- Email: [email protected]
Bridging anticoagulation therapy
CRVASA 614 1–7 cor et vasa xxx (2018) e1–e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.elsevier.com/locate/crvasa
Review article
Bridging anticoagulation therapy Štefan Volovár a,*, Radka Tancošová b, Richard Rokyta a a
Cardiology Department, University Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic b 1st Department of Internal Medicine, University Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
article info
abstract
Article history:
Oral anticoagulation therapy is used in patients with various diagnoses to reduce the risk of
Received 6 November 2017
thromboembolic events or to induce a hypocoagulation state to facilitate dissolution of a
Received in revised form
thrombus. In clinical practice we often encounter anticoagulated patients, many of whom
21 April 2018
have been diagnosed with nonvalvular atrial fibrillation. Each year a significant number of
Accepted 24 April 2018
these patients undergo a medical procedure, which, in some cases, requires temporary
Available online xxx
discontinuation of anticoagulation therapy. However without anticoagulation therapy, the
Keywords:
with fast onset and rapid cessation of action can be used to reduce risk while patients are
patient is at increased risk of thromboembolic events. Therefore, parenteral anticoagulants Bridging therapy
without adequate oral anticoagulation. Here we summarized the currently available data,
Periprocedural anticoagulation
which has been drawn from guidelines and other expert documents of European Society of
Thromboembolic risk
Cardiology (ESC), American College of Cardiology (ACC) and American College of Chest
Bleeding risk
Physicians (CHEST). The vast majority of available studies, including the only single randomized, double-blind, placebo-controlled BRIDGE trial, report an increased risk of major bleeding in patients on bridging therapy. A subanalysis of the RE-LY trial, also found that thromboembolic risk in patients with bridging therapy was significantly higher. The most detailed recommendation for use of bridging therapy in patients with nonvalvular atrial fibrillation was provided by the 2017 Expert Consensus of the ACC, while the ESC only marginally discusses bridging therapy in their expert documents. Bridging is not generally necessary in patients taking non-vitamin K oral anticoagulants (NOACs), but if clinical circumstances require it, the risks and benefits are the same as with vitamin K antagonist (VKA) anticoagulation. Data on the use of NOACs for bridging therapy are scarce. © 2018 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
* Corresponding author at: Cardiology Department, University Hospital in Pilsen, Alej Svobody 80, 30460 Pilsen, Czech Republic. E-mail address: [email protected] (Š. Volovár). https://doi.org/10.1016/j.crvasa.2018.04.002 0010-8650/© 2018 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e2
cor et vasa xxx (2018) e1–e7
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Thromboembolic events vs. bleeding. . . . . . Available data . . . . . . . . . . . . . . . . . . . . . . . . Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . Bridging therapy in patients anticoagulated Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . Ethical statement . . . . . . . . . . . . . . . . . . . . . Funding body . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
........... ........... ........... ........... with NOACs. ........... ........... ........... ........... ...........
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
Introduction Anticoagulation therapy significantly reduces the risk of systemic embolization in patients with atrial fibrillation and is currently an integral part of the treatment strategy in most patients with this diagnosis. Traditional anticoagulation in patients with atrial fibrillation used warfarin, since it was the only available vitamin K antagonist (VKA). In recent years, we have seen the emergence of a new group of anticoagulants called non-vitamin K oral anticoagulants (NOACs). Despite the clear benefits of this drug group, VKA are still widely used. Data from the GARFIELD-AF registry, which includes data from patients with atrial fibrillation from 35 countries, including the Czech Republic, shows that prescriptions of NOACs are growing steadily. In a cohort from 2010 to 2011, only 4.2% of patients were on NOACs, while 53.2% of patients were on VKAs. In a cohort of patients from 2014 to 2015, 37.0% of patients were taking NOACs and 34.0% were taking VKAs [1]. Based on practice, however, it can be assumed that in the Czech Republic the proportional representation of VKA to NOACs is higher. VKAs act as inhibitors of the enzyme epoxide reductase, which catalyses formation of the reduced form of vitamin K, which is needed as a cofactor for g-carboxylation of coagulation factors II, VII, IX, and X, which determines their efficacy. This mechanism of action results in a gradual onset of VKA anticoagulation, as well as slow cessation of anticoagulation. The slow cessation is caused by the persistence of preformed gamma-carboxylated coagulation factors in the blood that built up during VKA therapy, which leads to throttled increased in the formation of gamma-carboxylated coagulation factors II, VII, IX, and X by liver after VKA discontinuation [2]. In practice, we encounter situations where we have to consider interruption of VKA anticoagulation. These are mostly surgical situations or other invasive procedures, where full anticoagulation would burden the patient with a significant risk of bleeding. However, when the INR (International Normalized Ratio) falls below the therapeutic range, the patient is at increased risk of thromboembolic events. To reduce this risk, it is common practice to administer anticoagulants with a fast onset and rapid cessation of action. Currently low weight molecular heparin (LWMH) or unfractionated heparin (UFH) is used to bridge the period when the
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
000 000 000 000 000 000 000 000 000 000
INR is in the subtherapeutic range. This procedure is called bridging anticoagulation therapy. In the periprocedural period, physicians must address 3 issues regarding anticoagulation: Is interruption of anticoagulation therapy necessary with respect to characteristics of the patient and procedure? If so, when should oral anticoagulation be stopped? Choice of an anticoagulant with rapid onset and cessation of action for use as a bridging therapy. When should oral anticoagulation be reinitiated? In the present article, we summarize currently available data as well as the expert opinions on bridging therapy, which, despite its widespread use in clinical practice, is controversial. Interruption and reinitiation of anticoagulation in the periprocedural period is not the main focus of this article and if readers are interested in further information, we refer them to the documents of the respective professional societies.
