Rivaroxaban and other non-vitamin K antagonist oral anticoagulants in the emergency treatment of thromboembolism
© Goldstein et al.; licensee Springer. 2013
Received: 30 May 2013
Accepted: 1 July 2013
Published: 16 July 2013
Pulmonary embolism (PE) is potentially fatal and often requires emergency management. Because PE associated with shock and/or hypotension carries a high risk of sudden death, emergency clinicians must rapidly make a diagnosis and initiate appropriate therapeutic strategies, usually involving anticoagulant treatment. Traditional anticoagulants, such as heparins and vitamin K antagonists, although effective and recommended by guidelines, are associated with limitations. Several targeted, orally administered anticoagulants that may overcome some of these constraints have been developed recently and undergone analysis in randomised, phase III clinical trials. Rivaroxaban, a direct factor Xa inhibitor, was non-inferior to standard therapy with enoxaparin plus a vitamin K antagonist for the prevention of recurrent, symptomatic venous thromboembolism (VTE) in patients with acute PE and led to a 50% reduction in major bleeding. Dabigatran, a direct thrombin inhibitor, was also non-inferior to standard therapy for the prevention of recurrent VTE or VTE-related death when given after a parenteral anticoagulant and had a similar incidence of major bleeding. The results of a phase III study of apixaban, another direct factor Xa inhibitor, for the acute treatment of VTE are expected in the near future. Rivaroxaban is now approved in Europe and the US for the treatment of acute PE and prevention of recurrent VTE. This article reviews the current guidance on the treatment of PE with special focus on the emergency setting, and considers data regarding rivaroxaban and the other non-vitamin K antagonist oral anticoagulants and their potential role, including patients who are and are not appropriate for treatment with these agents. Issues such as drug interactions, reversal of anticoagulant effect and coagulation monitoring are also discussed.
KeywordsAcute thrombosis Emergency setting Oral anticoagulant Pulmonary embolism
Pulmonary embolism (PE) is a potentially life-threatening emergency. In approximately 80% of cases, PE results from the embolisation of a deep venous thrombus [1, 2]. Approximately 60% of patients with proven proximal deep vein thrombosis (DVT) also show evidence of PE, and the absence of DVT in a patient with PE could indicate that the fresh venous thrombus has already embolised [1, 2]. Patients with PE have case fatality rates of 7-11% owing to the acute episode or a subsequent recurrence, which is higher than that associated with proximal DVT .
The standard antithrombotic treatment for DVT and PE is parenteral unfractionated heparin (UFH) or low molecular weight heparin (LMWH, e.g. enoxaparin), transitioning to an oral vitamin K antagonist (VKA) such as warfarin. Fondaparinux is a parenteral alternative to heparins. These agents are effective but have limitations, some of which may be overcome by the more recently developed non-VKA oral anticoagulants (OACs) . Based on the phase III EINSTEIN trials, the direct factor Xa inhibitor rivaroxaban is now approved in Europe and the US for the treatment of DVT and PE as well as the prevention of recurrent DVT and PE in adults [5, 6]. In addition, treatment studies involving the direct thrombin inhibitor dabigatran have also been completed, and studies of the direct factor Xa inhibitors apixaban and edoxaban are ongoing. This review describes the current guidelines for the treatment of patients with acute PE and considers the potential role of non-VKA OACs in this paradigm.
Literature sources for this article were retrieved via PubMed based on a series of searches using the names of anticoagulant classes and specific generic names of the agents discussed herein, in various combinations with Boolean operators and the terms ‘deep vein thrombosis’, ‘pulmonary embolism’, ‘venous thromboembolism’ and ‘treatment’. Articles returned by these searches were reviewed for relevance to the subject of this review, and the reference lists of other pertinent review articles and guidelines documents were examined for additional sources of information, such as congress abstracts.
Current guidelines on the emergency treatment of pulmonary embolism
The most recent international guidelines for the treatment of venous thromboembolism (VTE) were released by the American College of Chest Physicians (ACCP) in 2012 . In Europe, the current European Society of Cardiology (ESC) recommendations covering PE were issued in 2008  and do not include non-VKA OACs.
