Hrev_master Veins and Lymphatics 2014; volume 3:4148 [page 52] [Veins and Lymphatics 2014; 3:4148] The recent clinical trials on use of the novel direct oral anticoagulants in patients with venous thromboembolism: a review Gualtiero Palareti Cardiovascular Medicine, University of Bologna, Italy Abstract Venous thromboembolism (VTE), encom- passing deep vein thrombosis and pulmonary embolism, requires an immediate anticoagula- tion, that has been carried out so far by admin- istering a parenteral anticoagulant drug (heparin or derivatives) overlapped with an oral vitamin K antagonist (VKA), more often warfarin. Several new direct oral anticoagu- lants (DOACs), with a mechanism of action completely different than VKA, have been developed in recent years. Recent clinical trials have investigated their use in VTE patients showing results at least equal for efficacy and safety, and sometime even better, as the stan- dard anticoagulant treatment. There are differ- ences in the design of the trials. In two cases the involved DOAC was administered immedi- ately after VTE diagnosis as a single drug treat- ment (rivaroxaban and apixaban), whereas in the other trials (involving dabigatran and edoxaban) the DOAC was administered after an initial course of approximately 7 days with heparin or derivatives. Some clinical trials have also investigated the use of DOACs for extended anticoagulant treatment after the acute phase. Aim of this article is to review the results of the currently available clinical trials that have compared the use of DOACs versus the standard of care in patients with VTE. Introduction Venous thromboembolism (VTE), that includes deep vein thrombosis (DVT) and pul- monary embolism (PE), is a frequent disease whose incidence is estimated of about 1.5 per 1,000 inhabitants per year.1 VTE is a potentially fatal disease and is associated with late com- plications such as the post thrombotic syn- drome.2 Consequently, VTE may be regarded as a major cause of morbidity and mortality, being the third cause of death due to cardiovascular diseases after myocardial infarction and stroke.3 In order to prevent thrombus exten- sion and its potential consequences, an imme- diate anticoagulation is necessary as soon as diagnosis is made, by administering one of the available parenteral fast acting drug, such as unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux, and overlapping this therapy by associating an oral vitamin K antagonist (VKA, more frequently warfarin), which have a slow onset of action that requires 5 to 10 days before achieving an appropriate anticoagulant effect [i.e., interna- tional normalized ratio (INR) between 2.0 and 3.0]. Current guidelines recommend giving effective anticoagulation to patients with acute VTE for at least 3 months; usually this performed by administering VKAs, at the exception of some special populations (such as patients with cancer or during pregnancy) in whom treatment with LMWH is recommended over VKA.4 Since the risk of recurrence is not negligible, the duration of anticoagulation often lasts longer beyond the first 3 months, as it is suggested for high-risk patients such as those with an unprovoked VTE episode. Treatment with VKA is very effective but is complex to carry out in a correct way. It is asso- ciated with noticeable burden for the health systems and demanding for the patients. VKA have several limitations, including: slow onset and offset of action, complex genetic control of their effect leading to highly variable individ- ual sensitivity, narrow therapeutic window, and a metabolism affected by many factors, including diet, drugs, hepatic dysfunction, other co-morbid conditions and alcohol intake. The dose/response of VKA is unpredictable and frequent