Ximelagatran, the New Oral Anticoagulant:Would Warfarin Survive the Challenge?

Shaker A. Mousa1 and Hikmat N. Abdel-Razeq2

1Albany College of Pharmacy and Pharmaceutical Research Institute, Albany, NY, USA,

and 2King Hussein Cancer Center, Amman, Jordan

Keywords: Anticoagulants — Atrial fibrillation — Melagatran — Thrombin in-

hibitors — Thromboprophylaxis — Venous thromboembolism — Warfarin —

Ximelagatran.

ABSTRACT

The last decade witnessed major advances in the prevention and treatment of venous as

well as of arterial thrombosis. Limitations of existing anticoagulants led to the devel-

opment of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor

(DTI) that is given orally, without the need for close monitoring. This compound was tried

in the treatment of active venous thromboembolism, and the results were encouraging.

Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of

stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective

trials compared ximelagatran with low molecular weight heparin or warfarin in prevention

of venous thromboembolism in patients undergoing major orthopedic procedures. The re-

sults of these clinical trials are reviewed in this article. Because of certain safety concerns

(increased liver enzymes, potential hepatonecrosis, and increased coronary events) xime-

lagatran has not yet been approved by the FDA. Additional studies may be required to ad-

dress these concerns. Ximelagatran has been approved, however, by the European regu-

latory authorities for short-term thromboprophylaxis. The success of ximelagatran or other

oral antithrombin agents would provide significant proof of the concept for the long-term

use of oral antithrombins in the prevention and treatment of both arterial and venous

thrombosis.

INTRODUCTION

Venous thromboembolism (VTE) leads to deep-vein thrombosis (DVT) and potentially

life-threatening pulmonary embolism (PE). Arterial embolism or thrombosis lead to ische-

331

Cardiovascular Drug ReviewsVol. 23, No. 4, pp. 331–344© 2005 Neva Press, Branford, Connecticut

Address correspondence and reprint requests to: Shaker Mousa, Ph.D., Professor of Pharmacology, Executive

VP and Chairman, The Pharmaceutical Research Institute, 106 New Scotland Avenue, Albany, NY 12208, USA;

Tel.: +1 (518) 694-7397, Fax: +1 (518) 694-7392, E-mail: mousas@acp.edu

mic heart disease and stroke. Both thrombotic diseases are common (36). In view of the

clinically silent nature of VTE, the total incidence, prevalence, and mortality rates are

probably underestimated.

The last decade has witnessed major advances in the prevention and treatment of both

venous and arterial thrombosis (Fig. 1). Weight-adjusted low molecular weight heparin

(LMWH) became the standard initial therapy for patients with established DVT (37).

Various antithrombotic agents have been proposed for the prevention and treatment of

venous and arterial thrombosis, but they all suffer from some limitations (2,11,41).

Although efficacy and safety are the main issues to be considered with any antithrom-

botic drug, convenience of the dosing schedule and the need for close monitoring are also

important factors in choosing anticoagulants. Vitamin K antagonist (warfarin) is a widely

used anticoagulant. However, given the frequent food and drug interactions for which

close monitoring is needed, it becomes difficult to maintain the therapeutic level of antico-

agulation (Tables 1 and 2, Fig. 2). Because of the lack of interactions with food and some-

what flatter dose-response relationship, it should be easier to establish and to maintain the

therapeutic levels of ximelagatran than those of warfarin (Fig. 2).

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

332 S. A. MOUSA AND H. N. ABDEL-RAZEQ

1993First commercially

available LMWH

1998First commercially

available DTI2001Firstcommerciallyavailablesyntheticfactor Xa inhibitor

1940sHeparincommerciallyavailable

1954Warfarincommerciallyavailable

O R A L A G E N T S

I N J E C T A B L E A G E N T S

1930 1940 1950 1960 1970 1980 1990 2000 2004

50 years

2005First oral DTI*

FIG. 1. The timeline of advances in the development of anticoagulant drugs. * The first oral DTI (ximelagatran)

received limited approval by the European regulatory authorities (but not by the FDA) for short-term

thromboprophylaxis immediately after major orthopedic surgery.

TABLE 1. Problems with warfarin

Delayed onset�offset

Unpredictable dose response

Narrow therapeutic range

Drug–drug, drug–food interactions

Problematic monitoring

Slow reversibility

Data from refs. 1 and 30.

