Editorial 1
Dual or triple therapy in patients with atrial fibrillation and drug-eluting stents? Antonia Sambola and David García-Dorado Coronary Artery Disease 2015, 00:000–000 Department of Cardiology, Vall d'Hebron Universty Hospital and Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
Autònoma de Barcelona, Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain Tel: + 34 932 746 07; fax: + 34 93 274 6063; e-mail: [email protected] Received 12 March 2015 Revised 31 March 2015 Accepted 31 March 2015
Correspondence to David Garcia-Dorado, MD, PhD, FESC, FACC, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat
Atrial fibrillation (AF) is associated with an increased risk of systemic embolization, cerebral embolism being the most catastrophic consequence. In patients with nonvalvular AF, oral anticoagulation (OAC) is especially recommended for those at medium or high risk of embolization, mainly to reduce the risk of stroke [1]. However, a percutaneous coronary intervention with stent implantation (PCI-S) requires dual-antiplatelet therapy (DAPT), commonly consisting of aspirin and a P2Y12 antagonist [2]. Between 5 and 10% of patients undergoing PCI-S are on OAC at the time of stenting. For these patients, guidelines recommend combining OAC with antiplatelet therapy, so-called triple therapy (TT), despite the increased risk of bleeding [2]. Although drug-eluting stents (DES) reduce the rates of target vessel revascularization compared with bare-metal stents [3], current guidelines recommend avoiding the use of DES in patients requiring long-term OAC undergoing PCI-S owing to an increased risk of bleeding associated with the prolonged use of TT [2,4]. Evidence available to date on the optimal type of stent in patients on chronic OAC yields conflicting results and the optimal antithrombotic strategy in these patients is also debated. Some studies reported a reduction in target vessel revascularization rates with an increased risk of bleeding with the use of DES in this population, whereas others found no differences in bleeding events [5,6]. The lack of randomized clinical trials and the small sample size of available studies have led to the recommendation of restricting the use of DES in patients with OAC indication. ‘Triple antithrombotic therapy versus dual antiplatelet therapy in patients with atrial fibrillation undergoing drug-eluting stent implantation’ from Kang et al., reported in this journal, is a retrospective observational study carried out in two centers that analyze the net clinical outcomes between the TT and the DAPT in patients with AF after PCI-S. This is a relevant clinical problem that remains unsolved because there are few studies addressing this dilemma. The study had no exclusion criteria and the follow-up was completed for all patients. A total of 367 patients were included in the analysis and 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
the median follow-up was 24 months. The DAPT was prescribed in 64.3% of patients and TT was administered to 35.7% of patients. A CHA2DS2-VASc score of 2 or more was significantly higher in the TT group compared with the DAPT group. The primary outcome measure was the 2-year net clinical outcomes, a composite of major bleeding and major adverse cardiac and cerebral events. Kang et al. report that TT is associated with worse 2-year net clinical outcomes (34.3 vs. 21.1%, P = 0.006) with a considerable increase in the risk of major bleeding (16.7 vs. 4.6%, P < 0.001) without any definite reduction in the major bleeding and major adverse cardiac and cerebral events (22.1 vs. 17.7%, P = 0.313). At first glance, these outcomes suggest a success for DAPT without warfarin. Yet, practice should not be changed on the basis of this study alone. First, because of the retrospective nature of this observational study with a small number of patients in both arms, less than 100 patients in each group of treatment, after propensityscore matching analysis, conclusions should be generalized to clinical practice with caution. Second, it is striking that after a propensity-score matching analysis, DAPTtreated patients showed no stroke whereas those treated with TT showed a rate of 4%, something unexpected in clinical practice. Moreover, it was not taken into consideration that peripheral emboli may have occurred during follow-up. In patients who require long-term administration of TT, alternative treatment strategies should be considered to balance the risk of thromboembolism and major bleeding [7,8]. We believe that a shorter duration of TT may be an option in this patient group while we await conclusive data from upcoming trials. Currently, a multicenter randomized trial (ISAR-TRIPLE) is ongoing to prove the efficacy and safety of the shortened duration of 6-week TT compared with 6-month TT in AF patients implanted with DES [9]. However, although there is some evidence supporting the strategy of combining OAC and clopidogrel in this group of patients as reported in the WOEST study [10], it cannot be ruled out that the omission of aspirin in patients who have undergone DES could determine a greater incidence of early and late stent thrombosis. In addition to these strategies, left atrial DOI: 10.1097/MCA.0000000000000257
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2 Coronary Artery Disease 2015, Vol 00 No 00
