Cited by 413Atrial Fibrillation Management and OutcomesAntiplatelet Therapy and Cardiovascular DiseasesAcute Myocardial Infarction Research

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Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention: A Nationwide Cohort Study

Lamberts, Morten, Olesen, Jonas Bjerring, Ruwald, Martin Huth, Hansen, Carolina Malta, Karasoy, Deniz, Kristensen, Søren Lund, Køber, Lars, Torp-Pedersen, Christian, Gislason, Gunnar Hilmar, Hansen, Morten Lock·2012·Circulation

DOI 10.1161/circulationaha.112.114967

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Abstract

Background—: Uncertainty remains over optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction and/or undergoing percutaneous coronary intervention. We investigated the risk and time frame for bleeding following myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation according to antithrombotic treatment. Methods and Results—: Patients with atrial fibrillation and admitted with myocardial infarction or for percutaneous coronary intervention between 2000 and 2009 (11 480 subjects, mean age 75.6 years [SD ±10.3], males 60.9%) were identified by individual level linkage of nationwide registries in Denmark. Fatal or nonfatal (requiring hospitalization) bleeding was determined according to antithrombotic treatment regimen: triple therapy (TT) with vitamin K antagonist (VKA)+aspirin+clopidogrel, VKA+antiplatelet, and dual antiplatelet therapy with aspirin+clopidogrel. We calculated crude incidence rates and adjusted hazard ratios by Cox regression models. Within 1 year, 728 bleeding events were recorded (6.3%); 79 were fatal (0.7%). Within 30 days, rates were 22.6, 20.3, and 14.3 bleeding events per 100 person-years for TT, VKA+antiplatelet, and dual antiplatelet therapy, respectively. Both early (within 90 days) and delayed (90–360 days) bleeding risk with TT exposure in relation to VKA+antiplatelet was increased; hazard ratio 1.47 (1.04;2.08) and 1.36 (0.95;1.95), respectively. No significant difference in thromboembolic risk was observed for TT versus VKA+antiplatelet; hazard ratio, 1.15 (0.95;1.40). Conclusions—: High risk of bleeding is immediately evident with TT after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.

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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
(2006) · The Lancet · doi:10.1016/s0140-6736(06)68845-4 · Cited by 1,952
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Anticoagulant and Antiplatelet Therapy Use in 426 Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention and Stent Implantation
Ruiz-Nodar, J. M., Marín, F., Hurtado, J. A., Valencia, J., Pinar, E., Pineda, J., Gimeno, J. R., Sogorb, F., Valdés, M., & Lip, G. Y. H. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.11.035 · Cited by 269 · cited 1×
“of total bleeding ( fatal events ) / person years at risk Triple therapy VKA + antiplatelet therapy Dual antiplatelet therap y VKA monotherapy Single antiplatelet therapy 27 ( 1) / 119 30 ( 2) / 148 37 ( 1) / 259 5 ( 1) / 59 48 ( 11) / 309 39 ( 0) / 193 38 ( 3) / 291 40 ( 2) / 596 9 ( 0) / 104 54 (12) / 561 21 ( 3) /…”

