(Adapted from Angiolillo et al.202 ) 1168 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] In a systematic review and meta-analysis (18 studies with 20,456 patients with AF; 7,203 patients received DAPT VKA and 13,253 patients received DAPT after PCI/stenting), Chaudhary et al280 showed that DAPT and VKA were associated with signi cantly lower risk of stroke, stent thrombosis, and all-cause mortality, but the risk of major bleeding was signi cantly higher in the DAPT and VKA group. Broadly similar conclusions were drawn from the systematic review and meta-analysis (17 studies, 104,639 patients) by Zhu et al281 where triple therapy (DAPT OAC) was associated with an increased risk of bleeding compared with DAPT alone, with no differences observed between triple therapy and the dual therapy for all-cause death, cardiovascular death, or thrombotic complications (ie, ACS, stent thrombosis, thromboembolism/stroke, and major adverse cardiac and cerebrovascular events). In both systematic reviews, there was marked heterogeneity in study size, patient population, intervention types, stent use, etc. Bennaghmouch et al282 reported a meta-analysis restricted to the subgroups of patients on aspirin therapy (n 21,722) from the 4 RCTs comparing VKA and NOACs (N 71,681) in AF patients. NOACs were more effective (outcome stroke or systemic embolism HR, 0.78 [95% CI, 0.67-0.91] and vascular death HR, 0.85 [95% CI, 0.76-0.93]) and as safe as VKA with respect to major bleeding (HR, 0.83 [95% CI, 0.69- 1.01]). NOACs were safer with respect to the reduction of ICH (HR, 0.38 [95% CI, 0.26-0.56]). Thus, it may be both safer and more effective to use NOACs compared with VKAs to treat patients with nonvalvular AF and concomitant aspirin therapy.


Thus, it may be both safer and more effective to use NOACs compared with VKAs to treat patients with nonvalvular AF and concomitant aspirin therapy. The largest observational cohort was reported by Lamberts et al,283 which included a total of 12,165 AF patients (60.7% male; mean age, 75.6 years) hospitalized with MI and/or undergoing PCI between 2001 and 2009. Relative to triple therapy (OAC plus DAPT; ie, aspirin plus clopidogrel), no increased risk of recurrent coronary events was seen for OAC plus clopidogrel (HR, 0.69; 95% CI, 0.48-1.00), OAC plus aspirin (HR, 0.96; 95% CI, 0.77-1.19), or aspirin plus clopidogrel (HR, 1.17; 95% CI, 0.96-1.42), but aspirin plus clopidogrel was associated with a higher risk of ischemic stroke (HR, 1.50; 95% CI, 1.03-2.20). OAC plus aspirin and aspirin plus clopidogrel were associated with a signi cant increased risk of all- cause death (HR of 1.52 [95% CI, 1.17-1.99] and HR of with triple therapy, bleeding risk was nonsigni cantly lower for OAC plus clopidogrel (HR, 0.78; 95% CI, 0.55- 1.12) and signi cantly lower for OAC plus aspirin and aspirin plus clopidogrel. Thus, OAC and clopidogrel was equal or better for both bene t and safety outcomes compared with triple therapy. However, this analysis provides limited information on the duration of therapies, quality of INR control, stent type, underlying bleeding risk pro le, etc. Randomized Trials: Prospective RCTs in AF patients presenting with ACS and/or undergoing PCI/stenting are limited. The rst trial was the What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting which randomized 573 adults receiving OACs (65% with AF) and undergoing PCI to clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy).


The rst trial was the What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting which randomized 573 adults receiving OACs (65% with AF) and undergoing PCI to clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy). The primary end point of any bleeding was seen in 19.4% receiving double therapy and 44.4% receiving triple therapy (HR, 0.36; 95% CI, 0.26-0.50; P < .0001). Of the secondary end points, there was no increase in the rate of thrombotic events, but all- cause mortality was higher in the triple-therapy arm. This trial was underpowered for ef cacy and safety end points, and the primary end point of any bleeding was driven by minor bleeds given that triple therapy was mandated for 12 months. The duration of triple therapy was also addressed by the Intracoronary Stenting and Antithrombotic Regimen- Testing of a Six-Week Versus a Six-Month Clopidogrel Treatment Regimen In Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting (ISAR-TRIPLE) study,285 an RCT in 614 patients receiving OAC plus aspirin, randomized to either 6 weeks of clopidogrel therapy (n 307) or 6 months of clopidogrel therapy (n 307). The primary end point (composite of death, MI, de nite stent thrombosis, stroke, or Thrombolysis In Myocardial Infarction major bleeding at 9 months) occurred in 30 patients (9.8%) in the 6-week group compared with 27 patients (8.8%) in the 6-month group (HR, 1.14; 95% CI, 0.68-1.91; P .63). There were no signi cant differences for the secondary combined ischemic end point of cardiac death, MI, de nite stent thrombosis, and 95% CI, 0.43-2.05; P .87) or the secondary bleeding end point of Thrombolysis In Myocardial Infarction 95% CI, 0.64-2.84; P .44).


