European Heart Journal Advance Access published January 6, 2014 European Heart Journal doi:10.1093/eurheartj/eht557
CLINICAL RESEARCH Thrombosis and antithrombotic therapy
Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry Jan Beyer-Westendorf1*, Vera Gelbricht 1, Kati Fo¨rster 1, Franziska Ebertz 1, Christina Ko¨hler1, Sebastian Werth 1, Eberhard Kuhlisch2, Thoralf Stange 2, Christoph Thieme 1, Katharina Daschkow1, and Norbert Weiss 1 1
Center for Vascular Medicine and Department of Medicine III, Division of Angiology, University Hospital ‘Carl Gustav Carus’ Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; and Institute for Medical Informatics and Biometry, Technical University Dresden, Dresden, Germany
2
Received 14 July 2013; revised 31 October 2013; accepted 4 December 2013
Aims
Patients receiving novel oral anticoagulants (NOACs) frequently undergo interventional procedures. Short half-lives and rapid onset of action allow for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach are lacking. We evaluated the peri-interventional NOAC management in unselected patients from daily care. ..................................................................................................................................................................................... Methods Effectiveness and safety data were collected from an ongoing, prospective, non-interventional registry of .2100 NOAC and results patients. Outcome events were adjudicated using standard event definitions. Of 2179 registered patients, 595 (27.3%) underwent 863 procedures (15.6% minimal, 74.3% minor, and 10.1% major procedures). Until Day 30 + 5 postprocedure, major cardiovascular events occurred in 1.0% of patients [95% confidence interval (95% CI) 0.5 –2.0] and major bleeding complications in 1.2% (95% CI 0.6 –2.1). Cardiovascular and major bleeding complications were highest after major procedures (4.6 and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events, but led to significantly higher rates of major bleeding complications (2.7%; 95% CI 1.1– 5.5) compared with no bridging (0.5%; 0.1 –1.4; P ¼ 0.010). Multivariate analysis demonstrated diabetes [odds ratio (OR) 13.2] and major procedures (OR 7.3) as independent risk factors for cardiovascular events. Major procedures (OR 16.8) were an independent risk factor for major bleeding complications. However, if major and non-major procedures were separately assessed, heparin bridging was not an independent risk factor for major bleeding. ..................................................................................................................................................................................... Conclusion Continuation or short-term interruption of NOAC is safe strategies for most invasive procedures. Patients at cardiovascular risk undergoing major procedures may benefit from heparin bridging, but bleeding risks need to be considered.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Oral anticoagulants † Apixaban † Dabigatran † Rivaroxaban † Bridging † Invasive procedures
Introduction For more than five decades, vitamin-K antagonists (VKAs) were the standard in the long-term anticoagulation for stroke prevention in atrial fibrillation (SPAF), for the treatment of venous thromboembolism (VTE), and for other indications. Many VKA patients need to undergo surgical or interventional procedures,1 and most interventions require temporary interruption of VKA therapy. VKA therapy is usually discontinued 5–7 days before the procedure.2 After
re-initiation of VKA anticoagulation, the therapeutic international normalized ratio range will be achieved only after another 5–7 days. As a consequence, many patients receive bridging therapy with low-molecular-weight heparin (LMWH) during this time.2 – 4 However, a recent meta-analysis of bridging studies demonstrated that LMWH bridging, although effective in preventing thromboembolic complications, increases the risk of peri-procedural bleeding complications.3 Large prospective trials are investigating the risk:benefit ratio of bridging VKA patients to LMWH in more detail.4
* Corresponding author. Tel: +49 351 4583659, Fax: +49 531 4584359, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014 . For permissions please email: [email protected]
