European Journal of Internal Medicine
Volume 20, Issue 6 , Pages 562-568, October 2009

A new era for anticoagulants

  • Massimo Franchini

      Affiliations

    • Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine, University Hospital of Parma, Italy
    • ,
  • Pier Mannuccio Mannucci

      Affiliations

    • Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy
    • Corresponding Author InformationCorresponding author. Via Pace, 9, 20122 Milan, Italy. Tel.: +39 0255035422; fax: +39 0250320723.

Received 8 April 2009; received in revised form 21 April 2009; accepted 15 May 2009. published online 02 July 2009.

Article Outline

Abstract 

Selective inhibitors of specific coagulation factors represent a new class of antithrombotic agents, designed to overcome the limitations of traditional anticoagulants. Available clinical studies indicate that the most promising new anticoagulants are those selectively targeting factor Xa and thrombin. Typically, the standard steps for clinical evaluation of new anticoagulants are thromboprophylaxis in high risk orthopedic surgery, followed by treatment of established venous thromboembolism, nonvalvular atrial fibrillation and acute coronary syndromes. These agents – that have the potential to be more effective and easier to use than conventional drugs such as heparins and vitamin K antagonists – will greatly expand our armamentarium for the prevention and treatment of arterial and venous thromboembolism. The current knowledge on these antithrombotic agents is summarized in this review, particularly focusing on the early results of clinical trials.

Keywords: Anticoagulants, Factor Xa inhibitors, Thrombin inhibitors, Venous thromboembolism, Thromboprophylaxis, Orthopedic surgery

 

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1. Introduction 

Venous and arterial thromboembolic diseases are still the most frequent cause of death and disability in high-income countries, and their incidence is dramatically increasing also in middle- and low-income countries. Antithrombotic drugs inhibiting coagulation or platelet function play a key role in the management of these patients. This review article deals only with anticoagulants, that currently include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), vitamin K antagonists (VKA) and the synthetic pentasaccharide fondaparinux [1], [2], [3]. Although the benefit of warfarin, the most commonly used VKA, is well established in a wide spectrum of thromboembolic disorders [4], its use is hampered by numerous limitations, such as delayed onset and offset of action, narrow therapeutic window, genetic variations of metabolism and food and drug interactions that warrant frequent monitoring and dose adjustment [5]. Like warfarin, UFH is highly efficacious but has a number of limitations that restrict its clinical use: its route of administration (mainly intravenous), significant binding to plasma and endothelial proteins, need for laboratory monitoring, risk of osteoporosis and the life-threatening thrombotic complications associated with heparin-induced thrombocytopenia (HIT) [6]. The limitations of UFH and warfarin led to the development of new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. LMWHs, derived from the depolymerization of UFH resulting in shorter chain lengths, have progressively replaced UFH, because they have a similar or greater efficacy and safety coupled with a number of advantages, such as longer half-life and more predictable dose-response that allows weight-adjusted fixed dosages with no need of laboratory monitoring [7]. However, the use of LMWH is still associated with the risk of HIT, although to a much lesser degree than for UFH, and the need for parenteral administration (mainly subcutaneous) renders its use sometimes problematic, especially in the outpatient setting.

Over the past decade, interest in anticoagulants has grown dramatically, as shown by the increasing number of drugs introduced in both preclinical and clinical development. In particular, research was focused on new agents selectively targeting specific steps in the coagulation cascade. For the most recently available among these drugs, the greatest advantage is that they can be administered orally and at fixed dosages.

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2. New anticoagulant drugs 

The new anticoagulants target a number of different steps in the coagulation system. However, the most advanced clinical development has been achieved for those inhibiting factor Xa (FXa) (either directly or indirectly via antithrombin) and thrombin (direct thrombin inhibitors) (Fig 1) [8], [9], [10], [11], [12]. They are usually small molecules that inhibit not only these coagulation enzymes when they circulate freely in plasma but also when they are thrombus bound. Of the new anticoagulants in clinical development (phase I and above), approximately 70% are inhibitors of factor Xa and 30% of thrombin, whereas there are at the moment relatively little efforts to develop new heparins (source: www.citeline.com/trialtrove.html). This review article will briefly mention only those who have reached phase III in clinical trials.

