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Ximelagatran: a new oral anticoagulant
Best Practice & Research Clinical Haematology Vol. 17, No. 1, pp. 139–152, 2004 doi:10.1016/j.beha.2004.03.005 available online at http://www.sciencedirect.com
9 Ximelagatran: a new oral anticoagulant Charles W. Francis*
MD
Hematology/Oncology Unit, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 610, Rochester, NY, USA
Vitamin K antagonists are effective oral anticoagulants, but they have limitations related to a narrow therapeutic range, food and drug interactions, slow onset of action and the need for routine coagulation monitoring. Ximelagatran is a promising new oral anticoagulant under investigation in advanced clinical trials. It is a prodrug that is converted after oral administration to melagatran, a direct thrombin inhibitor, with a peak effect after 2 hours and a half-life of approximately 3 hours with primarily renal excretion. Administration results in prolongation of coagulation tests, but routine monitoring is not required because of reliable absorption and predictable effects. A large clinical trials program has demonstrated effectiveness in prophylaxis of deep vein thrombosis (DVT) following major orthopedic surgery, treatment of symptomatic DVT, prevention of embolism in patients with atrial fibrillation, and prophylaxis of recurrent events after acute myocardial infarction. Bleeding complications have been similar to those with standard therapy, with no unexpected adverse effects except for elevation of serum transaminase levels in over 6% of patients beginning after 1 month of therapy. Ximelagatran may be an alternative oral anticoagulant for patients currently taking vitamin K antagonists. Key words: ximelagatran; melagatran; warfarin; coumarins; vitamin K antagonists; deep vein thrombosis; pulmonary embolism; atrial fibrillation; stroke; myocardial infarction.
The vitamin K antagonists such as warfarin have remained the only oral anticoagulants available since their introduction in 1942. Although effective and widely used for a broad range of indications, they have serious limitations. Close monitoring to maintain the international normalized ratio (INR) within a desired range is required to maintain effectiveness and minimize bleeding complications because of the narrow therapeutic range. Also, they have a slow onset of action so therapy must be initiated with a parenteral anticoagulant when a rapid effect is needed. Vitamin K antagonists also have prolonged action after stopping, which creates difficulties in managing bleeding complications or when treatment must be interrupted for invasive procedures. Dosing is complicated by numerous interactions with food and drugs, and marked biological variations in response between patients. Several new parenteral anticoagulants acting at different sites in the coagulation system have been introduced in recent years, but the vitamin K antagonists have remained the only choice for oral anticoagulation. * Tel.: þ 1-585-275-3761; Fax: þ1-585-473-4314. E-mail address: [email protected] (C.W. Francis). 1521-6926/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
140 C. W. Francis
An alternative oral anticoagulant remains an important unmet clinical need. Oral agents in early clinical trials include heparin derivatives with oral bioavailability1 – 3 and inhibitors of Factor Xa.4,5 However, the new oral drug showing greatest promise is ximelagatran (Exantaw), a direct thrombin inhibitor that has been tested in phase III clinical trials for several indications in over 17 000 patients worldwide. Thrombin is an excellent target for an anticoagulant. It is a central enzyme in hemostasis with important effects on coagulation, platelets, fibrinolysis and vascular cell function6 (Table 1). The most prominent procoagulant effect of thrombin is the conversion of fibrinogen to fibrin by cleavage of fibrinopeptides A and B. However, it also has an important effect in feedback amplification of coagulation, as small amounts of thrombin proteolytically activate Factors V and VIII, and this greatly increases their Table 1. Thrombin actions. Coagulation Cleavage of fibrinopeptides A and B from fibrinogen to form fibrin Activation of Factor XIII (to crosslink fibrin) Activation of Factors V and VIII (cofactors for Factor Xa and Factor IXa, respectively) Activation of Factor XI Anticoagulation Activation of Protein C (requires binding of thrombin to thrombomodulin) Fibrinolysis inhibition Activation of thrombin-activatable fibrinolysis inhibitor Cellular effects Platelet activation Endothelial cells Stimulates production of nitric oxide, prostacyclin platelet-activating factor and plasminogen activator inhibitor Stimulates secretion of von Willebrand factor Stimulates surface expression of P-selectin Smooth muscle cells Downregulates purinergic receptors (receptors for adenosine disphosphate and adenosine triphosphate) Increases intracellular calcium Mitogenic Fibroblasts Mitogenic Lymphocytes Mitogenic Monocytes Chemotactic and mitogenic Neutrophils Activates Other suggested activities Neuron outgrowth Restenosis Atherosclerosis Neovascularization/angiogenesis Tumorigenesis Embryogenesis in developing heart, blood vessels, brain, hematopoiesis and several epithelial tissues
Ximelagatran: a new oral anticoagulant 141
cofactor activities. Thrombin also converts Factor XI to Factor XIa, which activates Factor XIII; this stabilizes fibrin by isopeptide cross-linking. Another important hemostatic effect is proteolytic activation of thrombin-activatable fibrinolysis inhibitor, which inhibits fibrinolysis by cleaving N-terminal lysines from fibrin to limit plasminogen binding. Additionally, thrombin is a potent platelet activator, and it has effects on a variety of vascular cells through activation of specific receptors. Thrombin also has an important anticoagulant effect after binding to the endothelial receptor, thrombomodulin, which enables it to convert Protein C to activated Protein C; this inactivates Factors Va and VIIIa. Therefore, thrombin inhibition may result in a variety of effects including inhibition of coagulation, platelet activation and fibrinolysis. However, it could potentially have a procoagulant effect under some circumstances through reduced formation of activated Protein C, and it may influence vascular responses to injury through blocking cellular effects. Clinical need has provided the impetus for the development of ximelagatran, and scientific advances in the biochemistry of thrombin have provided the necessary background and tools. In particular, detailed structural information, including resolution of its crystal structure, and characterization of its interaction with substrates including fibrinogen have been important milestones. Development of ximelagatran has also been aided by the introduction of the parenteral direct thrombin inhibitors argatroban, desirudin and bivalirudin, that are approved for use in heparin-induced thrombocytopenia and percutaneous coronary interventions.7 This provided relevant biochemical, physiological and clinical data about the effects of direct thrombin inhibitors, including a convincing demonstration that an agent targeting thrombin alone could be an effective anticoagulant. This is a very new concept as the commonly used agents affect multiple sites.8 Vitamin K antagonists decrease the synthesis of Factors II, VII, IX and X and also Proteins C and S. Both heparin and low-molecular-weight heparins (LMWHs) act through antithrombin III to inhibit all of the coagulation serine proteases including thrombin, Factor Xa and others. Thus, the clinical effectiveness of an agent acting at a single site in hemostasis was uncertain until the successful clinical use of the parenteral direct thrombin inhibitors and also fondaparinux, a specific inhibitor of Factor Xa.
PROPERTIES Ximelagatran is an inactive prodrug derivative of melagatran, a potent direct thrombin inhibitor (Table 2). Development of the novel, derivatized prodrug approach was essential because melagatran and other active direct thrombin inhibitors exhibit poor intestinal absorption.9,10 Whereas melagatran has a high affinity for thrombin with a Ki of 2 nM, ximelagatran is more than 100-fold less active.9 – 13 However, following oral administration, ximelagatran is rapidly and nearly completely absorbed with a Cmax of 0.33 hours, and food has little effect on absorption.10 – 14 Ximelagatran is metabolized rapidly with a half-life of unmetabolized ximelagatran of 0.34 hours, and approximately 20% is converted to melagatran with a low interindividual variability in the area under the curve of approximately 20% (Figure 1).10,14 Other metabolites include ethylmelagatran and OH-melagatran that form in small amounts and are eliminated rapidly. The tmax of melagatran following oral ximelagatran is approximately 2 hours.10,14,15 Melagatran, the active metabolite of ximelagatran, is a competitive, reversible active site inhibitor of thrombin. It also has significant activity towards trypsin and does not require antithrombin.9,11 It is a dipeptide whose structure mimics the sequence N-terminal to the cleavage site for thrombin on the fibrinogen Aa chain. Melagatran
142 C. W. Francis
Table 2. Properties of ximelagatran and melagatran. Ximelagatran †Inactive prodrug derivative of melagatran †Good intestinal absorption with minimal effect of food †Approximately 20% converted to melagatran after oral dosing †Tmax for melagatran after oral dose is 2 hours †CV for plasma area under the curve (AUC) of melagatran after oral dose of ximelagtatran is 20% Melagatran †Direct, competitive, reversible, active site inhibitor of thrombin with Ki , 2 nM Inhibits thrombin bound to fibrin or thrombomodulin †Tmax after SQ administration 0.5–1 hour for saline formulation and 2 hours for depot formulation †Linear, dose-proportional increase in plasma AUC after oral ximelagatran †Half-life is ,3 hours †Less than 15% bound to plasma proteins †Over 80% excreted unchanged in urine †Half-life prolonged with decreased renal function
produces similar inhibition of fluid-phase thrombin and of thrombin bound to either fibrin clots or fibrin monomers, and it is significantly more active against clot-bound thrombin than the larger direct thrombin inhibitor, hirudin.1,16 It also inhibits thrombin complexed with thrombomodulin and activation of Protein C effectively at clinically relevant concentrations.17,18 This could possibly result in a paradoxical procoagulant effect in some settings and needs to be considered in interpreting dose-response and clinical outcomes. Melagatran also inhibits platelet activation and cleavage of protease activated receptor-1 in a dose-dependent manner.19,20 Melagatran can be administered either subcutaneously or intravenously but has poor oral bioavailability. Over 80% of melagatran is excreted unchanged in the urine, so the plasma half-life and concentration increase with declining renal function. The reduced clearance of melagatran in older subjects correlates well with declining renal function.10,14,21,22 Protein binding is less than 15% and the half-life in normal young subjects is approximately 3 hours.10,14 Melagatran prolongs most coagulation tests. The partial thromboplastin time is prolonged in a concentration-dependent manner, but the relationship between Prothrombinase
XIMELAGATRAN
Va, lipid Xa MELAGATRAN
Prothrombin
Platelet activation
Thrombin
Fibrin formation
Fibrinolysis inhibition
Cellular effects
Figure 1. Following oral administration, ximelagatran is converted to melagatran, a direct inhibitor of thrombin.
