2021 Focused Update Consensus Guidelines of the Asia Pacific Heart Rhythm Society on Stroke Prevention in Atrial Fibrillation: Executive Summary

Elderly Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883-891 9 Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-992 10 Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369(22):2093-2104 11 Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383(9921):955-962 12
The prevalence of atrial fibrillation (AF) is increasing in recent decades, and the prevalence in the elderly population has increased more rapidly worldwide and also in Asians. 1-3 Stroke prevention in older AF patients is important as stroke risk increases dramatically with age. 4,5 However, oral anticoagulation (OAC) treatment has been underutilized in the elderly. In pivotal trials of non-vitamin K antagonist oral anticoagulants (NOACs), the proportions of elderly patients (age ! 75 years) included ranged from 31 to 43%. 7-10 Metaanalyses of pivotal NOAC trials showed no interaction between different age groups and efficacy/safety of NOAC compared with warfarin. 11 Generally, the higher event rate in the elderly population resulted in a larger absolute risk reduction from NOAC compared with warfarin, but the presence of interaction by different age groups varied by different clinical outcomes in each NOAC trial (Supplementary . For very elderly (defined as !90 years), a previous observational study reported that OAC treatment may be considered for stroke prevention, with NOACs being the more favorable choice. In a further analysis of 64,169 AF patients !65 years of age, the clear safety signal in favor of NOACs over warfarin was evident irrespective of age strata [bib_ref] Outcomes of direct oral anticoagulants in patients with mitral stenosis, Kim [/bib_ref] [bib_ref] Protocol, rationale and design of DAbigatran for Stroke PreVention In Atrial Fibrillation..., Zhou [/bib_ref] [bib_ref] Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review, Guttmann [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy, Olivotto [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of apical hypertrophic cardiomyopathy, Lee [/bib_ref] [bib_ref] Temporal trends of the prevalence and incidence of atrial fibrillation and stroke..., Choi [/bib_ref] [bib_ref] Hypertrophic cardiomyopathy in patients with atrial fibrillation: prevalence and associated stroke risks..., Jung [/bib_ref] [bib_ref] Stroke risk stratification for atrial fibrillation patients with hypertrophic cardiomyopathy, Jung [/bib_ref] [bib_ref] Novel oral anticoagulants for primary stroke prevention in hypertrophic cardiomyopathy patients with..., Lee [/bib_ref] [bib_ref] Effectiveness and safety of nonvitamin K antagonist oral anticoagulants in patients with..., Jung [/bib_ref] [bib_ref] ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial..., Hankey [/bib_ref] [bib_ref] Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran:..., Hart [/bib_ref] [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] [bib_ref] Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous..., Ntaios [/bib_ref] [bib_ref] Effectiveness and safety of direct oral anticoagulant for secondary prevention in asians..., Park [/bib_ref] [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] [bib_ref] Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and..., Nielsen [/bib_ref] [bib_ref] Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial..., Nielsen [/bib_ref] [bib_ref] Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral..., Ottosen [/bib_ref] [bib_ref] Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis, Murthy [/bib_ref] , !90 years), being most marked in very older adults. 5 Actually, the introduction of NOACs has changed the land-scape for stroke prevention in elderly (!85 years) Asian AF patients. The initiation rates of OACs after AF, which was newly diagnosed, in the elderly significantly increased from 9.5 to 34.3%, mainly due to the introduction of NOACs (from 0 to 26.2%), and the 1-year risk of ischemic stroke (IS) after AF diagnosis decreased in the era of NOACs. In a recent report from Taiwan which focused on "clinically complex" very elderly (!90 years) AF patients with a history of intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), or chronic kidney disease (CKD), NOACs were still associated with a lower risk of composite adverse events compared with warfarin or non-OACs. 17 Therefore, "old age" itself should not be the sole reason to withhold OACs for stroke prevention.
What is the "optimal" dose of NOAC in the elderly AF patients with a high bleeding risk is an important and difficult issue. higher incidence of major bleeding than placebo (HR: 1.87, p 14 0.09). However, it should be emphasized that the results of ELDERCARE-AF just proved the concept that even the off-labeling low-dose edoxaban was better than nonuse of OACs (rather than being against the use of standard-dose NOACs). NOACs at the on-labeling dose should still be considered first for stroke prevention in elderly AF patients until high-quality data of direct comparisons of different dosing NOACs are available.

