Ximelagatran versus warfarin for prophylaxis of venous thromboembolism in major orthopedic surgery: systematic review of randomized controlled trials

ABSTRACT BACKGROUND: Ximelagatran has been recently studied for prophylaxis in surgical orthopedic cases. PURPOSE: We proposed to establish whether interventions involving ximelagatran, as compared with warfarin, would increase thromboembolic prophylaxis in patients undergoing major orthopedic knee surgery. DATA SOURCE: Studies with random assignment were identified by an electronic search of the medical literature up to 2006. Data were doubleentered into the Review Manager software, version 4.2.5. DATA SYNTHESIS: We included three wellconducted clinical trials involving 4,914 participants. Sub-groups with two dosages of ximelagatran (24 mg and 36 mg, b.i.d.), were defined. Ximelagatran showed significantly lower frequency of total venous thromboembolism (VTE) than warfarin, but only with the 36-mg dosage (risk relative, RR: 0.72; 95% confidence interval, CI: 0.64-0.81; p < 0.00001). For the 24-mg subgroup, total VTE frequency was similar (RR: 0.86; 95% CI: 0.73-1.01; p = 0.06). No significant differences were shown with either ximelagatran dosage for deep vein thrombosis (DVT), pulmonary embolism, any bleeding or severe bleeding. At the end of the treatment, alanine aminotransferase (ALT) elevation was less frequent in the 24-mg ximelagatran sub-group (RR: 0.33; 95% CI: 0.12-0.91; p = 0.03], but during the follow-up period, the ALT elevation rate was greater in the 36-mg ximelagatran group (RR: 6.97; 95% CI: 1.26-38.50; p = 0.03]. CONCLUSIONS: Ximelagatran appears to be more effective than warfarin when used in higher dosages (36 mg b.i.d.), but at the expense of increased frequency of ALT elevation during the follow-up period.


INTRODUCTION
Venous thromboembolism (VTE) is a common complication among hospital inpatients.Those undergoing major orthopedic surgery, which includes hip and knee arthroplasty and hip fracture repair, are a group that is at particularly high risk of VTE, and routine thromboprophylaxis is mandatory.The rates of venographic deep vein thrombosis (DVT) and proximal DVT, seven to fourteen days after major orthopedic surgery in patients receiving no prophylaxis, are approximately 40 to 60% and 10 to 30%, respectively. 1,2uidelines recommend the use of anticoagulants for the prevention of VTE in these cases, but this treatment has some limitations.Oral vitamin K antagonists (VKA) are subject to several drug interactions and need careful monitoring.Lowmolecular weight heparins (LMWH) are apparently more benefi cial than unfractionated heparin (UH) and warfarin, but they require subcutaneous administration.This is inconvenient for some patients and may be associated with higher risk of bleeding than is warfarin, especially if heparin therapy is started soon after surgery. 2 More recently, a new generation of anticoagulants has been tested for major orthopedic surgery prophylaxis.Randomized clinical trials have shown that recombinant hirudin beginning just before surgery is more effi cacious than low-dose unfractio nated heparin (LDUH) 3,4 and LMWH, 5 with no differences in bleeding.However, hirudin has not been approved for prophylactic use in the United States.Fondaparinux, a synthetic subcutaneously injected pentasaccharide similar to LMWH, has been found to be more effective than VKA in preventing asymptomatic and symptomatic in-hospital VTE by indirect comparison, and has been approved for prophylaxis in the United States. 2 The most recent anticoagulant presented is ximelagatran, an oral direct antithrombin inhibitor.It is rapidly absorbed and converted to its active form, melagatran, which can also be applied subcutaneously. 6It has been studied mainly in orthopedic surgery prophylaxis in comparison with LMWH or warfarin. 7o this date, there have been two systematic reviews summarizing the results of these trials.Both of these meta-analyses compared sub-groups dealing with the ti ming of initial a dministration of melagatran/ ximelagatran versus LMWH. 8,9We therefore proposed to establish whether interventions involving ximelagatran would increase thromboembolic prophylaxis in patients undergoing major orthopedic knee surgery, in comparison with warfarin.