appendage occlusion can be considered in suitable patients [11]. Despite the limitations, the current study reported by Kang et al. will certainly lead to larger confirmatory studies with the aim of defining the optimum balance between anticoagulant and antiplatelet therapy in patients with AF and DES who require both forms of treatment. Evidence suggests that bleeding complications, especially major bleeding episodes, predict longterm mortality in patients undergoing PCI not only because of the bleeding event itself but also because of the consequences of bleeding [12] such as discontinuation of treatment leading to thrombotic complications. Clinicians are becoming increasingly aware of the importance of reducing the risk of bleeding in this group of patients, and this study provides an innovative stimulus, but one that requires further confirmation in the future.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071–2104. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk Vli M, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)
developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35:2541–2619. 3 Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007; 370:937–948. 4 Faxon DP, Eikelboom JW, Berger PB, Holmes DR Jr, Bhatt DL, Moliterno DJ, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North American perspective: executive summary. Circ Cardiovasc Interv 2011; 4:522–534. 5 Annala AP, Karjalainen PP, Biancari F, Niemelä M, Ylitalo A, Vikman S, et al. Long-term safety of drug-eluting stents in patients on warfarin treatment. Ann Med 2012; 44:271–278. 6 Ruiz-Nodar JM, Marín F, Sánchez-Payá J, Hurtado JA, Valencia-Martín J, Manzano-Fernández S, et al. Efficacy and safety of drug-eluting stent use in patients with atrial fibrillation. Eur Heart J 2009; 30:932–939. 7 Sambola A, Ferreira-González I, Angel J, Alfonso F, Maristany J, Rodríguez O, et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009; 95:1483–1488. 8 Sambola A, Montoro JB, Del Blanco BG, Llavero N, Barrabés JA, Alfonso F, et al. Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting: design of the MUSICA-2 randomized trial. Am Heart J 2013; 166:669–675. 9 Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, de Smet BJ, Herrman JP, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–1115. 10 Fiedler KA, Byrne RA, Schulz S, Sibbing D, Mehilli J, Ibrahim T, et al. Rationale and design of The Intracoronary Stenting and Antithrombotic Regimen-Testing of a six-week versus a six-month clopidogrel treatment Regimen In Patients with concomitant aspirin and oraL anticoagulant therapy following drug-Eluting stenting (ISAR-TRIPLE) study. Am Heart J 2014; 167:459–465.e1. 11 Landmesser U, Holmes DR Jr. Left atrial appendage closure: a percutaneous transcatheter approach for stroke prevention in atrial fibrillation. Eur Heart J 2012; 33:698–704. 12 Doyle BJ, Ting HH, Bell MR, Lennon RJ, Mathew V, Singh M, et al. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17 901 patients treated at the Mayo Clinic from 1994 to 2005. JACC Cardiovasc Interv 2008; 1:202–209.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Dual or triple therapy in patients with atrial fibrillation and drug-eluting stents? Antonia Sambola and David García-Dorado Coronary Artery Disease 2015, 00:000–000 Department of Cardiology, Vall d'Hebron Universty Hospital and Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
Autònoma de Barcelona, Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain Tel: + 34 932 746 07; fax: + 34 93 274 6063; e-mail: [email protected] Received 12 March 2015 Revised 31 March 2015 Accepted 31 March 2015
Correspondence to David Garcia-Dorado, MD, PhD, FESC, FACC, Department of Cardiology, Vall d’Hebron University Hospital and Research Institute, Universitat
Atrial fibrillation (AF) is associated with an increased risk of systemic embolization, cerebral embolism being the most catastrophic consequence. In patients with nonvalvular AF, oral anticoagulation (OAC) is especially recommended for those at medium or high risk of embolization, mainly to reduce the risk of stroke [1]. However, a percutaneous coronary intervention with stent implantation (PCI-S) requires dual-antiplatelet therapy (DAPT), commonly consisting of aspirin and a P2Y12 antagonist [2]. Between 5 and 10% of patients undergoing PCI-S are on OAC at the time of stenting. For these patients, guidelines recommend combining OAC with antiplatelet therapy, so-called triple therapy (TT), despite the increased risk of bleeding [2]. Although drug-eluting stents (DES) reduce the rates of target vessel revascularization compared with bare-metal stents [3], current guidelines recommend avoiding the use of DES in patients requiring long-term OAC undergoing PCI-S owing to an increased risk of bleeding associated with the prolonged use of TT [2,4]. Evidence available to date on the optimal type of stent in patients on chronic OAC yields conflicting results and the optimal antithrombotic strategy in these patients is also debated. Some studies reported a reduction in target vessel revascularization rates with an increased risk of bleeding with the use of DES in this population, whereas others found no differences in bleeding events [5,6]. The lack of randomized clinical trials and the small sample size of available studies have led to the recommendation of restricting the use of DES in patients with OAC indication. ‘Triple antithrombotic therapy versus dual antiplatelet therapy in patients with atrial fibrillation undergoing drug-eluting stent implantation’ from Kang et al., reported in this journal, is a retrospective observational study carried out in two centers that analyze the net clinical outcomes between the TT and the DAPT in patients with AF after PCI-S. This is a relevant clinical problem that remains unsolved because there are few studies addressing this dilemma. The study had no exclusion criteria and the follow-up was completed for all patients. A total of 367 patients were included in the analysis and 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
