The APHRS's 2013 statement on antithrombotic therapy of patients with nonvalvular atrial fibrillation

Abstract

Atrial fibrillation (AF) has been gaining much attention as one of the major causes of cerebral infarction [1]. For practitioners to effectively manage this risk, it is imperative to establish an antithrombotic treatment for AF patients. To date, guidelines for antithrombotic treatment in the management of AF patients have been published in the United States [2], [3], Europe [4], [5], Australia [6], Canada [7], [8], and Japan [9], which include verification of the efficacy of direct thrombin and factor Xa inhibitors. A look at the needs of patient populations in the Asia-Pacific region shows that antithrombotic treatment has not yet been defined and no such guidelines exist. The Asia Pacific Heart Rhythm Society (APHRS)—Practice Guideline Subcommittee conducted a Web-based survey from June 2011 to August 2011 to elucidate the current status of antithrombotic treatment in 9 countries. When research was completed, the APHRS published a report entitled, “Fact-finding survey of antithrombotic treatment for prevention of cerebral and systemic thromboembolism in patients with non-valvular atrial fibrillation in 9 countries of the Asia-Pacific region” in the Journal of Arrhythmia [10]. The survey revealed substantial differences in antithrombotic treatments among the 9 surveyed countries. Although the overall survey size was small, in that only 50 physicians per country participated, and further research is still necessary, we believe that the results provide a good foundation to continue the process of creating usable, safe antithrombotic treatment guidelines for patients in Asia-Pacific countries. Among the many results noted in the survey are as follows: (1) there were large differences in the stance of using antiplatelet agents for low-risk patients with a CHADS2 score of 0–1; (2) warfarin was markedly underused in some countries; and (3) warfarin was quickly replaced by dabigatran, such that dabigatran was more frequently used than warfarin in some countries. Since antithrombotic therapy for patients with AF is rapidly changing with the increasing use of dabigatran, rivaroxaban, and apixaban, some of the primary issues that will influence the future revision of various guidelines (HRS [Heart Rhythm Society], ESC [European Society of Cardiology], ACC [American College of Cardiology], CCS [Canadian Cardiovascular Society], JCS [Japanese Circulation Society], etc.) would be how to use warfarin and other drugs for different indications and to determine the most accurate clinical position of each drug. In particular, there are data currently suggesting that the bleeding risk associated with newer anticoagulants is lower than that of warfarin [11]-[14]. Therefore, a central point in the new guidelines or statements would be to expand the indications of these newer anticoagulant drugs to include low-risk patients (CHADS2 score 0/1) and to reconsider the indications of antiplatelet agents, including acetylsalicylic acid (ASA). Under such circumstances, it is mandatory to publish the APHRS's “Statement on antithrombotic therapy of AF” with the aim of unifying the variety of antithrombotic therapies in Asia-Pacific countries and promoting the appropriate use of anticoagulants, including newly launched drugs. When developing guidelines on antithrombotic therapy, we must consider that novel anticoagulants are approved in different countries at different times. Since the primary role of guidelines is to describe how to use currently available drugs, guidelines used in a country should describe regimens of drugs currently available in that country. However, the approval status of dabigatran, rivaroxaban, apixaban, and edoxaban as of the end of 2012 differs among Asia-Pacific countries (Table 1), and this may pose a problem in establishing a common guideline document for those countries. Table 2 lists current guidelines for antithrombotic therapy in AF. The Joint Working Groups for the Guidelines for Pharmacotherapy of Atrial Fibrillation (JCS 2008, referred to as the “JCS 2008” guidelines hereinafter) [9] published an urgent statement on antithrombotic therapy of AF in 2011 after the launch of dabigatran in Japan [15]. The ESC 2010 guidelines for the management of AF (referred to as the “ESC 2010” guidelines) [4] recommend risk stratification according to the CHADS2 score, and recommend the CHA2DS2-VASc score in low-risk patients with a CHADS2 score of 0/1. Although all relevant guidelines describe that oral anticoagulants (OACs) are indicated for patients with a CHADS2 score of ≥2, the indication differs across guidelines. The ESC 2010 guidelines describe that dabigatran may be considered an alternative to warfarin; the “Quick Reference Guide: Atrial Fibrillation Information for the Health Practitioner” proposed by the government of Western Australia (referred to as the “Australian 2011” guidelines) [6] lists warfarin only; the evidence-based clinical practice guidelines for antithrombotic therapy for AF proposed by the American College of Chest Physicians (referred to as the “ACCP 2012” guidelines) [3] made recommendations