## Low body weight
Although there is no absolute cut-off for defining low body weight (LBW), Asians tend to be smaller and leaner than non-Asians (e.g., 20 kg less on average in ENGAGE AF-TIMI 48) 20 ; thus, patients with LBW are more common among Asians than among non-Asians. The effects of NOACs are closely related to plasma concentrations, which are affected by body distribution volume. 21 Extremely LBW may influence the efficacy and safety of NOACs. Although NOACs have shown better net clinical benefits than warfarin, being underweight has been associated with an increased risk of major bleeding in patients taking NOACs. 22 Body weight 60 kg was a dose reduction criterion for apixaban and edoxaban. 9,10 For apixaban, there was no interaction between different body weight groups ( 60, 61-120, and >120 kg) and the efficacy of apixaban compared with warfarin. 23 In terms of safety outcome such as major bleeding, a large relative risk reduction was observed in patients with 60 kg than those with 61 to 120 and >120 kg. 23 For edoxaban versus warfarin, there was no significant interaction between different body mass index (BMI) category groups and the outcomes; however, the underweight patients defined as BMI <18.5 kg/m 2 occupied a small proportion of the total population (0.8%, n 14 177). 24 A recent subanalysis of ENGAGE AF-TIMI 48 trial which focused on patients at extremes of body weight has demonstrated that the pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of body weight, resulting in similar efficacy compared with warfarin, while major or clinically relevant nonmajor bleeding and net outcomes were most favorable with edoxaban as compared with warfarin in LBW patients. 25 For rivaroxaban, limited data are available for patients with <60 or <50 kg. In recent observational data including a large population of AF patients with 60 kg taking OACs (n 14 21,589), NOAC was associated with lower risks of IS and major bleeding than warfarin and these results were largely consistent in patients with <50 kg. 26 Also, on-label NOAC dosing should still be applied in patients with LBW to achieve the best net clinical benefit. 26

## Chronic kidney disease
CKD is an independent predictor of risk of thromboembolic and bleeding events. 27 All NOACs have some degree of renal elimination, with the greatest renal dependency for excretion with dabigatran (80%) and the least with renal dependency for apixaban (27%). However, there are no head-to-head NOAC comparison trials and therefore insufficient evidence to recommend one agent over another. The dose adapted on the basis of CCr according to approved indications (Supplementary [fig_ref] References 1: Go AS, Hylek EM, Phillips KA, et al [/fig_ref].
There have been several meta-analyses addressing the efficacy and safety of NOACs compared with warfarin in patients with mild to moderate CKD. [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] [bib_ref] Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with chronic kidney..., Ando [/bib_ref] The data are consistent across studies that all NOACs are associated with lower risks of thromboembolic events compared with warfarin in patients with mild to moderate CKD (CCr: 30-79 mL/min). [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] For major bleeding, NOAC showed significantly lower risk of major bleeding compared with warfarin in patients with mild CKD (defined as CCr 50-79 mL/min); however, there was no significant difference between NOAC and warfarin in patients with moderate CKD (defined as CCr 30-49 mL/min). [bib_ref] Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized..., Sardar [/bib_ref] [bib_ref] Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on..., Nielsen [/bib_ref] Indirect comparisons suggested that apixaban and edoxaban high-dose regimens might be more likely associated with a better net clinical profile in AF patients with moderate CKD (defined as CCr from 25-30 to 50 mL/min). 30

## End-stage renal disease undergoing hemodialysis
The CHA 2 DS 2 -VASc score could also be used to predict IS risk in AF patients with end-stage renal disease (ESRD) undergoing dialysis. [bib_ref] Incidence and prediction of ischemic stroke among atrial fibrillation patients with end-stage..., Chao [/bib_ref] However, the benefit of OAC treatment in patients with AF and ESRD has been controversial. In a Korean nationwide cohort study, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (HR: 1.44, 95% confidence interval [CI]: 1.09-1.91) without any benefit for preventing thromboembolic events. [bib_ref] Warfarin use in patients with atrial fibrillation undergoing hemodialysis: a nationwide populationbased..., Yoon [/bib_ref] Warfarin-based OAC treatment did not show definite benefit for patients with ESRD and AF compared with no antithrombotic therapy. Recently, there has been a few studies suggesting that apixaban or rivaroxaban can be a safer alternative to warfarin in those population. [bib_ref] Outcomes associated with apixaban use in patients with end-stage kidney disease and..., Siontis [/bib_ref] [bib_ref] Safety and efficacy of apixaban versus warfarin in patients with end-stage