Remark: There is limited evidence to guide the optimal treatment of patients with AF and carotid stenosis not requiring revascularisation. Remark: Short-term concomitant antiplatelet therapy (dual or mono) is generally used in the immediate post- revascularization period (eg, 1-3 months). Patients Presenting With ESUS: In North America and Europe, about 1 in 4 ischemic strokes remain of uncertain etiology (ie, not attributable to de nite cardiac embolism, large artery atherosclerosis, or small artery disease), despite adequate investigation, and are termed Because most cryptogenic strokes are embolic, a more recent concept of ESUS has been developed. ESUS has been de ned as ischemic stroke detected by CT or MRI that, after a standardized and adequate diagnostic pathway including brain imaging, echocardiography, cardiac rhythm monitoring for at least 24 h, and imaging of the intracranial and extracranial arteries supplying the affected brain area: is not lacunar (subcortical, < 15 mm diameter); where there is absence of extracranial or intracranial atherosclerosis causing $ 50% luminal stenosis in the arteries supplying the area of ischemia; no major-risk cardioembolic source of embolism (permanent or paroxysmal AF, sustained atrial utter, intra-cardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent [< 4 weeks] MI, left ventricular ejection fraction < 30%, valvular vegetations, or infective endocarditis); and no other speci c cause of stroke identi ed (eg, arteritis, dissection, migraine/vasospasm, Thus, ESUS is a subcategory of cryptogenic stroke, accounting for about 1 in 6 ischemic strokes.357 A careful and systematic diagnostic workup in patients with ESUS is needed as there might be important management differences between underlying embolic sources if detected, such as aortic arch atheroma, patent foramen ovale, and paroxysmal AF. This brief section only refers to the latter. As a general principle, AF can be detected in a high proportion of ESUS patients, if we look harder, look longer and look with more sophisticated monitoring Screening consecutive patients with ischemic stroke with routine Holter or event loop recorder monitoring will identify new AF/atrial utter in Two RCTs clearly showed that prolonged cardiac monitoring increases the detection of occult AF in patients with TIA or acute ischemic stroke presenting in sinus rhythm. In Cryptogenic Stroke and Underlying Atrial Fibrillation [CRYSTAL AF], 441 patients randomly assigned to prolonged ambulatory cardiac monitoring with a subcutaneous implantable loop recorder or to a control group with conventional follow- up, detected more AF in the monitored group while in a 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event: A Randomized Controlled Trial [EMBRACE], 572 patients randomly assigned to additional ambulatory monitoring with a 30-day external loop recorder (intervention group) or a 24-h Holter monitor (control group) found more AF in the intervention group (16.1% vs 3.2% in the control group; In a systematic review and meta-analysis, Sposato described a much higher rate of AF detection after multi-phase sequential cardiac monitoring, at 23.7% (Table 10). Despite this, one recent analysis only found that 2.6% and 9.7% of stroke patients had ambulatory ECG monitoring in the 7 days and 12 months poststroke, leading to underdiagnosis.359 Unsurprisingly, AF is more likely to be detected in elderly patients with more prolonged monitoring, especially if there is evidence of prior embolic cortical or cerebellar In a retrospective analysis, newly detected atrial tachycardia or AF (atrial tachycardia/AF > 5 min on any day) was identi ed in 30% patients with implantable cardiac rhythm devices and $ 1 stroke risk factors during a follow-up of 1.1 years.362 The presence of atrial tachycardia/AF > 6 h on $ 1 day increased signi cantly with increased CHADS2 scores. Similarly, the Prevalence of Sub-Clinical Atrial Fibrillation Using an Implantable Cardiac Monitor in Patient With Cardiovascular Risk Factors [ASSERT-II] study reported that subclinical AF lasting $ 5 min was present in 34.4% per year, in a prospective cohort of elderly patients with risk factors but no prior stroke.363 Of note, data from the Athens Stroke Registry show that the CHADS2 and CHA2DS2-VASc scores are independently associated with the risk of ischemic stroke/TIA recurrence and death in ESUS patients, with the risk of stroke recurrence and death in patients with a CHA2DS2-VASc score $ 2 being approximately threefold and 15-fold higher compared with that in patients with a score of 0, respectively.364 If ESUS is phenotypically different from AF-associated stroke, we should see differences in stroke severity and outcomes; however, no difference in National Institutes of Health Stroke Scale score was evident in ESUS where AF was detected on follow-up, compared with where no AF was Nevertheless, it remains possible that within ESUS there is a spectrum of underlying proximal embolic sources, suggested by the strong effect of age on recurrence risk and mortality.366 Current guidelines recommend use of antiplatelet agents including aspirin in ESUS patients316 unless AF is detected (often requiring prolonged workup, as above), when such patients would be managed with oral anticoagulation. The available data (mainly from retrospective observational studies) suggest a sizeable rate of stroke recurrence (> 4% per year) despite the frequent use of antiplatelet agents in clinical practice.354 Thus, there is an important clinical need for more effective antithrombotic therapy for ESUS. Since a large proportion of ESUS are likely to be due to undetected AF, oral anticoagulation is a theoretically attractive option. Ongoing randomized trials comparing NOACs with aspirin in ESUS patients are in progress. Prior to data from these trials, physicians might, in the meantime, consider the use of anticoagulation in parallel with continued cardiac evaluation (eg, prolonged rhythm monitoring) after discussion and consideration of patient preference. AHREs Detected by Cardiac Implanted Electronic Devices Cardiac implanted electrical devices (CIEDs) with an atrial lead or with capability of rhythm