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Apixaban in Patients with Atrial Fibrillation
Open accessAbstract
BACKGROUND: Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS: In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS: Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).
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“It is superior to no treatment or aspirin in patients with different profiles for stroke risk.”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [354]
In the citing paper
“apixaban significantly reduced stroke or systemic embolism by 55% compared with aspirin, with no significant difference in rates of major bleeding or intracranial haemorrhage.354,403”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [354]
In the citing paper
“Antiplatelet therapy increases bleeding risk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antiplatelet monotherapy; P < 0.001), 433 with bleeding rates that are similar to those on OAC.354,362,431,434”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [354]
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Citations
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“Among patients with AF who are at high risk for stroke and for whom VKA therapy is unsuitable or refused by patients, apixaban substantially reduced the risk of stroke, as compared with aspirin, with no significant increase in the risk of major bleeding or intracranial bleeding (Connolly et al., 2011).”
BackgroundPotpara, T., Dagres, N., Mujović, N. M., Vasić, D., Ašanin, M., Nedeljkovic, M. A., Marín, F. R., Fauchier, L., Blomström‐Lundqvist, C., & Lip, G. Y. H. (2016) · Advances in Therapy · doi:10.1007/s12325-016-0458-7 · Cited by 16
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“[7] There was no significant difference in major bleeding risk between apixaban and aspirin (1.”
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Black‐Maier, E., Piccini, J. P., & Granger, C. B. (2019) · Journal of Cardiovascular Electrophysiology · doi:10.1111/jce.14182 · Cited by 16
“Interpretation of the ASAP‐TOO results will need to be placed in the context of AVERROES (Apixiban in Patients with Atrial Fibrillation).(10) The AVERROES investigators randomized 5599 patients with AF deemed unsuitable for VKA therapy to apixiban 5mg twice daily or aspirin with a primary outcome of stroke or systemic…”
BackgroundMethodInfluentialDamulin, I. V., Andreev, D. A., & Salpagarova, Z. K. (2015) · Neurology neuropsychiatry Psychosomatics · doi:10.14412/2074-2711-2015-1-80-86 · Cited by 16
Atrial Fibrillation Begets Myocardial Infarction
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“…K oral anticoagulants (NOAC) and apixaban showing major benefits in stroke reduction but no significant increase in bleeding risk compared to aspirin in similar patients in the AVERROES trial (2007–2010) [12], the role of ASA+CLO in long-term stroke prevention in NVAF has diminished substantially.”
BackgroundAarnink, E. W., Maarse, M., Fierro, N., Mazzone, P., Beneduce, A., Tondo, C., Gasperetti, A., Pracoń, R., Demkow, M., Zieliński, K., et al. (2024) · JACC: Cardiovascular Interventions · doi:10.1016/j.jcin.2024.04.012 · Cited by 15
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“Apixaban, according to the AVERROES [23] study, showed potential in preventing stroke.”
MethodEfficacy and safety of novel anticoagulants compared with established agents
Rybak, I., Ehle, M., Buckley, L. F., & Fanikos, J. R. (2011) · Therapeutic Advances in Hematology · doi:10.1177/2040620711408489 · Cited by 15
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Bleeding with anticoagulant treatments
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Sex, Stroke, and Atrial Fibrillation
Hart, R. G., Eikelboom, J. W., & Pearce, L. A. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.2691 · Cited by 15
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Progress for Stroke Prevention With Atrial Fibrillation
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Diagnosis and Management of Spontaneous Intracerebral Hemorrhage
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“Trials of novel oral anticoagulants (NOACs) in otherwise healthy patients with atrial fibrillation showed NOACs to be equivalent or superior to warfarin for stroke prevention and to be associated with lower rates of ICH.(11,12) However, NOAC-associated ICH may be difficult to treat.”