Thromboembolic events vs. bleeding The essence of bridging anticoagulation therapy is to minimize the risk of thromboembolic events in the periprocedural period while maintaining the lowest risk of bleeding events. To properly select patients who will benefit from bridging therapy, we need to estimate the risk of thromboembolic and bleeding events as accurately as possible. Several scoring systems have been developed to predict the risk of thromboembolic events in patients with nonvalvular atrial fibrillation. The CHADS2 score, which has good predictive value, was developed in 2001 using a combination of the AFI and SPAF scoring systems [3]. In subsequent observations, 1.4% of patients who were classified as low-risk patients (CHADS2 0–1), according to the CHADS2 score, had a thromboembolic event within 1 year. Therefore, an effort was made to create a scoring system with even better predictive value. This effort culminated in 2009 with the Birmingham 2009 scoring system. This system is now better known by the CHA2DS2VASc acronym [4]. Several observational registries and studies correlated CHA2DS2-VASc score with the incidence of ischemic stroke (IS) or thromboembolic events in general. The most extensive work of this kind was the Swedish Atrial Fibrillation cohort study. It was a prospective study with a sample of 90,490 patients who never used anticoagulant therapy, Table 1
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e3
cor et vasa xxx (2018) e1–e7
[5]. Results from similar studies and registries allow us to estimate the annual risk of thromboembolic events or IS based on clinical scoring systems. Extrapolation of the annual risk of thromboembolic events calculated by scoring systems, such as CHA2DS2-VASc, to the short periprocedural period during which warfarin anticoagulation is interrupted appears to have attractive implications, but has not yet been validated. However, we do not have a better predictive tool than the scoring systems mentioned above, of which CHA2DS2-VASc appears to be the most valid, in terms of quantifying risk of thromboembolic events during the periprocedural period [6]. Several scoring systems have been designed to predict the risk of bleeding events. One of the most commonly used is the HASBLED score. This scoring system was created in 2010 to determine the 1-year risk of major bleeding in patients with atrial fibrillation. HAS-BLED was then compared to other scoring systems. The work of Lip et al. demonstrated that HAS-BLED had a higher predictive value for major bleeding than the HEMORR2HAGES scoring system and the systems developed by Shireman et al., Kuijer et al., and Beyth et al. [7,8]. In 2013, the ABC scoring system was created to predict the risk of bleeding, and has demonstrated a greater predictive value than HAS-BLED or ORBIT. However, to calculate the ABC score we need to estimate growth differentiation factor 15 (GDF-15), which is not routinely available, thus making this system, at least in common clinical practice, almost unusable [9]. Although the HAS-BLED score is not the best in terms of predicting the risk of bleeding over longer periods of time, it is exceedingly practical and, unlike the ABC score, was validated in the BORDER registry for prediction of bleeding risks during periprocedural periods in patients bridged by LWMH or UFH. HAS-BLED ≥3 was an independent predictive marker of bleeding in this registry [10]. When using scoring systems, it is important to note that some parameters are the same for the prediction of thromboembolic as well as bleeding risks (such as older age, arterial hypertension, or stroke history); patients with greater risk of thromboembolic events also usually have a greater risk of bleeding.
Available data Although in clinical practice we often need to temporarily discontinue VKA and consider bridging anticoagulation
therapy, the amount of data available is relatively small and limited to observational studies or prospective studies with single arms and small numbers of patients. One of the most cited recent works on bridging therapy is the BRIDGE study [11]. It was a randomized, double-blind, placebo-controlled study that compared the risk of bleeding and thromboembolic events in a group of 1884 patients, with nonvalvular atrial fibrillation, who were randomized to receive LWMH or placebo subcutaneously during temporary discontinuation of VKA anticoagulation prior to an invasive procedure. During the 30-day follow-up, the incidence of IS, transient ischemic attack (TIA) or systemic embolization, were 0.4% in the placebo arm and 0.3% in the LWMH arm. Thus, the non-inferiority of placebo, relative to LWMH in reducing the risk of thromboembolic events in the periprocedural period was demonstrated. However, bridging therapy with LWMH resulted in a significantly greater risk of major bleeding, which occurred in 1.3% of patients in the placebo arm and in 3.2% in the LWMH arm. The incidence of acute myocardial infarction, deep vein thrombosis, pulmonary embolism, or death from any cause was not significantly greater in the placebo arm. The incidence of minor bleeding was also significantly higher in patients in the LWMH arm. The BRIDGE study is, so far, the largest prospective, placebo-controlled study to investigate the efficacy and safety of heparin bridging therapy, but it did have some limitations. The mean CHADS2 score of the study population was 2.3, which corresponds to the mean value of the score in atrial fibrillation registries; less than 15% of patients had a CHADS2 score ≥4. The proportion of patients who discontinued anticoagulation due to a major or highbleeding-risk surgery/procedure was low. This group of patients accounted for only 10.6% of the total study population. The observed incidence of thromboembolic events was lower than expected in both arms, which reduced the statistical power of the study. Therefore, results of this study cannot be extrapolated to patients with higher CHADS2 scores or to patients undergoing surgery or procedures classified in this study as major or having a high-bleeding-risk, Table 2. Currently, the ongoing double-blind, randomized, placebocontrolled PERIOP 2 study (NCT number in ClinicalTrials.gov: NCT00432796), should provide an answer to the question whether bridging therapy is beneficial in patients with mechanical valve prosthesis, atrial fibrillation, or atrial flutter
Table 1 – Percentage risk of ischemic stroke, TIA and peripheral emboli per year after adjustment to acetylsalicylic acid treatment (modified by L. Friberg, M. Rosenqvist, G.Y.H. Lip, Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study, European Heart Journal 33 (2012) 1500–1510). CHA2DS2-VASc 0 1 2 3 4 5 6 7 8 9
Ischemic stroke
Stroke/TIA/peripheral emboli
0.2 0.6 2.5 3.7 5.5 8.4 11.4 13.1 12.6 14.4
0.3 1.0 3.3 5.3 7.8 11.7 15.9 18.4 17.9 20.3
TIA – transitory ischemic attack.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e4
cor et vasa xxx (2018) e1–e7
Table 2 – Classification of type of surgery or procedure in the BRIDGE study (modified from J.D. Douketis, A.C. Spyropoulos, S. Kaatz, et al., Perioperative bridging anticoagulation in patients with atrial fibrillation, The New England Journal of Medicine 373 (2015) 823–833). Minor or low-bleeding-risk surgery or procedure Gastrointestinal endoscopy (with/without biopsy) Cardiac catheterization (with/without percutaneous coronary intervention) Dental surgery or other dental procedure Dermatologic surgery or other dermatologic procedure Ophthalmologic procedure (including cataract removal) Other surgery or procedure that last <1 h Major or high-bleeding-risk surgery or procedure Intraabdominal surgery Intrathoracic surgery Major orthopedic surgery Surgical revascularization of peripheral arteries Urologic surgery Insertion of permanent pacemaker or implantable cardioverter defibrillator Major non-surgical procedure (e.g. biopsy of kidney or prostate) Other surgery or procedure that last ≥1 h
associated with high thromboembolic risk. Completion date of the study is estimated to be December 2017 [12]. Many other prospective studies with single arm and observational registries found a similar incidence of major bleeding as the BRIDGE study, ranging from 3.3 to 3.6% [13–15]. It should be noted that the definition of 'major bleeding' differed slightly from one study to another. In the multicenter, prospective, single-arm PROSPECT study, 260 patients were periprocedurally bridged with LWMH using a protocol very similar to the BRIDGE study. It found that the incidence of major bleeding was dramatically higher in patients who underwent major surgery. In this group of patients, major bleeding occurred in up to 20% compared to 0.5% in the group of patients who underwent minor surgery or invasive nonsurgical procedures with low bleeding risks. The overall incidence of major bleeding was 3.5% [13]. A subanalysis of the RE-LY trial found a greater risk of major bleeding in patients anticoagulated with VKA and bridged vs. non-bridged patients compared to most other studies (6.8% bridged vs. 1.6% non-bridged). Bridging therapy also surprisingly resulted in a significantly greater risk of thromboembolic events (1.8% vs. 0.3%, p = 0.007). The mean CHADS2 score was 2.1 and there were no significant differences in patient characteristics between the two arms [12,16]. Results of the BRIDGE trial were confirmed in common clinical practice conditions by the ORBIT-AF observational registry, which included 2200 patients who had their anticoagulation therapy (dabigatran or VKA) temporarily discontinued. Of the 2200 patients, 24% had bridging therapy, mostly with LWMH. The incidence of major bleeding was significantly higher in patients on bridging therapy (3.6% vs. 1.2%, p = 0.0007) and after multivariate adjustment, there was a trend toward a higher incidence of cardiovascular events, which was, however, statistically insignificant (odds ratio 1.62, p = 0.07). The mean CHADS2 score was 2.39 [14]. Results of trials with bridging therapy were summarized in a metaanalysis of 34 studies with 12,278 patients who were
anticoagulated using VKA. The pooled incidence of thromboembolic events was slightly higher with bridging therapy (0.9% vs. 0.6%, odds ratio 0.30), while incidence of major bleeding was significantly higher in patients with bridging therapy (4.2% vs. 0.9%) [12,17].
