Case presentation: A 69-year-old

Transcription

1 CLINICIAN UPDATE Prevention of Venous Thromboembolism in Total Knee and Hip Replacement David Warwick, MD, FRCS, FRCS(Orth) Case presentation: A 69-year-old woman had a cemented hip replacement 15 years previously, which initially fared well but then gradually failed because of aseptic loosening. She developed pain in her hip and was scheduled for a revision total hip replacement. A formal venous thromboembolism (VTE) risk assessment was undertaken before surgery according to the Hospital s policy for all orthopedic admissions. The risk assessment identified 2 conflicting issues. First, the patient had a particularly high risk of VTE, having had an above-knee deep vein thrombosis after her primary hip replacement and now required a major surgery, namely a revision hip arthroplasty. Second, she had a greater than usual risk of bleeding after surgery because of her obesity and the need for a large soft-tissue exposure, long-term aspirin, and supplementary bone graft from her iliac crest. The surgeon was faced with a common orthopedic problem, providing effective VTE prophylaxis without causing an equally important problem of surgical bleeding. Introduction Hip and knee replacement operations are now commonly performed, around 1 million annually in the United States and about the same number in Europe. These procedures are among the most successful and life-changing interventions available. However, the release of thromboplastins from dissected soft tissue and especially reamed bone, as well as venous stasis both during surgery and during relative postoperative immobility, provoke a high rate of thromboembolism. Several measures reduce the risk of VTE, but orthopedic surgeons are intuitively and properly concerned about the potential hemorrhagic side effect of pharmacological prophylaxis, which is associated with prolonged recovery, wound failure, and even periprosthetic infection. 1 After all, following the Hippocratic principle of primum non nocere, the most thrombosceptic surgeons have even argued that whereas a thombosis is an act of God, bleeding is caused by a surgeon. Who is to say that a symptomatic leg thrombosis is any more important than a symptomatic wound bleed or that a fatal embolism is more important than a fatal cerebral or retroperitoneal bleed? Studies of all-cause mortality in orthopedics have shown no clear change in mortality rates with or without prophylaxis. 2 The symptomatic nonfatal VTE rate of around 3% to 4% without prophylaxis may be no different from the increased rate of bleeding induced by pharmacological prophylaxis. A balanced approach, individualized for each patient, is therefore required to secure the safest outcome. Available Options and Evidence There are many consensus statements and meta-analyses, a few of which we cite General It is likely that early mobilization, careful surgical technique, and adequate rehydration will all reduce the risk of VTE after joint arthroplasty. Mechanical Graduated compression stockings are of some benefit but must be well fitted. Mechanical foot or calf compressors are effective as well in total hip arthroplasty and total knee arthroplasty, although probably not quite as effective as the best pharmacological methods. They have the drawbacks of impracticality and lack of compliance, espe- From the Department of Orthopaedic Surgery, University of Southampton, Southampton, United Kingdom. Correspondence to David Warwick, MD, Orthopaedic Surgery, University of Southampton, Southampton, United Kingdom SO16 6UY. davidwarwick@me.com (Circulation. 2012;125: ) 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 2152 Circulation May 1, 2012 Table 1. Drawbacks of Warfarin and Aspirin, Advantages of New Oral Agents Drawbacks of Warfarin Needs 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 during his or her most thrombogenic phase Interaction with many drugs and alcohol Probably not as effective as LMWH Drawbacks of Aspirin Only weak antithrombotic effect so limited efficacy Evidence base controversial GI bleeding, wound bleeding Controversial professional support. Not recommended by NICE or ACCP, but recommended by first AAOS guidelines. Caution advised in 2011 AAOS guidelines. Not licensed for thromboprophylaxis Advantages of new oral agents At least as effective as enoxaparin Comparable bleeding profile No drug interactions No monitoring Can be used for out-of-hospital prophylaxis Less prone to HIT than LMWH Disadvantages of new oral agents Poor reversibility Caution in certain groups (eg, renal impairment) Only recently available, no long-term experience (vs LMWH) LMWH indicates low molecular-weight heparin; NICE, National Institute for Health and Clinical Excellence; ACCP, American College of Chest Physicians; AAOS, American Academy of Orthopaedic Surgeons; and HIT, heparin induced thrombocytopaenia. cially once the patient starts to mobilize. They also tend to be quite expensive. They have the advantage of freedom from hemorrhagic side effects, which appeals to the surgeon s intuition. Neuraxial Anesthesia Neuraxial anesthesia reduces VTE in arthroplasty and also reduces overall mortality. 