Ximelagatran: A clinical perspective

European Journal of Internal Medicine 16 (2005) 267 – 278 www.elsevier.com/locate/ejim

Review article

Ximelagatran: A clinical perspectivei C.J. Boosa,c,*, A. Hintonb, G.Y.H. Lipc a

Department of Cardiology, Southampton General Hospital, Tremona Rd, Southampton, UK Medicine for the Care of the Elderly, Southampton General Hospital, Tremona Rd, Southampton, UK c Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, B18 7QH, UK b

Received 21 January 2005; accepted 1 February 2005

Abstract Ximelagatran is a novel oral anticoagulant belonging to a class of drugs known as direct thrombin inhibitors. Numerous recent large-scale, randomised controlled clinical trials have given the drug a large clinical platform. These include data on the thromboprophylaxis of venous thromboembolism following major orthopaedic surgery and knee arthroscopy, as well as in the treatment of deep vein thrombosis and prevention of stroke with nonvalvular atrial fibrillation. One phase II study has also shown the efficacy and safety of ximelagatran in secondary prevention post-myocardial infarction. Unfortunately, approximately 6% of patients develop usually self-limiting derangement of liver dysfunction, and frequent monitoring of liver function is likely to be recommended for the first 6 months of treatment. Unlike the vitamin K antagonists, ximelagatran has a wide therapeutic interval with few food, alcohol or drug interactions, and it does not require anticoagulant monitoring. The aim of this overview is to review the clinical trials pertaining to this new drug, which is the first new oral anticoagulant for over 60 years, and one that is likely to influence our management of thrombosis-related disorders. D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Ximelagatran; Warfarin; Thromboembolism; Atrial fibrillation

Contents 1. 2.

3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Heparins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Indirect factor Xa inhibitors . . . . . . . . . . . . . . . . . . . . . . 2.3. Vitamin K antagonists . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Direct thrombin inhibitors . . . . . . . . . . . . . . . . . . . . . . . Ximelagatran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention of venous thromboembolism in orthopaedic surgery . . . . . . . Management of venous thromboembolism . . . . . . . . . . . . . . . . . . 5.1. Ximelagatran for long-term secondary prevention and acute treatment Thromboprophylaxis for atrial fibrillation . . . . . . . . . . . . . . . . . . Post-myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . .

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GYHL has received funding for research, educational symposia, consultancy and lecturing from different manufacturers of drugs used in the treatment of atrial fibrillation and thrombosis, including AstraZeneca, who manufacture ximelagatran. * Corresponding author. Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, B18 7QH, UK. Tel./fax: +44 121 507 5080. 0953-6205/$ - see front matter D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2005.02.005

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8. Adverse effects of ximelagatran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Thrombosis is the single largest underlying pathophysiological cause of disease or death in the western world [1– 3]. Indeed, thrombosis contributes to deep vein thrombosis (DVT), pulmonary embolism (PE), unstable angina, acute myocardial infarction (MI), embolic and thrombotic stroke and peripheral artery occlusion. The generation of thrombin is the key step in thrombus formation. The latter leads to platelet activation and the final pathway of coagulation, with the generation of fibrin from fibrinogen. Hence, the prevention of thrombin generation either directly or indirectly is the main aim of anticoagulation. Ximelagatran (Exanta\, AstraZeneca) is a novel oral anticoagulant belonging to a class of drugs known as direct thrombin inhibitors. It represents the first new oral anticoagulant in over 50 years. Numerous recent large-scale, randomised controlled clinical trials have given the drug a large clinical platform. These include data for the thromboprophylaxis of venous thromboembolism (VTE) following major orthopaedic surgery and knee arthroscopy, the treatment of DVT, the prevention of stroke in nonvalvular atrial fibrillation (AF) and prevention of cardiovascular endpoints post-MI [4]. Unlike the vitamin K antagonists, ximelagatran has a wide therapeutic interval with few food, alcohol or drug interactions, and it does not require anticoagulant monitoring [5]. The aim of this overview is to review the clinical trials pertaining to this new drug, which is likely to influence our management of thrombosis-related disorders.

2. Anticoagulants Current anticoagulation practice involves the use of drugs that inhibit thrombin directly or indirectly by interacting with other clotting factors. Anticoagulants in current use can broadly be divided into the heparins, vitamin K antagonists and new agents, such as the factor Xa inhibitors and direct thrombin inhibitors.

response, necessitating frequent anticoagulation monitoring [5]. In addition, UH can cause heparin-induced thrombocytopenia [8,9]. The LMWHs present clear advantages over UH in view of their predictable anticoagulation profile without the requirement for anticoagulation monitoring [6,7]. Although LMWHs can cause heparin-induced thrombocytopenia, the risk is lower than for UH [8]. Also, UH and LMWH may both cause osteoporosis [10,11]. Nonetheless, the clinical applications for LMWHs continue to expand, with confirmed benefits for the prevention of VTE in highrisk medical patients [12,13]. 2.2. Indirect factor Xa inhibitors Fondaparinux is an indirect factor Xa inhibitor, being a synthetic analogue of the antithrombin-binding pentasaccharide sequence found in heparin and LMWH [14,15]. It has proven efficacy for the thromboprophylaxis of patients undergoing major orthopaedic surgery, and in general medical and surgical patients [16 –20]. The Matisse DVT and PE trials have also confirmed the efficacy of fondaparinux for the treatment of VTE [21,22]. Idraparinux is a more highly sulphated derivative of fondaparinux, with a higher binding affinity for antithrombin (Table 1). Consequently, it has a significantly longer half-life than fondaparinux, allowing once weekly dosing [23,24]. The recent phase II PERSIST study has demonstrated its safety in the treatment of proximal DVT [25]. The ongoing AMADEUS study is comparing this agent to warfarin as thromboprophylaxis in AF [24]. Like the heparins, these agents also require parenteral administration.