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Antithrombotic Regimens in Patients With Percutaneous Coronary Intervention Whom an Anticoagulant Is Indicated: A Systematic Review and Network Meta-Analysis
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Patel, S. M., Morrow, D., Kidd, S. K., Goodrich, E. L., Scirica, B., & Bonaca, M. P. (2019) · Vascular Medicine · doi:10.1177/1358863x19826681 · Cited by 4
The Year in Cardiothoracic and Vascular Anesthesia: Selected Highlights from 2018
Evans, A. S., Weiner, M. M., Jain, A., Patel, P. A., Jayaraman, A. L., Townsley, M. M., Shah, R. S., Gutsche, J. T., Renew, J. R., Ha, B., et al. (2018) · Journal of Cardiothoracic and Vascular Anesthesia · doi:10.1053/j.jvca.2018.10.017 · Cited by 5
Risk and benefit of dual antiplatelet treatment among non-revascularized myocardial infarction patients in different age groups
Juul, N., Gislason, G., Olesen, J., Lamberts, M., Hansen, M. L., Karasoy, D., Christiansen, C., Torp-Pedersen, C., & Sørensen, R. (2017) · European heart journal. Acute cardiovascular care · doi:10.1177/2048872614538848 · Cited by 4
Self-citation
Triple Antithrombotic Therapy and Outcomes in Post‐PCI Patients Undergoing Non‐cardiac Surgery
Valle, J. A., Graham, L. A., DeRussy, A. J., Itani, K. M. F., Hawn, M. T., & Maddox, T. M. (2016) · World Journal of Surgery · doi:10.1007/s00268-016-3725-5 · Cited by 3
High platelet reactivity after P2Y12-inhibition in patients with atrial fibrillation and coronary stenting
Rilinger, J., Meyer, M., Schnabel, K., Weik, P., Charlet, A., Esser, J., Zhou, Q., Bode, C., Moser, M., Diehl, P., et al. (2016) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-016-1397-5 · Cited by 4
“For thromboembolic outcome MACCE (Major Adverse Cardiac and Cerebrovascular Events) including cardiovascular death, myocardial infarction (MI) and ischemic stroke was applied [20].”
Antithrombotics in atrial fibrillation and coronary disease
Velagapudi, P., Turagam, M. K., Agrawal, H., Mittal, M., Kocheril, A. G., & Aggarwal, K. B. (2014) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2014.937427 · Cited by 5
“The 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12] recommends treatment with TAT for 1 month after a BMS and for 3–6 months after a DES, after which the recommendation is to continue warfarin (INR 2–3) and a single antiplatelet agent for at least 12 month…”
BackgroundInfluential
Antithrombotic therapy in patients after valve surgery with special attention to the combination of anticoagulant and antiplatelet therapy
Brtko, M., & Dusek, J. (2013) · Cor et Vasa · doi:10.1016/j.crvasa.2013.01.009 · Cited by 4
Left atrial appendage closure in nonvalvular atrial fibrillation patients with percutaneous coronary intervention
Yu, Y., Xu, J., Wang, L., Ye, Z., Chen, Z., & Chen, F. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02865-6 · Cited by 3
“The increased risk of bleeding involved with triple therapy is deemed to outweigh the benefits of thromboembolic risk reduction [16, 17].”
Background
Assessment of Intracoronary Adenosine-Induced Hyperemia in Patients with Atrial Fibrillation in Comparison with Patients in Sinus Rhythm
Bentea, G. P., Berdaoui, B., Samyn, S., Morissens, M., van de Borne, P., & Rodriguez, J. C. (2022) · The Cardiology · doi:10.1159/000525781 · Cited by 3
Temporal Trends of Antithrombotic Therapy in Patients With Acute Myocardial Infarction and Atrial Fibrillation: Insight From the KAMIR-NIH Registry
Lee, O., Kim, Y., Cho, D., Kim, J.-S., Kim, B.-K., Choi, D., Hong, M., Jeong, M., & Jang, Y. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.762090 · Cited by 3
Management of antithrombotic therapy in patients with atrial fibrillation and acute coronary syndromes
Pop, C., Ţînţ, D., & Petriş, A. O. (2021) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2203076 · Cited by 4
“In our case scenario, all patients taking OAC are at an increased risk of bleeding compared to those not taking OAC, and the risk is higher in the first weeks after initiation of anticoagulation [36, 108].”
Background
Anticoagulation for the treatment of left ventricular thrombus in patients with acute myocardial infarction and renal impairment.
Sia, C., Leow, A., Tan, B., Yeo, L., Chan, M., & Loh, J. (2021) · Polish Archives of Internal Medicine · doi:10.20452/pamw.16073 · Cited by 3
Evolution of Antithrombotic Management of Atrial Fibrillation After Percutaneous Coronary Intervention Over 10 Years and Guidelines Uptake
Beaulieu, M.-C., Boivin‐Proulx, L., Matteau, A., Mansour, S., Gobeil, J., & Potter, B. J. (2021) · CJC Open · doi:10.1016/j.cjco.2021.04.002 · Cited by 4
Role and Timing of Aspirin Therapy Following PCI in Patients With Atrial Fibrillation
Cannon, C. P. (2021) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2020.12.017 · Cited by 3
Long term risk and costs of bleeding in men and women treated with triple antithrombotic therapy–An observational study
Holm, A., Henriksson, M., Alfredsson, J., Janzon, M., Johansson, T., Swahn, E., Vial, D., & Lawesson, S. S. (2021) · PLoS ONE · doi:10.1371/journal.pone.0248359 · Cited by 4
