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Published on 12 April 2011

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A new future for oral anticoagulation

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Sharron Millen
Head of Clinical Pharmacy & Chair UKCPA (HAT)
Southampton University Hospitals NHS Trust

Duncan McRobbie
Associate Chief Pharmacist
Guy’s and St Thomas’ NHS Foundation Trust
UK

Anticoagulation is a routine part of patient management for prophylaxis and treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (SPAF). Until recently there was little choice when it came to selecting a drug. Prophylaxis of VTE was managed primarily with low-molecular weight heparins (LMWH), treatment of VTE usually with a combination of LMWH and warfarin, and warfarin remains the main anticoagulant of choice for SPAF. The new wave of oral anticoagulants may provide alternatives in selected patient groups as the evidence evolves and licences are granted.

Introduction of new agents
In 2007, the first new oral anticoagulant in over three decades was launched. Ximelagatran (Astra-Zeneca), a direct thrombin inhibitor, was initially licensed for the prevention of VTE in patients undergoing major elective orthopaedic surgery (total hip or knee replacement). Much larger studies in the atrial fibrillation (AF) population demonstrated non-inferiority to warfarin without the inconvenience of monitoring. However, a small number of cases of serious hepatotoxicity were reported in this larger population and the drug was withdrawn from the market.1

Dabigatran, a new reversible direct thrombin inhibitor, was licensed in 2008 for the prevention of VTE in high-risk surgical patients. Given orally as the prodrug, dabigatran etexilate, it is rapidly absorbed from the gastro-intestinal tract and has a rapid onset of anticoagulant activity, with plasma levels peaking at two hours. The half-life ranges between 12 and 17 hours, producing a predictable anticoagulant effect, and eliminating the need for anticoagulation monitoring. With predominantly renal elimination, dose adjustment is required in patients with compromised renal function.2

Rivaroxiban is the first oral factor Xa inhibitor to receive approval. With high bioavailability (nearly 80%), predictable plasma levels (peaking after three to four hours) and a mean half-life ranging from five to nine hours in young individuals, and from 11 to 13 hours in the elderly, rivaroxiban can be administered at a fixed dose and does not need laboratory monitoring.2

Both these drugs received European and Canadian approval for prophylaxis of VTE in orthopaedic patients undergoing elective hip and knee replacements in 2008. Neither the trials nor clinical practice have shown any signs of hepatotoxicity.

Idraparinux is a once-weekly subcutaneous factor Xa inhibitor, and while not an oral agent, it does not require dose adjustment and may offer convenience in some patients.

Other oral factor Xa inhibitors including apixaban (Bristol-Myers Squibb/Pfizer), edoxaban tosylate (Daiichi-Sankyo), betrixaban (Portola Pharmaceuticals/Merck) and YM150 (Astellas) are currently in various stages of development. There are also other agents with different mechanisms of anticoagulation activity in the pipeline, including a factor IXa inhibitor, TTP889 (TransTech Pharma) and an orally active glycosaminoglycan enhancer, odiparcil (SmithKline Beecham).

Once these agents are available to prescribers, there will be more options available and better flexibility of treatments for patients. However, whether the   patients themselves will be concordant with drugs which they may perceive to be less important than drugs requiring intensive monitoring or invasive administration remains to be seen.

VTE prophylaxis in the UK
Hospital-acquired VTE is a recognised problem in the UK. Each year, it is estimated that as many as 32,000 people in the UK die as a result of blood clots they get while in hospital. This is more than 25 times the number who die from methacillin-resistant Staphylococcus aureus and more than the total combined deaths per year from breast cancer, AIDS and road traffic accidents.3 As a result, prevention of VTE has become a major priority for the NHS over the past 12 months. National targets for VTE reduction have been set, with financial penalties for hospitals not achieving them.

Changes in the management of anticoagulation in patients at risk of VTE have already been seen. Trials with both dabigatran and rivaroxaban have demonstrated equivalence with LMWH in prophylaxis of deep vein thrombosis (DVT) in patients undergoing high-risk orthopaedic surgery.4–8 Following their launch, the uptake of dabigatran and rivaroxiban was slow, until their use was supported initially by National Institute of Health and Clinical Excellence (NICE) technology appraisals9,10 and then subsequently through incorporation within formal NICE guidance on the prevention of VTE in patients undergoing elective hip and knee replacement.11 NICE is the principal driver for therapeutic treatment guidelines in the UK, although local implementation of national guidance may include other consensus guidance.12

Trials with apixiban have had mixed results, with ADVANCE-1 failing to demonstrate non-inferiority against the US recommended dose of 30mg twice a day in patients undergoing knee replacement.13 However, in ADVANCE-2 apixaban was more efficacious than the European dose of 40mg of enoxaparin, with similar bleeding, in the same indication.14 ADVANCE-3, comparing apixaban against the European dose has been completed but not yet published.15 Trials of the newer agents in the prophylaxis of VTE in medical patients are ongoing.

