New anticoagulants for treatment of venous thromboembolism

European Journal of Internal Medicine 23 (2012) 692–695

Contents lists available at SciVerse ScienceDirect

European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Review article

New anticoagulants for treatment of venous thromboembolism Massimo Franchini a, Pier Mannuccio Mannucci b,⁎ a b

Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy Scientific Direction, IRCCS Cà Granda Foundation Maggiore Hospital, Milan, Italy

a r t i c l e

i n f o

Article history: Received 19 September 2012 Accepted 3 October 2012 Available online 23 October 2012 Keywords: Dabigatran Rivaroxaban Apixaban Edoxaban Deep vein thrombosis Pulmonary embolism

a b s t r a c t Venous thromboembolism (VTE) is a major cause of morbidity and mortality and anticoagulation is the cornerstone of treatment. Although effective, traditional anticoagulants (i.e., heparins and vitamin K antagonists) have significant limitations and there are several unmet needs. Therefore, new drugs have been developed, including direct factor Xa inhibitors (e.g., rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g., dabigatran etexilate). The characteristics of these agents and the main results of published clinical studies dealing with VTE treatment are critically summarized in this article. © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Venous thromboembolism (VTE), a clinical entity which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of morbidity and mortality [1]. In the general population, the annual incidence of first-time VTE events is approximately 1 per 1000 persons [1–3]. In hospitalized patients, VTE is 100 times more frequent than in the general population [1], and varies with the reasons for admission. With no thromboprophylaxis objectively diagnosed DVT ranges from 10% to 20% in medical patients up to 80% in high-risk surgical and critical care patients [4]. Fatal PE, the most devastating consequence of VTE, ranges from 0.01% among low-risk surgical patients to 5% among hospitalized patients with multiple risk factors [5]. Thus, PE is actually considered the commonest avoidable cause of hospital death [4]. The socio-economic burden of VTE for the health care system is very heavy, not only owing to acute disease (i.e., DVT and PE) but also to late consequences, because patients with a first episode of VTE are at high risk of recurrence [6], recurrence rate being approximately 20% after 3 years, 30% after 5 years, and 40% after 10 years [7]. Another adverse effect of DVT is the post-thrombotic syndrome (characterized by chronic pain, pigmentation, swelling and ulcerations in the legs), which occurs in up to 50% of DVT cases usually within 1–2 years [8]. In

⁎ Corresponding author at: Scientific Direction, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital, Via Pace 9, 20122 Milan, Italy. Tel.: +39 02 5503 5414; fax: +39 02 54 100 125. E-mail address: [email protected] (P.M. Mannucci).

addition, PE predisposes to chronic pulmonary hypertension, that affects up to 4% of patients within 2 years after the first episode of symptomatic PE [5]. Thus, VTE should be considered an acute and chronic illness at the same time [6]. The current standard treatment of acute VTE is a two-drug anticoagulant regimen meant to prevent thrombus extension and its consequences. Fast-acting parenteral anticoagulants such as unfractionated heparin (UFH), low molecular-weight heparins (LMWH) and the synthetic pentasaccharide fondaparinux are overlapped in the first 5– 10 days after diagnosis with more slowly acting drugs such as warfarin or other vitamin K antagonists (VKAs), that are continued alone for variable time periods after a therapeutic range has been attained [9]. However, this dual therapeutic approach has a number of limitations, (Table 1), that make its implementation challenging both for patients and physicians. Most importantly, VKAs are associated with hemorrhagic complications, that cause deaths, emergency room and hospital admissions. Another important limitation of UFH, LMWH and fondaparinux is the need for parenteral administration (intravenous or subcutaneous), while that of oral VKAs is requirement for frequent coagulation monitoring and dose adjustment due to unpredictable pharmacokinetic and pharmacodynamic profiles of these drugs and their multiple interactions with food and drugs [10–13]. These challenges have prompted the search for new anticoagulant drugs at least equally efficacious, with a more favorable balance between risk of hemorrhage and the benefit of preventing recurrent VTE and a more practical profile (i.e., oral administration, no laboratory monitoring). This review will focus on the currently available evidence on the use of these anticoagulants for treatment (secondary prophylaxis) of VTE.