Literature search
We The databases were searched using a comprehensive search strategy for randomized controlled trials, along with MeSH (medical subject headings) and text words, including the following exhaustive list of synonyms: melagatran, ximelagatran, prophylaxis, thromboembolism, venous thrombosis, thrombophlebitis and pul-monary embolism.Unpublished studies were sought by contacting the AstraZeneca company and conducting structured internet searches.The bibliographic references of relevant review articles were also examined for eligible trials.References to the relevant studies identifi ed and advertisement folders were also scrutinized for additional citations.

Data collection Data collection
Two reviewers (WBY and RAY) independently screened the trials identifi ed through the literature search, extracted the data, assessed trial quality and analyzed the results.Two other reviewers (RPED and FHAM) were consulted whenever there was any disagreement.If consensus was not reached, data from the trials in question were not included unless or until the authors of the trial were able to resolve the contentious issues.
A standard form was initially used to extract the following information: characteristics of the study (design and randomization methods); participants; interventions; and outcomes (types of outcome measurements, timing of outcomes and adverse events).

Endpoints Endpoints
The primary outcome measurement was the frequency of total VTE: DVT at any site; pulmonary embolism (PE); or unexplained death during treatment.The secondary outcome measurements were: (ALT) elevation to three times above the upper normal limit; • Death (due to any cause) during the study period and follow-up (up to six months after surgery); • Follow-up.

Assessing methodological Assessing methodological quality quality
The methodological quality of the trials included in this review was judged using the Cochrane instrument approach, as recommended by the Cochrane Handbook, 10 since scales and check lists are not a reliable method for assessing the validity of a primary study. 11andomization methods, allocation concealment, single or double blinding, intentionto-treat analysis and sample size calculations were also recorded.

Data analysis Data analysis
Analysis was undertaken according to Cochrane Collaboration guidelines.Metaanalysis for each outcome was performed by appropriately using the Review Manager software, version 4.2 (Cochrane Collaboration, Oxford, UK).For dichotomous data, relative risk (RR) was used as the effect measurement.For continuous data, the weighted mean difference was used, in which the effect estimates from individual studies were weighted by dispersion measurements.
Heterogeneity measurement was necessary in this analysis.Inconsistency among the pooled estimates was quantifi ed using the I2= [(Q -df )/Q] x 100% test, where Q is the chi-squared statistic and df is degrees of freedom.This illustrates the percentage of the variability in effect estimates that results from heterogeneity rather than sampling error. 10,12n this review, subgroup analysis was performed considering the two different ximelagatran dosage schemes.

Literature search results
All the trials were identifi able by electronic databases with no exceptions.4][15] No articles were excluded.All studies gave details concerning the method used to detect VTE as well as defi nitions of clinical and laboratory outcomes, which were comparable between trials.

Characteristics of included Characteristics of included studies studies
All studies were double-blinded randomized controlled trials, and it was reported in two of the studies that the randomization was performed using a computer-generated randomization list. 13,14No details of allocation concealment were given in any of the studies.In one study, 14 the trial was also double-dummy.In all studies, safety analysis was performed on an "intention-to-treat" basis.Independent and blinded assessment of outcomes by a Central Adjudication Committee was reported in all studies.
The three studies involved 5,284 randomized patients, including 4,914 older persons (mean ages ranged from 66.9 to 68.0 years old).They were conducted in 115 13 to 116 14 centers in the United States, Canada, Israel, Mexico and Brazil 13,14 and in 74 hospitals (or centers) in the United States and Canada. 15he orthopedic surgery performed was knee replacement in two studies 13,14 and knee arthroplasty in one study. 15rug administration was oral in all groups.4][15] In one study, 15 the authors used 24-mg b.i.d.oral ximelagatran.Francis et al. 13 compared two dosages of ximelagatran (24 mg b.i.d. and 36 mg b.i.d.) and Colwell et al. 14 used 36-mg b.i.d.ximelagatran, none of which was preceded by subcutaneous melagatran.Therefore, two subgroups were considered for comparison: "Low dose" (24 mg b.i.d.) and "High dose" (36 mg b.i.d.).The use of graduated elastic stockings was not specifi ed in any of the three studies; planned pneumatic compression prophylaxis was an exclusion criterion in two studies. 13,14afety and mortality were adjudicated by an independent committee in all studies.Deaths due to all causes and with any dosages during and after treatment were considered for analysis.
The heterogeneity tests were not significant in any of the analysis.

