Antithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified

doi:10.1016/j.cjca.2018.08.028

Canadian Journal of Cardiology

Volume 34, Issue 11, November 2018, Pages 1426-1436

https://doi.org/10.1016/j.cjca.2018.08.028 Get rights and content

Abstract

Atrial fibrillation (AF) is a progressive chronic disease characterized by exacerbations and periods of remission. It is estimated that up to 20% to 30% of those with AF also have coronary artery disease (CAD), and 5% to 15% will require percutaneous coronary intervention (PCI). In patients with concomitant AF and CAD, management remains challenging and requires a careful and balanced assessment of the risk of bleeding against the anticipated impact on ischemic outcomes (AF-related stroke and systemic embolism, as well as ischemic coronary events). Oral anticoagulation (OAC) is indicated for the prevention of AF-related stroke and systemic embolism, whereas antiplatelet therapy is indicated for the prevention of coronary events. Each offers a relative efficacy benefit (dual antiplatelet therapy [DAPT] is more effective than OAC alone in reducing cardiovascular death, myocardial infarction, stent thrombosis, and ischemic coronary events in a population with acute coronary syndromes [ACS]), but with a relative compromise (DAPT is significantly inferior to OAC for the prevention of stroke/systemic embolism in an AF population at increased risk of stroke). The purpose of this review is to explore the current evidence and rationale for antithrombotic treatment strategies in patients with both AF and CAD. Specifically, there is a focus on how to best tailor the therapeutic choices (OAC and antiplatelet therapy) to individual patients based on their underlying coronary presentation.

Résumé

La fibrillation auriculaire (FA) est une maladie chronique évolutive qui est caractérisée par des périodes d’exacerbation et de rémission. On estime que de 20 % à 30 % des patients atteints de FA ont aussi une maladie coronarienne (MC) et que de 5 % à 15 % auront besoin d’une intervention coronarienne percutanée (ICP). Chez les patients atteints d’une FA et d’une MC concomitantes, la prise en charge est difficile et exige une évaluation prudente et équilibrée du risque d’hémorragie par rapport aux répercussions anticipées sur les événements ischémiques (par ex., l’accident vasculaire cérébral (AVC) lié à la FA, l’embolie systémique et les événements ischémiques coronariens). L’anticoagulation orale (ACO) est indiquée dans la prévention de l'AVC lié à la FA et l’embolie systémique, tandis que le traitement antiplaquettaire est indiqué dans la prévention des événements coronariens. Chacun offre un avantage relatif en matière d’efficacité (par ex., la bithérapie antiplaquettaire [BTAP] est plus efficace que l’ACO seule dans la réduction de la mortalité cardiovasculaire, l’infarctus du myocarde, la thrombose de l’endoprothèse et les événements ischémiques coronariens dans une population atteinte d’un syndrome coronarien aigu), néanmoins, selon un compromis relatif (par ex., la BTAD est significativement inférieure à l’ACO dans la prévention de l'AVC et de l’embolie systémique dans une population atteinte de FA chez qui le risque d'AVC est accru). L’objectif de la présente revue est d’examiner les données probantes actuelles et les raisons qui justifient les stratégies de traitement antithrombotique chez les patients atteints de FA et de MC. En particulier, on se penche sur la meilleure façon d’adapter les choix thérapeutiques (ACO et traitement antiplaquettaire) aux patients en tenant compte de leur tableau clinique individuel de MC sous-jacente.