Intrinsic Pathway

Extrinsic pathway Warfarin inhibits clotting factors II,VII,IX and X

X

Xa Xa inhibitors eg Idraparinux and Fondaparinux

Prothrombin

Thrombin Heparins: unfractionated and low molecular

2.1. Heparins Unfractionated heparin (UH) acts indirectly via antithrombin III to inhibit both thrombin and factor Xa, whereas low molecular weight heparins (LMWH) act primarily by preferentially inhibiting factor Xa (Fig. 1) [6,7]. Current agents have several limitations. UH must be administered parenterally and has an unpredictable anticoagulation

274 276 276

Fibrinogen

Fibrin Antithrombin III thrombus

Fig. 1. Simplified overview of the coagulation cascade illustrating the sites of action of commonly known anticoagulants.

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269

Table 1 Comparison of the key characteristics of several novel anticoagulants Agent

Half-life

Route of administration

Clearance

Frequency of administration

Anticoagulant monitoring

Indirect factor Xa inhibitors Fondaparinux 17.2 h Idraparinux 130 h

SC SC

Renal Renal

OD Once weekly

Unnecessary Unnecessary

Direct thrombin inhibitors Argatroban Lepirubin Hirudin Bivalirudin Ximelagatran

IV IV/SC IV/SC IV IV

Hepatic Renal Renal Hepatic Renal

IVI IVI IVI IVI b.i.d.

APTT APTT APTT APTT Unnecessary

45 – 60 min 90 min 60 – 120 min 25 min 3–4 h

OD—once daily; b.i.d.—twice daily; APTT—activated partial thromboplastin time; IVI—intravenous infusion; sc—subcutaneously.

2.3. Vitamin K antagonists

3. Ximelagatran

The only orally active anticoagulants currently available are the vitamin K antagonists, such as warfarin. Although effective, they have a narrow therapeutic window, with marked individual variability in dose response and metabolism [26]. Unfortunately, routine coagulation monitoring, with regular venepuncture, is necessary to ensure that a therapeutic level has been achieved. In addition, the vitamin K antagonists suffer from multiple food and drug interactions and have a slow on and off set of action [27 –30]. These limitations are further compounded by physicians’ fears of prescribing these agents due to concerns about bleeding risks and poor patient compliance [31].

After oral administration, ximelagatran (a pro-drug) is rapidly bioconverted to its active form melagatran [36]. The maximum plasma concentration of melagatran is achieved within 2 –3 h of oral ximelagatran administration, with a mean half-life elimination of 3 h (Table 1). This allows the drug to be easily administered within both the hospital and outpatient setting. Melagatran has been shown to be a potent, rapidly binding competitive inhibitor of human alpha-thrombin [37]. The inhibition of thrombin by melagatran is manifested by prolongation of plasma coagulation such as the prothrombin, thrombin and activated partial thromboplastin time [38,39]. Unlike warfarin and other vitamin K antagonists, ximelagatran has a very wide therapeutic interval that enables it to be administered safely across a wide range of doses without an increased risk of bleeding. It has a predictable and stable pharmacokinetic profile and is unaffected by patient body weight, age, sex, or ethnic origin [40 – 42]. The metabolism of melagatran is independent of the hepatic cytochrome P450 system, leading to a low potential for drug interactions [43 – 46]. Unlike warfarin, ximelagatran has no known food interactions and does not require coagulation monitoring or dose adjustment [47]. Recent studies have also demonstrated that the pharmacokinetics and pharmacodynamics of oral ximelagatran are unaffected by alcohol or aspirin [48,49]. Melagatran is excreted mainly through the renal route. Hence, a reduction in dose and/or an increase in the administration interval is recommended in patients with severe renal impairment (defined as a creatinine clearance of <30 ml/ min) [50]. At present, there is no antidote approved for rapid reversal of the effect of melagatran, but there has been limited success with activated prothrombin complex concentrates [51].

2.4. Direct thrombin inhibitors In contrast to all heparin products, which act indirectly via antithrombin (AT) to inhibit both thrombin and factor Xa, the direct thrombin inhibitors (DTI) bind to thrombin specifically and inhibit its catalytic activity without involvement of AT (Fig. 1). Smaller DTIs, such as melagatran, offer the advantage of inhibition of both free circulating and clot-bound thrombin [27,32]. Hence, DTIs may provide more effective inhibition of thrombus progression than agents such as unfractionated and low molecular weight heparins that inhibit free thrombin only [33,34]. In addition, DTIs have few plasma protein and platelet interactions. DTIs do not bind to PF4 on platelets, so their activity is preserved in the vicinity of platelet-rich thrombi and they consequently do not cause heparin-induced thrombocytopenia [35]. With the exception of ximelagatran, all currently available DTIs (such as argatroban, lepirudin and hirudin) have to be parenterally administered (Table 1). Their use has been currently limited to anticoagulation for patients with heparin-induced thrombocytopenia and as an adjunct in percutaneous coronary intervention. Again, there is no current reversal or antagonist drug, although this is less of an issue given their relatively short half-lives.

