana M Al-Khatib, M.D. M.H.S.

Gillian D Sanders, Ph.D.

Abstract

Background:

Aim:

Methods:

Results:

Limitations:

Conclusion:

Primary Funding Source:

INTRODUCTION

METHODS

Defining the Key Questions

Data Sources and Study Selection

Data Extraction and Quality Assessment of Individual Studies

Data Synthesis and Analysis

Strength of Evidence

Role of the Funding Source

RESULTS

Figure 1. Literature Flow Diagram.

Predicting Thromboembolic Risk in Patients with AF

Table 1.

Figure 2A-F. Summary Estimate of C-Statistics for Prediction Ability of Clinical Tools For Thromboembolic Risk.

Table 2A.

Predicting Bleeding Risk in Patients with AF

Table 2B.

DISCUSSION

Findings in Relation to What is Already Known

Limitations of the Evidence Base and the Comparative Effectiveness Review Process

Research Recommendations

Conclusions

ACKNOWLEDGMENTS

Appendix

PubMed® Search Strategy (February 14, 2018)

Appendix Table 1.

PubMed® Search Strategy (August 14, 2012)

Embase® Search Strategy (February 14, 2018)

Embase® Search Strategy (August 14, 2012)

Cochrane Search Strategy (February 14, 2018)

Cochrane Search Strategy (August 14, 2012)

PubMed® Search Strategy (February 12, 2018)

Grey Literature Searches

ClinicalTrials.gov (February 9, 2018)

ClinicalTrials.gov (August 22, 2012)

WHO: International Clinical Trials Registry Platform Search Portal (August 17, 2012)

ProQuest COS Conference Papers Index (August 14, 2012)

Appendix Table 2.

Appendix Table 3.

Appendix Table 4.

Appendix Table 5.

Footnotes

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

PubMed^® Search Strategy (February 14, 2018)

PubMed^® Search Strategy (August 14, 2012)

Embase^® Search Strategy (February 14, 2018)

Embase^® Search Strategy (August 14, 2012)

PubMed^® Search Strategy (February 12, 2018)

KQs 1-6
Condition	atrial fibrillation OR afib OR atrial flutter
Recruiting status	ALL

KQ1, KQ2, KQ3, KQ6
#1	All (atrial fibrillation OR afib OR atrial flutter)
#3	All (stroke OR thromboembolism OR thromboembolic OR "brain ischemia" OR “brain ischaemia” OR (transient AND (ischemic OR ischaemic) AND attack) OR TIA OR hemorrhage OR hemorrhaging OR bleeding OR bleed OR hemorrhagic OR haemorrhage OR haemorrhaging OR haemorrhagic)
#4	#1 AND #2 AND #3

KQ4
#1	All (atrial fibrillation OR afib OR atrial flutter)
#2	All (Anticoagulants OR anticoagulation OR warfarin OR coumadin OR vitamin k OR Heparin OR enoxaparin OR lovenox OR rivaroxaban OR xarelto OR dabigatran OR pradaxa OR apixaban OR eliquis OR edoxaban OR lixiana)
#3	All (Surgery OR procedures OR procedure)
#4	#1 AND #2 AND #3

KQ5
#1	All (atrial fibrillation OR afib OR atrial flutter)
#2	All (warfarin OR Coumadin)
#3	All (Antithrombins OR antithrombin OR (direct AND thrombin AND (inhibitors OR inhibitor)) OR anticoagulant OR anticoagulants)
#6	#1 AND #2 AND #3