renal..., Chokesuwattanaskul [/bib_ref] [bib_ref] Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney..., Coleman [/bib_ref] [bib_ref] Safety and efficacy of vitamin K antagonists versus rivaroxaban in hemodialysis patients..., De Vriese [/bib_ref] There was no difference in the risks of stroke/SE between apixaban (n 14 2,351) and warfarin (n 14 23,172) (HR: 0.88, 95% CI: 0.69-1.12), but apixaban was associated with a significantly lower risk of major bleeding (HR: 0.72, 95% CI: 0.59-0.87). [bib_ref] Outcomes associated with apixaban use in patients with end-stage kidney disease and..., Siontis [/bib_ref] Among patients with nonvalvular AF and stage 4 or 5 CKD or undergoing hemodialysis, rivaroxaban (n 14 1,896) did not significantly reduce stroke or SE (HR: 0.55, 95% CI: 0.27-1.10) or IS (HR: 0.67, 95% CI: 0.30-1.50) alone, but it was associated with a significant reduction of major bleeding by 32% compared with warfarin (n 14 4,848). [bib_ref] Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and severe kidney..., Coleman [/bib_ref] Despite some favorable data of NOACs, a recent meta-analysis which included 16 observational studies (2 of the 16 investigated NOACs) showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. [bib_ref] Oral anticoagulation for patients with atrial fibrillation on long-term hemodialysis, Kuno [/bib_ref] Also, a recent cohort study and meta-analysis from Taiwan demonstrated that the use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared with those without OAC use. Besides, NOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. 38

## Abnormal liver function
Liver disease is often accompanied by a combination of complex abnormalities of the coagulation pathways, [bib_ref] The coagulopathy of chronic liver disease, Tripodi [/bib_ref] [bib_ref] Coagulation in Liver Disease Group. Coagulation disorders and hemostasis in liver disease:..., Caldwell [/bib_ref] thus, patients with advanced liver disease have higher risks of thromboembolism and bleeding. [bib_ref] The complex role of anticoagulation in cirrhosis: an updated review of where..., Khoury [/bib_ref] [bib_ref] Oral anticoagulation in patients with liver disease, Qamar [/bib_ref] In addition, significant impairment of liver function can affect hepatic clearance and drug metabolism. [bib_ref] The importance of patientspecific factors for hepatic drug response and toxicity, Lauschke [/bib_ref] However, even in patients with liver cirrhosis, warfarin-based OAC was associated with a lower risk of IS and a positive net benefit compared with no antithrombotic therapy. [bib_ref] Liver cirrhosis in patients with atrial fibrillation: would oral anticoagulation have a..., Kuo [/bib_ref] The use of warfarin in patients with advanced liver disease is challenging due to intrinsically prolonged prothrombin time. [bib_ref] Stratifying the risks of oral anticoagulation in patients with liver disease, Efird [/bib_ref] Although NOAC could be considered as an alternative to warfarin, patients with liver function abnormalities (i.e., active or significant liver disease including vital hepatitis and cirrhosis, alanine transaminase/aspartate transaminase/alkaline phosphatase !2-3 times the upper limit of normal or bilirubin !1.5 times the ULN) were largely excluded from the pivotal NOAC clinical trials. 7-9 Although NOACs were not associated with an increased risk of serious liver injury irrespective of baseline liver status, 46 data about optimal OAC treatment in patients with liver function impairment were limited. In a small retrospective cohort study including patients with impaired liver function (n 14 633), NOAC showed similar risks of stroke or SE, major bleeding, and GIB compared with warfarin. [bib_ref] Efficacy and safety of non-vitamin K antagonist oral anticoagulants in atrial fibrillation..., Wang [/bib_ref] In a posthoc analysis of ENGAGE AF-TIMI 48 trial, bleeding, but not thromboembolic events, was increased in patients with liver disease, and a history of liver disease did not alter the relative efficacy and safety of higher dose edoxaban compared with warfarin. [bib_ref] Edoxaban versus warfarin in patients with atrial fibrillation and history of liver..., Qamar [/bib_ref] Also, in a large Asian population with AF and liver disease, NOACs showed better effectiveness and safety than warfarin, which was consistent in those with significant active liver disease, defined as in the pivotal clinical trials. [bib_ref] Direct oral anticoagulants in patients with atrial fibrillation and liver disease, Lee [/bib_ref] All four NOACs may be used in patients with mild and transient liver function abnormalities including Child-Turcotte-Pugh A cirrhosis, and dabigatran, apixaban, and edoxaban may be used with caution in patients with Child B cirrhosis. [bib_ref] Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when..., Intagliata [/bib_ref] [bib_ref] The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in..., Hum [/bib_ref] Rivaroxaban use should be avoided in patients with Child B cirrhosis and all four NOACs are contraindicated in patients with Child C cirrhosis and any liver disease combined