4. Prevention of venous thromboembolism in orthopaedic surgery Early work in the clinical trials of ximelagatran has been directed at patients who are at risk of VTE, mainly in the

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field of orthopaedic surgery (Table 2). Without prophylaxis, 50 – 80% of patients undergoing total hip replacement (THR), total knee replacement (TKR), or hip fracture surgery develop DVT [52 – 54]. Thromboprophylaxis with UH or LMWH reduces this risk by 71% compared with placebo but is only available by injection and, therefore, is cumbersome to use, especially in the outpatient setting. There is also increasing evidence to suggest that extended prophylaxis, for at least a month post-major orthopaedic surgery, would further reduce the risk of VTE [55]. Given the limitations of warfarin, the increasing demand for shorter hospital stays and the need for longer periods of prophylaxis, there is clearly a desire for a new, easier to administer, and yet effective, oral anticoagulant. The METHRO (MElagatran for THRombin inhibition in Orthopaedic surgery) trials were the first to show evidence that melagatran was a potential alternative to LMWHs in the prophylaxis of VTE [56]. The METHRO I study was a pilot dose-ranging study comparing dalteparin with the combination of subcutaneous (sc) melagatran and oral ximelagatran in patients undergoing total THR or TKR, based mainly

in Europe [57]. In METHRO I, 33 patients received dalteparin 5000 IU sc once daily, starting the evening prior to surgery, for 8 –11 days and 103 patients received sc melagatran (1, 2 or 4 mg twice daily) for 2 days preoperatively, followed by oral ximelagatran (6, 12 or 24 mg twice daily) for 6 – 9 days postoperatively. The combination of melagatran and ximelagatran was as effective as the dalteparin group in preventing VTE, with no difference between the three dose levels. DVT was found in 20.5% (16/78) patients on ximelagatran and 18.5% (5/27) on dalteparin. There was no difference in incidence of haemorrhagic complications between the two groups and no dose response in the ximelagatran group. The METHRO II study was a larger multi-centred, randomised, controlled, double-dummy dose response trial of melagatran/ximelagatran against dalteparin, again in patients (1876) with total hip or knee replacements [58]. In this study, 381 patients were assigned to dalteparin 5000 IU sc once daily from the evening before the surgery. The remaining 1495 were divided into four dose categories of melagatran sc (1.0 mg, 1.5 mg, 2.25 mg, or 3.00 mg twice

Table 2 Summary of clinical trials involving ximelagatran for the treatment and prevention of venous thromboembolism Trial

Number of patients

Type of operation

Trial design

Results

Bleeding risks

Prevention of VTE with THR/TKR

Melagatran sc /variable dose oral ximelagatran versus dalteparin Variable melagatran sc/ ximelagatran versus Daltaparin

Melagatran/Ximelagatran as effective as dalteparin in preventing VTE (venography) Dose-dependent decrease in VTE with ximelagatran. Highest dose (24 mg b.i.d.) ximelagatran associated with less VTE Trend in favour of enoxaparin for primary endpoint of VTE or unexplained death Enoxaparin was superior to ximelagatran for the prevention of VTE Comparable efficacy of ximelagatran in the prevention of VTE Ximelagatran at least as effective as warfarin for the prevention of VTE Lower rate of major and total VTE in the melagatran/ ximelagatran group Higher dose ximelagatran superior to warfarin in prevention of composite primary endpoint of VTE and all-cause death Better than warfarin for the composite primary endpoint of total VTE and all-cause mortality

No difference in bleeding rates

METHRO I

136

METHRO II

1876

Prevention of VTE THR/TKR

METHRO III

2788

Prevention of VTE with/TKR

Platinum Hip

1838

Prevention of VTE with THR

Heit JA et al.

600

Prevention of VTE

Platinum Knee

680

Prevention of VTE with knee arthroplasty

EXPRESS

2835

Prevention of VTE with THR/TKR

EXULT A

2301

Prevention of VTE

EXULT B

2303

Prevention of VTE with TKR

Melagatran sc/ximelagatran 24 mg b.i.d versus enoxaparin sc 40 mg o.d. Ximelagatran 24 mg b.i.d or sc enoxaparin 30 mg b.i.d. Variable dose ximelagatran b.i.d versus enoxaparin sc 30 mg b.i.d. Ximelagatran versus warfarin

Melagatran sc/ximelagatran 24 mg b.i.d. versus enoxaparin sc 40 mg o.d. Ximelagatran 24 mg or 36 mg b.i.d. versus warfarin for 7 – 12 days

Ximelagatran 36 mg b.i.d. day or warfarin for 7 – 12 days

More bleeding than fixed dose dalteparin

Similar bleeding rates between the two groups No difference in major bleeding Comparable

Comparable

Similar bleeding rates

No difference in bleeding rates

Comparable

TKR—total knee replacement; THR—total hip replacement; METHRO—Melagatran for THRombin inhibition in Orthopaedic surgery; EXPRESS— Expanded Prophylaxis Evaluation Surgery Study; EXULT—Exanta Used to Lesson Thrombosis; VTE—venous thromboembolism; o.d.—once daily; b.i.d.— twice daily; sc—subcutaneous; DVT—deep vein thrombosis.

