the main conventional anticoagulant treatments have included parenteral drugs , such as unfractionated heparin ( ufh ) and low - molecular - weight heparin ( lmwh ) . because of their molecular chemical characteristics , heparins are not absorbed easily in the gastrointestinal tract ; however , parenteral drugs are very poorly suited for long - term anticoagulant therapy . in contrast , since its commercialization in the 1960s , the vitamin k antagonist warfarin has contributed to clinical medicine through its use as the only oral anticoagulant . however , warfarin is limited in many ways , and its use entails a large burden . specifically , warfarin has delayed drug efficacy , requires careful monitoring and frequent dose adjustments , requires different doses for each individual according to cyp2c9 activity , has a narrow safety range , is interactive with food - derived vitamin k and a large number of drugs , and requires patient education . in recent years , activated factor x ( factor xa ) , which is an important serine protease in the coagulation cascade , and nonpeptide low molecular weight compounds that interfere with thrombin have been developed as oral anticoagulants designed to replace warfarin . these drugs do not require monitoring , and there is hope that they can be used as new anticoagulants that overcome the aforementioned problems with warfarin . their clinical targets are the prevention of thromboembolism in atrial fibrillation , primary prevention of venous thromboembolism ( vte ) in orthopedic surgery , and treatment of vte . in japan , dabigatran , rivaroxaban , apixaban , and edoxaban are used to prevent thromboembolism in atrial fibrillation ; only edoxaban is used in the primary prevention of vte in orthopedic surgery , and edoxaban , rivaroxaban , and apixaban are used in the treatment of vte ( table 1 ) . crnm , clinically relevant no major bleeding ; n / a , not available ; ttr , target therapeutic range ; vte , venous thromboembolism here , we provide an outline of these new oral anticoagulants ; that is , the direct oral anticoagulants ( doacs ) , and in particular their efficacy in the treatment of vte and future prospects for their use . the new anticoagulants that overcome the problems associated with conventional drugs boast assured efficacy with little individual variation in only a single dose and they do not require monitoring . in addition , they are extremely safe , have a wide therapeutic range , are less hemorrhagic , and have rapid onset action . in japan , all of the doacs used for vte therapy are factor xa inhibitors ( fig . factor xa is further upstream in the coagulation cascade compared to thrombin , and one molecule of factor xa produces 1000 molecules of thrombin . therefore , rather than inhibiting the enzymatic activity of thrombin , it is thought that inhibiting this production would be a more efficient way to suppress the coagulation response . in addition , although thrombin has a negative feedback action on blood coagulation systems other than blood coagulation activation , because factor xa is selective to the blood coagulation system , it is more appropriate for use as a drug discovery target molecule . structures of the oral factor xa inhibitors edoxaban , rivaroxaban , and apixaban in the search for drugs that could be used as anticoagulants that do not have the same problems as warfarin , compounds with high oral absorbability were discovered and investigated . however , because most are strongly basic in nature , they have insufficient oral absorbability . before oral factor xa , indirect factor xa inhibitor , fondaparinux , which is injectable and dependent upon antithrombin , was available for use in the treatment and prevention of vte . then , in recent years , compounds that maintain xa activity due to their reduced alkalinity and that have excellent oral absorbability were discovered and developed into multiple direct factor xa inhibitors . rivaroxaban and edoxaban are administered once a day , and apixaban is administered twice a day . each drug reaches maximum blood concentration within 4 h after administration , and their short half - life of approximately half a day means that they act extremely quickly and exhibit anticoagulant effects from the day of administration . most are metabolized in the liver by cytochrome p450 , which means that the renal excretion rate of unaltered substances is relatively low . edoxaban was shown to be effective and safe in the international clinical hokusai - vte trial , which included japanese patients . a subanalysis of the east asian population , including japanese , also found that they are effective . rivaroxaban was effective and safe in the international clinical einstein pulmonary embolism ( pe)/deep vein thrombosis ( dvt ) trial , and apixaban was effective and safe in the international clinical amplify trial . they were found to be safe for japanese patients in the j - einstein trial and the amplify - j trial . the hokusai - vte trial began treating subjects with edoxaban after administering parenteral anticoagulants for at least 5 days to early - phase patients and then assessed the effectiveness and safety . the einstein pe / dvt trial conducted treatment in the initial phase after onset of vte using only oral drugs by administering rivaroxaban during the initial 3 weeks at 1.5-fold the usual dose . the j - einstein trial of japanese subjects administered rivaroxaban 3 weeks after onset at a reduced dose that was three - quarters that used in the einstein pe / dvt trial . the amplify trial conducted treatment in the initial phase after onset of vte using only oral drugs by administering apixaban during the initial week at 2-fold the usual dose . comparisons in all these trials of doacs and warfarin indicated that the effectiveness ( that is , the recurrence rate of symptomatic vte ) was not inferior and that safety ( that is , the onset rate of hemorrhagic complications ) of doacs was superior . a subanalysis of the hokusai - vte trial on pe at nt - probnp  500 pg / ml indicated that edoxaban showed