0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2012.10.001

M. Franchini, P.M. Mannucci / European Journal of Internal Medicine 23 (2012) 692–695 Table 1 Main limitations of anticoagulant agents currently used for treatment of VTE (beside the risk of bleeding). • Unfractioned heparin Parenteral administration Heparin induced thrombocytopenia (high risk) Inability to inactivate fibrin-bound thrombin and platelet-bound factor Xa Variable bioavailability Laboratory monitoring required Animal origin • Low molecular weight heparins Parenteral administration Heparin induced thrombocytopenia (low risk) Inability to inactivate fibrin-bound thrombin and platelet-bound factor Xa Bleeding risk in patients with renal insufficiency Animal origin • Fondaparinux Parenteral administration Bleeding risk in patients with renal insufficiency • Warfarin and vitamin K antagonists Slow onset and offset of action Narrow therapeutic window Requirement of laboratory monitoring and dose adjustment Multiple food and drug interactions Decrease of naturally occurring anticoagulant protein C and S

2. New anticoagulant drugs for VTE treatment The new anticoagulants are all direct and target-specific inhibitors acting at the level of a specific step of the coagulation cascade. The thrombin inhibitor dabigatran etexilate and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban are all in advanced phase III of clinical development for treatment of acute VTE, but only rivaroxaban is licensed for this therapeutic indication at the time of writing [11–13]. All available for oral administration in fixed doses with no the need for laboratory monitoring, their pharmacological characteristics are summarized in Table 2 and the main published results of clinical trials for dabigatran etexilate and rivaroxaban are in Table 3. We shall also briefly mention in the text results of studies published so far only preliminarily.

2.1. Dabigatran etexilate Dabigatran etexilate is a direct thrombin inhibitor rapidly converted to the active form dabigatran once absorbed from the gastrointestinal tract. The plasma half-life of dabigatran is 12–14 h and the major route of elimination is the kidney, which accounts for 80% of drug clearance. Accordingly, elimination is longer in patient with chronic renal insufficiency: for instance, half-life is 13.8 h in normal volunteers, 16.6 h in mild, 18.7 in moderate and 22.5 in severe renal insufficiency [14].

Table 2 Characteristics of the novel oral anticoagulants. Characteristics

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Target Bioavailability Prodrug Protein binding Tmax (h) T 1/2(hs) Dosing Renal clearance Interactions

Thrombin 6% Yes 35% 1.5 14–17 Twice daily 80% P-Gp

Factor Xa 80% No 93% 2.5 7–11 Once daily 60% CYP3A4 P-GP

Factor Xa 60% No 97% 3 8–15 Twice daily 25% CYP3A4 P-GP

Factor Xa 62% No 50% 1–5 8–10 Once daily 35% CYP3A4 P-GP

Legend: P-GP: p-glycoprotein, CYP3A4: cytochrome P450.