BackgroundManagement of Atrial Fibrillation in Elderly Adults
Desai, Y. B., El‐Chami, M. F., León, A. R., & Merchant, F. M. (2016) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14483 · Cited by 16
“A cohort study of 13,559 individuals with AF (mean age 71 15, with 28% of total person-years of follow-up from individuals aged ≥80) demonstrated that the rate of ICH was relatively flat from age 60 to 80 but then rose sharply after the age of 80 (Figure 1).17 This pattern was observed in individuals who were and were…”
ResultInfluentialYoshioka, H., Sato, H., Hatakeyama, H., & Hisaka, A. (2018) · Blood Advances · doi:10.1182/bloodadvances.2017013805 · Cited by 15
Weir, M. R., & Kreutz, R. H. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.06.018 · Cited by 15
Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization
Khachatryan, T., Hauschild, C., Hoff, J., Contractor, T. A., Khachatryan, A., Tran, H. N., Matsuo, B., Jacobson, A. K., & Hilliard, A. A. (2019) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-019-00344-6 · Cited by 15
“Furthermore, the AVERROES trial demonstrated the superiority of apixaban in preventing stroke or systemic embolism compared with aspirin in patients with NVAF who were not suitable candidates for warfarin therapy [54].”
BackgroundMedikamenteninduzierte gastrointestinale Blutung
Fischbach, W. (2019) · Der Internist · doi:10.1007/s00108-019-0610-y · Cited by 15
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“4% ICH rate per year in patients treated with apixaban.(29) Another study also found that the rivaroxaban-associated ICH rate was 0.”
BackgroundShantsila, E., & Lip, G. Y. H. (2010) · doi:10.1007/978-1-908517-08-1_5 · Cited by 15
Cantú-Brito, C. G., Silva, G. S., & Ameriso, S. F. (2017) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/1076029617734309 · Cited by 14
“0% of treated patients are still likely to experience an acute ischemic stroke each year.(45-48,50,51) Thrombolytic therapy with recombinant tissue-type plasminogen activator is appropriate when given shortly after the onset of ischemic stroke ( 4.”
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The safety of NOACs in atrial fibrillation patient subgroups: A narrative review
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Antiarrhythmic drugs and strategies
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Antithrombotic Therapy in the Prevention of Stroke
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“The AVERROES trials [54,55] and the ARISTOTLE-AF study [56] demonstrated that apixaban was superior to warfarin in reducing the risk of recurrence of stroke and systemic”
MethodJamieson, M. J., Byon, W., Dettloff, R. W., Crawford, M., Gargalovic, P. S., Merali, S. J., Onorato, J. M., Quintero, A., & Russ, C. (2022) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-022-00524-x · Cited by 15
Plasma angiopoietin-2 and its association with heart failure in patients with atrial fibrillation
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“aspirin in patients with AF who were considered to be unsuitable for oral anticoagulation with a vitamin K antagonist.(22) Between 2007 and 2009, a total of 5599 patients were enrolled.”
BackgroundTodo, K., Okazaki, S., Doijiri, R., Yamazaki, H., Sonoda, K., Koge, J., Iwata, T., Ueno, Y., Yamagami, H., Kimura, N., et al. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.031508 · Cited by 14
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“74 In an analysis of key subgroups in the 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) trial, the effects of rivaroxaban versus warfarin were found to be similar across…”
Efficacy and Toxicity of Factor Xa Inhibitors
Bondarenko, M., Curti, C., Montana, M., Rathelot, P., & Vanelle, P. (2013) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j33p49 · Cited by 14
“Treating 1000 patients with apixaban rather than with aspirin for one year would prevent 21 strokes or systemic emboli, 9 deaths and 33 hospitalizations for cardiovascular causes at the cost of 2 major haemorrhages (43).”
BackgroundMadan, S., Shah, S., Partovi, S., & Parikh, S. A. (2014) · PubMed Central · doi:10.3978/j.issn.2223-3652.2014.08.01 · Cited by 14
“In the AVERROES trial (apixaban versus acetylsalicyclic acid to prevent stroke in AF patients who have failed or are unsuitable for vitamin K antagonist treatment), apixaban was compared to aspirin alone for stroke prevention (42).”