9 However, the anesthetist will need to consider whether the insertion of a spinal or epidural catheter may be compromised by the risk of a neuraxial bleed when an anticoagulant is given concomitantly. Meticulous timing and adherence to published anesthetic guidelines is essential. Older Oral Agents Aspirin and warfarin (Coumadin) are widely used in North America, although warfarin is now generally regarded as obsolete in Europe. Aspirin is controversial (Table 1). Injectable Agents Low molecular-weight heparin has become the standard on the basis of 2 decades of clinical experience and a large number of well conducted studies. There is good evidence that, used carefully, low molecular-weight heparin is effective and does not carry an unacceptable bleeding risk. Fondaparinux (pentasaccharide) is also very effective in reducing VTE but carries, as do all pharmacological agents, a risk of bleeding side effects. 10 New Oral Agents The past 3 years have seen the advent of new oral agents, anti Xa or direct thrombin inhibitors. The anti Xa agent rivaroxaban is available in the United States for VTE prophylaxis in total hip arthroplasty and total knee arthroplasty. In Europe, the direct thrombin inhibitor dabigatran and the anti Xa agent apixaban are now also approved for hip and knee arthroplasty. 11,12 The data suggest that the thromboprophylactic efficacy and bleeding risk of these new agents is at least equivalent to the clinical trial comparator, enoxaparin. There are no direct comparisons between these new oral agents to test relative differences in efficacy or bleeding. These drugs have the important advantage over injectable agents of oral administration, which allows practical administration for a longer duration, especially after hospital discharge. They have the further advantage over existing oral agents relative to efficacy (aspirin), as well as avoidance of monitoring and potential drug interactions (warfarin). They are likely to change the way that prophylaxis is administered in orthopedic patients, in particular meeting the previously unmet need for pragmatic out-of-hospital prophylaxis. The various pharmacological options are summarized in Table 2. There may be discrepancies between the official manufacturer s product information, based on clinical trial programs, and the pragmatic and considered protocols advised by professional guidelines. These discrepancies are an underlying theme of this article. When to Start, When to Finish The thrombotic process starts as soon as the arthroplasty starts, and so thromboprophylaxis must be started as close to surgery as possible. 13 Pharmacological prophylaxis can be started before surgery, but if too close there will be a risk of bleeding; if too far before surgery, the drug effect will have decayed before the thrombotic process commences. Preoperative administration is also compromised because an unexpected delay in surgery or an earlier than expected procedure will exacerbate these problems. Postoperative administration is therefore more reliable with regard to a precise time for com-

3 Warwick Prevention of VTE in THR and TKR 2153 Table 2. Pharmaceutical Options in Total Hip Arthroplasty and Total Knee Arthroplasty Generic Name Brand Name Class Manufacturer Route Timing Frequency Enoxaparin Lovenox (US) LMWH Sanofi-Aventis sc Postop 12 hours Twice daily Enoxaparin Clexane (Europe) LMWH Sanofi-Aventis sc Preop 12 hours Once daily Dalteparin Fragmin LMWH Pfizer Inc/Eisai Inc sc Preop Once daily Tinzeparin (not yet licensed Innohep LMWH Leo Pharmaceuticals sc Preop Once daily in US; approved in Europe) Fondaparinux Arixtra Pentasaccharide GlaxoSmithKline sc 6 8 hours postop Once daily Warfarin Coumadin Jantoven Vitamin K antagonist Bristol-Myers-Squibb po variable Once daily Upsher-Smith Apixaban (not yet licensed Eliquis Anti-Xa Bristol-Myers Squibb/Pfizer po hours postop Twice daily in US; approved in Europe) Rivaroxaban Xarelto Anti-Xa Bayer po Postop 8 hours Once daily Dabigatran (not yet licensed in US; approved in Europe) Pradaxa Direct thrombin inhibitor