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Bivalirudin use during percutaneous coronary intervention in patients on chronic warfarin therapy
Thrombosis Research 133 (2014) 695–696
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Bivalirudin use during percutaneous coronary intervention in patients on chronic warfarin therapy
Dear Editors,
About 5 to 8 % of patients referred for percutaneous coronary intervention (PCI) have an indication for long-term oral anticoagulation (OAC), mainly due to atrial fibrillation (AF) [1]. Intravenous direct thrombin inhibitor, bivalirudin (Angiox, The Medicines company LTD, UK), is increasingly used in the setting of primary PCI for ST elevation myocardial infarction, and acute coronary syndromes, since it has provided a similar reduction in major adverse cardiac events but lower bleeding events, when compared to heparin and heparin plus glycoprotein inhibitors (GPIs) [2,3]. At present, however, there are no published data on safety and efficacy of bivalirudin in combination with OAC, because these patients have been excluded from clinical trials. In this study, we sought to assess the rates of major adverse cardiac and cerebrovascular events (MACCE), as well as bleeding and access site complications in patients on chronic warfarin therapy undergoing PCI with periprocedural bivalirudin vs. heparin plus GPIs use. This analysis is based on data collected from two study protocols evaluating thrombotic and bleeding complications of coronary interventions in Western Finland and Europe [4–6]. Patients with bivalirudin and heparin plus GPI use were derived from four Finnish PCI centers over the same follow-up period. The primary endpoints were MACCE, mortality and bleeding complications at 30 days. A MACCE was defined as the occurrence of any of the following post-PCI: death, myocardial infarction, the target vessel revascularization (emergency or elective coronary-artery bypass grafting or repeated PCI), stent thrombosis, or stroke. Bleeding complications were classified as ‘major bleeding’ according to the TIMI criteria [7] and access site complications. Stent thrombosis was adjudicated according to Academic Research Consortium Criteria as definite and probable [8]. This study complies with the Declaration of Helsinki. The Ethics Committees of the participating hospitals approved the study protocol. Written informed consent or a waiver of the requirement of written informed consent was obtained. PCI was performed in 1104 patients on warfarin and periprocedural bivalirudin was used in 51 (4.6%) patients. The indication for warfarin was atrial fibrillation in 135/138 (98%) and pulmonary embolism in 3/138 (2%) patients. There was a wide variation (0–9.5%) in its use among participating hospitals and it was only used in centres performing PCI without conventional heparin bridging.
0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2014.01.038
Baseline clinical and procedural characteristics as well as clinical outcome are presented in Table 1. Compared to patients with GPI use, the indication for bivalirudin use was less often acute coronary syndrome, and it was used also in elective cases (47.1%). In stable patients, mean International Normalized Ratio (INR) level was 1.9 (1.0-2.9) and other indication included high thrombus burden. At 30 days, the incidence of in-hospital access site complications was comparable, but the rate of MACCE and TIMI major bleeding events were significantly higher in patients with heparin plus GPI compared to bivalirudin use. Patients on chronic warfarin undergoing PCI are at high risk for bleeding complications as well as MACCE, especially when treated for acute coronary syndromes [9]. Current guidelines recommend bridging therapy with heparins in patients considered being at high risk of thrombo-embolism [10]. However, uninterrupted warfarin is an emerging option because it may decrease the rate of bleeding complications in a favourable balance with thrombotic complications [11]. Nevertheless, additional anticoagulation or antithrombotic treatment is often warranted in these patients due to sub-therapeutic INR levels, acute coronary syndrome or high intracoronary thrombus burden. While the issue with subtherapeutic warfarin anticoagulation may be solved with additional periprocedural heparin [6], additional antithrombotic strategy is currently based on GPI use. Unfortunately, bleeding complications seem to represent a significant limitation to the effectiveness of GPIs, since the use of GPIs has been associated with a 3 to 13-fold risk of in-hospital major bleeding in warfarin-treated patients. Up to 20% of patients may have a major bleeding event when GPIs are added on top of aggressive anticoagulation [5,9,11]. In the light of the available data on GPIs in this patient subset, bivalirudin could be an option in patients at high thrombotic risk or with high thrombus burden. The strength of our analysis is to identify and include all consecutive warfarin-treated patients from the records. However, this study carries all the inherent limitations of a retrospective study and low sample size. In conclusion, our study provides the first ‘real-world’ experience on the use of bivalirudin in AF patients on chronic warfarin treatment. The rate of 30-day major bleeding and MACCE were lower compared to heparin plus GPI use also in this high risk patient subset suggesting that bivalirudin might be an option when additional antithrombotic treatment is needed during PCI.