2.1. Indirect factor Xa inhibitors 

This subgroup includes fondaparinux and idraparinux, which have specific characteristics that distinguish them from UFH and LMWH (Table 1). Both are synthetic and act by indirectly enhancing the rate of FXa inactivation through antithrombin, thereby quenching thrombin generation. Neither fondaparinux nor idraparinux interacts with plasma proteins other than antithrombin, and hence produce a predictable anticoagulant response with no need for coagulation monitoring. Fondaparinux and idraparinux do not cause HIT because they do not bind to platelet factor 4 (PF4), so that they can be also used for the treatment of the thrombotic complications often associated with the development of HIT [13]. These agents do not interact with protamine sulphate, the antidote for heparin, and lack of specific antidotes is still a challenge owing to their long or very long half-life. However, recombinant activated factor VII counteracts the inhibition of thrombin generation caused by these pentasaccharides, even though current clinical evidence for their reversal of bleeding complications is scarce [14].

Table 1. Comparison of the characteristics of the parenteral anticoagulants unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), fondaparinux and idraparinux.
CharacteristicsUFHLMWHFondaparinuxIdraparinux
SourceBiologicalBiologicalSyntheticSynthetic
Molecular weight (Da)15,000500015001500
TargetXa and thrombinXa and thrombinXaXa
Bioavailability (%)3090100100
Half-life (h)14–61780–130
Renal excretionNoYesYesYes
AntidoteCompletePartialNoNo
Heparin-induced thrombocytopenia<5%<1%NoNo
2.1.1. Fondaparinux 

Fondaparinux is licensed for the prevention of venous thromboembolism (VTE) following such high risk orthopedic operations as hip fracture surgery, total hip replacement and total knee replacement, but also after major abdominal surgery for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and acute coronary syndromes. Fondaparinux has almost complete bioavailability after subcutaneous injection, and a plasma half-life of approximately 17 h that permits once-daily administration at fixed dosages with no need for laboratory monitoring [15]. The drug is excreted unchanged in the urine and is contraindicated in patients with severe renal failure [8].

2.1.1. Prophylaxis of venous thromboembolism 

Until recently, major orthopedic surgery was known to be still associated with a particularly high risk of VTE in spite of thromboprophylaxis and is typically the first clinical setting used to evaluate new drugs for thromboprophylaxis. It must be pointed out that most often in orthopedic surgery the main outcome for thromboprophylaxis trials was non-symptomatic venographically-detected venous thrombosis, a surrogate for clinical relevance that is not free from debate. Fondaparinux was more effective than the LMWH enoxaparin in 4 large phase III trials including a total of 7344 patients undergoing surgery for hip fracture (PENTasaccharide in HIp-FRActure Surgery Study [PENTHFRA] [16]), elective hip (European Pentasaccharide Hip Elective SUrgery Study [EPHESUS] [17] and PENTAsaccharide in Total Hip Replacement Surgery Study [PENTATHLON] [18]) or knee arthroplasty (PENTAsaccharide in MAjor Knee Surgery Study [PENTAMAKS] [19]). A meta-analysis of these studies has shown that fondaparinux, at a dose of 2.5 mg given subcutaneously once daily starting 6 h after hip or knee surgery, reduces the risk of VTE by 55% compared with enoxaparin. Although major bleeding occurred more frequently in the fondaparinux-treated group (P=0.008), the incidence of severe bleeding (leading to death, reoperation, or occurring in critical organs) was not different between the two drugs [20]. However, the definition of severe bleeding was made post-hoc, and it is unlikely that the pooled trials were sufficiently powered to detect a significant difference between the two drugs for such a rare event.

Thromboprophylaxis of extended duration with fondaparinux has been evaluated in a phase III trial (PENTasaccharide in HIp-FRActure Surgery-Plus [PENTHFRA-Plus]) conducted in 656 patients undergoing surgery for hip fracture [21]. Prolonging the duration of prophylaxis with fondaparinux (2.5 mg subcutaneously once daily) from 1 week to 4 weeks after fracture dramatically decreased the rate of venographically documented DVT from 35% to 1.4%, (P=0.001), and that of symptomatic VTE from 2.7% to 0.3% (P=0.021).