discrimination (ie, implantable cardiac monitors) allow continuous monitoring of the cardiac rhythm and appropriate detection of atrial tachyarrhythmias, including AF, as AHREs as well as storing arrhythmia electrograms in the device s memory for review and speci c diagnosis. AHREs, currently de ned as episodes of at least 5 min of atrial tachyarrhythmias/AF with an atrial rate >180 beats/min, are usually asymptomatic, discovered during routine device follow-up, and classi ed in terms of duration of the single episode or time spent in atrial tachyarrhythmias during a day (from minutes to Although temporal cutoffs for detection and storage of AHRE data as short as 30 to 60 s have been used, the diagnostic accuracy is reliable when episodes $ 5 min in duration are considered, since, using this cutoff, the appropriateness in AF detection is 95%, minimizing the risk of over-sensing due to detection of artifacts caused by myopotentials or other sources of electrical Individual patient analysis of electrograms corresponding to AHREs is clinically indicated to exclude artifacts or other causes of inappropriate detection of atrial tachyarrhythmias or AF. Electrograms of AHREs correspond to intracardiac electrograms recorded from right atrial appendage or right atrium so a diagnosis of tachyarrhythmias can easily be made through analysis of tracings recorded in the device s memory.157 After detection of AHREs by CIEDs, conventional Holter or other ECG long-term recordings (ie, patient-operated devices) can be considered in speci c cases (eg, unavailable electrograms or unclear diagnosis at device electrograms analysis). The possibility of continuous monitoring of AF through implanted devices has led to new terms, such as AF burden, de ned as the overall time spent in AF during a speci ed period of time,368,376-378 and subclinical AF, corresponding to episodes of atrial tachyarrhythmias with duration between 5 min and 24 h, detected by a CIED in patients without clinical history or clinical symptoms of AF.367,370-372 The prevalence of AHRE, often reported as AF burden, among patients implanted with CIEDs varies, depending on underlying heart disease, periods of observation, and above all previous history of clinically overt atrial tachyarrhythmias, including AF. In the ASSERT study, subclinical atrial tachyarrhythmias with at least 6 min duration were detected within 3 months in approximately 10% of patients implanted with a CIED.371 During a follow-up period of 2.5 years, additional subclinical atrial tachyarrhythmias occurred in approximately 25% of patients, and around 16% of those who had subclinical atrial tachyarrhythmias developed symptomatic AF.371 Considering these ndings, as well as data from the literature reported in e-Table 20, there is evidence that AHREs with a duration > 5 to 6 min are common in patients implanted with CIEDs. In patients implanted with CIEDs for conventional indications, AHREs, with a short duration, ranging from 3 atrial premature complexes to 15 to 20 s, are currently considered of no speci c clinical signi cance since this type of AHRE was found not to be signi cantly 1178 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] associated with episodes of longer duration, or with an increased risk of stroke or systemic For this reason, most of the interest in patients with CIEDs is focused on AHRE with a duration $ 5 to 6 min, a nding associated with a substantial risk of subsequently presenting clinical AF (HR, 5.5-6.0), initially reported by the ancillary Atrial Diagnostics Ancillary Study of the Mode Selection Trial and then by the ASSERT study,371 where CIED-detected AHREs > 6 min were followed by clinical AF detected by a surface ECG in approximately 16% of patients at 2.5 years of follow-up (e-Table 21). The association between CIED-detected atrial tachyarrhythmias of variable durations and stroke or systemic thromboembolism has been evaluated by several studies that overall collected data on > 22,000 patients, taking into account the maximum duration of AHRE episode, or the maximum daily AF burden (ie, the maximum time spent in adjudicated AF in 1 day of the follow-up period).371,379-387 The studies show that AHRE burden with a duration $ 5 to 6 min are signi cantly associated with an increase in the risk of stroke or systemic thromboembolism (HR, 2-9). In a re-analysis of the ASSERT study,388 the increase in the risk of stroke occurred only when the longest duration of the various episodes of detected AHREs was > 24 h. The largest dataset of patients with CIED-detected AHREs was analyzed in the Stroke Prevention Strategies Based on Atrial Fibrillation Information From Implanted Devices [SOS AF] project, with a pooling of 3 prospective studies (Phase IV Long Term Observational Study of Patients Implanted With Medtronic CRDM Implantable Cardiac Devices [PANORAMA], Italian Clinical Services Project, and A Prospective Study of the Clinical Signi cance of Atrial Arrhythmias Detected by Implanted Device Diagnostics [TRENDS]) resulting in During a median follow-up of 24 months, 43% of an unselected cohort of patients with implanted devices experienced $ 1 day with $ 5 min of AHRE burden, and a 1-h threshold of AHRE burden was associated with an HR for ischemic stroke of 2.11 (95% CI, 1.22-3.64; P .008), although the absolute risk of ischemic stroke in patients with AHREs was low (0.39% annual rate in the whole cohort). Similarly, the found that an AHRE burden of 5.5 h in a day, in a 30-day period, was associated with a twofold increase in the adjusted risk of stroke (absolute risk of thromboembolism around 1.8% per year).383 Integration of AHRE presence, duration, or burden ($ 5 min or $ 24 h) into risk scores for thromboembolism may modestly improve c-statistics of both the CHADS2 and CHA2DS2-VASc scores for predicting stroke.389 The clinical signi cance of AHRE is presumably different from that of clinically identi ed AF since the latter, detected using conventional surface ECG methods, corresponds to a much higher AF burden as compared with patients with AHRE detected by continuous monitoring via a CIED.370,372 The actual rates of stroke or systemic embolic events reported in studies