Arixtra

Despite increasing scientific investigation, the best method for preventing post-operative deep-vein thrombosis remains unclear. In the wake of the publication of the Pulmonary Embolism Prevention trial and the Scottish Intercollegiate Guidelines Network (SIGN) on the prevention of thromboembolism, we felt that it was timely to survey current thromboprophylactic practices. Questionnaires were sent to all consultants on the register of the British Orthopaedic Association. The rate of response was 62%. The survey showed a dramatic change in practice towards the use of chemoprophylaxis since the review by Morris and Mitchell in 1976. We found that there was a greater uniformity of opinion and prescribing practices in Scotland, consistent with the SIGN guidelines, than in the rest of the UK. We argue in favour of the use of such documents which are based on a qualitative review of current scientific literature.

Morris and Mitchell1 carried out a survey in 1976 into the practice of British Consultant Orthopaedic surgeons regarding the prevention of deep-vein thrombosis (DVT) in patients with fracture of the hip. They reported that 51% of those who replied offered no prophylaxis to patients. Of those who used prophylaxis, most (36%) relied on physical methods and 3% used warfarin. Since that time many studies have addressed the challenge of reducing the risk of DVT while minimising bleeding complications. The picture, however, remains unclear. The Pulmonary Embolism Prevention (PEP) trial2 published in 2000 randomised 13 356 patients from Australia, New Zealand, South Africa, Sweden and the UK to receive either placebo or aspirin after fracture of the hip as prophylaxis against DVT.

Those patients receiving aspirin were shown to have a reduction in the rate of DVT of 36%. The Scottish Intercollegiate Guidelines Network (SIGN)3 produced guidelines for thromboprophylaxis in 1995, which were revised in 2002. These cite the above trial and state that "all patients with hip fracture should receive aspirin (150 mg orally, started on admission and continued for 35 days) unless contraindicated". We felt that in the wake of these two publications it was now timely to look at the current thromboprophylactic practice of British orthopaedic surgeons and in particular the impact of the published SIGN guidelines.

Patients and Methods

Orthopaedic surgeons were identified from the register of the British Orthopaedic Association. Questionnaires were sent with a covering letter from the senior author (IJB) and a replypaid envelope. They were asked to complete a tick-box questionnaire covering one A4 sheet describing their use of thromboprophylaxis in surgery for fracture of the hip. In phase 1, questionnaires were sent to their home address in November 2002; non-responders were sent a further questionnaire in January 2003 (phase 2). In March 2003, questionnaires were sent to the hospital addresses of those who had not replied (phase 3). The respondents were then classified into regions (Table I).

The surgeons were asked if they routinely performed surgery for fracture of the hip. Those who did were asked if they routinely used antithrombotic therapy for these patients and whether there was a departmental policy for such prophylaxis. They were then asked specifically about the type of pharmacological or mechanical prophylaxis which they favoured, the time of initiation relative to surgery and the duration of treatment. We were interested in the responders' reasons for using thromboprophylaxis and whether they would continue chemoprophylaxis after discharge and if so which drug they would use. Finally, they were asked whether the SIGN guidelines would change their practice and indeed if they had changed their method of prophylaxis during the last three years.

Results

A total of 1658 orthopaedic surgeons were sent questionnaires. In phase I, there were 897 (54%) respondents. By the end of phase III, a total of 1019 (62%) had responded. Of these 11% were from Scotland, 4% from Wales and 80% from England. There was one response from the Republic of Ireland and none from Northern Ireland (Table II). Of those who responded, 640 (63%) routinely performed surgery for fracture of the hip and of these 587 (92%; 81% to 95%) routinely used thromboprophylaxis with little variation by region. The routine use of thromboprophylaxis was higher in those who reported a departmental policy on prophylaxis for DVT (95%) compared with those without (74%). Five hundred and twenty (81%) surgeons reported that their department had such a policy. Five hundred and thirty-two (83%) respondents used chemoprophylaxis. This varied from 67% in Wales to 91% in Scotland, with the regions of England between these two. The use of both chemical and mechanical thromboprophylaxis showed no change with length of time in consultant practice (Table III).

When aspirin was excluded, low-molecular-weight heparin (LMWH) was the most commonly used drug (59%), more so in England (43% to 83%) and Wales (49%) than in Scotland (34%) where, in keeping with the SIGN guidelines, aspirin was used by 46 of the 78 (59%) who routinely performed surgery for fracture of the hip. Aspirin was used by less than 20% of surgeons in Wales (15%), West Midlands (19%) and London (11%). Elsewhere, the use of aspirin was fairly consistent, varying between 32% and 42%. Low-dose heparin, Arixtra (fondaparinux sodium; SanofiSynthelabo, Guildford, UK) and warfarin were not widely used (6%, 1% and 1%, respectively). Of the respondents, 34 used aspirin in conjunction with other chemical thromboprophylaxis. Most surgeons (51%) started chemothromboprophylaxis before the operation; 25% did so after it. Only 5% began prophylaxis intra-operatively. It was found that 70% of surgeons who treat fractures of the hip use mechanical prophylaxis, mostly in conjunction with chemical prophylaxis, but 8% use mechanical prophylaxis alone. This consists mainly of graded elastic stockings, above-knee stockings being used by 66% of surgeons. Eighty-eight (14%) used intermittent calf compression and 48 (8%) reported using foot pumps.

The use of extended prophylaxis was much more strongly supported in Scotland with 62% of consultants in favour of continuing prophylaxis after discharge compared with 37% in Wales and between 20% and 45% in England. Of those who supported the use of extended prophylaxis, 78% favoured aspirin over warfarin (3%) or LMWH (13%). In Scotland, 44 of the 48 (92%) consultants who favoured the extended use of prophylaxis use aspirin. When asked for reasons why they gave thromboprophylaxis at all, most (56%) quoted medical and legal reasons, but 171 (27%) gave medical reasons alone, and 34 (5%) legal reasons alone. The introduction of the SIGN guidelines had changed the practice of only 26% of consultants overall; 46% had not been influenced and 27% did not know.

Noteworthy was the fact that 60% of consultants in Scotland reported that the SIGN guidelines had changed or would change their practice.

Discussion

Stevens, Fardin and Freeark4 showed in 1968 that there was a risk of 40% of DVT after surgery for fracture of the femoral neck as demonstrated on routine venography without thromboprophylaxis. Sevitt and Gallagher5 had showed a significant reduction in the rate of post-operative DVT with the use of oral anticoagulation. The same significant reduction in DVT was demonstrated in high-risk patients when oral anticoagulation was started before operation6 (an incidence of DVT of 35% in a control group compared with 10% on warfarin). However, Salzman et al6 reported a major risk of haemorrhage of 7%, highlighting one of the critical problems of chemical prophylaxis. This was identified as one of the main reasons why many surgeons did not use it.1 Since then, methods of prophylaxis have been sought which provide adequate prophylaxis without the risk of bleeding.

Recent studies have investigated agents such as fondaparinux sodium' (Arixtra), a synthetic pentasaccharide selective factor-Xa inhibitor which is administered subcutaneously once daily using a prefilled syringe, or LMWH.8 Both were found to be effective but Arixtra had the greater success in reducing the rate of DVT with an equivalent major risk of bleeding. Researchers have also studied older agents such as aspirin.2 In their large multicentre, randomised placebo-controlled study of aspirin, the PEP trial collaborative group showed a reduction of 29% in the risk of DVT with aspirin compared with a control group and a reduction of 43% in fatal pulmonary embolism in patients with hip fractures, although they were unable to show a reduction in the overall mortality. There was no increased risk of major haemorrhage, although the requirement for transfusion was increased.