MethodChang, K., Wang, Y.-C., Ko, P.-Y., Wu, H.-P., Chen, Y.-W., Muo, C., Sung, F.-C., Li, T., & Hsu, C. Y. (2014) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2014.08.015 · Cited by 14
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“Novel oral anticoagulants, direct thrombin inhibitors (for example, dabigatran), and oral direct factor Xa inhibitors (for example, rivaroxaban and apixaban) have been tested in several clinical trials (RELY, ROCKET-AF, AVERROES, and ARISTOTLE) [25-28], and data from these trials did not show worse results in the inci…”
Overvad, T. F., Larsen, T. B., Albertsen, I. E., Rasmussen, L. H., & Lip, G. Y. H. (2013) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2013.839214 · Cited by 14
Current State of Anticoagulants to Treat Deep Venous Thrombosis
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Anticoagulation Therapy for Atrial Fibrillation in Patients With Alzheimer’s Disease
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Bleeding risks with novel oral anticoagulants especially rivaroxaban versus aspirin: a meta-analysis
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Antithrombotic Therapy for Prevention of Various Thrombotic Diseases
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“All the trial results show the effects of new-generation oral anticoagulants as compared with dose-adjusted warfarin, except for one trial with apixaban comparing aspirin [Connolly et al., 2011].”
ResultParoxysmal atrial fibrillation and the hazards of under-treatment
Aronis, K. N., Thigpen, J. L., Tripodis, Y., Dillon, C., Forster, K., Henault, L. E., Quinn, E. K., Berger, P. B., Limdi, N. A., & Hylek, E. M. (2015) · International Journal of Cardiology · doi:10.1016/j.ijcard.2015.09.006 · Cited by 14
“Eligible patients had ECG-confirmed AF at the time of stroke admission or within 6 months consistent with the study population definition used in recent AF trials.[45, 46] All stroke events underwent final review by site neurologists.”
Halperin, J. L., & Dorian, P. (2014) · Current Cardiology Reviews · doi:10.2174/1573403x10666140513104523 · Cited by 13
“A separate large clinical trial, AVERROES, compared apixaban to aspirin for prevention of stroke and systemic embolism in 5,599 patients with AF for whom VKA therapy was deemed unsuitable [10].”
Meschia, J. F., Bushnell, C., Boden-Albala, B. M., Braun, L. T., Bravata, D. M., Chaturvedi, S., Creager, M. A., Eckel, R. H., Fornage, M., Goldstein, L. B., et al. (2014) · Cited by 15
Apixaban to prevent stroke in patients with atrial fibrillation: a review
Peterson, B. E., Al‐Khatib, S. M., & Granger, C. B. (2016) · Therapeutic Advances in Cardiovascular Disease · doi:10.1177/1753944716652787 · Cited by 14
Kooistra, H., Piersma-Wichers, M. G., Kluin‐Nelemans, H. C., Veeger, N. J. G. M., & Meijer, K. (2016) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.115.002612 · Cited by 14
Liu, C., & Chen, H.-C. (2016) · Clinical Drug Investigation · doi:10.1007/s40261-016-0487-7 · Cited by 15
“ICHs were further classified as minor, major, or fatal [24].”
BackgroundThe risk of gastrointestinal hemorrhage with non-vitamin K antagonist oral anticoagulants
Oh, H. J., Ryu, K. H., Park, B. J., & Yoon, B. (2021) · Medicine · doi:10.1097/md.0000000000025216 · Cited by 33
Systemic Embolic Events (SEE) in Atrial Fibrillation
Chatterjee, N. A., & Lubitz, S. A. (2015) · Circulation · doi:10.1161/circulationaha.115.018172 · Cited by 14
Hohnloser, S. H., & Connolly, S. J. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr344 · Cited by 14
Vyas, V., Vyas, V., Sharma, A., & Kumar, P. A. (2025) · Reviews in Cardiovascular Medicine · doi:10.31083/rcm39233 · Cited by 15
“There was no notable difference in major bleeding events between the two treatment groups [26].”