There were no signi cant differences for the secondary combined ischemic end point of cardiac death, MI, de nite stent thrombosis, and 95% CI, 0.43-2.05; P .87) or the secondary bleeding end point of Thrombolysis In Myocardial Infarction 95% CI, 0.64-2.84; P .44). Thus, 6 weeks of triple therapy was not superior to 6 months of therapy with respect to net clinical outcomes, suggesting that physicians should weigh the trade-off between ischemic and bleeding risk when choosing a shorter or longer duration of triple therapy. In an open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial brillation who undergo percutaneous coronary intervention (PIONEER AF- 2,124 patients with AF undergoing PCI with stenting were randomized to low-dose rivaroxaban (15 mg once daily, reduced to 10 mg with moderate renal impairment) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard VKA (once daily) plus DAPT for 1, 6, or 12 months (group 3). The rates of clinically signi cant bleeding were lower in the 2 groups receiving rivaroxaban than in the VKA group (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; HR for group 1 group 2 vs group 3, 0.63; 95% CI, 0.50-0.80; P < .001). The rates of death from cardiovascular causes, MI, or stroke were similar in the 3 groups, but the trial was underpowered for ef cacy end points. There was only a minority of newer P2Y12 inhibitors used as APT.


There was only a minority of newer P2Y12 inhibitors used as APT. There was an associated reduction in hospitalizations in the 2 rivaroxaban arms, compared with VKA.287 The RE-DUAL PCI (A Prospective, Randomized, Phase 3b Study Comparing the Safety and Ef cacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting) randomized 2,725 patients with AF who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1-3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients ($ 80 years of age; $ 70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The incidence of the primary end point (major or clinically relevant nonmajor bleeding) was 15.4% in the 110-mg dual-therapy group compared with 26.9% in the triple-therapy group (HR, 0.52; 95% CI, 0.42 to 0.63; P < .001 for noninferiority; P < .001 for superiority) and 20.2% in the 150-mg dual-therapy group compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States noninferiority). The incidence of the composite ef cacy end point of thromboembolic events (MI, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in the 2 dual-therapy groups combined compared with 13.4% in the triple- therapy group (HR, 1.04; 95% CI, 0.84-1.29; P .005 for noninferiority).


The incidence of the composite ef cacy end point of thromboembolic events (MI, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in the 2 dual-therapy groups combined compared with 13.4% in the triple- therapy group (HR, 1.04; 95% CI, 0.84-1.29; P .005 for noninferiority). Thus, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. In contrast to the PIONEER-AF trial, the RE-DUAL PCI trial tested dabigatran doses (110 mg and 150 mg bid) which are licensed for stroke prevention in AF. There are limited data on the use of the newer P2Y12 inhibitors (ticagrelor, prasugrel) with OAC. Observational cohorts in AF patients report a higher bleeding rate where these newer APT agents are used as part of a triple-therapy regimen, compared with when clopidogrel is used as part of the triple-therapy Only a minority of patients in PIONEER AF-PCI had newer P2Y12 agents, whereas the largest experience in AF patients was in the RE-DUAL PCI trial, which allowed ticagrelor in combination with dabigatran 110 mg or 150 mg bid. In the GEMINI-ACS-1 trial (A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary 3,037 patients with ACS (ie, essentially a non-AF population) were randomly assigned to either aspirin 100 mg or rivaroxaban 2.5 mg bid, and the subsequent choice of clopidogrel (44%) or ticagrelor (in 56%) during trial conduct was nonrandomized.


In the GEMINI-ACS-1 trial (A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary 3,037 patients with ACS (ie, essentially a non-AF population) were randomly assigned to either aspirin 100 mg or rivaroxaban 2.5 mg bid, and the subsequent choice of clopidogrel (44%) or ticagrelor (in 56%) during trial conduct was nonrandomized. Low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of ACS patients had similar risks of clinically signi cant bleeding (5%) as aspirin and a P2Y12 inhibitor (HR, 1.09; 95% CI, 0.80-1.50; P .5840). Stable Vascular Disease: The presence of vascular disease adds to stroke risk in patients with AF. In the Danish registries, AF patients with vascular disease (prior MI, prior PAD, or aortic plaque) as a single risk factor have a high stroke rate of 4.85 per 100 person-years.291 This corresponds to CHA2DS2-VASc 1 for males and CHA2DS2-VASc 2 for females, with rates of 4.53 and 1170 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] 5.69, respectively. Contrasting low risk CHA2DS2-VASc (ie, score 0 [male] or 1 [female]) as a reference population vs those with $1 additional stroke risk factors (ie, CHA2DS2-VASc score 1 [males] or 2 [females]), the risk attributable to vascular disease had a crude HR of 2.7 PAD may confer an ischemic stroke risk that is much higher than that seen in Western populations.38 In AF patients with stable coronary artery disease, there is no evidence that adding APT to OAC reduces stroke/ systemic embolism, death, or MI. However, the risk of majorbleeding and ICH is substantially increased with the addition of APT to OAC.


