Eligibility and Preference of New Oral Anticoagulants in Patients With Atrial Fibrillation Comparison Between Patients With Versus Without Stroke

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1 Eligibility and Preference of New Oral Anticoagulants in Patients With Atrial Fibrillation Comparison Between Patients With Versus Without Stroke Chang Hyo Yoon, MD; Yoon Kyung Park, MD; Suk Jae Kim, MD; Mi-ji Lee, MD; Sookyung Ryoo, MD; Gyeong-Moon Kim, MD, PD; Chin-Sang Chung, MD, PhD; Kwang Ho Lee, MD, PhD; June Soo Kim, MD, PhD; Oh Young Bang, MD, PhD Background and Purpose Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy Methods We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured. Results The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8% 40.5%) and planned cardioversion (5.1% 7.7%) for nonstroke patients, and a low creatinine clearance (5.6% 9.2%) and higher risk of bleeding (15.2% 20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) (P<0.05 in both cases). Conclusions Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs. (Stroke. 2014;45: ) Key Words: atrial fibrillation randomized trial stroke warfarin Results of 4 phase III randomized controlled trials (RCTs) on 4 new oral anticoagulants (NOACs), dabigatran, apixaban, rivaroxaban, and edoxaban, have recently been introduced. 1 4 NOACs are either noninferior or superior to warfarin in prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) but are superior to warfarin in reducing hemorrhagic stroke. Evidence from these trials forms the basis for national and international guidelines for the management of nearly all such patients in clinical practice. The inclusion and exclusion criteria in randomized trials are defined by steering committee based on feedback from regulatory agencies, eg, the US Food and Drug Administration or European Medicines Agency. However, abundant and strict enrollment criteria may limit the validity and the applicability of results of RCTs to clinical practice. Recent studies of antiplatelet therapy for prevention of ischemic stroke and surgical treatment for intracranial hemorrhage showed that patients with ischemic stroke or intracranial hemorrhage enrolled in RCTs are only partially representative of patients in clinical practice. 5,6 Both studies suggested the use of less strict enrollment criteria to enhance generalizability. Moreover, a population-based study showed Received March 27, 2014; final revision received July 23, 2014; accepted July 28, From the Department of Neurology (C.H.Y., Y.K.P., S.J.K., M.-j.L., S.R., G.-M.K., C.-S.C., K.H.L., O.Y.B.) and Department of Cardiology (J.S.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Oh Young Bang, MD, PhD, Department of Neurology, Samsung Medical Center, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul , South Korea. neuroboy50@naver.com 2014 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 2984 Stroke October 2014 Table 1. Inclusion and Exclusion Criteria Inclusion criteria RE-LY ROCKET ARISTOTLE ENGAGE One of followings: 1. Prior stroke, TIA, systemic embolism 2. EF<4 3. Symptomatic HF 4. >75 y old 5. >65 y old+dm, HTH, or coronary heart disease Prior ischemic stroke, TIA, systemic embolism or Two of followings: 1. Heart failure or EF 35% 2. HTN 3. Age 75 y 4. DM One of followings: 1. Age 75 y 2. Prior stroke, TIA, or systemic embolus 3. Symptomatic CHF within 3 month or EF 4 4. DM 5. HTN 2 Exclusion criteria Cardiac-related conditions Valvular disease Hemodynamic relevant Mitral stenosis Mitral stenosis Mitral stenosis Prosthetic heart valve Exclude Exclude Exclude (only mechanical) Planned cardioversion/ Ablation Other cardiac diseases Hemorrhage risk-related criteria GI bleeding/ulcer Within 1 y/1 month Within 6 months Within 1 y/1 y History of bleeding Chronic hemorrhagic disorder Exclude Exclude Exclude Intracranial neoplasm, Exclude vascular malformation, or aneurysm Major surgery or trauma or planned major surgery Thrombocytopenia or anemia Uncontrolled HTN Concomitant conditions/treatment Severe stroke/ any Within 