Ximelagatran: a new oral anticoagulant 143
concentration and prolongation is non-linear.15 The thrombin time increases directly in proportion to melagatran concentration but is very sensitive within the therapeutic range.11 Melagatran prolongs prothrombin time assays, but the effect depends on both the thromboplastin used and the dilution of the sample. Melagatran was added to normal plasma and the effects were investigated using 17 commercially available prothrombin time kits.23 Depending on the specific assay used, an INR of 2.0 could be obtained with melagatran concentrations as low as 0.55 mmol/L or as high as 2.9 mmol/L, and currently available prothrombin time-based systems are not suitable for monitoring plasma levels. The ecarin clotting time may be the best coagulation test for assessing plasma levels24, but it is not widely available. Monitoring of coagulation tests has not been performed in clinical trials and should not be needed for routine use.
CLINICAL TRIALS Orthopedic surgery A large clinical trials program in both venous and arterial disease has been undertaken with ximelagatran. An initial focus has been the prevention of venous thromboembolism (VTE) following orthopedic surgery. This is a demanding model to evaluate potential efficacy because of the documented high rate of venographically diagnosed thrombosis, and a stringent test of safety because of the risk of bleeding at the site of major surgery. Dosing has followed different patterns in European compared with North American trials. In Europe, the regimens used have combined subcutaneous administration of melagatran before or after surgery followed by oral ximelagatran. This approach was designed to provide optimal prophylaxis using the parenteral agent during surgery, when thrombosis may begin, and then follow with more convenient oral administration. The Methro II trial enrolled both hip and knee replacement patients25 and compared four dosing combinations of melagatran/ximelagatran with a standard regimen of dalteparin in a prospective, randomized trial in patients undergoing hip or knee arthroplasty with mandatory bilateral venography at 7– 10 days (Table 3). The results showed both a promising and statistically significant dose-dependent reduction in VTE and also a significantly lower rate of thrombosis with the highest dose regimen of melagatran/ximelagatran compared with dalteparin.26 There was, however, a dosedependent increase in blood transfusions in the melagatran/ximelagatran groups after total hip replacement, with rates of severe bleeding of 1.1 and 5% in the lowest and highest dose groups, respectively. Nearly all of the bleeding complications were at the surgical site. The Methro II study demonstrated good efficacy but increased bleeding, so the regimen was altered in two subsequent phase III trials. In the EXPRESS trial27, melagatran 2 mg was given subcutaneously before surgery, followed by 3 mg in the evening after surgery, and this was followed by oral ximelagatran 24 mg twice daily until venography (Table 4). The comparison group in this randomized double-blind study of both hip and knee replacement patients received enoxaparin 40 mg daily starting the evening before surgery. Bilateral venography was performed after 8– 11 days of treatment. The results showed a significantly lower rate of thrombosis in the melagatran/ximelagatran group (20.3%) compared with the enoxaparin group (26.6%, P , 0:001). However, severe bleeding primarily at the surgical site was also significantly increased with melagatran/ximelagatran (3.1%) compared with enoxaparin (1.2%)
144 C. W. Francis
Table 3. Dose-guiding studies of ximelagatran. Study name (Ref)
Treatment
Hip or knee replacement
METHRO II
Melagatran/ximelagatranb
(25)
1.0/8 mg 1.5/12 mg 2.25/18 mg 3.0/24 mg Dalteparin 5000 U QDd
364 377 375 379 381
39% 24% 24% 15% 28%
1.1% 2.1% 2.9% 5.0% 2.4%
(28)
Ximelagatran 8 mge 12 mg 18 mg 24 mg Enoxaparin 30 mgf
63 101 87 95 97
27% 20% 29% 16% 23%
0 0 1.6% 0 0.8%
Venographicg response 76% 65% 64% 72% 69%
1.5% 1.5% 0 0 2.7%
Compositei 12% 14% 12% 13% 16%
2% 1% 3% 2% 1%
Knee replacement
DVT treatment
Myocardial infarction
THRIVE I (32)
ESTEEM (36)
Ximelagatran 24 mg 36 mg 48 mg 60 mg Dalteparin/warfarinh
Ximelagatran 24 mg 30 mg 48 mg 60 mg Placebo
n
Efficacy endpoint
Bleedinga
Group
VTEc
54 57 59 60 65
307 303 311 324 638
VTE, venous thromboembolism; DVT, deep vein thrombosis. Severe or major bleeding. b Melagatran given immediately before surgery and 7– 11 hours post operation and twice daily until oral ximelagatran could be given. Ximelagatran was given orally twice daily. c Confirmed VTE with bilateral venography at 7– 10 days. d First dose given the evening before surgery. e Oral ximelagatran twice daily starting 12 –24 hours post operation. f Enoxaparin 30 mg SQ twice daily starting 12–24 hours post operation. g Change in extent of thrombus after 2 weeks judged by repeat venography. h Dalteparin 200 u/kg SQ daily followed by warfarin. i All-cause mortality, non-fatal myocardial infarction and severe recurrent ischemia over 6 months. a
ðP , 0:001Þ; and transfusion requirements were also higher in the melagatran/ ximelagatran-treated patients. The subsequent Methro III study26 enrolled 2788 patients having hip or knee replacement in a similar randomized double-blind comparison of melagatran/ ximelagatran with enoxaparin. However, in this study, the pre-operative melagatran dose was dropped, and the regimen included a single dose of melagatran 3 mg given
Ximelagatran: a new oral anticoagulant 145
Table 4. Phase III trials of ximelagatran. Orthopedic surgery prophylaxis Group
Study name (Ref)
Treatment
n
VTE
P
Major bleeding
P
1141
20.3%
,0.001
3.1%
,0.001
1184 1146
26.6% 31.0%
NS
1.2% 1.4%
NS
1122
27.3%
276
19.2%
261 614
25.7% 24.9%
629
20.3%
0.003g
0.8%
608 782
27.6% 7.9%
,0.05
0.7% 0.8%
775
4.6%
Treatment
n
Stroke and systemic emboli
P
Major bleeding
P
Ximelagatranf
1704
1.6%/year
NS
1.3%/year
NS
Warfarin
1703
2.3%/year
Melagatran/ximelagatran (Europe) Hip or knee Express (26) Melagatrana/ ximelagatranb replacement Enoxaparinc Hip or knee Methro III (27) Melagatrand/ replacement ximelagatranb Enoxaparine Ximelagatran only (North America) Knee (29) Ximelagatranb replacement Warfarin Knee EXULT (30) Ximelagatran replacement 24 mgb Ximelagatran 36 mgf Warfarin Hip (31) Ximelagatranb replacement Enoxaparine Other indications Group Study name (Ref)
Atrial fibrillation
SPORTIF III (35)
1.7% NS
1.7%
NS
0.9% 0.8%
NS
NS
0.9%
1.8%/year
Recurrence DVT treatment Long-term THRIVE III (33) Acute
a
THRIVE treatment (34)
Ximelagatranh Placebo Ximelagatranf
612 611 1240
2.0% 11.6% 2.1%
Enoxaparin/ warfarin
1249
2.0%
,0.0001 NS
1.0% 0.8% 1.3%
NS NS
2.2%
Melagatran 2 mg SC immediately before operation; 3 mg SC the evening of surgery. 24 g PO q 12 hours. c Enoxaparin 40 mg SC 12 hours before operation and then daily. d Melagatran 3 mg SC 4– 12 hours post operation; then ximelagatran 24 mg PO b.i.d. when able to take oral medication. e Enoxaparin 30 mg SC q 12 starting 12–24 hours post operation. f 36 mg PO q 12 hours. g Comparison for ximelagatran 36 mg with warfarin. h Ximelagatran 24 mg SC b.i.d. starting after 6 months of standard treatment. b
146 C. W. Francis
4 –12 hours postoperatively followed by oral ximelagatran 24 mg twice daily. Bilateral venography was performed after 8 – 11 days. There was no increased bleeding in the melagatran/ximelagatran group in this study, but neither was there improved efficacy over enoxaparin, with relatively high rates of 31.0 and 27.3% in the ximelagatran/ melagatran and enoxaparin groups, respectively. The subgroup having total hip replacement showed better results with enoxaparin (19.4%) compared with melagatran/ximelagatran (25.4%, P ¼ 0:004). North American studies have used only ximelagatran with no melagatran, and separate trials have been conducted in hip and knee arthroplasty patients. A dosefinding study in patients having total knee replacement compared four doses of ximelagatran with enoxaparin.28 Rates of VTE using unilateral venography were between 16 and 29% in ximelagatran patients without clear evidence of a dosedependent efficacy effect. The group receiving the highest dose (24 mg) had a thrombosis rate of 16%; this was not significantly different from the rate of enoxaparin. Bleeding events were uncommon (Table 3). Although there was no clear dose-dependent effect on efficacy or bleeding, ximelagatran 24 mg twice daily was selected for a subsequent larger phase III trial (Table 4). The comparator for this double-blind, randomized trial was warfarin, which is widely used for prophylaxis in orthopedic surgery in North America, and treatment was given for 7– 12 days until unilateral venography.29 The results showed a VTE rate of 19.2% in the ximelagatran group which was lower than in warfarin-treated patients (25.7%), but this was not statistically significant ðP ¼ 0:07Þ: Major and minor bleeding events were also not significantly different in the two treatment groups. The conclusion from this study was that the ximelagatran regimen was at least as effective as warfarin. Considering that the results of the phase II dose-guiding study were ambiguous, and that the phase III study with total knee replacement showed a trend in favor of ximelagatran, a larger phase III trial was conducted. This compared prophylaxis using warfarin or ximelagatran