Conflict of Interest Statement None declared.
696
Letter to the Editors-in-Chief
Table 1 Baseline clinical and procedural characteristics and 30-day clinical outcome of the two groups. Variable
Bivalirudin group (N = 51)
Heparin + GPI group (N = 87)
p value
Male gender Age, (years) CHADS2 score Pre-PCI International Normalized Ratio Diabetes mellitus Hypertension Previous stroke Previous MI Previous PCI Indication for PCI Stable angina pectoris Unstable angina pectoris Non-ST-elevation MI ST-elevation MI Patients with drug eluting stents Stent diameter (mm) Total stent length (mm) Balloon angioplasty Procedural success Femoral sheath Length of hospital stay (d) Medication at discharge/at event Warfarin + aspirin + clopidogrel Aspirin + clopidogrel Warfarin + clopidogrel MACCE All-cause death MI TVR Definite/probable ST Stroke TIMI major bleeding Access site complications
33 (64.7) 74.0 [13.0] 2.0 [2.0] 1.8 [1.0]
59 (67.8) 74.0 [13.0] 1.0 [2.0] 2.1 [1.0]
0.71 0.64 0.27 0.62
9 (17.6) 35 (68.6) 9 (17.6) 14 (27.5) 8 (15.7)
21 (24.1) 66 (75.9) 9 (10.3) 24 (27.6) 12 (13.8)
0.40 0.43 0.30 1.0 0.81
24 (47.1) 5 (9.8) 11 (21.6) 8 (15.7) 14 (27.5)
13 (14.9) 15 (17.2) 23 (26.4) 36 (41.4) 17 (20.7)
b0.001 0.32 0.55 0.002 0.40
3.5 [0.5] 17.0 [11] 3 (5.9) 51 (100) 43 (84.3) 1 [5]
3.0 [0.5] 16.0 [6.0] 0 82 (94.3) 73 (83.9) 4 [7]
0.10 0.86 0.16 0.16 1.0 b0.001
38 (74.5)
59 (67.8)
0.45
9 (17.6) 3 (5.9) 2 (3.9) 1 (2) 1 (2) 0 1 (2) 1 (2) 0 6 (11.8)
17 (19.5) 7 (8.0) 16 (18.4) 9 (10.3) 3 (3.4) 5 (5.7) 0 0 8 (9.2) 13 (14.9)
0.83 0.75 0.02 0.09 1.0 0.16 0.37 0.37 0.03 0.80
Data are presented as median [IQR] or count (%) where appropriate.
[5] Lahtela H, Karjalainen PP, Niemelä M, et al. Are glycoprotein inhibitors safe during percutaneous coronary intervention in patients on chronic warfarin treatment? Thromb Haemost 2009;102(6):1227–33. [6] Kiviniemi T, Karjalainen P, Pietilä M, et al. Comparison of additional versus no additional heparin during therapeutic oral anticoagulation in patients undergoing percutaneous coronary intervention. Am J Cardiol 2012;110(1):30–5. [7] Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) trial— Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11(1):1–11. [8] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation 2007;115(17):2344–51. [9] Subherwal S, Peterson ED, Chen AY, et al. Admission international normalized ratio levels, early treatment strategies, and major bleeding risk among Non–ST-Segment– Elevation myocardial infarction patients on home warfarin therapy / clinical perspective. Circulation 2012;125(11):1414–23. [10] Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic Therapy*American college of chest physicians evidence-based clinical practice guidelines. Chest, 133(6_suppl); 2008 299S–339S. [11] Airaksinen K, Schlitt A, Rubboli A, Karjalainen P, Lip GY. How to manage antithrombotic treatment during percutaneous coronary interventions in patients receiving long-term oral anticoagulation: To "bridge" or not to "bridge"? EuroIntervention 2011;6(4):520–6.