Page 2 of 9 Over the past 2 years, novel oral anticoagulants (NOACs) such as apixaban, dabigatran, and rivaroxaban have become approved for long-term oral anticoagulation and, consequently, there are more cardiovascular risk patients who are receiving these agents. Large Phase III trials in SPAF and VTE treatments compared different NOACs against VKAs and consistently demonstrated high efficacy and safety for the novel drugs.5 – 8 In a post hoc analysis of the periprocedural management of patients on either dabigatran or warfarin in the open-label RE-LY trial, patients on dabigatran had similar rates of cardiovascular or major bleeding events as for those on warfarin.9 However, the authors found that pre-procedural interruption of anticoagulation was significantly shorter for dabigatran (49 h) than for warfarin (114 h), and that the use of heparin bridging was less frequent (16% of dabigatran patients vs. 28% of warfarin patients). These observations reflect the specific pharmacological profile of all NOACs. Short half-lives reduce the interval of pre-procedural interruption down to 1 or 2 days, and a fast onset of action achieves rapid restitution of anticoagulant activity after the procedure. Therefore, for NOAC patients undergoing invasive procedures, anticoagulant-free time intervals are expected to be shorter than for patients on VKAs. Expert opinions thus recommend against heparin bridging therapy for NOAC patients undergoing procedures.10 – 12 However, these recommendations currently lack scientific evidence. Therefore, data on the management and safety of surgical or interventional procedures in the daily care of unselected NOAC patients are scarce and urgently needed.4 Using data from a large, regional, prospective NOAC registry, we evaluated the management and safety of peri-interventional NOAC use in a large cohort of patients from daily care.
Methods Patients The Dresden NOAC registry (NCT01588119) is a large prospective registry in the administrative district of Dresden (Saxony), Germany. In this ongoing project, a network of .230 physicians from private practices and hospitals enrol NOAC patients, who are prospectively followed up by the central registry office. Patients are eligible if the following inclusion criteria are met: † Planned NOAC anticoagulation for at least 3 months. † Therapeutic NOAC indication including SPAF, deep vein thrombosis (DVT), pulmonary embolism (PE), and other indications. † Age .18 years. † Written informed consent. † Availability for follow-up by telephone visits. No exclusion criteria apply. Patients are followed up by telephone visits at 30 days after enrolment and quarterly thereafter to collect data on the effectiveness, safety, and management of NOAC therapy in daily care. For all patients with a reported surgical or interventional procedure during follow-up, contact to the family physician, interventionalist, or surgeon was established. Reports, hospital charts, laboratory test results, death certificates, and any other documentation relating to the invasive procedure were collected as applicable.
Surgical or interventional procedures Based on the bleeding risk categories provided in the chapter ‘Perioperative Management of Antithrombotic Therapy’ of the 9th ACCP consensus
J. Beyer-Westendorf et al.
document1 and the ‘European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants’,12 we defined three categories of procedures (minimal, minor, and major procedures), according to the severity of tissue trauma and the risk of peri-procedural bleeding. Minimal procedures were procedures with little tissue trauma, such as: † Superficial skin and oral mucosal surgery, including skin biopsies. † Wound revisions. † Non-extraction dental treatment. Minor procedures were procedures with little tissue trauma, but relevant bleeding risk, such as: † † † † † † † † †
Transluminal cardiac, arterial, and venous interventions. Pacemaker-related surgery. Pleura and ascites puncture. Cataract surgery. Arthroscopy, endoscopy, laparoscopy. Organ biopsies. Dental extraction. Hernia repair. Intramuscular and paravertebral injections.
Major procedures were procedures with relevant tissue trauma and high bleeding risk, such as: † † † †
Open pelvic, abdominal and thoracic surgery. Brain surgery. Major orthopaedic and trauma surgery. Vascular surgery.
Data collection Among other variables, the following data were collected: † Type, day, and time of last intake of NOAC before procedure. † Type, date, and outcome of procedure. † Peri-procedural type of anticoagulation and dosage (in the case of heparin bridging). † Exact day and time of NOAC restart (in the case of NOAC interruption). † Rates, severity, and management of major cardiovascular events and peri-procedural bleeding complications until Day 30 + 5.