only for dabigatran, which was approved for use in AF, among novel OACs as an alternative to warfarin; and the focused 2012 update of the CCS AF guidelines (referred to as the “CCS 2012” guidelines) [8] suggest that when OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin, since all these drugs are associated with less intracranial hemorrhage (ICH) and are much simpler to use. However, the CCS 2012 guidelines describe that the preference for one of the novel OACs over warfarin is less marked among patients already receiving warfarin with stable international normalized ratio (INR) and no bleeding complications. The ESC 2012 focused update guidelines [5] use a description of novel OACs to include apixaban, which was not approved yet at the time of revision. It should be emphasized, however, that in the ROCKET AF [13] (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, patients with a CHADS2 score of ≥2 were investigated and thus rivaroxaban should be indicated for this population of patients. The JCS's urgent statement [15] recommends that factor Xa inhibitors currently under development will be included as drugs “recommended” or “can be considered” for use according to the CHADS2 score of patients evaluated in clinical trials. On the basis of this consideration, the JCS's urgent statement placed dabigatran as a drug of choice for patients with a CHADS2 score of 1 and warfarin as a drug that “can be considered.” As Table 2 shows, all guidelines recommend OACs for patients with a CHADS2 score of ≥2, whereas recommendations for low-risk patients with a CHADS2 score of 0/1 differ slightly across guidelines. Evidence indicating that novel OACs decrease the risk of ICH by half as compared with warfarin has affected the recommendations of guideline documents. The ESC 2010 guidelines are the first among the guidelines reviewed to introduce the CHA2DS2-VASc score, and recommend physicians to classify low-risk patients with a CHADS2 score of 0/1 into 3 subgroups. In the CHA2DS2-VASc score, the major risk factors (2 points) are prior stroke or transient ischemic attack (TIA), and older age (≥75 years), and the clinically relevant nonmajor risk factors (1 point) are heart failure, hypertension, diabetes mellitus, female sex, age 65−74 years, and vascular disease. The ESC 2010 guidelines recommend OAC for patients with a CHA2DS2-VASc score of ≥2, OAC or ASA (OAC is more preferable) for patients with a score of 1, and no treatment or ASA for those with a score of 0 (no treatment is more preferable). Dabigatran is the OAC of choice. The JCS 2008 guidelines adopted a similar concept, and describe that physicians may consider warfarin and dabigatran for patients with risk factors other than those used in the CHADS2 score, such as age 65−74 years, female sex, and having coronary artery as those with a CHADS2 score of The 2011 guidelines and the 2012 guidelines use the CHADS2 score differ slightly in treatment for patients with a CHADS2 score of 0 and On the other the CCS 2012 guidelines use the of the CHA2DS2-VASc score factors in a different from those in the ESC 2010 guidelines. The CCS 2012 guidelines factors that were defined as clinically relevant nonmajor factors in the ESC 2010 guidelines and recommend the treatment for patients with a CHADS2 score of OAC for those of age or female patients with vascular ASA for female patients or those with vascular and no treatment for patients The CCS 2012 guidelines recommend OAC for patients with a CHADS2 score of In all ASA is as an alternative to As there is a among guidelines in female as a risk factor in the of low-risk patients by using the CHA2DS2-VASc As Table 3 shows, the ESC 2012 focused update guidelines [5] recommend the use of the CHA2DS2-VASc score in the of all including patients. However, the ESC 2012 focused update guidelines recommend antithrombotic for patients and AF since the risk of stroke is considered in this patient population In the CHA2DS2-VASc score, is a clinically relevant nonmajor risk factor with a CHA2DS2-VASc score of female patients may be considered at risk are of patients of age should have a CHA2DS2-VASc score of and are to receive The APHRS statement similar for female patients. In the APHRS we the use of the CHA2DS2-VASc score in the 9 countries [10]. A survey conducted in June to August 2011 revealed that and of physicians are using the CHADS2 and CHA2DS2-VASc The CHA2DS2-VASc score is used by more than half of the in and Australia whereas the CHADS2 score is used in Japan and Since has the of the CHA2DS2-VASc score, and use is in many the APHRS to recommend the use of this score in the and practitioners in the Asia-Pacific region should be to use the CHA2DS2-VASc score as a risk for have indicated that the CHA2DS2-VASc score is to the CHADS2 score in of stroke risk and the risk of stroke is among patients with a CHA2DS2-VASc score of 0 in antithrombotic therapy is not and may the risk of proposed that antithrombotic therapy should be in all patients with AF other than those with a CHA2DS2-VASc score of 0 and those with a risk of bleeding patients with a of bleeding and patients with that more patients will be indicated for antithrombotic