PICOTS Element	Inclusion Criteria	Exclusion Criteria
Populations	Adults (≥18 years of age) Patients with nonvalvular AF (including atrial flutter): Paroxysmal AF (recurrent episodes that self-terminate in less than 7 days) Persistent AF (recurrent episodes that last more than 7 days until stopped) Permanent AF (continuous) Patients with AF who experience acute coronary syndrome Subgroups of interest for KQ 3 include (but are not limited to): Age Sex Race/ethnicity Presence of heart disease Type of AF Comorbid conditions (such as moderate to severe chronic kidney disease (eGFR<60), dementia) When in therapeutic range When non-adherent to medication Previous thromboembolic event Previous bleed Pregnant	Patients who have known reversible causes of AF (including but not limited to postoperative, hyperthyroidism) All subjects are <18 years of age, or some subjects are under <18 years of age but results are not broken down by age
Interventions	KQ 1: Clinical and imaging tools and associated risk factors for assessment/evaluation of thromboembolic risk: Clinical tools include: CHADS2 score CHADS2-VASc score Framingham risk score ABC stroke risk score Individual risk factors include: INR level Duration and frequency of AF Age Prior stroke Type of AF Cognitive impairment Falls risk Presence of heart disease Presence and severity of CKD DM Sex Race/ethnicity Cancer HIV Imaging tools include: Transthoracic echo (TTE) Transesophageal echo (TEE) CT scans Cardiac MRIs KQ 2: Clinical tools and individual risk factors for assessment/evaluation of intracranial hemorrhage bleeding risk: Clinical tools include: HAS-BLED score HEMORR2HAGES score ATRIA score Bleeding Risk Index ABC Bleeding Risk score Individual risk factors include: INR level Duration and frequency of AF Age Prior stroke Type of AF Cognitive impairment Falls risk Presence of heart disease Presence and severity of CKD DM Sex Race/ethnicity Cancer HIV KQ 3: Anticoagulation, antiplatelet, and procedural interventions: Anticoagulation therapies: VKAs: Warfarin Newer anticoagulants (direct oral anticoagulants [DOACs]) Direct thrombin Inh-DTI: Dabigatran Factor Xa inhibitors: Rivaroxaban Apixaban Edoxaban Antiplatelet therapies: Clopidogrel Aspirin Dipyridamole Combinations of antiplatelets Aspirin+dipyridamole Procedures: Surgeries (e.g., left atrial appendage occlusion, resection/removal) Minimally invasive (e.g., Atriclip, LARIAT) Transcatheter (WATCHMAN™, AMPLATZER™, PLAATO)	None
Comparators	KQ 1: Other clinical or imaging tools listed for assessing thromboembolic risk KQ 2: Other clinical tools listed for assessing bleeding risk KQ 3: Other anticoagulation therapies, antiplatelet therapies, or procedural interventions for preventing thromboembolic events	For KQ 3, studies that did not include an active comparator
Outcomes	Assessment of clinical and imaging tool efficacy for predicting thromboembolic risk and bleeding events (KQs 1 and 2): Diagnostic accuracy efficacy Diagnostic thinking efficacy (defined as how using diagnostic technologies help or confirm the diagnosis of the referring provider) Therapeutic efficacy (defined as how the intended treatment plan compares with the actual treatment pursued before and after the diagnostic examination) Patient outcome efficacy (defined as the change in patient outcomes as a result of the diagnostic examination) Patient-centered outcomes for KQ 3 (and for KQ 1 [thromboembolic outcomes] and KQ 2 [bleeding outcomes] under “Patient outcome efficacy”): Thromboembolic outcomes: Cerebrovascular infarction TIA Systemic embolism (excludes PE and DVT) Bleeding outcomes: Hemorrhagic stroke Intracranial hemorrhage (intracerebral hemorrhage, subdural hematoma) Major and minor bleed (stratified by type and location)^a Other clinical outcomes: Mortality All-cause mortality Cardiovascular mortality Myocardial infarction Infection Heart block Esophageal fistula Cardiac tamponade Dyspepsia Health-related quality of life Functional capacity Health services utilization (e.g., hospital admissions, outpatient office visits, ER visits, prescription drug use) Long-term adherence to therapy Cognitive function	Study does not include any outcomes of interest
Timing	Timing of followup not limited	None
Setting	Inpatient and outpatient	Studies which were conducted exclusively in Asia, Africa, or the Middle East^b
Study design	Original peer-reviewed data N ≥20 patients RCTs, prospective and retrospective observational studies	Not a clinical study (e.g., editorial, nonsystematic review, letter to the editor, case series, case reports) Abstract-only or poster publications; articles that have been retracted or withdrawn Because studies with fewer than 20 subjects are often pilot studies or studies of lower quality,^110,111 we excluded them from our review Systematic reviews, meta-analyses, or methods articles (used for background and component references only) Observational studies that are only relevant to KQ 3 (treatment), have fewer than 1000 patients, and only target pharmacological interventions^c
Publications	English-language publications Published on or after January 1, 2000	Non–English-language publications^d Relevant systematic reviews, meta-analyses, or methods articles (will be used for background only)