the median follow-up was 24 months. The DAPT was prescribed in 64.3% of patients and TT was administered to 35.7% of patients. A CHA2DS2-VASc score of 2 or more was significantly higher in the TT group compared with the DAPT group. The primary outcome measure was the 2-year net clinical outcomes, a composite of major bleeding and major adverse cardiac and cerebral events. Kang et al. report that TT is associated with worse 2-year net clinical outcomes (34.3 vs. 21.1%, P = 0.006) with a considerable increase in the risk of major bleeding (16.7 vs. 4.6%, P < 0.001) without any definite reduction in the major bleeding and major adverse cardiac and cerebral events (22.1 vs. 17.7%, P = 0.313). At first glance, these outcomes suggest a success for DAPT without warfarin. Yet, practice should not be changed on the basis of this study alone. First, because of the retrospective nature of this observational study with a small number of patients in both arms, less than 100 patients in each group of treatment, after propensityscore matching analysis, conclusions should be generalized to clinical practice with caution. Second, it is striking that after a propensity-score matching analysis, DAPTtreated patients showed no stroke whereas those treated with TT showed a rate of 4%, something unexpected in clinical practice. Moreover, it was not taken into consideration that peripheral emboli may have occurred during follow-up. In patients who require long-term administration of TT, alternative treatment strategies should be considered to balance the risk of thromboembolism and major bleeding [7,8]. We believe that a shorter duration of TT may be an option in this patient group while we await conclusive data from upcoming trials. Currently, a multicenter randomized trial (ISAR-TRIPLE) is ongoing to prove the efficacy and safety of the shortened duration of 6-week TT compared with 6-month TT in AF patients implanted with DES [9]. However, although there is some evidence supporting the strategy of combining OAC and clopidogrel in this group of patients as reported in the WOEST study [10], it cannot be ruled out that the omission of aspirin in patients who have undergone DES could determine a greater incidence of early and late stent thrombosis. In addition to these strategies, left atrial DOI: 10.1097/MCA.0000000000000257
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2 Coronary Artery Disease 2015, Vol 00 No 00
appendage occlusion can be considered in suitable patients [11]. Despite the limitations, the current study reported by Kang et al. will certainly lead to larger confirmatory studies with the aim of defining the optimum balance between anticoagulant and antiplatelet therapy in patients with AF and DES who require both forms of treatment. Evidence suggests that bleeding complications, especially major bleeding episodes, predict longterm mortality in patients undergoing PCI not only because of the bleeding event itself but also because of the consequences of bleeding [12] such as discontinuation of treatment leading to thrombotic complications. Clinicians are becoming increasingly aware of the importance of reducing the risk of bleeding in this group of patients, and this study provides an innovative stimulus, but one that requires further confirmation in the future.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071–2104. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk Vli M, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)
developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35:2541–2619. 3 Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007; 370:937–948. 4 Faxon DP, Eikelboom JW, Berger PB, Holmes DR Jr, Bhatt DL, Moliterno DJ, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North American perspective: executive summary. Circ Cardiovasc Interv 2011; 4:522–534. 5 Annala AP, Karjalainen PP, Biancari F, Niemelä M, Ylitalo A, Vikman S, et al. Long-term safety of drug-eluting stents in patients on warfarin treatment. Ann Med 2012; 44:271–278. 6 Ruiz-Nodar JM, Marín F, Sánchez-Payá J, Hurtado JA, Valencia-Martín J, Manzano-Fernández S, et al. Efficacy and safety of drug-eluting stent use in patients with atrial fibrillation. Eur Heart J 2009; 30:932–939. 7 Sambola A, Ferreira-González I, Angel J, Alfonso F, Maristany J, Rodríguez O, et al. Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study. Heart 2009; 95:1483–1488. 8 Sambola A, Montoro JB, Del Blanco BG, Llavero N, Barrabés JA, Alfonso F, et al. Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting: design of the MUSICA-2 randomized trial. Am Heart J 2013; 166:669–675. 9 Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, de Smet BJ, Herrman JP, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–1115. 10 Fiedler KA, Byrne RA, Schulz S, Sibbing D, Mehilli J, Ibrahim T, et al. Rationale and design of The Intracoronary Stenting and Antithrombotic Regimen-Testing of a six-week versus a six-month clopidogrel treatment Regimen In Patients with concomitant aspirin and oraL anticoagulant therapy following drug-Eluting stenting (ISAR-TRIPLE) study. Am Heart J 2014; 167:459–465.e1. 11 Landmesser U, Holmes DR Jr. Left atrial appendage closure: a percutaneous transcatheter approach for stroke prevention in atrial fibrillation. Eur Heart J 2012; 33:698–704. 12 Doyle BJ, Ting HH, Bell MR, Lennon RJ, Mathew V, Singh M, et al. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17 901 patients treated at the Mayo Clinic from 1994 to 2005. JACC Cardiovasc Interv 2008; 1:202–209.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
