For example, higher CHADS2 and CHA2DS2-VASc scores are also associated with greater bleeding risk, but the HAS-BLED score outperforms the CHADS2 and CHA2DS2-VASc scores for predicting which was also evident in the systematic review by Zhu et al.106 Composite risk scores that include stroke and bleeding end points have also been proposed but have not been shown to perform incrementally better over the individual scores.107,108 The bleeding risk scores in AF are also predictive of bleeding in non-AF populations; for example, in patients with ACS undergoing PCI-stenting.109 Adding more clinical variables marginally improves the predictive value (at least statistically), but the c-indexes still remain approximately 0.6. The addition of biomarkers would all improve the c-indexes (to approximately 0.65) over scores based on clinical risk factors alone. Many of these risk scores have been derived from highly selected clinical trial cohorts (often anticoagulated), with the biomarkers measured at baseline (or within a few months of study entry) then end points determined many years later. Biomarkers are also expensive, and may be subject to laboratory variability, inter-assay differences, diurnal variation and may change in individual patients depending on how risk factors and drug treatments change over time. Many biomarkers (eg, troponin, natriuretic peptides, in ammatory markers, coagulation markers, etc) are also predictive of stroke, bleeding, death, HF, hospitalization,110 and even noncardiovascular conditions such as glaucoma progression (eg, as in the case of growth differentiation factor-15 used in the ABC-bleed score).111 The performance of biomarker-based scores in real-world clinical practice (outside highly selected trial cohorts) has also been disappointing,112,113 given that baseline (or near-baseline) determination of biomarkers to predict bleeding risks after many years is bedeviled by the changing clinical risk pro le of patient s risks as well as modi cation of risk factors.


Many biomarkers (eg, troponin, natriuretic peptides, in ammatory markers, coagulation markers, etc) are also predictive of stroke, bleeding, death, HF, hospitalization,110 and even noncardiovascular conditions such as glaucoma progression (eg, as in the case of growth differentiation factor-15 used in the ABC-bleed score).111 The performance of biomarker-based scores in real-world clinical practice (outside highly selected trial cohorts) has also been disappointing,112,113 given that baseline (or near-baseline) determination of biomarkers to predict bleeding risks after many years is bedeviled by the changing clinical risk pro le of patient s risks as well as modi cation of risk factors. Given that modi able bleeding risk factors should be addressed in all patients, the appropriate and responsible way to use a clinical risk score is to identify those patients at particularly high risk, for appropriate early review and follow-up (eg, in 4 weeks, rather than 4- 6 months) and depending on the outcome of interest, to address the associated modi able risk factors accordingly (Figs 2, 3). A high bleeding risk score is not a reason to withhold OAC, as the net clinical bene t is even greater in those patients with high bleeding risk. While bleeding risk is highly dynamic and depends on many potentially modi able bleeding risk factors,114 simply focusing on bleeding risk assessment using modi able bleeding risk factors alone is an inferior strategy compared with using a validated bleeding risk score which has been designed to formally assess bleeding score.78-80 A comparison of the different bleeding risk scores has been addressed in 2 systematic reviews, and the studies are summarized in e-Table 10. As with stroke risk scores, most bleeding risk scores based on simple clinical risk factors only have modest predictive value for identifying the high risk patients who sustain events (c-indexes approximately 0.6).


As with stroke risk scores, most bleeding risk scores based on simple clinical risk factors only have modest predictive value for identifying the high risk patients who sustain events (c-indexes approximately 0.6). The systematic review by Caldeira et al115 reported that the sensitivity, speci city and diagnostic ORs were, comparing HAS-BLED with ATRIA, sensitivity, speci city, and diagnostic ORs were, respectively, 0.41 (95% CI, 0.35- ATRIA. They concluded that HAS-BLED, due to its sensitivity (compared with other scores) and ease to apply, is recommended for the assessment of AF patients major bleeding risk. The systematic review by Zhu et al106 (11 studies) found that discrimination analysis demonstrates that HAS- BLED has no signi cant C-statistic differences for predicting bleeding risk in the low (RR, 1.16; 95% CI, 0.63-2.13; P .64) risk strati cation but underpredicts risk in the moderate (RR, 0.66; 95% CI, 0.51-0.86; P risk strata (e-Table 11). Zhu et al106 concluded that the HAS-BLED score performed better than the HEMORR2HAGES and ATRIA bleeding scores but was superior to the CHADS2 and CHA2DS2-VASc stroke scores for bleeding prediction. In a real-world AF cohort, there was no long-term advantage of the ABC- bleeding score over the HAS-BLED score, for predicting bleeding; in contrast, HAS-BLED was better in identifying those patients at low risk of bleeding.113 Given that the patient pathway may include AF patients initially on no antithrombotic therapy, aspirin, or anticoagulants, and the latter can include VKAs or NOACs, a bleeding risk score needs to be applicable throughout the patient pathway.


In a real-world AF cohort, there was no long-term advantage of the ABC- bleeding score over the HAS-BLED score, for predicting bleeding; in contrast, HAS-BLED was better in identifying those patients at low risk of bleeding.113 Given that the patient pathway may include AF patients initially on no antithrombotic therapy, aspirin, or anticoagulants, and the latter can include VKAs or NOACs, a bleeding risk score needs to be applicable throughout the patient pathway. The HAS-BLED score has been validated in AF patients from clinical trial and nontrial cohorts, whether on no antithrombotic therapy, aspirin or anticoagulants, VKA or non-VKA anticoagulants, and is predictive of bleeding in AF and non-AF cohorts, and in different ethnic groups.98,114,116 It is also the only bleeding score predictive of The HAS-BLED score has also been shown to be similar or outperform older bleeding scores, as well as more Patient with AF; Eligible for Oral Anticoagulation Bleeding risk assessment Identifies at risk patients for more regular review and follow-up A high risk bleeding risk score is not a reason or excuse to withhold OAC Low risk = No action High risk = Patient flagged up for review EHR and electronic alerts For patients with an increased risk of bleeding the bene t of OAC usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important Do not withhold OAC solely because the patient is at risk of falls - Uncontrolled hypertension - Labile INRs (if on VKA) - Concomitant use of aspirin and NSAIDs in anticoagulated patient - Alcohol excess Review and address potentially reversible bleeding risk factors Figure 3 Practical application of bleeding risk assessment in patients with AF. AF atrial brillation; EHR electronic health record. See Figure 1 and 2 legends for expansion of other abbreviations.


See Figure 1 and 2 legends for expansion of other abbreviations. 1150 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] simple bleeding scores that include fewer clinical parameters. Among VKA-treated patients, the nonconsideration of TTR would also mean that the HEMORR2HAGES, ORBIT, and ATRIA scores would all perform suboptimally in VKA-treated patients.118,119 Finally, bleeding risk assessment is dynamic, and should be formally reassessed and recorded at every patient contact. Indeed, follow-up HAS-BLED or delta HAS- BLED score was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of modi able bleeding risk factors.77 Recommendations 3. For patients with AF, bleeding risk assessment should be performed in all patients with AF at every patient contact and should initially focus on potentially modi able bleeding risk factors (Strong recommendation, low quality evidence). Remark: Modi able risk factors may include: Uncontrolled blood pressure, Labile INRs (in a patient taking VKA), Alcohol excess; Concomitant use of NSAIDs or aspirin, in an anticoagulated patient, bleeding tendency or predisposition (eg, treat gastric ulcer, optimize renal or liver function, etc). 4. For patients with AF, we recommend use of the HAS-BLED score to address modi able bleeding risk factors in all AF patients. Those potentially at high risk (HAS-BLED score 3) warrant more frequent and regular reviews or follow-up (Strong recommendation, moderate quality evidence). Remark: Given that bleeding risk is highly dynamic, attention to modi able bleeding risk factors should be prioritized during every patient contact or review. 5. In VKA-treated patients, we recommend use of the HAS-BLED score for bleeding risk assessment (Weak recommendation, low quality evidence). Remark: A high HAS-BLED score ($ 3) is rarely a reason to avoid anticoagulation.


Remark: A high HAS-BLED score ($ 3) is rarely a reason to avoid anticoagulation. The individual modi able components of the score, when reviewed with the patient, can serve to ameliorate bleed risk Anti-Thrombotic Therapy and Other Approaches for Stroke Prevention The principal goal of OAC in AF is to reduce the risk of stroke and systemic embolism, while minimizing the incremental bleeding risk associated with OAC. Although these outcomes may be in part mechanistically related to lower risk of bleeding and ischemic stroke compared with therapies in the control arms, cardiovascular composite or survival outcomes presently do not re ect the primary rationale for therapy. Randomized Trials: VKAs Compared With Placebo or Control: In a meta-analysis of 2,900 subjects from 6 randomized trials, adjusted-dose warfarin was associated with a 64% relative risk reduction in stroke (95% CI, 49-74) (e-Table 12). The absolute risk reduction was 2.7% per year (from 4.5% per year in control subjects) in primary prevention subjects and 8.4% per year (from 12% per year in control subjects) in secondary Aspirin and APT Compared With Placebo or Control: In a meta-analysis of 8 trials of 4,876 subjects, APT compared with control or placebo was associated with a 22% (95% CI, 6-35) relative risk reduction in stroke The Stroke Prevention in AF (SPAF-I) study demonstrated decrease in risk of stroke from 6.3% per year in placebo subjects to 3.6% per year but a meta-analysis of 7 trials of 3,990 subjects found no signi cant bene t. SPAF-I was the only trial suggestive of a bene t for aspirin compared with placebo, but there was internal heterogeneity between the anticoagulation-eligible and anticoagulation-ineligible subgroups, and given the trial was stopped early, the effect size could have been exaggerated.


The absolute risk reduction was 2.7% per year (from 4.5% per year in control subjects) in primary prevention subjects and 8.4% per year (from 12% per year in control subjects) in secondary Aspirin and APT Compared With Placebo or Control: In a meta-analysis of 8 trials of 4,876 subjects, APT compared with control or placebo was associated with a 22% (95% CI, 6-35) relative risk reduction in stroke The Stroke Prevention in AF (SPAF-I) study demonstrated decrease in risk of stroke from 6.3% per year in placebo subjects to 3.6% per year but a meta-analysis of 7 trials of 3,990 subjects found no signi cant bene t. SPAF-I was the only trial suggestive of a bene t for aspirin compared with placebo, but there was internal heterogeneity between the anticoagulation-eligible and anticoagulation-ineligible subgroups, and given the trial was stopped early, the effect size could have been exaggerated. Aspirin also showed no bene t in the elderly, or in preventing severe strokes. All these trials had signi cant heterogeneity in study design, variability in aspirin dose tested, short follow-up, and predated contemporary use of oral anticoagulation in AF. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-A) trial, which also predated the investigation of NOACs, compared aspirin plus clopidogrel vs aspirin monotherapy among patients in whom VKA was The study found a decrease in risk of stroke with dual antiplatelet therapy (DAPT), but the major bleeding rates with aspirin-clopidogrel were comparable to rates seen with warfarin (approximately 2% per year).