evaluating CIED-detected AHREs are often lower than what would be predicted by CHADS2 and CHA2DS2-VASc scores, and this may be related to concurrent treatment with OACs in each study, risk of under-reporting, and confounding. Also, the temporal relationship between ischemic stroke and AF is less strict than expected, since stroke may occur without the concurrent presence of atrial tachyarrhythmias or AF at the time of stroke or in the days before. These ndings suggest that the relationship between AF and stroke can be complex, with AF involved but not always in a causative role (mediated by a left atrial thrombus), but also simply representing a marker of increased vascular risk.368,372 Two RCTs are ongoing evaluating the ef cacy and risk/bene t ratio of oral anticoagulation to no oral anticoagulation (aspirin only) in patients with CIED- detected AHRE (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation [ARTESiA; and Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate In the absence of the results of these ongoing trials, management of patients with CIEDs-detected AHREs requires cardiological clinical evaluation, clinical decision-making, and follow up (Fig 7). OACs could be considered as a result of an individualized clinical assessment taking into account overall AHRE burden (in the range of multiple hours rather than few minutes) and speci cally presence of AHRE > 24 h, individual stroke risk (CHA2DS2-VASc), predicted risk/bene t of oral anticoagulation (speci cally risk of major bleeding), and informed patient preferences. Recommendations 41. For patients that present with a clinically documented episode of AF (12-lead ECG or other means, eg, external devices with validated rhythm detection), we suggest that the presence or absence of symptoms must not in uence the process of decision- making with regard to the need for anticoagulation based on risk strati cation (Ungraded consensus-based statement). 42. In cases of AHRE (atrial high-rate episodes) detected by a CIED of at least 5 min duration, we suggest that direct analysis of electrograms corresponding to AHRE is clinically indicated to exclude artifacts or other causes of inappropriate detection of atrial tachyarrhythmias or AF (Ungraded consensus-based statement). Remark: In patients with CIED-detected AHRE, a complete cardiological evaluation is indicated, with 12-lead ECG, general assessment of clinical conditions, and clinical risk strati cation for stroke using CHA2DS2-VASc score. Remark: There is no evidence in support or against prescription of oral anticoagulants in patients at risk of stroke (intermediate to high risk according to CHA2DS2-VASc) who present with AHREs, corresponding to atrial tachyarrhythmias/AF at electrograms assessment of less than 24 h duration. 43. In patients with AF, we suggest prescription of oral anticoagulants as a result of an individualized clinical assessment taking into account overall AHRE burden (in the range of hours rather than minutes) and speci cally, the presence of AHRE > 24 h, individual stroke risk (using CHA2DS2-VASc), predicted risk/bene t of oral anticoagulation and informed patient preferences (Ungraded consensus- based statement). Remark: In patients with CIED-detected AHRE, continued patient follow-up is recommended, preferentially combining clinical follow-up with remote monitoring of the CIED or else more frequent device interrogation than standard for CIED follow- up, to detect the development of clinical AF (symptomatic or asymptomatic), to monitor the evolution of AHRE or AF burden and speci cally the transition to AHRE lasting more than 24 h, onset or worsening of heart failure, or any clinical change that might suggest a change in clinical pro le or clinical conditions. Detection of AHRE Patient with a CIED, no previous AF and detection of AHRE ( 5-6 min and Clinical evaluation of device data and evaluation of patient cardiac status and profile Analysis of device electrograms (AF/atrial tachyarrhythmias confirmed? Artifacts excluded?) Consideration for ECG recordings (Holter, patient-operated devices) in specific cases (eg, unavailable electrograms or unclear diagnosis at device electrograms analysis) Clinical risk stratification for stroke (CHA2DS2VASc-score)? Clinical cardiological evaluation + 12-lead ECG If diagnosis of AF or atrial flutter and intermediate (CHA2DS2VASc score = 1 in males and = 2 in females) or high risk (CHA2DS2VASc score 2 in males and 3 in females): - Monitoring of AHRE evolution (remote monitoring is advised) - Clinical follow-up for evaluating if AHRE >24 h and/or clinical AF develops, as well as changes in patient status/clinical profile (eg, heart failure) - Individual considerations for prescription of OAC considering overall AHRE burden and AHRE >24 h, individual CHA2DS2VASc, predicted risk benefit of OAC (specifically risk of major bleeding) and patient preferences Clinical decision-making and follow-up Figure 7 Flowchart for clinical management and decision-making in patients with CIEDs-detected AHRE. AHRE atrial high-rate episode; CIED cardiac implanted electrical device. See Figure 1, 3, and 4 legends for expansion of other abbreviations. 1180 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Atrial Flutter The risk of thromboembolism and stroke in patients with atrial utter has been evaluated in relatively few studies compared with AF. However, patients with atrial utter frequently present phases of AF alternated with phases of classical utter or regular atrial rhythm.392-394 A systematic review on the thromboembolic risk associated with atrial utter, including 52 articles, found that thromboembolic event rates after cardioversion varied from 0% to 6% with a follow-up from 1 week to 6 Echocardiographic studies reported prevalence of intra-atrial thrombi from 0% to 38% and a prevalence of spontaneous echo contrast up One ablation study in non-anticoagulated patients with atrial utter reported thromboembolic events in 13.9% of cases.416 The differences in patient selection, type of study, and, importantly, use of oral anticoagulation explain the heterogeneity of reported data regarding echo ndings and thromboembolic complications. Observational