Haj, A. K., Paul, D. S., Jurgens, S. J., Eswaran, H., Weng, L.-C. C., Ryu, J. H., Espada, A. R., Chaudhry, S. A., Feingold, L. M., Burke, K., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62789-5 · Cited by 13
Ткачева, О. Н., Vorobyeva, N. M., Kotovskaya, Y. V., Рунихина, Н. К., Strazhesko, I. D., Вадимовна, В. С., Drapkina, O. M., Komarov, A. L., Orlova, Y. A., Панченко, Е. П., et al. (2021) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/1728-8800-2021-2847 · Cited by 14
Shahbazi-Derakhshi, P., Abbasi, M., Akbarzadeh, A., Mokhtarzadeh, A., Hosseinpour, H., & Soleymani, J. (2023) · RSC Advances · doi:10.1039/d3ra03293k · Cited by 13
Stroke Prevention in Atrial Fibrillation: Concepts and Controversies
Ahmad, Y., & Lip, G. Y. H. (2012) · Current Cardiology Reviews · doi:10.2174/157340312803760820 · Cited by 14
The Evolving Role of Stroke Prediction Schemes for Patients With Atrial Fibrillation
Ha, A. C. T., & Healey, J. S. (2013) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2013.06.001 · Cited by 13
COCCHERI, S., & Orlando, D. (2012) · Internal and Emergency Medicine · doi:10.1007/s11739-012-0886-6 · Cited by 13
Ineligibility for Anticoagulation in Patients with Atrial Fibrillation
Conde, I. D., & Halperin, J. L. (2013) · The American Journal of Medicine · doi:10.1016/j.amjmed.2012.07.001 · Cited by 12
The Link between Atrial Fibrillation and Stroke in Women
Madias, C. A., & Trohman, R. G. (2011) · Women s Health · doi:10.2217/whe.11.29 · Cited by 13
“As compared to aspirin, the novel factor Xa inhibitor, apixaban, reduced the risk of stroke and systemic embolism without significantly increasing the bleeding risk in patients with AF who were deemed unsuitable for management with vitamin K antagonists [54].”
ResultDEEDWANIA, P. C., & Huang, G. W. (2012) · Core evidence · doi:10.2147/ce.s25637 · Cited by 13
Management of patients with stroke treated with direct oral anticoagulants
Seiffge, D. J., Polymeris, A. A., Fladt, J. C., Lyrer, P. A., Engelter, S. T., & Marchis, G. M. D. (2018) · Journal of Neurology · doi:10.1007/s00415-018-9061-y · Cited by 13
Blankestijn, P. J., Carrero, J. J., Clase, C. M., Deo, R., Herzog, C. A., Kasner, S. E., PASSMAN, R. S., Pecoits‐Filho, R., Reinecke, H., Shroff, G. R., et al. (2019) · Nephrology (Saint-Petersburg) · doi:10.24884/1561-6274-2019-23-2-18-40 · Cited by 13
Renal Disease and Atrial Fibrillation
Stefil, M., Nabrdalik, K., & Lip, G. Y. H. (2021) · Cardiac Electrophysiology Clinics · doi:10.1016/j.ccep.2020.11.001 · Cited by 13
Critical Analysis of Apixaban Dose Adjustment Criteria
Vu, A., Qu, T. T., Ryu, R. J., Nandkeolyar, S., Jacobson, A. K., & Hong, L. T. (2021) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/10760296211021158 · Cited by 14
Costs and clinical consequences of suboptimal atrial fibrillation management
Singh, S. N. (2012) · ClinicoEconomics and Outcomes Research · doi:10.2147/ceor.s30090 · Cited by 13
“64 In the AVERROES study, apixaban reduced the risk of stroke or systemic embolism without significantly increasing major bleeding or intracranial hemorrhage, 65 while the ARISTOTLE study demonstrated that apixaban was superior to warfarin in preventing stroke or systemic embolism.”
Leal, S., Moreno, R., Almeida, M., Silva, J. A., & López-Sendón, J. L. (2012) · Current Cardiology Reviews · doi:10.2174/157340312801215827 · Cited by 13
Potential new uses of non–vitamin K antagonist oral anticoagulants to treat and prevent stroke
Yaghi, S. R., Kamel, H., & Elkind, M. S. V. (2015) · Neurology · doi:10.1212/wnl.0000000000001817 · Cited by 13
“regimens and high risk of hemorrhage, apixaban reduced the risk of stroke with similar major bleeding risk compared with aspirin.(6) Thus, one may logically consider the use of these agents in these other situations in which anticoagulation is often used or recommended.”