The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-A) trial, which also predated the investigation of NOACs, compared aspirin plus clopidogrel vs aspirin monotherapy among patients in whom VKA was The study found a decrease in risk of stroke with dual antiplatelet therapy (DAPT), but the major bleeding rates with aspirin-clopidogrel were comparable to rates seen with warfarin (approximately 2% per year). VKAs Compared With APT: Of 12 studies comparing warfarin vs APT, warfarin was associated with a 39% relative risk reduction (95% CI, 22-52) in strokes In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W), the largest of these studies, warfarin was superior to DAPT to warfarin for stroke and a TABLE 4 ] Phase 3 AF Trials of NOAC vs Warfarin: Summary of Key Ef cacy and Safety Results Outcome Trial ENGAGE AF-TIMI 4876 Dabigatran (n 6,076) Dabigatran (n 6,015) Warfarin (n Rivaroxaban (n 7,131) Warfarin (n Apixaban (n 9,120) Warfarin (n Edoxaban (n 7,035) Edoxaban (n 7,034) Warfarin (n 7,036) Ef cacy Stroke/SEE Event rate (%/y) Ischemic stroke Event rate (%/y) Hemorrhagic stroke Event rate (%/y) P < .001 < .001 NA .02 NA < .001 NA < .001 < .001 NA MI Event rate (%/y) All-cause death Event rate (%/y) Safety Major bleeding Event rate (%/y) ICH Event rate (%/y) (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] cardiovascular composite outcome, with similar rates of NOACs Compared With VKAs: Several NOACs that directly inhibit thrombin (factor IIa) or activated factor X (factor Xa) have been approved as alternatives to VKAs for stroke prevention in AF.


VKAs Compared With APT: Of 12 studies comparing warfarin vs APT, warfarin was associated with a 39% relative risk reduction (95% CI, 22-52) in strokes In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W), the largest of these studies, warfarin was superior to DAPT to warfarin for stroke and a TABLE 4 ] Phase 3 AF Trials of NOAC vs Warfarin: Summary of Key Ef cacy and Safety Results Outcome Trial ENGAGE AF-TIMI 4876 Dabigatran (n 6,076) Dabigatran (n 6,015) Warfarin (n Rivaroxaban (n 7,131) Warfarin (n Apixaban (n 9,120) Warfarin (n Edoxaban (n 7,035) Edoxaban (n 7,034) Warfarin (n 7,036) Ef cacy Stroke/SEE Event rate (%/y) Ischemic stroke Event rate (%/y) Hemorrhagic stroke Event rate (%/y) P < .001 < .001 NA .02 NA < .001 NA < .001 < .001 NA MI Event rate (%/y) All-cause death Event rate (%/y) Safety Major bleeding Event rate (%/y) ICH Event rate (%/y) (Continued) Evidence-Based Medicine [ # C H E S T N O V E M B E R ] cardiovascular composite outcome, with similar rates of NOACs Compared With VKAs: Several NOACs that directly inhibit thrombin (factor IIa) or activated factor X (factor Xa) have been approved as alternatives to VKAs for stroke prevention in AF. They differ from VKAs in that they have a rapid onset/offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. The predictable anticoagulant effects of the NOACs enable their administration in xed doses without the need for routine coagulation monitoring, thereby simplifying therapy.


The predictable anticoagulant effects of the NOACs enable their administration in xed doses without the need for routine coagulation monitoring, thereby simplifying therapy. Individually in their respective phase 3 trials (Table 4), dabigatran, rivaroxaban, apixaban, and edoxaban have been shown to be at least as safe and effective as warfarin for preventing stroke and systemic embolism in patients A meta-analysis of the four phase 3 trials compared patients taking NOACs (higher dose) (n 42,411) with warfarin (n 29,272) (e-Table 15).124 NOACs signi cantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR, 0.81; 95% CI, 0.73- 0.91; P < .0001). The bene t was driven primarily by a 51% reduction in hemorrhagic stroke (RR, 0.49; 95% CI, 0.38-0.64; P < .0001). Ischemic stroke was similar between NOACs and warfarin (RR, 0.92; 95% CI, 0.83- 1.02; P .10). NOACs were also associated with a signi cant 10% reduction in all-cause mortality (RR, safety, NOACs were associated with a nonsigni cant 14% reduction in major bleeding (RR, 0.86; 95% CI, 0.73-1.00; P .06) but a substantial 52% reduction in ICH (RR, 0.48; 95% CI, 0.39-0.59; P < .0001). NOACs were, however, associated with a signi cant increase in P .04). The relative ef cacy and safety of NOACs were consistent across all patient subgroups with the exception that the relative reduction in major bleeding with NOACs was greater at centers with poor INR control as de ned as a center-based TTR < 66% (RR, 0.69; 95% CI, 0.59-0.81; P interaction .02).


The relative ef cacy and safety of NOACs were consistent across all patient subgroups with the exception that the relative reduction in major bleeding with NOACs was greater at centers with poor INR control as de ned as a center-based TTR < 66% (RR, 0.69; 95% CI, 0.59-0.81; P interaction .02). Lower dose NOAC regimens (dabigatran 110 mg and edoxaban 30/15 mg) showed similar overall reductions in stroke or systemic embolism but a more favorable bleeding pro le than warfarin but were associated with more ischemic strokes (the lower dose regimen edoxaban 30/15 mg is not approved for the stroke prevention indication). TABLE ] (Continued) Outcome Trial RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI Dabigatran mg (n Dabigatran mg (n Warfarin (n Rivaroxaban mg (n Warfarin (n Apixaban mg (n Warfarin (n Edoxaban mg (n Edoxaban mg (n Warfarin (n HR CI) NA NA NA NA P < < NA NA < NA < < NA GI bleeding Event rate (%/y) HR CI) NA NA NA NA P NA < NA NA < NA ARISTOTLE Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE AF-TIMI Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis In Myocardial Infarction study HR hazard ratio; RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET AF Rivaroxaban Once Daily Oral Direct Factor Xa Inhibi- tion Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; SEE systemic embolic events. See Table legend for expansion of other abbreviations. NOACs vs Aspirin: Apixaban is the only NOAC that has been compared with aspirin in AF patients.


NOACs vs Aspirin: Apixaban is the only NOAC that has been compared with aspirin in AF patients. The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial compared apixaban 5 mg bid with aspirin in AF patients who were not candidates for VKA The trial was stopped early for bene t as apixaban signi cantly reduced the risk of stroke or systemic embolism compared with aspirin (HR, 0.45; 95% CI, 0.32-0.62; P < .001) (e-Table 16). There was no signi cant difference in major bleeding (HR, 1.13; 95% CI, 0.74-1.75; P .57) between apixaban and aspirin. Real-World Observational Data: With the availability of large health-care system administrative data and the advent of quality improvement and postmarketing anticoagulation registries, the number of observational outcome studies on OAC in AF far outnumber randomized trials. Although these data have helped to successfully identify treatment variation and gaps in care, the use of these data for comparative effectiveness and safety studies of OACs must be interpreted with prudence. Despite the use of sophisticated, high quality methods to minimize confounding and bias and improve causal inference, even very small amounts of residual confounding by treatment selection or measurement error can attenuate or amplify the small absolute risk differences observed in the randomized trials. Similarly, de nitive conclusions cannot be drawn from indirect comparisons such as network meta-analyses of NOACs to each other due to small absolute risk differences. Real-world or observational data are generally insuf cient to guide selection of individual anticoagulant drugs.


Real-world or observational data are generally insuf cient to guide selection of individual anticoagulant drugs. Therefore, observational data are best used to reaf rm that real-world effectiveness is concordant with clinical trial ef cacy, based on both quality of care and generalizability.126 A meta-analysis of real-world observational studies of dabigatran was consistent with ndings from Randomized Evaluation of Long-term Anticoagulant Therapy with Dabigatran Etexilate (RE-LY). Compared with VKA, risk of stroke with dabigatran vs warfarin was Dabigatran was also associated with a lower risk of intracranial bleeding (HR, 0.45; 95% CI, 0.38-0.52) and lower risk of death (HR, 0.73; 95% CI, 0.61-0.87). Risk of gastrointestinal bleeding was higher. One systematic review and meta-analysis provided comparative effectiveness and safety data for rivaroxaban vs dabigatran (n 3 trials), rivaroxaban vs warfarin (n 11 trials), or both (n 3 trials) for stroke prevention in AF.128 Overall, the risks of stroke/ systemic thromboembolism with rivaroxaban were similar compared with dabigatran but were signi cantly reduced when compared with warfarin (HR, 0.75; 95% CI, 0.64-0.85). Major bleeding risk was signi cantly higher with rivaroxaban vs dabigatran (HR, 1.38; 95% CI, 1.27-1.49) but similar to warfarin (HR, 0.99; 95% CI, 0.91-1.07). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding but similar risk of acute MI and ICH compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute MI but a higher risk of gastrointestinal bleeding and lower risk of ICH.


When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute MI but a higher risk of gastrointestinal bleeding and lower risk of ICH. Another large analysis of 3 Danish nationwide databases of 61,678 patients found that NOACs were at least as safe and effective as warfarin, with small but signi cant differences in risk of stroke, death, and bleeding across rivaroxaban, apixaban, and dabigatran.129 However, a new-user Food and Drug Administration Medicare analysis of 118,891 patients found that rivaroxaban compared with dabigatran had a statistical trend toward a decreased risk of stroke (HR, 0.81; 95% CI, 0.65-1.01) and signi cantly increased risk of intracranial (HR, 1.47; 95% CI, 1.32-1.67) and major non-intracranial (HR, Absolute risk differences were small (2.0-2.1 per 1,000 person-years) and well within a range vulnerable to confounding.