Section snippets

Antithrombotic Therapy for Patients With AF and Stable CAD

There is strong evidence supporting these recommendations for patients with either AF or CAD alone. In patients with stable CAD (absence of ACS or PCI for the preceding 12 months), aspirin (ASA) therapy has been shown to be effective in the primary and secondary prevention of major coronary events (relative risk reduction [RRR] of 18% and 20% vs control, respectively).⁶ However, in those with AF, the reduction in stroke and systemic embolism with antiplatelet therapy (RRR 22% vs placebo) is

Dual vs Triple Therapy for Patients With AF and ACS or PCI

The concomitant management of AF and CAD is the patient with a strong indication for OAC therapy is more complicated following an ACS or following PCI. In these circumstances, patients are at increased risk for both AF-related stroke/systemic embolism as well as ischemic coronary events (eg, recurrent MI and/or stent thrombosis). The combination of OAC with DAPT (triple antithrombotic therapy) has been used in this patient population in an attempt to reduce atherothrombotic and cardioembolic

WOEST

The What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST) study randomized 573 patients with a need for anticoagulation undergoing PCI (25% to 30%) to dual-pathway therapy (DT-OAC and clopidogrel) or to triple therapy (OAC, clopidogrel, and ASA).23, 24 Treatment was continued for 1 month after bare metal stent (BMS): 35% of patients and for 1 year after drug-eluting stent (DES): 65% of patients. The primary outcome of

Limitations

There are several notable limitations to these trials. First, a large proportion of patients were undergoing elective PCI (72% in WOEST, 48% in PIONEER AF-PCI, and 44% in RE-DUAL). As patients presenting with ACS carry higher risk than patients with stable ischemic coronary disease, it is possible that ischemic event rates (eg, stent thrombosis or MI) may be underestimated. Second, measures to decrease bleeding risk (eg, radial approach, femoral-closure device, routine proton pump inhibitors

NOACs as Part of the Dual- or Triple-Therapy Regimen

The pivotal phase 3 clinical trials for prevention of stroke or systemic embolic events in patients with AF demonstrated a nonsignificant 14% reduction in major bleeding with NOAC therapy when compared with warfarin (95% CI 0.73-1.00).²⁹ The majority of the bleeding-reduction benefit was achieved through reductions in hemorrhagic stroke, subdural, epidural, and subarachnoid bleeding (relative risk [RR] 0.48; 95% CI 0.39-0.59), with a corresponding increase in gastrointestinal bleeding being

P2y12 Inhibitors as Part of the Combination-Therapy Regimen

In patients with no indication for OAC, antiplatelet guidelines recommend the use of prasugrel or ticagrelor in preference to clopidogrel as a component of DAPT in settings of ACS owing to their greater efficacy at reducing recurrent MI (OR vs clopidogrel of 0.85; 95% CI 0.76-0.97 for ticagrelor, and 0.89; 95% CI 0.82-0.98 for prasugrel), and stent thrombosis (OR 0.74, 95% CI 0.58-0.94 for ticagrelor vs clopidogrel, and OR 0.48, 95% CI 0.36-0.64 for prasugrel vs clopidogrel, respectively).4, 34

Duration of Triple Antithrombotic Therapy

The benefit of triple therapy is established in selected subgroups (ie, high-risk PCI). However, the reduction in recurrent MI and stent thrombosis must be balanced against the increased bleeding risk with triple therapy. Importantly, it is well described that the rate of bleeding with triple therapy peaks at a level that is more than twice as high as the rate of acute coronary events (recurrent MI and stent thrombosis) within the first month of triple therapy.²¹ Thereafter, the risk of

Summary

The optimal antithrombotic therapeutic regimen for a given patient should be individualized based on a thorough, careful, and balanced assessment of the patients’ risks of AF-related stroke and systemic embolism, the risk of ischemic coronary events (eg, stent thrombosis and recurrent MI), as well as the anticipated risk of bleeding. For nonvalvular AF, the risk of stroke and systemic embolism can be estimated from the Canadian Cardiovascular Society (CCS) Algorithm (or other comparable schema).

Conclusion

The management of patients with concomitant AF and CAD is challenging and requires a comprehensive assessment of the competing risks of the therapeutic options.