with significant coagulopathy and an increased risk of clinically relevant bleeding. [bib_ref] Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single..., Kubitza [/bib_ref] Valvular Heart Disease AF often coexists with various types of valvular heart diseases (VHDs). Valvular AF is defined as patients with AF and VHD including moderate to severe rheumatic mitral stenosis or having mechanical prosthetic valve (Evaluated Heart valves, Rheumatic or Artificial, EHRA type 1 VHDs). [bib_ref] Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint..., Lip [/bib_ref] Patients with valvular AF have significantly higher risks of thromboembolic events than those with nonvalvular AF. [bib_ref] What is 'valvular' atrial fibrillation? A reappraisal, Caterina [/bib_ref] Other VHDs are defined as EHRA type 2 VHDs 54 and these patients also showed higher thromboembolic and bleeding risk. [bib_ref] Thromboembolism and bleeding complications in anticoagulated patients with atrial fibrillation and native..., Melgaard [/bib_ref] The efficacy of warfarin in stroke prevention in patients with valvular AF has long been established. Although the [fig_ref] References 1: Go AS, Hylek EM, Phillips KA, et al [/fig_ref] Recommendations about the dosing of NOACs according to renal function. bid, twice daily; CCr, creatinine clearance; ESRD, end-stage renal disease; qd, once daily; NOACs, non-vitamin K antagonist oral anticoagulants; RRT, renal replacement therapy.
pivotal clinical trials of NOACs did not include patients with valvular AF (EHRA type 1 VHDs), patients with EHRA type 2 VHDs were allowed to participate. [bib_ref] Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular..., Ezekowitz [/bib_ref] [bib_ref] Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular..., Avezum [/bib_ref] [bib_ref] ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban..., Breithardt [/bib_ref] [bib_ref] Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI..., Caterina [/bib_ref] The efficacy and safety of NOACs do not appear to be different with respect to the valvular status of patients, including those with bioprosthetic valves, 61 and the pooled high-dose NOAC group shows a significantly lower risk of thromboembolic events and a similar risk of major bleeding compared with the warfarin group 62 and consistent results were observed in a large Asian nationwide cohort with VHDs. [bib_ref] Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular..., Moon [/bib_ref] There has been only one published randomized controlled study comparing warfarin and NOAC in patients with mechanical prosthetic valves. [bib_ref] RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves, Eikelboom [/bib_ref] This study was prematurely terminated because of excessive thromboembolic and bleeding events with dabigatran. [bib_ref] RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves, Eikelboom [/bib_ref] Although there was a signal for the positive net benefit of NOACs compared with warfarin in patients with mitral stenosis, 65 further randomized clinical trials are needed to consider NOAC as an alternative to warfarin in patients with rheumatic mitral stenosis. [bib_ref] Protocol, rationale and design of DAbigatran for Stroke PreVention In Atrial Fibrillation..., Zhou [/bib_ref] Hypertrophic Cardiomyopathy AF is the most common cardiac arrhythmia in patients with hypertrophic cardiomyopathy. [bib_ref] Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review, Guttmann [/bib_ref] Observational data highlight a high stroke risk in patients with hypertrophic cardiomyopathy and AF, confirming the need for OAC. [bib_ref] Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy, Olivotto [/bib_ref] [bib_ref] Impact of atrial fibrillation on the clinical course of apical hypertrophic cardiomyopathy, Lee [/bib_ref] In a large nationwide observational cohort including Asian population, the annual risk of AF-associated stroke in hypertrophic cardiomyopathy was over 1% even in younger patients and those with CHA 2 DS 2 -VASc score of 0 or 1 point. [bib_ref] Temporal trends of the prevalence and incidence of atrial fibrillation and stroke..., Choi [/bib_ref] Consistent with these results, the risk of stroke in patients with hypertrophic cardiomyopathy and AF without any CHA 2 DS 2 -VASc stroke risk factors was similar to that of those patients without hypertrophic cardiomyopathy with CHA 2 DS 2 -VASc score of 3. 71,72 Despite the higher stroke risk, the use of OACs among patients with hypertrophic cardiomyopathy and AF is suboptimal in the daily practice. [bib_ref] Hypertrophic cardiomyopathy in patients with atrial fibrillation: prevalence and associated stroke risks..., Jung [/bib_ref] Although most experience was from warfarin, recent observational studies demonstrated that NOACs were associated with lower risks of thromboembolic events and major bleeding compared with warfarin. [bib_ref] Novel oral anticoagulants for primary stroke prevention in hypertrophic cardiomyopathy patients with..., Lee [/bib_ref] [bib_ref] Effectiveness and safety of nonvitamin K antagonist oral anticoagulants in patients with..., Jung [/bib_ref] Prior Stroke and ICH