Another large analysis of 3 Danish nationwide databases of 61,678 patients found that NOACs were at least as safe and effective as warfarin, with small but signi cant differences in risk of stroke, death, and bleeding across rivaroxaban, apixaban, and dabigatran.129 However, a new-user Food and Drug Administration Medicare analysis of 118,891 patients found that rivaroxaban compared with dabigatran had a statistical trend toward a decreased risk of stroke (HR, 0.81; 95% CI, 0.65-1.01) and signi cantly increased risk of intracranial (HR, 1.47; 95% CI, 1.32-1.67) and major non-intracranial (HR, Absolute risk differences were small (2.0-2.1 per 1,000 person-years) and well within a range vulnerable to confounding. Different Ethnic Groups: Asian AF patients have a higher risk of ICH compared with whites when VKAs The higher risk of bleeding on VKA in Asians vs non-Asians has also been observed in major clinical trials of NOACs,132 even though Asians received a lower intensity of anticoagulation with VKA.133 In a recent meta-analysis comprising 5 NOAC trials (RE-LY, ROCKET AF, Japanese Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [J-ROCKET AF], Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE], and Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation- Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48]), the effects of NOACs vs warfarin in 1154 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Asians vs non-Asians were compared.134 For standard- dose NOACs (dabigatran 150 mg, rivaroxaban 20 mg, apixaban 5 mg, and edoxaban 60 mg), the effect sizes of the primary ef cacy end point (stroke and systemic embolism) and the primary safety end point (major bleeding) were greater in Asians vs non-Asians.


Different Ethnic Groups: Asian AF patients have a higher risk of ICH compared with whites when VKAs The higher risk of bleeding on VKA in Asians vs non-Asians has also been observed in major clinical trials of NOACs,132 even though Asians received a lower intensity of anticoagulation with VKA.133 In a recent meta-analysis comprising 5 NOAC trials (RE-LY, ROCKET AF, Japanese Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [J-ROCKET AF], Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE], and Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation- Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48]), the effects of NOACs vs warfarin in 1154 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Asians vs non-Asians were compared.134 For standard- dose NOACs (dabigatran 150 mg, rivaroxaban 20 mg, apixaban 5 mg, and edoxaban 60 mg), the effect sizes of the primary ef cacy end point (stroke and systemic embolism) and the primary safety end point (major bleeding) were greater in Asians vs non-Asians. The risk reduction in hemorrhagic stroke and gastrointestinal bleeding was also greater in Asians vs non-Asians. These data suggest that standard-dose NOACs, when compared with warfarin, were more effective and safer in Asians than in non-Asians. The ef cacy and safety of low-dose NOACs (dabigatran 110 mg, rivaroxaban 15 mg, and edoxaban 30 mg), when compared with warfarin, appear similar among Asians and non-Asians.


The ef cacy and safety of low-dose NOACs (dabigatran 110 mg, rivaroxaban 15 mg, and edoxaban 30 mg), when compared with warfarin, appear similar among Asians and non-Asians. There are several real-world studies from Asia comparing NOACs with warfarin.135,136 Despite low- dose NOACs, such as dabigatran 110 mg or rivaroxaban 15 mg/10 mg, being more commonly used than standard-dose NOACs (dabigatran 150 mg or rivaroxaban 20 mg), the use of NOACs was associated with reduced risk of ischemic stroke or systemic embolization, major bleeding, ICH, and total mortality compared with warfarin. Published data suggest that NOACs are preferentially indicated for stroke prevention in Asians.37 Other Investigational Drugs: Although NOACs are safer than VKAs, serious bleeding still occurs. The potential for bleeding often discourages initiation of anticoagulant therapy in patients deemed to be at high risk of bleeding, and patients who experience a bleed frequently have permanent or prolonged discontinuation of their anticoagulant. Therefore, continued interest remains in developing even safer anticoagulants than thrombin and factor Xa inhibitors. Current investigation has focused on the upstream targets factor XI and factor XII in the contact pathway, as emerging research has elucidated their critical role in thrombosis with minimal or no role in Strategies to target factor XII or factor XI include antisense oligonucleotides that reduce hepatic synthesis of the clotting proteins, monoclonal antibodies that block activation or activity, aptamers, small molecules that block the active site or induce allosteric modulation, and polyanion antagoniststhat attenuate contact activation by nullifying stimulators of the pathway.7 Human data are limited. The factor XI-directed antisense oligonucleotide IONIS-416858 was compared with enoxaparin in 300 patients undergoing elective knee arthroplasty.


The factor XI-directed antisense oligonucleotide IONIS-416858 was compared with enoxaparin in 300 patients undergoing elective knee arthroplasty. Patients were randomized to receive IONIS-416858 at doses of 200 or 300 mg starting 35 days prior to surgery, or enoxaparin at a dose of 40 mg starting after the surgery. The 200 mg IONIS-416858 regimen was noninferior and the 300 mg IONIS-416858 regimen was superior compared with enoxaparin in preventing the composite end point of asymptomatic DVT, symptomatic DVT or pulmonary embolism, or VTE- The rates of major or clinically relevant nonmajor bleeding were 3% in both IONIS- 416858 groups and 8% in the enoxaparin group. With respect to patients with AF, potential unmet needs addressed by these agents include patients at high risk for bleeding, such as those with end-stage renal disease who are on hemodialysis (ongoing phase 2 study).141 Another area of interest is in patients with mechanical heart valves. Data from a phase 2 trial of dabigatran in patients with mechanical heart valves (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement [RE-ALIGN]) demonstrated inferior ef cacy and more bleeding, compared with warfarin.142 Factor XI-directed strategies may be very effective in this setting because factor XI depletion abolished mechanical valve- induced thrombin generation in vitro.140 Recommendations 6. For patients with AF, we recommend against antiplatelet therapy alone (monotherapy or aspirin in combination with clopidogrel) for stroke prevention alone, regardless of stroke risk (Strong recommendation, moderate quality evidence). Remark: Patients with AF might have other indications for antiplatelet drugs (eg, acute coronary syndrome, stents). 7. In patients with AF who are eligible for OAC, we recommend NOACs over VKA (Strong recommendation, moderate quality evidence).


In patients with AF who are eligible for OAC, we recommend NOACs over VKA (Strong recommendation, moderate quality evidence). Remark: Patient and caregiver preferences, cost, formulary considerations, anticipated medication adherence or compliance with INR testing and dose adjustment should be incorporated into clinical decision-making. 8. In patients on VKAs with consistently low time in INR therapeutic range (eg, TTR < 65%), we recommend considering interventions to improve TTR or switching to NOACs (Strong recommendation, moderate quality evidence). Remark: Action required if TTR < 65% - implement additional measures (more regular INR tests; review medication adherence; address other factors known to in uence INR control; education/counseling) to improve INR control. 9. In patients with prior unprovoked bleeding, warfarin-associated bleeding, or at high risk of bleeding, we suggest using apixaban, edoxaban, or dabigatran 110 mg (where available) as all demonstrate signi cantly less major bleeding compared with warfarin (Weak recommendation, very low quality evidence). Remark: In patients with prior gastrointestinal bleeding apixaban or dabigatran 110 mg bid may be preferable as they are the only NOACs not associated with an increased risk of gastrointestinal bleeding compared with warfarin. Remark: Dabigatran 150 mg twice daily recommended in patients at high risk of ischemic stroke as only agent/ dose with superior ef cacy compared with warfarin. However, bleeding risk would need to be assessed and patients monitored. Adjusted-Dose Oral VKA Therapy The VKAs are a class of OACs; the most commonly used are the 4-hydroxycoumarins and include warfarin, phenprocoumon, and acenocoumarol.143 Less commonly used VKAs are phenindione and uindione, which are 1,3-indandione derivatives. Geographical variation in VKA popularity is evident, with warfarin commonly used worldwide but acenocoumarol being popular in Spain and phenprocoumon in Germany. In randomized clinical trials, most have used warfarin.


Geographical variation in VKA popularity is evident, with warfarin commonly used worldwide but acenocoumarol being popular in Spain and phenprocoumon in Germany. In randomized clinical trials, most have used warfarin. Optimal INR Target Range in AF: For stroke prevention in patients with AF receiving a VKA, the optimal INR target range is 2.0 to 3.0,144 aiming for an INR value of 2.5 to maximize the proportion of time spent in the therapeutic INR range. Numerous observational studies of AF patients have demonstrated that the risk of thromboembolism/ischemic stroke is greater when INR is < 2.0,81,83,85,145-147 whereas INR levels > 3.0 are associated with a greater incidence of major bleeding, especially ICH when the INR rises above All the phase 3 NOAC trials employed an INR target of 2.0 to 3.0 among patients receiving ; J-ROCKET employed a lower INR target of 1.6 to 2.6 for the Japanese population.148 In some Asian countries, there is the perception that a lower target INR range (eg, 1.6-2.6) should be used, especially in the elderly. Only 1 small prospective randomized trial allocated 115 secondary prevention AF patients to a conventional-intensity group (INR, 2.2 to 3.5) or a low-intensity group (INR, 1.5 to 2.1).149 Major hemorrhagic complications occurred in 6 patients in the conventional-intensity group (6.6% per year) compared with the low-intensity group (0% per year; P .01). Other Asian registries have suggested that low intensity (INR, 1.5-2.5) was associated with less bleeding, but no information on quality of INR control was reported. There is currently no robust evidence for implementing a target INR range of 1.6 to 2.6, and therefore the conventional, evidence-based INR target of 2.0 to 3.0 should be employed globally.


There is currently no robust evidence for implementing a target INR range of 1.6 to 2.6, and therefore the conventional, evidence-based INR target of 2.0 to 3.0 should be employed globally. Importance of TTR INR Range: The proportion of time spent within the therapeutic INR range (INR, 2.0 to 3.0) is intrinsically linked to the risk of adverse events. The temporal pattern of INR control is most commonly calculated using the Rosendaal method of linear interpolation between 2 consecutive INR values,150 known as the TTR or by the percentage of INRs within However, a limitation of the Rosendaal method of interpolation is that INRs > 42 days apart have generally not been interpolated in studies due to large uncertainties in uctuation. Although TTR and percentage of INRs within therapeutic range are highly they are not equivalent and should not be used interchangeably. TTR is a widely accepted and validated measure of anticoagulation control and predicts adverse events in patients receiving VKA,153-155 and is the quality and performance measure of choice for specialized anticoagulation clinics. Numerous studies have demonstrated that the risk of thromboembolism, major bleeding, and death is lower when the proportion of TTR is higher, at least Indeed, random one off INR values give little insight into the degree of anticoagulation control, and many adverse outcomes (eg, bleeding) occur even within the therapeutic INR range of 2.0 to Thus, when VKAs are used, attention should be focused on the average individual TTR as a measure of the quality of anticoagulation control.