Outcome parameters Rates of outcome events were evaluated until Day 30 + 5 after procedure. Repeated interventions in the same patient were separately evaluated. Statistical analyses were performed for all procedures and also for subtypes of minimal, minor, or major procedures. The primary effectiveness outcome was a composite endpoint of fatal or non-fatal major cardiovascular events consisting of centrally adjudicated: † Acute coronary syndrome, including unstable angina, non-STelevation infarction, and ST-elevation infarction. † Stroke or transient ischaemic attack or systemic embolism. † DVT or PE. Secondary effectiveness outcomes were non-major cardiovascular events and death from cardiovascular disease. The primary safety outcome was the rate of major bleeding using the International Society of Thrombosis and Haemostasis (ISTH) definition.13 The outcome of major bleeding was defined as overt bleeding with any of the following: † Documented transfusion of at least two units of red blood cells. † Drop in haemoglobin .2 g/L.
Page 3 of 9
Bold indicates statistical significance (P , 0.05). SPAF, stroke prevention in atrial fibrillation; VTE, venous thromboembolism; NOAC, novel oral anticoagulants; BMI, body mass index; SD, standard deviation; IQR, inter-quartile range; GFR, glomerular filtration rate. a Impaired renal function was defined as current or history of GFR of ,50 mL/min.
0.810
0.632 .0.999
0.770 2 (2)
10 (11.5) 100 (15.6)
2 (1) 2 (2)
Impaired renal functiona, n (%)
15 (11.1)
2 (1)
125 (14.5)
HAS-BLED score, median (IQR)
0.962 0.028
.0.999 .0.999
0.696 0.026 16 (18.4) 9 (10.3)
12 (13.8) 89 (13.9)
139 (21.7) 25 (3.9) 187 (21.7) 37 (4.3) Malignant disease, n (%) Concomitant antiplatelet therapy, n (%)
18 (13.3) 119 (13.8) Prior stroke or systemic embolism, n (%)
32 (23.7) 3 (2.2)
0.532 0.036
.0.999
0.424 .0.999
.0.999
CLINICAL RESEARCH Thrombosis and antithrombotic therapy
Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry Jan Beyer-Westendorf1*, Vera Gelbricht 1, Kati Fo¨rster 1, Franziska Ebertz 1, Christina Ko¨hler1, Sebastian Werth 1, Eberhard Kuhlisch2, Thoralf Stange 2, Christoph Thieme 1, Katharina Daschkow1, and Norbert Weiss 1 1
Center for Vascular Medicine and Department of Medicine III, Division of Angiology, University Hospital ‘Carl Gustav Carus’ Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; and Institute for Medical Informatics and Biometry, Technical University Dresden, Dresden, Germany
2
Received 14 July 2013; revised 31 October 2013; accepted 4 December 2013
Aims
Patients receiving novel oral anticoagulants (NOACs) frequently undergo interventional procedures. Short half-lives and rapid onset of action allow for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach are lacking. We evaluated the peri-interventional NOAC management in unselected patients from daily care. ..................................................................................................................................................................................... Methods Effectiveness and safety data were collected from an ongoing, prospective, non-interventional registry of .2100 NOAC and results patients. Outcome events were adjudicated using standard event definitions. Of 2179 registered patients, 595 (27.3%) underwent 863 procedures (15.6% minimal, 74.3% minor, and 10.1% major procedures). Until Day 30 + 5 postprocedure, major cardiovascular events occurred in 1.0% of patients [95% confidence interval (95% CI) 0.5 –2.0] and major bleeding complications in 1.2% (95% CI 0.6 –2.1). Cardiovascular and major bleeding complications were highest after major procedures (4.6 and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events, but led to significantly higher rates of major bleeding complications (2.7%; 95% CI 1.1– 5.5) compared with no bridging (0.5%; 0.1 –1.4; P ¼ 0.010). Multivariate analysis demonstrated diabetes [odds ratio (OR) 13.2] and major procedures (OR 7.3) as independent risk factors for cardiovascular events. Major procedures (OR 16.8) were an independent risk factor for major bleeding complications. However, if major and non-major procedures were separately assessed, heparin bridging was not an independent risk factor for major bleeding. ..................................................................................................................................................................................... Conclusion Continuation or short-term interruption of NOAC is safe strategies for most invasive procedures. Patients at cardiovascular risk undergoing major procedures may benefit from heparin bridging, but bleeding risks need to be considered.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Oral anticoagulants † Apixaban † Dabigatran † Rivaroxaban † Bridging † Invasive procedures
