chestjournal.org TABLE 2 ] CHEST Grading System Grade of Recommendation Bene t vs Risk and Burdens Methodologic Strength of Supporting Evidence Implications Strong recommendation, High quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We are very con dent that the true effect lies close to that of the estimate of the effect Recommendation can apply to most patients in most circumstances. Further research is very unlikely to change our con dence in the estimate of effect Strong recommendation, Moderate-quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We are moderately con dent in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Recommendation can apply to most patients in most circumstances. Higher quality research may well have an important impact on our con dence in the estimate of effect and may change the estimate Strong recommendation, Low quality evidence Bene ts clearly outweigh risk and burdens, or vice versa Our con dence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Recommendation can apply to most patients in many circumstances. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Strong recommendation, very low quality evidence Bene ts clearly outweigh risk and burdens, or vice versa We have very little con dence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Recommendation can apply to most patients in many circumstances. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Weak (conditional) recommendation, High quality evidence Bene ts closely balanced with risks and burden We are very con dent that the true effect lies close to that of the estimate of the effect The best action may differ depending on circumstances or patients or societal values. Further research is very unlikely to change our con dence in the estimate of effect Weak (conditional) recommendation, Moderate-quality evidence Bene ts closely balanced with risks and burden We are moderately con dent in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Best action may differ depending on circumstances or patients or societal values. Higher quality research may well have an important impact on our con dence in the estimate of effect and may change the estimate Weak (conditional) recommendation, Low quality evidence Uncertainty in the estimates of bene ts, risks, and burden; bene ts, risk and burden may be closely balanced Our con dence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] Consistent with the ninth edition of the guideline, the outcomes most relevant to patients with AF include death, nonfatal stroke, systemic embolism, nonfatal major extracranial bleeding, and the burden and lifestyle limitations associated with outpatient antithrombotic To facilitate decision-making, the term stroke in this guideline includes both ischemic stroke and hemorrhagic stroke, which together with systemic embolism was the principal outcome in most stroke prevention trials. Additional considerations were all- cause and cardiovascular mortality. For bleeding outcomes, we focused on major bleeding, which was the principal safety outcome in most stroke prevention trials. Major bleeding included intracranial bleeding, the most severe and disabling form of anticoagulant-related bleeding. Literature Searches and Study Selection To inform our guideline development, we searched for relevant articles published since the last formal literature search performed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition), which were published in 2012.3 Searches were also conducted speci cally for existing guidelines and systematic reviews. In cases in which existing, good quality systematic review(s) were retrieved, the results of the review informed our recommendations. Speci cally, for literature regarding the assessment of stroke risk in patients with AF, we searched MEDLINE via PubMed and the Cochrane Library for articles published from October 2009 to October 2017 using the search terms atrial brillation, atrial utter, risk assessment, risk factors, risk strati cation, stroke, and thromboembolism. For literature regarding prevention of stroke and thromboembolism in patients with AF, we searched MEDLINE via PubMed and the Cochrane Library for articles published from January 1, 2007, to October 2017 using the search terms coumarins, warfarin, dicumarol, phenprocoumon, acenocoumarol, fondaparinux, idraparinux, aspirin, tri usal, indobufen, dabigatran, ximelagatran, rivaroxaban, apixaban, ticlopidine, clopidogrel, catheter ablation, watchman, PLAATO, cardioversion, atrial brillation, and atrial utter. Titles and abstracts of the search results were reviewed independently and in parallel to identify potentially relevant articles based on the inclusion and exclusion criteria from the PICO elements. Discrepancies were resolved by discussion. Studies deemed eligible then underwent a second round of full-text screening following the same methodology used during title/abstract review. Important data from each included study were then extracted into structured evidence tables. Risk of Bias Assessment The methodologist assessed the risk of bias in all included studies. The Cochrane Risk of Bias tool was used to assess the risk of bias for randomized controlled trials (RCTs)5 and the Risk of Bias in Non- randomized Studies of Interventions (ROBINS-I) tool to evaluate risk of bias for observational studies.6 In cases in which existing systematic reviews were available, we used the Documentation and Appraisal Review Tool to assess methodological quality.7 Meta-analysis When individual studies were available or an existing meta-analysis needed to be updated, we used the Cochrane Collaboration Review Manager, version 5.2,8 to pool the results across individual studies. We used a random-effects model and the method of DerSimonian and Laird to pool the individual estimates.9 Risk ratio (RR) was used to report the results for dichotomous outcomes and mean difference for continuous outcomes with accompanying 95% CIs. Statistical TABLE ] (Continued) Grade of Recommendation Bene t vs Risk and Burdens Methodologic Strength of Supporting Evidence Implications Weak (conditional) recommendation, very- low quality evidence Uncertainty in the estimates of bene ts, risks, and burden; bene ts, risk and burden may be closely balanced We have very little con dence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Other alternatives may be equally reasonable. Higher quality research is likely to have an important impact on our con dence in the estimate of effect and may well change the estimate Ungraded consensus-based suggestions Ungraded Consensus- Based Statement Uncertainty due to lack of evidence but expert opinion that bene ts outweigh risk and burdens or vice versa Insuf cient evidence for a graded recommendation Future research may well have an important impact on our con dence in the estimate of effect and may change the estimate heterogeneity of the pooled results was assessed using the Higgins I2 and the c2 tests. A Higgins I2 value of $ 50% or c2 P < .05 was considered to represent signi cant heterogeneity. Assessing the Overall Quality of the Evidence The overall certainty (quality) of the evidence was assessed for each critical or important outcome of interest using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) Evidence pro les were created using the Guideline Development Tool, which categorized the overall quality of the body of evidence into 1 of 4 levels: high, moderate, low, or very low. Drafting Recommendations The panel drafted and graded recommendations based on the results of the meta-analyses and evidence pro les. Recommendations were graded according to CHEST s grading system, which uses the GRADE approach (Table 2).11,12 The recommendations were either strong or weak according to this approach. Strong recommendations use the