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Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke?
EJINME-03332; No of Pages 2 European Journal of Internal Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke? Keywords: Atrial fibrillation Coronary stenting Oral anticoagulant Antiplatelet agent
Thromboprophylaxis for patients with coronary artery disease and atrial fibrillation (AF) is problematic when there is a low or moderate risk of stroke (CHADS2 score = 0 or 1), particularly when patients experience an acute coronary syndrome or undergo intracoronary stent implantation. Some physicians may be reluctant to prescribe oral anticoagulation (OAC) in these patients and several recent guidelines propose slightly different management in such settings [1,2]. Our goal was to evaluate whether treatment with an OAC is appreciably beneficial in these AF patients. All patients with AF and stent implantation seen between 2000 and 2010 in 3 academic hospitals were identified in a database and followed up for mortality, stroke and bleeding events. The CHADS2 score was calculated for each patient as initially described, based on 2 points for a history of stroke or TIA, and 1 point each for age ≥ 75, hypertension, diabetes, and cardiac failure. Individual patient management decisions, such as the type of revascularization performed, type of stent implanted, as well as the regimen of oral anticoagulation and/or antiplatelet drugs at discharge were decided by the interventional cardiologist and/or the responsible clinical cardiologist. Comparisons between groups were made using chi-square tests to compare categorical variables, and the Student t test for continuous variables. We evaluated association between use of OAC and the occurrence of selected events at 1-year follow-up with calculation of Odds Ratios (OR) and 95% confidence intervals (CI). A p value b 0.05 was considered statistically significant. Among all patients seen between 2000 and 2010, 343 had AF, coronary stent placement and low or moderate risk of stroke, estimated by CHADS2 score = 0 or 1. The characteristics of these patients are shown in Table 1. In these patients, OAC was prescribed on an individual basis for 144 patients (42%) and no OAC in the remaining 199 patients (58%). During a 1-year follow-up, 17 strokes/thromboembolic events (5.0%), 29 major bleedings (8.5%) and 30 deaths (8.7%) were recorded. Patients under OAC had a non-significant lower risk of stroke than those not treated with OAC (2.8% vs 6.5%, OR 0.43 95% CI 0.14–1.28, p = 0.14), a non-significant higher risk of bleeding (11.8% vs 6.0%, OR 1.96 95% CI 0.97–3.97, p = 0.08), but we were able to find a lower allcause mortality (4.9% vs. 11.6%, OR 0.42 95% CI 0.19–0.95, p = 0.03). In retrospective analyses of AF patients at high embolic risk who had undergone percutaneous coronary intervention with stent, it has already been found that non-anticoagulation with coumarins at discharge may increase mortality and the risk of thromboembolic events [3]. Our present analysis seems to confirm these findings in a population of patients supposed to be at relatively low risk of stroke.