Introduction For more than five decades, vitamin-K antagonists (VKAs) were the standard in the long-term anticoagulation for stroke prevention in atrial fibrillation (SPAF), for the treatment of venous thromboembolism (VTE), and for other indications. Many VKA patients need to undergo surgical or interventional procedures,1 and most interventions require temporary interruption of VKA therapy. VKA therapy is usually discontinued 5–7 days before the procedure.2 After
re-initiation of VKA anticoagulation, the therapeutic international normalized ratio range will be achieved only after another 5–7 days. As a consequence, many patients receive bridging therapy with low-molecular-weight heparin (LMWH) during this time.2 – 4 However, a recent meta-analysis of bridging studies demonstrated that LMWH bridging, although effective in preventing thromboembolic complications, increases the risk of peri-procedural bleeding complications.3 Large prospective trials are investigating the risk:benefit ratio of bridging VKA patients to LMWH in more detail.4
* Corresponding author. Tel: +49 351 4583659, Fax: +49 531 4584359, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014 . For permissions please email: [email protected]
Page 2 of 9 Over the past 2 years, novel oral anticoagulants (NOACs) such as apixaban, dabigatran, and rivaroxaban have become approved for long-term oral anticoagulation and, consequently, there are more cardiovascular risk patients who are receiving these agents. Large Phase III trials in SPAF and VTE treatments compared different NOACs against VKAs and consistently demonstrated high efficacy and safety for the novel drugs.5 – 8 In a post hoc analysis of the periprocedural management of patients on either dabigatran or warfarin in the open-label RE-LY trial, patients on dabigatran had similar rates of cardiovascular or major bleeding events as for those on warfarin.9 However, the authors found that pre-procedural interruption of anticoagulation was significantly shorter for dabigatran (49 h) than for warfarin (114 h), and that the use of heparin bridging was less frequent (16% of dabigatran patients vs. 28% of warfarin patients). These observations reflect the specific pharmacological profile of all NOACs. Short half-lives reduce the interval of pre-procedural interruption down to 1 or 2 days, and a fast onset of action achieves rapid restitution of anticoagulant activity after the procedure. Therefore, for NOAC patients undergoing invasive procedures, anticoagulant-free time intervals are expected to be shorter than for patients on VKAs. Expert opinions thus recommend against heparin bridging therapy for NOAC patients undergoing procedures.10 – 12 However, these recommendations currently lack scientific evidence. Therefore, data on the management and safety of surgical or interventional procedures in the daily care of unselected NOAC patients are scarce and urgently needed.4 Using data from a large, regional, prospective NOAC registry, we evaluated the management and safety of peri-interventional NOAC use in a large cohort of patients from daily care.
Methods Patients The Dresden NOAC registry (NCT01588119) is a large prospective registry in the administrative district of Dresden (Saxony), Germany. In this ongoing project, a network of .230 physicians from private practices and hospitals enrol NOAC patients, who are prospectively followed up by the central registry office. Patients are eligible if the following inclusion criteria are met: † Planned NOAC anticoagulation for at least 3 months. † Therapeutic NOAC indication including SPAF, deep vein thrombosis (DVT), pulmonary embolism (PE), and other indications. † Age .18 years. † Written informed consent. † Availability for follow-up by telephone visits. No exclusion criteria apply. Patients are followed up by telephone visits at 30 days after enrolment and quarterly thereafter to collect data on the effectiveness, safety, and management of NOAC therapy in daily care. For all patients with a reported surgical or interventional procedure during follow-up, contact to the family physician, interventionalist, or surgeon was established. Reports, hospital charts, laboratory test results, death certificates, and any other documentation relating to the invasive procedure were collected as applicable.