6 mo/14 days Within 3 mo/14 days Within 7 days Within 30 days stroke, TIA MI, ACS, PCI Within 30 days Use of antiplatelet/fibrilolytics None/within 48 h Aspirin >100 mg or +thienopyridine/within 10 days NSAIDs or CytP450 inhibitor/inducer Aspirin >165 mg or +thienopyridine Thienopyridine or nonaspirin antiplatelet Exclude Exclude WBC (cells/μl) <3000 Contraindication to warfarin use CrCL 30 ml/min 30 ml/min <25 ml/min or <30 ml/min s-creatinine >2.5 mg/dl Active liver disease, including positive HBV antigen/hcv antibody Study participation/follow-up related Serious concomitant illness expectancy Drug addiction or alcohol abuse Cancer diagnosis within 6 mo or life expectancy <3 y Life expectancy <2 y Life expectancy <1 y Cancer diagnosis within 5 y or life expectancy <1 y Inability to monitor INR Exclude Exclude Exclude ACS indicates acute coronary syndrome; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial;, congestive heart failure, hypertension, age >75 yr, diabetes mellitus, and prior stroke or TIA; CytP450, cytochrome p450; DM, diabetes mellitus; EF, ejection fraction; ENGAGE-AF-TIMI 48, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; GI, gastrointestinal; HBV, hepatitis B; HCV, hepatitis C; HF, heart failure; HTN, hypertension; INR, international normalized ratio; MI, myocardial infarction; NSAIDs, nonsteroidal anti-inflammatory drugs; PCI, percutaneous coronary intervention; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ROCKET-AF, Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA, transient ischemic attack; and WBC, white blood cell.

3 Yoon et al Eligibility of New Oral Anticoagulants 2985 that compared with randomized control trials on NOACs, patients who were discharged with AF differed in that they were older and more comorbid, more like to have severe/ recent stroke, and on polypharmacy, which suggest that the patients enrolled in the randomized trials may deviate from the real-world practice. 7 We hypothesized that the current enrollment criteria of the clinical trials of NOACs may not representative of patients with AF, and analysis of eligibility of patients in clinical practice may guide the future direction for drug development. Thus, we estimated the eligibility for participation in landmark trials of NOACs of an unselected group of AF patients with or without stroke or transient ischemic attack (transient ischemic attack [TIA]). In addition, we compared features favoring NOAC use between patients with versus without stroke/tia. Patients and Methods Patient Selection This study used a retrospective cohort design based on data of consecutive patients encountered at a University Medical Center from October 2011 to October Patients were included in this study if (1) they had AF, (2) they were taking warfarin with a target international normalized ratio (INR) range of 2.0 to 3.0, and (3) who were followed up for >6 months. Patients with and without ischemic stroke or TIA were included in this study. Patients with ischemic stroke or TIA were identified as having suffered focal symptoms and relevant lesions on diffusion-weighted imaging for patients with stroke and no lesions for patients with TIA. The local institutional review board approved the study, and informed consent was obtained from participants before commencement of the study. Work-Up Patients received long-term warfarin treatment with a target INR range of 2.0 to 3.0. After stabilization, maintenance dosing within the therapeutic range was achieved by performing periodic INRs. Compliance with warfarin treatment was regularly monitored, and patients received education for warfarin diet by a pharmacist at an anticoagulation service. Dose assessment was performed every 1 to 3 months. For the calculation of the proportion of time in therapeutic range of INR levels, Rosendaal s method was used. 8 INR levels after 1 month of initiation of warfarin were used to define the quality of anticoagulation control (labile INRs during warfarin maintenance). In addition, we excluded INRs during temporary or permanent