However, the risk of majorbleeding and ICH is substantially increased with the addition of APT to OAC. The largest cohort was reported by Lamberts et al293 where 8,700 AF patients (mean age, 74.2 years; 38% women) with stable coronary artery disease (de ned as 12 months from an acute coronary event) followed up for a mean 3.3 years, found the risk of MI/coronary death was similar for VKA plus aspirin (HR, 1.12; 95% CI, 0.94-1.34) and VKA plus clopidogrel (HR, 1.53; 95% CI, 0.93-2.52), relative to VKA monotherapy. However, the risk of bleeding increased > 50% when aspirin (HR, 1.50; 95% CI, 1.23-1.82) or clopidogrel (HR, 1.84; 95% CI, 1.11-3.06) was added to VKA. In the RCTs of NOACs compared with warfarin, aspirin at < 100 mg daily was allowed. Ancillary analyses show no added bene t of adding aspirin on stroke or mortality rates; however, absolute bleeding rates were higher with combination therapy, but the relative ef cacy and safety with NOAC vs warfarin use were maintained irrespective of aspirin use.294 Only the RE-LY trial showed data for combination of dabigatran with aspirin and/or clopidogrel, and as expected, major bleeding risks were increased with a single APT and further increased where 2 APTs were used.295 Less data are evident for OAC use in AF patients with stable isolated PAD or carotid disease, in relation to OAC use. However, it is reasonable to assume that data for coronary artery disease would be generally applicable to PAD or carotid disease.


However, it is reasonable to assume that data for coronary artery disease would be generally applicable to PAD or carotid disease. One post hoc from the ROCKET-AF trial reported that the ef cacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR, 1.19; 95% CI, 0.63-2.22) and without PAD (HR, there was a higher risk of major bleeding or non- major, clinically relevant bleeding with rivaroxaban when compared with warfarin in AF patients with PAD (HR, 1.40; 95% CI, 1.06-1.86) compared with those without PAD (HR, 1.03; 95% CI, 0.95-1.11; interaction P .037). Recommendations 20. In AF patients presenting with an ACS and/or undergoing PCI/stenting, we recommend assessment of stroke risk using the CHA2DS2-VASc score (Strong recommendation, moderate quality evidence). Remark: All such patients are not low risk and should be considered for concomitant OAC. 21. In AF patients presenting with an ACS and/or undergoing PCI/stenting, we suggest attention to modi able bleeding risk factors at every patient contact, and assessment of bleeding risk using the HAS-BLED score (Weak recommendation, low quality evidence). Remark: Where bleeding risk is high (HAS-BLED $ 3), there should be more regular review and follow-up. 22. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is low (HAS-BLED 0-2) relative to risk for recurrent ACS and/or stent thrombosis, we suggest triple therapy for 1 month, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) until 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 23.


In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is low (HAS-BLED 0-2) relative to risk for recurrent ACS and/or stent thrombosis, we suggest triple therapy for 1 month, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) until 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 23. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is high (HAS- BLED 3), we suggest triple therapy for 1 month, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) for 6 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 24. In AF patients requiring OAC undergoing elective PCI/stenting, where bleeding risk is unusually high and thrombotic risk relatively low, we suggest use of OAC plus single antiplatelet (preferably clopidogrel) for 6 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). Remark: Patients at unusually high bleeding risk may include patients with HAS-BLED $ 3 and recent acute bleeding event. High thrombotic risk may include those with left main stent, multivessel PCI/stenting, etc. 25. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting, where bleeding risk is low (HAS-BLED 0-2) relative to risk for ACS or stent thrombosis, we suggest triple therapy for 6 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) until 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 26. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting, where bleeding risk is high (HAS-BLED 3), we suggest triple therapy for 1- 3 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) up to 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 27.