Acknowledgements

We acknowledge the Coast Salish peoples, including the xʷməθkwəýəm (Musqueam), Skwxwú7mesh (Squamish), Stó:lō and Səl̓ílwətaʔ/Selilwitulh (Tsleil-Waututh) Nations, and the Kanien’keha:ka (Mohawk) peoples, upon whose traditional territories we live and work.

Funding Sources

Drs Andrade and Deyell are supported by Michael Smith Foundation for Health Research Scholar Awards.

Disclosures

J.G.A.: consulting fees/honoraria from Bayer, BMS Pfizer, Medtronic, Servier; Clinical Trials-Medtronic, BMS-Pfizer, Bayer, Servier. M.W.D.: consulting fees/honoraria from Biosense Webster, Abbott Canada. G.C.W.: consulting fees/honoraria from AstraZeneca, Bayer, Novartis. L.M.: consulting fees/honoraria-Abbott Canada, Bayer, BMS Pfizer, Boehringer Ingelheim, Johnson & Johnson, Servier; clinical trials for Johnson & Johnson, Servier.

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Cited by (12)

Medical record data-enabled machine learning can enhance prediction of left atrial appendage thrombosis in nonvalvular atrial fibrillation
2023, Thrombosis Research
As a major complication of non-valvular atrial fibrillation (NVAF), left atrial appendage (LAA) thrombosis is associated with cerebral ischemic strokes, as well as high morbidity. Due to insufficient incorporation of risk factors, most current scoring methods are limited to the analysis of relationships between clinical characteristics and LAA thrombosis rather than detecting potential risk. Therefore, this study proposes a clinical data-driven machine learning method to predict LAA thrombosis of NVAF.
Patients with NVAF from January 2014 to June 2022 were enrolled from Southwest Hospital. We selected 40 variables for analysis, including demographic data, medical history records, laboratory results, and the structure of LAA. Three machine learning algorithms were adopted to construct classifiers for the prediction of LAA thrombosis risk. The most important variables related to LAA thrombosis and their influences were recognized by SHapley Addictive exPlanations method. In addition, we compared our model with CHADS2 and CHADS2-VASc scoring methods.
A total of 713 participants were recruited, including 127 patients with LAA thrombosis and 586 patients with no obvious thrombosis. The consensus models based on Random Forest and eXtreme Gradient Boosting LAA thrombosis prediction (RXTP) achieved the best accuracy of 0.865, significantly outperforming CHADS2 score and CHA2DS2-VASc score (0.757 and 0.754, respectively). The SHAP results showed that B-type natriuretic peptide, left atrial appendage width, C-reactive protein, Fibrinogen and estimated glomerular filtration rate are closely related to the risk of LAA thrombosis in nonvalvular atrial fibrillation.
The RXTP-NVAF model is the most effective model with the greatest ROC value and recall rate. The summarized risk factors obtained from SHAP enable the optimization of the treatment strategy, thereby preventing thromboembolism events and the occurrence of cardiogenic ischemic stroke.
Optimisation of oral anticoagulants for patients with atrial fibrillation within 12 months after percutaneous coronary intervention: A meta-analysis and systematic review
2021, IJC Heart and Vasculature
Citation Excerpt :
Among AF patients, approximately 20% to 40% also have coronary artery disease, and these patients most likely require percutaneous coronary intervention (PCI) to restore coronary blood flow [5]. In such cases, patients should take both oral anticoagulants (OACs) and antiplatelet therapy to decrease the risk of stent thrombosis and other thrombotic events [6–8]. Currently, the 2018 North American perspective [9] proposes that PCI for AF patients with high thrombosis and low bleeding risks should be replaced with dual antithrombotic therapy (OAC + single antiplatelet therapy; DAT) after 1 month of triple antithrombotic therapy (vitamin K antagonist [VKA] plus a P2Y12 inhibitor and aspirin; TAT).
The optimal antithrombotic strategy, especially regarding oral anticoagulants (OACs) for atrial fibrillation (AF) patients with bleeding and thrombosis risk after percutaneous coronary intervention (PCI), remains unknown. This study explored the optimal oral anticoagulants for AF patients after PCI using a meta-analysis.