coagulation monitoring and dose- adjustments are needed to ensure efficacy of treatment and to minimize the risk of bleeding complications. Several direct oral anticoagulants (DOAC) have been developed to overcome some limita- tions of VKAs and to improve the quality of life of patients who need anticoagulation. Recent large randomized clinical trials have investi- gated their use in VTE patients (as well as in other clinical indications, e.g. non valvular atri- al fibrillation) showing results at least equal for efficacy and safety, and sometimes even better, as the standard anticoagulant treat- ment. Aim of this article is to review the results of the currently available clinical trials that have compared the use of DOACs versus the stan- dard of care in patients with VTE. The novel direct oral anticoag- ulants The DOACs are different drugs, with differ- ent characteristics and mechanisms of action. Dabigatran is a direct inhibitor of thrombin (factor IIa), while rivaroxaban, apixaban and edoxaban (still not available in our country) are inhibitors of activated factor X (factor Xa) (some DOAC characteristics are shown in Table 1).5-8 They do not need routine laboratory monitoring, they can be given in fixed doses once or twice daily per os, and have less food or drug interactions than VKA. However, they are not free from drawbacks. Their anticoagulant effect weakens quickly in case of poor compliance, and specific anti- dotes are not yet available. Treatment of acute venous thromboembolism All the four mentioned DOACs have results of randomized clinical trials in patients with acute VTE. All the trials were designed to show a non-inferior efficacy and safety versus the standard treatment. Some differences were present among the trials, regarding the stud- ied population (patients with acute VTE, or acute DVT only, or acute non-hemodynamic PE), the treatment durations and the blinding. But the most important difference regarded the initial treatment: in the study with dabiga- tran9 and that with edoxaban10 the initial treat- ment was performed in all patients with heparin (unfractionated or LMWH) for an average period of 7 days, and then the patients were randomized to receive the investigated drug or the standard treatment (warfarin). In the trial with rivaroxaban (the two Einstein studies11,12) and in that with apixaban13 the patients in the experimental arm received that single drug treatment since the beginning. Exclusion criteria in all the trials were the presence of contraindications to standard anti- coagulation with heparin or VKAs, PE with hemodynamic instability, use of thrombectomy or of fibrinolysis, or positioning of a vena cava Correspondence: Gualtiero Palareti, Cardiova - scular Medicine, University of Bologna, via Massarenti 9, 40138 Bologna, Italy. E-mail: gualtiero.palareti@unibo.it; gualtiero. palareti@gmail.com Key words: venous thromboembolism, anticoagu- lation, trials, direct oral anticoagulants, warfarin. Received for publication: 22 May 2014. Revision received: Not required. Accepted for publication: 9 October 2014. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright G. Palareti, 2014 Licensee PAGEPress, Italy Veins and Lymphatics 2014; 3:4148 doi:10.4081/vl.2014.4148 No n c om me rci al us e o nly Review [Veins and Lymphatics 2014; 3:4148] [page 53] filter. For details on results of the trials see Table 2.9-15 Dabigatran In the randomized, double-blind, RE- COVER study,9 were included 2564 patients with acute VTE who, after an initial treatment with parenteral anticoagulation therapy with LMWH or UFH (for a median of 9 days), were randomized to receive dabigatran at a dose of 150 mg bis in die (b.i.d.) or dose-adjusted warfarin to achieve an INR of 2.0 to 3.0. Duration of