The thromboprophylactic use of fondaparinux was also evaluated in general surgical and medical patients. In a double-blind trial of 2048 subjects undergoing major abdominal surgery (PEntasaccharide GenerAl SUrgery Study [PEGASUS]), patients were randomly assigned to prophylaxis with fondaparinux (2.5 mg subcutaneously once daily) or dalteparin (2500 IU 2 h preoperatively and 6 h postoperatively and then 5000 IU postoperatively once daily for 5 to 9 days) [22]. The primary outcome (i.e., a composite of venographically documented DVT, symptomatic DVT and non-fatal and fatal PE), as assessed on postoperative day 10, occurred in 4.6% of the fondaparinux group and in 6.1% of the dalteparin group. Major bleeding occurred in 3.4% and 2.4%, respectively. Both differences are not statistically significant. In a double-blind study (ARixtra for ThromboEmbolism Prevention in a Medical Indications Study [ARTEMIS]), 849 acutely ill, medical patients aged 60 years or older were randomly assigned to receive in hospital fondaparinux (2.5 mg once daily) or placebo for 6 to 14 days [23]. The VTE rate at day 15 was 5.6% of the fondaparinux group and 10.5% of the placebo group, a statistically significant difference (P 0.03). Major bleeding while on therapy was infrequent and occurred in only 0.2% of patients in either group.

2.1.2. Treatment of venous thromboembolism 

Fondaparinux has also been evaluated for the treatment of VTE in 2 double-blind, noninferiority, randomized clinical trials. The MATISSE (Mondial Assessment of Thromboembolism treatment Initiated by Synthetic pentasaccharide with Symptomatic Endpoints) trial included 2205 patients with DVT were assigned to receive either fondaparinux (7.5 mg subcutaneously once daily) or enoxaparin (1 mg/kg subcutaneously twice daily) for 5 days followed by a minimum of a 3-month course of treatment with VKA [24]. At 3 months, recurrent symptomatic VTE was observed in 3.9% and 4.1% of the fondaparinux and enoxaparin groups respectively, major bleeding rates being 1.1% and 1.2%. In the open-label, noninferiority trial MATISSE-PE, 2213 patients with PE were assigned to fondaparinux (5, 7.5, or 10 mg subcutaneously once daily, according to patient weight) or UFH (by continuous infusion) for 5 days followed by a minimum of 3-month therapy with VKA [25]. At 3 months, the rate of recurrent symptomatic VTE was 3.8% and 5.0% in the fondaparinux or UFH groups and major bleeding rates were 1.3% and 1.1%. Overall, these trials show that fondaparinux is in general at least as effective and safe as UFH for initial treatment of PE, and as LMWH for the initial treatment of VTE.

2.1.3. Treatment of acute coronary syndromes 

The Fifth and Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5 and 6) trials evaluated the efficacy of fondaparinux (2.5 mg once daily) compared with a heparin-based strategy (dose-adjusted UFH or the LMWH enoxaparin) in patients with non-ST and ST-segment elevation acute coronary syndromes [26], [27]. A combined analysis of these 2 studies was recently performed, including 26,512 patients [28]. Fondaparinux was slightly superior to heparins in reducing the composite end point of death, myocardial infarction or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). In addition, fondaparinux reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than the heparins (11.1% versus 9.3%; HR, 0.83; P<0.0001). A disadvantage of fondaparinux in acute coronary syndromes is a risk of catheter thrombus formation unless supplemental heparin is flushed through the catheter.