studies demonstrated an increased risk of stroke (RR, compared with control subjects at long-term follow-up. A report from the Danish nationwide registry on patients undergoing an atrial utter ablation or an AF ablation procedure between 2000 and 2013 found that the rate of thromboembolic events for atrial utter patients was 0.46 per 100 person-years, not signi cantly different from that of patients presenting with AF (HR adjusted for several variables including The role of anticoagulant therapy for patients with atrial utter has not been evaluated in large randomized clinical trials, but because these patients often have concomitant AF or are at increased risk of developing AF, it is reasonable to base decisions regarding antithrombotic therapy on the same risk strati cation schemes and scores used for AF.3 Recommendation 44. For patients with atrial utter, we suggest that antithrombotic therapy decisions follow the same risk-based recommendations as for AF. (Ungraded consensus-based statement). Pregnancy AF and atrial utter are very rare during pregnancy, unless when there is an underlying structural heart disease or hyperthyroidism.417 Lone AF is uncommon in pregnancy and is associated with older age and late In countries where the prevalence of rheumatic heart disease is still high or among immigrants from these areas to Western countries, the prevalence of AF in pregnancy may be commonly related to rheumatic heart disease.418 Peri-partum cardiomyopathy AF is common, with a prevalence that may reach 10%, and may severely impair hemodynamic In a registry of > 250,000 pregnancies in Southern AF was evident in 0.6 per 1,000, more frequently in white women (1.1 per 1,000 pregnancies), and was associated with more advanced age, higher BMI, hypertension, hyperlipidemia, and diabetes. Decision-making on antithrombotic therapy during pregnancy has been reviewed in detail in the 9th Edition of the Antithrombotic Therapy and Prevention Guidelines; here we provide an update with recommendations focused on AF.421 The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. Pregnancy-induced changes in hemostasis lead to a state of hypercoagulability, so in a woman with AF at risk of stroke/thromboembolism in the non-pregnant state, pregnancy will increase this risk threefold to fourfold.421,422 VKAs cross the placenta and have the potential to cause fetal wastage, bleeding in the fetus, and teratogenicity. The most common fetal anomaly developing as a consequence of fetal exposure to warfarin consists of midfacial hypoplasia and stippled epiphyses and typically occurs after in utero exposure to VKAs during the rst trimester of pregnancy.421 VKAs have also been associated with CNS abnormalities after exposure during any trimester, but these complications are There is general consensus that in order to minimize the risk of warfarin embryopathy, it is reasonable to avoid warfarin between weeks 6 and 12 of gestation because of the high risk of fetal defects, especially if the dose of warfarin is higher than 5 mg per LMWH does not cross the placenta, and there is no evidence that LMWH causes teratogenicity or increases fetal bleeding. Because of accelerated clearance, LMWH has a shorter half-life and lower peak plasma concentration during pregnancy, thus potentially requiring higher doses. For this reason, use of LMWH (such as between weeks 6 and 12) has to be managed with dose adjustment according to weight and target anti-Xa level (4-6 h post-dose 0.8-1.2 U/mL). UFH does not cross the placenta and therefore can be safely used in pregnancy. However, it carries some risk of heparin-induced thrombocytopenia and osteopenia, which may lead to symptomatic vertebral fracture in Moreover, the pharmacokinetic changes of pregnancy result in a shorter half-life and lower peak plasma concentration of heparin compounds, with the need to titrate doses in order to keep the mid-interval aPTT (6 h post dose $ twice control values). Since both the risk of heparin- induced thrombocytopenia and the risk of osteoporosis are lower with LMWH than with UFH, the former is preferred as subcutaneous treatment during pregnancy. Pregnant women were excluded from participating in clinical trials evaluating NOACs. Given the rather low molecular weight of NOACs and data on placental transfer in rats, all NOACs are expected to cross the Hence, use of NOACs in pregnancy should be avoided. Limited data are available on the consequences of exposure to NOACs, but women inadvertently exposed to an NOAC in early pregnancy before diagnosis of pregnancy) can be reassured, since the risk of embryopathy seems low. In case of planned pregnancy, avoidance of NOACs should be considered (with switching to LMWH). Regarding breast-feeding, warfarin, in view of its characteristics (polar, non-lipophilic, and highly protein bound), can be considered safe since 2 reports showed that warfarin is not detected in breast milk and does not induce an anticoagulant effect in the breast-fed infant when breast-feeding mothers consume the drug.424,425 Acenocoumarol, which is commonly used in Europe, has similar properties.426,427 Use of UFH and LMWH in breast-feeding women appears safe. No clinical data on the effect of NOACs on breast-fed infants are available, and therefore the recommendation is against use these medications in breast-feeding women. A ow chart on how to manage women with AF during pregnancy is shown in Figure 8. Recommendations 45. For women receiving OAC for prevention of stroke/TE in AF who become pregnant, we suggest discontinuation of OAC with a VKA between weeks 6 and 12 and replacement by LMWH twice daily (with dose adjustment according to weight and target anti- Xa level 4-6 h post-dose 0.8-1.2 U/mL), especially in patients with a warfarin dose required of > 5 mg/day (or phenprocoumon > 3 mg/day or acenocoumarol > 2 mg/day). OAC should then be discontinued and replaced by adjusted-dose LMWH (target anti-Xa level 4-6 h post-dose 0.8-1.2 U/mL) in the 36th week of gestation (Ungraded consensus-based statement). 