693

The first study that evaluated the new anticoagulants in the treatment of VTE dealt with dabigatran and was published in 2009 [15]. In the double-blind, non-inferiority RE-COVER [15], a total of 2539 patients with acute VTE (approximately 20% also had PE) were randomized to dabigatran (150 mg twice daily) or warfarin (dosage adjusted to an INR of 2 to 3) for 6 months, after initial parenteral UFH or LMWH for 5–10 days. Table 3 shows that rates of primary efficacy events (recurrent symptomatic objectively confirmed VTE and related deaths) were very similar in the dabigatran- and warfarin-treated groups (P b 0.001 for non-inferiority). Major bleeding and any bleeding occurred at very similar rates for both treatment regimens. This fully published study is accompanied by additional studies so far reported only in abstract form. In the RE-COVER II, a RE-COVER replica, dabigatran was again non-inferior to warfarin in 1279 additional patients with acute VTE [16]. The authors reported that the efficacy and safety of dabigatran were similar in Asian patients who were poorly represented in RE-COVER. Dabigatran was also evaluated in the so called extension studies, meant to evaluate this drug in patients who had completed and stopped the traditional VKA treatment of VTE. In RE-SONATE [17], dabigatran therapy (150 mg twice daily) was compared with placebo in patients with VTE who had stopped standard VKA therapy after 6 to 18 months. Over the next 6 months dabigatran significantly reduced the rate of recurrent VTE compared to placebo (0.4% vs 5.6%, hazard ratio, HR, 0.08, 95% CI 0.02–0.025, p b 0.0001), with a 0.39% rate of major bleeding versus no bleeding in the placebo group (p= 0.5). As it could be expected, clinically relevant non-major bleeding was significantly increased compared to placebo in the dabigatran group (HR 2.9, 95% CI 1.5–5.6, p = 0.001) [17]. In RE-MEDY, patients with VTE initially treated for 3 to 12 months with VKA were randomized to dabigatran (150 mg twice daily) or warfarin for an additional period of 6 to 36 months [18]. Recurrent VTE occurred at a rate of 1.8% in dabigatran-treated patients, 1.3% in warfarin-treated patients, rates of any bleeding episode being 19% and 26% respectively (HR 0.71, 95% CI 0.61–0.83). In a non-planned analysis, acute coronary syndromes were more frequent in dabigatran – than in warfarin – treated patients (0.9 vs 0.2%, p=0.02 for non-inferiority) [18]. Overall, these results indicate that a fixed twice-daily dosage of dabigatran alone has an efficacy and safety profile at least equal to that of warfarin preceded by heparins for the treatment of acute VTE (Table 3). For extended maintenance therapy, dabigatran is much more efficacious than placebo in the prevention of recurrence, but with an increased risk of bleeding complications. Dabigatran has not yet been approved for VTE treatment by FDA and EMA, but it has been approved for primary prophylaxis of VTE in patients undergoing knee and hip replacement. Hence its price for the VTE indication is not known, although it is expected to be much higher than that of traditional anticoagulants. 2.2. Rivaroxaban Rivaroxaban is a selective, direct factor Xa inhibitor with a half-life of 7–11 h. The drug has a high oral bioavailability (80%) and peak plasma concentrations are reached within 2.5–4 h after oral administration. Rivaroxaban has a dual mode of elimination, two thirds of its excretion being through the kidneys and one third by liver metabolism (Table 2). Table 3 gives the main results of the clinical phase III EINSTEIN study program, designed to broadly evaluate rivaroxaban in the treatment of VTE, that included 3449 patients in the DVT study [19], 1197 in the EINSTEIN extension study [19], and 4832 in the PE study [20]. In EINSTEIN DVT, patients with acute symptomatic DVT were randomized at the time of diagnosis to 15 mg rivaroxaban twice daily (changing after 3 weeks to 20 mg once daily) or standard therapy with enoxaparin followed by VKAs. At variance with dabigatran studies that chose to treat patients at the beginning with heparins and VKA and then to randomize them to the new anticoagulant or VKA, in EINSTEIN

694

M. Franchini, P.M. Mannucci / European Journal of Internal Medicine 23 (2012) 692–695

Table 3 Published VTE treatment studies with novel anticoagulants. RE-COVER [15]

EINSTEIN DVT [19]

EINSTEIN Extension [19]

EINSTEIN PE [20]

Drug Study design Dosing schedule

Dabigratan vs. warfarin Double-blind Dabigatran 150 mg bid

Rivaroxaban vs. placebo Double blind Rivaroxaban 20 mg od

Treatment duration Patient number Recurrent VTE

6m 2564 2.4% vs. 2.1% P b 0.001 (non-inferiority) 1.6% vs. 1.9%

Rivaroxaban vs. VKA Open label Rivaroxaban 15 mg bid for 3 weeks, followed by 20 mg od 3, 6 or 12 m 3449 2.1% vs. 3.0% P b 0.0001 (non-inferiority) 8.1% vs 8.1% (P = 0.77)