wording we recommend and weak recommendations use the wording we suggest. The implications of the strength of recommendation are summarized in e-Table 2. In instances in which there was insuf cient evidence, but a clinically relevant area was felt to require a guiding comment, a weak suggestion was developed and Ungraded Consensus-Based Statement replaced the grade.13 In developing our treatment recommendations, we attempted to account for patient values and preferences regarding these outcomes, and had 2 patient advocates (Mellanie True Hills and D. A. L.) who participated in the panel discussion, and speci cally addressed patient-centered issues. Consensus Development All drafted recommendations and suggestions were presented to the panel in an anonymous online voting survey to reach consensus and gather feedback. Panelists were requested to indicate their level of agreement on each statement based on a 5-point Likert scale derived from the GRADE grid.14 Panelists with COIs related to the individual recommendations recused themselves from voting on those statements. Of note, the chair (G. Y. H. L.) recused himself from any voting on recommendations. According to CHEST policy, each recommendation and statement required a 75% voting participation rate and at least 80% consensus to pass. Any recommendation or suggestion that did not meet these criteria was revised by the panel based on the feedback, and a new survey that incorporated those revisions was completed. Peer Review Process Reviewers from the Guideline Oversight Committee, the CHEST Board of Regents, and the CHEST journal reviewed the methods used and the content of the manuscript for consistency, accuracy, and completeness. The manuscript was revised according to feedback from the reviewers. Stroke Risk in AF The extensive data on epidemiologic burden of stroke associated with AF and well as the pathophysiology is detailed in e-Appendix 1. It is beyond the scope of this document to consider the epidemiology of all comorbidities in AF. In summary, health-care systems face increasing prevalence, incidence, and lifetime risk of AF, which is as high as 1 in 4 in contemporary studies in high-income Epidemiologic studies largely represent Western countries and white populations.16 However, reported prevalence varies substantially by world region (e-Fig 1) and with more rigorous screening methods to detect AF. Individuals with AF have increased risk of stroke (fourfold to vefold increase), HF (twofold to threefold fold increase), and mortality (twofold increase) (see e-Appendix 1). Patients with AF also experience higher rates of morbidity and hospital admissions, as well as early dementia. The high AF-attributable risk of stroke, especially in the elderly, is evident since at least 1 in 3 to 4 individuals with an ischemic stroke, and > 80% of those with ischemic stroke of cardioembolic subtype, also have Overall, non-white ethnicity shows evidence of association with lower risk of incident AF. Several of the risk factors for incident AF are also risk factors for stroke in AF.18 Primary prevention strategies for AF have not been conclusively proven in randomized trials, and opportunistic screening is the recommended strategy to detect AF at the population-level.19 A systematic review of the associations of 23 cardiovascular risk factors and incident AF including 20,420,175 participants and 576,602 AF events, respectively, found hypertension, obesity, taller height, and coronary heart disease showed consistent, direct associations with incident AF.18 Ethnic differences in comorbidities in AF patients have been reported Hypertension is the leading comorbid risk factor and is equally distributed in different races. Coronary heart disease seems more common in whites and the Middle East, than in Asians. The annual risk of AF-associated stroke in Asians is higher than that in and the risk of stroke may start to increase at a younger age in Asians.37 Classi cation of AF AF is classi ed as paroxysmal (self-terminating within 7 days), persistent (continuous for > 7 days), long- standing persistent (continuous for > 1 year), or permanent (chronic). AF becomes increasingly persistent and resistant to therapy over time, perhaps due to the development of atrial brosis, as well as other pathophysiological processes (e-Fig 2). AF and atrial utter frequently co-exist, and share similar risk factors for arrhythmia development and stroke risk.39 Lone AF 1142 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] is a low risk patient group that is a diagnosis of exclusion, after ensuring no comorbidity risk factors are Lone atrial utter (without any recognizable underlying disease), like lone AF, is also rare: only 2% of atrial utter patients.41 The role of anticoagulation in atrial utter has not been assessed in clinical trials, but since individuals with atrial utter often have concomitant AF or are at increased risk of developing AF, the risk of stroke and thromboembolism is assumed to be the same, and the same risk strati cation approaches are recommended. Risk Factors for Ischemic Stroke: Clinical Risk Factors for Ischemic Stroke in AF: Although AF is an independent risk factor for stroke, not all patients with AF have equal stroke risk. To correctly assess the risk of stroke in order to inform anticoagulation, risk prediction or strati cation tools have been developed, based on the risk factors most strongly and consistently associated with stroke. A systematic review of stroke risk factors found that prior stroke or transient ischemic attack (TIA) (15 of 16 studies positive; RR, 2.86), hypertension (11 of 20 studies positive; RR, 2.27), aging (9 of 13 studies positive; RR, 1.46 per decade increase), structural heart disease (9 of 13 studies positive; RR, 2.0), and diabetes (9 of 14 studies positive; RR, 1.62) were independent predictors of stroke. Supportive evidence was found for sex (8 of 22 studies positive; RR, 1.67), vascular disease studies positive; RR, 1.85).42 Nonparoxysmal AF is associated with a highly signi cant increase in thromboembolism (multivariable adjusted hazard ratio In individuals with HF, AF is associated with worse prognosis than sinus rhythm.44,45 HF is an independent predictor of stroke/thromboembolism, mortality, and other clinical outcomes in individuals with AF, compared with no HF.46 Moreover, HF is a predictor of development of AF and has been incorporated in tools for risk prediction of incident AF.47 All-cause mortality is higher in AF patients with HF with reduced ejection fraction compared with HF with preserved ejection although stroke risk (RR, 0.85; 95% CI, 0.70-1.03; P .094) and HF hospitalization (RR, 1.21; 95% CI, 0.96-1.53; P .115) are not signi cantly different.48 CKD is an independent predictor of risk of stroke/ thromboembolism. AF patients with an estimated glomerular ltration rate < 60 mL/min compared with those with an estimated glomerular ltration rate $ 60 mL/min have increased risk of stroke/ P < .001), with a 0.41% (0.17%-0.65%) annual increase in rate for a 10 mL/min decrease in renal function.49 The risk is higher in individuals requiring renal replacement therapy (HR, 1.83; 95% CI, 1.57-2.14; P < .001). There is also an increased risk of bleeding in individuals with AF and CKD, compared with those without CKD.50 Conversely, AF is associated with an increased risk of The clinical relevance of renal function is not only for risk prediction but also for choice of anticoagulation and other (see AF and CKD section). Over the last decade, rigorous detection strategies have shown that the prevalence of AF in cryptogenic stroke is likely to be as high as 30%.55 A systematic review and meta-analysis after TIA has shown a pooled AF detection rate for all methods of 4% (95% CI, 2-7).56 Echocardiographic Risk Factors: The role of