Limitations of existing anticoagulants have led to the development of newer anticoagu-

lants. LMWHs are widely used. A more recently developed alternative, a pentasaccharide,

fondaparinux, is not yet widely accepted. Both, LMWHs and fondaparinux, are given sub-

cutaneously. Currently, the greatest need is for an anticoagulant that can be given orally

for prevention as well as for the treatment of arterial thromboembolism or VTE without

the need for close monitoring.

One of the newly studied anticoagulants is melagatran, which is poorly absorbed. To

improve oral absorption it has been chemically modified to ximelagatran (Figs. 3 and 4).

Following ingestion, ximelagatran is absorbed from the small intestine and undergoes

rapid biotransformation to melagatran, the active form (21). Ximelagatran has been eval-

uated for prevention of VTE in patients undergoing major orthopedic procedures and for

prevention of stroke in patients with nonvalvular atrial fibrillation. It has been also tested

in the treatment of established VTE.

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

XIMELAGATRAN 333

Odds

Ratio

05.0 6.0 8.0

INR

1.0 2.0 3.0 4.0 7.0

5.0

15.0

10.0

1.0

FIG. 2. The narrow therapeutic window for warfarin with regard to efficacy and safety. INR, International Nor-

malized Ratio; Solid line, stroke; dotted line, intracranial bleeding. Arrows indicate therapeutic range of stroke

treatment. Below this range, the therapeutic benefit is not optimal. Exceeding this range has no benefit, but only

increases risk of intracranial bleeding (data from refs. 31 and 32).

TABLE 2. Warfarin issues

Pharmacokinetics:

� Reduced absorption

� Metabolized by CYP450s (especially 2C9)

� Genetic polymorphisms (especially 2C9)

� Protein binding

Pharmacodynamics

� Varied intake of vitamin K-containing foods

Data from refs. 10, 13, 21, 27, 29, 33, 34, 39, and 46.

PHARMACOLOGY

Melagatran is a small molecular weight, competitive, and reversible direct inhibitor of

thrombin (20). Because of low membrane permeability, melagatran is not suitable for oral

administration (10). Ximelagatran is given orally, whereas melagatran is administered

subcutaneously. Orally administered ximelagatran is rapidly absorbed and converted to its

active form, melagatran. Following a single dose of ximelagatran, 24 or 36 mg, the

maximal blood levels of melagatran are reached within approximately 2 h. The bioavail-

ability of melagatran after ximelagatran administration is approximately 20%. Coadmini-

stration with food has no significant effect on the pharmacokinetic properties of ximelaga-

tran (Fig. 4). By s.c. administration to healthy volunteers melagatran is rapidly absorbed,

and it reaches maximal blood concentration at approximately 30 min. Only a small pro-

portion of the drug is bound to plasma proteins. By s.c. administration melagatran has an

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

334 S. A. MOUSA AND H. N. ABDEL-RAZEQ

NH

N

O

NH

O

NH2

NH

O

OH

Melagatran

O

NH

N

NH

O

NH2

O

ON OH

H C3 CH2

Ximelagatran

Reversible Binding at Active Site

• Oral pro-drug formulationtransformed after absorptionto active melagatran

• Absorbed in small intestine

Melagatran

FIG. 3. Structure of ximelagatran�melagatran and its binding site on thrombin.

elimination half-life of approximately 2 h. Melagatran is eliminated predominantly in the

urine within the first 12 h after administration of either oral ximelagatran or subcutaneous

melagatran. The pharmacokinetic profile of melagatran is not significantly affected by

obesity or mild or moderate liver dysfunction. However, the pharmacokinetics of the drug

in patients with severe renal impairment is markedly different from that in individuals

with normal renal function. The exposure to melagatran is higher in patients with severe

renal impairment than in individuals with normal renal function (12). Melagatran has no

known food interactions and no clinically significant drug interactions involving cyto-

chrome P450 enzymes (Table 2, Fig. 4).