Extended prophylaxis
The evidence for extended thromboprophylaxis in patients after surgery is continually evolving. Existing data supports extended VTE prophylaxis with LMWH in patients undergoing surgery for abdominal cancers. The oral agents in this setting could reduce the time needed to train patients or carers to inject, and reduce patient discomfort and inconvenience.
The Royal College of Obstetrics and Gynaecology has recently produced guidance advocating seven days of VTE thromboprophylaxis post caesarean section. It is unlikely that these new agents will be licensed for such a specialist indication; however, an oral agent may be considered advantageous in this setting, due to the high risk associated with the release of sharps to a household of sleep-deprived parents with young children.

Treatment of VTE
Current treatment for DVT and pulmonary embolism (PE) is LMWH followed by a vitamin K antagonist (VKA), usually warfarin. LMWH treatment is continued until the international normalised ratio (INR) is >2, but the optimum length of VKA treatment depends on the patient condition and risk factors. This treatment is effective but inconvenient for the patient, requiring both injections and regular monitoring.

Several trials are supporting a progression to oral anticoagulants in patients requiring treatment for DVT and PE. The RECOVER study demonstrated that dabigatran was non-inferior to warfarin in reducing symptomatic objectively confirmed  recurrence of VTE in patients with acute VTE, DVT and/or PE, who were initially treated with parenteral anticoagulants. Major bleeding was not different between the two groups.16

The Einstein DVT study was reported at the European Society of Cardiology in September 2010. In this study 15mg of rivaroxaban twice-daily for three weeks followed by 20mg daily was compared to standard therapy with LMWH followed by warfarin or another VKA. Rivaroxaban demonstrated non-inferiority and neither major or minor bleeding rates differed.17

In patients with DVT, once-weekly subcutaneous idraparinux for three or six months had an efficacy similar to that of heparin plus a VKA. However, in patients with PE, idraparinux was less efficacious than standard therapy.18

Acute coronary syndrome
Various combinations of anti-platelet agents and anticoagulants reduce mortality and subsequent cardiac events in patients with acute coronary syndrome (ACS). Traditional combinations of aspirin, clopidogrel and either unfractionated heparin or LMWH are continually being challenged by both newer and more potent anti-platelet agents and anticoagulants.

Phase II studies with rivaroxaban (ATLAS ACS-TIMI 46) and apixaban (APPRAISE) in ACS have led to randomised, double-blind, placebo controlled studies that will evaluate the efficacy and safety of rivaroxaban (2.5mg or 5mg twice-daily) or apixaban (2.5mg or 5mg twice-daily) in addition to standard care in patients with a recent ACS. The apixiban study (APPRAISE-2), in Japanese patients only, is expected to complete recruitment early in 2011, while rivaroxaban recruitment is expected to complete in mid-2011.

Stroke prevention in AF
Decreases in atrial contractility reduce blood flow and increase the chance of clot formation in patients with AF who are five times more likely to have a stroke than people without AF. Three out of four AF-related strokes can be prevented by adequate anticoagulation and patients are risk assessed for appropriate prophylaxis to ensure that they get appropriate pharmacological prophylaxis.

The choice of anticoagulant strategy is determined by the CHADS2 score which predicts the risk of stroke. Recently, this has been adapted to incorporate vascular risk factors. By using bleeding risk predictors (eg, the HAS-BLED score) clinicians can be guided to balance the bleeding and stroke risk of anticoagulants.19

Warfarin has been shown to reduce the risk of stroke by approximately 67%. Aspirin is less effective, giving only a 25% risk reduction. A significant number of patients with a high risk of stroke are not prescribed warfarin because of bleeding risks and the inconvenience of regular monitoring.