Study	CHADS₂	Framingham	CHA₂DS₂-VASc	ABC-Stroke
Abraham, 2013⁴¹	Continuous: 0.65 (95% CI 0.62 to 0.67) Categorical: 0.65 (95% CI 0.62 to 0.67)		Continuous: 0.67 (95% CI 0.65 to 0.69) Categorical: 0.67 (95% CI 0.65 to 0.69)
Abumuaileq, 2015¹¹²			Continuous: Non-anticoagulated cohort: 0.69 (95 % CI 0.53 to 0.85) Anticoagulated cohort: 0.72 (95% CI 0.63 to 0.82)
Banerjee, 2013⁷²	Categorical: 0.64 (95% CI 0.61 to 0.67)		Categorical: 0.64 (95% CI 0.62 to 0.67)
Banerjee, 2014¹¹³	Continuous: 0.641 (95% CI 0.607 to 0.676)		Continuous: 0.621 (95% CI 0.616 to 0.683)
Baruch, 2007³⁴	Categorical (Classic): 0.64 (95% CI 0.61 to 0.67) Categorical (Revised): 0.64 (95% CI 0.61 to 0.67)	Categorical: 0.62 (95% CI 0.59 to 0.66)	Categorical: 0.65 (95% CI 0.61 to 0.68)
Fang, 2008³³	Continuous: All patients: 0.60 Categorical: All patients: 0.58 Off therapy: 0.67	Continuous: All patients: 0.64 Categorical: All patients: 0.62 Off therapy: 0.69
Friberg, 2012¹⁸	Continuous: 0.66 (95% CI 0.65 to 0.66) Categorical (Revised): 0.61 (95% CI 0.61 to 0.62) Categorical (Classic): 0.64 (95% CI 0.64 to 0.65)	Continuous: 0.67 (95% CI 0.66 to 0.67) Categorical: 0.64 (95% CI 0.64 to 0.65)	Continuous: 0.67 (95% CI 0.67 to 0.68) Categorical: 0.56 (95% CI 0.56 to 0.57)
Friberg, 2015⁷¹	Continuous: 0.72 (95% CI 0.72 to 0.73)		Continuous: 0.71 (95% CI 0.71 to 0.72)
Gage, 2001³⁵	Continuous: 0.82 (95% CI 0.80 to 0.84)
Hijazi, 2016⁵⁶			Continuous: Derivation cohort: 0.62 (95% CI 0.60 to 0.65) Validation cohort: 0.58 (95% CI 0.49 to 0.67)	Categorical: Derivation cohort, TnI: 0.68 (95% CI 0.65 to 0.71) Derivation cohort, TnT: 0.67 (95% CI 0.65 to 0.70) Validation cohort, TnT: 0.66 (95% CI 0.58 to 0.74)
Primary paper: Granger, 2011⁵⁷ Relevant companion: Hijazi, 2017¹¹⁴				Categorical: Baseline data: TnI: 0.71 (95% CI 0.66 to 0.76) TnT: 0.70 (95% CI 0.65 to 0.75) 2 months: TnI: 0.72 (95% CI 0.66 to 0.77) TnT: 0.70 (95% CI 0.65 to 0.76)
Primary paper: O’Brien, 2015⁹⁰ Relevant companion: Inohara, 2017⁹⁵			Continuous: 0.679 (95% CI 0.651 to 0.707)
Larsen, 2012⁴⁴	Continuous: 0.68 (95% CI 0.59 to 0.76)		Continuous: 0.69 (95% CI 0.60 to 0.77)
Lip, 2010³⁷	Continuous: 0.60 (95% CI 0.49 to 0.72) Categorical (Classic): 0.56 (95% CI 0.44 to 0.66) Categorical (Revised): 0.59 (95% CI 0.48 to 0.70)	Continuous: 0.69 (95% CI 0.60 to 0.78) Categorical: 0.64 (95% CI 0.53 to 0.74)
McAlister, 2017¹¹⁵	Categorical: 0.663 (95% CI 0.652 to 0.675)		Categorical: 0.661 (95% CI 0.649 to 0.672)
Oldgren, 2016⁵⁸			Continuous: 0.60 (95% CI 0.57 to 0.64)	Categorical: 0.65 (95% CI 0.61to 0.69)