Guidelines The European Society of Cardiology (ESC), in its guidelines and other expert documents, only briefly discusses the issue of bridging therapy. The 2016 Clinical Practice Guidelines for the Management of Atrial Fibrillation stated that if temporary interruption of oral anticoagulation is necessary, the use of bridging therapy does not have any benefits, except for patients with a mechanical valve prosthesis. This document is based only on results from the above-mentioned BRIDGE study [18]. The ESC Task Force on Thrombosis states in one of its position papers, that in patients with a mechanical valve prosthesis, it is recommended to use UFH for bridging after the INR falls below the therapeutic range. UFH administration should be discontinued 4–6 h prior to the procedure and should be restarted as soon as possible after the procedure [19]. The American College of Cardiology (ACC), in 2017, published the Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation, which also discussed, in detail, the issue of bridging therapy. In cases of temporary discontinuation of oral anticoagulation, the ACC recommends establishing the annual risk of thromboembolic events based on the CHA2DS2-VASc score. In patients with a low risk of thromboembolic events (<5% per year, CHA2DS2-VASc ≤4, and without a history of ischemic stroke, TIA, or systemic embolism) bridging therapy was not recommended. In patients with a moderate risk (5–10% per year, CHA2DS2-VASc 5–6, or with a history of ischemic stroke, TIA, or systemic embolism in the past 3 or more months) it was recommended that the risk of bleeding should be established. If there was an increased risk of bleeding, bridging therapy was not recommended. In patients without an increased risk of bleeding, it is recommended that clinical judgment be followed, however, in patients with a history of ischemic stroke, TIA, or systemic embolism it is recommended rather to bridge and in other patients it is recommended rather not to bridge. Finally, in patients with high risk of thromboembolic events (>10% per year, CHA2DS2-VASc 7–9, or with history of ischemic stroke, TIA, or systemic embolism within 3 months), the ACC recommends bridging therapy, Fig. 1. Parenteral anticoagulants should be given after the INR falls below therapeutic levels, but more than 24 h after the first omitted dose of VKA. When using UFH, the ACC recommends termination 4–6 h prior to the procedure and if LWMH is used it recommends termination at least 24 h prior to the procedure [6]. Guidelines for perioperative management of antithrombotic therapy, which discusses the issue of bridging therapy, were also published by the American College of Chest Physicians (CHEST) in 2012. Since then several important studies have been published [10,13,15,16]. The guidelines use CHADS2 scores. The CHEST algorithm for bridging therapy is presented in Fig. 2 [20].
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7 cor et vasa xxx (2018) e1–e7
e5
Fig. 1 – Algorithm for bridging therapy indication in patients with nonvalvular atrial fibrillation and need of temporary discontinuation of oral anticoagulation according to the American College of Cardiology 2017 Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation. TIA – transitory ischemic attack.
Fig. 2 – Algorithm for bridging therapy indication in patients with mechanical valve prosthesis or venous thromboembolism and need of temporary discontinuation of oral anticoagulation according to American College of Chest Physicians 2012 Guidelines for Perioperative Management of the Antithrombotic Therapy (modified from J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, et al., Perioperative management of antithrombotic therapy, Chest 141 (2012) 326–350). VTE – venous thromboembolism; TIA – transitory ischemic attack. *Risk factors: atrial fibrillation, history of ischemic stroke or TIA, arterial hypertension, diabetes mellitus, congestive heart failure, age ≥75 years. **High risk patients also include those with history of ischemic event in periprocedural period and temporary interruption of VKA anticoagulation or those undergoing certain types of surgery associated with an increased risk of ischemic events.
Bridging therapy in patients anticoagulated with NOACs Because of the short biological half-life, rapid onset, and rapid cessation of action, bridging anticoagulation therapy in NOACs
patients is not usually necessary, even in cases with a high risk of thromboembolic events. However, in clinical practice there may be situations where an interruption of NOACs is necessary and after the procedure there can sometimes be delays in readministering the NOAC. This may occur if another invasive procedure is needed during the short postprocedural
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e6
cor et vasa xxx (2018) e1–e7
period, or in cases where there is an intolerance to oral medication or an inability to administer drugs per os. In such cases, bridging with LWMH or UFH may be considered in patients with a high risk of thromboembolic events [6]. According to the European Heart Rhythm Association Practical Guide for the use of NOACs in Patients with Non-valvular Atrial Fibrillation, it is appropriate to initiate treatment with LWMH using a prophylactic or intermediate dose 6–8 h after an invasive procedure that involves patient immobilization, while full anticoagulation with NOAC can be postponed 48– 72 h after the invasive procedure [21]. Currently available data show that bridging therapy in patients anticoagulated with NOAC is associated with the same risks and benefits as in patients anticoagulated with VKA. In the prospective Dresden NOAC registry, 595 patients anticoagulated with NOAC underwent a total of 863 procedures. In 78.3% anticoagulation was temporarily discontinued and in 30% of those, bridging anticoagulation therapy was initiated. Approximately three-quarters of patients received rivaroxaban, the remaining received mainly dabigatran. Apixaban was used only in 0.5% of patients. The use of bridging therapy was associated with an insignificantly higher incidence of thromboembolic events (acute coronary syndrome, IS, TIA, systemic embolization, deep vein thrombosis, and pulmonary embolism) and with a significantly higher risk of major bleeding (2.7% vs. 0.5%, p = 0.01), which was caused predominantly by a greater risk of bleeding after major surgery. The risk of minor bleeding was the same in both groups [22]. A subanalysis of the RE-LY study, which focused on bridging anticoagulation therapy, found that bridging therapy was more commonly used in patients anticoagulated with VKA than with dabigatran (27.5% vs. 15.4%, p < 0.001). In patients receiving dabigatran, bridging therapy was associated with a significantly higher risk of major bleeding compared to no bridging therapy (6.5% vs. 1.8%, p < 0.001), and with an insignificantly lower risk of thromboembolic events (1.2% vs. 0.6%, p = 0.16), and systemic embolization (0.5% vs. 0.3%, p = 0.46) [16]. Similarly, in the subanalysis of the ROCKET-AF study, bridging therapy was associated with a greater risk of bleeding and a comparable risk of thromboembolic events; however, only 6% of patients with temporarily discontinued anticoagulation (warfarin or rivaroxaban) had bridging therapy initiated with heparin [23,24]. Shivakumara et al. suggested that use of dabigatran, instead of heparin, as a bridging agent be examined. However, the study was prematurely terminated in January 2017 for a lack of enrolled patients. Similar studies are still lacking, and no professional societies recommend using NOACs as bridging agents [12].