Death Death
In the ximelagatran groups and warfarin groups, there were respectively eleven and eight deaths during the treatment period and eight and one deaths during the followup period.The causes of death were not specifi ed, and only the frequency of fatal PE was highlighted: only one death in the ximelagatran group 14 and one death in the warfarin group 13 were reported.No significant difference between the groups was found regarding the frequency of deaths during the study follow-up periods with either dosage of ximelagatran: 24 mg b.i.d.(RR: 0.98; 95% CI: 0.14-6.94;p = 0.98) or 36 mg b.i.d.(RR: 1.66; 95% CI: 0.40-6.92;p = 0.49).

DISCUSSION
For nearly 50 years, anticoagulation therapy has been dominated by unfractionated heparin and oral vitamin K antagonists (VKA), and only more recently have low molecular weight heparins (LMWH) been introduced.The wide clinical experience accumulated with these drugs over the years has helped to develop evidence-based guidelines and defi ne their place in the primary and secondary prevention of venous and arterial thromboembolic diseases.However, some limitations of VKA, such as slow onset of action, interaction with numerous foods and drugs, and the need for careful monitoring, plus the limitations of LMWHs, i.e. parenteral administration only, bleeding risks (particularly when administered soon after orthopedic surgery) and thrombocytopenia risk, 16 have stimulated the search for new anticoagulants.The ideal profi le of an anticoagulant should be: oral and parenteral administration; no requirements for coagulation monitoring; wide therapeutic window; appropriate elimination half-life; rapid onset of action; minimal interaction with food and other drugs; low  non-specifi c plasma protein binding; ability to inhibit free and clot-bound thrombin; not crossing placental barrier; non-animal; easily obtainable; low cost; and antidote available.A number of new anticoagulant agents have been studied in an attempt to match this profi le, including direct thrombin inhibitors, inhibitors of factor Xa, factor IXa, factor VIIa-tissue factor complex, and factor Va-factor VIIa complex. 17Among the new drugs is ximelagatran, the fi rst oral thrombin inhibitor (DTI).Ximelagatran is rapidly and completely converted to its active form melagatran, which exerts antithrombotic effects.A number of characteristics have been identifi ed in studies, such as: predictable pharmacokinetic profi le that is not affected by age, ethnicity or body weight; non-interaction with food; low potential for drug interaction; and wide therapeutic window.These suggest that ximelagatran can be used with fi xed-dose regimens and without coagulation monitoring, which would facilitate self-administration and adherence to treatment, particularly during the six-day postoperative period after discharge. 9One limitation would be the lack of an antidote in the event of severe bleeding.
Patients undergoing orthopedic surgery are at high risk of developing thromboembolic complications.The frequency of DVT in the absence of prophylaxis has been found to be 5-77% in hip replacement and 22-80% in knee replacement. 1 In a meta-analysis on thromboembolic prophylaxis in total knee arthroplasty, 18 comparison of several agents used in DVT prophylaxis (LMWH, warfarin, aspirin, heparin, mechanical methods, antithrombin III and dextran) with placebo, showed that for total DVT, all agents except dextran and aspirin, provided signifi cantly better protection than did placebo (p < 0.0001).In particular, LMWH showed absolute frequencies of distal and proximal DVT of, respectively, 24.4% (95% CI: 20.3-29.0)and 5.9% (95% CI: 4.0-8.5).The American College of Chest Physicians (ACCP) recommends routine thromboprophylaxis using LMWH (at the usual high-risk dose), fondaparinux, or adjusted-dose VKA (target INR, 2.5; INR range, 2.0 to 3.0). 2 Thus, LMWH and warfarin are good comparators for studies on the effi cacy of new agents for knee surgery thromboprophylaxis.