discontinuation, and during the first 1 month after treatment was restarted. Once a patient was enrolled, we obtained a medical history, performed a physical examination, and asked about concomitant medications, such as the use of antiplatelet agents, nonsteroidal anti-inflammatory drugs, and cytochrome P450 inhibitors/inducers. Blood tests were performed to measure creatinine clearance and liver disease. Variables that could potentially affect vascular events were recorded for each patient, which included congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA ( ) score and hemorrhagic (anticoagulation and risk factors in atrial fibrillation [ATRIA]) 9 risk schemes. In this study, we used ATRIA score for bleeding risk scheme instead of the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/ alcohol) score, because labile INRs are a key component of the HAS- BLED risk scheme. 10 Eligibility for Participation in the NOAC Trials and Preference to NOACs Than Warfarain We applied the enrollment criteria of 4 NOAC trials (Randomized Evaluation of Long-Term Anticoagulant Therapy [RE-LY], 1 Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], 2 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial [ARISTOTLE], 3 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation [ENGAGE-AF-TIMI 48]) (Table 1; Table I in the online-only Data Supplement). The inclusion and exclusion criteria were applied to each patient, and eligibility for participation in the NOAC trials was measured. In this study, recent or severely disabling stroke was not considered as a contraindication of NOACs trials. In addition, we also evaluated features favoring NOAC use in each patient, which included labile INR (time in therapeutic range [TTR] <66%) and bleeding risk (ATRIA score). A recent metaanalysis of NOACs trials showed a greater relative reduction in major bleeding with NOACs when TTR was <66%. 11 In addition, the current guideline suggests that assessment of bleeding risk should be considered in the choice of anticoagulant in patients with AF. 12 Statistical Analyses The differences in the clinical and laboratory parameters were evaluated by one-way ANOVA with post hoc analysis using the Fisher least-square difference or Kruskall Wallis test for continuous variables, and Pearson χ 2, Fisher exact test, or linear by linear association for categorical variables. An independent t test or the Mann Whitney U test was used to evaluate differences in the factors between the groups. All statistical analyses were performed using commercially available software (SPSS for Window, version 18.0; SPSS Inc., Chicago, IL). A P<0.05 was considered statistically significant. Results Six hundred ninety-five patients were included in this study. When compared with patients without stroke/tia, patients with stroke/tia were older and had a lower TTR, especially in those with severe disability (modified Rankin scale) (Figure I in the online-only Data Supplement), and bleeding tendency as measured by ATRIA was much higher in patients with stroke/tia ( in both cases) (Table 2). Creatinine clearance was lower in patients with stroke/tia than in nonstroke patients (P=0.037). The proportions of patients fulfilling the trial enrollment criteria varied, ranged from 39. to 72.8%, depending on Table 2. Characteristics of Patients Stroke/TIA (n=500) Nonstroke (n=196) Age, mean±sd 73.9± ±21.8 <0.001 Symptomatic heart failure, n (%) 72 (14.4%) 26 (13.3%) Ejection fraction, mean±sd 59.4± ± Hypertension, n (%) 375 (75.) 152 (77.9%) Diabetes mellitus, n (%) 161 (32.2%) 62 (31.8%) 0.918, mean±sd 3.71± ±1.77 <0.001 ATRIA score, mean±sd 3.06± ±2.16 <0.001 Lability of INR TTR (%), mean±sd 54.4± ±34.9 <0.001 TTR 66% 153 (32.6%) 112 (57.7%) <0.001 CrCL, mean±sd 56.8± ± Modified Rankin score 3 42 (11.1%) ATRIA indicates anticoagulation and risk factors in atrial fibrillation;, congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA; CrCL, creatinine clearance; INR, international normalized ratio; TIA, transient ischemic attack; and TTR; time in therapeutic range.