Grade of recommendation/level of evidence
High-risk PE (with hypotension and/or cardiogenic shock)
Thrombolytic therapy (for patients who do not have a high risk of bleeding)
2C (ACCP)/1A (ESC)
Accompanied by immediate i.v. UFH
Non-high-risk PE, including suspected PE
Initial parenteral anticoagulation or rivaroxaban*LMWH or fondaparinux preferred over:
1B (ACCP)/1A (ESC)
2B/C (ACCP)/1A (ESC)
2B/C (ACCP)/1A (ESC)
For patients at high risk of bleeding and those with severe renal dysfunction, UFH with an aPTT target range of 1.5-2.5 times the normal range
Initial treatment with UFH, LMWH or fondaparinux should continue for at least 5 days, with concurrent VKA started as soon as possible
1B (ACCP)/1A (ESC)
Parenteral treatment to be discontinued after achieving target INR levels for at least 2 consecutive days
1B (ACCP)/1C (ESC)
Established anticoagulants for the treatment of pulmonary embolism
UFH, given either subcutaneously or intravenously, binds to antithrombin to catalyse the inactivation of serine proteases involved in the coagulation cascade . However, binding to other plasma proteins also leads to unpredictable pharmacokinetics and pharmacodynamics, necessitating close biological monitoring and regular dose adjustments, and may induce side effects including heparin-induced thrombocytopenia (HIT) . LMWHs, which are also administered parenterally as weight-based doses, have a longer half-life than UFH and are more specific for antithrombin, making them more predictable and associated with fewer non-haemorrhagic side effects . As a result, LMWHs have largely replaced UFH, except in certain circumstances such as in patients with severe renal impairment [creatinine clearance (CrCl) < 30 ml/min], in which UFH is preferred because it does not accumulate in patients with compromised renal function (Table 1) . In the randomised COLUMBUS study, which included more than 1,000 patients, LMWH (sodium reviparin) given as treatment for symptomatic VTE for 12 weeks in combination with VKA was as effective as UFH/VKA (incidence of VTE recurrence 5.3% vs. 4.9%; absolute difference of 0.4 percentage points indicating equivalence by the pre-defined criteria), with no difference in major bleeding (3.1% vs. 2.3%; P = 0.63) or mortality (7.1% vs. 7.6%; P = 0.89) .
The parenteral indirect factor Xa inhibitor fondaparinux is a synthetic pentasaccharide that is more specific for antithrombin than LMWH and has a longer half-life. It does not require routine monitoring and is not associated with a risk of HIT . In a randomised phase III study in patients with symptomatic PE, fondaparinux was non-inferior to UFH for prevention of recurrent VTE when both were given for initial anticoagulation before transition to a VKA [3.8% incidence of VTE recurrence at 3 months with fondaparinux vs. 5.0% with UFH; absolute difference −1.2% (95% confidence interval −3.0% to 0.5%)]; the incidence of major bleeding was similar for both treatments (1.3% vs. 1.1%, respectively) . A similarly designed study including patients with DVT reported equivalent outcomes between fondaparinux and enoxaparin for efficacy [3.9% incidence of recurrent VTE at 3 months vs. 4.1%, respectively; absolute difference −0.15% (95% confidence interval −1.8% to 1.5%)] and major bleeding (1.1% vs. 1.2%, respectively) .
Initial parenteral anticoagulation provides a swift onset of action, which is important in acute thrombosis treatment. On the other hand, a potential for overdose exists owing to the long half-lives of LMWH and fondaparinux, and although protamine sulphate is able to partially neutralise LMWH, no reversal agent exists for fondaparinux . For longer term prevention of recurrent thrombosis, oral VKAs have traditionally been prescribed to patients when they leave hospital. VKAs do not induce HIT, but they are associated with various other problems. These include numerous food and drug interactions that lead to unpredictable pharmacokinetics and pharmacodynamics, which in turn necessitate regular coagulation monitoring and repeated dose adjustment .
Rivaroxaban and other non-vitamin K antagonist oral anticoagulants for the treatment of pulmonary embolism
The direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran, have been developed to address the limitations of traditional anticoagulants. They are administered orally, have a fast onset of action, and their predictable pharmacokinetics and pharmacodynamics across a broad range of patients allow for fixed doses without routine coagulation monitoring . Currently, rivaroxaban is the only such agent to be approved in Europe and the US for the treatment of DVT and PE and the prevention of recurrent DVT and PE, at an initial dose of 15 mg twice daily for 3 weeks followed by 20 mg once daily for an individualised duration of anticoagulation [5, 6].