at two doses (24 or 36 mg twice daily) in a trial of similar design except that bilateral venography was performed.30 This study (EXULT) showed a significantly ðP ¼ 0:003Þ lower rate of VTE in the 36-mg ximelagatran group (20.3%) compared with warfarin (27.6%). Bleeding events did not differ. This study indicated greater efficacy of the 36-mg dose without increased bleeding, and highlighted problems with the limited information available from the phase II study. A separate randomized double-blind study was performed in patients having hip replacement using the lower (24 mg) dose and a comparator group that received enoxaparin.31 Rates of venographically diagnosed thrombosis were very low (7.9% with ximelagatran and 4.6% with enoxaparin), but the outcome was significantly ðP , 0:05Þ better with enoxaparin. Overall, the results in this large clinical trial program of prophylaxis in orthopedic surgery have been mixed. A significant problem was the failure to identify a clear dosedependent effect on efficacy and safety using the range of oral ximelagatran doses tested in the North American phase II study. This led to the choice of a 24-mg regimen for the initial phase III trials in hip and knee replacement that showed equivalent or inferior efficacy to standard prophylaxis. The 36-mg regimen had superior efficacy with no increase in bleeding and was better than warfarin in the randomized trial in knee replacement and clearly better than the historical rates with no prophylaxis. This demonstrates that the 36-mg ximelagatran regimen is a suitable alternative for warfarin in high-risk patients having orthopedic surgery. Additional studies using the 36-mg dose in patients having hip replacement and possibly hip fracture will be needed to provide additional information. The choice of ximelagatran 24 mg for the European studies may
Ximelagatran: a new oral anticoagulant 147
also have resulted in suboptimal efficacy. In addition, the regimen using melagatran administered immediately pre-operatively resulted in increased bleeding at the surgical site, which was not surprising considering that peak levels could be reached during the procedure. Omission of the pre-operative dose resulted in decreased surgical site bleeding, but efficacy may have been compromised, particularly using ximelagatran 24 mg (Table 4). Treatment of VTE Treatment of symptomatic deep vein thrombosis (DVT) includes two phases, with initial administration of heparin or LMWH followed by a longer period of anticoagulation with a vitamin K antagonist. Ximelagatran could potentially be effective for both phases because it has a rapid onset of anticoagulant effect, making it suitable for initial therapy, and because oral dosing is convenient for long-term therapy. In a phase II dose-guiding study, four doses of ximelagatran were compared with standard treatment of acute symptomatic DVT.32 The endpoint was the change in volume of thrombosis judged by venography after 2 weeks of therapy, and appeared similar in all treatment groups with minimal bleeding. The conclusions of this small study were that ximelagatran was promising and appeared to have a wide therapeutic margin because results were similar using doses from 24 to 60 mg twice daily (Table 3).33 This was followed by two phase III studies in VTE using different designs (Table 4). The THRIVE III study34 was a randomized, double-blind trial examining extended prophylaxis, initiated after an initial 6 months of anticoagulation in 1233 patients who presented with DVT or pulmonary embolism (PE). Patients received either placebo or ximelagatran 24 mg twice daily for an additional 8 months without monitoring of coagulation tests. The primary endpoint for efficacy was recurrent VTE, and this occurred in significantly fewer patients receiving ximelagatran (2.0%) compared with placebo (11.6%, P , 0:001). The incidence of major hemorrhage was low and not significantly different in the two groups. The study clearly demonstrated the effectiveness of ximelagatran 24 mg in long-term prophylaxis. The THRIVE treatment study35 was designed to demonstrate non-inferiority of ximelagatran to standard treatment for acute DVT. In a randomized, double-blind study, patients with DVTwith or without PE were allocated to standard treatment with either enoxaparin or ximelagatran 36 mg twice daily beginning at diagnosis and for a period of 6 months. There was no coagulation monitoring for ximelagatran, whereas warfarin anticoagulation had a target INR of 2.5. Objectively confirmed recurrent VTE occurred in 2.1% of 1240 patients in the ximelagatran group and 2.0% of 1249 patients in the enoxaparin/warfarin group. This result satisfied the non-inferiority criteria with a 95% confidence interval of 2 1.02 þ 1.3% for the difference in recurrent VTE between the ximelagatran and enoxaparin/warfarin groups. Major bleeding occurred in 1.3% of ximelagatran patients and 2.2% of enoxaparin/warfarin patients, a non-significant difference. This study demonstrated that oral ximelagatran without monitoring of coagulation tests may be a suitable alternative to standard treatment using LMWH followed by warfarin for the treatment of patients with symptomatic DVT. Atrial fibrillation Anticoagulation with a vitamin K antagonist is highly effective in preventing stroke in patients with atrial fibrillation, with a risk reduction of over 50%. Many patients are not
148 C. W. Francis
treated, however, because of problems with monitoring warfarin and fear of bleeding complications. The use of ximelagatran in atrial fibrillation was evaluated in the SPORTIF III trial, a phase III, randomized, open-labeled study involving 3407 patients with atrial fibrillation and one or more additional risk factors for stroke (Table 4).36 The study was designed to test the hypothesis that ximelagatran 36 mg twice daily was not inferior to standard treatment with warfarin in preventing stroke and systemic embolic events. After 21 months of treatment, an embolic event had occurred in 2.3%/year of warfarin-treated patients and 1.6%/year of ximelagatran-treated patients in an intentto-treat analysis, clearly demonstrating non-inferiority. A secondary analysis of events on-treatment demonstrated a significant ðP ¼ 0:018Þ risk reduction of 41% for stroke and systemic embolism with ximelagatran (1.3%/year) compared with standard treatment (2.2%/year). There was no significant difference in major bleeding between the two groups; 1.3%/year in ximelagatran-treated patients and 1.8%/year in warfarintreated patients. These results indicate that ximelagatran 36 mg twice daily without coagulation monitoring is at least as effective and safe as warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Myocardial infarction Antiplatelet therapy reduces the risk of myocardial infarction, stroke or vascular death after myocardial infarction, and long-term anticoagulation with an oral vitamin K antagonist can further reduce cardiovascular events. However, such treatment is restricted because of the risks of bleeding and problems with coagulation monitoring and dose adjustment. The ESTEEM trial evaluated the potential value of ximelagatran for secondary prophylaxis after myocardial infarction (Table 3).37 This prospective, doubleblind, placebo-controlled, dose-guiding study evaluated 1883 patients with a recent ST-elevation or a non-ST-elevation myocardial infarction, and randomized participants within 14 days of the event to one of four doses of oral ximelagatran or placebo. All patients received aspirin and were randomized 1/1/1/2 to oral ximelagatran at doses of 24, 36, 48 or 60 mg twice daily, respectively, or to placebo for 6 months. The primary efficacy outcome was the dose response of ximelagatran compared with placebo for the occurrence of all-cause death, non-fatal myocardial infarction and severe recurrent ischemia. The results indicated that there was no efficacy dose-response between the ximelagatran groups. The primary outcome occurred in 12 –14% of patients in each of the four ximelagatran groups and 16% in the placebo group. Combining all groups, oral ximelagatran significantly reduced the risk of the primary endpoint compared with placebo from 16.3 to 12.7% ðP ¼ 0:036Þ: Major bleeding occurred in 1– 3% in the ximelagatran groups and 1% with placebo, a non-significant difference. However, the occurrence of total bleeding, including both major and minor, was higher with ximelagatran-treated patients (22%) compared with placebo-treated patients (13%). The results of this large phase II trial demonstrated that treatment with ximelagatran and aspirin was more effective than aspirin alone in preventing major cardiovascular events during 6 months of treatment in patients with a recent myocardial infarction. LIVER FUNCTION TEST ABNORMALITIES An unexpected problem has been the occurrence of abnormal liver function tests (LFTs) in patients treated with ximelagatran for longer than 1 month. This problem was not detected in preclinical studies, and the initial clinical trials did not plan detailed
Ximelagatran: a new oral anticoagulant 149
8 7 6
Percent
5 4 3 2 1 0 23
35 Placebo
>5
23
35
>5
Ximelagatran
Figure 2. Elevations of alanine transaminase levels in the ESTEEM trial.37 The percent of subjects with peak levels of 2 –3, 3–5 or .5 £ upper limit of normal are shown for the placebo group and the combined ximelagatran groups.