4 2986 Stroke October 2014 A RELY A-fib Stroke (n=500) B RELY A-fib non-stroke (n=196) 34.4% 65.6% 35.2% ROCKET-AF 27.2% 27.7% 45.1% 18.5% ROCKET-AF 41. Not indicated Contraindicated 64.8% ARISTOTLE 40.5% ARISTOTLE 27.2% 72.8% ENGAGE 21.5% 10.8% 67.7% ENGAGE C (%) Cardiac related Bleeding risk Concomitant conditions 42.6% Study participation 57.4% RELY ROCKET-AF ARISTOTLE ENGAGE D (%) Cardiac related Bleeding risk Figure. Numbers of eligible patients (A and B) and the reasons for exclusion (C and D) among studies Concomitant conditions 39. Study participation the differences in indications/contraindications of studies (lower in ENGAGE-AF-TIMI 48 than others) and presence or absence of stroke/tia (Figure). It was higher in patients with stroke (57.4% 72.8%) than in nonstroke patients ( %). When compared with nonstroke patients, patients with stroke/tia were more likely to meet inclusion criteria but were more likely to be excluded from the studies. Characteristics of eligible patients were similar among the studies but differed between with versus without stroke or Table 3. Differences in Patient Characteristics Among the Studies: Stroke/TIA TIA (Tables 3 and 4). In patients without stroke/tia, eligible patients were older and had a higher score (P<0.01 in both cases) than ineligible patients. On the contrary, in patients with stroke/tia, eligible patients were younger, less likely to have symptomatic heart failure, and had a lower and ATRIA score and a higher TTR compared with ineligible patients (P<0.05 in all cases). The main reasons for contraindications of NOACs were also similar among the studies but differed between with versus RE-LY ROCKET ARISTOTLE ENGAGE (n=328) (n=172) (n=324) (n=176) (n=324) (n=136) (n=287) (n=213) Age, y 73.0± ± * 72.8± ± * 73.5± ± ± ± Symp. HF 36 (11.) 36 (20.9%) 0.03* 38 (11.7%) 34 (19.3%) 0.021* 44 (12.1%) 28(20.6%) 0.016* 32 (11.1%) 40 (18.8%) 0.016* EF, % 59.8± ± ± ± ± ± ± ± HTN 244 (74.4%) 131(76.2%) (74.7%) 133 (75.6%) (75.3%) 101(74.3%) (75.3%) 159 (74.6%) DM 97 (29.6%) 64 (37.4%) (29.) 67 (38.1%) 0.038* 113 (31.) 48 (35.3%) (31.4%) 71 (33.3%) ± ± * 3.61± ± * 3.67± ± ± ± * ATRIA 2.46± ±4.74 <0.001* 2.50± ±4.80 <0.001* 2.68± ±4.84 <0.001* 2.52± ±4.80 <0.001* TTR 66% 109 (33.2%) 44 (25.6%) (33.6%) 44 (25.) (37.3%) 32 (23.5%) 0.021* 92 (32.1%) 61 (28.6%) ARISTOTLE indicates Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial; ATRIA, anticoagulation and risk factors in atrial fibrillation;, congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA; DM, diabetes mellitus; EF, ejection fraction; ENGAGE- AF-TIMI 48, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; HF, heart failure; HTN, hypertension; RE-LY, Randomized Evaluation of Long- Term Anticoagulant Therapy; ROCKET-AF, Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; TIA, transient ischemic attack; and TTR, time in therapeutic range. *P<0.05.