In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting, where bleeding risk is high (HAS-BLED 3), we suggest triple therapy for 1- 3 months, followed by dual therapy with OAC plus single antiplatelet (preferably clopidogrel) up to 12 months, following which OAC monotherapy can be used (Weak recommendation, low quality evidence). 27. In AF patients requiring OAC presenting with an ACS, undergoing PCI/stenting where bleeding risk is unusually high and thrombotic risk low, we suggest OAC plus single antiplatelet (preferably clopidogrel) for 6-9 months may be considered, following which OAC monotherapy can be used. (Weak recommendation, low quality evidence). Remark: Patients at unusually high bleeding risk may include patients with HAS-BLED $ 3 and recent acute bleeding event. High thrombotic risk may include those with left main stent, multivessel PCI/stenting, etc. 28. In AF patients with ACS or undergoing PCI in whom OAC is recommended, we suggest using VKA with TTR > 65-70% (INR range 2.0-3.0), or to use an NOAC at a dose licensed for stroke prevention in AF (Weak recommendation, low quality evidence). Remark: Only dabigatran 150 mg bid or (not licensed in USA) 110 mg bid or rivaroxaban 15mg qd are currently supported by clinical trial evidence. An NOAC based strategy has lower bleeding risk compared to a VKA- based strategy. 29. In AF patients in which aspirin is concomitantly used with OAC, we suggest a dose of 75-100 mg qd with concomitant use of PPI to minimize gastrointestinal bleeding (Weak recommendation, low quality evidence). 30. In AF patients in which a P2Y12 inhibitor is concomitantly used with OAC, we suggest the use of clopidogrel (Weak recommendation, low quality evidence). Remark: Newer agents (eg, ticagrelor) can be considered where bleeding risk is low.


Remark: Newer agents (eg, ticagrelor) can be considered where bleeding risk is low. Data on the combination of ticagrelor with either dabigatran 110 mg bid or 150 bid (without concomitant aspirin use) are available from the RE-DUAL PCI trial. *31. For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation, we suggest OAC with either an NOAC or adjusted- dose VKA therapy alone (target international normalized ratio [INR] range, 2.0-3.0) rather than the combination of OAC and aspirin (Weak recommendation, low quality evidence).


For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation, we suggest OAC with either an NOAC or adjusted- dose VKA therapy alone (target international normalized ratio [INR] range, 2.0-3.0) rather than the combination of OAC and aspirin (Weak recommendation, low quality evidence). Catheter or Surgical Ablation, Electrophysiological Procedures Periprocedural Anticoagulation for Catheter Ablation and Implantable Devices: Randomized trials have shown that uninterrupted warfarin is safe and superior to warfarin interruption for implantation of cardiac implantable electronic devices.7 For catheter ablation, anticoagulation guidelines pertinent to cardioversion generally apply to periprocedural anticoagulation and are detailed in a recent professional society expert consensus In a randomized trial of 1,584 patients, uninterrupted warfarin, compared with interruption with heparin bridging, has been shown to have a lower risk of periprocedural stroke and bleeding.298 A randomized trial of uninterrupted rivaroxaban vs uninterrupted VKA in AF ablation demonstrated similar event rates in both arms.299 A similar randomized trial of uninterrupted dabigatran found that dabigatran was associated with fewer bleeding complications than uninterrupted warfarin.300 Although these studies were open-label, they strongly support the use of uninterrupted anticoagulation for electrophysiology procedures (Table 9).298-301 Two recent systematic reviews with meta-analyses that include studies with such patients consistent with Long-term Anticoagulation After Restoration of Sinus Rhythm Clinical observations indicate that AF and stroke are often temporally discordant, with stroke occurring during periods of sinus rhythm in the majority of patients with paroxysmal AF.304,305 After catheter ablation, discontinuation of OAC is associated with an increased risk of stroke.297 Similarly, postoperative AF may confer a long-term risk of stroke.


Catheter or Surgical Ablation, Electrophysiological Procedures Periprocedural Anticoagulation for Catheter Ablation and Implantable Devices: Randomized trials have shown that uninterrupted warfarin is safe and superior to warfarin interruption for implantation of cardiac implantable electronic devices.7 For catheter ablation, anticoagulation guidelines pertinent to cardioversion generally apply to periprocedural anticoagulation and are detailed in a recent professional society expert consensus In a randomized trial of 1,584 patients, uninterrupted warfarin, compared with interruption with heparin bridging, has been shown to have a lower risk of periprocedural stroke and bleeding.298 A randomized trial of uninterrupted rivaroxaban vs uninterrupted VKA in AF ablation demonstrated similar event rates in both arms.299 A similar randomized trial of uninterrupted dabigatran found that dabigatran was associated with fewer bleeding complications than uninterrupted warfarin.300 Although these studies were open-label, they strongly support the use of uninterrupted anticoagulation for electrophysiology procedures (Table 9).298-301 Two recent systematic reviews with meta-analyses that include studies with such patients consistent with Long-term Anticoagulation After Restoration of Sinus Rhythm Clinical observations indicate that AF and stroke are often temporally discordant, with stroke occurring during periods of sinus rhythm in the majority of patients with paroxysmal AF.304,305 After catheter ablation, discontinuation of OAC is associated with an increased risk of stroke.297 Similarly, postoperative AF may confer a long-term risk of stroke. In a US claims analysis of 1.7 million patients hospitalized for surgery, perioperative AF was associated with an increased long-term risk of ischemic stroke, 1172 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] especially following noncardiac surgery.306 It is not known to what extent the risk was mediated by AF recurrence (often asymptomatic) or was independent of rhythm.