Because patients with atrial fibrillation or coronary syndrome are likely to be on other

medications as well, several investigators studied the potential drug interaction with xime-

lagatran. Digoxin had no effect on pharmacokinetics or pharmacodynamics of ximelaga-

tran and vice versa (44). Similar results were obtained with the “cholesterol-lowering

drug,” atorvastatin that is commonly used in patients with atrial fibrillation or coronary

syndrome (44). For detailed preclinical pharmacology of ximelagatran see Haas (22) and

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

XIMELAGATRAN 335

NH

N

O

NH

O

NH2

NH

O

OH

• Rapid oral absorptionand biotransformation to melagatran

• Peak concentration ( ) at ~2 hCmax

• Half-life 4 to 5 h in patients

• ~80% renal excretion

• No CYP450 or metabolism

• Low plasma protein binding

• Low potentialfor food/drug interactions

• No coagulation monitoring required

• Fixed dosing with no inter-or intra-patient variability

• Rapid onset and offsetFibrinogen

Recognition Site

Exosite 1

Exosite 2

HeparinBinding Site

Thrombin

Melagatran

Active site

FIG. 4. Pharmacological properties of ximelagatran and mechanism of action; following ingestion, ximelaga-

tran will be converted to the active form melagatran. Melagatran binds to the active site of thrombin, thus inhib-

iting thrombin-mediated cleavage of fibrinogen to fibrin and clot formation. Data from ref. 23.

Weitz (47) and for metabolism and pharmacokinetics see Clement et al. (4), Cullberg et al.

(7), and Wolzt et al. (49).

MECHANISM OF ACTION

Activation of the extrinsic or intrinsic pathways will ultimately lead to activation of

factor X to factor Xa, which will lead to activation of prothrombin to thrombin and, ulti-

mately, the conversion of fibrinogen to fibrin and clot formation. Melagatran binds to the

active site of thrombin, thus inhibiting thrombin-mediated cleavage of fibrinogen to fibrin

(20), thereby preventing clot formation (Fig. 4).

LONG-TERM USE

During clinical development, at least 37 cases of severe liver injury (defined as ele-

vation of alanine aminotransferase [ALT] > 3� upper limit of normal [ULN] with con-

current increase in total bilirubin [TBL] > 2� ULN) were observed among patients ran-

domized to ximelagatran. The relative risk of severe liver injury was 6.6 (95% CI

2.6–16.9) compared with warfarin�placebo, with one affected person in each 200 treated

with ximelagatran. Preliminary analyses suggest that the risk of severe liver injury begins

within the first month of therapy.

Based on the observation of Zimmerman (50) that at least 10% of individuals with

severe drug-induced liver injury (as defined above) progress to liver failure, liver trans-

plant, or death, ximelagatran-associated fatal liver injury or liver failure could occur in as

many as 1 in 2000 patients treated long-term (i.e., 10% of 1 in 200) Consistent with this

prediction, 3 deaths associated with severe liver injury occurred in the ximelagatran

clinical development program, for a proportion of 1 fatal liver injury in 2,300 patients ex-

posed to ximelagatran (n = 6,948 ximelagatran-treated patients, mean treatment duration

of 357 days).

To address ximelagatran-induced hepatotoxicity associated with long-term use, the

sponsor (AstraZeneca) proposed an ALT-monitoring program similar to the program used

during clinical development. This program consisted of baseline and monthly ALT assess-

ments, with more frequent testing and discontinuation linked to different thresholds of

ALT elevation relative to the ULN. The initial algorithm specified an ALT > 7 times the

ULN as a threshold for drug discontinuation, but this was revised to 5 times the ULN after

the occurrence of a death associated with severe liver injury. Cases of severe liver injury

and a case of fatal liver injury continued to be observed after the implementation of the re-

vised algorithm. More conservative algorithms were not tested, so it remains unknown

whether timely discontinuation with any ALT elevation can prevent irreversible life-

threatening liver injury with ximelagatran.

In the clinical development program, severe liver injury, including fatal liver injury, oc-

curred even though compliance with ALT testing and discontinuation met or exceeded

83%. The sponsor has not provided sufficient information whether timely transaminase

monitoring and early discontinuation of the drug at the first signs of liver toxicity could

prevent severe liver injury and associated fatalities with ximelagatran. Even if the evi-

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

336 S. A. MOUSA AND H. N. ABDEL-RAZEQ

dence would be sufficient to support the claim that monitoring can reduce the risk of

severe liver injury and associated fatalities, the sponsor’s projected lower adherence with

recommended ALT monitoring in clinical use has the potential to lead to a higher inci-

dence of severe liver injury than was observed in clinical development.