testing of LF. However, routine screening detected an increased frequency of elevated serum transaminase levels in patients treated long term with ximelagatran in the THRIVE III, THRIVE treatment, SPORTIF and ESTEEM trials. Detailed reporting of laboratory results and analysis of systematic events are not available for unpublished studies. However, the findings in the ESTEEM trial may be representative (Figure 2).37 Serum alanine aminotransferase levels peaked after 60– 120 days and returned to normal within 60 –90 days whether treatment was continued or stopped. Five of 1245 patients treated with ximelagatran had clinical jaundice with concurrent elevation of bilirubin and alanine aminotransferase. No evidence of permanent liver toxicity was detected. Of 147 patients with alanine aminotransferase elevated to over three times the upper limit of normal, all but one returned to prestudy levels or less than twice the upper limit of normal. An important finding has been that elevations in LFTs begin to occur during the second month of treatment, and no significant increase has been found in the short-term prophylaxis trials. The clinical significance of these elevations in LFTs is important for the further development of ximelagatran. No symptomatic hepatotoxicity has been reported other than jaundice, and there has apparently been no evidence of permanent liver damage. These results, however, have occurred in the setting of controlled clinical trials with routine monitoring of LFTs and close supervision. The need for monitoring of LFTs will have to be considered in the clinical use of ximelagatran.
SUMMARY Ximelagatran is a prodrug formulation of the potent direct thrombin inhibitor melagatran that is administered orally and exhibits predictable absorption without food or drug effects. Following oral administration of ximelagatran, the peak melagatran
150 C. W. Francis
concentration occurs after 2 hours and the half-life is approximately 3 hours, necessitating twice-daily administration. Excretion is through the kidneys, and elevated levels can occur in patients with renal dysfunction. Coagulation tests including the prothrombin time, partial thromboplastin time and thrombin time are prolonged after administration, but routine monitoring has not been required because of the predictable pharmacological effect. In major orthopedic surgery, ximelagatran has shown effectiveness in the prevention of DVT, although identification of the best dose has been difficult. Ximelagatran 36 mg twice daily was superior to warfarin in patients undergoing knee replacement whereas ximelagatran 24 mg twice daily provided comparable efficacy. Following total hip replacement, ximelagatran 24 mg twice daily was inferior to enoxaparin. Ximelagatran was superior to placebo in preventing recurrent thrombosis after an initial 6 months of standard therapy in patients with symptomatic DVT or PE. The efficacy of ximelagatran was not inferior to standard therapy with enoxaparin and warfarin in patients presenting with acute DVT with or without PE with comparable bleeding complications. In patients with atrial fibrillation, ximelagatran was not inferior to warfarin in the prevention of stroke and systemic embolism with comparable bleeding complications. In a phase II study in patients with acute myocardial infarction, ximelagatran showed superior efficacy to warfarin in preventing death, recurrent myocardial infarction or severe recurrent ischemia. Elevation of serum transaminase levels occurred in over 6% of patients who were treated for longer than 1 month. In conclusion, ximelagatran is a promising oral anticoagulant offering an alternative to warfarin for a broad range of indications. Further studies will be needed to define its efficacy in prophylaxis after major orthopedic surgery, including hip replacement and hip fracture, and also its role in extended prophylaxis. A larger phase III trial will be needed to confirm its efficacy in the secondary prophylaxis of coronary events following acute myocardial infarction. Elevation of serum transaminase levels is of concern for treatment longer than 1 month. Although serious liver toxicity has not been observed in closely regulated clinical trials, monitoring and supervision will be needed for routine use. Practice points † † † † †
not yet FDA approved orally administered with rapid onset of effect twice-daily dosing no routine coagulation monitoring favorable results in prophylaxis of DVT in orthopedics, treatment of DVT, treatment of atrial fibrillation, and secondary prevention of myocardial infarction † monitoring of LFTs needed with use over 1 month
Research agenda † further studies to define role in hip replacement and hip fracture and to define optimal duration of prophylaxis † confirmatory study needed to establish efficacy in treatment of DVT † need to establish basis for elevation in LFTs and clinical significance
Ximelagatran: a new oral anticoagulant 151
REFERENCES 1. Gonze MD, Manord JD, Leone-Bay A, et al. Orally administered heparin for preventing deep venous thrombosis. American Journal of Surgery 1998; 176: 176–178. 2. Baughman RA, Kapoor SC, Agarwal RK, et al. Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans. Circulation 1998; 98: 1610–1615. 3. Pineo GF, Hull RD & Marder VJ. Orally active heparin and low-molecular-weight heparin. Current Opinions of Pulmonary Medicine 2001; 7: 344–348. 4. Moll S & Roberts HR. Overview of anticoagulant drugs for the future. Seminars in Hematology 2002; 39: 145–157. 5. Sato K, Kawasaki T, Taniuchi Y, et al. YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time. European Journal of Pharmacology 1997; 339: 141–146. 6. Jenny NS & Mann KG. Thrombin. In Colman RW, Hirsh J & Marder VJ (eds) Hemostasis and Thrombosis: Basic Principles and Practice, 4th edn. ; 2001, pp 171–189. 7. Kaplan KL & Francis CW. Direct thrombin inhibitors. Seminars in Hematology 2002; 39: 187–196. 8. Bauer KA. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Seminars in Thromobsis and Hemostasis 2002; 28(supplement 2): 15–24. 9. Gustafsson D, Nystrom J, N S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/ 95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thrombosis Research 2001; 101: 171 –181. 10. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metabolism and Disposition 2003; 31: 294– 305. 11. Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thrombosis and Haemostasis 1998; 79: 110 –118. 12. Elg M, Gustafsson D & Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thrombosis and Haemostasis 1997; 78: 1286– 1292. 13. Deinum J, Gustavsson L, Gyzander E, et al. A thermodynamic characterization of the binding of thrombin inhibitors to human thrombin, combining biosensor technology, stopped-flow spectrophotometry, and microcalorimetry. Analytical Biochemistry 2002; 300: 152–162. 14. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clinical Pharmacokinetics 2003; 42: 381 –392. 15. Wahlander K, Lapidus L, Olsson CG, et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thrombosis Research 2002; 107: 93 –99. 16. Klement P, Carlsson S, Rak J, et al. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. Journal of Thrombosis Haemostasis 2003; 1: 587–594. 17. Mattsson C, Menschik-Lundin A, Nylander S, et al. Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro. Thrombosis Research 2001; 104: 475–486. 18. Linder R, Frebelius S, Jansson K, et al. Inhibition of endothelial cell-mediated generation of activated protein C by direct and antithrombin-dependent thrombin inhibitors. Blood Coagulation and Fibrinolysis 2003; 14: 139– 146. 19. Nylander S & Mattsson C. Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action. Blood Coagulation and Fibrinolysis 2003; 14: 159–167. 20. Sarich TC, Wolzt M, Eriksson UG, et al. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. Journal of American College of Cardiology 2003; 41: 557– 564. 21. Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors. European Journal of Clinical Pharmacology 2002; 57: 751 –758. 22. Eriksson H, Eriksson UG, Frison L, et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thrombosis and Haemostasis 1999; 81: 358–363. 23. Mattsson C, Menschiek-Lundin A, Wahlander K, et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thrombosis and Haemostasis 2001; 86: 611 –615. 24. Hafner G, Roser M & Nauck M. Methods for the monitoring of direct thrombin inhibitors. Seminars in Thrombosis and Hemostasis 2002; 28: 425–430.
152 C. W. Francis 25. Eriksson BI, Bergqvist D, Kalebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441–1447. 26. Eriksson BI, Agnelli G, Cohen AT, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thrombosis and Haemostasis 2003; 89: 288–296. 27. Eriksson BI. The oral direct thrombin inhibitor ximelagatran, and its subcutaneous (sc) form melagatran, compared with enoxaparin for prophylaxis of venous thromboembolism (VTE) in total hip or total knee replacement (THR or TKR): the EXPRESS study. Blood 2002; 100: 82a. 28. Heit JA, Colwell CW, Francis CW, et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Archieves of Internal Medicine 2001; 161: 2215– 2221. 29. Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Annals of Internal Medicine 2002; 137: 648– 655. 30. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. New England Journal of Medicine 2003; 349: 1703–1712. 31. Colwell CW, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. Journal of Thrombosis and Haemostasis 2003; 1: 2119–2130. 32. Eriksson H, Wahlander K, Gustafsson D, et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. Journal of Thrombosis and Haemostasis 2003; 1: 41– 47. 33. Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. New England Journal of Medicine 2003; 349: 1713–1721. 34. Eriksson H, Wahlander K & Lundstrom T. Extended secondary prevention with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial. Blood 2002; 100: 81a. 35. Huisman M. Efficancy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute symptomatic deep vein thrombosis with or without pulmonary embolism, a double-blind, multinational trial. Abstracts of the XIX Congress of the ISTH, 2003.. 36. Halperin J. The stroke prophylaxic using an oral thrombin inhibitor in atrial fibrillation trial (SPORTIF III). American Heart Journal 2003; : 146. 37. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789–797.