In a US claims analysis of 1.7 million patients hospitalized for surgery, perioperative AF was associated with an increased long-term risk of ischemic stroke, 1172 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] especially following noncardiac surgery.306 It is not known to what extent the risk was mediated by AF recurrence (often asymptomatic) or was independent of rhythm. Thus, patients should be anticoagulated according to their thromboembolic risk pro le based on CHA2DS2-VASc, regardless of whether sinus rhythm has been restored via ablation, cardioversion, or other means. Recommendations 32. In patients with AF in whom catheter ablation of AF or implantation of cardiac electronic implantable devices is planned, we suggest performing the procedure on uninterrupted VKA (within the INR therapeutic range), dabigatran or rivaroxaban (Weak recommendation, low quality evidence). 33. In patients in whom sinus rhythm has been restored, we suggest that long-term anticoagulation should be based on the patient s CHA2DS2-VASc thromboembolic risk pro le, regardless of whether sinus rhythm has been restored via ablation, cardioversion (even spontaneous), or other means (Weak recommendation, low quality evidence). Cerebrovascular Disease AF Patients Presenting With an Acute Ischemic Stroke or TIA: In AF-associated acute ischemic stroke, the risk of early recurrence is high: for example, the International Stroke Trial reported a 4.8% risk of recurrent stroke in those with AF within the rst while other studies suggest a recurrence risk of between 0.4% and 1.3% per day in the rst 7 to AF-related ischemic strokes are more often disabling or fatal than other types, with longer hospital stays and higher costs,312 so preventing early recurrence is a key clinical challenge. The safety and bene t of OAC in acute stroke have not been established.


The safety and bene t of OAC in acute stroke have not been established. Early anticoagulation (ie, in the rst few days) might increase the risk of symptomatic ICH, including hemorrhagic transformation of the infarct (estimated at approximately 1% per day313 ), leading to clinical uncertainty about when to start anticoagulation. Studies reported an 8% to 10% risk of recurrent ischemic stroke and a 2% to 4% risk of symptomatic ICH within 90 days of AF-related ischemic stroke.314,315 Current Uncertainty Regarding Optimal Timing of Anticoagulation: Current guidelines do not provide clear recommendations on the timing of OAC after acute AF-related stroke. US guidelines suggest that TABLE ] Summary of Studies of Periprocedural Anticoagulation for Catheter Ablation of AF and Implantation of Cardiac Electronic Implantable Devices Trial Population Interventions Results COMPARE Catheter ablation of AF N Uninterrupted warfarin vs interrupted warfarin with low-molecular weight bridging Signi cant reduction in stroke vs TIA vs and minor bleeding with uninterrupted warfarin VENTURE-AF Catheter ablation of AF N Uninterrupted rivaroxaban vs uninterrupted VKA No difference in overall low incidence of major bleeding or thromboembolic events RE-CIRCUIT Catheter ablation of AF N Uninterrupted dabigatran vs uninterrupted warfarin Signi cant reduction in major bleeding events with dabigatran vs BRUISE-CONTROL Pacemaker or de brillator implantation N Uninterrupted warfarin vs interrupted warfarin with heparin bridging Signi cant reduction in pocket hematoma vs BRUISE-CONTROL Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; COMPARE Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation; RE-CIRCUIT Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy trial; VENTURE-AF a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial brillation.


US guidelines suggest that TABLE ] Summary of Studies of Periprocedural Anticoagulation for Catheter Ablation of AF and Implantation of Cardiac Electronic Implantable Devices Trial Population Interventions Results COMPARE Catheter ablation of AF N Uninterrupted warfarin vs interrupted warfarin with low-molecular weight bridging Signi cant reduction in stroke vs TIA vs and minor bleeding with uninterrupted warfarin VENTURE-AF Catheter ablation of AF N Uninterrupted rivaroxaban vs uninterrupted VKA No difference in overall low incidence of major bleeding or thromboembolic events RE-CIRCUIT Catheter ablation of AF N Uninterrupted dabigatran vs uninterrupted warfarin Signi cant reduction in major bleeding events with dabigatran vs BRUISE-CONTROL Pacemaker or de brillator implantation N Uninterrupted warfarin vs interrupted warfarin with heparin bridging Signi cant reduction in pocket hematoma vs BRUISE-CONTROL Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; COMPARE Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation; RE-CIRCUIT Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy trial; VENTURE-AF a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial brillation. See Table and legends for expansion of abbreviations. commencing OAC within 14 days is reasonable,316 while recent European Society of Cardiology guidelines recommend starting anticoagulation according to based only on expert consensus. Current UK guidelines recommend delaying anticoagulation for 14 days for disabling stroke (Intercollegiate Stroke Working Party, National Clinical Guideline for Stroke 2016; https://www.strokeaudit.org).