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daily) just before surgery, and then oral ximelagatran (8 mg, 12 mg, 18 mg or 24 mg twice a day) the day after surgery for a total of 8– 11 days. The highest dose of melagatran/ ximelagatran was associated with significantly fewer VTE events than the dalteparin group (15.1% versus 28.2%, p < 0.0001), with no difference in the bleeding rates. There was a strong inverse relationship between the dose of melagatran/ximelagatran and VTE, and a dose response relationship was demonstrated for the risk of bleeding. In a smaller (600-patient) dose-finding phase II North American study, Heit et al. showed comparable results in dose, efficacy and safety as the METHRO trials. Oral ximelagatran 8 mg, 12 mg or 24 mg twice daily was given 12 –24 h post-total knee replacement or enoxaparin 30 mg sc twice daily for 6 – 12 days [59]. There was no difference in the rate of overall VTE (22.7% versus 15.8%) and proximal DVT or PE (3.1% versus 3.2%) for enoxaparin compared with the 24-mg ximelagatran group ( p = 0.3). There was no significant increased bleeding with ximelagatran. The METHRO III study was another comparison of ximelagatran and enoxaparin. This again represented a large multi-centre, double-blind, double-dummy, parallel-group study, but this time in patients who were having an elective THR or TKR [60]. In this study, 2788 patients were given either 40 mg of enoxaparin sc once daily starting 12 h preoperatively or melagatran 3 mg sc 4– 12 h postoperatively and then 24 mg of ximelagatran twice daily for 8– 11 days. There was no significant difference in the risk of bleeding between the two groups, again suggesting a comparable safety profile. However, VTE occurred more frequently in the ximelagatran group (335/1146, or 31.0%, compared to 306/1122, or 27.3%), a difference in risk of 3.7% ( p = 0.053). This was accounted for by a higher rate of distal DVT in the THR surgery patients on ximelagatran, which was statistically significant ( p = 0.004). In the post hoc analysis, it appeared that the VTE rate was much higher for patients in whom melagatran was started later than 8 h after surgery, suggesting that the timing of treatment is important. Bleeding was comparable between the two groups. In the recent multi-centre Platinum Hip study, conducted principally in the USA and Canada, it was shown that sc enoxaparin was superior to oral ximelagatran for the prevention of VTE following THR, although again there was no difference in the major bleeding rate between the two drugs [61]. In this study, 1838 patients received either 24 mg of ximelagatran twice a day or enoxaparin 30 mg twice a day for 7 –12 days, starting the day after surgery. In contrast, the EXPRESS (Expanded Prophylaxis Evaluation Surgery Study) showed ximelagatran to be superior to enoxaparin in preventing VTE in patients undergoing THR or TKR. In this large (2835-patient) randomised, double-blind, parallel-group study, one group of patients received sc melagatran 2 mg immediately before surgery and 3 mg in the evening after surgery, followed by

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24 mg oral ximelagatran twice daily for 8– 11 days [62,63]. The parallel group had sc enoxaparin 40 mg once daily, starting the evening before surgery. There was a reduction in the primary endpoints of total VTE (20.3% in the melagatran group versus 26.6% in the enoxaparin group, p = 0.0003) and major VTE (2.3% in the melagatran group versus 6.3% in the enoxaparin group, p = 0.0000018, respectively). However, although there were no fatal or critical organ bleeding episodes, the investigator judged ‘‘excessive bleeds’’ in the melagatran group to be higher (3.1%) than in the enoxaparin group (1.2%; p < 0.001). Overall, it appears that ximelagatran 24 mg b.i.d with sc melagatran dose regimen preoperatively is as effective as the LMWHs. In North America, warfarin is the standard oral prophylaxis for TKR, so in the EXULT (Exanta Used to Lesson Thrombosis) trials, 7– 12 days of treatment with ximelagatran was compared to warfarin. EXULT A was a phase II dose-finding study of 2301 patients that concluded that ximelagatran 36 mg (and not 24 mg) twice daily provided superior efficacy with respect to the primary composite endpoint of VTE and death from all causes (20.3% versus 27.6%, p = 0.003) [64]. There was no increase in bleeding events and no need for coagulation monitoring or dose changes. In the subsequent EXULT B trial, 2303 patients undergoing TKR were randomised to receive ximelagatran 36 mg twice daily plus warfarin placebo or warfarin (target INR 2.5) and ximelagatran placebo for 7– 12 days [65]. Again, ximelagatran was shown to be statistically better than warfarin for the composite primary endpoint of total VTE and all-cause mortality (31.9% for warfarin and for 22.5% for ximelagatran, p < 0.001), giving an absolute risk reduction of 9.3% (95% CI: 5.45 –13.3%). The number needed to treat was 11 to avoid one such event (95% CI: 8– 18). The bleeding events were again comparable. However, the main driver of the combined endpoint in both EXULT A and B was a reduction in the less clinically meaningful, asymptomatic distal DVTs diagnosed by venography (19.2% versus 26.7% in EXULT A and 21.4% versus 31.1% in EXULT B). In addition, ximelagatran was compared with warfarin, which is not routinely used for short-term use as VTE prophylaxis with orthopaedic surgery. Also, warfarin would have taken several days to achieve a therapeutic plasma level, as compared to hours for ximelagatran, making comparisons between the two agents appear unfair. The Platinum Knee study compared the efficacy and safety of ximelagatran and warfarin for prophylaxis of VTE in 680 patients undergoing total knee arthroplasty [66]. Patients were blindly randomised to 7 –12 days of treatment with ximelagatran 24 mg twice daily, starting the morning of the surgery, or warfarin (target INR 2.5), starting the evening of the day of surgery. The incidence of VTE was 19.2% (53/276 patients) in the ximelagatran group and 25.7% (67/261 patients) in the warfarin group