therapy when novel OACs more available as alternative agents to In the of it is to that the 3 novel OACs rivaroxaban, and are In an that the 3 novel OACs have clinical than warfarin in patients at risk of bleeding and drugs were to be dabigatran, or to warfarin in the prevention of stroke ischemic stroke a efficacy as AF causes ischemic and not only dabigatran was to be and have lower risk of ICH than When the of new drugs is in the it is that antithrombotic therapy will be indicated for patients with a lower risk of stroke than those currently indicated for However, dabigatran at was associated with an risk of bleeding in patients or older In patients of and dabigatran were and to warfarin, in of the risk of major In the ROCKET AF trial, the risk of bleeding from including and was among patients receiving rivaroxaban than those receiving warfarin In a of the ROCKET AF trial, rivaroxaban was to warfarin in of the risk of bleeding in patients apixaban and rivaroxaban a to and when were to patients with and in of apixaban, for a of patients with 2 or more of the age years, In the of dabigatran, were used in patients with to and in a of age and it was that the may be considered in patients with a of Since patients with AF must continue antithrombotic therapy for the of the of new antithrombotic agents in patients is the differences in it may be in Asia-Pacific countries that patients of age should receive warfarin as the therapy, and patients of age should have as by the JCS 2008 guidelines. patients should receive dabigatran at the whereas in those and of age the may be considered have 1 or more risk factors for is as the risk factor of stroke and However, have that the clinical of warfarin with and was among patients of have that the clinical of warfarin is when the risk of ICH is to the risk of that warfarin is to prevention of stroke among patients when this drug the risk of bleeding in this patient problem is that the indications of each drug differ among Asia-Pacific and it is to provide recommendations that are with the indications in each country. For in the 3 novel OACs are indicated for prevention of ischemic stroke and systemic in patients with AF” of the results of the risk according to the CHADS2 The Health in Japan the use of these drugs when are to patients with a CHADS2 score of to these circumstances, the APHRS statement (Table lists dabigatran, rivaroxaban, and apixaban and the use of each of these drugs with warfarin in to physicians in Asia-Pacific countries these drugs to anticoagulant therapy in each patient when these drugs are approved in the relevant country. that physicians will the most of the statement in with the in each country. point in Table 2 is that the of ASA differs across different guidelines. the JCS 2008 guidelines not recommend ASA for patients with AF and the CCS 2012 guidelines not recommend ASA for patients with a CHADS2 score of 0 and clinically relevant nonmajor other guidelines ASA for patients with a CHADS2 score of 0/1. Since it has been that bleeding of ASA are more common in patients guidelines appropriate for patients in Asia-Pacific countries are The ESC 2010 and CCS 2012 guidelines recommend or and as an of the risk of ASA than warfarin has to be for patients with a risk of It is to the of antithrombotic therapy in patients in the of stroke and bleeding are However, the results of the not a clinical of ASA in patients with a risk of suggest that guidelines for patients in Asia-Pacific countries should not recommend as the JCS 2008 guidelines The ESC guidelines have a update [5] and the use of ASA for patients with CHA2DS2-VASc score of ASA should be considered in patients or In the APHRS we that ASA is not in As 1 shows, the results of the APHRS survey revealed differences among physicians in the 9 countries in of the on the CHADS2 and CHA2DS2-VASc in risk of patients with AF. than of physicians in and are using the CHA2DS2-VASc score, whereas of the CHADS2 score for in and of physicians in Japan use the CHADS2 score, whereas of physicians in use the CHA2DS2-VASc score to the risk of AF patients. of score for risk from with from the of OACs and the of ASA among patients with a CHADS2 score of 0/1 for the CHA2DS2-VASc score should be adopted in the APHRS's The use of antithrombotic therapy according to the CHADS2 score among the 9 countries In patients with a CHADS2 score of 0 the of use of OACs novel was and in most antiplatelet agents are used In patients with a CHADS2 score of 1, OACs and antiplatelet agents were used by half of the physicians each In for patients with a CHADS2 score of OACs warfarin, direct thrombin and use with were used at an as as of the according to CHADS2 from with from for patients with no risk factors from with from for patients with 1 risk factor from with from for patients with risk factors or from with from at antithrombotic therapy for each CHADS2 score in each country. For patients with CHADS2 score of 0 of the physicians used antiplatelet agents in of the and A of of the physicians used antiplatelet agents in and use with OACs was in In of the physicians used antiplatelet agents used no the treatment stance in Japan is For patients