Principal outcomes of phase III studies of non-VKA OACs for acute VTE treatment
Primary efficacy outcome
EINSTEIN PE 
Oral rivaroxaban 15 mg bid for 3 weeks then 20 mg od vs. enoxaparin s.c. 1.0 mg/kg bid for ≥ 5 days plus VKA started ≤ 48 h after randomisation
≥ 18 years with confirmed acute symptomatic PE with or without DVT (n = 4,832)
3, 6 or 12 months
Symptomatic, recurrent VTE: 2.1% vs. 1.8% (P = 0.003 for non-inferiority)
Major or non-major clinically relevant bleeding: 10.3% vs. 11.4% (P = 0.23)
Major bleeding: 1.1% vs. 2.2% (P = 0.003)
EINSTEIN DVT 
As for EINSTEIN PE
≥ 18 years with confirmed proximal DVT without symptomatic PE (n = 3,449)
3, 6 or 12 months
Symptomatic, recurrent VTE: 2.1% vs. 3.0% (P < 0.001 for non-inferiority)
Major and non-major clinically relevant bleeding: 8.1% vs. 8.1% (P = 0.77)
Major bleeding: 0.8% vs. 1.2% (P = 0.21)
Parenteral anticoagulant indication then oral dabigatran etexilate 150 mg bid vs. oral warfarin (INR 2.0-3.0) od
≥ 18 years with acute, symptomatic VTE (n = 2,564)
Symptomatic VTE or VTE-related death: 2.4% vs. 2.1% (P < 0.001 for non-inferiority)
Major or non-major clinically relevant bleeding: 5.6% vs. 8.8% (P = 0.002)
Major bleeding: 1.6% vs. 1.9% (HR = 0.82; 95% CI 0.45-1.48)
RE-COVER II 
As for RE-COVER
≥ 18 years with acute, symptomatic VTE (n = 2,568)
Symptomatic VTE or VTE-related death: 2.4% vs. 2.2% (P < 0.0001 for non-inferiority)
Any bleeding: 200 vs. 285 patients (HR = 0.67; 95% CI 0.56-0.81)
Major bleeding: 15 vs. 22 patients (HR = 0.69; 95% CI 0.36-1.32)
Considerations for clinical practice in the emergency department
With a rapid onset of action, parenteral agents represent the routine choice for initial anticoagulation, but non-VKA OACs also show promise in this setting. Rivaroxaban is a specific factor Xa-targeting anticoagulant that provides a comparable speed of onset to enoxaparin [5, 23], but without the risk of heparin-induced side effects . Unlike the indirect factor Xa inhibitor fondaparinux, rivaroxaban is administered orally, binds directly to factor Xa without the need for antithrombin , and inhibits free, prothrombinase-associated and clot-associated factor Xa . As the only non-VKA OAC currently approved for the treatment of DVT and PE, the following observations apply specifically to rivaroxaban, but some may also be relevant to non-VKA OACs as a class.
Overall, the EINSTEIN trials indicate that the risk of bleeding is similar between single-agent rivaroxaban and dual-drug LMWH/VKA. In EINSTEIN PE, there was no difference in the incidence of clinically relevant bleeding between the treatment arms in the acute phase of treatment (the first 21 days during which rivaroxaban was given at 15 mg twice daily), and, overall, major bleeding episodes were 50% less frequent with rivaroxaban . Nevertheless, all anticoagulants confer a risk of bleeding, and it is important to pay attention to any clinical sign of bleeding. If appropriate, laboratory testing of haemoglobin/haematocrit and comparison with baseline values could indicate possible occult bleeding [5, 26]. Anticoagulated patients who are at increased risk of bleeding, such as those with current or historical bleeding disorders, arterial hypertension, gastrointestinal ulcerations, vascular abnormalities or recent central nervous system trauma, should be monitored carefully for a drop in haemoglobin or blood pressure that may indicate bleeding. As with all anticoagulants, rivaroxaban should not be given to haemodynamically unstable patients, those who require pulmonary embolectomy or those receiving fibrinolytic agents [5, 26].