One previous meta-analysis comparing timing of administration and treatment using melagatran/ximelagatran and LMWH in major orthopedic surgery has been published. 8In that study, the relationships between the effi cacy, safety and timing of initial administration of the drugs were analyzed.Six studies [19][20][21][22][23][24] with a total of 8,450 patients were included in the meta-analysis.Pooled analysis showed that melagatran/ximelagatran administered preoperatively seemed to be more effective than when administered postoperatively, regarding the effect on total DVT (respectively, RR: 0.68; 95% CI: 0.51-0.89;and RR: 1.14; 95% CI: 0.77-1.69).Conversely, preoperative administration seemed to increase the need for blood transfusions (respectively, RR: 1.08; 95% CI: 1.07-1.14;and RR: 0.95; 95% CI: 0.90-0.99)and the proportion of severe bleeding (respectively, RR: 2.51; 95% CI: 1.60-3.92;and RR: 0.85; 95% CI: 0.52-1.40).The authors concluded that there was a relationship between venous thromboembolic or hemorrhagic risk and the timing of the fi rst administration of melagatran/ximelagatran and suggested that, in terms of benefi t-risk ratio, there should be postoperative administration of melagatran/ ximelagatran for thromboprophylaxis in major orthopedic surgery.
In another meta-analysis 9 including the same six articles but now involving 10,051 patients, similar fi ndings were obtained.In comparison with postoperative ximelagatran, LMWH had a signifi cantly lower rate of VTE (odds ratio, OR: 0.68; 95% CI: 0.56-0.82;p < 0.001), with no difference in bleeding rate (OR: 1.09; 95% CI; 0.62-1.94;p = 0.76) in hip surgery or knee surgery.Compared with ximelagatran administered immediately before surgery, LMWH had a signifi cantly higher rate of VTE in both hip surgery (OR: 1.87; 95% CI: 1.20-2.92;p = 0.006) and knee surgery (OR: 1.49; 95% CI: 1.14-1.93;p = 0.003), but less bleeding (respectively, OR: 0.30; 95% CI: 0.17-0.53;p < 0.001; and OR: 0.71; 95% CI: 0.30-1.67;p = 0.43).Thus, it was demonstrated that benefi ts in VTE prevention using ximelagatran were gained at the expense of an increased risk of serious bleeding.The studies included presented signifi cant heterogeneity, and had to be grouped according to surgical subtype and also according to the timing of melagatran/ximelagatran administration, in order to reach meaningful conclusions. 8,9n the present review, the comparison with warfarin had less heterogeneity because the timings of administration of the study drug and the comparator were similar, ximelagatran was always administered without previous subcutaneous melagatran, the primary outcome (DVT) was diagnosed by bilateral venography in most studies, and the type of surgery was always knee surgery.Heterogeneity was present only in relation to the ximelagatran dosages, which warranted subgroup analysis.Although the number of patients studied was around half of the number in the comparison with LMWH, the total population included was signifi cant (total = 4,914).Thus, in the present systematic review, ximelagatran had a signifi cantly lower rate of total VTE than did warfarin in knee surgery, but only when it was used in higher dosages (36 mg b.i.d.).No difference was found in relation to major VTE or PE.This effi cacy was not gained at the expense of increased bleeding, which was similar to warfarin at any ximelagatran dosage scheme.Perhaps the starting time for ximelagatran (in the morning after surgery) was benefi cial for preventing bleeding complications.Safety analysis was impaired because of the lack of information on mean and standard deviations of blood loss volumes, blood drainage, blood volume transfused, and bleeding index.Contacts with authors through the AstraZeneca Medical Department in Brazil were unsuccessful in obtaining these data.
The frequency of ALT of more than three times the upper limit of the normal range at the end of the study period was practically the same for both treatments.However, the frequency of ALT in the "high-dosage" ximelagatran subgroup was greater than in the warfarin group during the follow-up period (four to six weeks after surgery). 