2.1.2. Idraparinux 

Idraparinux is a second generation synthetic pentasaccharide, derived from hypermethylation of fondaparinux and has a plasma half-life as long as 80–130 h that allows once-weekly subcutaneous administration [12]. Idraparinux has been evaluated not only in the initial treatment of DVT and PE, but also in the extended secondary prophylaxis of VTE and the long-term prevention of stroke in patients with atrial fibrillation. The phase III van Gogh open-label noninferiority trials randomized 2904 patients with acute symptomatic DVT and 2215 patients with PE to either a 3- or 6-month course of once-weekly idraparinux (at a dose of 2.5 mg) or to conventional anticoagulant therapy with UFH followed by VKA [29]. In DVT, the primary efficacy outcome, i.e., the rate of recurrent venous thromboembolism at 3 months, was similar in the idraparinux and conventionally treated groups (2.9% and 3.0%, respectively). At 3 months, clinically relevant bleeds were less common with idraparinux (4.5% and 7.0%, respectively; P=0.004). However, in the PE patients, idraparinux was less effective than conventional anticoagulant therapy at 3 months, with a rate of recurrent VTE of 3.4% in those treated with idraparinux and of 1.6% in those on conventional therapy. Rates of clinically relevant bleeding episodes at 3 months in patients treated with idraparinux or conventional anticoagulant therapy were 5.8% and 8.2%, respectively. Overall, the van Gogh trials showed that idraparinux has an efficacy similar to that of heparins plus VKA in the initial treatment of DVT, but is less efficacious than standard anticoagulant therapy in PE. The therapeutic efficacy of long-term idraparinux was evaluated in the van Gogh extension trial, which enrolled 1215 patients from the DVT or PE trials who, after having received 6 months of treatment with either idraparinux or VKA [30], were randomized to an additional 6 months of treatment with either subcutaneous idraparinux (2.5 mg once weekly) or placebo. Compared with placebo, idraparinux reduced the rate of recurrent VTE from 3.7% to 1.0% (P=0.002). However, major bleeding occurred in 3.7% of patients randomized to idraparinux and included 3 fatal intracranial bleeds, whereas there was no major bleeding in patients randomized to placebo. These findings suggest that, although effective, long-term treatment with idraparinux is associated with an increased risk of bleeding. These views are strengthened by the Amadeus trial in patients with atrial fibrillation, stopped after randomization of 4576 patients because there was a significantly higher number of clinically relevant bleeds (including intracranial) with idraparinux than with VKA (19.7 versus 11.7% and 1.1 versus 0.4%, respectively) [31]. The main drawback of idraparinux is the delayed elimination from the body after prolonged administration, which explains the increased rate of bleeding complications [32]. In addition, there is no specific antidote to neutralize its activity. A biotinylated form of the drug, which has avidin as a specific antidote, is currently undergoing clinical trials [11], with the goal to improve the benefit-to-risk profile.

2.2. Direct FXa inhibitors 

Actually, the FXa inhibitors most advanced in terms of clinical validation are rivaroxaban and apixaban (Table 2).

Table 2. Comparison of the characteristics of the new oral anticoagulants.
RivaroxabanApixabanDabigatran
TargetFactor XaFactor XaThrombin
AntidoteNoneNoneNone
SourceSyntheticSyntheticSynthetic
ProdrugNoNoYes
Bioavailability (%)60–8050–854–10
Renal excretion (%)652580
Half-life6–99–1514–17
Approved indicationThromboprophylaxis in major orthopedic surgeryNone yetThromboprophylaxis in major orthopedic surgery
2.2.1. Rivaroxaban 

Rivaroxaban is a selective direct inhibitor of FXa given orally, absorbed via the gastrointestinal tract with a high bioavailability and excreted via renal (two thirds) and fecal (one third) routes [33], [34]. The relatively long half-life of this agent allows oral administration once or twice daily.

2.2.1. Prevention of venous thromboembolism 

At a daily dose of 10 mg, rivaroxaban was evaluated in the phase III REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE (RECORD) program, which includes two double-blind studies in total hip replacement and two in total knee replacement, enrolling more than 10,000 patients. The protocols of these studies and the main results are summarized in Table 3. In RECORD 1, rivaroxaban 10 mg daily (starting 6 h after surgery) was compared with enoxaparin 40 mg daily (starting the evening preceding surgery) for 5 weeks in patients undergoing total hip arthroplasty [35]. RECORD 2 compared a 5-week prophylactic regimen of rivaroxaban with the 10 to 14 days regimen of the LMWH enoxaparin 40 mg once daily (followed by placebo until day 35). In all studies rivaroxaban was superior to the LMWH enoxaparin with respect to the primary efficacy outcome, i.e. a composite of total VTE (symptomatic and asymptomatic DVT and non-fatal PE) and all-cause mortality. Of note, in RECORD 2 and 3, symptomatic VTE events (a secondary end point) were also reduced by 80% and 66% respectively. Major bleedings were rare in the all 4 studies, with no statistically significant difference between the arms.