Numerous studies have demonstrated that the risk of thromboembolism, major bleeding, and death is lower when the proportion of TTR is higher, at least Indeed, random one off INR values give little insight into the degree of anticoagulation control, and many adverse outcomes (eg, bleeding) occur even within the therapeutic INR range of 2.0 to Thus, when VKAs are used, attention should be focused on the average individual TTR as a measure of the quality of anticoagulation control. Clinical guidelines on the management of AF advocate an individual TTR of at least $ 65%157,158 to maximize ef cacy and safety, and this should be the treatment target, although in clinical practice this may be more dif cult to achieve.153-156,159 An analysis of anticoagulation control in the Global Anticoagulation Registry in the Field [GARFIELD-AF] registry (n 9,934), a global observational study, revealed that only 1156 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] 41.1% had TTR $ 65% and of all the INR values, only 51.4% were in the therapeutic range (INR, 2.0 to 3.0), with one-third being subtherapeutic.155 After adjustment, the risk of stroke/systemic embolism (HR, 95% CI, 1.87-3.06), and major bleeding (HR, 1.54; 95% CI, 1.04-2.26) was greater with TTR < 65%, when compared with TTR $ 65%.155 TTR varies widely by geographical region (TTR $ 65%, An analysis of individual TTR from Swedish registries (n 40,449) revealed an overall mean individual TTR of 68.6% and signi cantly lower annual rates of thromboembolism (2.37% vs 4.41%), all-cause mortality when individual TTR was $ 70% compared with individual TTR < 70%, respectively.154 Recommendation 10.


Clinical guidelines on the management of AF advocate an individual TTR of at least $ 65%157,158 to maximize ef cacy and safety, and this should be the treatment target, although in clinical practice this may be more dif cult to achieve.153-156,159 An analysis of anticoagulation control in the Global Anticoagulation Registry in the Field [GARFIELD-AF] registry (n 9,934), a global observational study, revealed that only 1156 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] 41.1% had TTR $ 65% and of all the INR values, only 51.4% were in the therapeutic range (INR, 2.0 to 3.0), with one-third being subtherapeutic.155 After adjustment, the risk of stroke/systemic embolism (HR, 95% CI, 1.87-3.06), and major bleeding (HR, 1.54; 95% CI, 1.04-2.26) was greater with TTR < 65%, when compared with TTR $ 65%.155 TTR varies widely by geographical region (TTR $ 65%, An analysis of individual TTR from Swedish registries (n 40,449) revealed an overall mean individual TTR of 68.6% and signi cantly lower annual rates of thromboembolism (2.37% vs 4.41%), all-cause mortality when individual TTR was $ 70% compared with individual TTR < 70%, respectively.154 Recommendation 10. For patients with non-valvular AF, when VKAs are used, we suggest the target should be INR 2.0-3.0, with attention to individual TTR, ideally 70% (Ungraded consensus-based statement). Remark: Action required if TTR sub-optimal (< 65-70%) - implement additional measures (more regular INR tests; review medication adherence; address other factors known to in uence INR control; education/counseling) to improve INR control or consider an NOAC. Remark: When possible, experienced specialized anticoagulation clinics should be utilized for VKA and INR management.


Remark: When possible, experienced specialized anticoagulation clinics should be utilized for VKA and INR management. Factors Affecting INR Control: Many factors affect TTR, including patient-related aspects (eg, age, sex, socioeconomic status, diet, ethnicity, hospitalization, length of time on VKA, medical and psychiatric comorbidities, nonadherence, polypharmacy, genetic and health-care system-related factors, particularly how VKA is managed (by country, setting of OAC management [eg, anticoagulation clinic vs physician/community-based practices]),90,161,162 distance to OAC clinic,161,162 self-monitoring/self- frequency of INR monitoring, etc.156 It is also important to note that site-level variation in VKA management has also been demonstrated in RCTs163-167 and for NOACs.168 The value of dietary measures to improve anticoagulation control is debatable, and it is perhaps more relevant to maintain a stable dietary habit, avoiding wide changes in the intake of vitamin K.169 Among patients initiating VKA, the time to achieve therapeutic range has also been related to the likelihood of achieving a subsequently good TTR.170,171 The more common clinical factors in uencing TTR have been used to formulate the SAMe-TT2R2 (awarding 1 point for each of the following: sex [female]; age <60 years; medical history [$3 comorbidities: hypertension, diabetes, coronary heart disease/myocardial infarction, peripheral artery disease, heart failure, prior stroke, lung disease, liver disease or renal failure]; treatments [such as amiodarone]; smoking status [double]; and race [non- Caucasian, double]) score172,173 (Table 5). This clinical score is based on routine clinical parameters, which can be used to identify patients who may be able to attain good anticoagulation control (eg, TTR $ 65%) with a VKA and those who probably will not, where an NOAC may be preferred or where other interventions (eg, more frequent INR monitoring, patient education/counseling, etc) may need to be implemented to ensure good INR control.


This clinical score is based on routine clinical parameters, which can be used to identify patients who may be able to attain good anticoagulation control (eg, TTR $ 65%) with a VKA and those who probably will not, where an NOAC may be preferred or where other interventions (eg, more frequent INR monitoring, patient education/counseling, etc) may need to be implemented to ensure good INR control. Many of the factors included in the SAMe- TT2R2 score have been associated with decreased adherence with NOACs and in the absence of trial data it is not clear if these patients would do substantially better on an NOAC or if they would do poorly anyway. The SAMe-TT2R2 score has been assessed in 15 exclusively AF cohorts,174-185 reporting its predictive ability to forecast good or poor anticoagulation control, with c-statistics ranging from However, these cohorts were predominantly elderly, Western (white) populations, and its predictive ability in non-Western populations has relatively limited data as only 3 studies have assessed with only 1 reporting c-statistics (c-statistic, 0.54; In the multi-ethnic non-white Singaporean population by Bernaitis et al,174 the SAMe- TT2R2 score was able to dichotomize the patients likely to do well on VKA, compared with those (score > 2) more likely to achieve poor TTR.


The SAMe-TT2R2 score has been assessed in 15 exclusively AF cohorts,174-185 reporting its predictive ability to forecast good or poor anticoagulation control, with c-statistics ranging from However, these cohorts were predominantly elderly, Western (white) populations, and its predictive ability in non-Western populations has relatively limited data as only 3 studies have assessed with only 1 reporting c-statistics (c-statistic, 0.54; In the multi-ethnic non-white Singaporean population by Bernaitis et al,174 the SAMe- TT2R2 score was able to dichotomize the patients likely to do well on VKA, compared with those (score > 2) more likely to achieve poor TTR. In the Loire Valley AF project, the SAMe-TT2R2 score was predictive of labile INR in AF patients who were VKA users, and was signi cantly associated with the adverse consequences of labile INR, including stroke, serious bleeding, and death; the score was nonpredictive in non-VKA users.179 The score has also been tested in some VTE populations, where it similarly identi es patients likely to achieve a good TTR.187,188 Patients with AF who require OAC should not have to fail with a VKA before they are offered an NOAC; the most appropriate OAC based on the patient s individual risk pro le and patient preference should be offered from the beginning of OAC therapy. However, in some health-care systems where the patient has to have a period on VKA and their TTR determined, before a decision to use an NOAC is approved, the SAMe-TT2R2 score could be used to aid decision-making.173 Recommendation 11. For patients with AF, we suggest the SAMe-TT2R2 score to aid decision-making to help identify patients likely to do well on VKA (Ungraded consensus-based statement). Remark: Those with score 0-2 are likely to achieve a good TTR.


Remark: Those with score 0-2 are likely to achieve a good TTR. Those with score > 2 are less likely to achieve a good TTR and would require more regular INR checks, education/counseling and frequent follow- up, or alternatively, an NOAC should be considered as a better management option if high medication adherence can be expected. Monitoring Anticoagulant Therapy: Point-of-Care Testing: There is an increasing demand for oral anticoagulation among AF patients189 and not all patients are suitable for NOACs; therefore, a large proportion requires VKA which necessitates INR monitoring. Point-of-care testing using a coagulometer (INR monitor) is more convenient and time-ef cient, particularly where patient s self-monitor and/or self- manage. Home or clinic point-of-care monitoring is an increasingly standard method of INR monitoring associated with an appropriate degree of precision and accuracy for clinical practice190 ; however, routine calibration is warranted, and quality control systems should adhere with the Food and Drug Administration medical devices regulation guidance.191 Patient Self-Monitoring and Self-Management: A recent Cochrane review91 evaluating the effect of self-monitoring or self-management of OAC therapy compared with standard OAC monitoring on thromboembolic events, major bleeding, and death revealed a signi cant decrease in thromboembolic events in 18 studies) and with both self-monitoring (RR, 0.69; participants in 11 studies), although not all patients were AF. There was no overall reduction in the risk of death studies); however, self-management did reduce all-cause participants in 8 studies). Neither self-monitoring nor self-management reduced the risk of major bleeding compared with standard OAC monitoring (RR, 0.95; 95% CI, 0.80-1.12; 8,018 participants in 20 studies). Rating of the quality of evidence was low to moderate, and the ndings should be interpreted accordingly.


Rating of the quality of evidence was low to moderate, and the ndings should be interpreted accordingly. The advantages of self-monitoring and self-management include convenience and freedom for the patient, patient empowerment/control over their condition and treatment, increased patient satisfaction, all of which may improve quality of life. However, this approach may not be a viable option for all patients requiring VKA therapy as it is initially expensive, requires mastery of the point-of-care device, and for those self-managing, the knowledge and ability to dose-adjust, plus the appropriate health-care system infrastructure and patient support which may not be feasible globally. For many AF patients, an NOAC might be a more suitable alternative. Practical Patient Management Algorithm The approach to stroke prevention in patients with AF can be simpli ed into a simple 3-step algorithm (Fig 4). The initial step is to determine the risk of stroke. As noted in the Stroke Risk in AF section, risk scores for stroke in patients with AF lack speci city, and are therefore not Acronym Risk Factors Points S Sex (female) 1 A Age (< 60 y) 1 Me Medical history ($ 2 from: hypertension, diabetes mellitus, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, and hepatic or renal disease) T Treatment (interacting drugs [eg, amiodarone]) 1 T Tobacco use (within 2 y) 2 R Race (non-white) 2 Maximum score 8 1158 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] clinically useful in identifying and categorizing high-risk patients.