Rivaroxaban vs. VKA Open label Rivaroxaban 15 mg bid for 3 weeks, followed by 20 mg od 3, 6 or 12 m 4832 2.1% vs. 1.8% P b 0.003 (non-inferiority) 1.1% vs. 2.2% (P = 0.003)

Major bleeding

6–12 m 1196 (pre-treatment b12 m) 1.3% vs. 7.1% P b 0.0001 0.7% vs. 0% (P = 0.11)

Abbreviations: w, weeks; m, months; od: once daily, bid: twice daily; VTE, venous thromboembolism; VKA, vitamin K antagonist.

DVT patients were randomized to upfront rivaroxaban at the time of diagnosis of acute DVT or to standard dual therapy with heparin and VKA. Table 3 shows that the primary endpoint of recurrent VTE occurred at a similar rate for rivaroxaban and heparin-VKA treated patients (pb 0.0001 for non-inferiority). There was also a similar rate of major and clinically relevant bleeding [19]. In EINSTEIN PE, patients with acute PE were randomized either to rivaroxaban 15 mg twice daily for 3 weeks (followed by rivaroxaban 20 mg once daily) or enoxaparin 1 mg/kg twice daily and VKA starting within 48 h, until an INR of 2.0 was reached for two consecutive days [20]. Table 3 shows that the primary endpoint of symptomatic recurrent VTE occurred at a similar rate in rivaroxaban-treated and enoxaparin/ VKA treated patients (p =0.003 for non-inferiority). Rivaroxaban was associated with a significantly lower rate of major bleeding (p= 0.003) [20]. In a subgroup analysis carried out in 843 elderly patients (more than 75 years of age), recurrent VTE occurred at a similar rate in the rivaroxaban group and in patients on standard therapy (2.5 vs 3.2), but major bleeding was much less frequent in the rivaroxaban group (1.1 vs 5.7%, p b 0.001) [21]. The EINSTEIN extension study [19] chose to evaluate whether or not extended duration of rivaroxaban administration (6–12 months) in patients who had previously completed 6–12 months of therapy in the EINSTEIN DVT study is superior to placebo with respect to the rate of recurrent VTE. VTE recurred in 1.3% of the rivaroxaban-treated patients versus 7.1% of the placebo-treated patients (pb 0.001 for superiority). There was no significant difference for the principal safety endpoint of major bleeding (0.7% in the rivaroxaban versus 0% in placebo patients, p = 0.11). Moreover, the combination of major bleeding or clinically relevant non-major bleeding occurred at the same rate (81%) in both patient groups. As for dabigatran, rivaroxaban is not at the moment licensed for the treatment of VTE by FDA nor by EMA, but only for primary prophylaxis of high-risk orthopedic surgery.

2.3. Apixaban Apixaban is another oral synthetic drug that targets selectively the active site of FXa. Like rivaroxaban it inhibits FXa bound within the prothrombinase complex as well as the free enzyme [22]. No more than one fourth of the drug is eliminated via the kidney, the rest via the hepatobiliary route. A phase III randomized, double-blind trial (AMPLIFY) is currently recruiting patients with acute VTE at increased risk for recurrence (NCT00643201) [23]. AMPLIFY plans to randomize a total of 4816 patients to receive treatment with conventional heparin therapy or apixaban, the latter at the dosage of 10 mg twice a day for the first 7 days followed by 5 mg twice a day for the following 6 months. In the AMPLIFY extension study 2430 patients who completed 6 to 12 months are randomized to an extended 12-month period of apixaban or placebo to determine the efficacy and safety of apixaban for the prevention of VTE recurrence (NCT00633893) [24]. The results of this study should be completed soon.