treatment was six months. The occurrence of primary outcome for efficacy was of 2.4% in patients treated with dabiga- tran and 2.1% in those receiving warfarin (time in therapeutic range 60%), confirming the non-inferiority of dabigatran vs warfarin (P<0.001). With regard to the safety, a major bleeding episode occurred in 1.6% and 1.9% of patients in dabigatran and warfarin groups, respectively [hazard ratio (HR) 0.82; 95% confidence interval (CI), 0.45 to 1.48]. The more frequent major bleeding event in the dabigatran group was gastrointestinal (nine events). Intracranial hemorrhage occurred in three patients treated with warfarin and in none receiving dabigatran. Rivaroxaban The Einstein VTE program consisted of two randomized trials of rivaroxaban: the Einstein- DVT11 and the Einstein-PE12 studies, that included patients with acute symptomatic DVT or PE, respectively; both studies allowed also different durations of treatment (3, 6 or 12 months), and after the completion of the ini- tial acute treatment, patients could be included in the Continued Treatment Study, a double blind, randomized, superiority study that com- pared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months. The Einstein-DVT study was a randomized, open-label, event-driven, trial that compared oral rivaroxaban alone (15 mg b.i.d. for 3 weeks, followed by 20 mg once daily) with the standard anticoagulation treatment (subcuta- neous enoxaparin followed by VKA, INR 2.0- 3.0) in 3449 patients with acute, symptomatic DVT and without symptomatic PE. The primary efficacy outcome occurred in 2.1% of patients who received rivaroxaban and in 3.0% of those who received LMWH+VKA (overall the time in therapeutic range for warfarin was 57.7%) and the HR was 0.68; 95% CI 0.44 to 1.04; with P<0.001 for non-inferiority. Major or clinically relevant non-major bleeds occurred in 8.1% and 8.1% of patients treated with rivaroxaban or standard therapy, respectively (HR with rivaroxaban, 0.97; 95% CI, 0.76-1.22; P=0.77). The Einstein-PE study was a randomized, open-label, event-driven, trial that involved 4832 patients with acute symptomatic non- hemodynamic PE with or without DVT. Rivaroxaban (at the dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily) was compared with standard therapy with LMWH followed by an adjusted-dose VKA for 3, 6, or 12 months. The primary efficacy outcomes in 2.1% of the rivaroxaban group and 1.8% of the standard therapy group (HR 1.12; 95% CI, 0.75- 1.68; P=0.003 for non-inferiority). The princi- pal safety outcome, that included major or clin- ically relevant non-major bleeding, occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group (HR 0.90; 95% CI, 0.76-1.07; P=0.23), with major bleeding events in 1.1% of patients treated with rivaroxaban and 2.2% in those receiving standard therapy Apixaban The double blind, double dummy Amplify study13 enrolled 5395 patients with acute DVT and/or PE who were randomized to receive apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily) or LMWH + warfarin (2.0-3.0 INR) for 6 months. The pri- mary efficacy outcome, that included recurrent symptomatic VTE or death VTE-related occurred in 2.3% in the apixaban group and 2.7% in the standard-therapy group (HR, 0.84; 95% CI 0.60-1.18; P<0.001 for non-inferiority). Principal safety outcomes included major bleeding alone and major bleeding plus clini- cally relevant non-major bleeding. Major bleed- ing occurred in 0.6% of patients who received apixaban and in 1.8% of those who received standard therapy (HR, 0.31; 95% CI, 0.17-0.55; P<0.001 for superiority). The composite out- come occurred in 4.3% of the patients in the apixaban group and in 9.7% of those in the conventional-therapy group (HR, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Edixaban