echocardiography in evaluation before cardioversion or ablation, and in predicting the presence of left atrial appendage (LAA) thrombus is dealt with in sections Cardioversion and Catheter or Surgical Ablation, Electrophysiological Procedures. There may also be a role in evaluating thromboembolic risk strati cation to select appropriate antithrombotic therapy. e-Table 4 summarizes major studies which have shown an association between transthoracic echocardiography (TTE) parameters and ischemic stroke. However, there are very limited data to suggest that there would be any incremental clinical bene t in risk prediction, and moreover there is no evidence that management (in terms of oral anticoagulant [OAC]) would be changed.57 Nevertheless, the most consistent independent predictor of ischemic stroke on TTE is the presence of moderate- severe left ventricular systolic dysfunction. In patients undergoing transesophageal echocardiography (TEE), and left atrial spontaneous echo are both associated with increased thromboembolism, as well as the presence of low LAA velocities and complex aortic plaque; however, the same limitations as for TTE parameters apply.57 Biomarkers: e-Table 5 summarizes important studies involving currently available biomarkers ( biological markers ) that have shown associations with stroke and thrombosis in AF, but both study design and scale of the studies limit possible conclusions. Caveats with the use of these biomarkers include the inter- and intra-patient and assay variability; some have a diurnal variation and can be highly in uenced by associated comorbidities and drug therapies. Many biomarkers are nonspeci c for a particular end point and can be equally predictive not only of stroke but bleeding, death, hospitalization, HF, etc, as well as noncardiac conditions (eg, glaucoma). The importance of biomarkers probably lies in the very low risk strata of clinical scores (eg, CHA2DS2-VASc 0-1 group) where they may in uence the decision to anticoagulate, yet there are limited data available in these patients. There are several other hurdles, including variations in availability in health-care systems, biomarker assays, access to laboratories, biomarkers diurnally, by comorbidities and by anticoagulation and other therapies. For these reasons, the clinical application of biomarkers in management of AF is unlikely to be signi cant. Other Potential Novel Risk Factors for Ischemic Stroke in AF: As with established risk factors, novel risk factors may improve prediction of thromboembolic risk in AF patients, where current risk scores are These novel factors include clinical risk factors (eg, burden of AF), serum biomarkers (eg, N-terminal pro B-type natriuretic peptide), imaging (eg, left atrial brosis on cardiac MRI), and echocardiography (eg, left atrial volume index and longitudinal strain). However, these factors are currently neither proven to signi cantly add to risk prediction, nor likely to in uence the decision to anticoagulate. Risk Strati cation for Stroke and Thromboembolism in AF: A comparison of features included in various published stroke risk strati cation schemes in AF is shown in e-Table 6. A summary of studies comparing the various stroke risk strati cation schema is available in e-Table 7. The risk strati cation scheme commonly used in many guidelines is the CHA2DS2-VASc (congestive heart failure, hypertension, age $ 75 years [doubled], diabetes, stroke/TIA/thromboembolism [doubled], vascular disease [prior myocardial infarction (MI), peripheral arterial disease (PAD), or aortic plaque], age 65-74 years, sex category [female]) score.1 All risk schemes based on clinical risk factors have broadly similar predictive value for high risk patients who sustain stroke and thromboembolism events (all c-indexes approximately 0.60-0.65). Adding more and more clinical variables and complexity (ie, simple vs more complex clinical risk scores) would only modestly increase the c-index to approximately 0.65 to 0.70. Many score comparisons focus on identi cation of high risk and do not focus on low risk end of the spectrum and so are not helpful for decision-making on whether to anticoagulate. Event rates per score point varies according to study setting, ethnicity, cohort, and community vs hospitalized population, etc (as might be expected).61 Also, reported events depends on use of highly selected clinical trial cohort vs real-world unselected, and anticoagulated vs non-anticoagulated patients.62 Mortality rates from observational cohorts may also include fatal strokes as postmortems are not mandated, outcomes are nonadjudicated (as in clinical trials), and cerebral imaging is not performed. Analytical methodology matters and outcomes depend on thresholds for treatment, varying risk pro le during the study (which does not remain static), and statistical analysis Some analyses which exclude patients on anticoagulants are awed by conditioning on the future methodology, and follow-up can be dependent on continuation in a (US) health-care plan. Ethnic differences are also evident in stroke risk related to AF. In a Taiwanese cohort, the risk of stroke was 1.78% per year in patients aged 50 to 64 years and a The risk exceeds the threshold for OAC use for stroke prevention. A modi ed CHA2DS2- VASc score has been proposed, assigning one point for The modi ed CHA2DS2- VASc score performed better than the CHA2DS2-VASc score in predicting ischemic stroke assessed by c-indexes and net reclassi cation index. For patients having a modi ed CHA2DS2-VASc score of 1 (males) or 2 (females) because of the resetting of the age threshold, use of warfarin was associated with a 30% lower risk of ischemic stroke and a similar risk of ICH compared with no treatment. Net clinical bene t analyses also favored the use of warfarin in different weighted models. These ndings suggest that the age-based treatment threshold for stroke prevention may need to be reset in East Adding biomarkers would (statistically) improve prediction, but c-indexes are still approximately 0.65 to 0.70. Recent studies in real-world cohorts do not support the clinical usefulness of biomarker-based scores over clinical risk scores such as the CHA2DS2-VASc score. The use of biomarkers has to balance the assay availability, laboratory variability, costs, and added complexity and lower practicality for everyday use. Also, many biomarker studies are based on anticoagulated 1144 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] highly selected clinical trial cohorts, with all included subjects already in the high risk group (CHA2DS2-VASc or CHADS2 [congestive heart failure, hypertension, age, diabetes, stroke (doubled)] score of 2 or greater). There are few/no studies on non-anticoagulated AF patients, to ascertain the true impact of biomarkers on (non- anticoagulation treated) stroke rates. Current studies do not inform whether the biomarkers will discriminate/ identify low risk in lower/intermediate risk patients who are not anticoagulated. Rather than focus on identifying high risk, the focus should be on initially identifying low risk patients. A low risk categorization by the CHA2DS2-VASc (0 in males and 1 in females) consistently identi es low risk patients, with event rates around 1% per year or under, notwithstanding the possible need to re-categorize the age 65 to 74 years criterion in Asians.65 The majority of published studies and systematic reviews suggest that the CHA2DS2-VASc score is generally better than CHADS2, Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and CHADS2 score plus age 65-74 years, used in Canadian guidelines (CHADS65) in identifying low risk patients, although the proportion of the population assigned as low risk is small. However, there are con icting data in different cohorts for performance of the ATRIA score (United Kingdom Clinical Practice Research Datalink [UK CPRD] and Swedish cohorts vs Danish and Taiwan cohorts). Differences between the ATRIA and CHA2DS2-VASc disappear when cut-points are optimized for stroke risk of the cohort. There are discrepancies between individual studies on the relative performance of ATRIA and CHA2DS2-VASc scores in identifying low risk patients, but the CHA2DS2-VASc score is easier to calculate. Rather than using risk scores in a categorical manner recognizing the various limitations of scores to predict high risk patients who sustain events and given that for each risk strata or given risk score point, we recognized there is wide variation in reported event rates based on reported study clinical setting, patient population, ethnicity, etc. Notwithstanding that the default should be stroke prevention for all AF patients unless deemed to be low risk, the focus should be to use scores to initially identify low risk patients who do not need antithrombotic therapy, rather than focus on identi cation of high risk patients. Prior guidelines have also opted for the CHA2DS2-VASc score to de ne a low risk group. The C in CHA2DS2-VASc refers to recent decompensated HF, irrespective of the ejection fraction (thus including HF with reduced ejection fraction or HF with preserved ejection fraction) or the presence of moderate-severe left ventricular systolic impairment on cardiac imaging, whether symptomatic or asymptomatic. The H refers to history of hypertension or uncontrolled BP, while S refers to stroke, systemic embolism, or a con rmed diagnosis of TIA. V refers to complicated vascular disease, including MI or PAD, or if performed, the presence of complex aortic plaque on TEE. Female sex (Sc criterion) is only relevant as a risk modi er if age > 65 or additional associated risk factors are present, given that females age < 65 with no other risk factors are not at excess stroke risk.66 Stroke risk is also dynamic, and risk should be re-assessed at every patient contact. This was seen in a study where the delta CHA2DS2VASc score, representing the change in stroke risk between between baseline and follow-up), was the best predictor for ischemic stroke.67 A stepwise approach to thromboprophylaxis would allow initial identi cation of low risk using CHA2DS2- VASc (Step 1), following which stroke prevention can be offered to all others (Step 2) irrespective of stroke point score or biomarkers used. This approach uses stroke risk scores in a reductionist manner to aid decision-making, and balances simplicity and practicality (and costs). Recommendations 1. For patients with AF, including those with paroxysmal AF, stroke risk should be assessed using a risk factor based approach, rather than an categorization into low, moderate/high risk strata. We recommend use of the CHA2DS2-VASc as a simple clinical based stroke risk score to initially identify low stroke risk patients who should not be offered antithrombotic therapy to prevent stroke and reduce mortality (Strong recommendation, moderate quality evidence). Remark: Low risk patients are generally those age < 65 and lone AF irrespective of sex (this includes those with a CHA2DS2-VASc score 0 in males, or 1 in females). 2. Subsequent to this initial step, for patients with AF, including those with paroxysmal AF, stroke prevention should be offered to those AF patients with one or more non-sex CHA2DS2-VASc stroke risk factors (score of 1 in a male or 2 in a female) (Strong recommendation, moderate quality evidence). Remark: Consideration of other less established clinical stroke risk factors, imaging (cardiac or cerebral), or biomarkers (urine, blood, or genetics) may re ne risk strati cation based on simple clinical factors. A complex risk schema using a variety of such data that could accurately place more patients in the low risk stratum not requiring anticoagulants than current simple clinically based scores (personalized medicine) should be the goal of future research, but it will be very dif cult to nd non-anticoagulated patient cohorts for prospective validation. Bleeding Risk in AF Observational Studies The rates of major bleeding on vitamin K antagonists (VKAs) among observational cohorts are shown in e-Table 8 and demonstrate highly variable rates, ranging Nevertheless, there is signi cant heterogeneity between the study population characteristics, the inclusion of inception vs experienced OAC cohorts, signi cant disparity in the exposure period (follow-up) and differences in the de nitions of major bleeding employed. In addition, information on the speci c risks of bleeding of the individual cohorts, using a validated bleeding risk score, are lacking, the de nitions of major bleeding were often not provided, and the quality of anticoagulation, such as time in therapeutic range (TTR), is generally lacking. Therefore, direct comparison of the rates of major bleeding on VKA between observational cohorts and with RCTs is problematic. Clinical Trials The de nitions of major bleeding are available in most clinical trials, especially in the non-vitamin K antagonist oral anticoagulant drug (NOAC) trials where International Society on Thrombosis and Haemostasis de nitions were used.71 Before the NOAC era, the rates of major bleeding due to VKA were generally in the range of 1% to 3% per year (e-Table 9). In the 5 NOAC the annual rates of major bleeding of warfarin were between 3% and 4% (Table 3). Data from NOACs trials are more reliable, because patients were randomized to treatment, the majority were double- blinded, and the quality of anticoagulation (such as TTR) was generally better than observational studies. The risk of major bleeding on NOACs, especially the low-dose regimen (dabigatran 110 mg and edoxaban 30 mg), was generally lower than that on warfarin, except in the Rivaroxaban Once daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.73 Risk Factors for Bleeding With NOAC, VKA, and Antiplatelet Therapy: Numerous risk factors for bleeding among AF patients receiving antithrombotic therapy have been identi ed and incorporated into bleeding risk scores (see section on Use of Bleeding Risk Scores). Bleeding risk varies from person to person depending on their pre-existing comorbidities, current antithrombotic regimen and adherence, concomitant medication, and lifestyle choices. Many of these factors cannot be altered but some are modi able or potentially modi able (Fig 2). In order to reduce antithrombotic treatment-associated bleeding, it is important to recognize that bleeding risk is also dynamic and should be reassessed at every patient review. While modi able bleeding risk factors that can be changed or managed should clearly be addressed as part of a holistic approach to AF patient assessment and management, nonmodi able bleeding risks are important drivers of bleeding events when occurring synergistically with An approach to bleeding risk assessment soley based only on modi able bleeding risk factors is an inferior assessment strategy compared with use of a formal bleeding risk score.78-80 BP Control: Good control of BP is vital to reduce the risk of stroke and is essential to decrease the risk of bleeding on antithrombotic therapy; adherence to current guidelines on the management of hypertension should be followed. Anticoagulation Control: Among patients receiving VKA, maintenance of an international normalized ratio (INR) in the therapeutic range (2.0-3.0) is essential. The proportion of time spent in this range (TTR) should be at least 65% but the ultimate aim/target should be 100% (see Optimal INR Target Range section). The risk of bleeding increases when the INR exceeds 3.0, particularly for ICH risk when INR > 3.5.81-86 INR control can potentially be improved by more frequent monitoring and review of factors in uencing INR control (diet-, alcohol-, and drug-interactions). There is evidence that improving patient education about INR control,87 INR management by dedicated anticoagulation clinics with experienced personnel,88-90 and self-monitoring/self-management in selected can increase TTR. Increasing patient s awareness of the importance of OAC medication adherence and the potential bleeding risks associated with overdose are also essential to minimize bleeding complications. 