“To our knowledge there are no gender analyses published from PLOS ONE | https://doi.org/10.1371/journal.pone.0248359 March 25, 2021 11 / 16 the big RCTs regarding DAT and TAT to guide in treatment strategies of ACS-patients in need of both anticoagulation and platelet inhibition [44].”
BackgroundInfluential
Single antiplatelet therapy with use of prasugrel in patients undergoing percutaneous coronary intervention
Otsuka, T., Ueki, Y., Kavaliauskaite, R., Zanchin, T., Bär, S., Stortecky, S., Pilgrim, T., Valgimigli, M., Meier, B., Heg, D., et al. (2021) · Catheterization and cardiovascular interventions · doi:10.1002/ccd.29650 · Cited by 3
Comparison of clinical outcomes between multiple antithrombotic therapy versus left atrial appendage occlusion with dual antiplatelet therapy in patients with atrial fibrillation undergoing drug-eluting stent implantation
Kook, H., Kim, H.-D., Uhm, J., Kim, Y., Kim, J., Pak, H., Lee, H., Choi, R. K., Kang, W. C., Shin, E., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0244723 · Cited by 4
“In a Danish registry, major bleeding events occur primarily during the early period of medication, mostly within 3 months from the onset of TAT [2, 4].”
Background
The prevalence of acute erosive-ulcerative gastroduodenal lesions in patients with cardiovascular diseases, taking anticoagulants and antiplatelet agents
Poliantsev, A. A., Frolov, D. V., Linchenko, D. V., Karpenko, S. N., Chernovolenko, A. A., & Dyachkova, Y. (2020) · Experimental and Clinical Gastroenterology · doi:10.31146/1682-8658-ecg-169-9-65-74 · Cited by 3
Antithrombotic treatment in patients with atrial fibrillation undergoing coronary angioplasty: rational convincement and supporting evidence
Ricottini, E., Nenna, A., Melfi, R., Giannone, S., Lusini, M., Sciascio, G. D., Chello, M., Ussia, G. P., & Grigioni, F. (2020) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2020.02.004 · Cited by 3
Anti-thrombotic therapy strategies with long-term anticoagulation after percutaneous coronary intervention – a systematic review and meta-analysis
Siddiqui, W. J., Khan, M. Y., Rawala, M. S., Jethwani, K., Khan, M. H., Alvarez, C., Kashif, R., Hasni, S. F., Aggarwal, S., Kohut, A. R., et al. (2019) · Journal of Community Hospital Internal Medicine Perspectives · doi:10.1080/20009666.2019.1611330 · Cited by 3
“cohort study found that the risk of bleeding with TATT was greatest within 30 days post-PCI [29].”
Background
Ischemic and bleeding outcomes of triple therapy in patients on chronic anticoagulation undergoing percutaneous coronary intervention: A meta-analysis of randomized trials
Dahal, K. B., Mustafa, U., Sharma, S. P., Apte, N. M., Bogabathina, H., Hanna, M., Watti, H., Azrin, M., Lee, J., Mina, G. S., et al. (2019) · JRSM Cardiovascular Disease · doi:10.1177/2048004019885572 · Cited by 4
Atrial fibrillation, intra-ventricular thrombus, and other anticoagulant indications relationship with adverse outcomes in acute anterior myocardial infarction patients
Bourezg, A., Bochaton, T., Mewton, N., Morel, O., Cayla, G., Rioufol, G., Bonnefoy‐Cudraz, E., Guérin, P., Elbaz, M., Boussaha, I., et al. (2018) · Journal of Cardiology · doi:10.1016/j.jjcc.2018.03.008 · Cited by 3
Economic evaluation of the use of non-vitamin K oral anticoagulants in patients with atrial fibrillation on antiplatelet therapy: a modelling analysis using the healthcare system in the Netherlands
Bennaghmouch, N., de Veer, A. J. W. M., Mahmoodi, B. K., Jofre‐Bonet, M., Lip, G. Y. H., Bode, K., & ten Berg, J. M. (2018) · European Heart Journal - Quality of Care and Clinical Outcomes · doi:10.1093/ehjqcco/qcy030 · Cited by 3
Optimum Antithrombotic Therapy in Patients Requiring Long-Term Anticoagulation and Undergoing Percutaneous Coronary Intervention
Agarwal, N., Mahtta, D., Rambarat, C. A., Elgendy, I. Y., & Mahmoud, A. N. (2018) · BioMed Research International · doi:10.1155/2018/5690640 · Cited by 3
Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome
Olivier, C. B., Turakhia, M. P., & Mahaffey, K. W. (2018) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2018.1424827 · Cited by 3
Use of beta-blockers and risk of serious upper gastrointestinal bleeding: a population-based case-control study
Reilev, M., Damkier, P., Rasmussen, L., Olesen, M., Ernst, M. T., Rishøj, R. M., Hansen, M. R., Broe, A., Dastrup, A., Hellfritzsch, M., et al. (2017) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x17734116 · Cited by 3
Self-citation
Triple therapy for percutaneous coronary intervention in atrial fibrillation: standard of care, or a nightmare soon to end?
Verheugt, F. W. A. (2015) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12936 · Cited by 2
Optimizing selection of antithrombotic therapy in patients requiring PCI and long term anticoagulation
Edupuganti, M. M. R., Marmagkiolis, K., Çilingiroğlu, M., Uretsky, B. F., & Hakeem, A. (2014) · Cardiovascular revascularization medicine · doi:10.1016/j.carrev.2014.07.006 · Cited by 3