Rivaroxaban is contraindicated in patients with active bleeding of clinical significance or a relevant likelihood of such bleeding caused by hepatic disease associated with coagulopathy, including cirrhotic patients classified as Child-Pugh B or C . Approximately one-third of the rivaroxaban dose is excreted renally as unchanged drug and a further third is metabolised to inactive metabolites and then excreted renally [27, 28]. No dose adjustment is generally required in patients with reduced renal function in the DVT/PE treatment setting, although caution should be applied in patients with CrCl 15–29 ml/min . It should be noted that patients with CrCl <30 ml/min were excluded from the EINSTEIN studies [12, 13]. Rivaroxaban is not recommended for patients with CrCl <15 ml/min, prosthetic heart valves or immediately life-threatening PE requiring thrombolysis or surgery (these patients were excluded from EINSTEIN PE). Only limited data are available on rivaroxaban use in cancer patients, who are generally at increased risk of both VTE and bleeding , but outcomes for rivaroxaban in the EINSTEIN trials for those patients with active cancer were generally consistent with results for the overall populations [12, 13].
Concomitant administration of rivaroxaban with strong competitive inhibitors of cytochrome P450 3A4 and P-glycoprotein (P-gp) – namely azole-antimycotics or HIV protease inhibitors, including ritonavir – should be avoided [5, 27]. Caution should be exercised when giving rivaroxaban to patients with moderate renal impairment (CrCl 30–49 ml/min) who are taking co-medications that could increase the risk of bleeding, such as antiplatelet agents, or could lead to a potential increase in rivaroxaban plasma concentrations (strong inhibitors of cytochrome P450 3A4 or P-gp, or moderate inhibitors of both). Conversely, strong P-gp inducers (e.g. rifampicin) could potentially cause an inadequate level of anticoagulation [5, 27]. Co-administration of rivaroxaban with other anticoagulants is contraindicated unless switching to or from rivaroxaban, and use of rivaroxaban in combination with dronedarone should be avoided . Some of these issues can be managed using clinical judgement or an alternative agent. However, a substantial proportion of patients are likely to be suitable for rivaroxaban because it has shown predictable properties regardless of demographic factors [29–33].
Because rivaroxaban has a relatively short half-life (5–13 h for a 10-mg dose) [5, 34], reversal of anticoagulation should not normally be required with rivaroxaban. There is currently no specific antidote to rivaroxaban , although the use of activated charcoal could be considered in the case of recent overdose. Nevertheless, administration of up to 600 mg rivaroxaban has been reported without an increase in bleeding . In the case of bleeding complications, rivaroxaban should be discontinued or delayed. Symptomatic treatment, such as mechanical compression, surgical haemostasis, fluid replacement and blood products, should be used in an individualised manner according to the nature and location of the bleeding. If these measures do not control bleeding, prothrombin complex concentrate, activated prothrombin complex concentrate or recombinant factor VIIa can be considered to reverse the anticoagulant effect, based on limited data [5, 26]. Protamine sulphate and vitamin K infusion will not affect rivaroxaban activity, and there is no experience with antifibrinolytic agents or systemic haemostatic drugs. Rivaroxaban is not dialysable .
Rivaroxaban, like the other non-VKA OACs, has predictable pharmacokinetic and pharmacodynamic properties [29–33], and coagulation monitoring is not routinely necessary. A specific calibrated anti-factor Xa chromogenic assay is the preferred method for measuring rivaroxaban plasma concentrations (and those of other factor Xa inhibitors) if required in an emergency [26, 36], but if unavailable, prothrombin time could be used. In the latter case, the reading must be made in seconds and compared against known rivaroxaban calibrators and controls; it must not be converted to an INR . These tests are proposed to rule out the presence of the drug before acute surgery or to confirm neutralisation. If emergency surgery is required, rivaroxaban should ideally be stopped at least 24 h before the intervention, taking into account the patient’s risk of bleeding against the potential benefit of surgery . Because of its relatively short half-life [5, 34], rivaroxaban can be stopped closer to the time of surgery than VKAs and then be restarted when post-surgical haemostasis is established. Because of the rapid onset of effect with rivaroxaban, and in contrast to VKAs, there is no need for LMWH bridging.
The emergency physician may be faced with a patient with atrial fibrillation, or one who has recently undergone major orthopaedic surgery, who is taking anticoagulants but has symptoms suggestive of an acute PE. Poor control or non-adherence to VKA therapy could increase such a possibility. There is no official recommendation for this situation, but if the patient is already receiving rivaroxaban the logical strategy would be to increase the anticoagulant dose to an appropriate level for VTE treatment, provided the patient’s benefit-risk profile for recurrent VTE, atrial fibrillation-related stroke and bleeding is felt to be in favour of such an approach. The patient could be receiving dabigatran, but because dabigatran is not currently indicated for VTE treatment, a transition to an alternative agent may be necessary in this case. It has been suggested that rivaroxaban may be administered concurrently with acetylsalicylic acid (ASA), provided that the dose of ASA does not exceed 100 mg per day . However, rivaroxaban 15 mg or 20 mg should not be combined with dual antiplatelet therapy (ASA plus clopidogrel, ticlopidine, prasugrel or ticagrelor) .