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( p = 0.007). Major bleeding/minor bleeding, respectively, was also similar in the two groups (ximelagatran 1.7%/ 7.8% and warfarin 0.9%/6.4%). Hence, ximelagatran appeared to be at least as effective as warfarin in preventing VTE post-TKR or knee arthroscopy, with similar tolerability and safety.

5. Management of venous thromboembolism The optimal duration for oral anticoagulation after a VTE is still a matter of debate, but is usually 3 –6 months [67,68]. After this, the risk of recurrence is still measurable at approximately 6% per year, but the risk of a major bleed on warfarin is about 1 –3% per year. In the ELATE study, conventional-intensity warfarin therapy was found to be more effective than low-intensity warfarin therapy for the long-term prevention of recurrent VTE, without an increased risk of bleeding [69]. In the PREVENT trial, 508 patients with idiopathic VTE, who had received full-dose anticoagulation therapy for a median of 6.5 months, were randomly assigned to placebo or low-intensity warfarin (target INR 1.5– 2.0) [70]. After a mean follow-up of 2.1 years, there was a 64% reduction in VTE ( p < 0.001) with long-term, low-intensity warfarin therapy. 5.1. Ximelagatran for long-term secondary prevention and acute treatment of VTE Ximelagatran is a more convenient anticoagulant that appears to offer a significant improvement in the treatment of PE and DVT (Table 3). The THRIVE III study investigated ximelagatran as long-term secondary prevention of VTE [71]. After an initial 6-month treatment with warfarin, 1233 patients were randomised in a double-blind fashion to ximelagatran 24 mg

twice daily or placebo for another 18 months. Baseline bilateral ultrasonography of the legs and perfusion scan of the lungs were performed. The primary endpoint of symptomatic recurrent VTE occurred in 12 patients assigned to ximelagatran and in 71 patients assigned to placebo ( p < 0.001). There was no statistically significant increase in bleeding (23.9% in the ximelagatran group versus 21.9% in the placebo group, p = 0.17). The numbers needed to treat to prevent one recurrent VTE event was 10. The cumulative risk of a transient elevation of the alanine aminotransferase (ALT) level to more than three times the upper limit of normal was 6.4% in the ximelagatran group, as compared to 1.2% in the placebo group ( p < 0.001). THRIVE (THRombin Inhibitor in VEnous thromboembolism) I was a phase II study that investigated the acute treatment of DVT of the lower extremity with ximelagatran to evaluate its efficacy and tolerability over a range of doses [72]. In this study, 350 patients were randomised to ximelagatran (24 mg, 36 mg, 48 mg or 60 mg twice daily) or dalteparin followed by warfarin. The results compared the initial thrombus size on the venography with that at 2 weeks. Regression in the size of the thrombus was similar in all groups, suggesting that not only was ximelagatran comparable to dalteparin, but that it had a wide therapeutic window. There was no difference in the overall rates of bleeding between the two groups. The THRIVE treatment trial was a large, multi-centre, double-blind, double-dummy randomised control trial comparing ximelagatran and warfarin in the treatment of DVT, with or without PE [73]. In this study, 2491 patients with acute DVT, of whom 37% had confirmed PE on perfusion – ventilation lung scan, were randomly assigned to ximelagatran 36 mg twice daily or sc enoxaparin 1 mg/kg twice daily for 5 days, followed by warfarin (INR 2.0 – 3.0) for 6 months. The primary outcome of non-inferiority of ximelagatran was achieved. There was no difference in adverse bleeding or mortality.

Table 3 Trials involving ximelagatran in the long-term secondary prevention of VTE and for the treatment of established VTE Trial

Number of Type of patients patients

Trial design

Long-term secondary prevention of VTE THRIVE III 1233 Patients who had already Ximelagatran 24 mg b.i.d. received 6 months of warfarin versus placebo for a further treatment for confirmed VTE 18 months

Treatment of established VTE THRIVE I 350 VTE treatment

THRIVE treatment

2491

DVT treatment

Dose-ranging ximelagatran versus dalteparin followed by warfarin 6 months of ximelagatran versus warfarin

Results

Bleeding risks

Reduced rate of symptomatic No difference in bleeding rate recurrence of VTE in the ximelagatran group. No difference in mortality

No difference in, change in No difference in bleeding thrombus size and regression between the two groups Ximelagatran not inferior to No difference in bleeding warfarin with no difference in mortality

VTE—venous thromboembolism; THRIVE—THRombin Inhibitor in VEnous thromboembolism; o.d.—once daily; b.i.d.—twice daily; sc—subcutaneous; DVT—deep vein thrombosis.