Table 3. Rivaroxaban for thromboprophylaxis in major orthopedic surgery: results of the phase III trials.
Study [reference]Patients (n)SurgeryStudy armsPrimary efficacy outcomeaPrimary safety outcomeb
RivaroxabanEnoxaparinPRivaroxabanEnoxaparinP
RECORD 1 [35]4541Hip arthroplastyRivaroxaban 10 mg o.d. 5 weeks1.1%3.7%<0.0010.3%0.1%0.18
Enoxaparin 40 mg o.d. 5 weeks
RECORD 2 [36]2509Hip arthroplastyRivaroxaban 10 mg o.d. 5 weeks2.0%9.3%<0.0010.1%0.1%–
Enoxaparin 40 mg o.d. 10–14 days
RECORD 3 [37]2531Knee arthroplastyRivaroxaban 10 mg o.d. 10–14 days9.6%18.9<0.0010.6%0.5%0.77
Enoxaparin 40 mg o.d. 10–14 days
RECORD 4 [38]2300Knee arthroplastyRivaroxaban 10 mg o.d. 10–14 days6.9%10.1%0.0120.7%0.3%0.11
Enoxaparin 30 mg b.i.d. 10–14 days

Abbreviations: o.d. once daily; b.i.d. twice daily.

aComposite of total VTE (any DVT, non-fatal PE) and death from all causes up to the end of treatment period.

bIncidence of major bleeding on treatment.

2.2.2. Treatment of venous thromboembolism 

Data on the efficacy and safety of rivaroxaban for treatment of acute VTE are currently stemming from two phase II studies that did enrol more than 1150 patients. The ODIXa (Oral DIrect factor Xa) Study randomized 613 patients to twice daily doses of 10, 20 or 30 mg, or a once-daily dose of 40 mg of rivaroxiban or to standard treatment with enoxaparin and VKA for 12 weeks [39]. The primary efficacy end point of smaller thrombus burden on day 21 with no recurrent VTE or VTE-related death did not differ significantly among the rivaroxaban dosage groups or in comparison with standard treatment (43.8 to 59.2% of patients receiving rivaroxaban achieved the primary efficacy end point versus 45.9% of patients receiving standard treatment). Rates of symptomatic recurrence and of major bleeding were low. The second study, the Einstein-DVT study, included 543 patients randomized to receive rivaroxaban 20, 30, or 40 mg once daily or standard treatment for 3 months [40]. As in the first study, there was no significant difference in the primary outcome (the composite of symptomatic, recurrent VTE and decrease of thrombus burden as measured by quantitative ultrasound) in the 4 treatment groups (the primary efficacy end point occurred in 5.4–6.6% of patients receiving rivaroxaban and in 9.9% of patients receiving standard treatment). Phase III studies of rivaroxaban for stroke prevention in patients with atrial fibrillation are currently ongoing (the Rivaroxaban Once daily oral direct FXa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation [ROCKET AF] study) [41].

2.2.2. 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. Cleared through the renal and fecal routes and given twice daily [5], apixaban was tested in 1217 orthopedic surgery patients in a dose finding study, which used 5 to 20 mg of apixaban compared with 30 mg of enoxaparin twice daily or warfarin [42]. Treatment continued for all patients for 10–14 days. The primary outcome of composite VTE and all-cause death in the combined apixaban groups were significantly lower than the rate in the enoxaparin- (P<0.02) and warfarin-treated (P<0.001) groups (8.6%, 15.6% and 26.6%, respectively). The incidence of major bleeding for the apixaban groups ranged from 0 to 3.3%, while there was no major bleeding in either of the other comparator arms. Apixaban has also been tested in the initial treatment of acute VTE in a phase II dose-ranging study. Five hundred and twenty patients were enrolled and treated for up to 91 days with apixaban (5 mg twice daily, 10 mg twice daily or 20 mg daily) or conventional treatment with either LMWH in combination with a VKA or fondaparinux plus a VKA (Botticelli trial) [43]. The primary outcome rates (the composite of symptomatic recurrent VTE and decrease of thrombotic burden as assessed by repeat ultrasound or perfusion lung scanning) varied from 2.6% to 6% in various groups with no significant difference, and rates of bleeding were comparable. Apixaban is currently being tested in additional settings, including treatment of acute coronary syndromes (APPRAISE-1 study), prevention of VTE in major orthopedic surgery (ADVANCE trials), and prevention of stroke in nonvalvular atrial fibrillation (AVERROES and ARISTOTLE studies) [44].

2.3. Direct thrombin inhibitors 

The direct thrombin inhibitors most extensively studied the moment are dabigatran etexilate and ximelagatran.

