Select Committee on Health Minutes of Evidence


Memorandum by Mr David Warwick (VT 1)

A SYNTHESIS OF RECENT RESEARCH CONCERNING THE PREVENTION OF VENOUS THROMBOEMBOLISM IN ORTHOPAEDIC SURGERY

  Thromboprophylaxis is a controversial and changing topic. Some new concepts are presented in this submission.

WHY PROPHYLAXIS REALLY IS NECESSARY

Some have questioned the very need for thromboprophylaxis. Various reasons are given to include the relatively low frequency of symptomatic thromboembolic events, the risk of bleeding, the possibility of late infection, the reliance on surrogate endpoints such as venography and finally "no evidence of effect" (the beta error 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 (The THRIFT Group 1998, International Concensus Statement 2001 Geerts et al 2002). Anecdote aside, there is no evidence that careful prophylaxis causes major wound bleeding, infection, implant loosening or death.

WHY THROMBOEMBOLISM REALLY IS IMPORTANT

  The fatal PE rate without prophylaxis after hip and knee replacement is probably in the region of 0.4%. One might say that 0.4% is a rare and therefore unimportant event rate. However, the individual who dies is 100% dead. With 1.25 million hip and knee replacements in Europe each year, 0.4% represents 5,000 fatalities annually or the capacity of an Airbus each month . . . Even very low death rates are important.

  Symptomatic venous thromboembolism (VTE) is the most common complication after arthroplasty (around 4%). This makes it more common 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 PE. John Charnley (Crawford et al 1968) showed, by comparing phenindione with control in a randomised trial of 900 patients, that extreme anticoagulation merely exchanges a reduction in fatal PE for an increase in fatal bleeding. However, more judicious anticoagulation can probably reduce death. Fatal PE is very rare indeed in patients taking prophylactic warfarin at adequate levels (for example, no fatalities in 3,000 consecutive hip arthroplasty patients (Amstutz et al 1989)). There is fairly good evidence that death rates can be reduced by heparin. A meta-analysis (Collins et al 1988) of all the early randomised trials of heparin in orthopaedic surgery and showed that the fatal PE rate was reduced by 66% in those receiving heparin rather than placebo or nothing. The overall death rate, as well as the fatal PE rate, was reduced by heparin. However, there was an increase in bleeding of two-thirds in those taking heparin (2% absolute increase) (Figure 1). Death rates are now so low even without prophylaxis that a randomised study is unlikely to be large enough (about 90,000 patients) to study death as an end point (Warwick et al 1995). We will have to rely upon surrogate endpoints.

  Symptomatic VTE. It has been argued (Warwick and Samama 2000) that the evidence for thromboprophylaxis is based apon a surrogate outcome—usually venography—rather than a clinical outcome. However, there is in fact evidence that reduced DVT rates correspond with reduced symptomatic event rates.

  The heparin meta-analysis paper (Collins et al 1988) showed a similar risk reduction for both asymptomatic DVT (scintigraphy or venography) of 67% (60.5% to 20.3%) and fatal PE of 68% (1.9% to 0.6%). (Figure 1). However, this paper was weakened because it was based apon a rather heterogenous group of small studies of various orthopaedic patients diagnosed primarily with iodinated fibrinogen.

  More robust data are now available. A meta-analysis (Hull et al 2001a) shows that extending the duration of LMWH for about five weeks after hip replacement will reduce the venographic DVT rate from 21% to 8.2% (risk reduction 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%, (risk reduction 62%). (Figure 2). Similarly, when placebo was compared with pentasaccharide in a double blind RCT for 4 weeks after hip fracture surgery, the venographic DVT risk was reduced by 95.9% (77/220 or 35% vs 3/208 or 1.4%) and the symptomatic event rate by a similar 88.8% (9/330 or 2.7% vs 1/326 or 0.3% (Erikkson et al 2003). (Figure 3).