Olesen, 2011²³	Covariates analyzed as categorical variables: Continuous: 0.78 (95% CI 0.76 to 0.80) Categorical: 0.81 (95% CI 0.80 to 0.83) Covariates analyzed as continuous variables: Continuous: 0.80 (95% CI 0.79 to 0.82) Categorical: 0.81 (95% CI 0.80 to 0.83)		Covariates analyzed as categorical variables: Continuous: 0.78 (95% CI 0.76 to 0.79) Categorical: 0.89 (95% CI 0.88 to 0.90) Covariates analyzed as continuous variables: Continuous: 0.79 (95% CI 0.78 to 0.81) Categorical: 0.89 (95% CI 0.88 to 0.90)
Olesen, 2012³⁹	Categorical: 0.63 (95% CI 0.62 to 0.65)		Continuous: 0.66 (95% CI 0.65 to 0.68)
Philippart 2016¹¹⁶			Categorical: 0.588 (95% CI 0.577-0.599) Continuous: 0.641 (95% CI 0.631-0.652)
Poli, 2009³⁰	Categorical: All patients: 0.68 On therapy: 0.52
Poli, 2011²⁶	Continuous (Revised): 0.72 (95% CI 0.64 to 0.80) Categorical (Classic): 0.68 (95% CI 0.61 to 0.76) Categorical (Revised): 0.60 (95% CI 0.51 to 0.67)		Continuous: 0.72 (95% CI 0.65 to 0.80) Categorical: 0.52 (95% CI 0.44 to 0.61)
Potpara, 2012²⁰	Categorical: 0.58 (95% CI 0.38 to 0.79)		Categorical: 0.72 (95% CI 0.61 to 0.84)
Rietbrock, 2008³²	Continuous (Classic): 0.68 (95% CI 0.68 to 0.69) Continuous (Revised): 0.72 (95% CI 0.72 to 0.73)
Primary paper: Rivera-Caravaca, 2017⁵⁴ Relevant companion: Rivera-Caravaca, 2017¹⁰²			Categorical (3.5 years): 0.600 (95% CI 0.567 to 0.625) Categorical (6.5 years): 0.620 (95% CI 0.590 to 0.648)	Categorical (3.5 years): 0.663 (95% CI 0.634 to 0.690) Categorical (6.5 years): 0.662 (95% CI 0.633 to 0.690)
Ruff, 2016⁴⁸			Continuous: 0.586 (95% CI 0.565 to 0.607)
Ruiz Ortiz, 2010²⁷	Continuous: 0.63 (95% CI 0.55 to 0.72)
Singer, 2013⁴²	Continuous: 0.69 (95% CI 0.67 to 0.71) Categorical: 0.66 (95% CI 0.64 to 0.68)		Continuous: 0.70 (95% CI 0.68 to 0.72) Categorical: 0.58 (95% CI 0.57 to 0.59)
van den Ham, 2015⁴⁵	Continuous: 0.68 (95% CI 0.67 to 0.69) Categorical (published low/moderate/high) 0.65 (95% CI 0.64 to 0.66) Categorical (optimized) 0.65 (95% CI 0.64 to 0.66)		Continuous: 0.68 (95% CI 0.67 to 0.69) Categorical (published low/moderate/high) 0.59 (95% CI 0.59 to 0.60) Categorical (optimized) 0.63 (95% CI 0.62 to 0.64)
Van Staa, 2011²⁴	Continuous: 0.66 (95% CI 0.64 to 0.68) Categorical: 0.65 (95% CI 0.63 to 0.67)	Continuous: 0.65 (95% CI 0.63 to 0.68) Categorical: 0.62 (95% CI 0.60 to 0.64)	Continuous: 0.67 (95% CI 0.65 to 0.69) Categorical: 0.60 (95% CI 0.59 to 0.61)
Wang, 2003⁵⁵	Categorical: 0.62	Categorical: 0.66 (SD 0.03)