1146 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] TABLE 3 ] Risk Factors, Risk Categories and Bleeding Events in the Validation Cohorts Risk Score Risk Factors (Score for Each Factor) Risk Categories Bleeding Events in Validation Cohort (per 100 patient-years) Low Intermediate High Low Intermediate High Agea ; biomarkersa (GDF-15 or cystatin C/CKD-EPI, cTnT-hs, and Hb); previous bleeda history (2); Y renal function (1); APT (1) Anemia (3); severe renal disease (3); age $ 75 [SBP (1); severe renal/hepatic disease (1 each); stroke (1); bleeding (1); labile INR (1); age > Hepatic/renal disease (1); ethanol abuse (1); malignancy; age > 75 y (1); YPlt (1); re-bleeding risk (2); [BP (1); anemia (1); genetic factors Shireman et al102 Age $ 70 y (0.49); female (0.31); previous bleed (0.58); recent bleed (0.62); alcohol/drug abuse Y reduced/decreased; [ elevated/increased; ABC Atrial brillation Better Care; APT antiplatelet therapy; ATRIA Anticoagulation and Risk Factors in Atrial Fibrillation; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; cTnT-hs high-sensitivity troponin T; DM diabetes mellitus; GDF-15 growth differentiation factor-15; HAS-BLED hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (.65), drugs/alcohol concomitantly (1 point each); Hb hemoglobin; Hct hematocrit; HEMORR2HAGES hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/function, hypertension, anemia, genetic factors, excessive fall risk, and stroke; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; ORBIT Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Registry; Plt platelet count or function; SBP systolic BP. See Table 1 legend for expansion of other abbreviation. (Partly reproduced with permission from Zulki y et al.103 ) a Score for each variable in ABC score is based on a nonogram (see reference100 ). b Bleeding event in original derivation cohort. c At 3 months. chestjournal.org Concomitant Medication Predisposing to Bleeding: Nonessential use of concomitant antiplatelet drugs and NSAIDs should be avoided since these medications increase the risk of bleeding in patients receiving OACs. Where concomitant antiplatelet therapy (APT) is necessary (ie, postcoronary stent implantation), the duration of combination OAC and antiplatelet drugs should be kept to the minimum.92 Since antiplatelet drugs/NSAIDs are widely available over-the-counter, patients need to be made aware of the bleeding risk associated with their use in combination with OAC. Alcohol Intake: Excessivealcoholintake(chronicorbinge- drinking) increases the risk of bleeding predominantly due to the risk of trauma, but in chronic alcohol abuse through poor medication adherence, hepatic and variceal disease. OACs should not initiated among patients consuming alcohol in excess > 14 U/week. There is no clear de nite thresholdwherebleedingriskisincreased.Patientsalsoneed to be made aware of the potential dangers associated with excessive alcohol consumption in combination with OAC/ antithrombotic therapy. Lifestyle Factors: Avoidance of work and/or leisure activities that have the potential to cause serious trauma (eg, contact sports, rock-climbing, occupations working at height or operating heavy machinery) should be advised. Bridging Periods Off Anticoagulation: Interruption of OAC should be avoided to reduce stroke risk since the majority of cardiovascular procedures (eg, pacemaker implantation or percutaneous coronary intervention [PCI]) can be safely performed on OAC. Bridging (ie, stopping OAC and providing anticoagulation cover with heparin) should be used in patients with mechanical heart valves but does not appear to be otherwise Appropriate Choice of OAC: Choice of OAC should be made on an individual basis after stroke and bleeding risk assessment and discussion with the patient. Before an NOAC is initiated, the patient s age, body weight, and renal function should be considered to allow for appropriate dose adaptation where necessary. Falls Risk and Cognitive Impairment: In frail patients and those at high risk of falls, an individual risk assessment needs to be undertaken prior to OAC initiation. In cases where the risk is that of mechanical falls, strategies to improve walking/reduce risk of tripping should be explored (ie, walking aids, appropriate footwear, home review to remove trip hazards), whereas neurological assessment is warranted if falls are unexplained. The bene ts of ischemic stroke reduction generally outweigh the risk of harm from serious bleeding with OAC use; one estimate was that Modi able bleeding risk factors Potentially modi able bleeding risk factors Nonmodi able bleeding risk factors Biomarkers Hypertension/elevated SBP INR control (target 2.0-3.0)a ; target TTR 65% Concomitant APTs and NSAIDs Excessive alcohol intake Nonadherence to OAC/APT Avoidance of hazardous hobbies/occupations Avoidance of bridging therapy with OAC Appropriate choice of OAC and correct doseb Extreme frailty excessive falls riskc VKA management strategyd Anemia Reduced platelet count or function Renal impairment (CrCI >30 mL/min) Age (>65 y) Previous major bleeding Severe renal impairment (dialysis or renal transplant) Severe hepatic disease (cirrhosis) Malignancy Genetic factors (eg, CYP 2C9 polymorphisms) Previous stroke, small vessel disease etc Diabetes mellitus Cognitive impairment/dementia Cystatin C/CKD-EPI cTnT-hs vWF (plus other coagulation markers) Figure 2 Risk factors for bleeding with oral anticoagulation and antiplatelet therapy. a For patients receiving VKA treatment. b Dose adaptation based on patient s age, body weight, and serum creatinine level. c Walking aids; appropriate footwear; home review to remove trip hazards; neurologic assessment where appropriate. d Increased INR monitoring, dedicated OAC clinicals, self-monitoring/self-management, educational/behavioral in- terventions. APTs antiplatelets; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; CrCl creatinine clearance; cTnT-hs high- sensitivity troponin T; CYP cytochrome P450; GDF-15 growth differentiation factor-15; INR international normalized ratio; NSAIDs nonsteroidal antiin ammatory drugs; SBP systolic blood pressure; vWF von Willebrand factor. See Figure 1 legend for expansion of other abbreviations. 