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6. Thromboprophylaxis for atrial fibrillation AF is the most common persistent tachyarrhythmia encountered in clinical practice. AF increases the risk of stroke fourfold to fivefold across all age groups, and it is the most common cause of embolic stroke [74]. Its frequency rises with age, affecting almost 5% of persons over the age of 60 years and nearly 10% over the age of 80 years [75]. Given the advent of an ageing population coupled with the greater survival of patients with cardiovascular disease, the stroke burden and prevalence of AF are set to dramatically increase in the future [75 – 77]. Consequently, AF has been considered by some to be a ‘‘new epidemic’’ of cardiovascular disease in western society [78,79]. Wafarin has been shown to significantly reduce the thromboembolic risk relative to both aspirin and placebo for patients in AF with risk factors for stroke [80,81].

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Hence, there is a compelling need to identify and to anticoagulate this large group of patients in society. The health burden of AF is enormous and represents 1% of all National Health Service expenditures in the UK [82]. There is, therefore, a great need to identify easier, safer and more cost-effective methods of anticoagulation. The SPORTIF (Stroke Prevention Using the ORal Thrombin Inhibitor in Patients with Nonvalvular Atrial Fibrillation) trials were a series of studies designed to compare unmonitored oral ximelagatran with dose-adjusted warfarin (target INR 2.5; range 2.0– 3.0) in patients with nonvalvular AF and at least one additional risk factor for stroke (Table 4) [28]. The SPORTIF II trial was a phase II randomised, doubleblind dose-guiding study designed to assess the tolerability of three different doses (20, 40 and 60 mg, mean dose 36 mg b.i.d) of ximelagatran compared with dose-adjusted warfarin (INR 2.0– 3.0) in 257 patients with AF at moderate risk of stroke [83]. All three doses of ximelagatran used compared

Table 4 Ximelagatran trials: prevention of thromboembolism in NVAF and in secondary prevention post-myocardial infarction Trial name

Number of Type of patients patients

Prevention of thromboembolism in NVAF fibrillation SPORTIF II 257 NVAF

SPORTIF III

3410

NVAF

SPORTIF IV

257

NVAF

SPORTIF V

3922

NVAF

Combined SPORTIF III and V data

NVAF

Trial design

Results

Phase II dose-finding tolerability All three ximelagatran doses study comparing variable-dose compared favourably with ximelagatran versus warfarin warfarin for the primary endpoint of thromboembolic events and bleeding Ximelagatran 36 mg b.i.d. versus Ximelagatran not inferior to warfarin warfarin for primary endpoint (total stroke or systemic embolism) 5-year follow-up of SPORTIF II Reduced total stroke with ximelagatran at 2-year follow-up. 5-year results awaited Ximelagatran versus warfarin Ximelagatran not inferior to warfarin for primary endpoint (total stroke or systemic embolism) Ximelagatran versus warfarin Primary events (any stroke or systemic embolic event) 1.6% versus 1.2%, p = 0.13. Pooled SPORTIF III and SPORTIF V data: incidence of primary events, major bleeding and death 5.2% versus 6.2% p = 0.038RRR: 16%

Secondary prevention post-myocardial infarction ESTEEM 1883 Post-MI patients Variable-dose ximelagatran versus (<14 days) placebo (in addition to standard therapy including 160 mg aspirin per day)

Primary endpoint (all-cause death, non-fatal myocardial infarction and severe recurrent ischaemia) significantly lower in ximelagatran group at 6-month follow-up

Bleeding rates

No difference

Less total haemorrhage with ximelagatran

Reduced bleeding with ximelagatran

Less total haemorrhage with ximelagatran

Reduced rate of combined minor and major bleeding with ximelagatran 37% versus 47% warfarin, p < 0.0001

No difference in major bleeding; however, more combined major/minor bleeding with ximelagatran

NVAF—non-valvular atrial fibrillation; SPORTIF—Stroke Prevention Using the ORal Thrombin Inhibitor in Patients with Non-valvular atrial Fibrillation; ESTEEM—Efficacy and Safety of the Oral Thrombin Inhibitor Ximelagatran in Combination with Aspirin, in PatiEnts with REcent Myocardial Damage; o.d.—once daily; b.i.d.—twice daily.