Tuomas Kiviniemi Heart Center, Turku University Hospital and University of Turku, Finland Corresponding author at: Heart Center, Turku University Hospital and University of Turku, Hämeentie 11, FIN-20520, Turku, Finland. Tel.: +358 2 3130787; fax: +358 2 3132030. E-mail address: tuoski@utu.fi. Pasi Karjalainen Heart Center, Satakunta Central Hospital, Finland Matti Niemelä Division of Cardiology, Department of Medicine, Oulu University Hospital, Finland Andrea Rubboli Division of Cardiology, Laboratory of Interventional Cardiology, Ospedale Maggiore, Bologna, Italy Gregory Y.H. Lip University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom
References [1] Lip GYH, Huber K, Andreotti F, et al. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: Executive summary—a consensus document of the european society of cardiology working group on thrombosis, endorsed by the european heart rhythm association (EHRA) and the european association of percutaneous cardiovascular interventions (EAPCI). Eur Heart J 2010;31(11):1311–8. [2] Kastrati A, Neumann F, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359(7):688–96. [3] Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358(21):2218–30. [4] Karjalainen PP, Vikman S, Niemelä M, et al. Safety of percutaneous coronary intervention during uninterrupted oral anticoagulant treatment. Eur Heart J 2008;29(8):1001–10.
Axel Schlitt Department of Medicine III, Martin Luther University Halle-Wittenberg, Germany Wail Nammas Heart Center, Turku University Hospital and University of Turku, Finland K.E. Juhani Airaksinen Heart Center, Turku University Hospital and University of Turku, Finland 23 December 2013
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Bivalirudin use during percutaneous coronary intervention in patients on chronic warfarin therapy
Dear Editors,
About 5 to 8 % of patients referred for percutaneous coronary intervention (PCI) have an indication for long-term oral anticoagulation (OAC), mainly due to atrial fibrillation (AF) [1]. Intravenous direct thrombin inhibitor, bivalirudin (Angiox, The Medicines company LTD, UK), is increasingly used in the setting of primary PCI for ST elevation myocardial infarction, and acute coronary syndromes, since it has provided a similar reduction in major adverse cardiac events but lower bleeding events, when compared to heparin and heparin plus glycoprotein inhibitors (GPIs) [2,3]. At present, however, there are no published data on safety and efficacy of bivalirudin in combination with OAC, because these patients have been excluded from clinical trials. In this study, we sought to assess the rates of major adverse cardiac and cerebrovascular events (MACCE), as well as bleeding and access site complications in patients on chronic warfarin therapy undergoing PCI with periprocedural bivalirudin vs. heparin plus GPIs use. This analysis is based on data collected from two study protocols evaluating thrombotic and bleeding complications of coronary interventions in Western Finland and Europe [4–6]. Patients with bivalirudin and heparin plus GPI use were derived from four Finnish PCI centers over the same follow-up period. The primary endpoints were MACCE, mortality and bleeding complications at 30 days. A MACCE was defined as the occurrence of any of the following post-PCI: death, myocardial infarction, the target vessel revascularization (emergency or elective coronary-artery bypass grafting or repeated PCI), stent thrombosis, or stroke. Bleeding complications were classified as ‘major bleeding’ according to the TIMI criteria [7] and access site complications. Stent thrombosis was adjudicated according to Academic Research Consortium Criteria as definite and probable [8]. This study complies with the Declaration of Helsinki. The Ethics Committees of the participating hospitals approved the study protocol. Written informed consent or a waiver of the requirement of written informed consent was obtained. PCI was performed in 1104 patients on warfarin and periprocedural bivalirudin was used in 51 (4.6%) patients. The indication for warfarin was atrial fibrillation in 135/138 (98%) and pulmonary embolism in 3/138 (2%) patients. There was a wide variation (0–9.5%) in its use among participating hospitals and it was only used in centres performing PCI without conventional heparin bridging.