1148 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] the patient would need to fall 295 times per year for the risk from falls to outweigh the bene ts of stroke In patients with cognitive impairment or dementia, OAC should only be withheld if there is no available caregiver who can guarantee medication adherence. Reversal of Biochemical Anomalies: Patients with anemia or reduced platelet count or function should be treated where possible to improve their hemoglobin or platelet count. Causes of renal impairment should be investigated and where possible reversed. Patients with liver function abnormalities were generally excluded from the randomized trials, and especially where there is abnormal clotting tests, such patients may be at higher risk of bleeding on VKA, possibly less so on NOACs; in cirrhotic patients, ischemic stroke reduction may outweigh bleeding risk.96,97 Bleeding Risk Assessment: Since 2006, six risk scores have been developed and validated for the assessment of bleeding risk in AF populations.98-103 The number of risk factors included in the bleeding risk schemas varies considerably, from three100 and the score or weighting associated with each risk factor also differs Age and prior bleeding are included as risk factors in all 6 bleeding risk scores but different age cutoffs are utilized, with 3 scores employing age 75 years or to indicate greater bleeding risk. Following age and prior bleeding, the most prevalent bleeding risk factors included in the scores are anemia,69,99-102 renal or uncontrolled and and prior stroke98,99 or hepatic A variety of other risk factors, including are included only in one bleeding risk score. For a comprehensive review of bleeding risk factors in AF patients see Zulki y et al.103 The bleeding risk scores range in the simplicity of calculation and the cutoffs employed to indicate low, intermediate, and high risk of bleeding, and the prevalence of bleeding events reported in the validation cohorts (Table 3). Use of Bleeding Risk Scores: As seen in Table 3, there are multiple bleeding risk scores that have been proposed for bleeding risk strati cation, with the HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older, reduced platelet count/ function, hypertension, anemia, genetic factors, excessive fall risk, and stroke), HAS-BLED (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile INR, elderly (0.65), drugs/alcohol concomitantly [1 point each]), ATRIA, ORBIT, and ABC-bleeding derived and validated in AF populations.103 The risk factors included vary by scores (Table 3), and their derivation from selected clinical trial cohorts or real- Various validation studies have been summarized in e-Table 10. Unsurprisingly, stroke risk scores are also associated with bleeding, as stroke and bleeding risks correlate with each other. For example, higher CHADS2 and CHA2DS2-VASc scores are also associated with greater bleeding risk, but the HAS-BLED score outperforms the CHADS2 and CHA2DS2-VASc scores for predicting which was also evident in the systematic review by Zhu et al.106 Composite risk scores that include stroke and bleeding end points have also been proposed but have not been shown to perform incrementally better over the individual scores.107,108 The bleeding risk scores in AF are also predictive of bleeding in non-AF populations; for example, in patients with ACS undergoing PCI-stenting.109 Adding more clinical variables marginally improves the predictive value (at least statistically), but the c-indexes still remain approximately 0.6. The addition of biomarkers would all improve the c-indexes (to approximately 0.65) over scores based on clinical risk factors alone. Many of these risk scores have been derived from highly selected clinical trial cohorts (often anticoagulated), with the biomarkers measured at baseline (or within a few months of study entry) then end points determined many years later. Biomarkers are also expensive, and may be subject to laboratory variability, inter-assay differences, diurnal variation and may change in individual patients depending on how risk factors and drug treatments change over time. Many biomarkers (eg, troponin, natriuretic peptides, in ammatory markers, coagulation markers, etc) are also predictive of stroke, bleeding, death, HF, hospitalization,110 and even noncardiovascular conditions such as glaucoma progression (eg, as in the case of growth differentiation factor-15 used in the ABC-bleed score).111 The performance of biomarker-based scores in real-world clinical practice (outside highly selected trial cohorts) has also been disappointing,112,113 given that baseline (or near-baseline) determination of biomarkers to predict bleeding risks after many years is bedeviled by the changing clinical risk pro le of patient s risks as well as modi cation of risk factors. Given that modi able bleeding risk factors should be addressed in all patients, the appropriate and responsible way to use a clinical risk score is to identify those patients at particularly high risk, for appropriate early review and follow-up (eg, in 4 weeks, rather than 4- 6 months) and depending on the outcome of interest, to address the associated modi able risk factors accordingly (Figs 2, 3). A high bleeding risk score is not a reason to withhold OAC, as the net clinical bene t is even greater in those patients with high bleeding risk. While bleeding risk is highly dynamic and depends on many potentially modi able bleeding risk factors,114 simply focusing on bleeding risk assessment using modi able bleeding risk factors alone is an inferior strategy compared with using a validated bleeding risk score which has been designed to formally assess bleeding score.78-80 A comparison of the different bleeding risk scores has been addressed in 2 systematic reviews, and the studies are summarized in e-Table 10. As with stroke risk scores, most bleeding risk scores based on simple clinical risk factors only have modest predictive value for identifying the high risk patients who sustain events (c-indexes approximately 0.6). The systematic review by Caldeira et al115 reported that the sensitivity, speci city and diagnostic ORs were, comparing HAS-BLED with ATRIA, sensitivity, speci city, and diagnostic ORs were, respectively, 0.41 (95% CI, 0.35- ATRIA. They concluded that HAS-BLED, due to its sensitivity (compared with other scores) and ease to apply, is recommended for the assessment of AF patients major bleeding risk. The systematic review by Zhu et al106 (11 studies) found that discrimination analysis demonstrates that HAS- BLED has no signi cant C-statistic differences for predicting bleeding risk in the low (RR, 1.16; 95% CI, 0.63-2.13; P .64) risk strati cation but underpredicts risk in the moderate (RR, 0.66; 95% CI, 0.51-0.86; P risk strata (e-Table 11). Zhu et al106 concluded that the HAS-BLED score performed better than the HEMORR2HAGES and ATRIA bleeding scores but was superior to the CHADS2 and CHA2DS2-VASc stroke scores for bleeding prediction. In a real-world AF cohort, there was no long-term advantage of the ABC- bleeding score over the HAS-BLED score, for predicting bleeding; in contrast, HAS-BLED was better in identifying those patients at low risk of bleeding.113 Given that the patient pathway may include AF patients initially on no antithrombotic therapy, aspirin, or anticoagulants, and the latter can include VKAs or NOACs, a bleeding risk score needs to be applicable throughout the patient pathway. The HAS-BLED score has been validated in AF patients from clinical trial and nontrial cohorts, whether on no antithrombotic therapy, aspirin or anticoagulants, VKA or non-VKA anticoagulants, and is predictive of bleeding in AF and non-AF cohorts, and in different ethnic groups.98,114,116 It is also the only bleeding score predictive of The HAS-BLED score has also been shown to be similar or outperform older bleeding scores, as well as more Patient with AF; Eligible for Oral Anticoagulation Bleeding risk assessment Identifies at risk patients for more regular review and follow-up A high risk bleeding risk score is not a reason or excuse to withhold OAC Low risk = No action High risk = Patient flagged up for review EHR and electronic alerts For patients with an increased risk of bleeding the bene t of OAC usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important Do not withhold OAC solely because the patient is at risk of falls - Uncontrolled hypertension - Labile INRs (if on VKA) - Concomitant use of aspirin and NSAIDs in anticoagulated patient - Alcohol excess Review and address potentially reversible bleeding risk factors Figure 3 Practical application of bleeding risk assessment in patients with AF. AF atrial brillation; EHR electronic health record. See Figure 1 and 2 legends for expansion of other abbreviations. 