tional studies and small prospective studies without placebo control. Currently, the BRIDGE study is the only large prospective, multicenter, double-blind, and placebo-controlled study. It included only patients anticoagulated with VKA for nonvalvular atrial fibrillation. The study found that bridging therapy was associated with a significantly greater risk of major bleeding. However, the thromboembolic risk was not significantly affected. Although the study had some limitations, several other studies with different designs came to similar conclusions. Based on BRIDGE study, the ESC does not recommend bridging therapy in patients with nonvalvular atrial fibrillation [18]. The ACC, in its expert consensus, stratifies patients based on their CHA2DS2-VASc score and recommends bridging only in patients with a high risk of thromboembolic events [6]. No randomized, double-blind, and placebo-controlled study is currently available to examine the use of bridging therapy in patients with mechanical valve prosthesis or high thromboembolic risk, who were underrepresented in the BRIDGE trial. However, the ongoing PERIOP 2 study should provide an answer to the question of whether bridging anticoagulation therapy in this group of patients would be beneficial. There is still a lack of data on the use of bridging therapy in patients anticoagulated for deep venous thrombosis, pulmonary embolism, or for other indications. Bridging therapy in patients anticoagulated with NOACs is in most cases unjustified except in specific clinical situations. Data from subanalyses of the RE-LY and ROCKET-AF studies and from the prospective Dresden NOAC registry show that use of bridging therapy is associated with the same outcomes as in patients anticoagulated with warfarin. Data on the use of NOACs instead of heparin as a bridging agent are scarce and no studies examining this problem have been completed.
Conflict of interest None declared.
Ethical statement Authors state that the research was conducted according to ethical standards.
Funding body This research was supported by MH CZ-DRO (Faculty Hospital in Pilsen – FNPl, 00669806) and by the Charles University Research Program Q38.
references
Conclusion Use of bridging anticoagulation therapy after temporary discontinuation of anticoagulation should optimally reduce periprocedural risk of thromboembolic events while avoiding a significantly increased risk of bleeding complications. The amount of data from evaluations of bridging anticoagulation therapy is relatively small and limited primarily to observa-
[1] A.J. Camm, G. Accetta, G. Ambrosio, et al., Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation, Heart (2016) 1–8. [2] J. Kvasnička, J. Hájková, P. Bobčíková, et al., Prevalence polymorfismů CYP2C9 a VKORC1 v České republice a zamyšlení nad výhledy antikoagulační léčby warfarinem, Cor et Vasa 53 (2011) 522–526.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7 cor et vasa xxx (2018) e1–e7
[3] B.F. Cage, A.D. Waterman, W. Shannon, et al., Validation of clinical classification schemes for predicting stroke, The Journal of the American Medical Association 285 (2001) 2864–2870. [4] G.Y.H. Lip, R. Nieuwlaat, R. Pisters, et al., Refining clinical risk stratification for predicting stroke and thormboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation, Chest 137 (2010) 263–272. [5] L. Friberg, M. Rosenqvist, G.Y.H. Lip, Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study, European Heart Journal 33 (2012) 1500–1510. [6] J.U. Doherty, T.J. Gluckman, W.J. Hucker, 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation, Journal of the American College of Cardiology 69 (2017) 871–898. [7] R. Pisters, D.A. Lane, R. Nieuwlaat, et al., A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest 138 (2010) 1093–1100. [8] G.Y. Lip, L. Frison, J.L. Halperin, D.A. Lane, Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation, Journal of the American College of Cardiology 57 (2011) 173–180. [9] Z. Hijazi, J. Oldgren, J. Lindbäck, et al., The novel biomarkerbased ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study, Lancet 387 (2016) 2302–2311. [10] H. Omran, R. Bauersachs, S. Rübenacker, et al., The HASBLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK Online bRiDging REgistRy (BORDER), Thrombosis and Haemostasis 108 (2012) 65–73. [11] J.D. Douketis, A.C. Spyropoulos, S. Kaatz, et al., Perioperative bridging anticoagulation in patients with atrial fibrillation, The New England Journal of Medicine 373 (2015) 823–833. [12] C.L. Garwood, B. Korkis, D. Grande, et al., Anticoagulation bridge therapy in patients with atrial fibrillation: recent updates providing a rebalance of risk and benefit, Pharmacotherapy 37 (2017) 712–724. [13] A.S. Dunn, A.C. Spyropoulos, A.G.G. Turpie, Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT), Journal of Thrombosis and Haemostasis 5 (2007) 2211–2218. [14] B.A. Steinberg, E.D. Peterson, S. Kim, et al., Use and outcomes associated with bridging during anticoagulation
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
e7
interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), Circulation 131 (2015) 488– 494. A.C. Spyropoulos, A.G.G. Turpie, A.S. Dunn, et al., Clinical outcomes with unfractionated heparin or low-molecularweight heparin as bridging therapy in patients on longterm oral anticoagulants: the REGIMEN registry, Journal of Thrombosis and Haemostasis 4 (2006) 1246–1252. J.D. Douketis, J.S. Healey, M. Brueckmann, et al., Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial, Thrombosis and Haemostasis 113 (2015) 625–632. D. Siegal, J. Yudin, S. Kaatz, et al., Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates, Circulation 126 (2012) 1630–1639. P. Kirchhof, S. Benussi, S. Kotecha, et al., 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS, European Heart Journal 37 (2016) 2893–2962. R. De Caterina, S. Husted, L. Wallentin, et al., Parenteral anticoagulants in heart disease: current status and perspectives, Thrombosis and Haemostasis 109 (2013) 769–786. J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, et al., Perioperative management of antithrombotic therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical guidelines, Chest 141 (2012) e326–e350. R. Čihák, L. Haman, M. Táborský, European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Summary of the document prepared by the Czech Society of Cardiology, Cor et Vasa 56 (2014) e42–e56. J. Beyer-Westendorf, V. Gelbricht, K. Förster, et al., Periinterventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry, European Heart Journal 35 (2014) 1888–1896. M.W. Sherwood, J.D. Douketis, M.R. Patel, et al., Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from ROCKET AF, Circulation 129 (2014) 1850–1859. A.C. Spyropoulos, A. Al-Badri, M.W. Sherwood, J.D. Douketis, Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticogulant requiring an elective procedure or surgery, Journal of Thrombosis and Haemostasis 14 (2016) 875–885.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.elsevier.com/locate/crvasa