13,14iver enzyme elevation has been of particular concern in long-term treatment trials using ximelagatran (6% in Sportif V, 25 6.3% in Sportif III 26 and 6% in Thrive III 27 ), which characteristically increased after 2-6 months.Thereafter, the liver enzyme levels returned to the baseline without clinical sequelae, regardless of whether or not the drug was continued, with a median to normalization of 129 days reported from Thrive III. 28In a post-hoc analysis, 29 the following risk factors for ALT elevation were identifi ed: treatment of acute coronary syndrome, treatment for acute VTE, female, low body mass index (< 27), and concomitant use of statins.Asian patients were at decreased risk.In the long-term trials, 0.37% of patients receiving ximelagatran and 0.08% of patients taking comparators presented associated bilirubin levels of twice the normal value within the next month, which raised some concerns about evolution to liver failure for these patients 29 (see authors' note below).Therefore, for long-term treatment, it would be important to have an algorithm for preventing ALT elevation and management for better results.The cause of this ALT elevation cause has not yet been clarifi ed in the literature.It has been stated that ALT elevation could be due to anything from cell toxicity or nuclear effect with protein induction to changes in membrane permeability. 28ALT elevation occurs not only with LMWH but also with warfarin, as demonstrated in the two trials included in the present review 13,14 Cardiovascular events were not reported in any of the three trials included in the present review.According to Gulseth, 29 disease-related adverse effects on coronary arteries occurred more frequently in the ximelagatran group: the frequency of myocardial infarction was 0.6% in the ximelagatran group and 0.21% in the warfarin group (p = 0.04951), 29 and myocardial infarction, angina and ischemia were also more frequent in the ximelagatran group (0.75%) than in the warfarin group (0.26%).In our meta-analysis, the mortality rates were similar in the comparison with warfarin. 13,14Except for PE, most deaths were not attributed to the treatment itself, as judged by the trials Central Committee.Because there are few reports and low incidence, further studies are necessary for defi nite conclusions to be reached.
The main competing agent for pharmacological prophylaxis in major orthopedic surgery is fondaparinux, which has recently received approval from the Food and Drug Administration (FDA) in the United States, for use in such cases. 2In a meta-analysis, fondaparinux versus enoxaparin for preventing VTE in major orthopedic surgery significantly reduced the incidence of VTE by day 11 (odds reduction: -55.2; 95% CI: -63.1, -45.8; p < 0.001), which was consistent for all types of surgery and subgroups.However, severe bleeding was more frequent in the fondaparinux-treated group (p = 0.008), although the rates of any bleeding or clinically relevant bleeding were similar. 30evertheless, the risk of VTE has been estimated in all these studies basically during short-duration prophylaxis programs.It is known that the risk of symptomatic non-fatal VTE occurring within three months after knee or hip replacement in patients who received short-duration (7-10 days) anticoagulant prophylaxis affects approximately one in every 32 patients, and that fatal pulmonary embolism occurs in one in every 1000 patients, and is more frequent in hip surgery. 31

Implications for practice Implications for practice
In the light of the currently available information on ximelagatran/melagatran versus warfarin for preventing VTE, ximelagatran appears to be more effective and safe when used in higher dosages (36 mg b.i.d.) for total VTE.Any occurrences of bleeding, severe bleeding and death were similar to fi ndings with warfarin, with any ximelagatran dosage scheme.However, ALT remained signifi cantly more frequently elevated in patients receiving the 36-mg b.i.d.dosage scheme during the follow-up period.

Authors' note
By the time the present article was sent for language revision, AstraZeneca had decided to withdraw the anticoagulant Exanta ® (melagatran/ximelagatran) from the international market and terminate its development.The withdrawal of Exanta was triggered by news of an adverse event regarding serious liver injury in the EXTEND clinical trial (personal communication by letter), which examined the use of Exanta in extended VTE prophylaxis in orthopedic surgery for 35 days postoperatively.Indeed, our conclusions were going in the same direction, and were rai sing some concerns relating to potential liver injury associated with the study drug.

Figure 4 .
Figure 4. Incidence of alanine aminotransferase (ALT) elevation greater than three times the upper limit of the normal range, during the follow-up period, with two dosages of ximelagatran versus warfarin in different studies.13,14