The evidence for the use of mechanical prophylaxis indicates that there is a reduction in the rate of DVT but again it is not clear whether this leads to an overall reduction in mortality.9 There are also problems with compliance because of skin abrasion and discomfort. When Kennedy et al10 compared an arteriovenous impulse system with aspirin he found no statistical difference in the rate of DVT, suggesting that this non-invasive technique provides equivalent prophylaxis without any increased risk of haemorrhage. However, it would appear from our survey that this view has not been widely adopted with only 8% of surgeons reporting its use.

Our survey has shown that since the study of Morris and Mitchell,1 the use of thromboprophylaxis has significantly increased, especially in units where there is a departmental policy on prophylaxis for DVT. The rate of response in both studies is comparable but does introduce a possible bias. It may be argued that those with a greater interest in thromboprophylaxis are likely to take time to complete and return a survey such as this and equally are more likely to have an active policy for prevention of DVT. The selection of chemoprophylactic agent favours drugs with a lower risk of haemorrhage, as may be expected but this may not reflect best practice based on clinical trials.11 The use of Arixtra is very low (1%) despite its proven efficacy and safety, with LMWH being the most widely used drug. This may be because Arixtra has only recently received its licence and it takes time for new drugs to be placed on hospital formularies. Of those who routinely perform surgery for fracture of the hip, 1% use warfarin and 6% LMWH, both of which produce a significant reduction in the rate of DVT but at the cost of increased bleeding episodes and transfusion requirements.12 There appears to be a large regional variation in prescribing practice which may have more to do with market forces than scientific evidence. Of particular interest is the dramatic difference in prescribing practice in Scotland where aspirin is favoured, compared with the rest of the UK. It is suggested that these differences are driven by the publication of the SIGN guidelines on thromboprophylaxis. These current guidelines have been criticised. Their development took two years and some argue that they put undue emphasis on the PEP trial which itself has subsequently been criticised.13-18 The SIGN guidelines are widely distributed and awareness among Scottish surgeons is high.

More recently, the focus has shifted to the timing and duration of prophylaxis. Unlike elective hip arthroplasty, there is evidence that patients with fracture of the hip form venous blood clots before they have surgery. The insult of the initial trauma and subsequent enforced immobility has been held to blame for the pre-operative rate of DVT,19 reported to be between 8% and 62%.4'20 However, we are not aware of any studies which compare these patients with an age-matched control group who have not sustained a fracture to see if there is a significant difference in the asymptomatic rate of DVT identified by venography. It should be noted that, in the study by Stevens et al' the preoperative rate of DVT increased from 8% to 14% if surgery was delayed from one to seven days.

Support for extended prophylaxis after discharge is not as strong as may be expected given the evidence for a prolonged thrombotic risk beyond the time of discharge from hospital.21 The reluctance of the surgeon may be related to concerns about patient compliance in a patient group who tend to be older and more frail, with more comorbidity, than those selected for elective hip arthroplasty. One recent multicentre, randomised, controlled trial compared extended prophylaxis for patients with hip fracture, continued for between 19 and 23 days, using Arixtra or a placebo after an initial six to eight days on Arixtra. The authors showed a relatively reduced risk in venographically-proven DVT of 95.9%, from 35.0% in the placebo group to 1.4%.22 There are concerns about the practicality of prolonged administration of Arixtra after discharge from hospital since it can only be administered parenterally, as well as those of funding because general practitioners are unlikely to be happy to bear the costs. However, there is strong evidence for its efficacy. In Scotland a higher proportion of surgeons support the use of extended prophylaxis, which may be related to the widespread use of aspirin. The latter is ideal for extended prophylaxis because it is administered orally and is well tolerated by most patients. Its efficacy in extended prophylaxis, however, has yet to be proven.

Our survey has shown an increase in the use of chemothromboprophylaxis since the study of Morris and Mitchell.1 In Scotland 60% of surgeons state that they have altered their prescribing practices as a result of the SIGN guidelines. There is greater consistency in prescribing practices with these guidelines in place than in the rest of the UK. This must provide support for initiatives to produce local and national guidelines, which are based on a methodical analysis of the available scientific literature, but emphasise the importance of a regular review of these documents to bring them up to date with the published literature.

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

References

1. Morris GK, Mitchell JRA. Prevention and diagnosis of venous thrombosis in patients with hip fractures: a survey of current practice. Lancet 1976;2:867-72.

2. Pulmonary Embolism Trial Collaborative Group. Prevention of pulmonary emboism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-302.

3. The Scottish Intercollegiate Guidelines Network (SIGN), http:// www.sign.ac.uk/guidelmes/fulltext/62/section 5.html (accessed 30/8/04).

4. Stevens J, Fardin R, Freeark RJ. Lower extremity thrombophlebitis in patients with femoral neck fractures: a venographic investigation and a review of the early and late significance of the findings. J Trauma 1968;8:527-34.

5. Sevitt S, Gallagher NG. Prevention of venous thrombosis and pulmonary embolism in injured patients: a trial of anticoagulant prophylaxis with phenindione in middle-aged and elderly patients with fractured necks of femur. Lancet 1959;2: 981-9.

6. Salzman EW, Harris WH, DeSanctis RW. Anticoagulation for prevention of thromboembolism following fractures of the hip. N Engl J Med 1966;275:122-30.

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8. Thaler HW, Roller RE, Greiner N, Sim E, Korniger C. Thromboprophylaxis with 60mg Enoxaparin is safe in hip trauma surgery. J Trauma 2001;51:518-21.

9. Handoll HH, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight hepdim and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database Syst Rev 2002;4: CD000305.

10. Kennedy JG, Soffe KE, Rogers BW, et al. Deep vein thrombosis prophylaxis in hip fractures: a comparison of the arteriovenous impulse system and aspirin. J Trauma 2000;48:268-72.

11. Warwick D. Current concepts in thromboprophylaxis following hip fracture. Current Orth 2003;17:215-22.

12. Moskovitz PA, Ellenberg SS, Feffer HL, et al. Low-dose heparin for the prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures J Bone Joint Surg [Am] 1978;60-A:1065-70.

13. Cohen A, Quinlan D. PEP trial: pulmonary embolism prevention. Lancet 2000;356: 247.

14. Cimminiello C. PEP trial: pulmonary embolism prevention. Lancet 2000;356:247-8.

15. Mahe I, Bergmann JF, Mahe E, Caulin C. PEP trial: pulmonary embolism prevention. Lancet 2000:356:248.

16. Tauzeeh SM. PEP trial: pulmonary embolism prevention. Lancet 2000;356:248.

17. Parker M. PEP trial: pulmonary embolism prevention. Lancet 2000;356:249.

18. Thomas DP. PEP trial: pulmonary embolism prevention. Lancet 2000;356:248.

19. Checketts RG, Bradley JG. Low-dose heparin in femoral neck fractures. Injury 1974;6:42-4.

20. Zahn HR, Skinner JA, Porteous MJ. The preoperative prevalence of deep vein thrombosis in patients with femoral neck fractures and delayed operation. Injury 1999;30:605-7.

21. Eikelbloom JW, Quinian DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001;358:9-15.

22. Eriksson Bl, Lessen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery. Arch Intern Med 2003;163:1337-42.

A. C. Watts,

I. J. Brenkel

From Queen Margaret Hospital, Dunfermline, Scotland

* A. C. Watts, BSc, MB BS, MRCS Ed, Specialist Registrar in Orthopaedics

* I. J. Brenkel, BSc, MBChB, FRCS Ed, Consultant Orthopaedic Surgeon

Department of Orthopaedic Surgery, Queen Margaret Hospital, Dunfermline, Fife KY2 0TT, UK.

Correspondence should be sent to Mr I. J. Brenkel; e-mail: ivanbrenkel@yahoo.co.uk

©2005 British Editorial Society of Bone and Joint Surgery

doi:10.1302/0301-620X.87B3. 15060 $2.00

J Bone Joint Surg [Br] 2005;87-B:296-300.

Received 22 October 2003; Accepted after revision 13 February 2004

Copyright British Editorial Society of Bone & Joint Surgery Mar 2005
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