Study Design	No. of Patients	Followup	Bleeding Risk	Risk of Bias
Presence and severity of CKD
Apostolakis, 2013⁵⁰ Observational	2293	NR	Major Bleeding Patients with more than mild CKD (CrCl 60 mL/min) had higher risk of major bleeding compare with patients with CrCl ≥60 mL/min: HR 1.58 (95% CI 1.05 to 2.39)^*	Low
Bassand, 2018¹¹⁷	28,628	2 years	Major Bleeding HR 1.74 (95% CI 1.34 to 2.26)	Low
Friberg, 2015⁷¹ Observational	283,969	Total: Median 2.1 years	Intracranial Bleeding Presence and severity of CKD: HR 1.50 (95% CI 1.28 to 1.74)^* Any Bleeding Presence and severity of CKD: HR 2.24 (95% CI 2.14 to 2.35)^*	Low
Jun, 2017⁷⁰ Observational	14,892	1 year	Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89 mL/min/1.73 m2 (HR 1.36; 95% CI 1.13 to 1.64).	Low
McAlister, 2017¹¹⁵ Observational	58,451	Median 31 months	eGFR, mL/min/1.73² ≥60 = 1.00 45-59 = 1.13 (95% CI 1.04 to 1.22) 30-44 = 1.25 (95% CI 1.14 to 1.37) <30 = 1.50 (95% CI 1.33 to 1.68)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 year (IQR 1.8)	Multivariable Analysis Major Bleeding HR 1.59 (95% CI 1.41 to 1.79)^*	Low
Pisters, 2010⁹ Observational	3456	1 year	Major Bleeding OR 2.86 (95% CI 1.33 to 6.18)^*	Low
Sherwood, 2015¹¹⁸ Observational	14,263	NR	Creatinine clearance (for each 5-U decrease to <60 ml/min) HR 1.06 (95% CI 1.01 to 1.12)^*	Low
Cognitive impairment
Orkaby, 2017¹¹⁹ Observational	2,572	Mean 2.2 person-years following diagnosis of dementia	After diagnosis of dementia no statistically significant decrease in risk of major bleeding (HR 0.78, 95% CI 0.61 to 1.01, P = .06).	Medium
INR
An, 2017¹²⁰ Observational	32,074	Total: 5 years Median 3.8 years	Patients whose TTRs were < 65%, had a 2 times higher risk of major bleeding (HR 2.10, 95% CI 1.96 to 2.24) compared with patients with the highest TTR quartile (≥ 73%)	Low
Haas, 2016⁴⁷ Observational	9,934	1 year	TTR <65% vs. ≥65% bleeding risk HR 1.54 (95% CI 1.04 to 2.26)	Low
Lind, 2012⁶⁷ Observational	19,179	34718.9 patient-years	The bleeding risk HR for the SDT_INR variable was 1.27 (95% CI 1.20 to 1.35), and the HR for TTR was 1.07 (95% CI 1.01 to 1.14)	High
Phelps, 2018¹²¹ Observational	8,405	1 year	Major Bleeding OR 0.62 (95% CI 0.43 to 0.89)	Moderate
Rivera-Caravaca, 2018¹²² Observational	1,361	6 months Median follow-up 214 days	Major bleeding rates per year: TTR <20% = 1.47 and ≥20% = 2.93; TTR <65% = 3.03 and ≥65% = 2.10	Low
Age
Bassand, 2018¹¹⁷	28,628	2 years	Major Bleeding (HRs) <65 = referent 65-69 = 1.30 (95% CI 0.86 to 1.96) 70-74=1.88 (95% CI 1.30 to 2.74) 75+=2.49 (95% CI 1.81 to 3.42)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 year (IQR 1.8)	Multivariable Analysis Major Bleeding Age: 65-74 yr HR 2.33 (95% CI 1.96 to 2.77)^* >75yr HR 3.28 (95% CI 2.80 to 3.83)^*	Low
Goodman, 2014¹²³ Observational	14,264	NR	Multivariable analysis Major Bleeding Age (per 5y increase) HR 1.17 (95% CI 1.12 to 1.23)^*	Low
Hankey, 2014¹²⁴ Observational	14,264	NR	Intracranial Bleeding Age: HR for 10 years increase 1.35 (95% CI 1.13 to 1.63)^*	Medium
Olesen, 2012¹⁷ Observational	6348	NR	Major Bleeding Age <65: Event Rate 0.39 (0.16 to 0.94) Age 65-74y: Event Rate 1.34 (0.60 to 2.97) Age>75: Event Rate 1.98 (1.10 to 3.58)	Medium