46. For women on treatment with long-term vitamin K antagonists who are attempting pregnancy and are candidates for LMWH substitution, we suggest performing frequent pregnancy tests and use LMWH instead of VKA when pregnancy is achieved rather than switching to LMWH while attempting pregnancy (Ungraded consensus-based statement). 47. For pregnant women, we suggest avoiding the use of NOACs (Ungraded consensus-based statement). Remark: For women on treatment with an NOAC we suggest switching to vitamin K antagonists, rather than switching to LMWH while attempting pregnancy. 48. For lactating women using warfarin, acenocoumarol, or UFH who wish to breast-feed, we suggest continuing the use of warfarin, Woman with AF on NOAC Woman with AF on VKA If planned pregnancy or diagnosis of pregnancy VKA until end of 5th week (LMWH as an alternative) VKA replaced by LMWH from 6th to 12th week LMWH replaced by VKA until 36th week (maintenance of LMWH as an alternative) VKA replaced by LMWH from 36th week to 24 h before delivery or cesarean section VKA or LMWH during lactation Figure 8 Management of women with AF during pregnancy is shown. LMWH low-molecular-weight heparin. See Figure 1 and 3 legends for expansion of other abbreviations. 1182 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] acenocoumarol, LMWH or UFH (Ungraded consensus-based statement). 49. For breast-feeding women, we suggest alternative anticoagulants rather than NOACs (Ungraded consensus-based statement). AF and CKD CKD is frequently present in patients with AF and has signi cant implications on the trajectory of AF, risk of stroke, and bleeding risk of anticoagulation. The presence of CKD or AF bi-directionally affects the incident risk of the other. Among patients with CKD, the prevalence of AF is substantially higher than in the general population, ranging from 16% to 21% in nondialysis dependent CKD and 15% to 40% in patients Among patients with AF, CKD is present in one-third of patients at the time of AF diagnosis51,429 although this may be substantially higher among cohorts of prevalent AF subjects. The impact of AF is illustrated in the systematic review by Odutayo et al,51 whereby the presence of AF increased CKD (HR, 1.64; 95% CI, 1.41 to 1.91), as well as major cardiovascular events (RR, 1.96; 95% CI, 1.53-2.51), sudden cardiac death (RR, 1.88; 1.36-2.60), HF (RR, 4.99; 95% CI, 3.04-8.22), and PAD (RR, 1.31; 95% CI, 1.19-1.45). AF, CKD, and Stroke: CKD increases the baseline risk of ischemic stroke in patients with AF.428 The pathophysiological mechanisms responsible for stroke and systemic embolism in these patients are multifactorial. The precise attributable risk of AF as a causal agent of cardioembolic stroke is therefore unclear, particularly where patients have substantially higher risk of atherothrombotic ischemic stroke due to hypertension, intracranial and carotid atherosclerosis, HF, and CAD. Second, CKD increases the competing risk of death from causes unrelated to AF-associated stroke and may attenuate expected bene t of stroke prevention therapy. In a recent analysis of 7 risk strati cation scores, all had substantially poorer discrimination in CKD patients than those without CKD (c-statistics, 0.50-59 vs 0.69- 0.70, respectively), and inclusion of CKD stage did not improve calibration or discrimination.430 One study from Taiwan showed that the CHA2DS2-VASc score could adequately risk stratify for ischemic stroke among a hemodialysis population (c-index, 0.682; superior to Third, moderate to severe CKD increases the risk of major and intracranial bleeding through a number of mechanisms, and the risk may be further increased by the use of oral anticoagulation or APT. The clinical bleeding risk scores (eg, HAS-BLED, ORBIT, RIA) all include CKD measures as part of their score calculation.103 Therefore, CKD is both a marker of risk of disease and of its therapy, and there is signi cant controversy as to the net clinical bene t of oral anticoagulation in severe CKD despite encouraging observational studies.432 Fourth, there are virtually no randomized trial data of oral anticoagulation in severe CKD (creatinine clearance [CrCl] < 25-30 mL/min). Some observational data suggest that warfarin may be harmful in end-stage renal disease patients on hemodialysis, with no reduction (or an increase) in stroke and an excess of major bleeding; however, many of these studies (largely from North America) do not report quality of anticoagulation control, as re ected by TTR.433-435 In contrast, European data suggest that there is a bene cial reduction in ischemic stroke which outweighs the increase in severe bleeding, where TTR is good (> 65%-70%).433-435 The latest systematic review and meta-analysis by Harel of 14 observational studies (20,398 participants) among hemodialysis with AF, found that the use of warfarin was not associated with ischemic stroke (14 or ICH (hemorrhagic stroke; 4 studies; 15,726 participants; concluded that warfarin was not associated with a clear bene t or harm among patients who have AF and receive dialysis. However, there was marked study heterogeneity including the inability to account for major confounders such as the quality of anticoagulation control (TTR). One study reported that in AF patients on peritoneal dialysis, warfarin reduced stroke and thromboembolism compared with aspirin or no antithrombotic therapy, with no excess in serious bleeds (ICH).246 The lack of clinical trial data in severe CKD is a major evidence gap with the NOACs, even though some regulatory agencies such as the Food and Drug Administration have approved reduced-dosed NOACs for severe CKD and dialysis on the basis of Fortunately, the pivotal NOAC randomized trials have demonstrated noninferiority of NOACs to warfarin among patients with CrCl of 30 to All the NOACs have some degree of renal elimination, Cmax, and half-life, with the greatest renal dependency for excretion with dabigatran (80%) and the least with renal dependency for apixaban (27%). However, there are no head-to-head NOAC trials and therefore insuf cient evidence to recommend one agent over another. Given these limitations, treatment should be individualized, and the dose adapted on the basis of CrCl according to licensed indications437 (Fig 9). Recommendations 50. For mild CKD (Stage II, CrCl 60-89 mL/min), we suggest that oral anticoagulation clinical decision- making and treatment recommendations match that of patients without CKD (Weak recommendation, very low quality evidence). 