  Thus 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 SHOULD BE CONSIDERED

  Until recently, most clinical trials studied the use of prophylaxis in arthroplasty for only seven to 10 days—whilst the patient was in hospital. With this strategy, LMWH would reduce the venographic DVT rate by 60% (2). However, there is consistent evidence from several sources that half of symptomatic VTE after knee replacement and two-thirds after hip replacement occur beyond the second week—usually when the patient has been discharged from hospital (White et al 1998, Colwell et al 1999, Dahl et al 2000). The Total Hip Replacement Outcome Study (Gregg et al 2000) shows that venous thromboembolism is the commonest cause of readmission after hip replacement. As described above, several recent randomised trials have consistently shown that the risk of thrombosis (both venographic and symptomatic) after hospital discharge in hip surgery can be reduced by two-thirds if low molecular weight heparin or pentasaccharide is continued for at least four weeks after surgery (Hull et al 2001a, Cohen et al 2001, Eikelboom 2001, Erikkson 2003). (Figure 3,4). The advantage for extended prophylaxis in knee replacement is not so clear.

  These studies show that the number-needed-to-treat (NNT) to prevent one symptomatic DVT or PE after hip replacement is 37; from this figure, one can calculate cost effectiveness. Because the cost of LMWH is relatively low, and the cost of investigation or treatment of thromboembolism relatively high, this is likely to be a cost effective approach (Friedman and Dunsworth 2000, Sarasin and Bounameaux 2000).

  Even if these statisics are not thought compelling enough to extend prophylaxis for five weeks, it should be remembered hospital stays after arthroplasty are falling. Discharge at four days after surgery is not uncommon and minimally invasive day case hip surgery is on the horizon. Even the most sceptical may realise that prophylaxis for only one day is probably too short. Thus the practical issue of administering prophylaxis after discharge is real—when do you need to stop it, who gives it, who will pay for it . . .

THE RISE AND FALL OF ASPIRIN

  Aspirin is superficially attractive. It is a cheap, readily available, familiar tablet. Surely if aspirin is given, the surgeon won't have to worry, the patient will be fine and the lawyers will be out of work. Initial meta-analysis suggested that aspirin might reduce the frequency of DVT and PE (ATC 1994). However, the recent PEP study (PEP 2000) showed aspirin is not as helpful as might have been hoped. (Figure 4) Over 13,000 hip fracture patients were randomised to have either aspirin or 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 what one would expect from LMWH and one-third from pentasaccharide) (Figure 5). This reduced risk of VTE was matched by an increased risk of transfusion, gastro-intestinal bleeding and wound bleeding (Fig 5). In the supplementary group of 4,000 hip and knee replacement patients, there was an insignificant difference in symptomatic VTE (Cohen and Quinlan 2000). In other words, aspirin has a relatively weak thromboprophylactic effect, carries an alternative complication rate and its use might deprive patients of safer or more effective prophylaxis. It is not recommended by the two largest evidence-based Consensus groups (Geerts et al 2001, ICC 2001). Furthermore, it is not licensed for thromboprophylaxis in the United Kingdom.

IS WARFARIN MORE TROUBLE THAN IT IS WORTH?

  Warfarin has been widely used in North America and the United Kingdom for prophylaxis. Used carefully, death is exceedingly rare and it is 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 and for this reason is regarded as more or less obsolete by many in Western Europe and Scandinavia. 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 judiciously—later and at a lower dose—there will be an interval of several days during which the patient will be unprotected—at their most thrombogenic time. Warfarin interacts with many drugs and alcohol. On objective comparison, it is difficult to see an advantage for Warfarin over LMWH or pentasaccharide, except that (arguably) it is more convenient to continue beyond discharge.

PENTASACCHARIDE

  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 7,300 hip replacement, knee replacement and hip fracture patients (Turpie et al 2002). The overall VTE rate at 11 days after surgery (venographic DVT plus symptomatic DVT or PE) was reduced from 13.7% with Enoxaparin to 6.8% with Arixtra (odds reduction 55.2%; 95% confidence interval 45.8 to 63.1%, p<0.001) (Figure 6). Some of this advantage in VTE (and disadvantage in bleeding) may be explained by a different timing schedule than LMWH—rather closer to surgery. With respect to bleeding, it is as well to remember that an omelette cannot be made without cracking an egg. Fondaparinux appeared to have some increased minor bleeding (so called bleeding index) but no major bleeding side effects in comparison with LMWH. It must be given at least six hours after surgery and after removal of the spinal/epidural catheter to avoid the risk of surgical or neuraxial (ie spinal) bleeding. The case for pentasaccharide has been critically analysed (Lowe et al 2003) with some discussion about cost, the choice of endpoint, the relevance of the bleeding and the means of reversal. Nevertheless, the risk reductions presented for DVT are enticing.