Pisters, 2010⁹ Observational	3456	1 year	Major Bleeding Age >65: OR 2.66 (1.33-5.32)^*	Low
Renoux, 2017¹²⁵ Observational	147,622	Mean follow up period 2.9 years	Female vs. Male for Major Bleeding <75 = HR 0.91 (95% CI 0.88 to 0.95) ≥75 = HR 0.96 (95% CI 0.89 to 1.02)	Low
Sherwood, 2015¹¹⁸ Observational	14,263	NR	Major Bleeding (Gastrointestinal) Age (for each 5-yr increase): HR 1.11 (1.06 to 1.17)^*	Low
Prior stroke
Bassand, 2018¹¹⁷	28,628	2-years	Major Bleeding HR 1.36 (95% CI 1.04 to 1.78)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 year (IQR 1.8)	Multivariable Analysis Major Bleeding HR 1.14 (95% CI 1.04 to 1.24)^*	Low
Hankey, 2014¹²⁴ Observational	14,264	NR	Intracranial Bleeding HR 1.42 (95% CI 1.02 to 1.96)^*	Medium
Pisters, 2010⁹ Observational	3456	1 year	Major Bleeding Prior stroke: OR 0.94 (95% CI 0.32 to 2.86)	Low
Hilkens, 2017¹²⁶ Observational	3623	2 years	C-statistic (95% CI) of risk scores for major bleeding in patients with a TIA or stroke on oral anticoagulants at 2 years HEMORR2 HAGES 0.63 (0.59 to 0.66) HAS-BLED 0.62 (0.58 to 0.65) ATRIA 0.66 (0.62 to 0.69)	Low
Presence of heart disease
Bassand, 2018¹¹⁷	28,628	2-years	Major Bleeding HR 1.07 (95% CI 0.84 to 1.36)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 year (IQR 1.8)	Multivariable Analysis Major Bleeding Presence of heart disease (Heart Failure): HR 1.15 (95% CI 1.07 to 1.24)^* (Hypertension) HR 1.25 (95% CI 1.16 to 1.33)^*	Low
Goodman, 2014¹²³ Observational	14,264	NR	Multivariable Model Major Bleeding Presence of heart disease (Hypertension): DBP >90 mm Hg (per 5-mm Hg increase) HR 1.28 (1.11 to 1.47)^*	Low
Hankey, 2014¹²⁴ Observational	14,264	NR	Intracranial Bleeding HR 0.65 (95% CI 0.47 to 0.89)^*	Medium
Pisters, 2010⁹ Observational	3456	1 year	Major Bleeding Presence of heart disease (PA>160mmHg): OR 0.60 (95% CI 0.21 to 1.72)	Low
Diabetes
Bassand, 2018¹¹⁷	28,628	2-years	Major Bleeding HR 0.92 (95% CI 0.71 to 1.18)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 yr (IQR 1.8)	Multivariable Analysis Major Bleeding HR 1.01 (95% CI 0.92 to 1.11)	Low
Sex
Bassand, 2018¹¹⁷	28,628	2 years	Major Bleeding HR (Women) 1.14 (95% CI 0.90 to 1.45)	Low
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 yr (IQR 1.8)	Multivariable Analysis Major Bleeding Female HR 0.79 (95% CI 0.73 to 0.85)^*	Low
Goodman, 2014¹²³ Observational	14,264	NR	Multivariable Model Major Bleeding Female vs. Male HR 0.82 (95% CI 0.70 to 0.95)^*	Low
Renoux, 2017¹²⁵ Observational	147,622	Mean follow up period 2.9 years	Female vs. Male for Major Bleeding <75 = HR 0.91 (95% CI 0.88 to 0.95) ≥75 = HR 0.96 (95% CI 0.89 to 1.02)	Low
Sherwood, 2015¹¹⁸ Observational	14,263	NR	Major Bleeding (Gastrointestinal) Male HR 1.21 (95% CI 1.01 to 1.44)^*	Low
Cancer
Friberg, 2012¹⁸ Observational	182,678	Total: Median 1.4 yr (IQR 1.8)	Multivariable Analysis Major Bleeding Cancer <3 years: HR 1.15 (95% CI 1.04 to 1.27)^*	Low
Race/Ethnicity
Bassand, 2018¹¹⁷	28,628	2-years	Major Bleeding (HRs) Caucasian / Hispanic / Latino (referent) Asian = 0.61 (95% CI 0.44 to 0.84) Other = 0.51 (95% CI 0.16 to 1.61)	Low
Hankey, 2014¹²⁴ Observational	14,264	NR	Intracranial Bleeding Asian HR 2.02 (95% CI1.39 to 2.94) Black HR 3.25 (95% CI 1.43 to 7.41)^*	Medium