Strategies to Reduce Bleeding Risk in Acute Coronary Syndromes and Percutaneous Coronary Intervention: New and Emerging Pharmacotherapeutic Considerations
Coons, J. C., & Miller, T. J. (2014) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1447 · Cited by 5
“48 Registry data indicate that this excess bleed risk becomes apparent as early as 30 days after initiation and persists over time.(49) The incidence of hospitalization for major bleeding at 1 year was 12.”
Background
Optimizing Antithrombotic Therapy After Coronary Stent Implantation in Patients on Chronic Oral Anticoagulation
Bennaghmouch, N., Sprenkeler, D., Qaderdan, K., & ten Berg, J. T. (2014) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-013-9536-2 · Cited by 3
“[24] consisting of 11,480 patients found that AF patients following MI or PCI are at immediate risk of clinically significant bleeding with recommended triple therapy use.”
Actualización ESC 2017 sobre el tratamiento antiagregante plaquetario doble en la enfermedad coronaria, desarrollada en colaboración con la EACTS
Valgimigli, A. D. G. D. T. M., Bueno, H., Byrne, R. A., Collet, J.-P., Costa, F., Jeppsson, A., Jüni, P., Kastrati, A., Kolh, P., Mauri, L., et al. (2018) · doi:10.1016/j.recesp.2017.11.014 · Cited by 3
Clinical characteristics, therapeutic strategies, and outcomes in elderly patients on oral anticoagulant therapy undergoing percutaneous coronary interventions: post-hoc analysis of the PERSEO Registry
Minardi, S., Rosa, S. D., Salvi, N., Andò, G., Talanas, G., D’angelo, C., Moretti, C., Mazza, T. M., Cortese, B., Musumeci, G., et al. (2025) · 老年心脏病学杂志：英文版 · doi:10.26599/1671-5411.2025.08.002 · Cited by 1
Chronic coronary syndrome and new-onset atrial fibrillation or venous thromboembolism: how best to manage antithrombotic therapy strategies
Rubboli, A., Angiolillo, D. J., Becattini, C., & Lip, G. Y. H. (2025) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvaf021 · Cited by 2
“5 , 15 , 16 The main results observed in the available datasets, albeit with no dedicated analysis of VTE patients subgroups and with VKA only as the OAC component of TAT, is that this latter AT regime is associated with an increased risk of bleeding.”
Antithrombotic therapy in patients with atrial fibrillation after percutaneous coronary intervention
Sammut, M. A., & Storey, R. F. (2024) · Expert Review of Cardiovascular Therapy · doi:10.1080/14779072.2024.2388265 · Cited by 2
“This combination, termed triple antith-rombotic therapy (TAT), has raised concern due to an increased risk of bleeding [23,24].”
Bleeding risk factors and real-world antithrombotic therapies in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention: a retrospective study
Fujita, K., Kohyama, N., Sato, M., Deguchi, T., Suzuki, H., Ebato, M., & Kogo, M. (2023) · Journal of Pharmaceutical Health Care and Sciences · doi:10.1186/s40780-023-00308-8 · Cited by 2
“On the other hand, some reports suggest that triple therapy after PCI is associated with an increased risk of bleeding, regardless of its duration [29].”
Background
Identification of Molecular Markers Predicting the Outcome of Anti-thrombotic Therapy After Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome and Atrial fibrillation: Evidence from a Meta-analysis and Experimental Study
Li, J.-R., Xin, H.-W., Zhang, B., Guo, Y.-H., Ding, Y.-Y., & Wu, X.-J. (2023) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-023-10416-3 · Cited by 2
“Many studies have shown that this therapy is necessary to prevent thrombotic and ischemic events, but it undoubtedly increases the risk of bleeding [20–22].”
Rationale and design of the optimal antithrombotic treatment for acute coronary syndrome patients with concomitant atrial fibrillation and implanted with new‐generation drug‐eluting stent: OPtimal management of anTIthroMbotic Agents (OPTIMA)‐4 trial
Gong, X., Hua, R., Bai, J., Wu, T., Wang, Q., Zhang, J., Zhang, W., Ying, L., Ke, Y., Wang, X., et al. (2023) · Clinical Cardiology · doi:10.1002/clc.24025 · Cited by 2
“Thus, for patients undergoing percutaneous coronary intervention (PCI) with concomitant AF, triple antithrombotic therapy (TATT) including both DAPT and OAC would be indicated.(3) However,”
Background
Changes in Antithrombotic Therapy Over Time and Durability of a Prasugrel WOEST-Like Regimen for Percutaneous Coronary Intervention Patients With Atrial Fibrillation ― Post Hoc Analysis of the PENDULUM Mono and PENDULUM Registries ―
Nakao, K., Kadota, K., Nakagawa, Y., Shite, J., Yokoi, H., Kozuma, K., Tanabe, K., Akasaka, T., Shinke, T., Ueno, T., et al. (2022) · Circulation Reports · doi:10.1253/circrep.cr-22-0032 · Cited by 3
Real-World Experience With Antiplatelet Agents After Percutaneous Coronary Intervention in Patients With an Indication for an Oral Anticoagulant
Tanner, R., Cronin, M., Macken, L., Murphy, R. T., Maree, A. O., Ullah, I., Cosgrave, J., O’Connor, S. A., & Daly, C. (2021) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000973 · Cited by 3
Ticagrelor: A Safe Option as Part of Triple Therapy?
Farooq, M. U. U. (2020) · Clinics and Practice · doi:10.4081/cp.2020.1221 · Cited by 2