Should it be determined that ximelagatran offers to selected populations of patients suf-

ficient benefits to counter the hepatotoxicity risk, consideration should be given to a re-

strictive medical audit program (RiskMAP) that would limit the risk for a population. One

example might be a performance-linked access system with a registry for patients entering

long-term ximelagatran therapy. Such a system should focus on appropriate education of

patients and providers about risk, as well as appropriate patient selection. We would also

advocate further quantification of the risk of hepatotoxicity over time and clarification of

the ability of ALT monitoring and early discontinuation of the drug to mitigate the risk of

severe liver injury and liver failure�fatal liver injury.

SHORT-TERM USE

During short-term use of ximelagatran (<12 days) the risk of severe liver injury appears

to be not greater than with warfarin. However, in two pivotal studies of total knee re-

placement (TKR) patients, the incidence of ALT elevation (> 3� ULN) at the follow-up

visit at six weeks after surgery was higher in ximelagatran- than in warfarin-treated pa-

tients (in 8 ximelagatran- vs. 1 warfarin-treated subject). It is not known whether delayed

onset of severe liver injury after short-term ximelagatran treatment could occur, since no

additional routine study visits were conducted.

Analysis of data from the LTE population shows that initial signs of liver injury

(ALT > 3� ULN) were observed during the first month of ximelagatran therapy in 6 of 37

patients who eventually developed severe liver injury (ALT > 3� ULN and TBL > 2�

ULN). This suggests that severe liver injury can potentially begin during the first month of

treatment with ximelagatran. Since practice guidelines recommend anticoagulation of

certain high-risk patients with TKR for more than 12 days, we anticipate that physicians

will want to treat some TKR patients for a longer period with ximelagatran. Since the risk

of severe liver injury could increase with longer duration of ximelagatran therapy, even

during the first month, “short-term” use of ximelagatran after TKR should be strictly

limited to prevent potential severe liver injury.

There is still a concern about the intrinsic risk and poorly characterized pace of

hepatotoxicity with ximelagatran. Should the benefits of ximelagatran therapy be con-

sidered sufficient to warrant approval of its use for short-term prevention of VTE in pa-

tients undergoing TKR, a RiskMAP should be implemented in collaboration with the

FDA. Such a program should provide an assurance that the total duration of therapy in in-

dividual patients does not exceed 12 days or whatever time period will be found to be

appropriate.

Other safety risk factors may also merit consideration of a RiskMAP for ximelagatran.

These factors include: (a) the risk of MI identified in the FDA Clinical Safety Review, and

(b) the absence of clear methods to control excessive bleeding, should it occur. Neither of

these risks was addressed by the sponsor. All studies with ximelagatran list the following

problems to be addressed in future studies: 1) need for monitoring, b) antidote, and

c) effect on activated protein C.

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

XIMELAGATRAN 337

TREATMENT OF ACUTE VTE

Current treatment of acute VTE consists of intravenous unfractionated heparin (UFH)

or subcutaneous LMWH, followed by oral vitamin K antagonists, such as warfarin. Xime-

lagatran has been evaluated in two large phase III clinical trials in the treatment of active

VTE. The first study (THRIVE) was a randomized, double-blind, non-inferiority trial in

which 2,489 patients with acute DVT (of whom 37% had confirmed PE) were randomly

assigned to receive either oral ximelagatran 36 mg b.i.d. for 6 months or subcutaneous

enoxaparin 1 mg�kg b.i.d. for a minimum of 5 days, followed by warfarin (target Interna-

tional Normalized Ratio [INR] 2.0–3.0) for 6 months. At baseline, bilateral compression

ultrasonography of the legs and ventilation-perfusion lung scanning were performed. The

primary end points were recurrence of VTE, as well as bleeding events and mortality. In

intention-to-treat analysis, recurrent VTE occurred in 2.1% of the ximelagatran group and

in 2.0% of the enoxaparin�warfarin group. Major bleeding occurred in 1.3% of ximelaga-

tran-treated patients and 2.2% of those given enoxaparin�warfarin (Fig. 5). These results

suggest that during 6 months of therapy, oral ximelagatran administered in fixed doses of

36 mg b.i.d. without laboratory monitoring was not inferior to enoxaparin�warfarin in pre-

venting recurrent VTE in patients with acute DVT with or without PE. Ximelagatran was

associated with a favorable outcome with respect to major bleeding (16).

One major problem encountered with ximelagatran was elevation of liver enzymes.

Laboratory evaluation showed that 9.6% of patients receiving ximelagatran had signif-

icant elevation in serum alanine aminotransferase (ALT) (> 3� ULN) compared with 2.0%

for patients receiving enoxaparin�warfarin.