2.4. Edoxaban Edoxaban is a selective direct factor Xa inhibitor with a half-life of 8–10 h. Renal secretion accounts for one third of its elimination [25]. A phase III study (HOKUSAI VTE, NCT00986154) is currently recruiting patients with acute DVT and/or PE. The randomization to 60 mg edoxaban once daily versus warfarin began in October 2009. Patients randomized in HOKUSAI VTE receive edoxaban or warfarin after an initial treatment period with heparin for 5 days. The primary endpoint is the composite of DVT, non-fatal, and fatal PE within 12 months from randomization. The secondary endpoint is the composite of recurrent DVT, non-fatal recurrent PE, all-cause mortality, and major or clinically relevant nonmajor bleeding on treatment. The trial plans to enroll 7500 patients and is estimated to be completed in September 2012 [26]. 3. Conclusion Selective thrombin and FXa inhibitors are a new class of anticoagulant drugs, designed to overcome the unmet needs of current therapy. They are orally active, reach full anticoagulant effect shortly after intake, have a relatively short half-life after discontinuation and in most clinical circumstances need no regular laboratory monitoring nor doseadjustment. Moreover, their ability to inactivate procoagulant enzymes bound to fibrin or activated platelets should help to prevent ongoing thrombus growth during traditional anticoagulant therapy. These characteristics render these agents more manageable and appealing for both patients and physicians than heparins or VKAs, even though the published clinical trials have shown so far only non-inferiority for dabigatran or rivaroxaban versus traditional anticoagulants in terms of efficacy. However, the new anticoagulants have a number of limitations in VTE, besides those of not being better in terms of bleeding complications (Table 4) (with the significant exception of rivaroxaban in the EINSTEIN PE study). A frequently aired concern is the lack of antidotes to reverse anticoagulant activity in case of bleeding. This is unlikely to be a significant problem in most clinical settings, because the relatively short half-life of these drugs makes their discontinuation sufficient in patients with normal clearance capacity. Unfortunately, dabigatran and rivaroxaban and, to a lesser extent, apixaban are excreted through the kidney, making them contraindicated in severe renal impairment (creatinine clearanceb 30 ml/min). In case of life-endangering bleeding,

Table 4 Challenges for the adoption of new anticoagulants in the treatment of venous thromboembolism. -

Widespread use of warfarin Balance between cost and efficacy No antidote Difficult assessment of patient compliance No head-to-head comparison of different drugs Difficult interpretation of non-inferiority trials Limited adherence to twice daily administration (for some of them)

M. Franchini, P.M. Mannucci / European Journal of Internal Medicine 23 (2012) 692–695

drug discontinuation may be insufficient to stop bleeding and the use of agents bypassing the drug-induced coagulation defect (prothrombin complex concentrates, recombinant factor VIIa) has been proposed, with some evidence of ex-vivo reversal of abnormal laboratory tests but as yet no evidence of clinical efficacy [27]. The relative short halflife of these drugs, beneficial as it is in terms of rapid onset and reversal of anticoagulation, implies the need to administer them in two daily doses (except for edoxaban, and also for rivaroxaban after the initial twice daily regimen), a regimen that is definitely reducing adherence (traditional VKA can be administered once daily). A big issue is the high cost of these drugs that, on the basis of the prices for licensed indications such as primary prophylaxis of VTE and prevention of cardioembolism in atrial fibrillation, is unlikely to be lower than 2–3 Euros per day. Based on the pricing in the UK and Canada and the data from the RE-LY trial, dabigatran was estimated to be more costeffective than warfarin in patients with atrial fibrillation at high risk of stroke [28,29]. However it must be borne in mind that in atrial fibrillation anticoagulants are very often a lifelong treatment, whereas the majority of patients with VTE are usually treated with anticoagulants for a relatively short period of time (from 3 to 12 months). Moreover, recent findings show that low-dose aspirin is a valid alternative to anticoagulants when clinicians plan to extend antithrombotic therapy beyond this period [30]. Thus the burden of laboratory monitoring for patients and healthcare providers is smaller for patients with VTE than that for those with atrial fibrillation, making the potential advantage of new anticoagulants less striking. All in all, we believe that new anticoagulants do represent a substantial step forward in the treatment of VTE. However, they are not free from limitations, making traditional anticoagulants still the mainstay of treatment for the next future.

