Evidence summary on oral anticoagulants and treatment/prevention of venous thromboembolism
Successful use of all anticoagulants requires careful patient selection and routine clinical monitoring, to minimise the risk of thrombosis and bleeding.
Treating and preventing recurrence of venous thromboembolism
One treatment option for rapid anticoagulation in acute symptomatic DVT and PE is parenteral anticoagulants such as heparins, overlapping the start of warfarin therapy. This dual therapy is continued until the patient's INR is stable and within therapeutic range (2.0–3.0), after which warfarin is continued as single therapy.1
Rivaroxaban — another option
- the initial and continuing treatment of confirmed, acute symptomatic deep vein thrombosis
- the initial and continuing treatment of confirmed, acute symptomatic pulmonary embolism
- the prevention of recurrent VTE.
See the NPS RADAR review Rivaroxaban for the treatment of DVT and PE, and for prevention of VTE recurrence for dosing details for different indications.
Rivaroxaban is no worse than enoxaparin plus warfarin for preventing VTE recurrence in initial treatment of acute DVT or PE
- In trials assessing efficacy and safety the following outcomes were similar in people treated with rivaroxaban compared with those treated with enoxaparin plus warfarin (or acenocoumarol*):3,4
- VTE recurrence
- major or clinically relevant non-major bleeding (measured as a composite outcome)
- In the key DVT treatment study, average time in therapeutic range for trial participants taking warfarin was only 58%.3 This may be lower than the average time in therapeutic range for Australian patients taking warfarin, who averaged 69% in a recent study.5
- In the key PE treatment study, incidence of major bleeding was lower in people with treated with rivaroxaban than in people treated with enoxaparin plus warfarin (or acenocoumarol).4
* Acenocoumarol is not marketed in Australia.
Prevention of VTE recurrence in people with a history of VTE
- For continuing treatment of people with a history of VTE the efficacy and safety of rivaroxaban has only been compared with placebo3
- Rivaroxaban reduced recurrence of VTE but increased the incidence of bleeding compared with placebo.3
Duration of treatment
Current recommendations for anticoagulant treatment durations are listed in the table below.6-11
Recommended duration of anticoagulant treatment of VTE
|Scenario||Recommended duration of treatment|
|First episode of VTE† provoked by a transient risk factor‡||3 months' anticoagulation7-10|
|First episode of isolated distal DVT||6 weeks' to 3 months' anticoagulation.6-11 Less than 3 months' treatment may be considered appropriate in low-risk patients with first episodes of isolated distal DVT provoked by a transient risk factor, after assessment by a specialist7,11|
|First unprovoked proximal DVT or PE||At least 3–6 months' anticoagulation.6-11 An extended duration should be considered based on patient preference and after specialist assessment of the benefits and harms. Some guidelines recommend 3 months' treatment for these patients, who are also at high risk of bleeding10|
|First episode of VTE† provoked by a persistent risk factor§||Extended duration of treatment is recommended with specialist assessment8,9|
|Recurrent unprovoked VTE†||Extended duration of treatment is recommended, with specialist assessment8,9|
† VTE: DVT or PE|
‡ Surgery, trauma, immobilisation > 3 days, pregnancy or postpartum, oral contraceptive or HRT
§ Such as cancer (low molecular weight heparin is preferred treatment), multiple thrombophilias, antiphospholipid syndrome
Length of treatment for patients requiring extended-duration anticoagulation is uncertain.
In people requiring treatment for longer than 3 months the benefits and harms of treatment can be closely matched, and duration of treatment should be individualised depending on their risk of bleeding.7,10
Re-evaluate the risk of VTE recurrence, bleeding risk, type of anticoagulation and patient preference annually.8,10
Continue anticoagulant treatment to prevent VTE recurrence until either:10
- the reduction in risk of VTE recurrence no longer outweighs the increase in bleeding risk
- the patient wishes to stop treatment, even if the reduction in the risk of VTE recurrence would outweigh the increase in bleeding risk.
Careful selection of oral anticoagulants based on individual patient situations is crucial
Do not switch to rivaroxaban in people who are non-adherent with warfarin
Consider switching to rivaroxaban from warfarin in people:
- who are not able to maintain a consistent INR within the therapeutic range 60–70% of the time despite all correctable factors for INR fluctuation having been addressed and adherence confirmed
- who experience drug or major drug–food interactions with warfarin
- with poor venous access for INR monitoring
- who are no longer able to undergo routine INR monitoring
- who have a preference for switching.