Study	BRI	HEMORR₂HAGES	HAS-BLED	ATRIA	ABC
Patients on warfarin
Apostolakis, 2012^82d	–	0.60 (95% CI 0.51 to 0.69)	0.65 (95% CI 0.56 to 0.73)	0.61 (95% CI 0.51 to 0.70)	–
Barnes, 2014⁸⁶	–	0.66 (95% CI 0.61-0.74)	0.69 (95% CI 0.63-0.75)	0.67 (95% CI 0.61 to 0.74)	–
Fang, 2011^76d,f	Categorical: 0.59 (95% CI 0.58 to 0.61) Continuous: 0.68 (95% CI 0.65 to 0.70)	Categorical: 0.67 (95% CI 0.65 to 0.70) Continuous: 0.71 (95% CI 0.69 to 0.73)	–	Categorical: 0.69 (95% CI 0.66 to 0.71) Continuous: 0.74 (95% CI 0.72 to 0.76)	–
Friberg, 2012^18d	–	0.63 (95% CI 0.61 to 0.64)	0.61 (95% CI 0.59 to 0.62)	–	–
Gage, 2006^79b,c	0.65 (SE 0.03)	0.67 (SE 0.04)	–	–	–
Hijazi, 2016⁹³	–	–	ARISTOTLE: 0.61 (0.58 to 0.63) RE-LY: 0.60 (0.56 to 0.64)	–	ARISTOTLE: 0.68 (0.65 to 0.70) RE-LY: 0.65 (0.61 to 0.70)
Jaspers Focks, 2016⁸⁸	–	Major bleeding = 0.57 (95% CI 0.50 to 0.63) Clinically relevant bleeding = 0.53 (95% CI 0.50 to 0.57) Any bleeding = 0.53 (95% CI 0.50 to 0.57)	Major Bleeding = 0.57 (95% CI 0.50 to 0.63) Clinically relevant bleeding = 0.50 (95% CI 0.47 to 0.54) Any bleeding = 0.51 (95% CI 0.47 to 0.54)	Major Bleeding = 0.58 (95% CI 0.51 to 0.64) Clinically relevant bleeding = 0.52 (95% CI 0.49 to 0.56) Any bleeding= 0.53 (95% CI 0.50 to 0.57)	–
Lip, 2011^77d	0.56 (95% CI 0.51 to 0.60)	0.61 (95% CI 0.56 to 0.65)	0.66 (95% CI 0.61 to 0.70)	–	–
Lip, 2012^85g	Categorical: 0.56 (95% CI 0.53 to 0.59) Continuous: 0.60 (95% CI 0.56 to 0.63)	Categorical: 0.53 (95% CI 0.50 to 0.57) Continuous: 0.59 (95% CI 0.56 to 0.62)	Categorical: 0.58 (95% CI 0.55 to 0.61) Continuous: 0.61 (95% CI 0.58 to 0.65)	Categorical: 0.55 (95% CI 0.52 to 0.59) Continuous: 0.60 (95% CI 0.56 to 0.63)	–