Review article
Bridging anticoagulation therapy Štefan Volovár a,*, Radka Tancošová b, Richard Rokyta a a
Cardiology Department, University Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic b 1st Department of Internal Medicine, University Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
article info
abstract
Article history:
Oral anticoagulation therapy is used in patients with various diagnoses to reduce the risk of
Received 6 November 2017
thromboembolic events or to induce a hypocoagulation state to facilitate dissolution of a
Received in revised form
thrombus. In clinical practice we often encounter anticoagulated patients, many of whom
21 April 2018
have been diagnosed with nonvalvular atrial fibrillation. Each year a significant number of
Accepted 24 April 2018
these patients undergo a medical procedure, which, in some cases, requires temporary
Available online xxx
discontinuation of anticoagulation therapy. However without anticoagulation therapy, the
Keywords:
with fast onset and rapid cessation of action can be used to reduce risk while patients are
patient is at increased risk of thromboembolic events. Therefore, parenteral anticoagulants Bridging therapy
without adequate oral anticoagulation. Here we summarized the currently available data,
Periprocedural anticoagulation
which has been drawn from guidelines and other expert documents of European Society of
Thromboembolic risk
Cardiology (ESC), American College of Cardiology (ACC) and American College of Chest
Bleeding risk
Physicians (CHEST). The vast majority of available studies, including the only single randomized, double-blind, placebo-controlled BRIDGE trial, report an increased risk of major bleeding in patients on bridging therapy. A subanalysis of the RE-LY trial, also found that thromboembolic risk in patients with bridging therapy was significantly higher. The most detailed recommendation for use of bridging therapy in patients with nonvalvular atrial fibrillation was provided by the 2017 Expert Consensus of the ACC, while the ESC only marginally discusses bridging therapy in their expert documents. Bridging is not generally necessary in patients taking non-vitamin K oral anticoagulants (NOACs), but if clinical circumstances require it, the risks and benefits are the same as with vitamin K antagonist (VKA) anticoagulation. Data on the use of NOACs for bridging therapy are scarce. © 2018 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
* Corresponding author at: Cardiology Department, University Hospital in Pilsen, Alej Svobody 80, 30460 Pilsen, Czech Republic. E-mail address: [email protected] (Š. Volovár). https://doi.org/10.1016/j.crvasa.2018.04.002 0010-8650/© 2018 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e2
cor et vasa xxx (2018) e1–e7
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Thromboembolic events vs. bleeding. . . . . . Available data . . . . . . . . . . . . . . . . . . . . . . . . Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . Bridging therapy in patients anticoagulated Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . Ethical statement . . . . . . . . . . . . . . . . . . . . . Funding body . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
........... ........... ........... ........... with NOACs. ........... ........... ........... ........... ...........
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
Introduction Anticoagulation therapy significantly reduces the risk of systemic embolization in patients with atrial fibrillation and is currently an integral part of the treatment strategy in most patients with this diagnosis. Traditional anticoagulation in patients with atrial fibrillation used warfarin, since it was the only available vitamin K antagonist (VKA). In recent years, we have seen the emergence of a new group of anticoagulants called non-vitamin K oral anticoagulants (NOACs). Despite the clear benefits of this drug group, VKA are still widely used. Data from the GARFIELD-AF registry, which includes data from patients with atrial fibrillation from 35 countries, including the Czech Republic, shows that prescriptions of NOACs are growing steadily. In a cohort from 2010 to 2011, only 4.2% of patients were on NOACs, while 53.2% of patients were on VKAs. In a cohort of patients from 2014 to 2015, 37.0% of patients were taking NOACs and 34.0% were taking VKAs [1]. Based on practice, however, it can be assumed that in the Czech Republic the proportional representation of VKA to NOACs is higher. VKAs act as inhibitors of the enzyme epoxide reductase, which catalyses formation of the reduced form of vitamin K, which is needed as a cofactor for g-carboxylation of coagulation factors II, VII, IX, and X, which determines their efficacy. This mechanism of action results in a gradual onset of VKA anticoagulation, as well as slow cessation of anticoagulation. The slow cessation is caused by the persistence of preformed gamma-carboxylated coagulation factors in the blood that built up during VKA therapy, which leads to throttled increased in the formation of gamma-carboxylated coagulation factors II, VII, IX, and X by liver after VKA discontinuation [2]. In practice, we encounter situations where we have to consider interruption of VKA anticoagulation. These are mostly surgical situations or other invasive procedures, where full anticoagulation would burden the patient with a significant risk of bleeding. However, when the INR (International Normalized Ratio) falls below the therapeutic range, the patient is at increased risk of thromboembolic events. To reduce this risk, it is common practice to administer anticoagulants with a fast onset and rapid cessation of action. Currently low weight molecular heparin (LWMH) or unfractionated heparin (UFH) is used to bridge the period when the
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
000 000 000 000 000 000 000 000 000 000
INR is in the subtherapeutic range. This procedure is called bridging anticoagulation therapy. In the periprocedural period, physicians must address 3 issues regarding anticoagulation: Is interruption of anticoagulation therapy necessary with respect to characteristics of the patient and procedure? If so, when should oral anticoagulation be stopped? Choice of an anticoagulant with rapid onset and cessation of action for use as a bridging therapy. When should oral anticoagulation be reinitiated? In the present article, we summarize currently available data as well as the expert opinions on bridging therapy, which, despite its widespread use in clinical practice, is controversial. Interruption and reinitiation of anticoagulation in the periprocedural period is not the main focus of this article and if readers are interested in further information, we refer them to the documents of the respective professional societies.