9 Ximelagatran: a new oral anticoagulant Charles W. Francis*
MD
Hematology/Oncology Unit, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 610, Rochester, NY, USA
Vitamin K antagonists are effective oral anticoagulants, but they have limitations related to a narrow therapeutic range, food and drug interactions, slow onset of action and the need for routine coagulation monitoring. Ximelagatran is a promising new oral anticoagulant under investigation in advanced clinical trials. It is a prodrug that is converted after oral administration to melagatran, a direct thrombin inhibitor, with a peak effect after 2 hours and a half-life of approximately 3 hours with primarily renal excretion. Administration results in prolongation of coagulation tests, but routine monitoring is not required because of reliable absorption and predictable effects. A large clinical trials program has demonstrated effectiveness in prophylaxis of deep vein thrombosis (DVT) following major orthopedic surgery, treatment of symptomatic DVT, prevention of embolism in patients with atrial fibrillation, and prophylaxis of recurrent events after acute myocardial infarction. Bleeding complications have been similar to those with standard therapy, with no unexpected adverse effects except for elevation of serum transaminase levels in over 6% of patients beginning after 1 month of therapy. Ximelagatran may be an alternative oral anticoagulant for patients currently taking vitamin K antagonists. Key words: ximelagatran; melagatran; warfarin; coumarins; vitamin K antagonists; deep vein thrombosis; pulmonary embolism; atrial fibrillation; stroke; myocardial infarction.
The vitamin K antagonists such as warfarin have remained the only oral anticoagulants available since their introduction in 1942. Although effective and widely used for a broad range of indications, they have serious limitations. Close monitoring to maintain the international normalized ratio (INR) within a desired range is required to maintain effectiveness and minimize bleeding complications because of the narrow therapeutic range. Also, they have a slow onset of action so therapy must be initiated with a parenteral anticoagulant when a rapid effect is needed. Vitamin K antagonists also have prolonged action after stopping, which creates difficulties in managing bleeding complications or when treatment must be interrupted for invasive procedures. Dosing is complicated by numerous interactions with food and drugs, and marked biological variations in response between patients. Several new parenteral anticoagulants acting at different sites in the coagulation system have been introduced in recent years, but the vitamin K antagonists have remained the only choice for oral anticoagulation. * Tel.: þ 1-585-275-3761; Fax: þ1-585-473-4314. E-mail address: [email protected] (C.W. Francis). 1521-6926/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
140 C. W. Francis
An alternative oral anticoagulant remains an important unmet clinical need. Oral agents in early clinical trials include heparin derivatives with oral bioavailability1 – 3 and inhibitors of Factor Xa.4,5 However, the new oral drug showing greatest promise is ximelagatran (Exantaw), a direct thrombin inhibitor that has been tested in phase III clinical trials for several indications in over 17 000 patients worldwide. Thrombin is an excellent target for an anticoagulant. It is a central enzyme in hemostasis with important effects on coagulation, platelets, fibrinolysis and vascular cell function6 (Table 1). The most prominent procoagulant effect of thrombin is the conversion of fibrinogen to fibrin by cleavage of fibrinopeptides A and B. However, it also has an important effect in feedback amplification of coagulation, as small amounts of thrombin proteolytically activate Factors V and VIII, and this greatly increases their Table 1. Thrombin actions. Coagulation Cleavage of fibrinopeptides A and B from fibrinogen to form fibrin Activation of Factor XIII (to crosslink fibrin) Activation of Factors V and VIII (cofactors for Factor Xa and Factor IXa, respectively) Activation of Factor XI Anticoagulation Activation of Protein C (requires binding of thrombin to thrombomodulin) Fibrinolysis inhibition Activation of thrombin-activatable fibrinolysis inhibitor Cellular effects Platelet activation Endothelial cells Stimulates production of nitric oxide, prostacyclin platelet-activating factor and plasminogen activator inhibitor Stimulates secretion of von Willebrand factor Stimulates surface expression of P-selectin Smooth muscle cells Downregulates purinergic receptors (receptors for adenosine disphosphate and adenosine triphosphate) Increases intracellular calcium Mitogenic Fibroblasts Mitogenic Lymphocytes Mitogenic Monocytes Chemotactic and mitogenic Neutrophils Activates Other suggested activities Neuron outgrowth Restenosis Atherosclerosis Neovascularization/angiogenesis Tumorigenesis Embryogenesis in developing heart, blood vessels, brain, hematopoiesis and several epithelial tissues
Ximelagatran: a new oral anticoagulant 141
cofactor activities. Thrombin also converts Factor XI to Factor XIa, which activates Factor XIII; this stabilizes fibrin by isopeptide cross-linking. Another important hemostatic effect is proteolytic activation of thrombin-activatable fibrinolysis inhibitor, which inhibits fibrinolysis by cleaving N-terminal lysines from fibrin to limit plasminogen binding. Additionally, thrombin is a potent platelet activator, and it has effects on a variety of vascular cells through activation of specific receptors. Thrombin also has an important anticoagulant effect after binding to the endothelial receptor, thrombomodulin, which enables it to convert Protein C to activated Protein C; this inactivates Factors Va and VIIIa. Therefore, thrombin inhibition may result in a variety of effects including inhibition of coagulation, platelet activation and fibrinolysis. However, it could potentially have a procoagulant effect under some circumstances through reduced formation of activated Protein C, and it may influence vascular responses to injury through blocking cellular effects. Clinical need has provided the impetus for the development of ximelagatran, and scientific advances in the biochemistry of thrombin have provided the necessary background and tools. In particular, detailed structural information, including resolution of its crystal structure, and characterization of its interaction with substrates including fibrinogen have been important milestones. Development of ximelagatran has also been aided by the introduction of the parenteral direct thrombin inhibitors argatroban, desirudin and bivalirudin, that are approved for use in heparin-induced thrombocytopenia and percutaneous coronary interventions.7 This provided relevant biochemical, physiological and clinical data about the effects of direct thrombin inhibitors, including a convincing demonstration that an agent targeting thrombin alone could be an effective anticoagulant. This is a very new concept as the commonly used agents affect multiple sites.8 Vitamin K antagonists decrease the synthesis of Factors II, VII, IX and X and also Proteins C and S. Both heparin and low-molecular-weight heparins (LMWHs) act through antithrombin III to inhibit all of the coagulation serine proteases including thrombin, Factor Xa and others. Thus, the clinical effectiveness of an agent acting at a single site in hemostasis was uncertain until the successful clinical use of the parenteral direct thrombin inhibitors and also fondaparinux, a specific inhibitor of Factor Xa.
PROPERTIES Ximelagatran is an inactive prodrug derivative of melagatran, a potent direct thrombin inhibitor (Table 2). Development of the novel, derivatized prodrug approach was essential because melagatran and other active direct thrombin inhibitors exhibit poor intestinal absorption.9,10 Whereas melagatran has a high affinity for thrombin with a Ki of 2 nM, ximelagatran is more than 100-fold less active.9 – 13 However, following oral administration, ximelagatran is rapidly and nearly completely absorbed with a Cmax of 0.33 hours, and food has little effect on absorption.10 – 14 Ximelagatran is metabolized rapidly with a half-life of unmetabolized ximelagatran of 0.34 hours, and approximately 20% is converted to melagatran with a low interindividual variability in the area under the curve of approximately 20% (Figure 1).10,14 Other metabolites include ethylmelagatran and OH-melagatran that form in small amounts and are eliminated rapidly. The tmax of melagatran following oral ximelagatran is approximately 2 hours.10,14,15 Melagatran, the active metabolite of ximelagatran, is a competitive, reversible active site inhibitor of thrombin. It also has significant activity towards trypsin and does not require antithrombin.9,11 It is a dipeptide whose structure mimics the sequence N-terminal to the cleavage site for thrombin on the fibrinogen Aa chain. Melagatran
142 C. W. Francis
Table 2. Properties of ximelagatran and melagatran. Ximelagatran †Inactive prodrug derivative of melagatran †Good intestinal absorption with minimal effect of food †Approximately 20% converted to melagatran after oral dosing †Tmax for melagatran after oral dose is 2 hours †CV for plasma area under the curve (AUC) of melagatran after oral dose of ximelagtatran is 20% Melagatran †Direct, competitive, reversible, active site inhibitor of thrombin with Ki , 2 nM Inhibits thrombin bound to fibrin or thrombomodulin †Tmax after SQ administration 0.5–1 hour for saline formulation and 2 hours for depot formulation †Linear, dose-proportional increase in plasma AUC after oral ximelagatran †Half-life is ,3 hours †Less than 15% bound to plasma proteins †Over 80% excreted unchanged in urine †Half-life prolonged with decreased renal function
produces similar inhibition of fluid-phase thrombin and of thrombin bound to either fibrin clots or fibrin monomers, and it is significantly more active against clot-bound thrombin than the larger direct thrombin inhibitor, hirudin.1,16 It also inhibits thrombin complexed with thrombomodulin and activation of Protein C effectively at clinically relevant concentrations.17,18 This could possibly result in a paradoxical procoagulant effect in some settings and needs to be considered in interpreting dose-response and clinical outcomes. Melagatran also inhibits platelet activation and cleavage of protease activated receptor-1 in a dose-dependent manner.19,20 Melagatran can be administered either subcutaneously or intravenously but has poor oral bioavailability. Over 80% of melagatran is excreted unchanged in the urine, so the plasma half-life and concentration increase with declining renal function. The reduced clearance of melagatran in older subjects correlates well with declining renal function.10,14,21,22 Protein binding is less than 15% and the half-life in normal young subjects is approximately 3 hours.10,14 Melagatran prolongs most coagulation tests. The partial thromboplastin time is prolonged in a concentration-dependent manner, but the relationship between Prothrombinase
XIMELAGATRAN
Va, lipid Xa MELAGATRAN
Prothrombin
Platelet activation
Thrombin
Fibrin formation
Fibrinolysis inhibition
Cellular effects
Figure 1. Following oral administration, ximelagatran is converted to melagatran, a direct inhibitor of thrombin.