Lip, 2017⁹⁴	–	–	0.58 (95% CI 0.57-0.59)	0.59 (95% CI 0.57-0.60)	–
Olesen, 2011^81d	–	Categorical: 0.78 (95% CI 0.75 to 0.82) Continuous: 0.77 (95% CI 0.73 to 0.81)	Categorical: 0.80 (95% CI 0.76 to 0.83) Continuous: 0.80 (95% CI 0.76 to 0.83)	–	–
Pisters, 2010^9d,e	–	0.64 (95% CI 0.53 to 0.75)	0.69 (95% CI 0.59 to 0.80)	–	–
Roldan, 2012^84h	–	–	Categorical: 0.68 (95% CI 0.65 to 0.71) Continuous: 0.71 (95% CI 0.68 to 0.74)	Categorical: 0.59 (95% CI 0.55 to 0.62) Continuous: 0.68 (95% CI 0.65 to 0.71)	–
Senoo, 2016⁹¹	–	–	0.65 (95% CI 0.56 to 0.73)	0.61 (95% CI 0.51 to 0.70)	–
Patients on aspirin alone
Friberg, 2012^18e	–	0.60 (95% CI 0.59 to 0.61)	0.59 (95% CI 0.58 to 0.60)	–	–
Gage, 2006^79b,c	0.69 (SE 0.05)	0.72 (SE 0.05)^b	–	–	–
Pisters, 2010^9d,e	–	0.83 (95% CI 0.68 to 0.98)	0.91 (95% CI 0.83 to 1.00)	–	–
Patients off antithrombotic therapy
Friberg, 2012^18e	–	0.69 (95% CI 0.67 to 0.70)	0.66 (95% CI 0.65 to 0.68)	–	–
Gage, 2006^79b,c	0.65 (SE 0.03)	0.66 (SE 0.04)	–	–	–
Lip, 2011^77d	0.50 (95% CI 0.44 to 0.57)	0.62 (95% CI 0.52 to 0.72)	0.66 (95% CI 0.55 to 0.74)	–	–
Lip, 2012^85f	Categorical: 0.58 (95% CI 0.54 to 0.62) Continuous: 0.60 (95% CI 0.56 to 0.64)	Categorical: 0.55 (95% CI 0.50 to 0.59) Continuous: 0.59 (95% CI 0.54 to 0.63)	Categorical: 0.60 (95% CI 0.54 to 0.64) Continuous: 0.60 (95% CI 0.56 to 0.64)	Categorical: 0.47 (95% CI 0.42 to 0.51) Continuous: 0.59 (95% CI 0.55 to 0.64)	–
Olesen, 2011^81d	–	Categorical: 0.77 (95% CI 0.74 to 0.80) Continuous: 0.79 (95% CI 0.73 to 0.79)	Categorical: 0.82 (95% CI 0.79 to 0.84) Continuous: 0.81 (95% CI 0.78 to 0.83)	–	–
Pisters, 2010^9d,e	–	0.81 (95% CI 0.00 to 1.00)	0.85 (95% CI 0.00 to 1.00)	–	–