Thromboembolic events vs. bleeding The essence of bridging anticoagulation therapy is to minimize the risk of thromboembolic events in the periprocedural period while maintaining the lowest risk of bleeding events. To properly select patients who will benefit from bridging therapy, we need to estimate the risk of thromboembolic and bleeding events as accurately as possible. Several scoring systems have been developed to predict the risk of thromboembolic events in patients with nonvalvular atrial fibrillation. The CHADS2 score, which has good predictive value, was developed in 2001 using a combination of the AFI and SPAF scoring systems [3]. In subsequent observations, 1.4% of patients who were classified as low-risk patients (CHADS2 0–1), according to the CHADS2 score, had a thromboembolic event within 1 year. Therefore, an effort was made to create a scoring system with even better predictive value. This effort culminated in 2009 with the Birmingham 2009 scoring system. This system is now better known by the CHA2DS2VASc acronym [4]. Several observational registries and studies correlated CHA2DS2-VASc score with the incidence of ischemic stroke (IS) or thromboembolic events in general. The most extensive work of this kind was the Swedish Atrial Fibrillation cohort study. It was a prospective study with a sample of 90,490 patients who never used anticoagulant therapy, Table 1
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e3
cor et vasa xxx (2018) e1–e7
[5]. Results from similar studies and registries allow us to estimate the annual risk of thromboembolic events or IS based on clinical scoring systems. Extrapolation of the annual risk of thromboembolic events calculated by scoring systems, such as CHA2DS2-VASc, to the short periprocedural period during which warfarin anticoagulation is interrupted appears to have attractive implications, but has not yet been validated. However, we do not have a better predictive tool than the scoring systems mentioned above, of which CHA2DS2-VASc appears to be the most valid, in terms of quantifying risk of thromboembolic events during the periprocedural period [6]. Several scoring systems have been designed to predict the risk of bleeding events. One of the most commonly used is the HASBLED score. This scoring system was created in 2010 to determine the 1-year risk of major bleeding in patients with atrial fibrillation. HAS-BLED was then compared to other scoring systems. The work of Lip et al. demonstrated that HAS-BLED had a higher predictive value for major bleeding than the HEMORR2HAGES scoring system and the systems developed by Shireman et al., Kuijer et al., and Beyth et al. [7,8]. In 2013, the ABC scoring system was created to predict the risk of bleeding, and has demonstrated a greater predictive value than HAS-BLED or ORBIT. However, to calculate the ABC score we need to estimate growth differentiation factor 15 (GDF-15), which is not routinely available, thus making this system, at least in common clinical practice, almost unusable [9]. Although the HAS-BLED score is not the best in terms of predicting the risk of bleeding over longer periods of time, it is exceedingly practical and, unlike the ABC score, was validated in the BORDER registry for prediction of bleeding risks during periprocedural periods in patients bridged by LWMH or UFH. HAS-BLED ≥3 was an independent predictive marker of bleeding in this registry [10]. When using scoring systems, it is important to note that some parameters are the same for the prediction of thromboembolic as well as bleeding risks (such as older age, arterial hypertension, or stroke history); patients with greater risk of thromboembolic events also usually have a greater risk of bleeding.
Available data Although in clinical practice we often need to temporarily discontinue VKA and consider bridging anticoagulation
therapy, the amount of data available is relatively small and limited to observational studies or prospective studies with single arms and small numbers of patients. One of the most cited recent works on bridging therapy is the BRIDGE study [11]. It was a randomized, double-blind, placebo-controlled study that compared the risk of bleeding and thromboembolic events in a group of 1884 patients, with nonvalvular atrial fibrillation, who were randomized to receive LWMH or placebo subcutaneously during temporary discontinuation of VKA anticoagulation prior to an invasive procedure. During the 30-day follow-up, the incidence of IS, transient ischemic attack (TIA) or systemic embolization, were 0.4% in the placebo arm and 0.3% in the LWMH arm. Thus, the non-inferiority of placebo, relative to LWMH in reducing the risk of thromboembolic events in the periprocedural period was demonstrated. However, bridging therapy with LWMH resulted in a significantly greater risk of major bleeding, which occurred in 1.3% of patients in the placebo arm and in 3.2% in the LWMH arm. The incidence of acute myocardial infarction, deep vein thrombosis, pulmonary embolism, or death from any cause was not significantly greater in the placebo arm. The incidence of minor bleeding was also significantly higher in patients in the LWMH arm. The BRIDGE study is, so far, the largest prospective, placebo-controlled study to investigate the efficacy and safety of heparin bridging therapy, but it did have some limitations. The mean CHADS2 score of the study population was 2.3, which corresponds to the mean value of the score in atrial fibrillation registries; less than 15% of patients had a CHADS2 score ≥4. The proportion of patients who discontinued anticoagulation due to a major or highbleeding-risk surgery/procedure was low. This group of patients accounted for only 10.6% of the total study population. The observed incidence of thromboembolic events was lower than expected in both arms, which reduced the statistical power of the study. Therefore, results of this study cannot be extrapolated to patients with higher CHADS2 scores or to patients undergoing surgery or procedures classified in this study as major or having a high-bleeding-risk, Table 2. Currently, the ongoing double-blind, randomized, placebocontrolled PERIOP 2 study (NCT number in ClinicalTrials.gov: NCT00432796), should provide an answer to the question whether bridging therapy is beneficial in patients with mechanical valve prosthesis, atrial fibrillation, or atrial flutter
Table 1 – Percentage risk of ischemic stroke, TIA and peripheral emboli per year after adjustment to acetylsalicylic acid treatment (modified by L. Friberg, M. Rosenqvist, G.Y.H. Lip, Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study, European Heart Journal 33 (2012) 1500–1510). CHA2DS2-VASc 0 1 2 3 4 5 6 7 8 9
Ischemic stroke
Stroke/TIA/peripheral emboli
0.2 0.6 2.5 3.7 5.5 8.4 11.4 13.1 12.6 14.4
0.3 1.0 3.3 5.3 7.8 11.7 15.9 18.4 17.9 20.3
TIA – transitory ischemic attack.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e4
cor et vasa xxx (2018) e1–e7
Table 2 – Classification of type of surgery or procedure in the BRIDGE study (modified from J.D. Douketis, A.C. Spyropoulos, S. Kaatz, et al., Perioperative bridging anticoagulation in patients with atrial fibrillation, The New England Journal of Medicine 373 (2015) 823–833). Minor or low-bleeding-risk surgery or procedure Gastrointestinal endoscopy (with/without biopsy) Cardiac catheterization (with/without percutaneous coronary intervention) Dental surgery or other dental procedure Dermatologic surgery or other dermatologic procedure Ophthalmologic procedure (including cataract removal) Other surgery or procedure that last <1 h Major or high-bleeding-risk surgery or procedure Intraabdominal surgery Intrathoracic surgery Major orthopedic surgery Surgical revascularization of peripheral arteries Urologic surgery Insertion of permanent pacemaker or implantable cardioverter defibrillator Major non-surgical procedure (e.g. biopsy of kidney or prostate) Other surgery or procedure that last ≥1 h
associated with high thromboembolic risk. Completion date of the study is estimated to be December 2017 [12]. Many other prospective studies with single arm and observational registries found a similar incidence of major bleeding as the BRIDGE study, ranging from 3.3 to 3.6% [13–15]. It should be noted that the definition of 'major bleeding' differed slightly from one study to another. In the multicenter, prospective, single-arm PROSPECT study, 260 patients were periprocedurally bridged with LWMH using a protocol very similar to the BRIDGE study. It found that the incidence of major bleeding was dramatically higher in patients who underwent major surgery. In this group of patients, major bleeding occurred in up to 20% compared to 0.5% in the group of patients who underwent minor surgery or invasive nonsurgical procedures with low bleeding risks. The overall incidence of major bleeding was 3.5% [13]. A subanalysis of the RE-LY trial found a greater risk of major bleeding in patients anticoagulated with VKA and bridged vs. non-bridged patients compared to most other studies (6.8% bridged vs. 1.6% non-bridged). Bridging therapy also surprisingly resulted in a significantly greater risk of thromboembolic events (1.8% vs. 0.3%, p = 0.007). The mean CHADS2 score was 2.1 and there were no significant differences in patient characteristics between the two arms [12,16]. Results of the BRIDGE trial were confirmed in common clinical practice conditions by the ORBIT-AF observational registry, which included 2200 patients who had their anticoagulation therapy (dabigatran or VKA) temporarily discontinued. Of the 2200 patients, 24% had bridging therapy, mostly with LWMH. The incidence of major bleeding was significantly higher in patients on bridging therapy (3.6% vs. 1.2%, p = 0.0007) and after multivariate adjustment, there was a trend toward a higher incidence of cardiovascular events, which was, however, statistically insignificant (odds ratio 1.62, p = 0.07). The mean CHADS2 score was 2.39 [14]. Results of trials with bridging therapy were summarized in a metaanalysis of 34 studies with 12,278 patients who were
anticoagulated using VKA. The pooled incidence of thromboembolic events was slightly higher with bridging therapy (0.9% vs. 0.6%, odds ratio 0.30), while incidence of major bleeding was significantly higher in patients with bridging therapy (4.2% vs. 0.9%) [12,17].