2.3.1. Dabigatran etexilate 

Dabigatran etexilate is an oral direct thrombin inhibitor rapidly converted to the active form dabigatran once absorbed from the gastrointestinal tract [45]. The plasma half-life of dabigatran is 14–17 h, allowing for once-daily dosing, and elimination is primarily via the kidney [5] (Table 2).

2.3.1. Prevention of venous thromboembolism 

Three phase III studies investigating dabigatran etexilate for the prevention of VTE following major orthopedic surgery have been completed. The direct thrombin inhibitor was evaluated for prophylaxis of VTE in doses of 150 or 220 mg once daily in patients undergoing total hip arthroplasty (RE-NOVATE study, versus enoxaparin 40 mg once daily) [46] or total knee arthroplasty (RE-MODEL, versus enoxaparin 40 mg once daily), and RE-MOBILIZE, versus enoxaparin 30 mg twice daily) [47], [48]. Enoxaparin was started the evening before surgery. The primary efficacy end point was the composite of DVT, PE and all-cause mortality. The main results of these studies are shown in Table 4. Non-inferiority was demonstrated versus enoxaparin for the two doses of dabigatran etexilate, both in RE-NOVATE and RE-MODEL, whereas non-inferiority was not met versus the enoxaparin regimen of 30 mg twice daily in the RE-MOBILIZE study. Major bleedings were rare in the three studies, with no statistically significant between-arm difference. Of note, a combined pre-specified pooled analysis of the phase III VTE prevention program showed that dabigatran (150 mg and 220 mg daily) was at least as effective as enoxaparin (40 mg daily or 30 mg twice daily) in the prevention of VTE in orthopedic surgery patients.

Table 4. Dabigatran etexilate for thromboprophylaxis in major orthopedic surgery: results of the phase III trials.
Study [reference]Patients (n)Surgery typeStudy armsPrimary efficacy outcomeaPrimary safety outcomeb
EnoxaparinDabigatranDabigatranEnoxaparinDabigatranDabigatran
150 mg (P)220 mg (P)150 mg (P)220 mg (P)
RE-NOVATE [46]3494Hip arthroplastyEnoxaparin 40 mg o.d., 28–35 days6.7%8.6% (<0.0001)c6.0% (<0.0001)c1.6%1.3% (0.60)2.0% (0.44)
Dabigatran etexilate 150 mg o.d., 28–35 days
Dabigatran etexilate 220 mg o.d., 28–35 days
RE-MODEL [47]2076Knee arthroplastyEnoxaparin 40 mg o.d., 6–10 days37.7%40.5% (0.017)c36.4% (0.0003)c1.3%1.3% (–)1.5% (0.82)
Dabigatran etexilate 150 mg o.d., 6–10 days
Dabigatran etexilate 220 mg o.d., 6–10 days
RE-MOBILIZE [48]2715Knee arthroplastyEnoxaparin 30 mg b.i.d., 12–15 days25.3%33.7% (0.0009)d31.7% (0.02)d1.4%0.6% (NA)0.6% (NA)
Dabigatran etexilate 150 mg b.i.d., 12–15 days
Dabigatran etexilate 220 mg b.i.d., 12–15 days

Abbreviations: o.d. once daily; b.i.d. twice daily; NA, not available.

aComposite of total (venographic and symptomatic) VTE and death from all causes.

bIncidence of major bleeding on treatment.

cNon-inferior to enoxaparin.

dInferior to enoxaparin.

2.3.2. Other indications 

Dabigatran etexilate is also being investigated in 3 phase III studies for the long-term treatment and secondary prevention of VTE (RE-SOLVE, RE-COVER and RE-MEDY trials). In the PETRO study, a phase II randomized, dose-guiding study for the prevention of cardioembolic stroke in 502 patients with atrial fibrillation, dabigatran etexilate (50, 150 or 300 mg twice daily for 12 weeks), alone or combined with aspirin (81 or 325 mg daily), was compared with warfarin [49]. There was a significant difference in major plus clinically relevant bleeding episodes (17% versus 6%, P=0.03) and total bleeding episodes (39% versus 13%, P=0.0003) between 300 mg dabigatran etexilate twice daily plus aspirin and 300 mg dabigatran etexilate twice daily without aspirin. Nevertheless, the study concluded that dabigatran 150 mg twice daily had similar efficacy and safety to warfarin, thus paving the way for a still ongoing phase III study (RE-LY trial) [44].