Problems arise in patients with AF undergoing PCI with stenting who may require complex antithrombotic strategies increasing the risk of bleeding. Combined aspirin–clopidogrel therapy is less effective in preventing stroke compared to OAC alone. OAC alone is nevertheless insufficient to prevent stent thrombosis. Triple therapy might be considered superior at preventing major adverse cardiac events, stroke, and stent thrombosis in these AF patients when compared to the combinations of warfarin plus aspirin or clopidogrel plus aspirin but has been associated with major bleeding rates as high as 7–10% at one year [4]. Physicians may thus be reluctant to use this strategy. Overall, there is a lack of published evidence on what is the optimal management strategy in patients with AF requiring OAC who need stent implantation. Only limited data have been provided by single-center reports or retrospective registry. So far, there was to our knowledge no such study in patients at relatively low risk of stroke. Actually, we observed a yearly 6.5% rate of stroke in the group with no OAC indicating that they were not low-risk patients. In our cohort, we found a non-significantly higher risk of severe bleeding in patients treated with OAC. Several studies underline the association of triple therapy with minor, rather than major, bleeding complications. In contrast, Gao found in 622 patients with AF who underwent PCI using a DES that the patients not treated with OAC had the highest incidence of stroke [4]. We also found that use of OAC was associated with a markedly reduced risk of stroke (although non-significant) and a significant lower risk of mortality, suggesting a relevant clinical benefit for OAC for supposed relatively low-risk patients. In recent documents on the optimal management of antithrombotic therapy in AF patients undergoing PCI/stenting, different antithrombotic strategies are currently recommended according to the clinical setting [1,2,5]. Timing of these therapies is also critical. At discharge, triple antithrombotic (OAC, aspirin plus clopidogrel) is most often recommended, ranging from at least 2 weeks for elective procedures with high haemorrhagic risk, up to 6 months for ACS procedures when the bleeding risk is low or intermediate in European guidelines. According to the type of procedure, this regime should then be followed by OAC plus clopidogrel up to the 12th months. Thereafter, warfarin is recommended alone lifelong. However, for patients with AF at low to intermediate risk of stroke, a dual antiplatelet therapy rather than triple therapy has also been suggested during the first 12 months after placement of an intracoronary stent in North American guidelines [5]. Our study was observational with no multivariable analysis since the population was relatively homogeneous. The randomized WOEST study [6] found that the combination warfarin + clopidogrel was superior to triple therapy (warfarin + clopidogrel + aspirin) in patients receiving stent with respect to bleeding complications while equally safe for prevention of thrombotic complications in patients with both indications for warfarin use and dual antiplatelet (clopidogrel + aspirin) treatment. However, the WOEST study has some limitations: a radial rather than femoral approach (used in 74% of the patients in the WOEST study) is now recommended for vascular access to keep the risk of bleeding to a minimum and only 39 patients had a relatively low risk of stroke with CHADS2 score 0–1. Thus, there is still a need for large prospective
http://dx.doi.org/10.1016/j.ejim.2016.08.022 0953-6205/© 2016 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Fauchier L, et al, Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke?, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.022
2
Letter to the Editor Table 1 Clinical characteristics of the cohort AF patients with stent implantation and CHADS2 score = 0 or 1 (n = 343). Male gender Age Paroxysmal AF Hypertension Diabetes Chronic kidney disease Heart failure Previous stroke/systemic embolism Previous treatment with OAC Diagnosis Non ST elevation ACS ST elevation ACS Stable angina Use of DES Treatment at discharge Aspirin Clopidogrel OAC
285 (83.1%) 68.0 ± 11.3 209 (60.9%) 120 (35.0%) 30 (8.7%) 29 (8.5%) 58 (16.9%) 0 (0%) 191 (55.7%) 152 (44.3%) 97 (28.3%) 94 (27.4%) 112 (32.7%) 309 (90.1%) 298 (86.9%) 144 (42.0%)
clinical studies to determine the optimal contemporary management of patients with AF undergoing coronary interventions. In one of the largest series of AF patients with coronary stent implantation and a CHADS2 score = 0–1, prescription of oral anticoagulation was associated with a trend towards lower risk of stroke and higher risk of bleeding, and with a significantly lower mortality. Author contributions All authors conceived and designed the study, collected or analysed or interpreted the data, drafted the article or revised it critically for important intellectual content, and gave final approval of the version to be published. Financial support This work was supported by Instituto de Salud Carlos III (research project: PI13/00513) and Fundación Séneca (grant number: 19245/PI/ 14). Conflict of interest LF has served as a consultant for Bayer, Medtronic, Novartis and Sanofi Aventis and has been on the speaker's bureau for Boehringher Ingelheim, Bayer, BMS Pfizer, Medtronic, and Sanofi Aventis. JMRN has received research grants and speaker fees from Medtronic, Boston Scientific and AstraZeneca. MV has received research grants and speaker fees from Medtronic and Boston Scientific. GYHL has served as a consultant for Bayer, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola and Boehringer Ingelheim and has been on the speaker's bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, DaiichiSankyo, Medtronic. FM has received funding for research, consultancy and lecturing from Boston Scientifics, Bayer, Astra Zeneca, DaiichiSankyo and Boehringer Ingelheim.
