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The new generation of oral anticoagulants

Walter Ageno
8 August, 2012  
Professor Walter Ageno
Associate Professor of Medicine,
Department of Clinical and
Experimental Medicine,
University of Insubria,
Varese, Italy
Currently available anticoagulants, including low molecular weight heparin (LMWH), parenteral  unfractionated heparin, fondaparinux and the oral vitamin K antagonists (VKA), are highly effective for both the prevention and treatment of venous thromboembolism (VTE) and the prevention of stroke in patients with atrial fibrillation, and their use in these settings is highly recommended by International guidelines. However, all these compounds have some limitations, such as subcutaneous administration or the need for careful monitoring. Over the past few years, a number of new anticoagulant drugs, both parenteral and oral, have been developed with the aim of improving the management of patients requiring anticoagulant therapies. 
The search for new anticoagulants has focused on several ideal characteristics that might fulfil some of the unmet requirements of conventional anticoagulant agents: universal dosing, no food or drug interactions, and rapid onset and offset of action, among others. Also, oral administration was considered more convenient than subcutaneous injection, in particular for patients receiving extended, out-of-hospital VTE prophylaxis and those treated for acute VTE.  
After extensive research programmes, a number of new oral anticoagulant drugs that selectively and directly inhibit thrombin or Factor Xa have been developed as promising alternatives to the existing anticoagulant agents. These compounds present predictable pharmacokinetics and pharmacodynamics that allow fixed dosing regimens. These new agents have been tested over the last few years in a number of settings, where they were compared with standard practice, usually either LMWH or VKAs. Following the favourable results of clinical trials, three of these new agents –namely dabigatran etexilate, rivaroxaban and apixaban – have been licensed in several countries. Current indications include the prevention of VTE in patients undergoing hip- and knee-replacement surgery, the treatment of deep vein thrombosis (DVT) and the prevention of stroke and systemic embolism in patients with atrial fibrillation. 
Given the availability of these drugs in clinical practice, it is important that practising clinicians become familiar with the principal characteristics of these drugs and with the results of phase III clinical trials in order to be able to offer the best available treatment options in terms of efficacy and, more importantly, in terms of safety, thus tailoring therapeutic strategies to the individual.  
Some of the principal pharmacokinetic and pharmacodynamic characteristics of these three agents are summarised in Table 1. The results of the published phase III trials are summarised in the following section. 
Dabigatran etexilate (Pradaxa)
Major orthopaedic surgery
Four randomised controlled trials (RCTs) have assessed the efficacy and safety of dabigatran etexilate for VTE prevention in patients undergoing total hip- and total knee-replacement surgery.(1–4) All trials were designed to show non-inferiority of dabigatran, 220mg and 150mg administered once daily (220mg only in the RE-NOVATE II study(2)), as compared with the standard treatment, subcutaneous enoxaparin. The results of these trials showed that both doses of dabigatran etexilate were as effective as the European regimen of enoxaparin – 40mg daily started the evening before surgery – in reducing the risk of VTE and VTE-related mortality after hip or knee arthroplasty and that both drugs have a similar bleeding profile. Dabigatran showed inferior efficacy to the North American regimen of enoxaparin – 30mg twice daily started post-operatively). The approved European regimen of dabigatran for patients undergoing elective major orthopaedic surgery is 220mg daily, with a first dose of 110mg to be administered one-to-four hours post-operatively. The lower dose of 150mg daily is recommended for certain patient groups, namely patients aged 75 years or older, patients with a moderate renal insufficiency (creatinine clearance 30–50ml/min), and patients taking concomitant drugs known to increase the plasma concentration of dabigatran, such as amiodarone and verapamil. 
Atrial fibrillation
The RELY trial compared two doses of dabigatran etexilate (110mg or 150mg twice daily) with dose-adjusted warfarin for stroke prevention in 18,000 patients with non-valvular atrial fibrillation and at least one risk factor for stroke.(5) The incidence of the primary outcome of stroke (including haemorrhagic stroke) or systemic embolism was significantly reduced with the higher dose of dabigatran as compared with warfarin, whereas the lower dose of dabigatran resulted in being non-inferior to warfarin. Conversely, the lower dose of dabigatran significantly reduced the incidence of major bleeding as compared to warfarin, whereas major bleeding incidence was similar between dabigatran 150mg twice daily and warfarin. Both dabigatran doses resulted in a statistically significant reduction in the rates of intracranial bleeding as compared to warfarin, whereas the administration of dabigatran (150mg) was associated with a statistically significant increase in gastrointestinal bleeding as compared with warfarin. The approved European regimen for dabigatran in patients with atrial fibrillation is 150mg twice daily, with the lower dose of 110mg twice daily suggested for certain patient groups, including patients aged 80 years or older, patients with moderate renal insufficiency, and patients on concomitant drugs that potentially interfere with the plasma concentration of dabigatran, such as verapamil.