BackgroundRecent advances in anticoagulant drug delivery
Park, J., & Byun, Y. (2015) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2016.1125880 · Cited by 13
Martsevich, S. Y., Navasardyan, A. R., Кутишенко, Н. П., Zakharova, A. V., Петровна, В. В., Дмитриева, Н. А., Lrozdova, L. Y., Zagrebelnyy, A. V., Lerman, O. V., Lukina, Y. V., et al. (2014) · Rational Pharmacotherapy in Cardiology · doi:10.20996/1819-6446-2014-10-6-625-630 · Cited by 13
Foody, J. M. (2017) · Clinical Interventions in Aging · doi:10.2147/cia.s111216 · Cited by 15
Tsai, C., Marcus, L. Q., Patel, P., & Battistella, M. (2017) · Canadian Journal of Kidney Health and Disease · doi:10.1177/2054358117735532 · Cited by 14
Bleeding Tolerance Among Patients With Atrial Fibrillation on Oral Anticoagulation
Rusin, G., Konieczyńska, M., Bijak, P., Desteghe, L., Heidbüchel, H., Malinowski, K. P., & Undas, A. (2019) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2019.09.004 · Cited by 13
Anti-thrombotic therapy in patients with atrial fibrillation and intracranial hemorrhage
Diener, H.-C., Stanford, S., Abdul-Rahim, A., Christensen, L., Hougaard, K. D., Bakhai, A., Veltkamp, R., & Worthmann, H. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.945435 · Cited by 12
“In the AVERROES trial in 5599 patients with atrial fibrillation unsuitable for VKAs patients were treated either with apixaban (5 mg twice daily) or aspirin (81–324 mg/day) [39].”
Background
Metadata
- Authors
- Connolly, S. J., Eikelboom, J., Joyner, C., Diener, H.-C., Hart, R., Golitsyn, S., Flaker, G., Avezum, A., Hohnloser, S. H., Diaz, R., Talajic, M., Zhu, J., Pais, P., Budaj, A., Parkhomenko, A., Jansky, P., Commerford, P., Tan, R. S., Sim, K.-H., Lewis, B. S., Van Mieghem, W., Lip, G. Y. H., Kim, J. H., Lanas-Zanetti, F., Gonzalez-Hermosillo, A., Dans, A. L., Munawar, M., O'Donnell, M., Lawrence, J., Lewis, G., Afzal, R., & Yusuf, S.
- Affiliations
- Population Health Research Institute (CA)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-03-03
- Volume
- 364
- Issue
- 9
- Pages
- 806-817
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2149388786
- Cited by
- 2,483
- References
- 23
- Citations by year
- 2026: 45 · 2025: 54 · 2024: 99 · 2023: 70 · 2022: 71 · 2021: 111 · 2020: 111 · 2019: 119 · 2018: 139 · 2017: 172 · 2016: 215 · 2015: 239 · 2014: 249 · 2013: 310 · 2012: 303
- FWCI
- 223.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Omeka S (Universidad de La Frontera) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Hamilton Health Sciences
- McMaster University
- Astellas Pharma
- Servier
- Institut de Cardiologie de Montréal
- St. Jude Medical
- Bayer Vital
- Cilag
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- apixaban, atrial fibrillation, factor Xa inhibitors, aspirin, stroke prevention, systemic embolism, vitamin K antagonists, major bleeding, intracranial hemorrhage, cardiovascular hospitalization, oral anticoagulation, early trial termination, cardiovascular mortality, cardiovascular risk stratification, subgroup analysis, bleeding risk stratification
- MeSH terms
- Aged, Aged, 80 and over, Aspirin, Atrial Fibrillation, Double-Blind Method, Embolism, Female, Fibrinolytic Agents, Hemorrhage, Humans, Male, Middle Aged, Pyrazoles, Pyridones, Risk Factors, Proportional Hazards Models, Stroke, Factor Xa Inhibitors
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