Surgical or interventional procedures Based on the bleeding risk categories provided in the chapter ‘Perioperative Management of Antithrombotic Therapy’ of the 9th ACCP consensus
J. Beyer-Westendorf et al.
document1 and the ‘European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants’,12 we defined three categories of procedures (minimal, minor, and major procedures), according to the severity of tissue trauma and the risk of peri-procedural bleeding. Minimal procedures were procedures with little tissue trauma, such as: † Superficial skin and oral mucosal surgery, including skin biopsies. † Wound revisions. † Non-extraction dental treatment. Minor procedures were procedures with little tissue trauma, but relevant bleeding risk, such as: † † † † † † † † †
Transluminal cardiac, arterial, and venous interventions. Pacemaker-related surgery. Pleura and ascites puncture. Cataract surgery. Arthroscopy, endoscopy, laparoscopy. Organ biopsies. Dental extraction. Hernia repair. Intramuscular and paravertebral injections.
Major procedures were procedures with relevant tissue trauma and high bleeding risk, such as: † † † †
Open pelvic, abdominal and thoracic surgery. Brain surgery. Major orthopaedic and trauma surgery. Vascular surgery.
Data collection Among other variables, the following data were collected: † Type, day, and time of last intake of NOAC before procedure. † Type, date, and outcome of procedure. † Peri-procedural type of anticoagulation and dosage (in the case of heparin bridging). † Exact day and time of NOAC restart (in the case of NOAC interruption). † Rates, severity, and management of major cardiovascular events and peri-procedural bleeding complications until Day 30 + 5.
Outcome parameters Rates of outcome events were evaluated until Day 30 + 5 after procedure. Repeated interventions in the same patient were separately evaluated. Statistical analyses were performed for all procedures and also for subtypes of minimal, minor, or major procedures. The primary effectiveness outcome was a composite endpoint of fatal or non-fatal major cardiovascular events consisting of centrally adjudicated: † Acute coronary syndrome, including unstable angina, non-STelevation infarction, and ST-elevation infarction. † Stroke or transient ischaemic attack or systemic embolism. † DVT or PE. Secondary effectiveness outcomes were non-major cardiovascular events and death from cardiovascular disease. The primary safety outcome was the rate of major bleeding using the International Society of Thrombosis and Haemostasis (ISTH) definition.13 The outcome of major bleeding was defined as overt bleeding with any of the following: † Documented transfusion of at least two units of red blood cells. † Drop in haemoglobin .2 g/L.
Page 3 of 9
Bold indicates statistical significance (P , 0.05). SPAF, stroke prevention in atrial fibrillation; VTE, venous thromboembolism; NOAC, novel oral anticoagulants; BMI, body mass index; SD, standard deviation; IQR, inter-quartile range; GFR, glomerular filtration rate. a Impaired renal function was defined as current or history of GFR of ,50 mL/min.
0.810
0.632 .0.999
0.770 2 (2)
10 (11.5) 100 (15.6)
2 (1) 2 (2)
Impaired renal functiona, n (%)
15 (11.1)
2 (1)
125 (14.5)
HAS-BLED score, median (IQR)
0.962 0.028
.0.999 .0.999
0.696 0.026 16 (18.4) 9 (10.3)
12 (13.8) 89 (13.9)
139 (21.7) 25 (3.9) 187 (21.7) 37 (4.3) Malignant disease, n (%) Concomitant antiplatelet therapy, n (%)
18 (13.3) 119 (13.8) Prior stroke or systemic embolism, n (%)
32 (23.7) 3 (2.2)
0.532 0.036
.0.999
0.424 .0.999
.0.999