1150 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] simple bleeding scores that include fewer clinical parameters. Among VKA-treated patients, the nonconsideration of TTR would also mean that the HEMORR2HAGES, ORBIT, and ATRIA scores would all perform suboptimally in VKA-treated patients.118,119 Finally, bleeding risk assessment is dynamic, and should be formally reassessed and recorded at every patient contact. Indeed, follow-up HAS-BLED or delta HAS- BLED score was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of modi able bleeding risk factors.77 Recommendations 3. For patients with AF, bleeding risk assessment should be performed in all patients with AF at every patient contact and should initially focus on potentially modi able bleeding risk factors (Strong recommendation, low quality evidence). Remark: Modi able risk factors may include: Uncontrolled blood pressure, Labile INRs (in a patient taking VKA), Alcohol excess; Concomitant use of NSAIDs or aspirin, in an anticoagulated patient, bleeding tendency or predisposition (eg, treat gastric ulcer, optimize renal or liver function, etc). 4. For patients with AF, we recommend use of the HAS-BLED score to address modi able bleeding risk factors in all AF patients. Those potentially at high risk (HAS-BLED score 3) warrant more frequent and regular reviews or follow-up (Strong recommendation, moderate quality evidence). Remark: Given that bleeding risk is highly dynamic, attention to modi able bleeding risk factors should be prioritized during every patient contact or review. 5. In VKA-treated patients, we recommend use of the HAS-BLED score for bleeding risk assessment (Weak recommendation, low quality evidence). Remark: A high HAS-BLED score ($ 3) is rarely a reason to avoid anticoagulation. The individual modi able components of the score, when reviewed with the patient, can serve to ameliorate bleed risk Anti-Thrombotic Therapy and Other Approaches for Stroke Prevention The principal goal of OAC in AF is to reduce the risk of stroke and systemic embolism, while minimizing the incremental bleeding risk associated with OAC. Although these outcomes may be in part mechanistically related to lower risk of bleeding and ischemic stroke compared with therapies in the control arms, cardiovascular composite or survival outcomes presently do not re ect the primary rationale for therapy. Randomized Trials: VKAs Compared With Placebo or Control: In a meta-analysis of 2,900 subjects from 6 randomized trials, adjusted-dose warfarin was associated with a 64% relative risk reduction in stroke (95% CI, 49-74) (e-Table 12). The absolute risk reduction was 2.7% per year (from 4.5% per year in control subjects) in primary prevention subjects and 8.4% per year (from 12% per year in control subjects) in secondary Aspirin and APT Compared With Placebo or Control: In a meta-analysis of 8 trials of 4,876 subjects, APT compared with control or placebo was associated with a 22% (95% CI, 6-35) relative risk reduction in stroke The Stroke Prevention in AF (SPAF-I) study demonstrated decrease in risk of stroke from 6.3% per year in placebo subjects to 3.6% per year but a meta-analysis of 7 trials of 3,990 subjects found no signi cant bene t. SPAF-I was the only trial suggestive of a bene t for aspirin compared with placebo, but there was internal heterogeneity between the anticoagulation-eligible and anticoagulation-ineligible subgroups, and given the trial was stopped early, the effect size could have been exaggerated. Aspirin also showed no bene t in the elderly, or in preventing severe strokes. All these trials had signi cant heterogeneity in study design, variability in aspirin dose tested, short follow-up, and predated contemporary use of oral anticoagulation in AF. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-A) trial, which also predated the investigation of NOACs, compared aspirin plus clopidogrel vs aspirin monotherapy among patients in whom VKA was The study found a decrease in risk of stroke with dual antiplatelet therapy (DAPT), but the major bleeding rates with aspirin-clopidogrel were comparable to rates seen with warfarin (approximately 2% per year). VKAs Compared With APT: Of 12 studies comparing warfarin vs APT, warfarin was associated with a 39% relative risk reduction (95% CI, 22-52) in strokes In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W), the largest of these studies, warfarin was superior to DAPT to warfarin for stroke and a TABLE 4 ] Phase 3 AF Trials of NOAC vs Warfarin: Summary of Key Ef cacy and Safety Results Outcome Trial ENGAGE AF-TIMI 4876 Dabigatran (n 6,076) Dabigatran (n 6,015) Warfarin (n Rivaroxaban (n 7,131) Warfarin (n Apixaban (n 9,120) Warfarin (n Edoxaban (n 7,035) Edoxaban (n 7,034) Warfarin (n 7,036) Ef cacy Stroke/SEE Event rate (%/y) Ischemic stroke Event rate (%/y) Hemorrhagic stroke Event rate (%/y) P < .001 < .001 NA .02 NA < .001 NA < .001 < .001 NA MI Event rate (%/y) All-cause death Event rate (%/y) Safety Major bleeding Event rate (%/y) ICH Event rate (%/y) (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] cardiovascular composite outcome, with similar rates of NOACs Compared With VKAs: Several NOACs that directly inhibit thrombin (factor IIa) or activated factor X (factor Xa) have been approved as alternatives to VKAs for stroke prevention in AF. They differ from VKAs in that they have a rapid onset/offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. The predictable anticoagulant effects of the NOACs enable their administration in xed doses without the need for routine coagulation monitoring, thereby simplifying therapy. Individually in their respective phase 3 trials (Table 4), dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be at least as safe and effective as warfarin for preventing stroke and systemic embolism in patients A meta-analysis of the four phase 3 trials compared patients taking NOACs (higher dose) (n 42,411) with warfarin (n 29,272) (e-Table 15).124 NOACs signi cantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR, 0.81; 95% CI, 0.73- 0.91; P < .0001). The bene t was driven primarily by a 51% reduction in hemorrhagic stroke (RR, 0.49; 95% CI, 0.38-0.64; P < .0001). Ischemic stroke was similar between NOACs and warfarin (RR, 0.92; 95% CI, 0.83- 1.02; P .10). NOACs were also associated with a signi cant 10% reduction in all-cause mortality (RR, safety, NOACs were associated with a nonsigni cant 14% reduction in major bleeding (RR, 0.86; 95% CI, 0.73-1.00; P .06) but a substantial 52% reduction in ICH (RR, 0.48; 95% CI, 0.39-0.59; P < .0001). NOACs were, however, associated with a signi cant increase in P .04). The relative ef cacy and safety of NOACs were consistent across all patient subgroups with the exception that the relative reduction in major bleeding with NOACs was greater at centers with poor INR control as de ned as a center-based TTR < 66% (RR, 0.69; 95% CI, 0.59-0.81; P interaction .02). Lower dose NOAC regimens (dabigatran 110 mg and edoxaban 30/15 mg) showed similar overall reductions in stroke or systemic embolism but a more favorable bleeding pro le than warfarin but were associated with more ischemic strokes (the lower dose regimen edoxaban 30/15 mg is not approved for the stroke prevention indication). TABLE ] (Continued) Outcome Trial RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI Dabigatran mg (n Dabigatran mg (n Warfarin (n Rivaroxaban mg (n Warfarin (n Apixaban mg (n Warfarin (n Edoxaban mg (n Edoxaban mg (n Warfarin (n HR CI) NA NA NA NA P < < NA NA < NA < < NA GI bleeding Event rate (%/y) HR CI) NA NA NA NA P NA < NA NA < NA ARISTOTLE Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE AF-TIMI Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis In Myocardial Infarction study HR hazard ratio; RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET AF Rivaroxaban Once Daily Oral Direct Factor Xa Inhibi- tion Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; SEE systemic