## Prior stroke
Prior stroke or transient ischemic attack (TIA) is a powerful predictor of subsequent stroke, with an increased risk by 2.2 to 2.5.When prescribing OACs to patients with prior stroke/TIA, physicians should consider that these patients are also at higher risk for ICH during OAC than those without prior stroke/TIA. [bib_ref] ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial..., Hankey [/bib_ref] [bib_ref] Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran:..., Hart [/bib_ref] [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] Previous pivotal randomized clinical trials of NOACs that included a varied number of patients with AF and a history of stroke/TIA reported following subgroup analyses for these population. [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] The efficacy and safety of NOACs between patients with and without prior stroke/TIA were similar, indicating that NOACs can be used safely even in patients with prior stroke/TIA. [bib_ref] ENGAGE AF-TIMI 48 Investigators. Outcomes with edoxaban versus warfarin in patients with..., Rost [/bib_ref] [bib_ref] ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with..., Hankey [/bib_ref] [bib_ref] RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation..., Diener [/bib_ref] An updated meta-analysis includ-ing 20,500 AF patients with previous stroke/TIA showed that NOACs were associated with a significant reduction of stroke, IS or SE, hemorrhagic stroke, and ICH compared with warfarin. [bib_ref] Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous..., Ntaios [/bib_ref] In a recent report from South Korea, NOACs were associated with lower risks of recurrent stroke, major bleeding, composite clinical outcomes, and mortality in Asian AF patients with a history of stroke. [bib_ref] Effectiveness and safety of direct oral anticoagulant for secondary prevention in asians..., Park [/bib_ref] The 2021 EHRA (European Heart Rhythm Association) practical guide on the use of NOACs suggests initiation of OACs between 1 and 28 days after an IS, depending on the presence of hemorrhagic transformation at brain imaging on admission and stroke severity. [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] For patients without hemorrhagic transformation, OACs could be considered between 1 and 12-14 days depending on the severity of stroke. For patients with hemorrhagic transformation, OACs would be considered once clinical status improved and significant reduction of hemorrhagic transformation was documented at follow-up brain computed tomography or magnetic resonance imaging performed 1 day before restarting/initiations of NOACs.
A multidisciplinary team approach including stroke neurologists and cardiologists should help in decision-making, taking patients' values and preferences into consideration. The suggestions about the use of OACs after acute IS are summarized in Supplementary . [bib_ref] European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K..., Steffel [/bib_ref] Prior ICH AF patients with a history of prior ICH have a higher risk of both IS and recurrent ICH. [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] The positive net clinical benefits of OAC therapy in patients with prior ICH were consistently observed in previous observational studies. [bib_ref] Restarting anticoagulant treatment after intracranial hemorrhage in patients with atrial fibrillation and..., Nielsen [/bib_ref] [bib_ref] Outcomes associated with resuming warfarin treatment after hemorrhagic stroke or traumatic intracranial..., Nielsen [/bib_ref] [bib_ref] Use of antithrombotic therapy and long-term clinical outcome among patients surviving intracerebral..., Ottosen [/bib_ref] [bib_ref] Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis, Murthy [/bib_ref] In a previous report from the Taiwan nationwide claims database, use of warfarin was found to be possibly beneficial for AF patients with prior ICH having a CHA 2 DS 2 -VASc score !6 compared with no antithrombotic therapy. [bib_ref] Use of oral anticoagulants for stroke prevention in patients with atrial fibrillation..., Chao [/bib_ref] Since all pivotal clinical trials of NOACs excluded patients with a history of spontaneous ICH, 7-10 data about comparisons between warfarin and NOACs among these patients were only available from retrospective observation studies. It seems that NOACs were associated with a lower risk of all-cause mortality (adjusted HR [aHR]: 0.517), ICH (aHR: 0.556), and major bleeding (aHR: 0.645) compared with warfarin, whereas the rate of IS was similar. [bib_ref] Association of ischemic stroke, major bleeding, and other adverse events with warfarin..., Tsai [/bib_ref] Similar findings have been reported from South Korea. [bib_ref] Oral anticoagulation in Asian patients with atrial fibrillation and a history of..., Lee [/bib_ref] The small randomized trial the Start or STop Anticoagulants Randomized Trial (SoSTART) was inconclusive, although rates of recurrent ICH were lower than expected.Therefore, among AF patients with prior ICH, OACs should generally still be considered with NOACs being as the preferred choice for stroke prevention.