51. For moderate CKD (Stage III, CrCl 30-59 mL/ min), we suggest oral anticoagulation in patients with a CHA2DS2-VASc 2 with label-adjusted NOACs or dose-adjusted vitamin K antagonists (Weak recommendation, very low quality evidence). Remark: With VKA, good quality anticoagulation control (TTR > 65-70%) is recommended. 52. In severe non-dialysis CKD (Stage IV, CrCl 15- 30 mL/min), we suggest using VKAs and selected NOACs (rivaroxaban 15 mg QD, apixaban 2.5 mg bid, edoxaban 30 mg QD and [in USA only] dabigatran 75 mg bid) with caution, based on pharmacokinetic data (Ungraded consensus-based statement). 53. In end-stage renal disease (CrCl < 15 mL/min or dialysis-dependent), we suggest that individualized decision-making is appropriate (Ungraded consensus- based statement). 54. In end-stage renal disease (CrCl < 15 mL/min or dialysis-dependent, we suggest using well- managed VKA with TTR > 65-70% (Ungraded consensus-based statement). Remark: NOACs should generally not be used, although in USA, apixaban 5 mg bid is approved for use in AF patients receiving hemodialysis. CrCl If TTR 70% 150 mg bida (or 110 mg bid) 150 mg bid (or non-US, 110 mg bid)a 75 mg bid in USa 15 mg qd 2.5 mg bid 5 mg bid in US onlyb 30 mg qd 5 mg bidb 30 mg qd 5 mg bidb 15 mg qd 20 mg qd 60 mg qd Closely monitor renal function, especially in NOAC users. Schedule for frequent clinical follow-up, look for development of new cardiovascular risk factors, comorbidities. Reassess and address bleeding risk factors. (Outside US) (Outside US) If TTR 70% If TTR 70% If TTR 70% Drug VKA Dabigatran Rivaroxaban Apixaban Edoxaban CrCl CrCl CrCl <15 mL/min or ESRD on RRT Figure 9 Suggested algorithm for the decision-making process in prescribing OAC therapy in patients with various degrees of renal function impairment. a The 110-mg dose is not available in the United States. Unless the patient is elderly or has high bleeding risk or is taking p-glycoprotein inhibitors, where dabigatran 110 mg bid is preferred, except in the United States, where the 110-mg dose is not available. b Use 2.5 mg bid if 2 of 3 of the following criteria are present: age > 80 years, weight < 60 kg, or serum creatinine > 133 mmol/L. c In the United States, caution is advised when CrCl is > 95 mL/min. ESRD end-stage renal disease; RRT renal replacement therapy. (Adapted from Lau et al.437 ) See Figure 1 and 2 legends for expansion of other abbreviations. 1184 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Remark: In patients with CKD who initiate OAC, concomitant antiplatelet therapy including low-dose aspirin is likely to substantially elevate bleeding risk and should be used very judiciously. AF With Associated Valvular Heart Disease A recent physician survey438 reported marked heterogeneity in the de nition of valvular and nonvalvular AF and variable management strategies, including NOACs in patients with valvular heart disease other than prosthetic heart valves or hemodynamically signi cant mitral stenosis. While hypertrophic cardiomyopathy is sometimes discussed in association with valvular AF, this will not be addressed in this section; speci c guidelines on this condition are available.439 The use of the term nonvalvular AF is unfortunate and misleading as patients with a wide range of valvular pathology and severity were enrolled in all of the phase 3 NOAC trials. The only valvular heart disease uniformly excluded from all the NOAC trials were signi cant (moderate or severe) mitral stenosis and mechanical heart valves. A meta-analysis of the four phase 3 AF trials comparing NOAC with warfarin found that although patients with valvular heart disease are at higher risk compared with those without valvular disease, the ef cacy and safety of NOACs vs warfarin are consistent regardless of the presence or absence of valvular heart disease.239 AF patients with mechanical heart valves should only be prescribed VKAs. Data from the only phase II trial of an NOAC, dabigatran, in patients with mechanical heart valves (RE-ALIGN trial) demonstrated inferior ef cacy and more bleeding.440 However, patients with bioprosthetic valves were included in the ARISTOTLE (apixban),theEffectiveAnticoagulationwith Factor Xa Next Generation in Atrial Fibrillation Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48) (edoxaban), and the relative ef cacy and safety of NOACs compared with warfarin was consistent in these patients, although the number of patients with bioprosthetic valves was limited (< 300). In keeping with a recent European consensus document, with endorsement by international learned societies, we propose that the term valvular AF is outdated. Given that any de nition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (Evaluated Heart valves, Rheumatic or Arti cial) categorization in relation to the type of oral anticoagulation (OAC) use in patients with AF (Table 11). This classi cation would have the advantage that it may easily evolve or be updated (type 1 may become type 2 or vice versa) when there are new results. For example, transcatheter mitral valve interventions (eg, to include both MitraClip and Mitral valve replacement) are emerging as a possible but more data are awaited, especially in relation to OAC use. Also, EHRA type 1 is broadly similar to the previously described mechanical and rheumatic mitral valvular AF (MARM-AF).444 Nondrug Alternatives and Perioperative Considerations Occlusion of the LAA With Devices or Surgical Techniques: Approximately 90% of the thrombi found in patients with non-valvular AF and 57% of the thrombi found in valvular AF are located in the LAA.445 TABLE 11 ] Summary Box: EHRA Categorization in Relation to the Type of OAC Used in Patients With AF De nition EHRA type 1 VHD AF patients with VHD needing therapy with a vitamin K antagonist (VKA)  Mitral stenosis (moderate-severe, of rheumatic origin)  Mechanical prosthetic valve replacement EHRA type 2 VHD AF patients with VHD needing therapy with a VKA or an NOAC, also taking into consideration CHA2DS2-VASc score risk