The Hokusai study10 was a randomized, dou- ble-blind, in which all patients included with acute VTE (4921 presented with DVT, and 3319 with PE) initially received heparin (or LMWH) and then were randomized to receive edoxa- ban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of creatinine clear- ance of 30-50 mL/min or body weight below 60 kg), or to receive warfarin (time in the thera- peutic range was 63.5%) for a duration of treatment of 3 to 12 months. Primary efficacy outcome (recurrent symp- tomatic VTE) occurred in 3.2% and in 3.5% of patients in the experimental arm and in the standard treatment group, respectively (HR 0.89; 95% CI, 0.70 to 1.13; P<0.001 for non- inferiority). The rate of recurrent VTE was par- ticularly low (3.3%) in PE patients with right ventricular dysfunction (assessed by measure- ment of N-terminal pro-brain natriuretic pep- tide levels) who received edoxaban group ver- sus those treated with warfarin (6.2%; HR 0.52; 95% CI, 0.28-0.98). Table 1. Main pharmacological characteristics of the new drugs. Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism of action Direct, selective factor Direct, selective Direct, selective Direct, selective IIa inhibitor factor Xa inhibitor factor Xa inhibitor factor Xa inhibitor Prodrug Yes No No No Hours to Cmax 25 2-46 1-37 1-28 Half-life (hours) 12-145 9-136 8-157 9-118 Elimination 80% renal 1/3 renal 25% renal 35% renal 20% biliary 1/3 renal (as inactive metabolites) 75% biliary 65% biliary 1/3 biliary Interactions P-Glycoprotein P-Glycoprotein and CYP3A4 P-Glycoprotein (minimal) and CYP3A4 P-Glycoprotein Food effect Absorption delayed Absorption delayed Not reported Not or minimal Protein binding (%) 35 90 87 40-59 Dosing b.i.d. Once daily b.i.d. Once daily b.i.d., bis in die. No n c om me rci al us e o nly Review [page 54] [Veins and Lymphatics 2014; 3:4148] T ab le 2 . R at es ( n o ./ 1 0 0 p at ie n t- ye ar ) o f p ri m ar y o u tc o m es a n d m aj o r b le ed in gs w it h d ir ec t an ti co ag u la n ts o r co m p ar at o rs i n r ec en t tr ia ls i n p at ie n ts t re at ed f o r ve n o u s th ro m b o em b o li sm . Tr ia l D O A C a ge nt ; d es ig n; n o. p at ie nt s; i ni ti al t he ra py ; d os in g R at es o f pr im ar y ef fi ca cy o ut co m es R at es o f m aj or b le ed in g ev en ts D O A C C om pa ra to r D O A C C om pa ra to r A cu te p ha se t re at m en t RE -C O VE R9 D ab ig at ra n; tr ea tm en t o f a cu te D VT o r PE ; 2 56 4; 1 .8 1. 3% 1 .6 % 1 .9 % in iti al tr ea tm en t w ith L M W H ( m ed ia n 9 d) ; 1 50 m g b. i.d . x 6 m on th s H R= 1. 44 ( 0. 78 -2 .6 4) H R= 0. 82 ( 0. 45 -1 .4 8) P< 0. 01 * L M W H + W Ei ns te in -D VT 11 R iv ar ox ab an ; a cu te a nd e xt en de d tr ea tm en t o f D VT p at ie nt s; 2 .1 % 3 .0 % 0 .8 % 1 .2 % 3 44 9, s in gl e dr ug tr ea tm en t s in ce th e be gi nn in g (3 , 6 o r 12 m on th s) ; H R= 0. 68 ( 0. 44 -1 .0 4) H R= 0. 65 ( 0. 33 -1 -3 0) L M W H + W 1 5 m g b. i.d . x 2 1 d th en 2 0 m g o. i.d . P < 0. 00 1* Ei ns te in -P E1 2 Ri va ro xa ba n; a cu te a nd e xt en de d tr ea tm en t o f P E pa tie nt s; 4 83 3; 2 .1 % 1 .8 % 1 .1 % 2 .2 % s in gl e dr ug tr ea tm en t s in ce th e be gi nn in g (3 , 6 o r 12 m on th s) ; H R= 1. 12 ( 0. 75 -1 .6 8) H R= 0. 49 ( 0. 31 -0 .7 9; 0 .0 03 ) L M W H + W 1 5 m g b. i.d . x 2 1 d th en 2 0 m g o. i.d . P = 0. 00 3* Am pl ify 13 Ap ix ab an ; t re at m en t o f a cu te D VT o r PE ; 2 60 9; s in gl e dr ug tr ea tm en t 2. 3% 2 .7 % 0. 6 1 .8 % s in ce th e be gi nn in g; 1 0 m g b. i.d . x 7 d th en 5 m g b. i.d . x 6 m on th s H R= 0. 84 ( 0. 60 -1 .1 8) R R= 0. 31 ( 0. 17 -0 .5 5) L M W H + W P < 0. 00 1* P< 0. 00 1° H ok us ai 10 E do xa ba n; a cu te a nd e xt en de d tr ea tm en t o f D VT o r PE ; 8 24 0; 3. 