As noted in the Stroke Risk in AF section, risk scores for stroke in patients with AF lack speci city, and are therefore not Acronym Risk Factors Points S Sex (female) 1 A Age (< 60 y) 1 Me Medical history ($ 2 from: hypertension, diabetes mellitus, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, and hepatic or renal disease) T Treatment (interacting drugs [eg, amiodarone]) 1 T Tobacco use (within 2 y) 2 R Race (non-white) 2 Maximum score 8 1158 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] clinically useful in identifying and categorizing high-risk patients. As noted in the Stroke Risk in AF section, we recommend the use of the CHA2DS2-VASc score given its superior sensitivity and ability to accurately and safely identify patients at low risk of stroke. Patients who are low risk (a score of 0 in males, 1 in females) do not require antithrombotic treatment. All AF patients with $ 1 stroke risk factors are candidates for stroke prevention with oral anticoagulation. At this point, it is important to assess the bleeding risk. Although the bene t of stroke prevention outweighs the risk of bleeding in almost all patients, calculation of the bleeding risk allows the practitioner to identify potentially modi able factors that elevate the bleeding risk (uncontrolled hypertension, concomitant use of antiplatelet or nonsteroidal agents, excessive alcohol intake; poor INR control [TTR < 65%] in VKA patients). In addition, patients identi ed as high risk for bleeding should be scheduled for more frequent follow-up and monitoring.


In addition, patients identi ed as high risk for bleeding should be scheduled for more frequent follow-up and monitoring. As noted in the Bleeding Risk in AF section, we make a consensus suggestion that the HAS-BLED score be used for this purpose, so those with a HAS-BLED score $ 3 can be identi ed as high risk for this reason. The nal decision point is to decide which OAC to use for stroke prevention. As noted in atrial tachycardia therapy and other approaches to stroke prevention, we recommend one of the NOACs (dabigatran, apixaban, edoxaban, or rivaroxaban) as rst line in patients with AF. These agents have not been compared head-to-head, and we therefore do not recommend one over the other. Local availability, cost, and patient comorbidities might Low stroke risk 0 in males 1 in females No antithrombotic treatment *Address modi able bleeding risk factors in all AF patients. High bleeding risk scores should not be used as a reason to withhold OAC. Calculate the HAS-BLED score. If HAS-BLED 3, address the modifiable bleeding risk factors and flag up patient for regular review and follow-up. Step 1 Identify low- risk patients Consider stroke prevention (ie, OAC) in all AF patients with 1 additional stroke risk factors* Begin NOAC (or VKA with high time in therapeutic range) Rationale: Step 1: CHA2DS2-VASc score has superior sensitivity and thus can identify low risk patients reliably (see Recommendations 1 and 2 for further rationale). Step 2: Higher bleeding risk scores lack specificity given the dynamic nature of bleeding risk. High risk scores should be used simply to identify potential modifiable factors and patients who may need more frequent follow-up. Step 3: We recommend NOACs as first line therapy for OAC.


Step 3: We recommend NOACs as first line therapy for OAC. lf VKA therapy is being considered, the SAMe-TT2R2 score can be used to identify patients who are good candidates for this approach. NOACs generally recommended as first line therapy for OAC If considering VKA, calculate Otherwise, regular review/frequent INR checks/ counselling for VKA users NOAC VKA treatment (eg, warfarin) or NOAC Figure 4 Practical management algorithm. CHA2DS2-VASc congestive heart failure, hypertension, age $ 75 (doubled), diabetes, stroke (doubled)- vascular disease, age 65-74 and sex category (female); HAS-BLED hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (0.65), drugs/alcohol concomitantly (1 point each); SAMe-TT2R2 score awarding 1 point for each of the following: sex (female); age <60 y; medical history ($3 comorbidities: hypertension, diabetes, coronary heart disease/myocardial infarction, peripheral artery disease, heart failure, prior stroke, lung disease, liver disease or renal failure); treatments (such as amiodarone); smoking status (double); and race (non-Caucasian, double). See Figure 1, 2, and 3 legends for expansion of other abbreviations. be considerations in choosing an agent (Table 6)124,127, for comparative information. The VKAs are still widely used and are an acceptable alternative with target TTR $ 70%. As outlined in the section Factors Affecting INR Control, we recommend that the SAMe-TT2R2 score be used to help identify patients likely to do well on VKA therapy. Managing Bleeding on OAC Bleeding on VKA: Management of active bleeding on a VKA depends on the severity (Fig 5).202 For all bleeding events, the site of bleeding should be assessed, with mechanical compression where appropriate, the time- point of the last dose of VKA should be obtained, with factors affecting bleeding risk documented (other medications, kidney function, alcohol abuse, other comorbidities) and hemodynamic status assessed (BP, pulse, etc).


Managing Bleeding on OAC Bleeding on VKA: Management of active bleeding on a VKA depends on the severity (Fig 5).202 For all bleeding events, the site of bleeding should be assessed, with mechanical compression where appropriate, the time- point of the last dose of VKA should be obtained, with factors affecting bleeding risk documented (other medications, kidney function, alcohol abuse, other comorbidities) and hemodynamic status assessed (BP, pulse, etc). Assessment of INR, prothrombin time (PT), and activated partial thromboplastin time (aPTT) is essential; other laboratory tests should include renal function, hemoglobin, hematocrit, and platelet count. For minor bleeding, VKA administration should be withheld until INR < 2.0. Management of moderate bleeding requires prompt identi cation and intervention to treat the cause and may also necessitate uid replacement and/or blood transfusion. Where bleeding is severe or life-threatening, immediate reversal of the anticoagulant effect is required and administration of IV vitamin K, fresh frozen plasma, and prothrombin complex concentrates (PCCs) should be considered to restore coagulation. PCCs are preferred over fresh-frozen plasma for reversal due to a higher concentration of clotting factors and less volume. Bleeding on NOAC (Fig 5): Many physicians and patients have been reluctant to embrace NOACs due to their perception that they are not able to effectively manage patients who present with bleeding, particularly without a speci c reversal agent or antidote.203 A helpful framework to consider when managing NOAC-related bleeding includes: (1) prevention of bleeding, (2) general principles and supportive measures, (3) nonspeci c hemostatic agents, and (4) NOAC-speci c reversal Minimize the Risk of Bleeding: Selecting the right dose of the NOAC is the most important step to minimize bleeding risk. Prescribing information for all NOACs includes dose reduction criteria to avoid increased drug exposure (primarily due to impaired renal function).


Prescribing information for all NOACs includes dose reduction criteria to avoid increased drug exposure (primarily due to impaired renal function). Concomitant administration of antiplatelet drugs and nonsteroidal antiin ammatory drugs should be avoided when possible as concomitant administration substantially increases bleeding risk. BP should be well controlled. General Supportive Measures: Given the short half-lives of these medications, minor bleeds may only require temporary discontinuation of anticoagulation for several doses. More signi cant bleeds may require additional supportive measures that include: local management (mechanical/surgical); volume resuscitation; and consideration of RBC and platelet transfusion, if In cases of overdose or in patients who took their last NOAC dose within 2 to 4 h, oral activated charcoal may attenuate absorption of drug.208-211 Laboratory Measurements: With respect to common coagulation tests, a prolonged aPTT indicates an anticoagulant effect of dabigatran, and a prolonged PT indicates an anticoagulant effect of the factor Xa However, the clinical utility of these common tests is limited due to the fact that a normal aPTT or PT does not exclude clinically relevant plasma levels of dabigatran and factor Xa inhibitors, respectively. The thrombin time (TT) is the most sensitive test for dabigatran; even low levels of dabigatran will prolong the TT so a normal TT excludes clinically relevant dabigatran concentrations. The dilute TT can be used to quantify dabigatran drug levels as it has good correlation across a wide range of dabigatran Chromogenic anti-factor Xa assays are recommended for rivaroxaban, apixaban, and edoxaban with calibration for the speci c agent.206 However, validation of these specialized coagulation tests is required, they are not universally available, and often have delayed turnaround time, which diminishes their usefulness in emergent situations. Asking patients when they took their last dose of NOAC is often the most practical method for quickly assessing residual anticoagulant activity.


Asking patients when they took their last dose of NOAC is often the most practical method for quickly assessing residual anticoagulant activity. Nonspeci c Hemostatic Agents: Hemostatic factors that have been studied as potential nonspeci c NOAC reversal agents including PCCs, activated PCC, recombinant activated factor VII, and fresh-frozen plasma. PCCs are the preferred nonspeci c hemostatic agent for NOAC reversal. PCCs are plasma-derived products that contain 3 (factors II, IX, and X) or 4 (addition of factor VII) clotting factors in addition to variable amounts of heparin and the natural coagulation inhibitors protein C and protein S. Animal studies have demonstrated that PCCs have variable ability to normalize anticoagulation parameters and prevent or 1160 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] TABLE 6 ] A Simpli ed Schema to Assist Physician Choice of Anticoagulant (VKA or Individual NOAC) According to Patient Characteristics Patient Characteristic Possible OAC Choice References to RCT Subgroup Data References to Real-World Data or Indirect Evidence Comments  Recurrent ischemic stroke/systemic embolism/TIA despite good anticoagulation control (TTR $ 70%). Consider agent with superior ef cacy for preventing both ischemic and hemorrhagic stroke D150 124 127 In general, any NOAC would be recommended, especially where warfarin control suboptimal (TTR < 65%). Ensure good adherence and avoid underdosing  Moderate-severe renal impairment CrCl 15-49 mL/min Aa Db R15 124 192 All RCTs excluded patients with Cockroft-Gault CrCl < 30 mL/min (< 25 mL/min, for apixaban)  High risk of GI bleeding A D110 124 127, 193  Major GI symptoms or dyspepsia. Also consider increased risk of bleeding  High risk of bleeding (HAS-BLED $ 3).


Also consider increased risk of bleeding  High risk of bleeding (HAS-BLED $ 3). Consider agent with the lowest bleeding risk  Once-daily dosing or preference to have lower pill burden E R VKA c  Asian patients. Consider agents with reduced risk of ICH and major bleed in Asian populations  Less likely to do well on VKA (SAMe-TT2R2 score > 2). Avoid any potential trial of VKA if possible NOAC preferred (A D E R) . 146, 179, 183 VKA with additional education, more regular follow-up, and frequent INR checks A apixaban; CrCl creatinine clearance; D dabigatran; E edoxaban; R rivaroxaban; TIA transient ischemic attack. See Table 1 and 2 legends for expansion of other abbreviations. a Reduced to 2.5 mg bid with two of three criteria from age $ 80 years, body weight # 60 kg, or serum creatinine concentration $ 133 mmol/L. b 110 mg bid for patients with a CrCl 30 to 49 mL/min (most countries, but not in the United States); in the United States only, 75 mg bid (available in the United States only) for patients with CrCl 15 to 29 mL/min (and only 150 mg bid dose available in the United States for CrCl > 30 mL/min). c Not available. d Dose to be halved if the patient has any of the following: CrCl 15 to 49 mL/min, body weight # 60 kg, or concomitant use of P-glycoprotein inhibitors. chestjournal.org attenuate bleeding across the NOACs.207,213-219 The limited data in humans are restricted to healthy volunteers. In 3 small (12-93 patients) randomized, placebo-controlled studies, PCC reversed the anticoagulant effect of rivaroxaban and edoxaban but There was a dose-dependent relationship with complete reversal with 50 U/kg and partial reversal with 25 U/kg.