CHEMICAL PROPHYLAXIS WITH NEURAXIAL ANAESTHESIA

  Neuraxial (ie spinal or epidural) anaesthesia conveys many benefits to orthopaedic patients (Rodgers et al 2000). The mortality after surgery is reduced by 30%, post-operative analgesia is enhanced and it is even weakly thromboprophylactic (Prins and Hirsh 1990). Initial European experience suggested that neuraxial anaesthesia could be safely used in the presence of prophylactic anticoagulants (Bergqvist 1992). 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 within at least six hours of each other (Horlocker 2001).


ORAL THROMBIN INHIBITORS

  The ideal chemical agent would be 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 (anti-platelet rather than anti-thrombotic) may fulfil this, but the efficacy is weak and there is no good evidence for its extended use. Warfarin has many disadvantages described above. Melagatran (AstraZeneca, 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; it is not known to interact with other medications. Recent trials show equivalence with LMWH in prophylaxis after arthroplasty (Erikkson 2001, Heit 2001, Erikkson 2002). 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: the closer to surgery that it is administered, the better the thromboprophylaxis but the greater chance of bleeding complications. If LMWH is given before surgery (as recommended in Europe), then because of a relatively short half life, serum levels will be too low for any prophylactic effect. If LMWH is delayed until after surgery (as recommended in North America), then 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" (Hull et al 2001b). 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. This risks throwing the baby out with the bathwater. The advantages of chemicals (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 following neuraxial anaesthesia. The advantages of mechanical prophylaxis such as the Foot Pump (no bleeding side effects, no interactions, reasonable efficacy) must be weighed against the disadvantages (compliance, refitting when mobilising, 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 particularly risk of thrombosis, the two can be combined in the hope of a synergistic effect (although this has not yet been studied). There are no clinical trials which have directly addressed this approach and perhaps there will not be.

CAN WE DESIGN A SENSIBLE, SAFE, EVIDENCED BASED APPROACH?

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

  It is wise for each orthopaedic Department to combine common sense with evidence and then publish guidelines for thromboprophylaxis. These guidelines can then be incorporated into care pathways. The author (hopefully not tainted by wild speculation or subconscious prejudice) suggests that the following would not be unreasonable:

  Risk assessment: all patients should have a risk assessment to detect particularly high risk (previous VTE, family history, malignancy, likely prolonged immobility or poor mobilisation.

  Hip replacement: regional anaesthesia and early mobilisation should be encouraged. For those surgeons who are comfortable with chemical prophylaxis (reassured by the literature and their experience) then they should start LMWH or pentasaccharide no less than six to eight hours after surgery and regional block. For those surgeons who are concerned about peri-operative bleeding, a mechanical device such as a Foot Pump should be started 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. Chemical prophylaxis should be started once the surgeon feels that the risk of bleeding has subsided and at least six hours after any indwelling epidural catheter has been removed. In an ideal world it should be continued for five weeks (notwithstanding the logistical issues of funding and administration).

  Hip fracture: In some patients, medical and social co-morbidity may occasionally suggest a more holistic approach. Otherwise, a mechanical device should be applied as soon after injury as possible (ie 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 soft tissue side effects 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/regional block as the surgeon feels is safe and continued for the entire hospital stay. For those going home in less than 10 days, or for those with other risk factors, chemical prophylaxis should be considered beyond discharge.

  Other orthopaedic operations: There are so few data on both epidemiology and prophylaxis that one has to resort to common sense. If the risk assessment suggests a minimal risk of VTE then the cost and potential side-effects of peri-operative 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 lower limb trauma and spinal surgery certainly carry a risk of symptomatic thromboembolism yet carry a greater threat of bleeding. A longer period of mechanical prophylaxis, followed by extended chemical prohylaxis when safe, seems sensible. Day case arthroscopy causes very occasional VTE problems yet practical prophylaxis is difficult (the patient will have gone home before it is safe to give chemicals). The best one can do is to carry out a careful risk assessment and provide anyone with a higher risk with an injection prior to discharge and follow with home-prophylaxis until fully mobile.

  Updating: Scientific knowledge, clinical experience and attitudes to risk change with time. It takes effort to get new medications on to a hospital formulary. It takes persuasion to change habits. A group of interested individuals in a department or hospital can keep the local guidelines acceptable and current.

CONCLUSION

  Opinions about and options for thromboprophylaxis are continuously developing; perhaps this article helps surgeons to think about this important aspect of surgical care.


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