Ximelagatran: a new oral anticoagulant 143
concentration and prolongation is non-linear.15 The thrombin time increases directly in proportion to melagatran concentration but is very sensitive within the therapeutic range.11 Melagatran prolongs prothrombin time assays, but the effect depends on both the thromboplastin used and the dilution of the sample. Melagatran was added to normal plasma and the effects were investigated using 17 commercially available prothrombin time kits.23 Depending on the specific assay used, an INR of 2.0 could be obtained with melagatran concentrations as low as 0.55 mmol/L or as high as 2.9 mmol/L, and currently available prothrombin time-based systems are not suitable for monitoring plasma levels. The ecarin clotting time may be the best coagulation test for assessing plasma levels24, but it is not widely available. Monitoring of coagulation tests has not been performed in clinical trials and should not be needed for routine use.
CLINICAL TRIALS Orthopedic surgery A large clinical trials program in both venous and arterial disease has been undertaken with ximelagatran. An initial focus has been the prevention of venous thromboembolism (VTE) following orthopedic surgery. This is a demanding model to evaluate potential efficacy because of the documented high rate of venographically diagnosed thrombosis, and a stringent test of safety because of the risk of bleeding at the site of major surgery. Dosing has followed different patterns in European compared with North American trials. In Europe, the regimens used have combined subcutaneous administration of melagatran before or after surgery followed by oral ximelagatran. This approach was designed to provide optimal prophylaxis using the parenteral agent during surgery, when thrombosis may begin, and then follow with more convenient oral administration. The Methro II trial enrolled both hip and knee replacement patients25 and compared four dosing combinations of melagatran/ximelagatran with a standard regimen of dalteparin in a prospective, randomized trial in patients undergoing hip or knee arthroplasty with mandatory bilateral venography at 7– 10 days (Table 3). The results showed both a promising and statistically significant dose-dependent reduction in VTE and also a significantly lower rate of thrombosis with the highest dose regimen of melagatran/ximelagatran compared with dalteparin.26 There was, however, a dosedependent increase in blood transfusions in the melagatran/ximelagatran groups after total hip replacement, with rates of severe bleeding of 1.1 and 5% in the lowest and highest dose groups, respectively. Nearly all of the bleeding complications were at the surgical site. The Methro II study demonstrated good efficacy but increased bleeding, so the regimen was altered in two subsequent phase III trials. In the EXPRESS trial27, melagatran 2 mg was given subcutaneously before surgery, followed by 3 mg in the evening after surgery, and this was followed by oral ximelagatran 24 mg twice daily until venography (Table 4). The comparison group in this randomized double-blind study of both hip and knee replacement patients received enoxaparin 40 mg daily starting the evening before surgery. Bilateral venography was performed after 8– 11 days of treatment. The results showed a significantly lower rate of thrombosis in the melagatran/ximelagatran group (20.3%) compared with the enoxaparin group (26.6%, P , 0:001). However, severe bleeding primarily at the surgical site was also significantly increased with melagatran/ximelagatran (3.1%) compared with enoxaparin (1.2%)
144 C. W. Francis
Table 3. Dose-guiding studies of ximelagatran. Study name (Ref)
Treatment
Hip or knee replacement
METHRO II
Melagatran/ximelagatranb
(25)
1.0/8 mg 1.5/12 mg 2.25/18 mg 3.0/24 mg Dalteparin 5000 U QDd
364 377 375 379 381
39% 24% 24% 15% 28%
1.1% 2.1% 2.9% 5.0% 2.4%
(28)
Ximelagatran 8 mge 12 mg 18 mg 24 mg Enoxaparin 30 mgf
63 101 87 95 97
27% 20% 29% 16% 23%
0 0 1.6% 0 0.8%
Venographicg response 76% 65% 64% 72% 69%
1.5% 1.5% 0 0 2.7%
Compositei 12% 14% 12% 13% 16%
2% 1% 3% 2% 1%
Knee replacement
DVT treatment
Myocardial infarction
THRIVE I (32)
ESTEEM (36)
Ximelagatran 24 mg 36 mg 48 mg 60 mg Dalteparin/warfarinh
Ximelagatran 24 mg 30 mg 48 mg 60 mg Placebo
n
Efficacy endpoint
Bleedinga
Group
VTEc
54 57 59 60 65
307 303 311 324 638
VTE, venous thromboembolism; DVT, deep vein thrombosis. Severe or major bleeding. b Melagatran given immediately before surgery and 7– 11 hours post operation and twice daily until oral ximelagatran could be given. Ximelagatran was given orally twice daily. c Confirmed VTE with bilateral venography at 7– 10 days. d First dose given the evening before surgery. e Oral ximelagatran twice daily starting 12 –24 hours post operation. f Enoxaparin 30 mg SQ twice daily starting 12–24 hours post operation. g Change in extent of thrombus after 2 weeks judged by repeat venography. h Dalteparin 200 u/kg SQ daily followed by warfarin. i All-cause mortality, non-fatal myocardial infarction and severe recurrent ischemia over 6 months. a
ðP , 0:001Þ; and transfusion requirements were also higher in the melagatran/ ximelagatran-treated patients. The subsequent Methro III study26 enrolled 2788 patients having hip or knee replacement in a similar randomized double-blind comparison of melagatran/ ximelagatran with enoxaparin. However, in this study, the pre-operative melagatran dose was dropped, and the regimen included a single dose of melagatran 3 mg given
Ximelagatran: a new oral anticoagulant 145
Table 4. Phase III trials of ximelagatran. Orthopedic surgery prophylaxis Group
Study name (Ref)
Treatment
n
VTE
P
Major bleeding
P
1141
20.3%
,0.001
3.1%
,0.001
1184 1146
26.6% 31.0%
NS
1.2% 1.4%
NS
1122
27.3%
276
19.2%
261 614
25.7% 24.9%
629
20.3%
0.003g
0.8%
608 782
27.6% 7.9%
,0.05
0.7% 0.8%
775
4.6%
Treatment
n
Stroke and systemic emboli
P
Major bleeding
P
Ximelagatranf
1704
1.6%/year
NS
1.3%/year
NS
Warfarin
1703
2.3%/year
Melagatran/ximelagatran (Europe) Hip or knee Express (26) Melagatrana/ ximelagatranb replacement Enoxaparinc Hip or knee Methro III (27) Melagatrand/ replacement ximelagatranb Enoxaparine Ximelagatran only (North America) Knee (29) Ximelagatranb replacement Warfarin Knee EXULT (30) Ximelagatran replacement 24 mgb Ximelagatran 36 mgf Warfarin Hip (31) Ximelagatranb replacement Enoxaparine Other indications Group Study name (Ref)
Atrial fibrillation
SPORTIF III (35)
1.7% NS
1.7%
NS
0.9% 0.8%
NS
NS
0.9%
1.8%/year
Recurrence DVT treatment Long-term THRIVE III (33) Acute
a
THRIVE treatment (34)
Ximelagatranh Placebo Ximelagatranf
612 611 1240
2.0% 11.6% 2.1%
Enoxaparin/ warfarin
1249
2.0%
,0.0001 NS
1.0% 0.8% 1.3%
NS NS
2.2%
Melagatran 2 mg SC immediately before operation; 3 mg SC the evening of surgery. 24 g PO q 12 hours. c Enoxaparin 40 mg SC 12 hours before operation and then daily. d Melagatran 3 mg SC 4– 12 hours post operation; then ximelagatran 24 mg PO b.i.d. when able to take oral medication. e Enoxaparin 30 mg SC q 12 starting 12–24 hours post operation. f 36 mg PO q 12 hours. g Comparison for ximelagatran 36 mg with warfarin. h Ximelagatran 24 mg SC b.i.d. starting after 6 months of standard treatment. b
146 C. W. Francis
4 –12 hours postoperatively followed by oral ximelagatran 24 mg twice daily. Bilateral venography was performed after 8 – 11 days. There was no increased bleeding in the melagatran/ximelagatran group in this study, but neither was there improved efficacy over enoxaparin, with relatively high rates of 31.0 and 27.3% in the ximelagatran/ melagatran and enoxaparin groups, respectively. The subgroup having total hip replacement showed better results with enoxaparin (19.4%) compared with melagatran/ximelagatran (25.4%, P ¼ 0:004). North American studies have used only ximelagatran with no melagatran, and separate trials have been conducted in hip and knee arthroplasty patients. A dosefinding study in patients having total knee replacement compared four doses of ximelagatran with enoxaparin.28 Rates of VTE using unilateral venography were between 16 and 29% in ximelagatran patients without clear evidence of a dosedependent efficacy effect. The group receiving the highest dose (24 mg) had a thrombosis rate of 16%; this was not significantly different from the rate of enoxaparin. Bleeding events were uncommon (Table 3). Although there was no clear dose-dependent effect on efficacy or bleeding, ximelagatran 24 mg twice daily was selected for a subsequent larger phase III trial (Table 4). The comparator for this double-blind, randomized trial was warfarin, which is widely used for prophylaxis in orthopedic surgery in North America, and treatment was given for 7– 12 days until unilateral venography.29 The results showed a VTE rate of 19.2% in the ximelagatran group which was lower than in warfarin-treated patients (25.7%), but this was not statistically significant ðP ¼ 0:07Þ: Major and minor bleeding events were also not significantly different in the two treatment groups. The conclusion from this study was that the ximelagatran regimen was at least as effective as warfarin. Considering that the results of the phase II dose-guiding study were ambiguous, and that the phase III study with total knee replacement showed a trend in favor of ximelagatran, a larger phase III trial was conducted. This compared prophylaxis using warfarin or ximelagatran at two doses (24 or 36 mg twice daily) in a trial of similar design except that bilateral venography was performed.30 This study (EXULT) showed a significantly ðP ¼ 0:003Þ lower rate of VTE in the 36-mg ximelagatran group (20.3%) compared with warfarin (27.6%). Bleeding events did not differ. This study indicated greater efficacy of the 36-mg dose without increased bleeding, and highlighted problems with the limited information available from the phase II study. A separate randomized double-blind study was performed in patients having hip replacement using the lower (24 mg) dose and a comparator group that received enoxaparin.31 Rates of venographically diagnosed thrombosis were very low (7.9% with ximelagatran and 4.6% with enoxaparin), but the outcome was significantly ðP , 0:05Þ better with enoxaparin. Overall, the results in this large clinical trial program of prophylaxis in orthopedic surgery have been mixed. A significant problem was the failure to identify a clear dosedependent effect on efficacy and safety using the range of oral ximelagatran doses tested in the North American phase II study. This led to the choice of a 24-mg regimen for the initial phase III trials in hip and knee replacement that showed equivalent or inferior efficacy to standard prophylaxis. The 36-mg regimen had superior efficacy with no increase in bleeding and was better than warfarin in the randomized trial in knee replacement and clearly better than the historical rates with no prophylaxis. This demonstrates that the 36-mg ximelagatran regimen is a suitable alternative for warfarin in high-risk patients having orthopedic surgery. Additional studies using the 36-mg dose in patients having hip replacement and possibly hip fracture will be needed to provide additional information. The choice of ximelagatran 24 mg for the European studies may