Guidelines The European Society of Cardiology (ESC), in its guidelines and other expert documents, only briefly discusses the issue of bridging therapy. The 2016 Clinical Practice Guidelines for the Management of Atrial Fibrillation stated that if temporary interruption of oral anticoagulation is necessary, the use of bridging therapy does not have any benefits, except for patients with a mechanical valve prosthesis. This document is based only on results from the above-mentioned BRIDGE study [18]. The ESC Task Force on Thrombosis states in one of its position papers, that in patients with a mechanical valve prosthesis, it is recommended to use UFH for bridging after the INR falls below the therapeutic range. UFH administration should be discontinued 4–6 h prior to the procedure and should be restarted as soon as possible after the procedure [19]. The American College of Cardiology (ACC), in 2017, published the Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation, which also discussed, in detail, the issue of bridging therapy. In cases of temporary discontinuation of oral anticoagulation, the ACC recommends establishing the annual risk of thromboembolic events based on the CHA2DS2-VASc score. In patients with a low risk of thromboembolic events (<5% per year, CHA2DS2-VASc ≤4, and without a history of ischemic stroke, TIA, or systemic embolism) bridging therapy was not recommended. In patients with a moderate risk (5–10% per year, CHA2DS2-VASc 5–6, or with a history of ischemic stroke, TIA, or systemic embolism in the past 3 or more months) it was recommended that the risk of bleeding should be established. If there was an increased risk of bleeding, bridging therapy was not recommended. In patients without an increased risk of bleeding, it is recommended that clinical judgment be followed, however, in patients with a history of ischemic stroke, TIA, or systemic embolism it is recommended rather to bridge and in other patients it is recommended rather not to bridge. Finally, in patients with high risk of thromboembolic events (>10% per year, CHA2DS2-VASc 7–9, or with history of ischemic stroke, TIA, or systemic embolism within 3 months), the ACC recommends bridging therapy, Fig. 1. Parenteral anticoagulants should be given after the INR falls below therapeutic levels, but more than 24 h after the first omitted dose of VKA. When using UFH, the ACC recommends termination 4–6 h prior to the procedure and if LWMH is used it recommends termination at least 24 h prior to the procedure [6]. Guidelines for perioperative management of antithrombotic therapy, which discusses the issue of bridging therapy, were also published by the American College of Chest Physicians (CHEST) in 2012. Since then several important studies have been published [10,13,15,16]. The guidelines use CHADS2 scores. The CHEST algorithm for bridging therapy is presented in Fig. 2 [20].
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7 cor et vasa xxx (2018) e1–e7
e5
Fig. 1 – Algorithm for bridging therapy indication in patients with nonvalvular atrial fibrillation and need of temporary discontinuation of oral anticoagulation according to the American College of Cardiology 2017 Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation. TIA – transitory ischemic attack.
Fig. 2 – Algorithm for bridging therapy indication in patients with mechanical valve prosthesis or venous thromboembolism and need of temporary discontinuation of oral anticoagulation according to American College of Chest Physicians 2012 Guidelines for Perioperative Management of the Antithrombotic Therapy (modified from J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, et al., Perioperative management of antithrombotic therapy, Chest 141 (2012) 326–350). VTE – venous thromboembolism; TIA – transitory ischemic attack. *Risk factors: atrial fibrillation, history of ischemic stroke or TIA, arterial hypertension, diabetes mellitus, congestive heart failure, age ≥75 years. **High risk patients also include those with history of ischemic event in periprocedural period and temporary interruption of VKA anticoagulation or those undergoing certain types of surgery associated with an increased risk of ischemic events.
Bridging therapy in patients anticoagulated with NOACs Because of the short biological half-life, rapid onset, and rapid cessation of action, bridging anticoagulation therapy in NOACs
patients is not usually necessary, even in cases with a high risk of thromboembolic events. However, in clinical practice there may be situations where an interruption of NOACs is necessary and after the procedure there can sometimes be delays in readministering the NOAC. This may occur if another invasive procedure is needed during the short postprocedural
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7
e6
cor et vasa xxx (2018) e1–e7
period, or in cases where there is an intolerance to oral medication or an inability to administer drugs per os. In such cases, bridging with LWMH or UFH may be considered in patients with a high risk of thromboembolic events [6]. According to the European Heart Rhythm Association Practical Guide for the use of NOACs in Patients with Non-valvular Atrial Fibrillation, it is appropriate to initiate treatment with LWMH using a prophylactic or intermediate dose 6–8 h after an invasive procedure that involves patient immobilization, while full anticoagulation with NOAC can be postponed 48– 72 h after the invasive procedure [21]. Currently available data show that bridging therapy in patients anticoagulated with NOAC is associated with the same risks and benefits as in patients anticoagulated with VKA. In the prospective Dresden NOAC registry, 595 patients anticoagulated with NOAC underwent a total of 863 procedures. In 78.3% anticoagulation was temporarily discontinued and in 30% of those, bridging anticoagulation therapy was initiated. Approximately three-quarters of patients received rivaroxaban, the remaining received mainly dabigatran. Apixaban was used only in 0.5% of patients. The use of bridging therapy was associated with an insignificantly higher incidence of thromboembolic events (acute coronary syndrome, IS, TIA, systemic embolization, deep vein thrombosis, and pulmonary embolism) and with a significantly higher risk of major bleeding (2.7% vs. 0.5%, p = 0.01), which was caused predominantly by a greater risk of bleeding after major surgery. The risk of minor bleeding was the same in both groups [22]. A subanalysis of the RE-LY study, which focused on bridging anticoagulation therapy, found that bridging therapy was more commonly used in patients anticoagulated with VKA than with dabigatran (27.5% vs. 15.4%, p < 0.001). In patients receiving dabigatran, bridging therapy was associated with a significantly higher risk of major bleeding compared to no bridging therapy (6.5% vs. 1.8%, p < 0.001), and with an insignificantly lower risk of thromboembolic events (1.2% vs. 0.6%, p = 0.16), and systemic embolization (0.5% vs. 0.3%, p = 0.46) [16]. Similarly, in the subanalysis of the ROCKET-AF study, bridging therapy was associated with a greater risk of bleeding and a comparable risk of thromboembolic events; however, only 6% of patients with temporarily discontinued anticoagulation (warfarin or rivaroxaban) had bridging therapy initiated with heparin [23,24]. Shivakumara et al. suggested that use of dabigatran, instead of heparin, as a bridging agent be examined. However, the study was prematurely terminated in January 2017 for a lack of enrolled patients. Similar studies are still lacking, and no professional societies recommend using NOACs as bridging agents [12].