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favourably with warfarin for the primary endpoint of thromboembolic events and bleeding over the 12-week short study. SPORTIF IV is an extension of the SPORTIF II study in which patients will be followed up for up to 5 years. A 2year follow-up of SPORTIF IV demonstrated that total stroke occurred in 0.9%/patient per year in the ximelagatran group and 2.6%/patient per year in the warfarin group. Major bleedings occurred in 0.9%/patient per year in the ximelagatran group and 2.6%/patient per year in the warfarin group. Transient ischaemic attacks (TIAs) occurred in 0.4%/patient per year in the ximelagatran group and in 2.6%/patient per year in the warfarin group [84]. The SPORTIF III and V are phase III trials that were designed with the objective of establishing the noninferiority of ximelagatran (fixed 36 mg twice daily) relative to warfarin (INR 2.0 – 3.0, monitoring interval < 4 weeks) for the primary efficacy outcome of prevention of all strokes (ischaemic and haemorrhagic) and systemic embolic events in patients with both persistent and paroxysmal NVAF [85]. The patients were required to have one or more of the following risk factors for stroke: hypertension, age > 75 years, previous stroke or TIA, left ventricle ejection fraction < 40% or symptomatic congestive heart failure, age > 65 years and coronary artery disease or diabetes mellitus. The SPORTIF III trial (n = 3410) used an open-label design with blinded endpoint adjudication, whereas SPORTIF V (n = 3922) was a double-blind, double-dummy trial using a sham INR to maintain blinding. SPORTIF III included patients from Europe, Asia, Australia and New Zealand, whilst SPORTIF V only included patients from North America. In SPORTIF III, the primary event rate (total stroke or systemic embolism) by intention-to-treat was 2.3% per year with warfarin (56 total) and 1.6% per year with ximelagatran (40 total, absolute risk reduction 0.7%, relative 29% risk reduction, p = 0.10) at a mean follow-up of 17.4 months [86]. The rates of disabling or fatal stroke, mortality and major bleeding were similar between groups. However, the total haemorrhage rate was lower with ximelagatran than with warfarin (29.8% versus 25.8% per year; relative risk reduction 14%; p = 0.007). The intention-to-treat analysis of SPORTIF V revealed no difference in the primary endpoint (total strokes and systemic embolic events) between ximelagatran (1.6% per year, total 51 events) and warfarin (1.2% per year, total 37 events, p = 0.13), supporting the non-inferiority of ximelagatran with respect to warfarin [87]. In addition, there was no difference in the rates of major bleeding between the two. Again, there were significantly fewer combined major and minor bleeding events with ximelagatran. Eighty-three percent of warfarin-treated patients remained within the extended INR range (1.8 –3.2), where no dose adjustment would have been necessary. This rate is far higher than that noted in usual clinical practice.

SPORTIF III and V are complementary studies that together represent the largest combined randomised trial of anticoagulation in AF to date. Closer analysis of the primary endpoint for SPORTIF III and V would suggest that, in the open-label SPORTIF III, ximelagatran appeared better than warfarin; yet, in the blinded SPORTIF V study, it actually fared 38% worse than warfarin. However, the combined data (Table 4) confirm the non-inferiority of ximelagatran as compared to warfarin for the prevention of embolic events and support the efficacy of ximelagatran in the prevention of strokes and thromboembolic events in patients with AF [88,89]. The rather large non-inferiority margin of 2% used in the SPORTIF III and V has been debated, given the low annual stroke rate observed in these two studies [90].

7. Post-myocardial infarction The ESTEEM study was a phase II trial designed with the objective of discovering whether treatment with ximelagatran and acetylsalicylic acid together would be more effective than acetylsalicylic acid alone in preventing major cardiovascular events in patients with recent MI (Table 4) [88]. A total of 1883 patients who had had an STelevation or non-ST-elevation MI within the previous 14 days were randomised to variable-dose oral ximelagatran (24 mg, 36 mg, 48 mg or 60 mg twice daily) or placebo, respectively, for 6 months. All patients received acetylsalicylic acid 160 mg once daily. ST-elevation MI was the index event for 66% of patients, of whom 51% had been treated with fibrinolytic therapy. The proportion of patients on angiotensin-converting inhibitors, beta-blockers and statin therapy during the study was 65%, 86% and 66%, respectively. The primary efficacy outcome was the dose response of ximelagatran compared to placebo for the occurrence of allcause death, non-fatal MI and severe recurrent ischaemia. On analysis by intention-to-treat, ximelagatran significantly reduced the risk for the primary endpoint compared to placebo from 16.3% (102/638) to 12.7% (154/1245, p = 0.036) for the combined ximelagatran groups versus placebo. There was no indication of a dose response between the ximelagatran groups and no difference in major bleeding events between the two groups.

8. Adverse effects of ximelagatran An adverse effect common to all anticoagulants is bleeding. In the ESTEEM study, the total bleeding rate was significantly higher in the ximelagatran/aspirin group (22%) than in the placebo/aspirin group (13%); however, the rates of major bleeding were not statistically significant (2% versus 1%, respectively). Warfarin has a very narrow therapeutic range. For patients in AF who require anticoagulation, an INR below 2.0 increases the frequency and

C.J. Boos et al. / European Journal of Internal Medicine 16 (2005) 267 – 278 Table 5 Ximelagatran trials with data demonstrating the percentage of patients with ALT greater than three times the upper limit of normal Trial

Trial design

THRIVE III

Long-term secondary prevention of VTE Treatment of VTE

THRIVE treatment SPORTIF III SPORTIF V ESTEEM

Stroke prevention in NVAF Stroke prevention in NVAF Post-MI patients (< 14 days)

Ximelagatran group (%)

Placebo group (%)

6.4

1.2

9.8

2.0

6.5 4.0 11.2

0.7 1.0 1.2

ALT—alanine transaminase; VTE—venous thromboembolism; NVAF— non-valvular atrial fibrillation; SPORTIF—Stroke Prevention Using the ORal Thrombin Inhibitor in Patients with Non-valvular Atrial Fibrillation; ESTEEM—Efficacy and Safety of the Oral Thrombin Inhibitor Ximelagatran in Combination with Aspirin, in PatiEnts with REcent Myocardial Damage.