5 Yoon et al Eligibility of New Oral Anticoagulants 2987 Table 4. Differences in Patient Characteristics Among the Studies: Nonstroke (n=88) RE-LY ROCKET ARISTOTLE ENGAGE (n=107) (n=80) (n=115) (n=132) (n=63) (n=76) (n=119) Age, y 74.8± ±25.1 <0.001* 73.5± ± * 72.7± ± * 73.7± ± * Symp. HF 15 (17.) 11 (10.3%) (21.2%) 9 (7.8%) 0.009* 20 (15.2%) 6 (9.5%) (19.7%) 11 (9.2%) EF, % 60.5± ± ± ± ± ± ± ± HTN 77 (87.5%) 75 (70.1%) 0.004* 77 (96.2%) 75 (65.2%) <0.001* 115 (87.1%) 37 (58.7%) <0.001* 73 (96.1%) 79 (66.4%) <0.001* DM 26 (29.5%) 36 (33.6%) (50.) 22 (19.1%) <0.001* 46 (34.8%) 16 (25.4%) (51.3%) 23 (19.3%) <0.001* 1.89± ± * 2.26± ±1.72 <0.001* 1.85± ±2.06 <0.001* 2.25± ±1.78 <0.001* ATRIA 2.30± ± ± ± ± ± * 2.37± ± * TTR 66% 52 (59.1%) 60 (56.1%) (58.8%) 65 (56.5%) (57.6%) 36 (57.1%) (57.9%) 68 (57.1%) ARISTOTLE indicates Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial; ATRIA, anticoagulation and risk factors in atrial fibrillation;, congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA; DM, diabetes mellitus; EF, ejection fraction; ENGAGE- AF-TIMI 48, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation; HF, heart failure; HTN, hypertension; RE-LY, Randomized Evaluation of Long- Term Anticoagulant Therapy; ROCKET-AF, Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and TTR, time in therapeutic range. *P<0.05. without stroke or TIA (Figure; Table II in the online-only Data Supplement). A lower score (10.8% 40.5%) and planned cardioversion (5.1% 7.7%) were the main reasons for ineligibility for RCTs for nonstroke patients and a low creatinine clearance (5.6% 9.2%) and higher risk of bleeding (15.2% 20.8%) for patients with stroke. Preference of NOACs could be determined by a low TTR, a high ATRIA score, and a high creatinine clearance. However, there was a negative correlation between creatinine clearance and ATRIA score, as well as a negative correlation between ATRIA and TTR (Table 5). Patients who had features favoring NOAC use (ie, a high ATRIA score) were more likely to have contraindications for NOACs use (ie, a low creatinine clearance). Age was commonly associated with these factors. Discussion The main findings of this study are (1) the proportions of patients fulfilling the trial enrollment criteria were varied greatly depending on the differences in indications/contraindications of studies and presence or absence of stroke/tia, and (2) patients enrolled in randomized clinical trials are only partly representative of patients with AF in clinical practice. Patients in whom NOACs were preferred, ie, at high bleeding risk and poor anticoagulation control with warfarin, were likely to be excluded in the NOAC trials. The reasons for ineligibility for participation in NOACs trials were different between patients with stroke and nonstroke patients. The main reasons in nonstroke patients were no need for anticoagulation, such as low scores or planned cardiac surgery/intervention. Valvular heart disease was another reason for exclusion in nonstroke patients in our study. The use of an NOAC in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications when compared with warfarain. 13 On the contrary, all ineligible patients with stroke needed anticoagulation therapy. When compared with eligible patients, they were older and had a high ATRIA score and low TTR. Therefore, our results suggest that patients with stroke enrolled in RCTs are not representative of most patients with stroke and AF. Specifically, many patients who definitely need anticoagulation (a high AF-stroke risk schemes including elderly and heart failure), particularly in whom NOACs were preferred because of the poor quality of anticoagulation therapy (ie, low TTR) and a high risk of bleeding (ie, ATRIA score), were excluded in this study. However, NOACs would be particularly helpful in such conditions. 12 High TTR (>7) is associated with the best efficacy and safety of warfarin, 14 and a greater reduction in major bleeding with NOACs versus warfarin was observed in patients with a lower TTR (<66%). 11 Why would patients in whom the use of NOACs would be preferred be excluded in the NOAC trials? Although there was no restriction in terms of age (except <18 years) in the trial enrollment criteria, age may be the key factors for the eligibility of the NOAC trials. A population study showed that patients in clinical practice were fairly older compared with participants in RCT on NOACs, and severe impair renal impairment was not infrequent in the elderly, particularly in patients aged >80 years (5 showed a creatinine clearance 50 ml/min). 7 The annual risk of stroke in untreated patients with AF is age Table 5. Correlations Between the Features Favoring New Oral Anticoagulant Use: Spearman Correlation Analysis Age CrCL ATRIA CrCL ATRIA TTR r= 0.578* r=0.456* r= 0.324* r=0.577* r= r=0.444* r= P=0.056 r=0.008 P=0.841 r= 0.213* r= 0.121* P=0.002 ATRIA indicates anticoagulation and risk factors in atrial fibrillation;, acronym for congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA; CrCL, creatinine clearance; and TTR, time in therapeutic range. *P<0.05.

