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Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial
Abstract
Background Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.Methods Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.Results The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively).Conclusion Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.
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“VKA therapy prevents stroke, non-central nervous system embolus, myocardial infarction, and vascular death better than single or dual antiplatelet therapy with aspirin and clopidogrel (annual risk of 5.6% for aspirin and clopidogrel vs. 3.9% with VKA therapy).431”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [431]
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“The ACTIVE-W trial compared clopidogrel plus ASA with VKA therapy, and the ACTIVE-A trial compared clopidogrel plus ASA with ASA alone in patients for whom therapy with a VKA was considered unsuitable.(12,13) The inclusion criteria for the AVERROES and ACTIVE trials were similar and are described in detail elsewhere.”
BackgroundMethodGeneral mechanisms of coagulation and targets of anticoagulants (Section I)
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Lip, G. Y. H. (2011) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2011.112 · Cited by 136
Wide Variation in Reported Rates of Stroke Across Cohorts of Patients With Atrial Fibrillation
Quinn, G. R., Severdija, O. N., Chang, Y., & Singer, D. E. (2016) · Circulation · doi:10.1161/circulationaha.116.024057 · Cited by 128
Görenek, B., Lundqvist, C. B., Brugada, J., Camm, A. J., Hindricks, G., Huber, K., Kirchhof, P. F., Kück, K., Kudaiberdieva, G., Lin, T., et al. (2014) · European Heart Journal Acute Cardiovascular Care · doi:10.1177/2048872614550583 · Cited by 128
“However, DAPT was inferior to warfarin in the ACTIVE-W study.(127) Table 2 summarizes the embolic, ischaemic and bleeding events in the ACTIVE-trials.”
MethodRubboli, A., Halperin, J. L., Airaksinen, J. K. E., Buerke, M., Eeckhout, É., Freedman, S. B., Gershlick, A., Schlitt, A., Tse, H., Verheugt, F. W. A., et al. (2008) · Annals of Medicine · doi:10.1080/07853890802089786 · Cited by 127
Connolly, S. J., Eikelboom, J. W., Dorian, P., Hohnloser, S. H., Gretler, D. D., Sinha, U., & Ezekowitz, M. D. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht039 · Cited by 124
“3% per year which is unexpectedly higher.(8,10,11,16) Rates of ischaemic stroke would be expected to be low on warfarin in patients with a mean CHADS2 score of 2 and with good INR control.”
BackgroundResultThe prothrombotic state in atrial fibrillation: pathophysiological and management implications
Khan, A. A., & Lip, G. Y. H. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy272 · Cited by 123
“treatment with aspirin and clopidogrel was less efficacious than warfarin for stroke prevention in AF.(128) These clinical findings are also corrobo-”
BackgroundInfluentialExtracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation
Bekwelem, W., Connolly, S. J., Halperin, J. L., Adabağ, S., Duval, S., Chrolavicius, S., Pogue, J. M., Ezekowitz, M. D., Eikelboom, J. W., Wallentin, L. C., et al. (2015) · Circulation · doi:10.1161/circulationaha.114.013243 · Cited by 122
Manzano‐Fernández, S., Pastor, F. J., Marín, F. R., Cambronero, F., Martínez, C. C., Pascual-Figal, D. A., Garrido, I. P., Pinar, E., Valdés, M., & Lip, G. Y. H. (2008) · CHEST Journal · doi:10.1378/chest.08-0350 · Cited by 120
Wang, T. Y., Robinson, L. A., Ou, F., Roe, M. T., Ohman, E. M., Gibler, W. B., Smith, S. C., Peterson, E. D., & Becker, R. C. (2007) · American Heart Journal · doi:10.1016/j.ahj.2007.09.003 · Cited by 119
Combination Antithrombotic Therapies
Gurbel, P. A., & Tantry, U. S. (2010) · Circulation · doi:10.1161/circulationaha.109.853085 · Cited by 121