embolic events. See Table legend for expansion of other abbreviations. NOACs vs Aspirin: Apixaban is the only NOAC that has been compared with aspirin in AF patients. The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial compared apixaban 5 mg bid with aspirin in AF patients who were not candidates for VKA The trial was stopped early for bene t as apixaban signi cantly reduced the risk of stroke or systemic embolism compared with aspirin (HR, 0.45; 95% CI, 0.32-0.62; P < .001) (e-Table 16). There was no signi cant difference in major bleeding (HR, 1.13; 95% CI, 0.74-1.75; P .57) between apixaban and aspirin. Real-World Observational Data: With the availability of large health-care system administrative data and the advent of quality improvement and postmarketing anticoagulation registries, the number of observational outcome studies on OAC in AF far outnumber randomized trials. Although these data have helped to successfully identify treatment variation and gaps in care, the use of these data for comparative effectiveness and safety studies of OACs must be interpreted with prudence. Despite the use of sophisticated, high quality methods to minimize confounding and bias and improve causal inference, even very small amounts of residual confounding by treatment selection or measurement error can attenuate or amplify the small absolute risk differences observed in the randomized trials. Similarly, de nitive conclusions cannot be drawn from indirect comparisons such as network meta-analyses of NOACs to each other due to small absolute risk differences. Real-world or observational data are generally insuf cient to guide selection of individual anticoagulant drugs. Therefore, observational data are best used to reaf rm that real-world effectiveness is concordant with clinical trial ef cacy, based on both quality of care and generalizability.126 A meta-analysis of real-world observational studies of dabigatran was consistent with ndings from Randomized Evaluation of Long-term Anticoagulant Therapy with Dabigatran Etexilate (RE-LY). Compared with VKA, risk of stroke with dabigatran vs warfarin was Dabigatran was also associated with a lower risk of intracranial bleeding (HR, 0.45; 95% CI, 0.38-0.52) and lower risk of death (HR, 0.73; 95% CI, 0.61-0.87). Risk of gastrointestinal bleeding was higher. One systematic review and meta-analysis provided comparative effectiveness and safety data for rivaroxaban vs dabigatran (n 3 trials), rivaroxaban vs warfarin (n 11 trials), or both (n 3 trials) for stroke prevention in AF.128 Overall, the risks of stroke/ systemic thromboembolism with rivaroxaban were similar compared with dabigatran but were signi cantly reduced when compared with warfarin (HR, 0.75; 95% CI, 0.64-0.85). Major bleeding risk was signi cantly higher with rivaroxaban vs dabigatran (HR, 1.38; 95% CI, 1.27-1.49) but similar to warfarin (HR, 0.99; 95% CI, 0.91-1.07). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding but similar risk of acute MI and ICH compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute MI but a higher risk of gastrointestinal bleeding and lower risk of ICH. Another large analysis of 3 Danish nationwide databases of 61,678 patients found that NOACs were at least as safe and effective as warfarin, with small but signi cant differences in risk of stroke, death, and bleeding across rivaroxaban, apixaban, and dabigatran.129 However, a new-user Food and Drug Administration Medicare analysis of 118,891 patients found that rivaroxaban compared with dabigatran had a statistical trend toward a decreased risk of stroke (HR, 0.81; 95% CI, 0.65-1.01) and signi cantly increased risk of intracranial (HR, 1.47; 95% CI, 1.32-1.67) and major non-intracranial (HR, Absolute risk differences were small (2.0-2.1 per 1,000 person-years) and well within a range vulnerable to confounding. Different Ethnic Groups: Asian AF patients have a higher risk of ICH compared with whites when VKAs The higher risk of bleeding on VKA in Asians vs non-Asians has also been observed in major clinical trials of NOACs,132 even though Asians received a lower intensity of anticoagulation with VKA.133 In a recent meta-analysis comprising 5 NOAC trials (RE-LY, ROCKET AF, Japanese Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [J-ROCKET AF], Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE], and Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation- Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48]), the effects of NOACs vs warfarin in 1154 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Asians vs non-Asians were compared.134 For standard- dose NOACs (dabigatran 150 mg, rivaroxaban 20 mg, apixaban 5 mg, and edoxaban 60 mg), the effect sizes of the primary ef cacy end point (stroke and systemic embolism) and the primary safety end point (major bleeding) were greater in Asians vs non-Asians. The risk reduction in hemorrhagic stroke and gastrointestinal bleeding was also greater in Asians vs non-Asians. These data suggest that standard-dose NOACs, when compared with warfarin, were more effective and safer in Asians than in non-Asians. The ef cacy and safety of low-dose NOACs (dabigatran 110 mg, rivaroxaban 15 mg, and edoxaban 30 mg), when compared with warfarin, appear similar among Asians and non-Asians. There are several real-world studies from Asia comparing NOACs with warfarin.135,136 Despite low- dose NOACs, such as dabigatran 110 mg or rivaroxaban 15 mg/10 mg, being more commonly used than standard-dose NOACs (dabigatran 150 mg or rivaroxaban 20 mg), the use of NOACs was associated with reduced risk of ischemic stroke or systemic embolization, major bleeding, ICH, and total mortality compared with warfarin. Published data suggest that NOACs are preferentially indicated for stroke prevention in Asians.37 Other Investigational Drugs: Although NOACs are safer than VKAs, serious bleeding still occurs. The potential for bleeding often discourages initiation of anticoagulant therapy in patients deemed to be at high risk of bleeding, and patients who experience a bleed frequently have permanent or prolonged discontinuation of their anticoagulant. Therefore, continued interest remains in developing even safer anticoagulants than thrombin and factor Xa inhibitors. Current investigation has focused on the upstream targets factor XI and factor XII in the contact pathway, as emerging research has elucidated their critical role in thrombosis with minimal or no role in Strategies to target factor XII or factor XI include antisense oligonucleotides that reduce hepatic synthesis of the clotting proteins, monoclonal antibodies that block activation or activity, aptamers, small molecules that block the active site or induce allosteric modulation, and polyanion antagoniststhat attenuate contact activation by nullifying stimulators of the pathway.7 Human data are limited. The factor XI-directed antisense oligonucleotide IONIS-416858 was compared with enoxaparin in 300 patients undergoing elective knee arthroplasty. Patients were randomized to receive IONIS-416858 at doses of 200 or 300 mg starting 35 days prior to surgery, or enoxaparin at a dose of 40 mg starting after the surgery. The 200 mg IONIS-416858 regimen was noninferior and the 300 mg IONIS-416858 regimen was superior compared with enoxaparin in preventing the composite end point of asymptomatic DVT, symptomatic DVT or pulmonary embolism, or VTE- The rates of major or clinically relevant nonmajor bleeding were 3% in both IONIS- 416858 groups and 8% in the enoxaparin group. With respect to patients with AF, potential unmet needs addressed by these agents include patients at high risk for bleeding, such as those with end-stage renal disease who are on hemodialysis (ongoing phase 2 study).141 Another area of interest is in patients with mechanical heart valves. 