In the second study (THRIVE III), Schulman and colleagues (45) used ximelagatran in

secondary prevention of VTE. In this study, 1,233 patients with VTE who finished 6

months of anticoagulant therapy were randomly assigned to extended secondary pre-

vention with ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

338 S. A. MOUSA AND H. N. ABDEL-RAZEQ

2.1%2.0%

1.3%*

2.2%

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Events

(%)

Ximelagatran

VTE Major Bleeding

Enoxaparin/warfarin

FIG. 5. Efficacy (VTE events) and safety (major bleeding) of ximelagatran vs. enoxaparin�warfarin in the treat-

ment of active venous thromboembolism (THRIVE Study [45]). VTE, venous thromboembolism; *P < 0.05.

monitoring of coagulation. At baseline, bilateral ultrasonography of the legs and perfusion

lung scanning were performed. Symptomatic recurrent VTE was confirmed in 12 of 612

(1.96%) patients assigned to ximelagatran and 71 of 611 (11.6%) patients assigned to

placebo (hazard ratio, 0.16; 95% confidence interval, 0.09 to 0.30; P < 0.001). The inci-

dence of major hemorrhage or death from any cause was similar in both groups. The cu-

mulative risk of a transient elevation of the ALT level to > 3� ULN was 6.4% in the

ximelagatran group as compared with 1.2% in the placebo group (P < 0.001) (45).

However, elevations in the aminotransferase levels were transient, and they were re-

stricted to the first 4 months of therapy. The aminotransferase elevations did not result in

progressive hepatic dysfunction, and the levels decreased spontaneously whether

treatment was continued or discontinued.

TREATMENT OF ATRIAL FIBRILLATION

Atrial fibrillation is a common cardiac arrhythmia, the prevalence of which increases

with age; 5% of those 70 years of age or older suffer from this arrhythmia. The most se-

rious clinical consequence of atrial fibrillation is stroke. Up to one-sixth of all ischemic

strokes are attributed to atrial fibrillation (43,48). Uncoordinated atrial contractions result

in sluggish blood flow and stasis, which may lead to atrial clot formation. This clot may

lead to the formation of embolus in the cerebral circulation. The nonvalvular emboli are

usually larger than emboli of valvular origin. This may explain the disabling and often

lethal strokes caused by such emboli. Primary prevention is, therefore, the only sensible

approach (25).

Among the very elderly, atrial fibrillation is the single most important cause of

ischemic stroke. Multiple randomized clinical trials involving patients with nonvalvular

atrial fibrillation have demonstrated the value of antithrombotic therapy for prevention of

stroke. Anticoagulation with warfarin reduces the risk of stroke by about two-thirds com-

pared with placebo (26). Given the limitations of warfarin therapy and the age of affected

patients, many patients who are candidates for warfarin therapy are not receiving it.

Two large phase III trials compared ximelagatran with warfarin for embolic events in

patients with atrial fibrillation (Fig. 5). The first study, Stroke Prevention using the Oral

direct Thrombin Inhibitor in atrial Fibrillation (SPORTIF III), was an open-label study

carried out in Europe, Asia, Australia, and New Zealand, in which 3,407 patients with

nonvalvular atrial fibrillation and one or more stroke risk factors were randomized to re-

ceive adjusted-dose warfarin (INR 2.0–3.0) or fixed-dose ximelagatran (36 mg twice

daily). Primary end points were stroke or systemic embolism. During 4,941 patient-years

of exposure (mean 17.4 months, SD 4.1), 96 patients had primary events (56 in the war-

farin group vs. 40 in the ximelagatran group). The primary event rate by intention to treat

was 2.3% per year with warfarin and 1.6% per year with ximelagatran (absolute risk re-

duction 0.7% [95% confidence interval (CI), –0.1 to 1.4], P = 0.10; relative risk reduction

29% [95% CI, –6.5 to 52]). Rates of transient, disabling, or fatal stroke; mortality; and

major bleeding were similar between the two groups, but combined minor and major hem-

orrhages were lower with ximelagatran than with warfarin (29.8 vs. 25.8% per year; rel-

ative risk reduction 14%; P = 0.007). Raised serum ALT was more common with ximela-

gatran (40).

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

XIMELAGATRAN 339

The second study, SPORTIF V, is similar but was double-blinded. Three thousand nine

hundred twenty-two patients were enrolled in this study at 409 North American sites (35).