Treatment of VTE
Dabigatran has been compared with warfarin in the treatment of VTE in the RECOVER trial.(6) Following an initial course of parenteral treatment, patients were randomised to dabigatran – 150mg twice daily – or to warfarin. After six months of treatment, the incidence of recurrent VTE or major bleeding was similar between the two drugs, with a statistically significant reduction in the incidence of any bleeding event in favour of dabigatran. 
Rivaroxaban (Xarelto) 
Major orthopaedic surgery
In the RECORD programme, rivaroxaban was compared with enoxaparin in patients undergoing total hip-replacement surgery and total knee-replacement surgery.(7–10)  In all RECORD studies, rivaroxaban significantly reduced the incidence of the primary efficacy outcome (total VTE) and all cause-mortality, with no statistically significant differences in the rates of major bleeding events. In three studies,(7–9) rivaroxaban was also superior to enoxaparin in reducing the risk of major VTE, including proximal deep vein thrombosis and symptomatic events. The approved European regimen for rivaroxaban in this setting is 10mg once daily started six-to-eight hours post-operatively, with no requested dose adjustments for specific patient subcategories. 
Atrial fibrillation
The ROCKET study was designed to assess the efficacy and safety of rivaroxaban in patients with atrial fibrillation and at least two additional risk factors for stroke(11). In this randomised, double-blind, double-dummy study, approximately 14,000 patients were randomised to receive rivaroxaban 20mg once daily (15mg once daily if creatinine clearance was between 30 and 49ml/min) or warfarin. The incidence of the primary outcome (stroke or systemic embolism) was similar between the two groups. Major bleeding events were similar between the two groups, but the incidence of intracranial haemorrhage was significantly lower in the rivaroxaban group than in the warfarin group. Rivaroxaban has been approved for clinical use in this setting by the Food and Drug Administration. The recommended dosing regimens are those used in the ROCKET trial. 
Treatment of VTE 
In the EINSTEIN DVT trial, rivaroxaban was administered at a dosage of 15mg twice a day for the first 3 weeks followed by 20mg once daily and was compared to standard therapy with LMWH and VKA(12). The primary outcome measure of symptomatic recurrent VTE was similar between the two groups as was the incidence of bleeding events. Rivaroxaban was also tested in the long-term secondary prevention of VTE in the EINSTEIN extension study.(12) In this randomised, double-blind, placebo-controlled study, patients who completed an anticoagulant treatment course of 6–12 months after the index VTE event were randomised to receive rivaroxaban (20mg a day) or placebo for an additional six or 12 months. During the treatment period, symptomatic recurrent VTE events were significantly reduced by rivaroxaban and major bleeding events were not statistically different between the two groups. Clinically relevant non-major bleeding was increased significantly in the rivaroxaban group.  
Apixaban (Eliquis) 
Major orthopaedic surgery
Apixaban (2.5mg) administered twice daily and started 12–24 hours post-operatively was compared with enoxaparin in three clinical trials carried out in patients undergoing total knee and total hip arthroplasty – the ADVANCE trials.(13–15) Based on the prespecified criterion for non-inferiority, the ADVANCE-1 study failed to show non-inferiority of apixaban compared to the twice-daily administration of enoxaparin 30mg, although apixaban demonstrated a favourable safety profile. In the ADVANCE-2 and ADVANCE-3 studies,(14,15) treatment with apixaban resulted in a statistically significant reduction in the primary efficacy endpoint of total VTE and all-cause mortality, and in a similar safety profile as the European regimen of enoxaparin (40mg started pre-operatively). In these two studies, apixaban also significantly reduced the risk of major VTE. Based on the results of ADVANCE-2 and 3 studies, the European Medicines Agency has approved the use of apixaban in this setting. 
Atrial fibrillation
In the AVERROES study, patients with atrial fibrillation who were deemed ineligible for VKA treatment were randomised to receive apixaban 5mg twice daily or aspirin 81–324mg once a day.(16) The study was prematurely stopped because of the clear superiority of apixaban over aspirin, with a similar safety profile. The ARISTOTLE compared apixaban 5mg twice daily and warfarin in approximately 18,000 patients with atrial fibrillation and at least one additional risk factor for stroke.(17) Patients aged 80 years or older, patients weighing 60kg or less, and patients with creatinine levels ≥1.5mg/dl received a lower dose of apixaban – 2.5mg twice daily. The incidence of stroke or systemic embolism was significantly reduced by apixaban, as well as the incidence of major bleeding and intracranial bleeding. Also, overall mortality was reduced significantly with the new oral anticoagulant drug. 