Ximelagatran: a new oral anticoagulant 147
also have resulted in suboptimal efficacy. In addition, the regimen using melagatran administered immediately pre-operatively resulted in increased bleeding at the surgical site, which was not surprising considering that peak levels could be reached during the procedure. Omission of the pre-operative dose resulted in decreased surgical site bleeding, but efficacy may have been compromised, particularly using ximelagatran 24 mg (Table 4). Treatment of VTE Treatment of symptomatic deep vein thrombosis (DVT) includes two phases, with initial administration of heparin or LMWH followed by a longer period of anticoagulation with a vitamin K antagonist. Ximelagatran could potentially be effective for both phases because it has a rapid onset of anticoagulant effect, making it suitable for initial therapy, and because oral dosing is convenient for long-term therapy. In a phase II dose-guiding study, four doses of ximelagatran were compared with standard treatment of acute symptomatic DVT.32 The endpoint was the change in volume of thrombosis judged by venography after 2 weeks of therapy, and appeared similar in all treatment groups with minimal bleeding. The conclusions of this small study were that ximelagatran was promising and appeared to have a wide therapeutic margin because results were similar using doses from 24 to 60 mg twice daily (Table 3).33 This was followed by two phase III studies in VTE using different designs (Table 4). The THRIVE III study34 was a randomized, double-blind trial examining extended prophylaxis, initiated after an initial 6 months of anticoagulation in 1233 patients who presented with DVT or pulmonary embolism (PE). Patients received either placebo or ximelagatran 24 mg twice daily for an additional 8 months without monitoring of coagulation tests. The primary endpoint for efficacy was recurrent VTE, and this occurred in significantly fewer patients receiving ximelagatran (2.0%) compared with placebo (11.6%, P , 0:001). The incidence of major hemorrhage was low and not significantly different in the two groups. The study clearly demonstrated the effectiveness of ximelagatran 24 mg in long-term prophylaxis. The THRIVE treatment study35 was designed to demonstrate non-inferiority of ximelagatran to standard treatment for acute DVT. In a randomized, double-blind study, patients with DVTwith or without PE were allocated to standard treatment with either enoxaparin or ximelagatran 36 mg twice daily beginning at diagnosis and for a period of 6 months. There was no coagulation monitoring for ximelagatran, whereas warfarin anticoagulation had a target INR of 2.5. Objectively confirmed recurrent VTE occurred in 2.1% of 1240 patients in the ximelagatran group and 2.0% of 1249 patients in the enoxaparin/warfarin group. This result satisfied the non-inferiority criteria with a 95% confidence interval of 2 1.02 þ 1.3% for the difference in recurrent VTE between the ximelagatran and enoxaparin/warfarin groups. Major bleeding occurred in 1.3% of ximelagatran patients and 2.2% of enoxaparin/warfarin patients, a non-significant difference. This study demonstrated that oral ximelagatran without monitoring of coagulation tests may be a suitable alternative to standard treatment using LMWH followed by warfarin for the treatment of patients with symptomatic DVT. Atrial fibrillation Anticoagulation with a vitamin K antagonist is highly effective in preventing stroke in patients with atrial fibrillation, with a risk reduction of over 50%. Many patients are not
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treated, however, because of problems with monitoring warfarin and fear of bleeding complications. The use of ximelagatran in atrial fibrillation was evaluated in the SPORTIF III trial, a phase III, randomized, open-labeled study involving 3407 patients with atrial fibrillation and one or more additional risk factors for stroke (Table 4).36 The study was designed to test the hypothesis that ximelagatran 36 mg twice daily was not inferior to standard treatment with warfarin in preventing stroke and systemic embolic events. After 21 months of treatment, an embolic event had occurred in 2.3%/year of warfarin-treated patients and 1.6%/year of ximelagatran-treated patients in an intentto-treat analysis, clearly demonstrating non-inferiority. A secondary analysis of events on-treatment demonstrated a significant ðP ¼ 0:018Þ risk reduction of 41% for stroke and systemic embolism with ximelagatran (1.3%/year) compared with standard treatment (2.2%/year). There was no significant difference in major bleeding between the two groups; 1.3%/year in ximelagatran-treated patients and 1.8%/year in warfarintreated patients. These results indicate that ximelagatran 36 mg twice daily without coagulation monitoring is at least as effective and safe as warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Myocardial infarction Antiplatelet therapy reduces the risk of myocardial infarction, stroke or vascular death after myocardial infarction, and long-term anticoagulation with an oral vitamin K antagonist can further reduce cardiovascular events. However, such treatment is restricted because of the risks of bleeding and problems with coagulation monitoring and dose adjustment. The ESTEEM trial evaluated the potential value of ximelagatran for secondary prophylaxis after myocardial infarction (Table 3).37 This prospective, doubleblind, placebo-controlled, dose-guiding study evaluated 1883 patients with a recent ST-elevation or a non-ST-elevation myocardial infarction, and randomized participants within 14 days of the event to one of four doses of oral ximelagatran or placebo. All patients received aspirin and were randomized 1/1/1/2 to oral ximelagatran at doses of 24, 36, 48 or 60 mg twice daily, respectively, or to placebo for 6 months. The primary efficacy outcome was the dose response of ximelagatran compared with placebo for the occurrence of all-cause death, non-fatal myocardial infarction and severe recurrent ischemia. The results indicated that there was no efficacy dose-response between the ximelagatran groups. The primary outcome occurred in 12 –14% of patients in each of the four ximelagatran groups and 16% in the placebo group. Combining all groups, oral ximelagatran significantly reduced the risk of the primary endpoint compared with placebo from 16.3 to 12.7% ðP ¼ 0:036Þ: Major bleeding occurred in 1– 3% in the ximelagatran groups and 1% with placebo, a non-significant difference. However, the occurrence of total bleeding, including both major and minor, was higher with ximelagatran-treated patients (22%) compared with placebo-treated patients (13%). The results of this large phase II trial demonstrated that treatment with ximelagatran and aspirin was more effective than aspirin alone in preventing major cardiovascular events during 6 months of treatment in patients with a recent myocardial infarction. LIVER FUNCTION TEST ABNORMALITIES An unexpected problem has been the occurrence of abnormal liver function tests (LFTs) in patients treated with ximelagatran for longer than 1 month. This problem was not detected in preclinical studies, and the initial clinical trials did not plan detailed
Ximelagatran: a new oral anticoagulant 149
8 7 6
Percent
5 4 3 2 1 0 23
35 Placebo
>5
23
35
>5
Ximelagatran
Figure 2. Elevations of alanine transaminase levels in the ESTEEM trial.37 The percent of subjects with peak levels of 2 –3, 3–5 or .5 £ upper limit of normal are shown for the placebo group and the combined ximelagatran groups.
testing of LF. However, routine screening detected an increased frequency of elevated serum transaminase levels in patients treated long term with ximelagatran in the THRIVE III, THRIVE treatment, SPORTIF and ESTEEM trials. Detailed reporting of laboratory results and analysis of systematic events are not available for unpublished studies. However, the findings in the ESTEEM trial may be representative (Figure 2).37 Serum alanine aminotransferase levels peaked after 60– 120 days and returned to normal within 60 –90 days whether treatment was continued or stopped. Five of 1245 patients treated with ximelagatran had clinical jaundice with concurrent elevation of bilirubin and alanine aminotransferase. No evidence of permanent liver toxicity was detected. Of 147 patients with alanine aminotransferase elevated to over three times the upper limit of normal, all but one returned to prestudy levels or less than twice the upper limit of normal. An important finding has been that elevations in LFTs begin to occur during the second month of treatment, and no significant increase has been found in the short-term prophylaxis trials. The clinical significance of these elevations in LFTs is important for the further development of ximelagatran. No symptomatic hepatotoxicity has been reported other than jaundice, and there has apparently been no evidence of permanent liver damage. These results, however, have occurred in the setting of controlled clinical trials with routine monitoring of LFTs and close supervision. The need for monitoring of LFTs will have to be considered in the clinical use of ximelagatran.