Current UK guidelines recommend delaying anticoagulation for 14 days for disabling stroke (Intercollegiate Stroke Working Party, National Clinical Guideline for Stroke 2016; https://www.strokeaudit.org). A recent observational study (n 1,029) suggested that anticoagulation at 4 to 14 days after cardioembolic stroke had the best outcome but did not have statistical power to determine bene t of earlier anticoagulation.318 Increasing cerebral infarct size is associated with increased risk of both symptomatic hemorrhagic transformation and early recurrent ischemia.313 A systematic review and meta-analysis of 7 randomized trials of UFH, LMWH, or heparinoids (n 4,624) started < 48 h vs aspirin or placebo, found that early anticoagulation was associated with nonsigni cantly reduced recurrent ischemic stroke but with increased intracranial bleeding, and no reduction in death or disability (e-Table 19).310 In contrast, other small studies suggested fewer ischemic strokes without an increase in intracranial bleeding, as well as reduced mortality and disability with early initiation of VKAs (to achieve therapeutic levels by day 7).315,319-321 Observational data suggest that the use of LMWH (as a bridging strategy) together with oral anticoagulation is associated with a higher risk of symptomatic hemorrhage.314,322-324 Observational studies suggest that early (< 14 days) anticoagulation with NOACs might be safe.314,315,318,325 One study reported improved outcomes and no early ICH with NOAC started at a median of 4 days poststroke (n 1,192).326,327 The Pre-Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation: a Prospective Multicenter Registry- based Non-inferiority Randomized Controlled Clinical Trial (TIMING) observational study of 249 patients with AF-associated acute ischemic stroke treated with OAC (< 5 days) reported in-hospital recurrent ischemic stroke in 4.4%, and symptomatic ICH in 3.1%.328 There are no large trials of NOACs including patients within 7 to14 days of a stroke, but 1 small study (Phase 2 Exploratory Clinical Study to Assess the Effects of Xarelto (Rivaroxaban) Versus Warfarin on Ischemia, Bleeding, and Hospital Stay in Acute Cerebral Infarction Patients With Non-valvular Atrial Fibrillation [Triple AXEL]) randomized 195 patients with AF-related acute ischemic stroke to rivaroxaban or warfarin < 5 days and found similar rates of symptomatic/asymptomatic MRI- de ned recurrent ischemia (approximately 30%) or intracranial bleeding (approximately 30%) at 4 weeks, with reduced hospital stay for rivaroxaban.329 Recommendations 34.


In AF patients with acute ischemic stroke, we suggest that very early anticoagulation (< 48 h) using heparinoids or VKA should not be used (Ungraded consensus-based statement). Remark: Heparinoids should not be used as bridging therapy in the acute phase of ischemic stroke because they appear to increase the risk of symptomatic intracranial hemorrhage without net bene t. The optimal timing of anticoagulation after acute ischemic stroke is unknown. 35. In AF patients with acute stroke without contraindications, we recommend that long-term oral anticoagulation is indicated as secondary prevention (Strong recommendation, high quality evidence). Remark: The optimal timing of anticoagulation early after acute ischemic stroke is unknown. Early use of NOACs shows promise but requires testing in randomized controlled trials. 36. In AF patients with acute ischemic stroke, we suggest that oral anticoagulation should usually be started within 2 weeks of acute ischemic stroke, but the optimal timing within this period is not known (Ungraded consensus-based statement). Remark: Although infarct size is clinically used to guide timing of anticoagulation, it is predictive of a higher risk of early recurrent ischemia, hemorrhagic transformation of the infarct, and poor outcome, so might not be helpful in determining the net bene t of early treatment. Remark: Anticoagulation with NOACs soon after stroke (earlier than 1 week) has not been tested in randomized trials, but shows promise in observational studies. AF Patients With Intracranial Hemorrhage (ICH): Spontaneous (nontraumatic) intracranial hemorrhage (ICH) causes about 1 in 10 strokes, and is caused by the rupture of a cerebral artery or arteriole, most often a small vessel affected by either hypertensive arteriopathy or cerebral amyloid angiopathy (CAA). ICH is the most feared, often lethal, complication of antithrombotic (anticoagulant and antiplatelet) therapy.