significantly more reduction in the onset of symptomatic vte than warfarin ( but less than heparin ) . when east asians , including japanese , were compared to non - east asians , doacs showed equal incidences for hemorrhagic complications , while warfarin had markedly higher incidence . therefore , administration to patients whose doacs blood levels may rise , such as the elderly , underweight patients , and patients with renal dysfunction , requires that sufficient attention be paid to the risk of hemorrhage . in addition , it must be kept in mind that there is no antidote at present ; therefore , when interventional procedures are being considered , the use of ufh and other drugs with shorter half - lives should be considered . currently , antidotes for xa inhibitors are being developed , and we look forward to their early clinical application . there are also reports indicating that vte often has complications in patients who are at risk of arteriosclerosis . in such cases , because the combined use of antiplatelet drugs and doacs increases the frequency of hemorrhage , the benefits and risks must be considered ; thus , lower doses of doacs should be considered . although three doacs can now be used in vte therapy , there are major differences in the initial administration regimens for each of them . because there is currently no evidence regarding this topic , it is very difficult to determine which doac should be used for which type of vte ( fig . in addition , although dose reduction criteria for edoxaban have been established and its effectiveness has been verified in phase iii trials , there are no dose reduction criteria for rivaroxaban or apixaban . there is a strong sense that dose reduction criteria for japanese , a population with many underweight and elderly members , are required , but there is no evidence regarding this issue at present . thus , many issues regarding doacs have not been elucidated in large - scale clinical trials , and there are many issues in which japanese and patients of european descent differ . it is necessary to conduct further clinical trials designed to provide answers to these unanswered questions . options for the regimen of direct oral anticoagulants for the initial treatment of venous thromboembolism in japan patients at a greater risk of thrombosis are more prone to choosing the dosing regimens in the upper regimen , while patients at a greater risk of bleeding are more prone to choosing the dosing regimens in the lower regimen . the possibility of recurrence during the chronic phase of vte means that it is necessary to consider the long - term use of anticoagulants , particularly in cases of unprovoked vte , in which this possibility remains at a constant rate for as long as 3 months after onset . doacs are safe anticoagulants that have a lower risk of hemorrhage than warfarin ; as a result , they can be used for longer periods of time in vte therapy . to further reduce the risk of hemorrhage with long - term use the amplify - ext trial indicated that apixaban administered continuously at a reduced dose of 2.5 mg per dose twice a day after 6 months after vte onset was effective . because doacs are effective immediately after administration , they do not have the same onset delay as seen in warfarin , which leads to reduced hospitalization during the acute phase of vvte . patients whose conditions are stable and in whom the risk of vte recurrence and hemorrhage is low may be discharged early and shifted to outpatient care . in addition , there seem to be no major problems with the use of doac therapy at vte onset in moderate or mild cases of dvt . however , it is necessary to emphasize the reliability of treatment in cases of symptomatic pe ; therefore , further studies are required to determine whether oral drug therapy alone at onset is sufficient for these cases . the prognostic improvement effect of lmwh in cases of vte complicating cancer has been elucidated , and lmwh is recommended for cancer patients with vte in europe and the united states . however , lmwh can not be used as a vte therapy in japan , which means that only warfarin can be used for long - term therapy . however , it is often difficult to adjust the dose of warfarin when used in combination with chemotherapy and because of fluctuations in platelet count . doacs can be administered more safely to cancer patients than warfarin , and currently , their clinical effectiveness is being investigated worldwide . when used as vte therapy , doacs are highly effective and have a great deal of potential . however , because there is little evidence regarding a variety of clinical questions ( table 3 ) , further clinical trials and clinical data are required for the development of doacs into safer drugs that are easier to use . mashio nakamura has received remuneration from daiichi sankyo company , limited , bayer yakuhin , ltd . , pfizer japan inc . and bristol - myers squibb k.k .. norikazu yamada has received honoraria from bayer yakuhin , ltd . and bristol - myers squibb k.k .. masaaki ito has received scholarship from bayer yakuhin , ltd . , pfizer japan inc .
direct oral anticoagulants ( doacs ) were developed to compensate for the demerits of warfarin . in japan , three factor xa inhibitors are used for the treatment of venous thromboembolism ( vte ) : edoxaban , rivaroxaban , and apixaban . despite problems , such as the inability to monitor their effect and the lack of an antidote , these inhibitors have the same efficacy as conventional treatment with warfarin , and they are associated with a significantly high degree of safety in relation to hemorrhagic complications . 
 east asians , including japanese , suffer from hemorrhage more frequently ; therefore , doacs are considered to be highly effective . 
 although there is no evidence to date , doacs may be effective in a wide variety of ways , including the possibility that they prevent recurrence over the long term , reduce the length of hospitalization , allow treatment to be started on an outpatient basis , and be effective in cancer patients .