Contraindicated in people with severe renal impairment
Rivaroxaban is contraindicated in people with CrCl < 30 mL/min when used for the treatment of DVT or PE and for the prevention of recurrence of VTE.
Routine clinical monitoring is essential with all oral anticoagulants
There is no antidote to the anticoagulant effects of the newer oral anticoagulants and no readily available and validated method of monitoring their activity in a primary care setting. Routine coagulation monitoring is not possible but routine clinical monitoring is essential.
Advise patients to seek urgent medical attention for unexplained bruising, blood in the urine or black stools.
Ensure good patient adherence to dosing, as the newer agents have a much shorter half-life than that of warfarin and the risk of thromboembolism due to treatment failure may be greater if a dose is missed.
Other indications and contraindications of newer oral anticoagulants
- Dabigatran is contraindicated in people with severe renal impairment (CrCl < 30 mL/min).15
- Rivaroxaban is contraindicated in people with CrCl < 15 mL/min when used for preventing VTE after total knee or total hip replacement.16
- Apixaban is contraindicated in people with CrCl < 25 mL/min.17
- Rivaroxaban and apixaban are contraindicated in people undergoing dialysis.16,17
For details of known drug interactions and use of newer oral anticoagulants in hepatic impairment see interactions with dabigatran, rivaroxaban and apixaban.
- Rossi S (ed). Australian Medicines Handbook, 2013. Adelaide: Australian Medicines Handbook Pty Ltd.
- National Prescribing Service. Rivaroxaban (Xarelto) for treatment of deep vein thrombosis and pulmonary embolism, and for prevention of venous thromboembolism recurrence. NPS RADAR, August 2013. http://www.nps.org.au/npsradar/rivaroxaban-dvt-pe
- EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510. [PubMed]
- EINSTEIN-PE Investigators E-P, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. [PubMed]
- Bereznicki LR, Madden AR, Peterson GM. The quality of international normalised ratio control in southern Tasmania. Med J Aust 2013;198:315. [PubMed]
- Baglin T, Bauer K, Douketis J, et al. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012;10:698–702. [PubMed]
- Boutitie F, Pinede L, Schulman S, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011;342:d3036. [PubMed]
- de Jong PG, Coppens M, Middeldorp S. Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term. Br J Haematol 2012;158:433–41. [PubMed]
- eTG complete [online]. Therapeutic Guidelines: Cardiovascular. Version 6. Melbourne: Therapeutic Guidelines Ltd, 2012. http://www.tg.org.au/index.php?sectionid=42
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S–94S. [PubMed]
- Raju NC, Hirsh J, Eikelboom JW. Duration of anticoagulant therapy for venous thromboembolism. Med J Aust 2009;190:659–60. [PubMed]
- National Prescribing Service Ltd. Dabigatran (Pradaxa) for preventing venous thromboembolism after hip or knee replacement surgery. NPS RADAR, April 2010. http://www.nps.org.au/publications/health-professional/nps-radar/2010/april-2010/dabigatran
- National Prescribing Service Ltd. Rivaroxaban (Xarelto) for preventing venous thromboembolism after hip or knee replacement surgery. NPS RADAR, August 2009. http://www.nps.org.au/publications/health-professional/nps-radar/2009/august-2009/rivaroxaban
- National Prescribing Service Ltd. Apixaban (Eliquis) for preventing venous thromboembolism after knee or hip replacement surgery. NPS RADAR, January 2012. http://www.nps.org.au/publications/health-professional/nps-radar/2012/january-2012/brief-item-apixaban
- Boehringer Ingelheim Pty Limited. Dabigatran Etexilate (Pradaxa) Product Information, November 2011. Updated 11 June 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=pi&q=dabigatran (accessed 28 January 2014).
- Bayer Australia Ltd. Xarelto (Rivaroxaban) Product Information. Updated 27 June 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-01020-3 (accessed 28 January 2014).
- Bristol-Myers Squibb Australia Pty. Ltd. Apixaban (Eliquis) Product Information. Updated 4 July 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-03072-3 (accessed 28 January 2014).