ICH is the most feared, often lethal, complication of antithrombotic (anticoagulant and antiplatelet) therapy. Recent data indicate that about 50% of people with ICH are taking an 1174 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] antithrombotic agent at the time of ICH.330 In a recent hospital ICH cohort study, 25% of patients had AF.331 Risk of Ischemic Stroke: Survivors of ICH with AF are at risk of further brain ischemia but also recurrent ICH. The use of antithrombotic therapy (antiplatelet agents and anticoagulants) following ICH thus presents a major clinical dilemma. The risk of ischemic stroke with and without antithrombotic treatment must be weighed carefully against the possible increase in ICH risk associated with antithrombotic therapy. The risk of ischemic stroke in people with AF is typically estimated using instruments such as the CHA2DS2-VASC score, and it seems reasonable to use this score in populations of ICH survivors.332 Risk of Recurrent ICH: The future risk of ICH is highly variable; the annual recurrence risk was between 1.8% and 7.4% in one recent systematic review of observational CT is a highly sensitive test for ICH and can classify the location as lobar (originating in the lobes of the brain) or deep (originating in the basal ganglia or The risk of recurrence has been reported to be higher for lobar ICH than after deep ICH,333 a nding which is probably related to different underlying small vessel diseases that cause ICH in the different locations. Although CT can de ne ICH location, it cannot reliably identify the underlying type of causal small vessel disease.


Although CT can de ne ICH location, it cannot reliably identify the underlying type of causal small vessel disease. MRI can identify biomarkers of small vessel disease, including cerebral microbleeds (CMBs), whose distribution can be used to diagnose CAA with high speci city in ICH cohorts.335 In a recent pooled analysis of observational studies, patients with ICH classi ed using CMBs as due to CAA had an approximately 7% annual recurrence risk, compared with about 1% for those not ful lling criteria for CAA.336 Since OACs increase the risk of ICH, some experts have recommended avoiding them in patients with ICH attributed to CAA. In survivors of ischemic stroke and TIA, CMBs are also associated with increased risk of ischemic stroke, although as the number of CMBs increases, the risk of future ICH increases more steeply than that of ischemic stroke.337 In ICH survivors, the number of CMBs is also associated with the risk of Balancing the Risks of Ischemic Stroke and Recurrent ICH: A decision analysis which modeled warfarin for AF in an ICH survivor suggested that in lobar ICH, avoiding warfarin increased quality-adjusted life years by 1.9, compared with 0.3 for deep ICH; the authors concluded that anticoagulation for AF should not be offered to patients with lobar ICH and only to survivors of deep ICH if the risk of ischemic events was high (> However, CMBs were not considered in this analysis. In contrast, recent real-world observational studies (including some very large registry datasets) from ICH survivors with AF suggest that anticoagulation might reduce mortality and ischemic complications, without an unacceptable increase in ICH.


In contrast, recent real-world observational studies (including some very large registry datasets) from ICH survivors with AF suggest that anticoagulation might reduce mortality and ischemic complications, without an unacceptable increase in ICH. A recent systematic review and meta-analysis of observational studies suggested that restarting anticoagulation was associated with a signi cantly lower risk of thromboembolic complications (pooled RR, 0.34; 95% CI, 0.25-0.45; Q 5.12; P for heterogeneity .28) with no increased risk of recurrent ICH (pooled RR, 1.01; 95% CI, 0.58-1.77; Q 24.68; P for heterogeneity < However, none of the real-world studies strati ed ICH by location, nor by CMB burden or distribution. Two small randomized studies of early anticoagulation after ICH were not able to con rm bene t There are no reliable randomized trial data to guide the timing of anticoagulation after ICH. In acute ICH, hematoma expansion is common and is aggravated by anticoagulation. Anticoagulants should therefore be reversed and avoided in acute ICH (< 24-48 h). A survival model based on observational data indicated that the total stroke risk (both ischemic and ICH) was lowest when anticoagulation was restarted after about 10 weeks, and a delay of at least 4 weeks after ICH was There are no large-scale RCTs to answer the question of whether long-term anticoagulation has net bene t in ICH survivors with AF. NOACs have an approximately 50% lower ICH risk than VKA124 and are therefore preferred in most ICH survivors, except where warfarin is indicated (eg, in those with metallic mechanical heart valves).