The difference in primary event rates by intention-to-treat analysis fell within the non-in-

feriority parameters. The rates of intracerebral bleeding and major hemorrhage were low

and comparable in the 2 groups, with a trend for major bleeding that favors ximelagatran.

Elevation of serum transaminase enzymes in the ximelagatran group reached beyond 3�

ULN in 6% of the ximelagatran group compared with 0.8% in the warfarin-treated pa-

tients (23).

In the two SPORTIF trials pooled together, 7,329 patients were randomized. Ninety-

one events (stroke and systemic embolization) were reported in patients allocated to the

ximelagatran group, as compared to 93 events in the warfarin group. In summary, both,

the individual studies and the pooled results, support the conclusion that ximelagatran is

not inferior to warfarin in preventing stroke and systemic embolization in patients with

nonvalvular atrial fibrillation (24,42). Meta-analysis further confirmed the comparable ef-

ficacy of ximelagatran and warfarin (26).

XIMELAGATRAN IN VTE PROPHYLAXIS

The European and North American studies of melagatran�ximelagatran in orthopedic

surgery were carried out in parallel. In the European trials, melagatran or ximelagatran

were administered early postoperatively and in some studies preoperatively as well as

postoperatively.

Major Orthopedic Surgery

Orthopedic surgery carries higher risk of VTE. Total hip replacement (THR) and TKR,

as well as hip fracture surgeries, are among the highest-risk procedures. In the absence of

prophylaxis, the incidence of venography-proven VTE exceeds 50% (38). The incidence

of symptomatic VTE, however, is much lower.

Despite overwhelming evidence of the efficacy of prophylaxis, several survey studies

documented wide practice variations. One study showed that >50% of the patients who

died of PE did not receive prophylaxis, despite having major risk factors and no contrain-

dications for antithrombotic therapy (18). In another study only one-third of the high-risk

patients received prophylaxis and, amazingly enough, one-third of the patients who re-

ceived prophylaxis had the inappropriate antithrombotic agent, according to the published

guidelines (3). More recently, Friedman et al. (17), utilizing the Global Orthopedic Reg-

istry (GLORY), collected data about in-hospital management and 12-month clinical

outcomes of patients undergoing elective THR or TKR in a range of practice environ-

ments across North and South America, Europe, Japan, and Australia. Data on the prophy-

lactic use in VTE was available for 3,259 THR and 4,247 TKR patients. Only 38% of US

patients and 54% of non-US patients received VTE prophylaxis according to the guide-

lines of American College of Chest Physicians (ACCP) regarding timing, duration, and

therapeutic range (19).

One major reason for this underutilization of prophylaxis stems from the fact that the

agents, either parenteral or oral, needed close monitoring. Ximelagatran has the advantage

of being an oral agent with no need for monitoring. If ximelagatran would be found ef-

Cardiovascular Drug Reviews, Vol. 23, No. 4, 2005

340 S. A. MOUSA AND H. N. ABDEL-RAZEQ

fective in VTE prevention in this setting, the percentage of patients receiving prophylactic

therapy would certainly increase.

Ximelagatran has been compared with either LMWH or warfarin in multiple clinical

trials involving patients undergoing major orthopedic procedures. In a phase II dose-

finding study, Heit and colleagues (28) randomly assigned 443 patients undergoing TKR

to receive enoxaparin at 30 mg subcutaneously b.i.d. or ximelagatran at different dose

levels. Both agents were started 12 to 24 h postoperatively and continued for 6 to 12 days.

The incidence of all VTEs was similar in the enoxaparin and in ximelagatran, 24 mg,

groups. Following this study, ximelagatran has been evaluated in several phase III trials in

patients undergoing elective knee or hip replacement surgery. In the METHRO-III study

(9), 2,778 patients undergoing THR or TKR surgery were randomized to receive either

3 mg of subcutaneous melagatran starting 4 to 12 h postoperatively, followed by 24 mg of

oral ximelagatran twice daily or 40 mg of subcutaneous enoxaparin once daily, starting

12 h preoperatively. Both groups were treated for 8 to 11 days. VTE, detected by man-

datory venography, occurred in 31.0% and 27.3% of patients in the ximelagatran and

enoxaparin groups, respectively, a difference in risk of 3.7% in favor of enoxaparin

(P = 0.053). This difference was entirely accounted for by distal DVT. However, the inci-

dences of major and symptomatic VTE events were comparable in the two treatment

groups. The two medications had a similar safety profile and were well tolerated (9).