severity of stroke, whilst an INR above 3.0 leads to a greater bleeding risk [30]. With ximelagatran, anticoagulation monitoring is not needed, and bleeding (major/minor) may be marginally less common than with warfarin. In the combined analysis of data from the SPORTIF III and V studies, there was a strong trend to a lower rate of major bleeding with ximelagatran compared to warfarin (1.9%/year versus 2.5%/year, respectively; p = 0.054). In addition, there was a significantly lower total (combined major and minor) annualised bleeding rate with ximelagatran (32%/year versus 39%/year with warfarin, respectively; p < 0.0001). This impressive result was seen despite a higher proportion of patients achieving therapeutic anticoagulation with warfarin than that in routine clinical practice [88]. One adverse effect of concern is abnormal liver function tests, which is mainly noted in the longer-term studies (Table 5). Deranged liver function appears to be an issue with anticoagulants that block specific coagulation pathways, and it is even seen during short-term administration of LMWH. For example, in the Platinum Hip Study, a rise in ALT greater than three times the upper limit of normal was noted in 6 of 840 patients treated with ximelagatran and in 42 of 847 patients treated with enoxaparin over the 7 –12 days of treatment [61]. In both SPORTIF III and V, significant elevations of serum ALT beyond three times the upper limit of normal were seen in 6% of ximelagatran patients compared to 0.8 – 1.0% in the warfarin group (Table 5). In THRIVE III, the figure was 9.8% for ximelagatran-treated patients, and in the ESTEEM study, the rise was even higher at 11.2%. In ESTEEM, there was a rise in serum transaminase greater than five times the upper limit of normal in 7% (range 3 – 9%, depending on the dose used) of ximelagatran-treated patients, with a 7% combined dose discontinuation rate due to concerns about liver dysfunction. The rise in serum transaminase for all of these studies typically occurred within 2 and 6 months after initiation of treatment and then normalised, whether or not treatment was continued.

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In the EXULT A, the rate of ALT elevations greater than three times the upper limit of normal was 2.1% for highdose ximelagatran versus 1.4% for warfarin; however, a greater proportion of ximelagatran-treated patients (0.27% versus 0.04% for warfarin) had similarly elevated ALT levels at 4 – 6 weeks after the operation, well after prophylactic therapy had stopped ( p = 0.09) [64 –93]. No severe liver dysfunction has been noted in short-term (< 35 days) trials. In long-term trials, there were 37 cases of severe injury with ximelagatran versus 5 in the comparator groups. Current data from longer-term treatment trials support a 0.5% incidence of severe liver dysfunction [94]. Furthermore, there is a numerical (but not statistically significant) increase in MI events for patients taking or recently stopping ximelagatran, which raises issues regarding Frebound_ hypercoagulability [95]. In a sub-study of 518 patients from the original ESTEEM study, long-term treatment with ximelagatran persistently reduced thrombin generation and fibrin turnover among patients who had suffered a recent MI. However, there was clear reactivation of the coagulation activity after discontinuation of ximelagatran [95]. With regard to the concerns and uncertainties over liver function and a possible increase in vascular events, the U.S. Federal Cardiovascular and Renal Drugs Advisory Committee (FDA) has recently recommended non-approval of Exanta for all of its application indications. These include the prevention of VTE in patients undergoing knee replacement surgery, the prevention of stroke and systemic embolism associated with AF and long-term secondary prevention after standard treatment for an episode of VTE [96]. AstraZeneca has proposed an ALT-monitoring program (RiskMAP) that is similar to that ultimately adopted in the clinical trials: baseline testing, followed by monthly testing for at least 6 months, with triggers for more frequent monitoring or discontinuation with specific ALT levels above the ULN [96]. However, there are concerns that compliance with the algorithm is likely to be far lower in routine clinical practice and might lead to a higher rate of liver dysfunction, with potentially serious consequences. Table 6 Relative advantages and disadvantages of ximelagatran Advantages Easy to use Wide therapeutic interval No need for therapeutic monitoring Fixed dosing Rapid onset of action No drug or food interactions Short onset/offset of action Disadvantages Likely to be expensive Need to monitor liver function No easy reversal agent Not inferior, though not superior, to warfarin

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Ximelagatran is currently approved for the prevention of VTE with orthopaedic surgery in seven European countries.

9. Conclusion Ximelagatran is a novel anticoagulant with significant promise. Numerous recent randomised studies have given ximelagatran a broad clinical platform. It has demonstrated efficacy in the prevention and treatment of VTE, in the prevention of stroke in patients with nonvalvular AF, and for the secondary prevention of combined cardiovascular endpoints post-MI. A summary of the relative advantages and disadvantages of ximelagatran is presented in Table 6. Current data would suggest that approximately 6% of patients develop self-limiting derangement of liver function, independent of whether treatment is continued or stopped, which would support the need for regular liver function monitoring for at least the first 6 months. Concerns over liver dysfunction and price are likely to limit its use at present, and further safety long-term data may therefore be needed. There are currently no data about its efficacy in the prevention of stroke and valvular thrombosis in patients with mechanical valves, or peri-cardioversion of AF, which would be greatly welcomed given ximelagatran’s relative advantages over warfarin.

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