6 2988 Stroke October 2014 dependent, being 1% in the 50 to 59 age group, 3% in the 60 to 90 age group, 1 in the 70 to 79 age group, and 24% in patients aged 80 to Patients at increased age have an increased risk of bleeding often because of a declining renal function and other unknown factors. The RE-LY trial investigators reported a significant interaction between age and NOACrelated bleeding complication, and low dose of dabigatran is currently recommended for patients aged 75 years. 15 Our results showed that AF-risk schemes, bleeding-risk scheme, and a poor quality of anticoagulation are associated with age as well as renal function. Because of the deterioration in kidney function with age, the target populations for NOACs were excluded in most NOAC trials. Recently, subgroup analysis of RCTs of NOACs in patients with renal impairment showed that NOACs reduced the risk of stroke/systemic embolism and major bleeding regardless of renal function. 16,17 Our analysis of eligibility of patients in clinical practice raised the importance of the use of less strict enrollment criteria, and the need for development of NOACs that can be used in elderly patients with AF and renal dysfunction. The strength of this study was the inclusion of a large number of unselected and consecutively enrolled patients with comprehensive evaluation of the quality of anticoagulation control, risk schemes for AF-related thromboembolic risk and hemorrhage, and renal function. This study also has limitations resulting from a single center at a university hospital in Korea. Additional studies are needed to confirm our results. However, patients characteristics in East Asians with AF are similar to those in elsewhere. For example, patients features in ROCKET-AF participants 2 were comparable with those in J-ROCKET-AF participants (exclusively Japanese), 18 which may strengthen the generalization of the results of this study (Table III in the online-only Data Supplement). In conclusion, our results confirm that patients enrolled on RCTs investigating NOACs are partly representative of patients with AF in clinical practice. Furthermore, we demonstrated that currently used enrollment criteria were not successful in selecting patients in whom NOACs are preferred. Further studies are needed for patients who are likely to have beneficial with NOACs with the use of less strict enrollment criteria. Sources of Funding This study was supported by the National Research Foundation of Korea, Ministry of Education, Science and Technology ( ). None. Disclosures References 1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365: Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369: Maasland L, van Oostenbrugge RJ, Franke CF, Scholte Op Reimer WJ, Koudstaal PJ, Dippel DW; Netherlands Stroke Survey Investigators. Patients enrolled in large randomized clinical trials of antiplatelet treatment for prevention after transient ischemic attack or ischemic stroke are not representative of patients in clinical practice: the Netherlands Stroke Survey. Stroke. 2009;40: Fonville AF, Samarasekera N, Hutchison A, Perry D, Roos YB, Al-Shahi Salman R. Eligibility for randomized trials of treatments specifically for intracerebral hemorrhage: community-based study. Stroke. 2013;44: Joppi R, Cinconze E, Mezzalira L, Pase D, Poggiani C, Rossi E, et al; Italian Horizon Scanning Project. Hospitalized patients with atrial fibrillation compared to those included in recent trials on novel oral anticoagulants: a population-based study. Eur J Intern Med. 2013;24: Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69: Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138: Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet. 2014;383: Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al; ESC Committee for Practice Guidelines (CPG) focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33: Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369: Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost. 2011;106: Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123: Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32: Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33: Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al; J-ROCKET AF Study Investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation the J-ROCKET AF study. Circ J. 2012;76: