Ximelagatran chemical structure
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Ximelagatran (Exanta® or Exarta®, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved. more...

Mefenamic acid
Metamizole sodium
MS Contin

Method of action

Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through dealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).


Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and atrial fibrillation. The efficacy of ximelagatran for these indications had been well-documented (Eriksson et al 2003, Frances et al 2004, Schulman et al 2004).

An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.


Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.

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New concepts in orthopaedic thromboprophylaxis
From Journal of Bone and Joint Surgery, 8/1/04 by Warwick, D

Thromboprophylaxis is a controversial and changing topic. Some have questioned its very need. Various objections have been raised as to its use including the relatively low incidence of symptomatic thromboembolic events, the risk of bleeding, the possibility of late infection, the reliance on surrogate end-points such as venography and finally 'no evidence of effect', when the beta error has been misinterpreted as 'evidence of no effect'. However, in our current environment of risk management, it would be wise to remember that the weight of evidence supports the view that thromboembolism is a potentially serious complication and that on the balance of probability the risk can be diminished.'"' There is no evidence that careful prophylaxis causes major wound bleeding, infection, loosening of the implant or death.

Why thromboembolism is important

The rate of fatal pulmonary embolism (PE) without prophylaxis after hip and knee replacement is probably in the region of 0.4%. It may be said that this figure constitutes a rare and unimportant incidence. However, with 1.25 million hip and knee replacements in Europe each year, 0.4% represents 5000 fatalities annually. Even very low death rates are important. Around 4% of patients suffer symptomatic venous thromboembolism (VTE) after arthroplasty. It is the most common complication, more than dislocation and infection combined. Every orthopaedic surgeon accepts the need for antibiotic prophylaxis to avoid infection and a meticulous surgical approach to avoid dislocation. Why not accept the need for safe and effective thromboprophylaxis?

Thromboprophylaxis really does work

Fatal P.E. Crawford, Hillman and Charnley4 showed that by comparing the use of phenindione with a control group in a randomised trial of 900 patients, extreme anticoagulation merely exchanged a reduction in fatal PE for an increase in fatal bleeding. However, more judicious anticoagulation can probably reduce the number of deaths. Fatal PE is very rare indeed in patients taking prophylactic warfarin at adequate levels. Amstutz ct aP had no fatalities in 3000 consecutive hip replacements using this drug. There is fairly good evidence that death rates can be reduced by heparin. A meta-analysis6 of all the early randomised trials of heparin in orthopaedic surgery showed that the rate of fatal PF, was reduced by 66% in patients receiving heparin rather than a placebo or nothing. The overall death rate, as well as the rate of fatal PE, was reduced by heparin. However, there was an increase in bleeding of two-thirds in those taking heparin (2% absolute increase). Death rates are now so low even without prophylaxis that a randomised study would require about 90 000 patients to study death as an end point. Hence we have to rely upon surrogate end-points.

Symptomatic VTE. Although it has been argued that the evidence for thromboprophylaxis is based upon a surrogate outcome (usually venography) rather than a clinical end-point,8 there is good evidence to show that reduced rates of deep-vein thrombosis (DVT) correspond to reduced levels of symptoms.

A meta-analysis of the use of heparin6 showed a similar reduction in risk for both asymptomatic DVT as assessed by scintigraphy or venography of 67% and of fatal PE of 68% (Fig. 1). However, this paper was weakened because it was based upon a heterogenous group of small studies of various orthopaedic patients in whom the presence of thrombi was diagnosed primarily by iodinated fibrinogen.

More robust data are now available. A further meta-analysis9 showed that extending the duration of use of low-molecular-weight heparin (EMWH) to about five weeks after hip replacement reduced the rate of DVT as diagnosed by venography from 21% to 8.2%, a risk reduction of 61%. These studies were large enough to show that the frequency of symptomatic VTE was reduced by the same proportion from 4.5% to 1.7%, a risk reduction of 62% (Fig. 2). Similarly, when a placebo was compared with pentasaccharide in a double-blind randomised controlled trial for four weeks after operations for hip fracture, the venographic demonstration of DVT was reduced by 95.9% and the symptomatic event rate by 88.8% (Fig. 3).10

We can now be confident that venographic surrogates do reflect clinical reality.

Chronic venous insufficiency. Whether joint replacement predisposes to chronic venous insufficiency, and whether this risk can be reduced by prophylaxis, is not yet known.

Extended prophylaxis

Until recently, most clinical trials studied the use of prophylaxis in arthroplasty for only seven to ten days while the patient was in hospital. With this strategy LMWH would reduce the rate of DVT detected by venography by 60%. However, there is consistent evidence to show that half of symptomatic venous thrombi after knee replacement and two-thirds after hip replacement occur after the second week, usually when the patient has been discharged from hospital.11"1 The total hip replacement outcome study14 showed that venous thromboembolism was the commonest cause of readmission after hip replacement. As noted above, several recent randomised trials have demonstrated that the risk of both venographic and symptomatic thrombosis after discharge from hospital after hip surgery can be reduced by two-thirds if LMWH or pentasaccharide are continued for at least four weeks after operation (Fig. 3).9'10'15,16 The benefits of extended prophylaxis in knee replacement are not clear.

These studies show that the number-needed-to-treat to prevent one case of symptomatic DVT or PE after hip replacement is 37. From this figure, the cost-effectiveness can be calculated. Because the cost of LMWH is relatively low, and that of investigation or treatment of thromboembolism relatively high, this is likely to be a cost-effective approach.17,18 Even if these statistics are not thought to be compelling enough to extend prophylaxis for five weeks, it should be remembered that hospital stays after arthroplasty are falling. Discharge four days after operation is not uncommon and minimally-invasive day-case hip surgery is on the horizon. Even the most sceptical of us may realise that prophylaxis for only one day is too short. Thus, the practical issue of administering prophylaxis after discharge is real. When should it be stopped? Who should administer it and who should pay for it?

The use of aspirin

The use of aspirin is superficially attractive. It is a cheap, readily available, familiar tablet. Initial meta-analysis suggested that aspirin might reduce the frequency of DVT and PE.19 However, a recent study20 has shown that aspirin is not as helpful as might have been hoped. Over 13000 patients with fracture of the hip were randomised to have either aspirin or a placebo. The death rate was identical in each group. The risk reduction for symptomatic VTE from 2.5% to 1.6% was only about 30%, half that which would be expected from using LMWH and one-third from using pentasaccharide (Fig. 4). The reduced risk of VTE was matched by an increased incidence of transfusion, gastro-intestinal bleeding and bleeding from the wound.21 In the supplementary group of 4000 patients with hip and knee replacement, there was an insignificant difference in symptomatic VTE. Thus, aspirin has a relatively weak thromboprophylactic effect, carries an alternative complication rate and its use may deprive patients of safer or more effective prophylaxis. It is not recommended by the two largest evidence-based consensus groups,2,3 and is not licensed for thromboprophylaxis in the UK.

Is warfarin more trouble than it is worth?

Warfarin has been widely used in North America and the UK for prophylaxis. If used carefully, death is exceedingly rare and it is almost as effective as LMWH in reducing venographic DVT. Its use is supported by the main consensus groups. It can be delivered beyond hospital discharge to protect against the risk of late-onset VTE. However, it has many drawbacks. It requires regular monitoring, which is expensive and time-consuming. If started too close to surgery or at too high a dose, there will be a risk of bleeding. If started later, and at a lower dose, there is an interval of several days in which the patient is unprotected during their most thrombogenic time. Warfarin interacts with many drugs and alcohol. It is difficult to see an advantage for warfarin over LMWH or pentasaccharide, except that it is perhaps more convenient to continue it beyond discharge.


Fondaparinux (Arixtra, Sanofi-Synthelabo, Guildford, UK) is a pentasaccharide which offers a new, effective and relatively safe pharmacological approach. It precisely inhibits factor Xa, which is a key component of coagulation. It has been meticulously compared with LMWH in over 7300 patients having hip and knee replacements and after fractures of the hip.22 The overall rate of VTE at 11 days after surgery was reduced from 13.7% with Enoxaparin to 6.8% with Arixtra (odds reduction 55.3%; 95% confidence interval 45.8 to 63.2, p

Chemical prophylaxis with neuraxial anaesthesia

Neuraxial (i.e. spinal or epidural) anaesthesia conveys many benefits to orthopaedic patients.24 The mortality after surgery is reduced by 30%, post-operative analgesia is enhanced and it is weakly thromboprophylactic.24 The initial European experience suggested that neuraxial anaesthesia could be used safely in the presence of prophylactic anticoagulants.26 However, more recently the American Food and Drug Administration has raised concerns that on occasions a spinal haematoma may develop. It is therefore prudent to avoid giving neuraxial anaesthesia and chemical prophylaxis together and individual guidelines should be followed.27

Oral thrombin inhibitors

The ideal chemical agent would he taken orally. This would overcome the difficulty of reconciling the clear need for extended prophylaxis with the pragmatic issue of who will administer it. Aspirin, which is antiplatelet rather than anticoagulent, may fulfil this, but its efficacy is weak and there is no good evidence for its extended use. Warfarin has many disadvantages, as already described. Melagatran (Astra-Zeneca, Luton, UK) is a recently-developed direct oral thrombin inhibitor which has a number of important advantages over warfarin. There is a wide therapeutic and safety window, no monitoring is needed and it is not known to interact with other drugs. Recent trials have shown equivalence with LMWH in prophylaxis after arthroplasty.28-30 Future trials may show its efficacy for extended prophylaxis in which case a pragmatic solution to this important problem would be available.

Just-in-time prophylaxis

There is a dilemma with chemical prophylaxis in that the closer to surgery that it is administered, the better is the thromboprophylaxis, but the greater is the chance of bleeding complications. If LMWH is given before surgery, as recommended in Lurope, because of a relatively short half life, the serum levels are too low for any prophylactic effect. If LMWH is delayed until after surgery, as is recommended in North America, the thrombi may have already begun to form during the very thrombogenic operation. Prophylaxis needs to be given close, but not too close, to surgery; so-called "just in time prophylaxis"." The optimum moment to administer LMWH or Fondaparinux is probably around six to eight hours after surgery.

Combined mechanical and chemical prophylaxis

The Art, rather than Science, of clinical medicine is to apply knowledge in a balanced way, tailored to the needs of the individual patient.

Thromboprophylaxis has been often regarded as a dichotomy; either chemical or mechanical. The advantages of drugs, namely their ease of use, relative cheapness and efficacy, must be weighed against the potential for bleeding both into the surgical wound and into the spinal cord after neuraxial anaesthesia. The advantages of mechanical prophylaxis such as the foot pump, with no bleeding, no drug interactions and reasonable efficacy must be taken into account against the disadvantages of compliance, refitting when mobilising and the impracticality of extended use. A sensible approach would be to use the foot pump as soon as possible after injury or surgery and then to switch to chemical prophylaxis once the risk of bleeding has subsided and for as long as the risk of thromboembolism pertains. For patients with a particular risk of thrombosis, the two can be combined in the hope of a synergistic effect. There are no clinical trials which have directly addressed this approach.

Can we design a sensible, safe, evidence-based approach?

Care pathways and guidelines are becoming endemic. They should ensure the routine and automatic provision of important care, yet allow flexibility when the circumstances of the individual patient require. This should give the patient the benefit of best practice and give the hospital protection against risk.

Each orthopaedic department should publish guidelines for thromboprophylaxis which combine common sense with available evidence. These can then be incorporated into care pathways. The following scheme may be considered.

Risk assessment. All patients should have a risk assessment to determine previous VTE, a family history, malignancy, the likelihood of prolonged immobility or poor mobilisation.

Hip replacement. Regional anaesthesia and early mobilisation should be encouraged. For those surgeons who are comfortable with chemical prophylaxis LMWH or pentasaccharide should be started not less than six to eight hours after surgery and regional block but at least 12 hours after any indwelling epidural catheter has been removed. For those surgeons who are concerned about perioperative bleeding, a mechanical device such as a foot pump should be fitted in the recovery room. It should be continued for the entire hospital stay for those thought to have a particularly high risk of VTE. Otherwise, it could be stopped once the patient begins to mobilise. If possible chemical prophylaxis should be continued for five weeks.

Hip fracture. In some patients, medical and social comorbidity may occasionally suggest a more holistic approach. Otherwise, a mechanical device should be applied as soon after injury as possible in the Emergency Department. The device should be used, and chemical prophylaxis instigated in the same way and for the same duration as hip replacement.

Knee replacement. The risk of side-effects on soft tissues is higher in knee replacement, yet VTE is more resistant to prophylaxis. Regional anaesthesia should be encouraged. A mechanical device should be started in recovery and continued, if tolerated, for as long as the patient is in hospital. Chemical prophylaxis should be started as soon after surgery as the surgeon feels is safe and continued for the entire stay in hospital. For those being discharged in less than ten days or with other risk factors, chemical prophylaxis should be considered beyond discharge.

Other orthopaedic operations. There are few data available on both epidemiology and prophylaxis in other orthopaedic procedures. If the risk assessment suggests a minimal risk of VTE then the cost and potential side-effects of perioperative chemical prophylaxis may not be justified. However, if there is a potential risk, then a sensibly-timed combination of mechanical and chemical prophylaxis should be devised. Major trauma of the lower limb and spinal surgery carry a risk of symptomatic thromboembolism but have a greater threat of bleeding. A longer period of mechanical prophylaxis, followed by extended chemical prophylaxis when safe, seems sensible. Day-case arthroscopy causes very occasional problems with VTE yet practical prophylaxis is difficult since the patient will have gone home before it is safe to give the drugs. The best course is to carry out a careful risk assessment and provide those with a higher risk with an injection before discharge and follow with home prophylaxis until the patient is fully mobile.

The author would like to thank Dr Ander Cohen, vascular physician. King's College Hospital, London for his advice.


1. THRlR Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients Phlebologyl 998; 13:87-97.

2. International Consensus Statement. Prevention of venous thromboembolism. lnt Angiol 2001:20:1-37.

3. Geerts WH, Heit JA, Clagett CP. Prevention of venous thromboembolism. Chest 2001:119:132-75.

4. Crawford WJ, Hillman F, Charnley J. A clinical trial of prophylactic anticoagulant therapy in elective hip surgery Internal Publication 14, Centre for Hip Surgery, Wrightngton Hospital

5. Amstutz H, Friscia DA, Dorey F, Carney BT. Warfarin prophylaxis to prevent mortality from pulmonary embolism after total hip replacement J Bone Joint Surg [Am] 1989:71-A:321-6.

6. Collins R, Scrimgeour A, Yusef S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. WfngJMecM 988:318:1162-73.

7. Warwick OJ, Williams MH, Bannister GC. Death and thromboembolic disease after total hip reptacement: a series of 1162 cases with no routine prophylaxis, JBone Joint Surg [Br] 1995;77-B:6-10

8. Warwick DJ, Samama MM. The contrast between radiological and clinical outcomes in orthopaedic thromboembolism J Bone Joint Surg [Br]2OOO;82-B:480-2.

9. Hull RD, Pineo GF, Stein PD, et al. Extended out of hospital low-molecular weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001:135:858-69.

10. Erikkson Bl, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondapainux after hip fracture surgery: a multicentre, randomized, placebo-controlled, double blind study. Arch Intern Med 2003:163:1337-42.

11. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998;158-1525-31

12. Colwell CW, CoIMs DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty: evaluation during hospitalisation and three months after discharge. JBone Joint Surg [Am]] 999:81 -A:932-9.

13. Dahl OE, Gudmunsen TE, Haukeland L. Late occurring clinical deep vein thrombosis in joint-operated patients Acta Orthop Scand2000:71:47-50.

14. Gregg PJ, Devlin HB. National total hip replacement outcome study http://www.rcseng.ac.uk. (accessed 21/06/041

15. Cohen A, Bailey CS, Alikhan R, Cooper OJ. Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty. Thrombosis and Haemostasis 2001:85:940-1.

16. Eikelboom JW, Quinlan DJ, Douketis JD. Extended duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet2001:358:9-15.

17. Friedman RJ, Ounsworth GA. Cost analysis of extended prophylaxis with enoxapann after hip arthroplasty. Clin Orthop 2000:370:171 -82.

18. Sarasin FP, Bounameaux H. Out of hospital anti-thrombotic prophylaxis after total hip replacement low molecular weight heparin. warfarin, aspirin or nothing Thromb Haemost 2002:87:586-92.

19. Anti-platelet Triallists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: reduction in venous thrombosis and pulmonary embolism by anti platelet prophylaxis amongst surgical and medical patients BMJ]994:308: 235-46.

20. PEP. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: pulmonary embolism prevention trial Lancet 2000:355:1295-302.

21. Cohen A, Quintan D. PEP trial Lancet 2000:356:247.

22. Turpie AGG, Bauer KA, Eriksson Bl, Lassen MR. Fondaparinux vs Enoxaparin for the prevention of venous thromboembolism in major orthopaedic surgery. Arch Iniern Med 2002:162:1833-40

23. Lowe GD, Sandercock PA, Rosendaal FR. Prevention of venous thromboembolism after major orthopaedic surgery: is fondaparinuxan advance? Lancet2003:362: 504-5.

24. Rodgers A, Walker N, Schug S, et al. Reduction of post-operative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials BMJ2000:321:1493-7.

25. Prins M, Hirsh J. A comparison of general anesthesia and regional anesthesia as a risk factor for deep vein thrombosis following hip surgery: a critical review. Thromb Haemost 1990:64:497-500.

26. Bergqvist D, Lindblad B, Matsch T. Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia: is there a risk? Acta Anaesthesiol Scand 1992:36:605-9.

27. HorlockerTT. Low molecular weight heparin and neuraxial anaesthesia Thrombosis Research 2001:101:141-54.

28. Erikkson Bl, 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. Thromb Haem 2003:89: 288-96

29. Heit JA, Colwell CW, Francis CW, et al. Comparison of the oral direct thrombin inhibitor, ximelagatran compared with dalteparin in the prophylaxis of venous thromboembolism after knee replacement. Arch Intern Merf2001;161:2215-21.

30. Erikkson Bl, Bergqvist D, Kalebo P. Ximelagatrain and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement. Lancet 2002:360:1441 -7

31. Hull RD, Pineo GF, Stein PD, et al. Timing of low molecular weight heparin prophylaxis against deep venous thrombosis in patients following elective hip arthroplasty. Arch Intern Med 2001:161:1952-60.

D. Warwick

From University of Southampton, Southampton, UK

* D.Warwick, MD, DIMC, FRCS, FRCS Orth, Consultant Orthopaedic Surgeon and Honorary Senior Lecturer Southampton University Hospitals, Tremona Road, Southampton S016 6UY, UK.

©2004 British Editorial Society of Bone and Joint Surgery

doi:10.1302/0301-620X.86B6. 15085S2.00

J Bone Joint Surg [Br] 2004;86-B:788-92.

Copyright British Editorial Society of Bone & Joint Surgery Aug 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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