Practical issues of the new drugs
There are currently three new anticoagulant drugs that have received approval for clinical use in a number of countries. Based on the results of clinical trials, these drugs appear to be effective and safe alternatives to standard anticoagulant treatment regimens, including LMWHs for the prevention and treatment of VTE, and VKAs for the treatment and long-term secondary prevention of VTE and the prevention of stroke in patients with atrial fibrillation. 
Some attempts have been made recently to compare these new agents, with the aim of identifying which new molecule or which new class of drugs (thrombin inhibitors or Factor Xa inhibitors) may be the best alternative to the standard of care in this setting.  Because there are no direct comparisons (and there are unlikely to be any over the next few years) all attempts at indirect comparison across studies should be taken very cautiously because of numerous differences in study design. Of more relevance to clinicians are the differences between the drugs, which include:
  • Renal clearance is paramount for dabigatran, but is less important with rivaroxaban and apixaban (see Table 1). Calculation of creatinine clearance is highly recommended when prescribing a new oral anticoagulant drug and, possibly, also during long-term treatments. Knowledge of renal function will allow prescribing of the right drug and the right dosages, where appropriate. 
  • Mechanisms of drugs interactions are different between direct anti-thrombins and direct anti-Factor Xa inhibitors (see Table 1). Although none of the new agents are expected to have relevant drug interactions, great caution is required witih drugs that strongly interfere with cytochrome P3A4 and/or P-glycoprotein, because they might induce important changes in the concentration of the new anticoagulants. Drugs with the greatest potential for interaction include amiodarone, verapamil, quinidine, and rifampicin for dabigatran etexilate; and ketoconazole, ritonavir, clarithromycin, rifampin, and diltiazem for rivaroxaban and apixaban. 
  • Each compound has different effects on routine laboratory tests, and specific tests to assess their concentration, when eventually available, are likely to be drug specific.
  • Reversal strategies are not likely to be the same for all molecules. No antidotes currently exist, so the management of major bleeding remains empirical. The use of fresh frozen plasma to help control bleeding has been suggested with dabigatran, and evidence derived from animal models suggests that prothrombin complex concentrates (PCCs) or recombinant factor VIIa may bypass the anticoagulant effect of high doses of dabigatran.(18) In vitro studies suggest that early administration of activated charcoal might reduce its adsorption thereby reducing the effects of the drug. Finally, dabigatran is potentially removable by haemodialysis, as was demonstrated in a study of subjects with end-stage renal disease. Owing to its high plasma protein binding, rivaroxaban is not dialysable. It is currently suggested that in cases of active bleeding, blood products should be administered. The use of PCCs or recombinant  factor VIIa should also be considered. Recently, a recombinant factor Xa has been developed and presented as a potential antidote for factor Xa inhibitors.(18) 
 
References
  1. Eriksson BI et al, for the RE-NOVATE Study Group.  Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.  Lancet 2007;370:949–56. 
  2. Eriksson BI et al, for the RE-NOVATE II Study Group.  Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II).  Thromb Haemost 2011;105:721–9.
  3. Eriksson BI et al, for the RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178–85.
  4. Ginsberg JS et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1–9.
  5. Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
  6. Schulman S et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–52.
  7. Eriksson BI et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358,2765–75. 
  8. Kakkar AK et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind randomized controlled trial. Lancet 2008;372:31–9.
  9. Lassen MR et al. Rivaroxaban for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358,2776–85.
  10. Turpie AG et al. Rivaroxaban versus enoxaparin for  thromboprophylaxis after total knee arthroplasty (RECORD 4): a randomized trial. Lancet 2009;373:1673–80.
  11. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
  12. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510.
  13. Lassen MR et al. Apixaban or enoxaparin for the thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594–604.
  14. Lassen MR et al. Apixaban versus enoxaparin for the thromboprophylaxis after knee replacement (ADVANCE -2): a randomized double blind trial. Lancet 2010;375:807–15. 
  15. Lassen MR et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487–98. 
  16. Connolly SJ et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17.
  17. Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.
  18. Romualdi E et al. Managing bleeding complications in patients treated with the old and the new anticoagulants. Curr Pharm Des 2010;16:3478–82.