References [1] Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. [2] Lip GYH, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35:3155–79. [3] Ruiz-Nodar JM, Marín F, Roldán V, Valencia J, Manzano-Fernández S, Caballero L, et al. Should we recommend oral anticoagulation therapy in patients with atrial fibrillation undergoing coronary artery stenting with a high HAS-BLED bleeding risk score? Circ Cardiovasc Interv 2012;5:459–66. [4] Gao F, Zhou YJ, Wang ZJ, Shen H, Liu XL, Nie B, et al. Comparison of different antithrombotic regimens for patients with atrial fibrillation undergoing drug-eluting stent implantation. Circ J 2010;74:701–8. [5] Rubboli A, Faxon DP, Airaksinen JK, Schlitt A, Marín F, Bhatt DL, et al. The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th Anniversary Overview. Thromb Haemost 2014;112:1080–7. [6] Dewilde WJM, Oirbans T, Verheugt FWA, 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;381:1107–15.
Laurent Fauchier Service de Cardiologie, Pôle Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France Juan M. Ruiz-Nodar Department of Cardiology, Hospital General Universitario de Alicante, Spain Mariano Valdés Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain Denis Angoulvant Service de Cardiologie, Pôle Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France Gregory Y.H. Lip University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, UK Francisco Marín Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain Corresponding author at: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Ctra Madrid-Cartagena s/n, Murcia, Spain. E-mail address: [email protected]. 10 August 2016 Available online xxxx
Please cite this article as: Fauchier L, et al, Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke?, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.022
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke? Keywords: Atrial fibrillation Coronary stenting Oral anticoagulant Antiplatelet agent
Thromboprophylaxis for patients with coronary artery disease and atrial fibrillation (AF) is problematic when there is a low or moderate risk of stroke (CHADS2 score = 0 or 1), particularly when patients experience an acute coronary syndrome or undergo intracoronary stent implantation. Some physicians may be reluctant to prescribe oral anticoagulation (OAC) in these patients and several recent guidelines propose slightly different management in such settings [1,2]. Our goal was to evaluate whether treatment with an OAC is appreciably beneficial in these AF patients. All patients with AF and stent implantation seen between 2000 and 2010 in 3 academic hospitals were identified in a database and followed up for mortality, stroke and bleeding events. The CHADS2 score was calculated for each patient as initially described, based on 2 points for a history of stroke or TIA, and 1 point each for age ≥ 75, hypertension, diabetes, and cardiac failure. Individual patient management decisions, such as the type of revascularization performed, type of stent implanted, as well as the regimen of oral anticoagulation and/or antiplatelet drugs at discharge were decided by the interventional cardiologist and/or the responsible clinical cardiologist. Comparisons between groups were made using chi-square tests to compare categorical variables, and the Student t test for continuous variables. We evaluated association between use of OAC and the occurrence of selected events at 1-year follow-up with calculation of Odds Ratios (OR) and 95% confidence intervals (CI). A p value b 0.05 was considered statistically significant. Among all patients seen between 2000 and 2010, 343 had AF, coronary stent placement and low or moderate risk of stroke, estimated by CHADS2 score = 0 or 1. The characteristics of these patients are shown in Table 1. In these patients, OAC was prescribed on an individual basis for 144 patients (42%) and no OAC in the remaining 199 patients (58%). During a 1-year follow-up, 17 strokes/thromboembolic events (5.0%), 29 major bleedings (8.5%) and 30 deaths (8.7%) were recorded. Patients under OAC had a non-significant lower risk of stroke than those not treated with OAC (2.8% vs 6.5%, OR 0.43 95% CI 0.14–1.28, p = 0.14), a non-significant higher risk of bleeding (11.8% vs 6.0%, OR 1.96 95% CI 0.97–3.97, p = 0.08), but we were able to find a lower allcause mortality (4.9% vs. 11.6%, OR 0.42 95% CI 0.19–0.95, p = 0.03). In retrospective analyses of AF patients at high embolic risk who had undergone percutaneous coronary intervention with stent, it has already been found that non-anticoagulation with coumarins at discharge may increase mortality and the risk of thromboembolic events [3]. Our present analysis seems to confirm these findings in a population of patients supposed to be at relatively low risk of stroke.