2.3.2. Ximelagatran 

Ximelagatran is a prodrug of the active site-directed thrombin inhibitor melagatran. After oral ingestion and absorption, ximelagatran is rapidly and completely bioconverted to melagatran, the active agent, that is eliminated through the kidneys, has a plasma half-life of 4–5 h and is administered orally twice daily [50]. In the early 2000s, ximelagatran underwent an extensive program of clinical trials to evaluate safety and efficacy for thromboprophylaxis in high risk orthopedic patients, treatment of VTE, prevention of cardioembolic stroke in patients with atrial fibrillation and prevention of recurrent ischemia in patients with recent myocardial infarction [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61]. The results suggested that ximelagatran could be an effective alternative to standard therapy in all these thrombotic conditions. Despite these favorable results, because of concerns regarding hepatotoxicity, ximelagatran was withdrawn from the market and further development since February 2006 [5].

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3. Conclusions 

The new anticoagulants, which inhibit thrombin or factor Xa, have the potential to be more effective and are definitely easier to use than such conventional anticoagulants as the heparins and vitamin K antagonists. Clinical studies with parenteral fondaparinux and oral rivaroxaban, apixaban and dabigatran indicate that inhibitors of factor Xa or thrombin are highly effective for the prevention of venous thromboembolism, particularly in the setting of major orthopedic surgery (the first licensed indications for these drugs). In this setting, heparins are efficacious but the incidence of venous thromboembolism is still unacceptably high despite their use in primary prophylaxis. Only rivaroxaban was so far shown to be superior in efficacy to low-molecular-weight heparins. Moreover, a substantial advantage of this drug (and of dabigatran) is their oral routes of administration, because some patients find it difficult to be injected subcutaneously low-molecular-weight heparins or fondaparinux when they are discharged from hospital and must continue thromboprophylaxis for at least 30 days at home. Cost is a challenge, because in most countries the price of new anticoagulants is higher than those of low-molecular-weight heparins. Another potential issue is that none of these agents has an antidote able to neutralize their activity in case of excessive bleeding. Finally, in internal medicine wards many elderly patients have abnormal renal function, and it is not established whether or not the new drugs are more or less dangerous in this context, because the corresponding studies generally excluded these patients.

It cannot be given for granted that an anticoagulant agent that is effective for a given thrombotic condition has automatically a satisfactory benefit-risk profile in another indication. Hence, each of these agents must be evaluated for each potential clinical indication. The oral inhibitors of FXa and thrombin are currently being tested in the secondary prophylaxis of established venous thromboembolism, acute coronary syndromes and the prevention of cardioembolic stroke in nonvalvular atrial fibrillation. Of these, the most appealing for the internist is the latter, because many elderly patients find it difficult to comply with the requirements of prophylaxis with vitamin K antagonists, such as frequent attendance of coagulation laboratories and clinics, variability of the prothrombin time INR due to interactions with diet, drugs and genetic polymorphisms. In all, the new anticoagulants have the potential to greatly expand the armamentarium of drugs available to prevent and treat thromboembolic diseases. Perhaps during the second decade of the third millennium vitamin K antagonists and heparins will disappear, there will be no distinction between anticoagulants used in the initial and long-term therapy of venous thromboembolism, oral or long acting anticoagulants will be mainly used and hopefully there will be an improved stratification for who must be treated lifelong. Yet, anticoagulated patients will still need attendance and care at anticoagulant clinics to assess compliance, to monitor progress and determine treatment duration. Anticoagulant clinics may also be needed to monitor off target effects, such as liver dysfunction. Challenges for the new anticoagulants remain their higher costs relative to heparins and vitamin K antagonists, and lack of appropriate antidotes.

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4. Learning points 


•Currently available anticoagulant drugs, such as heparins and vitamin K antagonists, are effective and inexpensive, but they need laboratory monitoring and/or parenteral administration.

•Newer drugs have the advantage of being given orally at fixed dosages and do not need laboratory monitoring.

•Yet, there are more expensive, have at the moment no antidote to block anticoagulation in case of severe bleeding, and their risk-benefit profile is not known in patients with abnormal renal function.

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References 

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PII: S0953-6205(09)00089-2

doi:10.1016/j.ejim.2009.05.004

European Journal of Internal Medicine
Volume 20, Issue 6 , Pages 562-568, October 2009

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