Boeringher Ingelheim po Postop 1 4 hours Once daily This is a guide only. Any drug on this table should only be prescribed after confirmation by the prescribing physician of all data on dose, duration, indications, and contra-indications. For duration of administration, refer to both professional guidelines and manufacturer s product information. LMWH indicates low molecular-weight heparin; sc, by injection; postop, after surgery; preop, before surgery; and po, by mouth. mencement, but there is still a balance between giving the drug too soon (and risking bleeding) and too late (and risking thrombosis) (Figure 1). The duration of risk of VTE must also be considered. The risk after knee replacement is around 2 weeks and for hip replacement 4 to 6 weeks. 14 The risk may be longer in some individuals with extra risk factors. Prophylaxis should be continued until the risk has diminished (Figure 2). Because joint replacement patients only remain in hospital for a few days, prophylaxis must be extended beyond hospital discharge. This raises practical issues which can be readily addressed with an effective oral agent. Injectable agents and mechanical devices are less practical after hospital discharge. Guidelines Prophylaxis in the United States and Europe is now usually determined by hospital policy informed by guidelines. Guidelines distill the evidence and provide a reasoned and balanced practical summary for the surgeon. 15 Regular application of guidelines should help facilitate the implementation of prophylaxis. Despite a similar evidence base, guidelines vary. 16 The American Academy of Orthopaedic Surgeons 5 prefers pulmonary embolism as an end point and, with a paucity of studies providing this end point, cannot make firm recommendations on the basis of comparative studies. The first version in 2007 tended toward aspirin and warfarin postoperatively; the latest 2011 iteration 17 recommends the avoidance of aspirin before surgery and recommends postoperative pharmacological methods or mechanical methods for hip and knee arthroplasty. Those with a higher risk of thrombosis should have both; those with a higher risk of bleeding should have mechanical methods. Other guidelines, such as those of the American College of Chest Physicians 4 and the International Consensus Statement 8 are based on a venographic surrogate; this approach supports much firmer recommendations because there are a large number of studies with adequate sample size and significant differences in proportions between randomized groups. New iterations of each are due in The United Kingdom National Institute for Clinical Excellence guidelines 6 are a little less prescriptive, allowing some flexibility in timing of administration and combinations of mechanical and chemical methods. Figure 1. Just-in-time prophylaxis. A Balanced Approach It is generally held that hip and knee replacement have a risk of VTE high

4 2154 Circulation May 1, 2012 Figure 2. Discrepancy between duration of prophylaxis and onset of symptomatic VTE. VTE indicates venous thromboembolism. Reproduced with permission and copyright of the British Editorial Society of Bone and Joint Surgery. 14 enough to justify universal prophylaxis. However, the type of prophylaxis, the time of initiation, and the duration of administration are a matter for the clinician to judge, balancing the risk of thrombosis and of bleeding. Further, cost effectiveness is an increasingly relevant issue in financially constrained health economies. Mechanical Pharmaceutical Combinations To minimize bleeding risk yet maximize efficacy of VTE prophylaxis, mechanical and chemical methods are combined to exploit the advantages of each and avoid the disadvantages. A mechanical device is used on the contralateral leg during surgery, then on both legs as soon as the operation is finished. It is continued for as long as it is tolerated. A drug is started postoperatively, but only when the bleeding risk has diminished. If the patient has a higher than usual risk of VTE (for example, a past history of VTE, a family history of VTE, intercurrent malignancy, or predicted prolonged immobility), then a higher risk of bleeding with pharmacological prophylaxis might be accepted. The drug may be started closer to surgery and continued for longer. Furthermore, additional mechanical methods can be added to augment and maximize prophylaxis. The patient is encouraged and cajoled to tolerate the mechanical device for as long as possible. If the patient has a higher than usual risk of bleeding (for example, higher body mass, history of bleeding diathesis, or enlarged surgical incision