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

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 disease as those with a CHADS2 score of 1. The Australian 2011 guidelines and the ACCP 2012 guidelines use the CHADS2 score but differ slightly in treatment for patients with a CHADS2 score of 0 and 1. On the other hand, the CCS 2012 guidelines use the concept of the CHA2DS2-VASc score but weigh factors in a way different from those in the ESC 2010 guidelines. The CCS 2012 guidelines weighed factors that were defined as clinically relevant nonmajor factors in the ESC 2010 guidelines differently, and recommend the following treatment for patients with a CHADS2 score of 0: OAC for those 65–74 years of age or female patients with vascular disease; ASA for female patients or those with vascular disease; and no treatment for male patients <65 years old. The CCS 2012 guidelines recommend OAC for patients with a CHADS2 score of 1. In all cases, ASA is recommended as an alternative to warfarin. As mentioned above, there is a slight difference among guidelines in handling female sex as a risk factor in the assessment of low-risk patients by using the CHA2DS2-VASc score. As Table 3 shows, the ESC 2012 focused update guidelines [5] recommend the use of the CHA2DS2-VASc score in the assessment of all patients, including high-risk patients. However, the ESC 2012 focused update guidelines recommend "no antithrombotic therapy" for patients "<65 years and lone AF (including females)" since the risk of stroke is considered low in this patient population [16]. In the CHA2DS2-VASc score, "female sex" is a clinically relevant nonmajor risk factor with a CHA2DS2-VASc score of "1," although female patients may be considered at low risk if they are "under 65 years of age." Female patients ≥65 years of age should have a CHA2DS2-VASc score of 2, and they are recommended to receive OAC. The present APHRS statement uses similar criteria for female patients. In the APHRS survey, we assessed the use of the CHA2DS2-VASc score in the 9 member countries [10]. A questionnaire survey conducted in June to August 2011 revealed that 47% and 45% of physicians are using the CHADS2 and CHA2DS2-VASc scores, respectively. The CHA2DS2-VASc score is used by more than half of the respondents in New Zealand (86%), India (59%), Singapore (57%), and Australia (54%), whereas the CHADS2 score is widely used in Japan (70%), Hong Kong (61%), and Taiwan (57%). Since evidence has shown the superiority of the CHA2DS2-VASc score, and its use is recommended in many countries, the APHRS decided to recommend the use of this score in the guideline. Both cardiologists and general practitioners in the Asia-Pacific region should be encouraged to use the CHA2DS2-VASc score as a basic risk assessment method for selecting better anticoagulation therapy. Friberg et al. [17] have indicated that the CHA2DS2-VASc score is superior to the CHADS2 score in terms of stroke risk stratification, and the risk of stroke is extremely low among patients with a CHA2DS2-VASc score of 0 in whom antithrombotic therapy is not beneficial and may even increase the risk of ICH. They proposed that antithrombotic therapy should be performed in all patients with AF other than those with a CHA2DS2-VASc score of 0 and those with a high risk of bleeding (e.g., patients with a history of massive bleeding and patients with malignant hypertension). They expect that more patients will be indicated for antithrombotic therapy when novel OACs become more available as alternative agents to warfarin. In the absence of head-to-head comparative studies, it is difficult to conclude that the 3 novel OACs (dabigatran, rivaroxaban, and apixaban) are equally useful. In an indirect model analysis, Banerjee et al. [18] concluded that the 3 novel OACs have net clinical benefits higher than warfarin in patients at high risk of bleeding and stroke. These drugs were shown to be superior (150 mg bid dabigatran, apixaban) or noninferior (rivaroxaban) to warfarin in the prevention of stroke (for ischemic stroke prevention, a true efficacy parameter as AF causes ischemic and not hemorrhagic stroke, only dabigatran was shown to be superior), and have lower risk of ICH than warfarin. When the net benefit of new drugs is clarified in the future, it is expected that antithrombotic therapy will also be indicated for patients with a lower risk of stroke than those currently indicated for warfarin. However, dabigatran at 150 mg bid was associated with an increased risk of extracranial bleeding in patients aged 75 years or older [19]. In patients <75 years of age, 110 and 150 mg bid dabigatran were superior and comparable to warfarin, respectively, in terms of the risk of major bleeding. In the ROCKET AF trial, the risk of bleeding from gastrointestinal sites, including upper, lower, and rectal sites, was higher among patients receiving rivaroxaban than those receiving warfarin [13]. In a subanalysis of the ROCKET AF trial, rivaroxaban was comparable to warfarin in terms of the risk of bleeding in elderly patients [20]. Both apixaban and rivaroxaban required a dose reduction to 2.5 mg bid and 15 mg od, respectively, when they were given to patients with moderate renal dysfunction (creatinine and in of apixaban, 2.5 mg bid for a of patients with 2 or more of the following age years, In the of dabigatran, were used in patients with to moderate renal and in a of age and renal dysfunction it was shown that the 110 mg bid dose 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 elderly patients is the differences in it may be in Asia-Pacific countries that patients years of age should receive warfarin as the therapy, and patients years of age should have as recommended by the JCS 2008 guidelines. elderly patients years should receive dabigatran at the 110 mg bid whereas in those 75 and years