Problems arise in patients with AF undergoing PCI with stenting who may require complex antithrombotic strategies increasing the risk of bleeding. Combined aspirin–clopidogrel therapy is less effective in preventing stroke compared to OAC alone. OAC alone is nevertheless insufficient to prevent stent thrombosis. Triple therapy might be considered superior at preventing major adverse cardiac events, stroke, and stent thrombosis in these AF patients when compared to the combinations of warfarin plus aspirin or clopidogrel plus aspirin but has been associated with major bleeding rates as high as 7–10% at one year [4]. Physicians may thus be reluctant to use this strategy. Overall, there is a lack of published evidence on what is the optimal management strategy in patients with AF requiring OAC who need stent implantation. Only limited data have been provided by single-center reports or retrospective registry. So far, there was to our knowledge no such study in patients at relatively low risk of stroke. Actually, we observed a yearly 6.5% rate of stroke in the group with no OAC indicating that they were not low-risk patients. In our cohort, we found a non-significantly higher risk of severe bleeding in patients treated with OAC. Several studies underline the association of triple therapy with minor, rather than major, bleeding complications. In contrast, Gao found in 622 patients with AF who underwent PCI using a DES that the patients not treated with OAC had the highest incidence of stroke [4]. We also found that use of OAC was associated with a markedly reduced risk of stroke (although non-significant) and a significant lower risk of mortality, suggesting a relevant clinical benefit for OAC for supposed relatively low-risk patients. In recent documents on the optimal management of antithrombotic therapy in AF patients undergoing PCI/stenting, different antithrombotic strategies are currently recommended according to the clinical setting [1,2,5]. Timing of these therapies is also critical. At discharge, triple antithrombotic (OAC, aspirin plus clopidogrel) is most often recommended, ranging from at least 2 weeks for elective procedures with high haemorrhagic risk, up to 6 months for ACS procedures when the bleeding risk is low or intermediate in European guidelines. According to the type of procedure, this regime should then be followed by OAC plus clopidogrel up to the 12th months. Thereafter, warfarin is recommended alone lifelong. However, for patients with AF at low to intermediate risk of stroke, a dual antiplatelet therapy rather than triple therapy has also been suggested during the first 12 months after placement of an intracoronary stent in North American guidelines [5]. Our study was observational with no multivariable analysis since the population was relatively homogeneous. The randomized WOEST study [6] found that the combination warfarin + clopidogrel was superior to triple therapy (warfarin + clopidogrel + aspirin) in patients receiving stent with respect to bleeding complications while equally safe for prevention of thrombotic complications in patients with both indications for warfarin use and dual antiplatelet (clopidogrel + aspirin) treatment. However, the WOEST study has some limitations: a radial rather than femoral approach (used in 74% of the patients in the WOEST study) is now recommended for vascular access to keep the risk of bleeding to a minimum and only 39 patients had a relatively low risk of stroke with CHADS2 score 0–1. Thus, there is still a need for large prospective
http://dx.doi.org/10.1016/j.ejim.2016.08.022 0953-6205/© 2016 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
Please cite this article as: Fauchier L, et al, Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke?, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.022
2