tional studies and small prospective studies without placebo control. Currently, the BRIDGE study is the only large prospective, multicenter, double-blind, and placebo-controlled study. It included only patients anticoagulated with VKA for nonvalvular atrial fibrillation. The study found that bridging therapy was associated with a significantly greater risk of major bleeding. However, the thromboembolic risk was not significantly affected. Although the study had some limitations, several other studies with different designs came to similar conclusions. Based on BRIDGE study, the ESC does not recommend bridging therapy in patients with nonvalvular atrial fibrillation [18]. The ACC, in its expert consensus, stratifies patients based on their CHA2DS2-VASc score and recommends bridging only in patients with a high risk of thromboembolic events [6]. No randomized, double-blind, and placebo-controlled study is currently available to examine the use of bridging therapy in patients with mechanical valve prosthesis or high thromboembolic risk, who were underrepresented in the BRIDGE trial. However, the ongoing PERIOP 2 study should provide an answer to the question of whether bridging anticoagulation therapy in this group of patients would be beneficial. There is still a lack of data on the use of bridging therapy in patients anticoagulated for deep venous thrombosis, pulmonary embolism, or for other indications. Bridging therapy in patients anticoagulated with NOACs is in most cases unjustified except in specific clinical situations. Data from subanalyses of the RE-LY and ROCKET-AF studies and from the prospective Dresden NOAC registry show that use of bridging therapy is associated with the same outcomes as in patients anticoagulated with warfarin. Data on the use of NOACs instead of heparin as a bridging agent are scarce and no studies examining this problem have been completed.
Conflict of interest None declared.
Ethical statement Authors state that the research was conducted according to ethical standards.
Funding body This research was supported by MH CZ-DRO (Faculty Hospital in Pilsen – FNPl, 00669806) and by the Charles University Research Program Q38.
references
Conclusion Use of bridging anticoagulation therapy after temporary discontinuation of anticoagulation should optimally reduce periprocedural risk of thromboembolic events while avoiding a significantly increased risk of bleeding complications. The amount of data from evaluations of bridging anticoagulation therapy is relatively small and limited primarily to observa-
[1] A.J. Camm, G. Accetta, G. Ambrosio, et al., Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation, Heart (2016) 1–8. [2] J. Kvasnička, J. Hájková, P. Bobčíková, et al., Prevalence polymorfismů CYP2C9 a VKORC1 v České republice a zamyšlení nad výhledy antikoagulační léčby warfarinem, Cor et Vasa 53 (2011) 522–526.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002
CRVASA 614 1–7 cor et vasa xxx (2018) e1–e7
[3] B.F. Cage, A.D. Waterman, W. Shannon, et al., Validation of clinical classification schemes for predicting stroke, The Journal of the American Medical Association 285 (2001) 2864–2870. [4] G.Y.H. Lip, R. Nieuwlaat, R. Pisters, et al., Refining clinical risk stratification for predicting stroke and thormboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation, Chest 137 (2010) 263–272. [5] L. Friberg, M. Rosenqvist, G.Y.H. Lip, Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study, European Heart Journal 33 (2012) 1500–1510. [6] J.U. Doherty, T.J. Gluckman, W.J. Hucker, 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation, Journal of the American College of Cardiology 69 (2017) 871–898. [7] R. Pisters, D.A. Lane, R. Nieuwlaat, et al., A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest 138 (2010) 1093–1100. [8] G.Y. Lip, L. Frison, J.L. Halperin, D.A. Lane, Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation, Journal of the American College of Cardiology 57 (2011) 173–180. [9] Z. Hijazi, J. Oldgren, J. Lindbäck, et al., The novel biomarkerbased ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study, Lancet 387 (2016) 2302–2311. [10] H. Omran, R. Bauersachs, S. Rübenacker, et al., The HASBLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK Online bRiDging REgistRy (BORDER), Thrombosis and Haemostasis 108 (2012) 65–73. [11] J.D. Douketis, A.C. Spyropoulos, S. Kaatz, et al., Perioperative bridging anticoagulation in patients with atrial fibrillation, The New England Journal of Medicine 373 (2015) 823–833. [12] C.L. Garwood, B. Korkis, D. Grande, et al., Anticoagulation bridge therapy in patients with atrial fibrillation: recent updates providing a rebalance of risk and benefit, Pharmacotherapy 37 (2017) 712–724. [13] A.S. Dunn, A.C. Spyropoulos, A.G.G. Turpie, Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT), Journal of Thrombosis and Haemostasis 5 (2007) 2211–2218. [14] B.A. Steinberg, E.D. Peterson, S. Kim, et al., Use and outcomes associated with bridging during anticoagulation
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
e7
interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), Circulation 131 (2015) 488– 494. A.C. Spyropoulos, A.G.G. Turpie, A.S. Dunn, et al., Clinical outcomes with unfractionated heparin or low-molecularweight heparin as bridging therapy in patients on longterm oral anticoagulants: the REGIMEN registry, Journal of Thrombosis and Haemostasis 4 (2006) 1246–1252. J.D. Douketis, J.S. Healey, M. Brueckmann, et al., Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial, Thrombosis and Haemostasis 113 (2015) 625–632. D. Siegal, J. Yudin, S. Kaatz, et al., Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates, Circulation 126 (2012) 1630–1639. P. Kirchhof, S. Benussi, S. Kotecha, et al., 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS, European Heart Journal 37 (2016) 2893–2962. R. De Caterina, S. Husted, L. Wallentin, et al., Parenteral anticoagulants in heart disease: current status and perspectives, Thrombosis and Haemostasis 109 (2013) 769–786. J.D. Douketis, A.C. Spyropoulos, F.A. Spencer, et al., Perioperative management of antithrombotic therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical guidelines, Chest 141 (2012) e326–e350. R. Čihák, L. Haman, M. Táborský, European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Summary of the document prepared by the Czech Society of Cardiology, Cor et Vasa 56 (2014) e42–e56. J. Beyer-Westendorf, V. Gelbricht, K. Förster, et al., Periinterventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry, European Heart Journal 35 (2014) 1888–1896. M.W. Sherwood, J.D. Douketis, M.R. Patel, et al., Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from ROCKET AF, Circulation 129 (2014) 1850–1859. A.C. Spyropoulos, A. Al-Badri, M.W. Sherwood, J.D. Douketis, Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticogulant requiring an elective procedure or surgery, Journal of Thrombosis and Haemostasis 14 (2016) 875–885.
Please cite this article in press as: Š. Volovár et al., Bridging anticoagulation therapy, Cor et Vasa (2018), https://doi.org/10.1016/j. crvasa.2018.04.002