of age the 110 mg bid dose may be considered if they also have 1 or more risk factors for bleeding. is as the risk factor of stroke and bleeding. However, et al. have that the net clinical benefit of warfarin increased with age, and was among patients years of Friberg et al. [17] have that the net clinical benefit of warfarin is even when the risk of ICH is to the risk of stroke. These that warfarin is to prevention of stroke among elderly patients even when this drug the risk of bleeding in this patient problem is that the indications of each drug differ among Asia-Pacific countries, and it is difficult 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 assessment according to the CHADS2 score. The Health in Japan the use of these drugs even when they 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 recommended 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 history or elderly and as an of the risk of bleeding. ASA than warfarin has to be recommended for patients with a high risk of bleeding. It is difficult to the net benefit of antithrombotic therapy in elderly patients in whom the of stroke and bleeding are However, the results of the not a net clinical benefit of ASA in patients with a high risk of bleeding. These 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 recommended in As 1 shows, the results of the APHRS survey revealed differences among physicians in the 9 countries in terms of the on the CHADS2 and CHA2DS2-VASc in risk assessment of patients with AF. than of physicians in New and Singapore are using the CHA2DS2-VASc score, whereas of the CHADS2 score for in and Hong of physicians in Japan use the CHADS2 score, whereas of physicians in New Zealand use the CHA2DS2-VASc score to the risk of AF patients. of score for risk from et al. 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 (including novel was extremely low and in most cases, 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 2, OACs (including warfarin, direct thrombin and use with were used at an high as high as of the according to CHADS2 score. from et al. with from for patients with no risk factors from et al. with from for patients with 1 risk factor from et al. with from for patients with risk factors or from et al. with from also 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 Hong and A of of the physicians used antiplatelet agents in New and if 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 India has a treatment in that of the physicians used antiplatelet agents and in In of the physicians used OACs in by in Singapore and in New OACs are used for low-risk patients in these countries. In other countries, of the physicians used For patients with CHADS2 score of 2 the of use of OACs (including warfarin, direct thrombin and use with is high in Hong New and of physicians in India used antiplatelet agents For patients with CHADS2 score of 2 with stroke, a similar was It be that the of use of OACs was high in patients with a CHADS2 score of 2, 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 evidence that ASA use only the bleeding risk and has no is in the JCS 2008 and treatment or the use of if treatment is is On the other hand, in of physicians use antiplatelet agents even for patients with a CHADS2 score of 1. are 2 with the use of warfarin in the clinical The first problem is patients with AF and no warfarin. use was lower in elderly patients in whom warfarin therapy is in Europe and the United States revealed of warfarin in patients with a higher risk for stroke In the present survey by the of high-risk patients with a CHADS2 score of 2 warfarin. The problem is regimens among patients receiving warfarin. 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 India may be more affected by the associated with the use of warfarin as compared with those in other Asia-Pacific countries. The survey also indicated that physicians in India not on data as the used from to to a high of the for the of warfarin in India is to associated with warfarin antithrombotic therapy is expected 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 et al. 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 recommended for patients with a high risk for stroke, although there is evidence that therapy benefits patients with AF. that many not AF patients warfarin for have a low risk for stroke. On the other hand, treatment with novel OACs with a of may be and after et al. the of patients with AF anticoagulant therapy at for the of anticoagulation therapy on 2 and the in the dabigatran and warfarin respectively, 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 difference the 2 The of stroke or systemic was low in the dabigatran and warfarin after of anticoagulant therapy. The of anticoagulant for was in the dabigatran than in the warfarin These suggest that novel OACs are more beneficial in patients expected to or that bleeding. In the APHRS survey, most respondents that OACs were or novel physicians will be to anticoagulant therapy the for complications. The APHRS survey not physicians performed therapy for patients. The survey revealed that of physicians in India OAC the risk of bleeding. they continue OAC of the of may be encouraged on the basis of the report by et al. as mentioned Although the bleeding risk is low even in patients physicians in all countries, that they OAC The survey revealed that of the physicians in Japan continue anticoagulation therapy but most in other countries the anticoagulation therapy the The risk of may increase of antithrombotic therapy, and this to that the patients have a risk of the anticoagulation therapy is It has been that thromboembolism in of patients with AF after of warfarin and have that be performed on patients receiving antithrombotic drugs et al. investigated a of patients were for AF and the of years, patients ICH. (INR) was