factor components  Mitral regurgitation  Mitral valve repair  Aortic stenosis  Aortic regurgitation  Tricuspid regurgitation  Tricuspid stenosis  Pulmonary regurgitation  Pulmonic stenosis  Bioprosthetic valve replacements  Trans-aortic valve intervention CHA2DS2-VASc congestive heart failure, hypertension, age $ 75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female); EHRA Evaluated Heart Valves, Rheumatic or Arti cial; VHD valvular heart disease. See Table 1 legend for expansion of other abbreviations. LAAO using speci c percutaneous devices (WATCHMAN, Amplatzer Cardiac Plug, or WaveCrest device or the Lariat endocardial and epicardial ligation technique) or occlusion during a cardiac surgery procedure with either LAA amputation and closure or a stapler device have been proposed and tested for patients with AF at high risk of stroke in the presence of a high risk of bleeding or in the presence of contraindications to OACs. Two randomized studies evaluated the WATCHMAN (Atritech, Inc) device vs warfarin: the Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation (PROTECT AF) and the Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL AF).446-452 In the PROTECT AF trial, the ef cacy of LAA closure with the device met the pre-speci ed criteria for non-inferiority vs warfarin, but the rate of adverse safety events in the intervention group was 4.4% with evidence of harmful periprocedural complications (pericardial effusion and procedure-related ischemic stroke). For acute complications, a learning curve appeared to be present, with serious pericardial effusions (requiring drainage) in 7.1% of the rst 3 implant patients at each site compared with 4.4% of subsequent patients.453 The serious complication rate of about 7% has been reported also for rst- or second-generation Amplatzer A recent systematic review network meta-analysis on the use of OACs and the Watchman device showed that the use of VKA, NOAC, and the Watchman device signi cantly reduce the risk of any stroke and systemic embolism as compared with placebo/control (Watchman device OR, 0.35; 95% CI, Data on the use of the WATCHMAN device in patients with contraindications to anticoagulation are very limited, and DAPT is needed for at least 6 weeks after the procedure, potentially exposing the patient to increased risk of bleeding.453 The Lariat device is based on an epicardial snare that requires positioning using a percutaneous approach to the epicardium through a pericardial access and in combination a percutaneous endocardial approach. In inexperienced operators, incomplete occlusion of the LAA after LARIAT ligation was relatively common (20% of cases) and was associated with risk of No randomized controlled study comparing this device with oral anticoagulation is currently available. In addition, the role of LAAO devices in AF patients also has to consider that no trials are available comparing these devices with NOACs. Thrombus formation on LAAO devices is also not uncommon (as high as 7.2% per year) and is associated with a risk of ischemic stroke during follow-up.458,459 Different surgical techniques have been applied for surgical exclusion of LAA (simple suture ligation, over- sewing of the LAA base without excision, appendage excision or amputation, surgical stapling), but data on TEE during follow-up suggest incomplete occlusion in up These observations and the lack of a clear bene t on stroke prevention evident from an RCT indicate that in patients with AF, these surgical techniques do not currently allow avoidance or interruption of oral anticoagulation in patients at risk of Recommendations 55. In patients with AF at high risk of ischemic stroke who have absolute contraindications for OAC, we suggest using LAA occlusion (Weak recommendation, low quality evidence). Remark: When taking into account LAAO as a potential option, the risk of bleeding related to antiplatelets agents that need to be prescribed in the rst months has to be considered and the possibility to use NOACs. 56. In AF patients at risk of ischemic stroke undergoing cardiac surgery, we suggest considering surgical exclusion of the LAA for stroke prevention, but the need for long-term OAC is unchanged (Weak recommendation, low quality evidence). Surgical Procedures and Interventions: Patients with AF on long-term prophylaxis with OACs may need surgical or interventional procedures that require appropriate management. Since bleeding risk may obviously be increased by the anticoagulant effect, interrupting anticoagulation for an intervention or a procedure transiently exposes the patient to increased risk of thromboembolism. Appropriate management requires balancing reducing the risk of thromboembolism and preventing excessive procedure- related bleeding. In the NOAC RCTs, surgical or other invasive procedures were required during a follow up of around 2 years in one-quarter of patients in RE-LY and one-third of patients in ROCKET AF and ARISTOTLE.72-74 1186 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] General principles of management can be considered, to be combined with individual clinical judgment, but they are derived from consensus of experts, since no data from RCTs are available to guide clinical decision- making. The following steps are important for appropriate management:  Estimation of the bleeding risk associated with a speci c intervention/procedure. The risk of bleeding can be predicted by the type of intervention and by its need, urgent or elective. e-Table 23 classi es surgical and interventional procedures according to bleeding risk as well as thromboembolic risk.205,464,465 The direct consequence of this evaluation is that in- terventions or procedure at very low bleeding risk, such as simple dental extractions or minor skin excision, can be planned and performed without interruption of oral anticoagulation. If the bleeding risk is substantial, then interruption of anticoagulation prior to the procedure intervention is needed to minimize the hemorrhagic risk, both in the intra-operative and immediate postoperative phase.  Estimation of patient thromboembolic risk. Calcu- late the CHA2DS2-VASc score (low risk if 0 or 1) but an additional transient increase in risk has to be considered in case of recent stroke or recent pulmo- nary embolism.  