with CHADS2 score of 1 has a treatment in that of the physicians used antiplatelet agents and in In of the physicians used OACs in by in and in OACs are used for low-risk patients in these countries. In other of the physicians used For patients with CHADS2 score of 2 the of use of OACs warfarin, direct thrombin and use with is in and of physicians in used antiplatelet agents For patients with CHADS2 score of 2 with a similar was It be that the of use of OACs was in patients with a CHADS2 score of in with the in The countries different treatment for low-risk patients with a CHADS2 score of 0/1. It is to a on the treatment of this patient when the APHRS's In particular, in that ASA use only the bleeding risk and has no is in the JCS 2008 and treatment or the use of treatment is is On the other in of physicians use antiplatelet agents for patients with a CHADS2 score of are 2 with the use of warfarin in the clinical The first problem is patients with AF and no use was lower in patients in warfarin therapy is in Europe and the United States revealed of warfarin in patients with a risk for stroke In the survey by the of patients with a CHADS2 score of 2 The problem is regimens among patients receiving an for To the efficacy of warfarin therapy, the time in should be at As the APHRS survey indicated, warfarin is underused in Physicians in may be more affected by the associated with the use of warfarin as compared with those in other Asia-Pacific countries. The survey indicated that physicians in not on data as the used from to to a of the for the of warfarin in is to associated with warfarin antithrombotic therapy is to when physicians the of novel such as the of the for treatment at a and or no clinically with and other drugs. The use of novel OACs may the status of warfarin in patients with 2 (1) For how should the anticoagulant be the and (2) a be used with Since patients with AF may be with stroke for and after which time warfarin therapy is therapy with or other drugs has been for patients with a risk for there is that therapy patients with AF. that many not AF patients warfarin for have a risk for On the other treatment with novel OACs with a of may be and after the of patients with AF anticoagulant therapy at for the of therapy on 2 and the in the dabigatran and warfarin and only a of the patients therapy in the warfarin and in the dabigatran in only of patients and the of bleeding was with no the 2 The of stroke or systemic was in the dabigatran and warfarin after of anticoagulant The of anticoagulant for was in the dabigatran than in the warfarin suggest that novel OACs are more in patients to or that In the APHRS most that OACs were or novel physicians will be to anticoagulant therapy the for complications. The APHRS survey not physicians therapy for patients. The survey revealed that of physicians in OAC the risk of continue OAC of the of may be on the basis of the report by as Although the bleeding risk is in patients physicians in all that OAC The survey revealed that of the physicians in Japan continue therapy most in other countries the therapy the The risk of may of antithrombotic therapy, and this to that the patients have a risk of the therapy is It has been that thromboembolism in of patients with AF after of warfarin and have that be on patients receiving antithrombotic drugs investigated a of patients were for AF and the of years, patients (INR) was lower among not different the other was associated with ICH risk in all however, the of risk was among were no The ratio for ICH with as was for for and for It has been that the of warfarin to the was the in patients and the in and patients were and patients It is an point to all the to the prevention of in patients with AF. have that an of to be associated with the of major bleeding or as compared with an of In the APHRS of physicians that different for different age of physicians and only of physicians on The age was on As shows, physicians in most the at in which is with the and at in patients. The JCS 2008 guidelines recommend that the be for patients of age and for patients of age on the basis of the results of a of patients in Japan in warfarin therapy to an of was to be safe and The results of the APHRS survey indicated that all countries used similar It is that the APHRS's statement should warfarin regimens for different age and of the international normalized ratio according to from with from international normalized ratio for and patients. from with from A of the data the risk of bleeding in patients In a and patients receiving warfarin, the of ischemic stroke and stroke were in than in patients. It is that a or factor is in this which has been for years, we should consider other factors no such differences were in a and patients receiving The and the in patients may be the for the of ischemic stroke and The of the revealed that the of patients with a of was among patients and in and the of patients with a of was and in and results suggest that patients are not receiving warfarin a of the among countries in the has indicated warfarin therapy in countries. In only in Australia and whereas was lower in Japan and (no data were available in It is that