2% 3 .5 % 1 .4 % 1 .6 % in iti al tr ea tm en t w ith L M W H ( m ed ia n 7 d) ; 6 0 m g o. i.d . H R = 0 .8 9 (0 .7 0- 1. 13 ) H R= 0. 84 ( 0. 59 -1 .2 1) L M W H + W P < 0. 00 1* E xt en de d tr ea tm en t RE -M ED Y D ab ig at ra n; e xt en de d tr ea tm en t a ft er th e fir st 3 m on th s; 1 50 m g b. i.d . RE -S O N AT E1 4 RE -M ED Y: 2 86 6; c om pa ra to r W 1 .8 % 1 .3 % 0 .9 % 1 .8 % H R= 1. 44 ( 0. 78 -2 .6 4) W H R= 0. 52 ( 0. 27 -1 .0 2) W P< 0. 01 * P = 0. 06 ° R E- SO N AT E: 1 36 3; c om pa ra to r pl ac eb o 0. 4 5 .6 0. 3% 0 H R= 0. 08 ( 0. 02 -0 .2 5) p la ce bo p la ce bo P < 0. 00 1° Am pl ify E xt en si on 15 A pi xa ba n; e xt en de d tr ea tm en t w ith 2 d iff er en t d os es : 2 .5 m g b. i.d .= 3. 8 2 .5 m g b. i.d .= 0. 2% 2 .5 m g b. i.d . o r 5 m g b. i.d .; 24 82 ; c om pa ra to r pl ac eb o H R= 0. 33 ( 0. 22 -0 .4 8) H R= 0. 49 ( 0. 09 -2 .6 4) 5 m g b. i.d .= 4. 2 1 1. 6 0 .5 % H R= 0. 36 ( 0. 25 -0 .5 3) p la ce bo 5 m g b. i.d .= 0. 1% p la ce bo P < 0. 00 1° H R= 0. 25 ( 0. 03 -2 .2 4) f or b ot h co m pa ri so ns D O AC , d ir ec t o ra l a nt ic oa gu la nt s; D VT , d ee p ve in th ro m bo si s; P E, p ul m on ar y em bo lis m ; L M W H , l ow m ol ec ul ar w ei gh t h ep ar in ; b .i. d. , b is in d ie ; H R, h az ar d ra tio ; o .i. d. , o pt im al im m un om od ul at in g do se ; R R, r el at iv e ri sk . * St at is tic al s ig ni fic an ce fo r no n- in fe ri or ity ; ° st at is tic al s ig ni fic an ce fo r su pe ri or ity . No n c om me rci al us e o nly Review [Veins and Lymphatics 2014; 3:4148] [page 55] The principal safety outcomes (major or clinically relevant non-major bleeding) occurred in 8.5% of patients in the edoxaban group and in 10.3% of those treated with war- farin (HR 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). Studies on extended treatment Some clinical trials have investigated the effects of DOACs in VTE patients treated for extended therapy after an initial therapy of at least 3 months from the index event. Among these studies, only the RE-MEDY (dabigatran) study14 had warfarin as comparator, while the others [Einstein-DVT Extended Treatment (rivaroxaban),11 the RE-SONATE (dabiga- tran)14 and Amplify Extension (apixaban)15 had placebo as comparator (Table 2).9-15 The Einstein-DVT continued-treat- ment study (rivaroxaban) In the Einstein-DVT it was carried out, in parallel, a double-blind superiority study that included 1196 patients who had completed 6 to 12 months of therapy after the index VTE event.11 They were randomized to receive rivaroxaban (20 mg once daily) or placebo for an additional 6 or 12 months. Recurrent events occurred in 1.3% of patients treated with rivaroxaban and in 7.1% of those receiving placebo (HR 0.18; 95% CI, 0.09-0.39; P<0.001). The principal safety outcome of major bleeding occurred in 4 patients (0.7%) in the rivaroxa- ban group and in none in the placebo group (P=0.11). However, major or clinically relevant non-major bleeds occurred in 6.0% and 1.2% in the rivaroxaban and placebo groups, respec- tively (P<0.001) The RE-MEDY and RE-SONATE study (dabigatran) In the RE-MEDY study14 2866 patients, who had received 3 to 12 months of anticoagulant therapy after a VTE episode, were randomized to treatment with dabigatran 150 mg twice daily or with warfarin (INR 2.0 to 3.0) for an additional period of 6 to 36 months. Recurrent symptomatic VTE occurred in 1.8% and 1.3% of patients treated with dabigatran and warfarin, respectively (HR 1.44; 95% CI 0.78 to 2.64; P=0.01 for non-inferiority). Major bleeds occurred in 0.9% and 1.8% in dabigatran- and warfarin-treated patients, respectively (HR 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabi- gatran (HR 0.54; 95% CI, 0.41 