For AF patients who experienced acute ICH, OAC treatment can be resumed/initiated after 4 to 8 weeks, especially when the cause of bleeding or the relevant risk factor has been treated.A multidisciplinary team approach including stroke neurologists and cardiologists should help in decision-making, taking patients' values and preferences into consideration. However, further studies are needed to find optimal timing point of OAC resumption and subgroups of patients who are more beneficial for early OAC resumption, especially in the NOAC era.

## Adherence issue
It is critical to educate patients about the importance of strict adherence. Strict adherence to NOAC intakes is more crucial as its anticoagulation effect diminishes within 12 to 24 hours after the last intake. [bib_ref] Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on..., Raparelli [/bib_ref] Although actual adherence of NOAC intake varied depending on the data sources and definition, 95-100 adherent NOAC users (proportion of days covered ! 80%) accounted for 64% of all NOAC users in a recent Asian real-world observational cohort study. [bib_ref] The optimal drug adherence to maximize the efficacy and safety of non-vitamin..., Kim [/bib_ref] Adherent use of NOAC showed better outcomes without increasing bleeding risk and maintaining !90% of adherence achieved optimal effectiveness of NOAC. [bib_ref] The optimal drug adherence to maximize the efficacy and safety of non-vitamin..., Kim [/bib_ref] Cost-effective and feasible tools should be developed for high-risk patients with low adherence. 102
[fig] References 1: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285 (18):2370-2375 2 Lee SR, Choi EK, Han KD, Cha MJ, Oh S. Trends in the incidence and prevalence of atrial fibrillation and estimated thromboembolic risk using the CHA 2 DS 2 -VASc score in the entire Korean population. Int J Cardiol 2017;236:226-231 3 Chao TF, Liu CJ, Tuan TC, et al. Lifetime risks, projected numbers, and adverse outcomes in Asian patients with atrial fibrillation: a report from the Taiwan nationwide AF cohort study. Chest 2018; 153(02):453-466 4 Chao TF, Wang KL, Liu CJ, et al. Age threshold for increased stroke risk among patients with atrial fibrillation: a nationwide cohort study from Taiwan. J Am Coll Cardiol 2015;66(12):1339-1347 5 ChaoTF, Chiang CE, Liao JN, Chen TJ, Lip GYH, Chen SA. Comparing the effectiveness and safety of nonvitamin K antagonist oral anticoagulants and warfarin in elderly Asian patients with atrial fibrillation: a nationwide cohort study. Chest 2020;157(05): 1266-1277 6 Cheng WH, Chiang CE, Lin YJ, et al. Non-vitamin K antagonist oral anticoagulants in elderly (!85 years) patients with newly diagnosed atrial fibrillation: changing clinical practice and outcomes for stroke prevention in a nationwide cohort study. Mayo Clin Proc 2021;96(01):52-65 7 Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12): 1139-1151 Supplementary Fig. S2 Use of OACs after acute ischemic stroke or TIA. The figure was redrawn and modified from the 2021 European Heart Rhythm Association Practical Guide on the use of NOACs in patients with AF by Steffel et al. 84 CT, computed tomography; MRI, magnetic resonance imaging; NOAC, non-vitamin K antagonist oral anticoagulant; TIA, transient ischemic attack. 8 Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. [/fig]