In 3 small (12-93 patients) randomized, placebo-controlled studies, PCC reversed the anticoagulant effect of rivaroxaban and edoxaban but There was a dose-dependent relationship with complete reversal with 50 U/kg and partial reversal with 25 U/kg. It is unclear whether normalizing coagulation parameters in healthy volunteers translates to improved outcomes in patients who are actively bleeding. Furthermore, the use of these agents in managing bleeding caused by VKA or in hemophiliac patients has been associated with an increased risk of thrombotic complications, especially when activated factors are Speci c Reversal Agents: Idarucizumab: Idarucizumab is a humanized monoclonal antibody fragment developed as a speci c reversal agent for dabigatran It binds with high af nity (350 times higher than thrombin) to free and thrombin-bound and binding is effectively irreversible.227 The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study was a phase 3, global, prospective, cohort study investigating the safety and ef cacy of 5 g idarucizumab (administered as two rapid 2.5 g IV boluses) in dabigatran-treated patients who present with uncontrolled or life-threatening bleeding (Group A) or non-bleeding patients who require emergent surgery or intervention (Group B).228 Idarucizumab resulted in immediate, complete, and sustained reversal of dabigatran. Median time to cessation of bleeding in Group A was between 2.5 h after reversal and in Group B, median time to surgery after reversal was 1.6 h with intraoperative hemostasis deemed normal by investigators in 93.4% of patients. Idarucizumab has worldwide approval and availability. Andexanet Alfa: Andexanet alfa (andexanet) is a speci c reversal agent for direct (apixaban, rivaroxaban, and edoxaban) and indirect (low-molecular-weight heparins [LMWHs] and fondaparinux) factor Xa inhibitors that act through antithrombin.


Andexanet Alfa: Andexanet alfa (andexanet) is a speci c reversal agent for direct (apixaban, rivaroxaban, and edoxaban) and indirect (low-molecular-weight heparins [LMWHs] and fondaparinux) factor Xa inhibitors that act through antithrombin. It is a modi ed human recombinant factor Xa decoy protein that is catalytically inactive due to replacement of an active-site serine with alanine and with deletion of the membrane binding domain, which eliminates the ability to assemble the prothrombinase complex. Andexanet retains the ability to bind to NOACs with high af nity and a 1:1 stoichiometric ratio and by sequestering factor Xa inhibitors within the vascular space, endogenous factor Xa activity is restored.229 Due to its pharmacodynamic half-life of 1 h, andexanet is administered as a bolus followed by an infusion. is evaluating the ef cacy and safety of andexanet in patients taking factor Xa inhibitors with acute major bleeding. Unlike RE-VERSE AD, this study does not include patients without bleeding but who require emergency or urgent procedures. A preliminary interim analysis of 67 patients demonstrated that an initial bolus and subsequent 2-h infusion of andexanet substantially reduced anti-factor Xa activity with clinically adjudicated effective hemostasis occuring in 79% of Andexanet is in late-stage review by regulatory authorities. Ciraparantag (PER977): Ciraparantag is a small synthetic water-soluble molecule developed as a reversal agent for unfractionated heparin (UFH), LMWHs, fondaparinux, and the oral direct Xa and IIa inhibitors.


Ciraparantag (PER977): Ciraparantag is a small synthetic water-soluble molecule developed as a reversal agent for unfractionated heparin (UFH), LMWHs, fondaparinux, and the oral direct Xa and IIa inhibitors. It binds to targets through noncovalent hydrogen bonding Minor bleeding NOAC: Delay 1 dose or 1 day VKA: Delay until INR 2.0 Bleeding on oral anticoagulation Severe or life-threatening bleeding Supportive measures as outlined for moderate bleeding + Reversal VKA: Consider PCC NOAC: Give NOAC-specific reversal agent or PCC if reversal agent not available Moderate bleeding Delay or discontinue NOAC or VKA Maintain diuresis/volume support Mechanical compression/intervention to establish hemostasis Transfusion: PRBCs, FFP (as plasma expander), platelets as necessary VKA: Consider adding vitamin K (1-10 mg IV) NOAC: Consider absorption- activated charcoal if last dose 2-4 h Figure 5 Management of patients with active bleeding on oral anticoagulation (NOAC and VKA). FFP fresh frozen plasma; PCC prothrombin complex concentrate; PRBC packed RBCs. See Figure 1 legend for expansion of other abbreviations. 1162 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] and charge-charge interactions thereby preventing the anticoagulants from binding to their endogenous Ciraparantag is earlier in its development program compared with other speci c reversal agents. Management Approach to Bleeding on NOACs: The vast majority of bleeds can be managed conservatively with temporary discontinuation of NOACs and supportive measures. Reversal agents should be used sparingly in the cases of severe and life-threatening bleeding, which includes bleeding causing hemodynamic compromise, ICH, bleeding into a critical organ or closed space, persistent bleeding despite general supportive measures and local hemostatic support, or risk of recurrent bleeding due to excess NOAC drug exposure due to delayed clearance of NOAC (eg, acute renal failure) or overdose.


Reversal agents should be used sparingly in the cases of severe and life-threatening bleeding, which includes bleeding causing hemodynamic compromise, ICH, bleeding into a critical organ or closed space, persistent bleeding despite general supportive measures and local hemostatic support, or risk of recurrent bleeding due to excess NOAC drug exposure due to delayed clearance of NOAC (eg, acute renal failure) or overdose. In a patient with serious bleeding, a speci c reversal agent (where available) should be used instead. General hemostatic agents as nonspeci c agents are less effective in reversing coagulation abnormalities, have not been shown to improve outcomes, and are potentially prothrombotic. Although coagulation testing will identify those patients with therapeutic levels of anticoagulation who will likely bene t from speci c reversal agents, and helps physicians to monitor the response to reversal, it is reasonable to administer speci c reversal agents immediately without waiting for a laboratory test con rming therapeutic levels of anticoagulation in patients who present with life-threatening bleeding presumed to be on an NOAC.


Although coagulation testing will identify those patients with therapeutic levels of anticoagulation who will likely bene t from speci c reversal agents, and helps physicians to monitor the response to reversal, it is reasonable to administer speci c reversal agents immediately without waiting for a laboratory test con rming therapeutic levels of anticoagulation in patients who present with life-threatening bleeding presumed to be on an NOAC. TABLE 7 ] Comparison of Speci c NOAC Reversal Agents Idaracizumab Andexanet alfa Ciraparantag Company Boehringer Ingelheim Portola Pharmaceuticals Perosphere Inc. Chemical structure Humanized monoclonal antibody fragment Recombinant truncated human factor Xa variant (decoy) Synthetic water-soluble cationic small molecule consisting of 2 L-arginine units connected with a piperazine containing linker chain Binding Noncompetitive binding to dabigatran Competitive binding to direct factor Xa inhibitors or to indirect factor Xa inhibitor- activated antithrombin Covalent hydrogen bonding Target af nity Approximately 350 greater af nity for dabigatran than factor IIa Af nity for direct factor Xa inhibitors similar to that of native factor Xa Not reported Onset < 5 min 2 min 5-10 min Half-life Initial: 47 min Terminal: 10.3 h Terminal: approximately 6 h Duration of action 24 h Elimination Kidney (protein catabolism) Not reported Not reported Anticoagulant(s) reversed Dabigatran Direct and indirect factor Xa inhibitorsa - Dabigatran - Argatroban - Low-molecular-weight heparins - Unfractionated heparin - Oral and parenteral factor Xa inhibitors Route and dose in clinical studies 5 g administered as 2 doses of 2.5 g IV over 5-10 min, 15 min apart (repeat dosing can be considered if recurrent bleeding or require second emergent procedure if elevated coagulation parameters) 400-800 mg IV bolus (30 mg/min) followed by infusion of 4-8 mg/minb 100-300 mg IV bolus Storage Refrigerated Refrigerated Room temperature (Adapted from Ruff et al.204 ) a For the indirect factor Xa inhibitors, andexanet alfa likely to completely reverse fondaparinux which only inhibits factor Xa but not low-molecular weight heparins which also inhibit factor IIa.


TABLE 7 ] Comparison of Speci c NOAC Reversal Agents Idaracizumab Andexanet alfa Ciraparantag Company Boehringer Ingelheim Portola Pharmaceuticals Perosphere Inc. Chemical structure Humanized monoclonal antibody fragment Recombinant truncated human factor Xa variant (decoy) Synthetic water-soluble cationic small molecule consisting of 2 L-arginine units connected with a piperazine containing linker chain Binding Noncompetitive binding to dabigatran Competitive binding to direct factor Xa inhibitors or to indirect factor Xa inhibitor- activated antithrombin Covalent hydrogen bonding Target af nity Approximately 350 greater af nity for dabigatran than factor IIa Af nity for direct factor Xa inhibitors similar to that of native factor Xa Not reported Onset < 5 min 2 min 5-10 min Half-life Initial: 47 min Terminal: 10.3 h Terminal: approximately 6 h Duration of action 24 h Elimination Kidney (protein catabolism) Not reported Not reported Anticoagulant(s) reversed Dabigatran Direct and indirect factor Xa inhibitorsa - Dabigatran - Argatroban - Low-molecular-weight heparins - Unfractionated heparin - Oral and parenteral factor Xa inhibitors Route and dose in clinical studies 5 g administered as 2 doses of 2.5 g IV over 5-10 min, 15 min apart (repeat dosing can be considered if recurrent bleeding or require second emergent procedure if elevated coagulation parameters) 400-800 mg IV bolus (30 mg/min) followed by infusion of 4-8 mg/minb 100-300 mg IV bolus Storage Refrigerated Refrigerated Room temperature (Adapted from Ruff et al.204 ) a For the indirect factor Xa inhibitors, andexanet alfa likely to completely reverse fondaparinux which only inhibits factor Xa but not low-molecular weight heparins which also inhibit factor IIa. b Lower dose to reverse apixaban, higher dose to reverse rivaroxaban. Practical Issues With VKA and NOAC Cardioversion Antithrombotic Therapy for Patients With AF Undergoing Cardioversion: In AF of documented short duration (ie, # 48 h), urgent cardioversion commonly occurs without prolonged pre-cardioversion anticoagulation.