this may the of ischemic stroke and stroke among patients. Physicians in countries should be to at an appropriate when patients receive warfarin therapy at a as in the JCS 2008 guidelines and this APHRS the of major bleeding was much in the than in the in the differences should be considered for the of In the Atrial Fibrillation Stroke in patients with AF the of the primary cerebral or was in patients receiving ASA than in patients not receiving ASA and the of bleeding in patients receiving ASA was which was the in patients not receiving ASA The was when these differences were in an The JCS 2008 guidelines thus with ASA in patients with AF. In patient in and with warfarin, are defined as those with a of and the of warfarin therapy in was similar to dabigatran The risk of major bleeding was in patients receiving dabigatran than those receiving warfarin, and the of ICH was lower in those receiving to these the American College of Heart on practice guidelines published a report on the use of dabigatran and dabigatran for the prevention of stroke in patients with AF of already warfarin with may have to by to In there are no differences in the of therapy patients with AF and AF the risk of stroke is similar these patient However, the APHRS survey revealed that physicians in and not this When physicians were antithrombotic therapy similar to that to AF patients to AF on in the 9 of the physicians in and whereas only in and The APHRS's statement will describe that patients with AF should receive antithrombotic therapy to patients with AF. In a of patients with AF the the of stroke or systemic the first after was in the warfarin and dabigatran However, there are no that may the international that therapy should be for 3 prior to and In the APHRS patients with and AF were In of the physicians used as or with antiplatelet agents for patients with AF, and there were differences among the countries. However, it may be a problem that as many as of the physicians with antiplatelet agents for patients in On the basis of the in antithrombotic therapy and the current of antithrombotic therapy in the APHRS we the recommendations (Table The ESC 2012 guidelines adopted a CHA2DS2-VASc score for risk and recommend novel OACs is an for patients with a CHA2DS2-VASc score of ≥2 and 1, and no treatment for those with a score of It is that ASA is not in this focused In the CHA2DS2-VASc score, the major risk factors (2 points) are prior stroke or and older age (≥75 years), and the clinically relevant nonmajor risk factors (1 point) are heart failure, hypertension, diabetes mellitus, female sex, age 65−74 years, and vascular disease. In the APHRS's patients should be into 3 patients with a CHA2DS2-VASc score of ≥2, 1, and with a CHA2DS2-VASc score of ≥2 should receive OAC novel OACs or those with a score of 1 should receive novel OACs rivaroxaban, and those with a score of 0 should receive no be considered an alternative in patients with a score of 1 since the and of rivaroxaban were evaluated in the ROCKET AF only in patients with CHADS2 score of to the ESC 2012 focused update female patients with as a risk factor a CHA2DS2-VASc score of should be as those with a score of be for patients with a CHA2DS2-VASc score of ≥2 and be for patients with a CHA2DS2-VASc score of 1 on the APHRS survey in patients with a CHADS2 score of 1 in that warfarin was by of with and patients with disease. with warfarin and have no bleeding complications. patients (≥75 of may be replaced by dabigatran guidelines recommend that the of warfarin is Since the JCS 2008 guidelines an of for patients of which not differ from in Asia-Pacific countries Australia and as in we recommend an of for patients of However, it is to at to the prevention of ischemic stroke and thromboembolism to treatment with with a of cerebral infarction or treatment with antiplatelet with ischemic heart disease. The risk of thromboembolism is in patients dabigatran 2 or warfarin the and on the when not receive therapy should be considered for patients with a risk for OACs should be used for patients to or a that causes In patients with a of the efficacy of warfarin therapy is to dabigatran in of the prevention of Although the of ICH was lower in the dabigatran the risk of major bleeding was than in those receiving OACs may not be used in of warfarin in patients with stable of with no bleeding complications. The risk of stroke in patients with AF is similar to those in patients with AF. with AF should thus antithrombotic therapy to those with AF. guidelines recommend that patients should continue warfarin therapy for 3 and after for has been in of the appropriate of treatment with novel OACs and after a of the that the of thromboembolism the first after was in patients receiving should consider the of novel In the Health drug of the of warfarin is whereas the of dabigatran and rivaroxaban is which a on patients. Physicians should OACs for patients by the and the of using novel which may various associated with warfarin therapy and decrease the risk of stroke and Physicians should be that there are no available for the treatment of bleeding by novel that physicians will the guidelines in practice these