Planning of the timing of anticoagulation inter- ruption. The timing of interruption is strictly dependent on the speci c anticoagulant the patient is receiving and CrCl. Important differences exist be- tween the management of patients treated with VKA The effect of warfarin can be monitored through INR; however, no standard labo- ratory test exists to measure the effect of NOACs. Discontinuation of warfarin is usually instituted 5 days before an elective surgical intervention, with INR checked the day before surgery, with the usual indication that surgery can be regularly planned if the INR is # 1.4 to 1.5 the day before surgery or the same day of surgery.465 For NOACs, the planning of interruption and resumption of therapy for surgical interventions/procedures is dependent on the type of procedure/intervention, the speci c agent used, and renal function, estimated by creatine clearance (using the Cockroft-Gault equation). In case of urgent sur- gery, reversal of anticoagulation or speci c measures may be required.205,466  Evaluation of the need for bridging. Pre-operative bridging can be considered in patients receiving VKA who are at particularly high risk of thromboembolism (eg, recent stroke, mechanical heart valve).465 In these cases, LMWH at therapeutic doses is usually pre- scribed starting 3 days before the procedure/inter- vention. Postoperative bridging includes administration of an LMWH when VKA is resumed in the postoperative period, with administration of both agents until achievement of a therapeutic INR. The role of bridging has been tested in a randomized trial, Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Ther- apy for an Elective Invasive Procedure or Surgery (BRIDGE), performed in patients on warfarin who were candidates for an invasive procedure (patients with mechanical valves were excluded).94 The risk of thromboembolism after the procedure was similar in patients with and without bridging, but the risk of major bleeding was higher in those who were bridged. Thus, we suggest that preoperative bridging is not required in AF patients treated with warfarin who do not have a particularly high risk of throm- boembolism and who do not have a mechanical valve.  In patients receiving NOACs, bridging is not required, but bridging could be considered in the postoperative phase if the patient cannot take oral medications for a prolonged period. Recommendations 57. In AF patients taking warfarin without high risk of thromboembolism or do not have a mechanical valve, we suggest preoperative management without bridging (Weak recommendation, low quality evidence). 58. In AF patients on antithrombotic prophylaxis with warfarin with a high risk of thromboembolism or with a mechanical valve, we suggest preoperative management with bridging (Weak recommendation, low quality evidence). 59. In AF patients on antithrombotic prophylaxis with an NOAC, we suggest preoperative management without bridging (Weak recommendation, low quality evidence). The Patient Patient knowledge and understanding of the stroke risk associated with AF and the bene t of OAC to prevent stroke are crucial to patient acceptance of anticoagulants, as well as adherence, and life-long persistence (in most cases), to OAC. However, research demonstrates that AF patients generally have poor awareness and knowledge about their condition,467-472 medications used to treat AF, particularly OAC, and do not clearly comprehend the bene t/risk associated with stroke prevention regimens.203,468-471,473-478 Although there is increasing advocacy from clinical and expert consensus2,203,479 to incorporate patient preferences for treatment into the decision-making process, a patient s ability to make an informed decision may be hindered by their lack of understanding about the relationship between AF and stroke and the ef cacy/safety of OAC for stroke prevention, particularly at diagnosis, when these decisions are invariably addressed. Assessment of patient s knowledge (using the AF Knowledge or Jessa Atrial Fibrillation Knowledge ), as well as their values and preferences, could be undertaken to ascertain gaps to be lled; this may lead to better decision-making and improved adherence and persistence. Patient education is essential to provide patients with suf cient information to enable them to make an informed decision about whether they wish to take OAC, and if they do, which OAC they would prefer.203,476,482 Education needs to be tailored to the person s desire for information and their level of health literacy to promote patient understanding. Recently, a prospective survey of 499 AF patients (with and without previous stroke) in the United States found that most (87%) desired more information about AF and how to reduce their risk of AF- AF patients perceive greater satisfaction with treatment if they are engaged in treatment decisions and provided with relevant information (verbal, visual, written, electronic/on-line resources, as appropriate, chosen by the patient), which is well communicated by their health-care providers,467,473,483 and updated over time. Full details on shared decision-making, patient preferences, and patient education/counseling are provided in e-Tables 24-26. Recommendations 60. In AF patients who have previously refused OAC, we suggest reinforcing educational messages at each contact with the patient and revisit OAC treatment decisions (Ungraded consensus-based statement). Remark: Patient and physician treatment objectives often differ signi cantly and it is important to elicit from the patient what outcomes of OAC treatment are important to them. Remark: Explain the risk of stroke and bene t/risks of treatment in terms the patient can understand and signpost the patient to appropriate educational resources Acknowledgments Financial/non nancial disclosure: See e-Table 1 for complete list of con icts of interest. Endorsements: This guideline has been endorsed by the AF Association, American College of Clinical Pharmacy (ACCP), Arrhythmia Alliance, and StopA b.org. 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