Practical Issues With VKA and NOAC Cardioversion Antithrombotic Therapy for Patients With AF Undergoing Cardioversion: In AF of documented short duration (ie, # 48 h), urgent cardioversion commonly occurs without prolonged pre-cardioversion anticoagulation. In the context of elective cardioversion, whether electrical or chemical, therapeutic anticoagulation either with adjusted-dose VKAs, or NOACs is currently recommended for a minimum of 3 weeks before, and for a minimum of 4 weeks after, the procedure. In AF of > 48 h duration or unknown duration, a TEE-guided approach provides an alternative strategy to guide anticoagulation management before cardioversion. In this section, we appraise and summarize the evidence and give recommendations for the use of antithrombotic therapy in patients undergoing electrical or pharmacologic cardioversion for AF (or atrial utter). In particular, the option of NOACs in the setting of cardioversion is reviewed. Cardioversion of AF of > 48 h or Unknown Duration VKA: Observational data support the use of VKA in the context of elective cardioversion, whether electrical or pharmacologic. A systematic review of 18 observational studies provides moderate-quality evidence for a lower risk of stroke or thromboembolism with peri- cardioversion anticoagulation (with VKA) vs no 0.48), but did not report major bleeding events.233 The recommended duration of a minimum of 3 weeks therapeutic anticoagulation with VKA before cardioversion and a minimum 4 weeks subsequently is arbitrary and has no trial basis, being based on indirect pathophysiological and observational data.


A systematic review of 18 observational studies provides moderate-quality evidence for a lower risk of stroke or thromboembolism with peri- cardioversion anticoagulation (with VKA) vs no 0.48), but did not report major bleeding events.233 The recommended duration of a minimum of 3 weeks therapeutic anticoagulation with VKA before cardioversion and a minimum 4 weeks subsequently is arbitrary and has no trial basis, being based on indirect pathophysiological and observational data. The rationale for maintenance of a therapeutic INR in the peri- cardioversion period is from observational data, showing that thromboembolism is signi cantly more common at INR of 1.5 to 2.4 before cardioversion than INR of 2.5 Retrospective observational studies suggest that, after cardioversion, the highest risk of stroke and thromboembolism is in the rst 72 h. In addition, most thromboembolic complications are within However, even if sinus rhythm is restored on ECG, TEE studies have shown that atrial mechanical dysfunction can persist for several weeks Recent Finnish registry data suggest that most post-cardioversion strokes are associated with not using anticoagulation.237 Although data relating to the impact of long-term anticoagulation post-cardioversion are lacking, relevant Swedish observational data suggest that discontinuation of warfarin after catheter ablation is not safe in high-risk patients, especially those individuals with a history of It is also worth noting that although the risk of ischemic stroke/thromboembolism is higher with non-paroxysmal vs paroxysmal AF (multivariable adjusted HR, 1.38; 95% CI, 1.19-1.61; P < .001), the pattern of AF does not affect the decision regarding long-term OAC. NOACs: Evidence is available for all 4 currently available NOACs: dabigatran, apixaban, rivaroxaban, and edoxaban. An existing systematic review from Renda et al239 compared the use of NOAC vs VKA in the setting of cardioversion in 6 studies.


An existing systematic review from Renda et al239 compared the use of NOAC vs VKA in the setting of cardioversion in 6 studies. Reported pooled RRs (relative risk reductions) were 0.82 (0.38-1.75) for stroke/systemic embolism, 0.72 (0.27-1.90) for mortality, and 0.72 (0.19-2.71) for MI, respectively, suggesting at least comparable ef cacy of NOACs with VKA in the setting of cardioversion (e-Table 17). It should be noted that despite these reassuring data, the included trials were underpowered for safety and ef cacy, and judged to be of poor quality. The need for consensus guidance is illustrated by the current wide variation in VKA and NOAC use in the setting of elective cardioversion.240,241 Available data support the use of rivaroxaban,242,243 in patients to be continued on these NOACs if scheduled for cardioversion. Similar observations were found in a randomized trial of apixaban vs warfarin (Eliquis Evaluated in Acute Cardioversion Compared to Usual Treatments for Anticoagulation in Subjects With Atrial A TEE-guided approach with abbreviated anticoagulation before cardioversion has been recommended as an alternative to the conventional approach of using a minimum of 3 weeks therapeutic pre-cardioversion anticoagulation as outlined above.248 In the TEE-guided strategy, patients receive VKA and once therapeutic, undergo a screening TEE. If the TEE identi es thrombus in either the atrial appendage or atrium, cardioversion is postponed, given the presumed high risk of thromboembolism. In the absence of thrombus, cardioversion is immediately performed. Given the need for accurate visualization of thrombus, the TEE-guided strategy requires an experienced 1164 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] echocardiographer.


Given the need for accurate visualization of thrombus, the TEE-guided strategy requires an experienced 1164 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] echocardiographer. The best data for the use of VKA in the TEE-guided approach are from the Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) RCT, which compared a TEE-guided strategy of abbreviated therapeutic anticoagulation with IV UFH (started 24 h before cardioversion) or warfarin (INR, 2.0-3.0) (started 5 days before cardioversion) vs a strategy of therapeutic anticoagulation for at least 3 weeks before Overall, the evidence is of low quality, and therefore the results are not conclusive with respect to either a bene t or harm with the TEE-guided strategy vs the conventional approach of 3 weeks of anticoagulation pre-cardioversion. For NOACs vs warfarin in the TEE-guided approach, our review found an existing systematic review and An updated search of this systematic review identi ed 1 additional study. Pooled results found that the relative RR for stroke/thromboembolism was 0.33 (95% CI, 0.06-1.68) for NOACs vs warfarin (e- Fig 3, e-Table 18). Although these data indicate safety and probable equivalence of NOACs in the TEE-guided approach vs VKA, the trials were underpowered to show ef cacy, and therefore the evidence is of low quality (e- Table 18). The advantage of NOACs is that their mode of action is quicker than VKA, and therefore there is no delay in waiting for a therapeutic INR. However, the need for strict adherence to the NOAC therapy must be emphasized to patients, particularly in the post- cardioversion period. Individuals who are very symptomatic due to AF may gain greatest bene t from the TEE-guided approach since cardioversion can be expedited by a thrombus- negative TEE.


Individuals who are very symptomatic due to AF may gain greatest bene t from the TEE-guided approach since cardioversion can be expedited by a thrombus- negative TEE. In addition, a TEE-guided approach can be used to avoid prolonged VKA before cardioversion, which is a particular consideration in patients at increased risk for bleeding. The NOACs now offer an alternative to prolonged anticoagulation before cardioversion. However, a risk-based approach to anticoagulation should be used, and avoiding anticoagulation with a TEE-guided strategy should only be considered in the absence of stroke risk factors and a low risk of recurrent AF. For patients undergoing a TEE-guided approach, LMWH at full VTE treatment doses or IV UFH (to maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3-0.7 IU/mL anti-factor Xa activity) should be started at the time of TEE and cardioversion performed within 24 h of the TEE if no thrombus is seen. Observational data and 1 RCT show that LMWH has similar ef cacy compared with heparin or warfarin for immediate anticoagulation before In the outpatient setting, a TEE-guided approach should involve initiation of VKA (INR, 2.5; range, 2.0-3.0) followed by the TEE and subsequent cardioversion scheduled 5 days later (if the INR is in therapeutic range at that time). The NOACs again offer an alternative in outpatient treatment before TEE- guided cardioversion, with no bridging therapy necessary. Among AF patients undergoing TEE, 10% have LAA thrombus with a 3.5-fold increased risk of stroke/ but no speci c data are available in the context of cardioversion. If atrial thrombus is seen on TEE, then there is heterogeneity in current clinical practice regarding both when or whether to perform the TEE again, as well as subsequent management of anticoagulation.


If atrial thrombus is seen on TEE, then there is heterogeneity in current clinical practice regarding both when or whether to perform the TEE again, as well as subsequent management of anticoagulation. There is no evidence to support re- imaging, although it is a reasonable strategy. Although current practice favors not performing cardioversion if re-imaging shows thrombus due to the presumed high risk of thromboembolism, there is a lack of direct data about the safety of cardioversion in the presence of thrombus. Taken together, a risk-based approach to anticoagulation can be recommended and with respect to TEE, individualization of therapy on a case-by-case basis is proposed. It should be noted that in a multicenter registry of AF patients undergoing catheter ablation, TEE-guided cardioversion did not show a bene t compared with uninterrupted NOAC therapy.257 Although there is no direct evidence to guide decision- making about long-term management of anticoagulation in patients who appear to be in sinus rhythm at 4 weeks after cardioversion, indirect evidence suggests strongly that long-term anticoagulation should be based on the risk of stroke rather than the apparent success of the cardioversion procedure. First, recurrence of AF at 1 year after cardioversion occurs in approximately one- half of patients, and therefore long-term stroke risk is Second, the Atrial Fibrillation Follow- up Investigation of Sinus Rhythm Management (AFFIRM) study, in which many patients stopped anticoagulation after initial (apparently) successful restoration of sinus rhythm, demonstrated similar rates of thromboembolism with a rhythm control strategy compared with a rate control strategy.262 Third, patients with paroxysmal AF are often asymptomatic during episodes of AF recurrence, with 1 series suggesting that only 1 in every 12 paroxysms are symptomatic.263 Recommendation 12.


First, recurrence of AF at 1 year after cardioversion occurs in approximately one- half of patients, and therefore long-term stroke risk is Second, the Atrial Fibrillation Follow- up Investigation of Sinus Rhythm Management (AFFIRM) study, in which many patients stopped anticoagulation after initial (apparently) successful restoration of sinus rhythm, demonstrated similar rates of thromboembolism with a rhythm control strategy compared with a rate control strategy.262 Third, patients with paroxysmal AF are often asymptomatic during episodes of AF recurrence, with 1 series suggesting that only 1 in every 12 paroxysms are symptomatic.263 Recommendation 12. For patients with AF of greater than 48 h or unknown duration undergoing elective electrical or pharmacologic cardioversion, we recommend therapeutic anticoagulation with well-managed VKA (INR 2-3) or an NOAC using dabigatran, rivaroxaban, edoxaban, or apixaban for at least 3 weeks before cardioversion or a transesophageal echocardiography (TEE)-guided approach with abbreviated anticoagulation before cardioversion rather than no anticoagulation (Strong recommendation, moderate quality evidence). Remark: With NOACs adherence and persistence should be strongly emphasized. 13. For patients with AF of greater than 48 h or unknown duration undergoing elective electrical or pharmacologic cardioversion, we recommend therapeutic anticoagulation (with VKA or NOAC) for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of the baseline risk of stroke (Strong recommendation, moderate quality evidence). Remark: Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk- based recommendations for long-term antithrombotic therapy in recommendations 1 and 2, and not on the basis of successful cardioversion. 14. In patients in which LAA thrombus is detected on TEE, cardioversion postponed, and OAC continued for another 4-12 weeks, to allow thrombus resolution or endothelization, we suggest that a decision on whether a repeat TEE is performed should be individualized (Ungraded consensus-based statement).