Randomised controlled trials were identified from PubMed, Embase, and the Cochrane Library through December 2020. Risk ratios, 95% confidence intervals, and random-effects models were used to compare different antithrombotic strategies through network meta-analysis, and the combination of antithrombotic agents was ranked according to the surface under the cumulative ranking curve and rankograms. Interval plots were drawn to observe pairwise comparisons between the different strategies.
Five studies of 11,532 patients were included. Factor IIa inhibitor 110 mg bid plus a P2Y12 inhibitor had the greatest advantage for reducing Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding; Factor Xa inhibitor plus a P2Y12 inhibitor had the greatest advantage for reducing International Society on Thrombosis and Hemostasis major bleeding. For patients at risk of stroke plus all-cause death, factor IIa inhibitor 150 mg bid plus a P2Y12 inhibitor should be prioritised, and for those at risk of myocardial infarction and stent thrombosis, vitamin K antagonists plus a P2Y12 inhibitor were preferred.
Factor IIa inhibitor 110 mg, factor IIa inhibitor 150 mg, factor Xa inhibitor and vitamin K antagonists should be selected in different situations.
Bleeding risks associated with anticoagulant therapies after percutaneous coronary intervention in Japanese patients with ischemic heart disease complicated by atrial fibrillation: A comparative study
2021, Journal of Cardiology
Citation Excerpt :
Atrial fibrillation (AF), a common type of tachyarrhythmia, is also frequently diagnosed in older patients and may cause heart function deterioration and thromboembolism [3]; examination of a Japanese health care database indicated that around 45% of AF patients had comorbid IHD [4]. For IHD patients with AF who undergo stenting by percutaneous coronary intervention (PCI), antithrombotic therapy is required for preventing stent thrombosis after PCI, and for thromboprophylaxis [5]. Based on recent evidence [6–13] suggesting higher rates of bleeding events in patients receiving triple therapy (i.e. oral anticoagulants, P2Y12 inhibitors, and aspirin) versus dual therapy, the 2017 revised European Dual Antiplatelet Therapy (DAPT) guideline [14] and 2018 US expert opinion [15] recommend short-term triple therapy and oral anticoagulants only after 1 year.
Current guidelines recommend early termination of triple therapy and the use of direct oral anticoagulants (DOAC) for non-valvular atrial fibrillation (NVAF) patients who undergo percutaneous coronary intervention (PCI), due to safety concerns. However, to date, real-world medication usage and safety outcomes (specifically bleeding) in NVAF patients with stent implantation have not been well assessed.
This was a retrospective, observational, medical database cohort study in Japanese ischemic heart disease (IHD) patients with NVAF who underwent PCI between 2012 and 2017. The primary outcome was clinically relevant bleeding; secondary outcomes included individual bleeding events. A multivariate analysis was conducted to identify risk factors affecting the occurrence of clinically relevant bleeding events.
The analysis population comprised 5695 patients [3530 received DOACs and 2165 received vitamin K antagonists (VKAs)]. The incidence of primary outcome events (clinically relevant bleeding/100 patient-years) was 6.05 in the DOAC group and 8.42 in the VKA group, resulting in a nonsignificant 21% lower risk in the DOAC group. The DOAC group also had a nonsignificant 24%, 24%, and 34% lower risk of bleeding requiring transfusion, intracranial bleeding, and lower gastrointestinal bleeding, respectively, compared with the VKA group. A multivariate analysis of the primary outcome showed a significantly higher risk of bleeding among older patients and those with lower body weight and abnormal renal function.
In this retrospective real-world evaluation of IHD patients with NVAF and PCI, DOAC-treated patients had a lower risk of developing clinically relevant bleeding compared with the VKA group.