Studies are supporting the use of oral anticoagulants in this patient population. The RE-LY study showed that the direct thrombin inhibitor dabigatran was non-inferior at 110mg twice a day and superior to warfarin in the 150mg twice a day dose in patients with documented AF and at least one other risk factor. The lower dose showed less bleeding than warfarin while bleeding rates were similar between the higher doses. Rates of intracranial haemorrhage were lower for both doses of dabigatran.20

Even in centres where INR control was excellent, dabigatran was non-inferior at the 110mg dose and superior at the 150mg dose to warfarin for prevention of stroke or systemic embolism.

There was a small increase in the number of MIs in the high-dose group although the absolute rate was low. Dyspepsia was significantly more frequent with both doses of dabigatran. The results of trials for the other oral anticoagulants are eagerly awaited.

Apixaban (Pfizer/Bristol-Myers Squibb), an oral factor Xa inhibitor, was recently reported as being superior to aspirin in patients with AF who were unable to take warfarin. The results of the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, were reported at the European Society of Cardiology 2010 Congress. This study was terminated early, as apixaban significantly reduced the risk of stroke or systemic embolism by 54% compared to aspirin. Overall bleeding rates were similar in both groups.21

The Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial, is a comparison of apixaban 5.0mg twice-daily versus warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. The trial is currently under way, and results are expected in April 2011.

ROCKET-AF is examining whether a once-daily dose of 20mg of rivaroxaban is non-inferior to warfarin in just over 14,000 patients with non-valvular AF who have a history of stroke or at least two additional independent risk factors. This trail has finished recruiting and is expected to report in November 2010.22

Other new oral factor Xa inhibitor edoxaban (Daiichi-Sankyo) is being tested in a phase III trial in more than 16,000 patients with AF, and betrixaban (Portola Pharmaceuticals/Merck) showed promise in a dose-finding phase II trial in patients with AF (EXPLORE-Xa).

In the open-labelled AMADEUS study, idraparinux had significantly more bleeding despite demonstrating non-inferiority with warfarin.

Conclusion
Warfarin and heparins have been the mainstay of therapy for a number of years. New oral anticoagulants provide an exciting opportunity to deliver the same or even better therapeutic outcomes with similar or potentially less bleeding risks. Fixed dosing, the lack of the requirement for monitoring, and less food and drug interactions provide additional benefits for patients. No doubt these agents will be more expensive than traditional therapy and will add to the financial burden of healthcare
systems.

References
1. Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee testimony. Available online at: www.fda.gov/ohrms/ dockets/ac/04/transcripts/2004- 4069T1.pdf
2. Eriksson BI, et al. Clin Pharmacokinet 2009;48:1-22.
3. House of Commons Health Committee. The prevention of Venous Thromboembolism in Hospitalised patients. The House of Commons, 2005.
4. Erikson BI, et al. Lancet 2007;370:949-56.
5. Erikson BI, et al. N Engl J Med 2008;358:2765-75.
6. Kakkar AK, et al. Lancet 2008;372:31-9.
7. Lassen MR, et al. N Engl J Med 2008;358:2776-86.
8. Turpie AG, et al. Lancet 2009;373:1673-80.
9. National Institute of Clinical Excellence, Rivaroxaban Technical Appraisal (TA170) April 2009.
10. National Institute of Health and Clinical Excellence, Dabigatran Technical Appraisal (TA157) September 2008.
11. National Institute of Clinical Excellence, Clinical Guidelines.  Reducing the risk of Venous Thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital CG92 NICE 2010.
12. Geets WH, et al. Chest 2008;133(Suppl.6):381S-453S.
13. Lassen MR, et al. N Engl J Med 2009;361:594-603.
14. Lassen MR, et al. Lancet 2010;375:807-15.
15. ADVANCE-3. Results presented during the International Congress on Thrombosis; Milan; July 8 2010.
16. Schulman S, et al. N Engl J Med 2009;361:2342-52.
17. Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Deep-vein Thrombosis without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation. Presented at European Society of Cardiology: Stockholm, September 2010.
18. van Gogh investigators; Buller HR et al. N Engl J Med 2007;357:1094-104.
19. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Guidelines for the management of atrial fibrillation. Eur Heart J 2010. doi:10.1093/eurheartj/ehq278.
20. Connolly SJ, et al. N Engl J Med 2009;361:1139-51.
21. Apixaban versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Treatment: a Randomized Double Blind Trial (AVERROES). Presented at ESC, Stockholm, 2010
22. Patel MR et al. 2010 European Stroke Conference: Barcelona, 27 May 2010.



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