0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2014.01.038
Baseline clinical and procedural characteristics as well as clinical outcome are presented in Table 1. Compared to patients with GPI use, the indication for bivalirudin use was less often acute coronary syndrome, and it was used also in elective cases (47.1%). In stable patients, mean International Normalized Ratio (INR) level was 1.9 (1.0-2.9) and other indication included high thrombus burden. At 30 days, the incidence of in-hospital access site complications was comparable, but the rate of MACCE and TIMI major bleeding events were significantly higher in patients with heparin plus GPI compared to bivalirudin use. Patients on chronic warfarin undergoing PCI are at high risk for bleeding complications as well as MACCE, especially when treated for acute coronary syndromes [9]. Current guidelines recommend bridging therapy with heparins in patients considered being at high risk of thrombo-embolism [10]. However, uninterrupted warfarin is an emerging option because it may decrease the rate of bleeding complications in a favourable balance with thrombotic complications [11]. Nevertheless, additional anticoagulation or antithrombotic treatment is often warranted in these patients due to sub-therapeutic INR levels, acute coronary syndrome or high intracoronary thrombus burden. While the issue with subtherapeutic warfarin anticoagulation may be solved with additional periprocedural heparin [6], additional antithrombotic strategy is currently based on GPI use. Unfortunately, bleeding complications seem to represent a significant limitation to the effectiveness of GPIs, since the use of GPIs has been associated with a 3 to 13-fold risk of in-hospital major bleeding in warfarin-treated patients. Up to 20% of patients may have a major bleeding event when GPIs are added on top of aggressive anticoagulation [5,9,11]. In the light of the available data on GPIs in this patient subset, bivalirudin could be an option in patients at high thrombotic risk or with high thrombus burden. The strength of our analysis is to identify and include all consecutive warfarin-treated patients from the records. However, this study carries all the inherent limitations of a retrospective study and low sample size. In conclusion, our study provides the first ‘real-world’ experience on the use of bivalirudin in AF patients on chronic warfarin treatment. The rate of 30-day major bleeding and MACCE were lower compared to heparin plus GPI use also in this high risk patient subset suggesting that bivalirudin might be an option when additional antithrombotic treatment is needed during PCI.
Conflict of Interest Statement None declared.
696
Letter to the Editors-in-Chief
Table 1 Baseline clinical and procedural characteristics and 30-day clinical outcome of the two groups. Variable
Bivalirudin group (N = 51)
Heparin + GPI group (N = 87)
p value
Male gender Age, (years) CHADS2 score Pre-PCI International Normalized Ratio Diabetes mellitus Hypertension Previous stroke Previous MI Previous PCI Indication for PCI Stable angina pectoris Unstable angina pectoris Non-ST-elevation MI ST-elevation MI Patients with drug eluting stents Stent diameter (mm) Total stent length (mm) Balloon angioplasty Procedural success Femoral sheath Length of hospital stay (d) Medication at discharge/at event Warfarin + aspirin + clopidogrel Aspirin + clopidogrel Warfarin + clopidogrel MACCE All-cause death MI TVR Definite/probable ST Stroke TIMI major bleeding Access site complications
33 (64.7) 74.0 [13.0] 2.0 [2.0] 1.8 [1.0]
59 (67.8) 74.0 [13.0] 1.0 [2.0] 2.1 [1.0]
0.71 0.64 0.27 0.62
9 (17.6) 35 (68.6) 9 (17.6) 14 (27.5) 8 (15.7)
21 (24.1) 66 (75.9) 9 (10.3) 24 (27.6) 12 (13.8)
0.40 0.43 0.30 1.0 0.81
24 (47.1) 5 (9.8) 11 (21.6) 8 (15.7) 14 (27.5)
13 (14.9) 15 (17.2) 23 (26.4) 36 (41.4) 17 (20.7)
b0.001 0.32 0.55 0.002 0.40
3.5 [0.5] 17.0 [11] 3 (5.9) 51 (100) 43 (84.3) 1 [5]
3.0 [0.5] 16.0 [6.0] 0 82 (94.3) 73 (83.9) 4 [7]
0.10 0.86 0.16 0.16 1.0 b0.001
38 (74.5)
59 (67.8)
0.45
9 (17.6) 3 (5.9) 2 (3.9) 1 (2) 1 (2) 0 1 (2) 1 (2) 0 6 (11.8)
17 (19.5) 7 (8.0) 16 (18.4) 9 (10.3) 3 (3.4) 5 (5.7) 0 0 8 (9.2) 13 (14.9)
0.83 0.75 0.02 0.09 1.0 0.16 0.37 0.37 0.03 0.80
Data are presented as median [IQR] or count (%) where appropriate.