Letter to the Editor Table 1 Clinical characteristics of the cohort AF patients with stent implantation and CHADS2 score = 0 or 1 (n = 343). Male gender Age Paroxysmal AF Hypertension Diabetes Chronic kidney disease Heart failure Previous stroke/systemic embolism Previous treatment with OAC Diagnosis Non ST elevation ACS ST elevation ACS Stable angina Use of DES Treatment at discharge Aspirin Clopidogrel OAC
285 (83.1%) 68.0 ± 11.3 209 (60.9%) 120 (35.0%) 30 (8.7%) 29 (8.5%) 58 (16.9%) 0 (0%) 191 (55.7%) 152 (44.3%) 97 (28.3%) 94 (27.4%) 112 (32.7%) 309 (90.1%) 298 (86.9%) 144 (42.0%)
clinical studies to determine the optimal contemporary management of patients with AF undergoing coronary interventions. In one of the largest series of AF patients with coronary stent implantation and a CHADS2 score = 0–1, prescription of oral anticoagulation was associated with a trend towards lower risk of stroke and higher risk of bleeding, and with a significantly lower mortality. Author contributions All authors conceived and designed the study, collected or analysed or interpreted the data, drafted the article or revised it critically for important intellectual content, and gave final approval of the version to be published. Financial support This work was supported by Instituto de Salud Carlos III (research project: PI13/00513) and Fundación Séneca (grant number: 19245/PI/ 14). Conflict of interest LF has served as a consultant for Bayer, Medtronic, Novartis and Sanofi Aventis and has been on the speaker's bureau for Boehringher Ingelheim, Bayer, BMS Pfizer, Medtronic, and Sanofi Aventis. JMRN has received research grants and speaker fees from Medtronic, Boston Scientific and AstraZeneca. MV has received research grants and speaker fees from Medtronic and Boston Scientific. GYHL has served as a consultant for Bayer, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic, Portola and Boehringer Ingelheim and has been on the speaker's bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, DaiichiSankyo, Medtronic. FM has received funding for research, consultancy and lecturing from Boston Scientifics, Bayer, Astra Zeneca, DaiichiSankyo and Boehringer Ingelheim.
References [1] Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. [2] Lip GYH, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35:3155–79. [3] Ruiz-Nodar JM, Marín F, Roldán V, Valencia J, Manzano-Fernández S, Caballero L, et al. Should we recommend oral anticoagulation therapy in patients with atrial fibrillation undergoing coronary artery stenting with a high HAS-BLED bleeding risk score? Circ Cardiovasc Interv 2012;5:459–66. [4] Gao F, Zhou YJ, Wang ZJ, Shen H, Liu XL, Nie B, et al. Comparison of different antithrombotic regimens for patients with atrial fibrillation undergoing drug-eluting stent implantation. Circ J 2010;74:701–8. [5] Rubboli A, Faxon DP, Airaksinen JK, Schlitt A, Marín F, Bhatt DL, et al. The optimal management of patients on oral anticoagulation undergoing coronary artery stenting. The 10th Anniversary Overview. Thromb Haemost 2014;112:1080–7. [6] Dewilde WJM, Oirbans T, Verheugt FWA, 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;381:1107–15.
Laurent Fauchier Service de Cardiologie, Pôle Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France Juan M. Ruiz-Nodar Department of Cardiology, Hospital General Universitario de Alicante, Spain Mariano Valdés Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain Denis Angoulvant Service de Cardiologie, Pôle Cœur Thorax Vasculaire, Centre Hospitalier Universitaire Trousseau et Faculté de Médecine, Université François Rabelais, Tours, France Gregory Y.H. Lip University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, UK Francisco Marín Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain Corresponding author at: Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Ctra Madrid-Cartagena s/n, Murcia, Spain. E-mail address: [email protected]. 10 August 2016 Available online xxxx
Please cite this article as: Fauchier L, et al, Is oral anticoagulation needed in patients with atrial fibrillation and stent implantation at low–moderate risk of stroke?, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.022