If a patient is receiving a VKA and control is suboptimal, switching to rivaroxaban for treatment is possible by discontinuing the VKA and starting rivaroxaban when the INR is below 2.5 . There are circumstances in which oral anticoagulation is not possible or adequate in the emergency setting – for example, when the patient is unable to swallow a capsule or tablet. In this case, initial parenteral anticoagulation remains appropriate for induction therapy. It is then possible to switch to rivaroxaban by giving the first dose at the same time that the next dose of LMWH or fondaparinux is scheduled .
Acute PE is a potentially life-threatening event that requires rapid, effective anticoagulant treatment. Non-VKA OACs, such as rivaroxaban, offer potential advantages over traditional antithrombotic agents for the treatment of VTE in many patients, simplifying their management without compromising antithrombotic efficacy or safety. Nevertheless, there are specific circumstances where these agents are not recommended, and clinical experience will serve to further define appropriate use.
American College of Chest Physicians
Deep vein thrombosis
European Society of Cardiology
International normalised ratio
Low molecular weight heparin
Vitamin K antagonist
The authors would like to acknowledge Stephen Purver, who provided medical writing services for this manuscript with funding from Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs, LLC. The sponsors reviewed a late-stage draft of the manuscript and provided comments, but the authors took the final decision on whether to incorporate any suggestions and to submit the manuscript.
- Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simonneau G: High prevalence of detectable deep venous thrombosis in patients with acute pulmonary embolism. Chest 1999, 116: 903–908. 10.1378/chest.116.4.903PubMedView ArticleGoogle Scholar
- Tapson VF: Acute pulmonary embolism. N Engl J Med 2008, 358: 1037–1052. 10.1056/NEJMra072753PubMedView ArticleGoogle Scholar
- Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, et al.: Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008, 29: 2276–2315.PubMedView ArticleGoogle Scholar
- Eikelboom JW, Weitz JI: New anticoagulants. Circulation 2010, 121: 1523–1532. 10.1161/CIRCULATIONAHA.109.853119PubMedView ArticleGoogle Scholar
- Bayer Pharma AG: Xarelto® (rivaroxaban) Summary of Product Characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Google Scholar
- Janssen Pharmaceuticals Inc: Xarelto® (rivaroxaban) Prescribing Information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022406s004lbl.pdf Google Scholar
- Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, et al.: Antithrombotic 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-e494S. 10.1378/chest.11-2301PubMed CentralPubMedView ArticleGoogle Scholar
- Garcia DA, Baglin TP, Weitz JI, Samama MM: Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012, 141: e24S-e43S. 10.1378/chest.11-2291PubMed CentralPubMedView ArticleGoogle Scholar
- The Columbus Investigators: Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997, 337: 657–662.View ArticleGoogle Scholar
- Büller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, van den Berg-Segers AE, Cariou R, et al.: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003, 349: 1695–1702.PubMedView ArticleGoogle Scholar
- Büller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, Segers AE, Cariou R, et al.: Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004, 140: 867–873. 10.7326/0003-4819-140-11-200406010-00007PubMedView ArticleGoogle Scholar
- The EINSTEIN–PE Investigators: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012, 366: 1287–1297.View ArticleGoogle Scholar
- The EINSTEIN Investigators: Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010, 363: 2499–2510.View ArticleGoogle Scholar
- Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, et al.: Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007, 98: 756–764.PubMedGoogle Scholar
- Büller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, Misselwitz F, Raskob G, Schellong S, Segers A, et al.: A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study. Blood 2008, 112: 2242–2247. 10.1182/blood-2008-05-160143PubMedView ArticleGoogle Scholar
- Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, Kakkar AK, Misselwitz F, Schellong S, ODIXa-DVT Study Investigators: Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (oral direct factor Xa inhibitor BAY 59–7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation 2007, 116: 180–187. 10.1161/CIRCULATIONAHA.106.668020PubMedView ArticleGoogle Scholar
- Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, Lundström T, Berkowitz SD, Nyström P, Thorsén M, et al.: Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005, 293: 681–689. 10.1001/jama.293.6.681PubMedView ArticleGoogle Scholar
- Büller HR, Cohen AT, Davidson B, Decousus H, Gallus AS, Gent M, Pillion G, Piovella F, Prins MH, van Gogh Investigators, et al.: Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007, 357: 1094–1104.PubMedView ArticleGoogle Scholar
- Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F: Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011, 50: 675–686. 10.2165/11595320-000000000-00000PubMedView ArticleGoogle Scholar
- Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, for the RE-COVER Study Group: Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009, 361: 2342–2352. 10.1056/NEJMoa0906598PubMedView ArticleGoogle Scholar
- Schulman S, Kakkar AK, Schellong SM, Goldhaber SZ, Eriksson H, Mismetti P, Christiansen AV, Schnee J, Kearon C: A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II) [abstract]. Blood (ASH Annual Meeting Abstracts) 2011, 118: Abstract 205.Google Scholar
- Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A: Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 2012, 345: e7498. 10.1136/bmj.e7498PubMed CentralPubMedView ArticleGoogle Scholar
- sanofi-aventis new zealand limited: Clexane® and Clexane Forte® (enoxaparin sodium). 2010. http://www.medsafe.govt.nz/profs/datasheet/c/clexaneinj.pdf Google Scholar
- Samama MM: The mechanism of action of rivaroxaban – an oral, direct factor Xa inhibitor – compared with other anticoagulants. Thromb Res 2011, 127: 497–504. 10.1016/j.thromres.2010.09.008PubMedView ArticleGoogle Scholar
- Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V: Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010, 30: 376–381. 10.1161/ATVBAHA.110.202978PubMedView ArticleGoogle Scholar
- Siegal DM, Crowther MA: Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J 2013, 34: 489–498. 10.1093/eurheartj/ehs408PubMedView ArticleGoogle Scholar
- Mueck W, Kubitza D, Becka M: Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013. 10.1111/bcp.12075Google Scholar
- Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D: Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs and humans. Drug Metab Dispos 2009, 37: 1056–1064. 10.1124/dmd.108.025569PubMedView ArticleGoogle Scholar
- Kubitza D, Becka M, Zuehlsdorf M, Mueck W: Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects. J Clin Pharmacol 2007, 47: 218–226. 10.1177/0091270006296058PubMedView ArticleGoogle Scholar
- Kubitza D, Becka M, Roth A, Mueck W: Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008, 24: 2757–2765. 10.1185/03007990802361499PubMedView ArticleGoogle Scholar
- Jiang J, Hu Y, Zhang J, Yang J, Mueck W, Kubitza D, Bauer RJ, Meng L, Hu P: Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban – an oral, direct factor Xa inhibitor – in elderly Chinese subjects. Thromb Haemost 2010, 103: 234–241.PubMedView ArticleGoogle Scholar
- Kubitza D, Becka M, Roth A, Mueck W: The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor Xa inhibitor. J Clin Pharmacol 2013, 53: 249–255. 10.1002/jcph.5PubMedView ArticleGoogle Scholar
- Zhao X, Sun P, Zhou Y, Liu Y, Zhang H, Mueck W, Kubitza D, Bauer RJ, Zhang H, Cui Y: Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br J Clin Pharmacol 2009, 68: 77–88. 10.1111/j.1365-2125.2009.03390.xPubMed CentralPubMedView ArticleGoogle Scholar
- Weinz C, Buetehorn U, Daehler HP, Kohlsdorfer C, Pleiss U, Sandmann S, Schlemmer KH, Schwarz T, Steinke W: Pharmacokinetics of BAY 59–7939 – an oral, direct factor Xa inhibitor – in rats and dogs. Xenobiotica 2005, 35: 891–910. 10.1080/00498250500250493PubMedView ArticleGoogle Scholar
- Peacock WF, Gearhart MM, Mills RM: Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol 2012, 35: 730–737. 10.1002/clc.22037PubMedView ArticleGoogle Scholar
- Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE: Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit 2010, 32: 673–679. 10.1097/FTD.0b013e3181f2f264PubMedView ArticleGoogle Scholar
- Turpie AGG, Kreutz R, Llau J, Norrving B, Haas S: Management consensus guidance for the use of rivaroxaban – an oral, direct factor Xa inhibitor. Thromb Haemost 2012, 108: 876–886. 10.1160/TH12-03-0209PubMedView ArticleGoogle Scholar
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