[5] [6] [7]

[8] [9]

[10] [11] [12] [13] [14]

[15]

[16]

[17]

[18]

[19]

Learning points [20]

• Traditional anticoagulants, such as heparins and vitamin K antagonists, are effective and inexpensive but must be administered parenterally and need frequent laboratory monitoring for dose adjustment. • Newer anticoagulants, such as factor Xa and thrombin inhibitors, can be given orally at fixed dosage and do not routinely need laboratory monitoring, thus appearing more manageable than traditional anticoagulant agents. • Possible limitations of these drugs are high costs, lack of specific antidotes and uncertain risk-benefit profile in patients with renal dysfunction. Moreover, bleeding complications usually occur at the same rate as for traditional anticoagulants.

[21] [22]

[23]

[24]

[25] [26]

Conflict of interests The authors state that they have no conflicts of interest. References [1] Heit JA, Melton III LJ, Lohse CM, Petterson TM, Silverstein MD, Mohr DN, et al. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin Proc 2001;76:1102-10. [2] White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I4-8. [3] Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93. [4] Guyatt GH, Eikelboom JW, Gould MK, Garcia DA, Crowther M, Murad MH, et al. Approach to outcome measurement in the prevention of thrombosis in surgical and

[27] [28]

[29]

[30]

695

medical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e185S-94S. Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med 2010;363:266-74. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009;29:298-310. Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007;92:199-205. Pesavento R, Bernardi E, Concolato A, Dalla Valle F, Pagnan A, Prandoni P. Postthrombotic syndrome. Semin Thromb Hemost 2006;32:744-51. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Thrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S. Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ Program 2006: 450-6. Hirsh J, O'Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: current and future advances. Circulation 2007;116:552-60. Franchini M, Mannucci PM. A new era for anticoagulants. Eur J Intern Med 2009;20: 562-8. Mannucci PM, Franchini M. Old and new anticoagulant drugs: a minireview. Ann Med 2011;43:116-23. Strangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259-68. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52. Schulman S, Kakkar AK, Schellong SM, Goldhaber SZ, Henry E, Mismetti P, et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II). ASH Annual Meeting, abstr #205; 2011. Schulman S, Baanstra D, Eriksson H, Goldhaber S, Kakkar A, Kearon C, et al. Dabigatran vs placebo for extend maintenance therapy of venous thromboembolism. J Thromb Haemost 2011;9:22 [Abstract O-MO-037]. Schulman S, Eriksson H, Goldhaber S, Kakkar A, Kearon C, Kvamme AM, et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism. J Thromb Haemost 2011;9:731 [Abstract O-TH-033]. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: 2499-510. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97. Buller HR, Lensing AWA, Prins M. Oral rivaroxaban for pulmonary embolism. N Engl J Med 2012;366:2525-7. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009;37:74-81. Efficacy and safety study of apixaban for the treatment of deep vein thrombosis or pulmonary embolism. http://clinicaltrials.gov/ct2/show/NCT00643201. [Accessed August 14, 2012]. Efficacy and safety study of apixaban for extended treatment of deep vein thrombosis or pulmonary embolism. http://clinicaltrials.gov/ct2/show/NCT00633893. [Accessed August 14, 2012]. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor Xa inhibitor. Drugs 2011;71:1503-26. Comparative investigation of Low Molecular Weight (LMW) heparin/edoxaban tosylate (DU176b) versus (LMW) heparin/warfarin in the treatment of symptomatic deep-vein blood clots and/or lung blood clots. (The Edoxaban Hokusai-VTE Study). http://clinicaltrials.gov/ct2/show/NCT00986154. [Accessed August 14, 2012]. Frank Peacock W, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol 2012, doi:10.1002/clc.22037. Freeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011;154:1–11. Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses. BMJ 2011;343:d6333. Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366: 1959-67.