In patients in which LAA thrombus is detected on TEE, cardioversion postponed, and OAC continued for another 4-12 weeks, to allow thrombus resolution or endothelization, we suggest that a decision on whether a repeat TEE is performed should be individualized (Ungraded consensus-based statement). Cardioversion of AF of 48 h Duration or Less: The duration of AF necessary for development of thrombus is not clear. Therefore, the threshold of AF duration below which pre-cardioversion anticoagulation can be safely avoided is not known. It is common practice to cardiovert without TEE or prolonged pre-cardioversion anticoagulation if AF is of short duration (< 48 h). The problem with this approach is the presence of left atrial thrombus on TEE in up to 14% of patients with AF of short duration in observational studies.264,265 In addition, the high prevalence of asymptomatic AF makes determining the exact duration of AF dif cult.266 If there is uncertainty about precise time of AF onset, then such patients should be managed as if AF > 48 h. A recent Finnish observational study of 5,116 successful cardioversions in 2,481 patients with acute (< 48 h) AF showed low incidence of stroke/thromboembolism during the 30 days following cardioversion, even without perioperative anticoagulation (0.7%).267 These results concur with low rates of stroke/thromboembolism in observational studies (Table 8).234,267-272 However, there is lower incidence of stroke/thromboembolism with cardioversions performed during anticoagulation (0.1% vs 0.7%; P .001), and with anticoagulation vs no anticoagulation in patients with a CHA2DS2-VASc score of $ 2 (0.2% vs 1.1%; P .001).


The problem with this approach is the presence of left atrial thrombus on TEE in up to 14% of patients with AF of short duration in observational studies.264,265 In addition, the high prevalence of asymptomatic AF makes determining the exact duration of AF dif cult.266 If there is uncertainty about precise time of AF onset, then such patients should be managed as if AF > 48 h. A recent Finnish observational study of 5,116 successful cardioversions in 2,481 patients with acute (< 48 h) AF showed low incidence of stroke/thromboembolism during the 30 days following cardioversion, even without perioperative anticoagulation (0.7%).267 These results concur with low rates of stroke/thromboembolism in observational studies (Table 8).234,267-272 However, there is lower incidence of stroke/thromboembolism with cardioversions performed during anticoagulation (0.1% vs 0.7%; P .001), and with anticoagulation vs no anticoagulation in patients with a CHA2DS2-VASc score of $ 2 (0.2% vs 1.1%; P .001). It should also be noted that there is a high risk of recurrence of the composite of cardioversion failure and recurrence of AF within Overall, the evidence suggests that peri-cardioversion anticoagulation is bene cial and that the decision regarding peri- and post-cardioversion anticoagulation should be based on risk of stroke/thromboembolism,267 even if an individual is presenting for the rst time with AF. Recommendations *15. For patients with AF of documented duration of 48 h or less undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (low-molecular- weight heparin or unfractionated heparin at full venous thromboembolism treatment doses) and proceeding to cardioversion rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach (Weak recommendation, low quality evidence). *16.


For patients with AF of documented duration of 48 h or less undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (low-molecular- weight heparin or unfractionated heparin at full venous thromboembolism treatment doses) and proceeding to cardioversion rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach (Weak recommendation, low quality evidence). *16. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), after successful cardioversion to sinus rhythm, we recommend therapeutic anticoagulation (with VKA or full adherence to NOAC therapy) for at least 4 weeks rather than no anticoagulation, regardless of baseline stroke risk (Weak recommendation, low quality evidence). Remark: Decisions about long-term anticoagulation after cardioversion should be made in accordance with our risk-based recommendations for long-term antithrombotic therapy in recommendations 1 and 2. 1166 Evidence-Based Medicine [ 1 5 4 # 5 C H E S T N O V E M B E R 2 0 1 8 ] Patients Undergoing Urgent Cardioversion for Hemodynamically Unstable AF: Our systematic review of anticoagulation vs no anticoagulation in patients with AF undergoing urgent cardioversion found no published data regarding the optimal anticoagulation strategy to use before or during urgent cardioversion for patients with AF and hemodynamic instability. On the basis of the above evidence for anticoagulation in elective cardioversion, initiation of anticoagulation immediately before urgent cardioversion (eg, with UFH or LMWH) would be expected to reduce the risk of stroke/thromboembolism based on studies of elective cardioversion. Initiation of anticoagulation therapy should not delay any emergency interventions required in order to stabilize the patient. Recommendations *17.


Initiation of anticoagulation therapy should not delay any emergency interventions required in order to stabilize the patient. Recommendations *17. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), we suggest that therapeutic-dose parenteral anticoagulation be started before cardioversion, if possible, but that initiation of anticoagulation must not delay any emergency intervention (Weak recommendation, low quality evidence). *18. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), after successful cardioversion to sinus rhythm, we suggest therapeutic anticoagulation for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of baseline stroke risk (Weak recommendation, low quality evidence). Remark: Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk-based recommendations for long-term antithrombotic therapy in recommendations 1 and 2. Patients Undergoing Elective or Urgent Cardioversion for Atrial Flutter There are no speci c trials which have considered electrical cardioversion in the context of atrial utter and associated anticoagulation. Despite the low risk of thromboembolism after cardioversion for atrial utter, which has been suggested by some observational studies, even in absence of anticoagulation, other studies have shown a similar risk of thromboembolism in patients after cardioversion for atrial utter and AF,234,274,275 perhaps due to co-existence of AF and atrial utter. Adults with congenital heart disease represent a growing, important population with atrial utter where long-term studies of outcomes with anticoagulation are required. Recommendation *19. For patients with atrial utter undergoing elective or urgent pharmacologic or electrical cardioversion, we suggest that the same approach to thromboprophylaxis be used as for patients with atrial brillation undergoing cardioversion (Ungraded consensus-based statement).


For patients with atrial utter undergoing elective or urgent pharmacologic or electrical cardioversion, we suggest that the same approach to thromboprophylaxis be used as for patients with atrial brillation undergoing cardioversion (Ungraded consensus-based statement). Patients With AF With Coronary Artery Disease ACS and/or PCI: AF commonly coexists with vascular disease, whether coronary, carotid, or PAD.92,276 Some AF patients with coronary disease may present with an ACS. Whether stable or acute, such patients may undergo percutaneous intervention with stent deployment. This section deals with the antithrombotic therapy management of this group of patients (Fig 6). There are 4 considerations when managing these patients, as follows92,277 : TABLE 8 ] Thromboembolic Complications in Patients With No Anticoagulation After Cardioversion of Acute (< 48 h) AF in Previous Studies Study No. Mean Age, y Male Success Rate TE Weigner et al268 Michael et al269 Burton et al270 Gallagher et al234 Stiell et al271 Xavier Scheuermeyer et al272 NA not available. See Table 1 legend for expansion of other abbreviations. (From Airaksinen et al.267 ) a All 3 thromboembolic events after spontaneous cardioversion and in elderly (>75 years) women. b Follow-up of 7 days. c Plus 1 probable thromboembolic event.  Stroke prevention, necessitating OAC, whether with VKA or NOAC.  Prevention of stent thrombosis, necessitating APT. There is evidence for using dual antiplatelet therapy (DAPT) for up to 12 months in non-AF patients.  Prevention of recurrent cardiac ischemia in an ACS patient, necessitating APT.


Prevention of recurrent cardiac ischemia in an ACS patient, necessitating APT. There is some evidence for using DAPT for beyond 12 months in non-AF patients from the DAPT and Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Pla- cebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trials, to reduce nonstent-related ischemic and stroke events, but at the risk of more bleeding  Serious bleeding risks (eg, ICH) with the combination of OAC and one or more antiplatelet drug. Additional considerations are the duration of treatment, acute or stable setting, type of APT, stent type, OAC type, bleeding risks, etc. Bleeding risk can be assessed by various bleeding risk scores, with the focus on modi able bleeding risk factors; however, the HAS- BLED score is predictive of bleeding in the setting of ACS and/or PCI-stenting.109 Coronary stent technology has also evolved, with small strut sizes necessitating shorter duration of DAPT (ie, aspirin plus a P2Y12 inhibitor such as clopidogrel). We are also in the era of NOACs, which may offer a better safety pro le compared with VKA-based therapy. Nonetheless, the latter may be relatively safe in the presence of well- managed anticoagulation control with high TTR.279 AF Patients Undergoing PCI: Various case series and cohort studies of AF patients undergoing PCI/stenting have been reported. These have been systematically reviewed as part of the 2014 and 2018 joint European consensus documents, endorsed by the Heart Rhythm Society and the Asia-Paci c Heart Rhythm Society, which provides consensus recommendations on optimal management of such patients.92,277 A similar North American expert consensus document has been O O C O O O C O Dual therapy with OAC plus inhibitor up to 12 mo. Triple therapy up to if possible. A.


These have been systematically reviewed as part of the 2014 and 2018 joint European consensus documents, endorsed by the Heart Rhythm Society and the Asia-Paci c Heart Rhythm Society, which provides consensus recommendations on optimal management of such patients.92,277 A similar North American expert consensus document has been O O C O O O C O Dual therapy with OAC plus inhibitor up to 12 mo. Triple therapy up to if possible. A. Balanced thrombotic/ bleeding risk B. High bleeding risk/low thrombotic risk C. High thrombotic risk/ low bleeding risk Time from treatment Initiation (eg, stent placed) mo mo mo mo Beyond mo Triple therapy OAC alone A Dual therapy with OAC plus inhibitor up to 12 mo. Triple therapy up to 6 mo if possible. Triple therapy A Oral anticoagulant with VKA (TTR >70%) or NOAC Aspirin Clopidogrel A C C Dual therapy with OAC plus inhibitor up to 12 mo. Text C O C Figure 6 A-C, Management of oral antiplatelet therapy in patients with (A) balanced thrombotic/bleeding risk, (B) low thrombotic/high bleeding risk, and (C) high thrombotic/low bleeding risk. See Figure 1 legend for expansion of abbreviations. (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.