The Canadian Cardiovascular Society Atrial Fibrillation Guidelines Program: A Look Back Over the Last 10 Years and a Look Forward
2020, Canadian Journal of Cardiology
Atrial fibrillation and ischemic heart disease: beyond stroke prevention
2020, Revista Espanola de Cardiologia Suplementos
El objetivo principal en el abordaje del paciente con fibrilación auricular es la reducción del riesgo de ictus mediante el tratamiento antitrombótico adecuado. Sin embargo, a pesar de una adecuada anticoagulación, sigue habiendo un importante riesgo residual de eventos isquémicos, particularmente infarto de miocardio y muerte de origen cardiovascular, que exige una protección más completa. Por lo tanto, en el paciente con fibrilación auricular, el tratamiento anticoagulante debería perseguir este doble objetivo, la reducción tanto del riesgo de ictus como de las complicaciones isquémicas. Diferentes estudios han demostrado que los antagonistas de la vitamina K solo disminuyen el riesgo de ictus y de eventos isquémicos cuando el control de la anticoagulación es óptimo, cosa que ocurre en un pequeño número de pacientes. Con respecto a los anticoagulantes orales de acción directa, aunque en general muestran un perfil de eficacia y seguridad mejor que los antagonistas de la vitamina K, parece que no todos ofrecerían la misma protección en cuanto a la reducción de los eventos isquémicos. Está demostrado que el rivaroxabán reduce de manera significativa (18%) el riesgo de infarto de miocardio. De hecho, los estudios muestran que el rivaroxabán proporciona una protección vascular más completa en diferentes contextos clínicos, no solo en el paciente con fibrilación auricular, sino también en el paciente con enfermedad vascular ateroesclerótica.
The main aim of management in patients with atrial fibrillation is to reduce the risk of stroke using appropriate antithrombotic treatment. However, despite adequate anticoagulation, there remains a substantial residual risk of ischemic events, particularly myocardial infarction and cardiovascular death. A more general approach is needed. Consequently, in patients with atrial fibrillation, anticoagulation treatment should seek to achieve the twin targets of reducing the risk of both stroke and ischemic events. Studies have demonstrated that vitamin K antagonists reduce the risk of stroke and ischemic events only when anticoagulation control is optimal, a situation that occurs in only a small number of patients. Direct oral anticoagulants are generally more effective and safer than vitamin K antagonists. However, not all direct oral anticoagulants appear to offer the same protection against ischemic events. It has been shown that rivaroxaban significantly reduces the risk of myocardial infarction (by 18%). In fact, studies demonstrate that rivaroxaban provides comprehensive vascular protection across a range of clinical scenarios, not only in patients with atrial fibrillation, but also in those with atherosclerotic vascular disease.
Dual-Antithrombotic Therapy With DOACs After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Atrial Fibrillation: A Meta-analysis of Randomized Controlled Trials
2020, Canadian Journal of Cardiology
The choice of antithrombotic therapy for atrial fibrillation (AF) patients who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is challenging. We aimed to assess outcomes between dual-antithrombotic therapy with the use of direct-acting oral anticoagulants (DOACs) plus an antiplatelet agent (dual therapy) compared with warfarin plus 2 antiplatelet agents (triple therapy) for AF patients after PCI or with ACS.
Systematic searches of multiple major databases were performed from their inception through September 2019. We included only randomized controlled trials. Odds ratios (ORs) were pooled with the use of a random-effects model.
We identified 4 randomized controlled trials, which included 7168 patients. Compared with triple-antithrombotic therapy with warfarin, dual-antithrombotic therapy with DOACs was associated with a significant reduction in major bleeding (OR 0.56, 95% confidence interval [CI] 0.38-0.82; P = 0.003) as well as major bleeding or clinically relevant nonmajor bleeding (OR 0.53, 95% CI 0.38-0.75; P < 0.001). The rate of composite of death and ischemic events (stroke and myocardial infarction) was not statistically different between groups (OR 1.21, 95% CI 0.99-1.49; P = 0.06). There was no significant difference between groups in the rate of death (OR 1.20, 95% CI 0.95-1.53; P = 0.13).