NOACs have an approximately 50% lower ICH risk than VKA124 and are therefore preferred in most ICH survivors, except where warfarin is indicated (eg, in those with metallic mechanical heart valves). Observational data suggest that ICH occurring on OAC are of similar size and with similar clinical outcome in patients taking VKA or NOACs.344 There are 2 ongoing randomized trials of antithrombotic use after ICH: APACHE-AF (http://apache-af.nl, aspirin vs apixaban vs no antithrombotics for the treatment of AF in patients after ICH) and Restart or Stop Antithrombotics Randomised Trial (RESTART) (www. restarttrial.org, antiplatelets vs no antiplatelets in patients with ICH with an indication for antiplatelets). LAA Occlusion in ICH Survivors: Randomized trials indicate that LAA occlusion (LAAO) has similar ef cacy to oral anticoagulation in patients with AF; thus, in ICH survivors with AF and high ischemic stroke risk, LAAO is a potentially attractive option to reduce ischemic stroke and systemic embolism from AF without the need to expose patients to a long-term risk of oral Observational data from 1,025 patients suggest that LAAO might be safe and effective in patients with a contraindication to long-term oral anticoagulation, but only a minority of patients (15%) in this study had suffered ICH.346 Small studies of ICH survivors suggest that LAAO, using antiplatelet treatment as periprocedural antithrombotic treatment, is safe and effective in this population, including those Randomized trials of LAAO, ideally in comparison to NOACs, are needed to de nitively determine the safety and ef cacy of each approach in ICH survivors. Recommendations 37. In patients with AF and high ischemic stroke risk, we suggest anticoagulation with an NOAC after acute spontaneous ICH (which includes subdural, subarachnoid, and intracerebral hemorrhages) after careful consideration of the risks and bene ts (Ungraded consensus-based statement).


In patients with AF and high ischemic stroke risk, we suggest anticoagulation with an NOAC after acute spontaneous ICH (which includes subdural, subarachnoid, and intracerebral hemorrhages) after careful consideration of the risks and bene ts (Ungraded consensus-based statement). Remark: The balance of net bene t from long-term oral anticoagulation might be more favorable in those with deep ICH or without neuroimaging evidence of cerebral amyloid angiopathy. Remark: In ICH survivors with AF, clinicians should aim to estimate the risk of recurrent ICH (using ICH location and, where available, MRI biomarkers including cerebral microbleeds) and the risk of ischemic stroke Remark: The optimal timing of anticoagulation after ICH is not known, but should be delayed beyond the acute phase (approximately 48 h) and probably for at least approximately 4 weeks. Randomized trials of NOACs and left atrial appendage occlusion are ongoing. 38. In ICH survivors at high risk of recurrent ICH (eg, those with probable cerebral amyloid angiopathy), we suggest left atrial appendage occlusion (Ungraded consensus-based statement). Remark: Cerebral amyloid angiopathy should be diagnosed using validated clinico-radiological criteria. AF Patients With Carotid Disease: Carotid stenosis is present in about 8% of people over the age of 60.349 A recent multicenter retrospective study found > 50% carotid stenosis in 18.3% of patients with AF, which was associated with a doubling of stroke risk.350 Thus, in patients with both carotid stenosis and AF, there are indications for both anticoagulation and APT, yet this combination, at least in the long term, is associated with high bleeding risk and is thus generally not recommended. Randomized trials show superiority for carotid endarterectomy over stenting in patients with symptomatic stenosis (> 50%) of the internal carotid This could reduce the need for combination therapy with OAC and antiplatelet drugs in those with AF.


Randomized trials show superiority for carotid endarterectomy over stenting in patients with symptomatic stenosis (> 50%) of the internal carotid This could reduce the need for combination therapy with OAC and antiplatelet drugs in those with AF. Current practice is to treat all potential stroke risk factors including AF and carotid stenosis. Those who have had successful carotid revascularization are typically managed with OAC alone. In patients with carotid stenosis not treated by revascularization (including those with asymptomatic disease) as well as AF, the optimal management is not known and requires further randomized data; meanwhile, decisions need to be tailored to the individual patient. Recommendations 39. In patients with AF and symptomatic carotid stenosis (> 50%), we suggest carotid revascularization with endarterectomy or stenting in addition to OAC as indicated (Weak recommendation, moderate quality evidence). TABLE 10 ] Phases of Screening for AF in Cryptogenic Stroke Patients, Methods and Incidence of AF Diagnosed355 4 Sequential Phases of Screening Cardiac Monitoring Methods % (95% CI) Diagnosed With Poststroke AF Phase 1 (emergency room) Phase 2 (in hospital) Serial ECG, continuous inpatient ECG monitoring, continuous inpatient cardiac telemetry, and in-hospital Holter monitoring Phase 3 ( rst ambulatory period) Phase 4 (second ambulatory period) Mobile cardiac outpatient telemetry, external loop recording, and implantable loop recording See Table 1 legend for expansion of abbreviation. 1176 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] 40. In patients with AF and carotid stenosis treated with revascularization, we suggest OAC therapy, without long-term antiplatelet therapy (Ungraded consensus-based statement). Remark: There is limited evidence to guide the optimal treatment of patients with AF and carotid stenosis not requiring revascularisation.


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.


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.


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).


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.


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.


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.


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.


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).


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 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).


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).


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).


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.


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.


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.


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).


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)?


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.


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.


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.


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.


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).


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.


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.


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.


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.


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).


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).


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.


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.


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.


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.