In another double-blind study (EXPRESS), 2,835 consecutive patients undergoing

THR or TKR were randomized to either melagatran�ximelagatran or enoxaparin (8).

Melagatran, 2 mg, was started immediately before surgery; 3 mg was then administered

postoperatively, both doses were administered subcutaneously, followed by 24 mg of oral

ximelagatran b.i.d. beginning the next day. Enoxaparin, 40 mg, was administered subcuta-

neously o.d., starting 12 h before surgery. Both treatments were continued for 8 to 11 days.

The rates of major and total VTE were significantly lower in the melagatran�ximelagatran

group compared with the enoxaparin group (2.3 vs. 6.3%, P = 0.0000018; and 20.3 vs.

26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding, and bleeding re-

quiring repeated surgery did not differ between the two groups. Excessive bleeding, as

judged by the investigator, was more frequent with melagatran�ximelagatran than with

enoxaparin (8).

Ximelagatran was also compared to enoxaparin in another randomized, North Ameri-

can study (Platinium-hip). In this study, Colwell et al. (6) randomized 1,838 patients un-

dergoing THR to receive fixed-dose oral ximelagatran 24 mg b.i.d. or subcutaneous

enoxaparin 30 mg b.i.d. for 7 to 12 days; both regimens were initiated the morning after

surgery. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran

group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference

of 3.3% and a 95% CI for the difference of 0.9% to 5.7%. Major bleeding events were ob-

served in 0.8% (7 of 906) of the ximelagatran-treated patients and in 0.9% (8 of 910) of

the enoxaparin-treated patients (P > 0.95). This study concluded that both ximelagatran

and enoxaparin decreased the overall rate of VTE compared with that reported histori-

cally. However, in this study, enoxaparin 30 mg b.i.d. was more effective than ximelaga-

tran 24 mg b.i.d. for prevention of VTE in THR. Oral ximelagatran was used without co-

agulation monitoring, was well tolerated, and had bleeding rates comparable to those of

enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients un-

dergoing THR is warranted.

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XIMELAGATRAN 341

Three other phase III trials compared ximelagatran to warfarin. In the first study (Plati-

nium-knee), 680 patients undergoing total knee arthroplasty were given oral ximelagatran

24 mg twice daily starting on the morning after surgery, or warfarin (target INR: 2.5

[range, 1.8–3.0]), starting on the evening of the day of surgery; both treatments were con-

tinued for 7 to 12 days following the surgery. Incidence of VTE was 19.2% (53 of 276 pa-

tients) in the ximelagatran group and 25.7% (67 of 261 patients) in the warfarin group

(difference, –6.5 percentage points [95% CI, –13.5 to 0.6 percentage points]; P = 0.070).

In the ximelagatran and warfarin groups, major bleeding occurred in 1.7 and 0.9% of pa-

tients, and minor bleeding occurred in 7.8 and 6.4% of patients, respectively. There was no

significant difference between the two groups in variables related to bleeding (15).

In the other two studies, ximelagatran was compared with warfarin. The EXULT-A

study (14) used ximelagatran at 24 or 36 mg, while EXULT-B study (5) used ximelagatran

at a 36-mg dose level. In both studies, ximelagatran, at 36 mg, was more effective than

warfarin in the prevention of VTE. The incidence of hemorrhagic complications were

similar with the two drugs.

CONCLUSIONS

The complexity of available anticoagulants and the need for close monitoring with

some drugs play a major role in the well-recognized underutilization of anticoagulant

therapy, at least in stroke prevention in patients with atrial fibrillation and in VTE pre-

vention in high-risk patients. Ximelagatran offers the solution: it is an oral drug given at a

fixed dose, it has no significant food or drug interaction, and it has no need for monitoring.

Studies have shown the usefulness of this new anticoagulant in several indications, such as

prevention of VTE in patients undergoing major orthopedic surgery and stroke prevention

in patients with nonvalvular atrial fibrillation. Additionally, ximelagatran was effective

and safe in the treatment of acute VTE. However, elevation of liver enzymes associated

with ximelagatran therapy is still a major obstacle preventing this drug from wider use.

More studies and longer follow-up periods are needed to further characterize the adverse

effect of this drug on the liver.

Acknowledgments. The authors would like to thank Gigi Palado, Pearl Weisinger, and Bahir

Skinner for their help in the preparation of this manuscript.

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