for revision surgery), then a slightly higher risk of VTE might be accepted, which would indicate starting an anticoagulant later and covering the interim with an effective mechanical method. The Solution in this Case The surgeon weighed the conflicting risks of bleeding and VTE. Because the patient had a higher risk of bleeding, it was decided to delay the pharmacological prophylaxis until the day after surgery. Mechanical prophylaxis was instituted as early as possible. The patient was given well-fitting graduated compression stockings on arrival in hospital and was encouraged to wear these for 6 weeks. In the operating room, mechanical foot compressors were applied to the opposite leg and activated throughout the procedure. At the end of the procedure, the foot compressor was applied to the operated leg as well. Compression was continued until the patient started to mobilize. The device was then removed only when the patient was tentatively mobilizing but was reattached by the nurse or physiotherapist immediately afterward. By the fifth day, the patient was mobilizing well and was discharged. It was deemed impractical to use the device at home. A new oral agent (Rivaroxaban 10 mg once daily) was given at 9:00 AM on the day after surgery. This delay was judged sensible to bring the drug close enough to surgery for prophylactic effect but to allow adequate hemostasis. The drug was prescribed for 5 weeks. The patient developed no hematoma and no symptomatic VTE. Disclosures Dr Warwick has received honoraria and traveling expenses from Boehringer Ingelheim (manufacturers of Dabigatran, a direct thrombin inhibitor) for 2 lectures in 2011 and 1 in The author received traveling expenses for his contribution to the International Consensus Statement Editorial Board in References 1. Parvizi J. Does excessive anticoagulation predispose to peri-prosthetic infection? Arthroplasty. 2007;22: Sharrock NE, Gonzalez Della Valle A, Go G, Lyman S, Salvati EA. Potent anticoagulants are associated with a higher all-cause mortality rate after hip and knee arthroplasty. Clin Orthop Rel Res. 2008;466: Sachdeva A, Dalton M, Amaragiri SV, Lees T. Elastic compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev. 2010: CD Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:381S 453S. 5. Johanson NA, Lachiewicz PF, Lieberman JR, Lotke PA, Parvizi J, Pellegrini V, Stringer TA, Tornetta P III, Haralson RH III, Watters WC III. American Academy of Orthopaedic Surgeons clinical practice guideline on prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Bone Joint Surg Am. 2009:-91: NICE Clinical Guideline 92 (2010): reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital Available at byid&o Accessed October 27, Kakkos SK, Caprini JA, Geroulakos G, Nicolaides AN, Stansby GP, Reddy DJ. Combined intermittent pneumatic compression and pharmacological prophylaxis for prevention of venous thromboembolism in high risk patients (a review.) Cochrane Database Syst Rev. 2008:CD Nicolaides AN, Breddin HK, Carpenter P, Coccheri S, Conard J, De Stefano V, Elkoofy

5 Warwick Prevention of VTE in THR and TKR 2155 N, Gerotziafas G, Guermazi S, Haas S, Hull R, Kalodiki E, Kristof V, Michiels JJ, Myers K, Pineo G, Prandoni P, Romeo G, Samama MM, Simonian S, Xenophonthos S. Prevention and treatment of venous thromboembolism: International Consensus Statement (guidelines according to scientific evidence). Int Angiol. 2006;25: Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, Baigent C. Towards evidence based guidelines for the prevention of venous thromboembolism: systematic review of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis. Health Technol Assess. 2005;49: Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162: Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363: Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375: Warwick D, Roschensher N. The critical thrombosis period in major orthopedic surgery: when to start and when to stop prophylaxis. Clin Appl Thromb Hemost. 2010;16: Warwick D, Friedman RJ, Agnelli G, Gil-Garay E, Johnson K, FitzGerald G, Turibio FM. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events. J Bone Joint Surg. 2007;89B: Warwick DJ, Dahl OE, Fisher WD. Orthopaedic thromboprophylaxis: limitations of current guidelines. J Bone Joint Surg Br. 2008;90: Eikelboom JW. American Academy of Orthopaedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135: Preventing venous thromboembolic disease in patients underoing elective hip and knee arthroplasty: evidence-based guideline and evidencereport. guidelines/vte/vte_full_guideline.pdf. Accessed November 19, 2011.