Authors: Lamberts, M., Olesen, J. B., Ruwald, M. H., Hansen, C. M., Karasoy, D., Kristensen, S. L., Køber, L., Torp-Pedersen, C., Gislason, G. H., & Hansen, M. L.
Affiliations: Copenhagen University Hospital (DK)
Gentofte Hospital (DK)
ORCID: Lamberts, Morten
Olesen, Jonas Bjerring
Ruwald, Martin Huth
Hansen, Carolina Malta
Karasoy, Deniz
Kristensen, Søren Lund
Køber, Lars
Torp-Pedersen, Christian
Gislason, Gunnar Hilmar
Hansen, Morten Lock
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2012-09-04
Volume: 126
Issue: 10
Pages: 1185-1193
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.112.114967
OpenAlex: W2108659563
Cited by: 413
References: 0
Citations by year: 2026: 7 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 16 · 2021: 24 · 2020: 36 · 2019: 42 · 2018: 42 · 2017: 43 · 2016: 37 · 2015: 40 · 2014: 41 · 2013: 53 · 2012: 6
FWCI: 28.82
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
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 › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords: atrial fibrillation, bleeding risk, triple therapy, vitamin K antagonists, clopidogrel, aspirin, antiplatelet therapy, dual antiplatelet therapy, myocardial infarction, percutaneous coronary intervention, thromboembolic risk, bleeding risk assessment
MeSH terms: Clopidogrel, Aged, Aged, 80 and over, Aspirin, Atrial Fibrillation, Denmark, Drug Therapy, Combination, Female, Fibrinolytic Agents, Hemorrhage, Humans, Male, Middle Aged, Myocardial Infarction, Platelet Aggregation Inhibitors, Registries, Risk Factors, Ticlopidine, Vitamin K, Cohort Studies, Comorbidity, Angioplasty, Balloon, Coronary, Stroke, Acute Coronary Syndrome

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Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention: A Nationwide Cohort Study

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