[5] Lahtela H, Karjalainen PP, Niemelä M, et al. Are glycoprotein inhibitors safe during percutaneous coronary intervention in patients on chronic warfarin treatment? Thromb Haemost 2009;102(6):1227–33. [6] Kiviniemi T, Karjalainen P, Pietilä M, et al. Comparison of additional versus no additional heparin during therapeutic oral anticoagulation in patients undergoing percutaneous coronary intervention. Am J Cardiol 2012;110(1):30–5. [7] Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) trial— Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11(1):1–11. [8] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation 2007;115(17):2344–51. [9] Subherwal S, Peterson ED, Chen AY, et al. Admission international normalized ratio levels, early treatment strategies, and major bleeding risk among Non–ST-Segment– Elevation myocardial infarction patients on home warfarin therapy / clinical perspective. Circulation 2012;125(11):1414–23. [10] Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic Therapy*American college of chest physicians evidence-based clinical practice guidelines. Chest, 133(6_suppl); 2008 299S–339S. [11] Airaksinen K, Schlitt A, Rubboli A, Karjalainen P, Lip GY. How to manage antithrombotic treatment during percutaneous coronary interventions in patients receiving long-term oral anticoagulation: To "bridge" or not to "bridge"? EuroIntervention 2011;6(4):520–6.
Tuomas Kiviniemi Heart Center, Turku University Hospital and University of Turku, Finland Corresponding author at: Heart Center, Turku University Hospital and University of Turku, Hämeentie 11, FIN-20520, Turku, Finland. Tel.: +358 2 3130787; fax: +358 2 3132030. E-mail address: tuoski@utu.fi. Pasi Karjalainen Heart Center, Satakunta Central Hospital, Finland Matti Niemelä Division of Cardiology, Department of Medicine, Oulu University Hospital, Finland Andrea Rubboli Division of Cardiology, Laboratory of Interventional Cardiology, Ospedale Maggiore, Bologna, Italy Gregory Y.H. Lip University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom
References [1] Lip GYH, Huber K, Andreotti F, et al. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: Executive summary—a consensus document of the european society of cardiology working group on thrombosis, endorsed by the european heart rhythm association (EHRA) and the european association of percutaneous cardiovascular interventions (EAPCI). Eur Heart J 2010;31(11):1311–8. [2] Kastrati A, Neumann F, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359(7):688–96. [3] Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358(21):2218–30. [4] Karjalainen PP, Vikman S, Niemelä M, et al. Safety of percutaneous coronary intervention during uninterrupted oral anticoagulant treatment. Eur Heart J 2008;29(8):1001–10.
Axel Schlitt Department of Medicine III, Martin Luther University Halle-Wittenberg, Germany Wail Nammas Heart Center, Turku University Hospital and University of Turku, Finland K.E. Juhani Airaksinen Heart Center, Turku University Hospital and University of Turku, Finland 23 December 2013