to 0.71). More acute coronary syndromes occurred in the dabigatran (0.9%) than in the warfarin group (0.2%) (P=0.02). The authors concluded that dabigatran was as effective as warfarin in the extended treatment of VTE; it was associated with a reduced risk for bleeding but an increased incidence of acute coronary events. In the double-blind, placebo-controlled RE- SONATE study14 1363 patients with VTE who had completed 6-18 months of anticoagulant therapy were randomized to receive dabiga- tran 150 mg b.i.d. daily or placebo for 6 more months. Recurrent VTE occurred in 0.4% of patients in the dabigatran group and in 5.6% in the placebo group (HR 0.08; 95% CI, 0.02-0.25; P<0.001 for superiority). Major bleeding occurred in 2 patients (gastrointestinal bleed- ing in both cases) in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 5.3% of patients in the dabigatran group (5.3%) and in 1.8% in the placebo group (HR 2.92; 95% CI, 1.52-5.60). One patient each in the dabigatran and placebo groups had an acute coronary syndrome. The authors con- cluded that an extended treatment with dabi- gatran was highly effective in reducing the rate of VTE recurrences as compared with placebo, and was associated with only a low risk for major bleeding. The Amplify-Ext study (apixaban) This was a randomized, double-blind study that compared the effects during one year of treatment with two doses of apixaban (2.5 mg and 5 mg, twice daily) or placebo in 2486 patients with VTE who had already received anticoagulation for 6-12 months. Primary effi- cacy outcomes occurred in 11.6% of patients treated with placebo, and in 3.8% who received 2.5 mg b.i.d. of apixaban and in 4.2 % of those who were treated with 5 mg b.i.d. of apixaban; with both apixaban doses the reduction of events was highly statistically significant (P<0.001). The rates of major bleeding were not different in the placebo group (0.5%), than in the 2.5-mg apixaban group (0.2%), and in the 5-mg apixaban group (0.1%). The authors concluded that the extended anticoagulation with apixaban at both adopted doses reduced the risk of recurrent VTE without increasing the rate of major bleeding. Conclusions The clinical trials on the use of DOACs in patients with acute VTE have all shown that the efficacy of these drugs on prevention of thrombotic complications was non-inferior to the standard treatment, consisting of initial administration heparin (or derivatives) fol- lowed by warfarin. Moreover, all the treatments with DOACs proved at least as safe and some- times even better than the comparator treat- ment. As regards the long-term therapy, it should be pointed-out that only one study (RE- MEDY14) was performed versus warfarin as comparator, while in all the others the com- parator was placebo. While the one DOAC (dabigatran) that was compared with warfarin proved similarly effective and with less major bleeding complications (though not reaching the statistical significance), the other DOACs compared to placebo proved more effective and with no higher rates of major bleeding. It is of interest to notice that altogether the results of these trials showed substantially lower bleeding rates in VTE patients compared with results in recent clinical trials on DOACs use in patients with non valvular atrial fibrilla- tion, a finding that could be due to the usually older age of the latter versus VTE patients (with more chronic medical conditions and concurrent medications) and the shorter dura- tion of the studies in VTE patients. References 1. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: The longitudinal investigation of thromboembolism etiolo- gy. Am J Med 2004;117:19-25. 2. Prandoni P, Lensing AWA, Cogo A, et al. 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