lower among but not different the other was associated with increased ICH risk in all however, the of risk was among were no sex The ratio for ICH with as was for for and for It has been that the dose of warfarin to the was the in patients and the in patients, and patients were and patients It is also an point to all the to the prevention of in patients with AF. et al. have that an of to be associated with the of major bleeding or as compared with an of In the APHRS survey, of physicians that they different for different age although of Australian physicians and only of New Zealand physicians on The age was years on As shows, physicians in most countries, the at in patients, which is with the and at in elderly patients. The JCS 2008 guidelines recommend that the be for patients years of age and for patients years of age on the basis of the results of a of elderly patients in Japan in whom 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 et al. with from international normalized ratio for and aged patients. from et al. with from A subanalysis of the data the risk of bleeding in patients In a and patients receiving warfarin, the of ischemic stroke and hemorrhagic stroke were higher in than in patients. It is that a or factor is in this which has been for years, but we should also consider other factors no such differences were in a and patients receiving The low and the low in patients may be the for the higher of ischemic stroke and hemorrhagic stroke. The subanalysis of the revealed that the of patients with a of was among patients and in patients, and the of patients with a of was and in and patients, respectively. These results suggest that patients are not receiving warfarin therapy. a of the among countries in the has indicated warfarin therapy in countries. In only in Australia Singapore and Hong Kong whereas was lower in Japan India and Taiwan (no data were available in New It is that this may the high of ischemic stroke and hemorrhagic stroke among patients. Physicians in countries should be encouraged to at an appropriate when elderly patients receive warfarin therapy at a low as recommended in the JCS 2008 guidelines and this APHRS the of major gastrointestinal bleeding was much in the than in the in the differences should also be considered for the of In the Atrial Fibrillation Stroke in patients with AF the of the primary cerebral or was higher 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 anticoagulation with ASA in patients with AF. In patient in and with warfarin, are defined as those with a of and respectively, the of warfarin therapy in was similar to 150 mg bid dabigatran The risk of major gastrointestinal bleeding was higher 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 recommended dabigatran for the prevention of stroke in patients with AF of although already warfarin with may have to by to In there are no differences in the of anticoagulation therapy patients with AF and AF the risk of stroke is similar these patient However, the APHRS survey revealed that physicians in and Taiwan not this When physicians were antithrombotic therapy similar to that given to AF patients also to AF on in the 9 countries, of the physicians in Hong and New whereas only in and The APHRS's statement will describe that patients with AF should receive antithrombotic therapy to patients with AF. In a subanalysis of patients with AF the the of stroke or systemic the first after was low in the warfarin and dabigatran However, there are no that may the international that therapy should be for 3 prior to and following In the APHRS survey, 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 survey, we the following recommendations (Table The ESC 2012 guidelines adopted a CHA2DS2-VASc score for risk stratification, 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 recommended 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 sex 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 years of may be replaced by dabigatran therapy. guidelines recommend that the of warfarin is Since the JCS 2008 guidelines recommended an of for patients years of age, which not differ from in Asia-Pacific countries Australia and New as shown in we recommend an of for patients years of However, it is to at to the prevention of ischemic stroke and hemorrhagic stroke. thromboembolism to treatment with OAC. with a history of cerebral infarction or treatment with antiplatelet with ischemic heart disease. The risk of thromboembolism is low in patients dabigatran 2 or warfarin the and on the following even when they not receive therapy. therapy should be considered for patients with a high risk for stroke. OACs should be used for patients expected to or a that causes bleeding. In patients with a of the efficacy of warfarin therapy is to 150 mg bid dabigatran in terms of the prevention of stroke. Although the of ICH was lower in the dabigatran the risk of major gastrointestinal bleeding was higher than in those receiving warfarin. OACs may not be used in of warfarin in patients with stable of anticoagulation 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 evidence for has been in terms of the appropriate of treatment with novel OACs and after although a subanalysis of the that the of thromboembolism the first after was low in patients receiving should also consider the of novel In the Health drug of the dose of warfarin is whereas the of dabigatran (150 mg and rivaroxaban mg is which a on patients. Physicians should OACs for patients by the and the benefits of using novel which may various associated with warfarin therapy and decrease the risk of stroke and bleeding. Physicians should also be that there are no available for the treatment of bleeding by novel that physicians will the present guidelines in practice these

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