In patients with AF and recent ACS or PCI, the use of dual-antithrombotic therapy with DOACs was associated with less major bleeding and less major bleeding or clinically relevant nonmajor bleeding compared with triple therapy. The use of dual therapy also showed nonsignificantly higher composite of death and ischemic events but no difference in mortality.
Il est difficile de choisir un traitement antithrombotique en cas de fibrillation auriculaire (FA) chez les patients ayant subi un syndrome coronarien aigu (SCA) ou une intervention coronarienne percutanée (ICP). Nous avons comparé les résultats obtenus avec une bithérapie antithrombotique comprenant un anticoagulant oral direct (AOD) et un antiplaquettaire (bithérapie) à ceux obtenus avec la warfarine associée à deux antiplaquettaires (trithérapie) après une ICP ou un SCA chez des patients présentant une FA.
Nous avons effectué des recherches exhaustives dans plusieurs grandes bases de données afin de retracer les études menées sur le sujet jusqu’en septembre 2019. Nous n’avons tenu compte que des essais contrôlés avec répartition aléatoire. Les rapports de cotes ont été regroupés à l’aide d’un modèle à effets aléatoires.
Nous avons relevé quatre essais contrôlés avec répartition aléatoire menés auprès d’un nombre total de 7168 patients. Comparativement à la trithérapie antithrombotique comprenant de la warfarine, la bithérapie antithrombotique comprenant un AOD a été associée à une réduction significative des hémorragies majeures (rapport de cotes [RC] de 0,56; intervalle de confiance [IC] à 95 % : 0,38-0,82; p = 0,003) ainsi que des hémorragies majeures ou hémorragies non majeures importantes sur le plan clinique (RC de 0,53 [IC à 95 % : 0,38-0,75], p < 0,001). Le taux du critère composé du décès ou d’un événement ischémique (accident vasculaire cérébral ou infarctus du myocarde) ne différait pas de manière statistiquement significative entre les deux groupes (RC de 1,21; IC à 95 % : 0,99-1,49, p = 0,06). Il n’y avait pas non plus de différence significative entre les deux groupes quant au taux de décès (RC de 1,20; IC à 95 % : 0,95-1,53; p = 0,13).
Chez les patients présentant une FA et ayant récemment subi un SCA ou une ICP, l’emploi d’une bithérapie antithrombotique comprenant un AOD a été associé à une diminution des hémorragies majeures et des hémorragies majeures ou hémorragies non majeures importantes sur le plan clinique, comparativement à l’emploi d’une trithérapie. Le recours à une bithérapie était par ailleurs associé à une hausse non significative de la fréquence des manifestations du critère composé du décès ou d’un événement ischémique; aucune différence n’a été observée quant à la mortalité.

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ReviewAntithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified

Abstract

Résumé

Section snippets

Antithrombotic Therapy for Patients With AF and Stable CAD

Dual vs Triple Therapy for Patients With AF and ACS or PCI

WOEST

Limitations

NOACs as Part of the Dual- or Triple-Therapy Regimen

P2y12 Inhibitors as Part of the Combination-Therapy Regimen

Duration of Triple Antithrombotic Therapy

Summary

Conclusion

Acknowledgements

Funding Sources

Disclosures

Can J Cardiol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

Lancet

Can J Cardiol

Lancet

Am Heart J

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

Lancet

Can J Cardiol

Can J Cardiol

J Am Coll Cardiol

Lancet

Can J Cardiol

The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms

Circ Res

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Europace

Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography

PLoS One

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

Lancet

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

Lancet

Review
Antithrombotic Therapy for Atrial Fibrillation and Coronary Disease Demystified