Atrial Fibrillation and Ischemic Stroke: A Clinical Review
Migdady, I., Russman, A., & Buletko, A. B. (2021) · Seminars in Neurology · doi:10.1055/s-0041-1726332 · Cited by 130
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Bax, J. J., Delgado, V., Bapat, V., Baumgartner, H., Collet, J., Erbel, R., Hamm, C. W., Kappetein, A. P., Leipsic, J. A., Leon, M. B., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu257 · Cited by 114
Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs
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Batra, G., Svennblad, B., Held, C., Jernberg, T., Johanson, P., Wallentin, L. C., & Oldgren, J. (2016) · Heart · doi:10.1136/heartjnl-2015-308678 · Cited by 112
Wang, Y., Zhang, S., Zhang, L., & Wang, C. (2012) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2011.00290.x · Cited by 113
Cameron, C. G., Coyle, D., Richter, T. A., Kelly, S., Gauthier, K., Steiner, S., Carrier, M., Coyle, K., Bai, A., Moulton, K., et al. (2014) · BMJ Open · doi:10.1136/bmjopen-2013-004301 · Cited by 113
“Of the 82 396 randomised patients included in the primary analysis, five large multicentre trials account for 78 296 patients (96%): ENGAGE AF-TIMI 48 (n=21 105),(20) ARISTOTLE (n=18 201),(21) RE-LY (n=18 113),(8) ROCKET-AF (n=14 264)(22) and ACTIVE-W (n=6706).(23) Most trials included stroke and SE as a primary effic…”
BackgroundBleeding Outcomes After Left Atrial Appendage Closure Compared With Long-Term Warfarin
Price, M. J., Reddy, V. Y., Valderrábano, M., Halperin, J. L., Gibson, D. N., Gordon, N. T., Huber, K. C., & Holmes, D. R. (2015) · JACC: Cardiovascular Interventions · doi:10.1016/j.jcin.2015.08.035 · Cited by 113
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Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients
Sellers, M., & Newby, L. K. (2011) · American Heart Journal · doi:10.1016/j.ahj.2010.11.002 · Cited by 111
Xu, H., Ruff, C. T., Giugliano, R. P., Murphy, S. A., Nordio, F., Patel, I. J., Shi, M., Mercuri, M. F., Antman, E. M., & Braunwald, E. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002587 · Cited by 111
“may be more protective in reducing vascular events in patients with CAD or at high risk of acute coronary events.(4,5) The choice of optimal antithrombotic management to prevent both thromboembolic and acute ischemic events in patients with AF and coexisting CAD is challenging given that combination therapy of anticoa…”
BackgroundCognitive Function and Anticoagulation Control in Patients With Atrial Fibrillation
Flaker, G. C., Pogue, J. M., Yusuf, S., Pfeffer, M. A., Goldhaber, S. Z., Granger, C. B., Anand, I. S., Hart, R. G., & Connolly, S. J. (2010) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.109.884171 · Cited by 111
Metadata
- Authors
- ‡
- Corresponding author
- ‡
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 367
- Issue
- 9526
- Pages
- 1903-1912
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2159193915
- Cited by
- 1,952
- References
- 24
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 33 · 2023: 44 · 2022: 44 · 2021: 68 · 2020: 68 · 2019: 82 · 2018: 92 · 2017: 87 · 2016: 107 · 2015: 118 · 2014: 134 · 2013: 155 · 2012: 208
- FWCI
- 77.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Sanofi
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- atrial fibrillation, clopidogrel, aspirin, oral anticoagulation, stroke prevention, vascular events, major bleeding, anticoagulation monitoring, clopidogrel resistance, irbesartan, antiplatelet therapy, vascular death, myocardial infarction
- MeSH terms
- Clopidogrel, Irbesartan, Aged, Anticoagulants, Aspirin, Atrial Fibrillation, Biphenyl Compounds, Drug Therapy, Combination, Humans, Platelet Aggregation Inhibitors, Risk Factors, Severity of Illness Index, Tetrazoles, Ticlopidine, International Normalized Ratio, Stroke
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