SUMMARY Ximelagatran is a prodrug formulation of the potent direct thrombin inhibitor melagatran that is administered orally and exhibits predictable absorption without food or drug effects. Following oral administration of ximelagatran, the peak melagatran
150 C. W. Francis
concentration occurs after 2 hours and the half-life is approximately 3 hours, necessitating twice-daily administration. Excretion is through the kidneys, and elevated levels can occur in patients with renal dysfunction. Coagulation tests including the prothrombin time, partial thromboplastin time and thrombin time are prolonged after administration, but routine monitoring has not been required because of the predictable pharmacological effect. In major orthopedic surgery, ximelagatran has shown effectiveness in the prevention of DVT, although identification of the best dose has been difficult. Ximelagatran 36 mg twice daily was superior to warfarin in patients undergoing knee replacement whereas ximelagatran 24 mg twice daily provided comparable efficacy. Following total hip replacement, ximelagatran 24 mg twice daily was inferior to enoxaparin. Ximelagatran was superior to placebo in preventing recurrent thrombosis after an initial 6 months of standard therapy in patients with symptomatic DVT or PE. The efficacy of ximelagatran was not inferior to standard therapy with enoxaparin and warfarin in patients presenting with acute DVT with or without PE with comparable bleeding complications. In patients with atrial fibrillation, ximelagatran was not inferior to warfarin in the prevention of stroke and systemic embolism with comparable bleeding complications. In a phase II study in patients with acute myocardial infarction, ximelagatran showed superior efficacy to warfarin in preventing death, recurrent myocardial infarction or severe recurrent ischemia. Elevation of serum transaminase levels occurred in over 6% of patients who were treated for longer than 1 month. In conclusion, ximelagatran is a promising oral anticoagulant offering an alternative to warfarin for a broad range of indications. Further studies will be needed to define its efficacy in prophylaxis after major orthopedic surgery, including hip replacement and hip fracture, and also its role in extended prophylaxis. A larger phase III trial will be needed to confirm its efficacy in the secondary prophylaxis of coronary events following acute myocardial infarction. Elevation of serum transaminase levels is of concern for treatment longer than 1 month. Although serious liver toxicity has not been observed in closely regulated clinical trials, monitoring and supervision will be needed for routine use. Practice points † † † † †
not yet FDA approved orally administered with rapid onset of effect twice-daily dosing no routine coagulation monitoring favorable results in prophylaxis of DVT in orthopedics, treatment of DVT, treatment of atrial fibrillation, and secondary prevention of myocardial infarction † monitoring of LFTs needed with use over 1 month
Research agenda † further studies to define role in hip replacement and hip fracture and to define optimal duration of prophylaxis † confirmatory study needed to establish efficacy in treatment of DVT † need to establish basis for elevation in LFTs and clinical significance
Ximelagatran: a new oral anticoagulant 151
REFERENCES 1. Gonze MD, Manord JD, Leone-Bay A, et al. Orally administered heparin for preventing deep venous thrombosis. American Journal of Surgery 1998; 176: 176–178. 2. Baughman RA, Kapoor SC, Agarwal RK, et al. Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans. Circulation 1998; 98: 1610–1615. 3. Pineo GF, Hull RD & Marder VJ. Orally active heparin and low-molecular-weight heparin. Current Opinions of Pulmonary Medicine 2001; 7: 344–348. 4. Moll S & Roberts HR. Overview of anticoagulant drugs for the future. Seminars in Hematology 2002; 39: 145–157. 5. Sato K, Kawasaki T, Taniuchi Y, et al. YM-60828, a novel factor Xa inhibitor: separation of its antithrombotic effects from its prolongation of bleeding time. European Journal of Pharmacology 1997; 339: 141–146. 6. Jenny NS & Mann KG. Thrombin. In Colman RW, Hirsh J & Marder VJ (eds) Hemostasis and Thrombosis: Basic Principles and Practice, 4th edn. ; 2001, pp 171–189. 7. Kaplan KL & Francis CW. Direct thrombin inhibitors. Seminars in Hematology 2002; 39: 187–196. 8. Bauer KA. Selective inhibition of coagulation factors: advances in antithrombotic therapy. Seminars in Thromobsis and Hemostasis 2002; 28(supplement 2): 15–24. 9. Gustafsson D, Nystrom J, N S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/ 95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thrombosis Research 2001; 101: 171 –181. 10. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metabolism and Disposition 2003; 31: 294– 305. 11. Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thrombosis and Haemostasis 1998; 79: 110 –118. 12. Elg M, Gustafsson D & Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thrombosis and Haemostasis 1997; 78: 1286– 1292. 13. Deinum J, Gustavsson L, Gyzander E, et al. A thermodynamic characterization of the binding of thrombin inhibitors to human thrombin, combining biosensor technology, stopped-flow spectrophotometry, and microcalorimetry. Analytical Biochemistry 2002; 300: 152–162. 14. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clinical Pharmacokinetics 2003; 42: 381 –392. 15. Wahlander K, Lapidus L, Olsson CG, et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thrombosis Research 2002; 107: 93 –99. 16. Klement P, Carlsson S, Rak J, et al. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. Journal of Thrombosis Haemostasis 2003; 1: 587–594. 17. Mattsson C, Menschik-Lundin A, Nylander S, et al. Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro. Thrombosis Research 2001; 104: 475–486. 18. Linder R, Frebelius S, Jansson K, et al. Inhibition of endothelial cell-mediated generation of activated protein C by direct and antithrombin-dependent thrombin inhibitors. Blood Coagulation and Fibrinolysis 2003; 14: 139– 146. 19. Nylander S & Mattsson C. Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action. Blood Coagulation and Fibrinolysis 2003; 14: 159–167. 20. Sarich TC, Wolzt M, Eriksson UG, et al. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. Journal of American College of Cardiology 2003; 41: 557– 564. 21. Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors. European Journal of Clinical Pharmacology 2002; 57: 751 –758. 22. Eriksson H, Eriksson UG, Frison L, et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thrombosis and Haemostasis 1999; 81: 358–363. 23. Mattsson C, Menschiek-Lundin A, Wahlander K, et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thrombosis and Haemostasis 2001; 86: 611 –615. 24. Hafner G, Roser M & Nauck M. Methods for the monitoring of direct thrombin inhibitors. Seminars in Thrombosis and Hemostasis 2002; 28: 425–430.
152 C. W. Francis 25. Eriksson BI, Bergqvist D, Kalebo P, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441–1447. 26. Eriksson BI, Agnelli G, Cohen AT, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thrombosis and Haemostasis 2003; 89: 288–296. 27. Eriksson BI. The oral direct thrombin inhibitor ximelagatran, and its subcutaneous (sc) form melagatran, compared with enoxaparin for prophylaxis of venous thromboembolism (VTE) in total hip or total knee replacement (THR or TKR): the EXPRESS study. Blood 2002; 100: 82a. 28. Heit JA, Colwell CW, Francis CW, et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Archieves of Internal Medicine 2001; 161: 2215– 2221. 29. Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial. Annals of Internal Medicine 2002; 137: 648– 655. 30. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. New England Journal of Medicine 2003; 349: 1703–1712. 31. Colwell CW, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. Journal of Thrombosis and Haemostasis 2003; 1: 2119–2130. 32. Eriksson H, Wahlander K, Gustafsson D, et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. Journal of Thrombosis and Haemostasis 2003; 1: 41– 47. 33. Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. New England Journal of Medicine 2003; 349: 1713–1721. 34. Eriksson H, Wahlander K & Lundstrom T. Extended secondary prevention with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial. Blood 2002; 100: 81a. 35. Huisman M. Efficancy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute symptomatic deep vein thrombosis with or without pulmonary embolism, a double-blind, multinational trial. Abstracts of the XIX Congress of the ISTH, 2003.. 36. Halperin J. The stroke prophylaxic using an oral thrombin inhibitor in atrial fibrillation trial (SPORTIF III). American Heart Journal 2003; : 146. 37. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789–797.