Venous thromboembolism remains the most common cause of hospital readmission and death after total joint arthroplasty. The 2008 American College of Chest Physicians (ACCP) guidelines, based on prospective randomized clinical trials with a venography endpoint, endorse the use of low-molecular-weight heparin, fondaparinux, or adjusted dose warfarin (target international normalized ratio, 2.5; range, 2-3) for up to 35 days after total hip arthroplasty (THA) and total knee arthroplasty (TKA). In the past, the ACCP has recommended against the use of aspirin, graduated compression stockings, or venous compression devices as the sole means of prophylaxis, but in 2008 they first recommended the optimal use of mechanical thromboprophylaxis with venous foot pumps or intermittent pneumatic compression devices in patients undergoing total joint arthroplasty who have a high risk of bleeding. When the high risk subsides, pharmacologic thromboprophylaxis is substituted for, or added to, mechanical methods.
Fractionated heparins and pentasaccharide are the most effective agents in reducing venographic deep venous thrombosis (DVT) after total joint arthroplasty with residual clot rates <5% after THA and 20% after TKA, but major or clinically meaningful bleeding occurs in 3% to 5% of patients. Newer Xa and thrombin inhibitors enjoy greater efficacy with equal or higher bleeding rates. Low-intensity warfarin (target international normalized ratio, 2.0) combines safety (bleeding rates <1%) with efficacy (readmission for clinical DVT or pulmonary embolism 0.2%) after total joint arthroplasty. Warfarin represents a therapeutic compromise by preventing clinical events in exchange for a lower bleeding rate; genetic testing will likely simplify warfarin use and reduce outlier responders.
Sir John Charnley reported long ago that, although it is an infrequent event, we need to worry about pulmonary embolism.1 The issue is one of balance and risk avoidance. Do we strive for absolute prevention of everything on a venogram with an accompanying increase in bleeding, or do we focus on preventing pulmonary embolism death and minimize the bleeding risk?
The American College of Chest Physicians (ACCP) has endorsed 3 agents (warfarin, low-molecular-weight heparin, and fondaparinux) and recommended against the use of aspirin and pneumatic compression alone for venous thromboembolic disease prophylaxis.2 The American Academy of Orthopaedic Surgeons (AAOS) has taken a different stance and stratifies risk of venous thromboembolic disease into 4 groups illustrating 1 important outcome: with an elevated risk of embolism and an elevated risk of bleeding, the bleeding risk trumps the elevated risk of embolism.3 This is illustrated by recommendations that are identical to those for a standard risk of embolism with an increased bleeding risk. With an elevated bleeding risk, the AAOS guidelines only recommend use of warfarin or aspirin in deference to an overwhelming concern to avoid perioperative bleeding complications; specifically, low-molecular-weight heparin or fondaparinux are not endorsed because of the associated concern for bleeding.
Aspirin deserves specific mention in this context. A National Institutes of Health Consensus Conference in 1986 concluded that aspirin was not useful for venous thromboembolic disease prophylaxis; nevertheless, in the 1990s, aspirin enjoyed a resurgence in popularity. The data suggest that this change was based largely on a perceived lack of complications rather than any demonstrated efficacy of aspirin in the prevention of pulmonary embolism. In the Antiplatelet Trialists Study, there were only 2 venogram trials with aspirin, 1 with total hip arthroplasties (THAs) and 1 with total knee arthroplasties (TKAs); these data are insufficient to prove anything.4
A meta-analysis from the University of Pennsylvania also suggested that aspirin was helpful but did not stratify the data source based on the type of anesthetic.5 If the original data are stratified for the type of anesthetic, aspirin appears to only have efficacy in preventing pulmonary embolism when used in conjunction with a regional anesthetic; and when was used in association with a general anesthetic, aspirin was no more effective than historical controls in preventing pulmonary embolism.
The most frequently quoted study is the Pulmonary Embolism Prevention trial, which was conducted in Australia and New Zealand as primarily a hip fracture study.6 There were 2600 elective THA patients, and there was no difference between aspirin and placebo in terms of efficacy in venous thromboembolic disease prevention. Moreover, one-third of these patients received fractionated heparin, and there was no stratification for type of anesthetic, both of which are known to strongly influence the occurrence of pulmonary embolism.
However, there are 2 pieces of recent data that suggest aspirin is helpful in a multimodal situation. One study with THA patients from the Hospital for Special Surgery suggests that the readmission rate for pulmonary embolism is approximately 3%, but 20% of patients received warfarin and all patients received a hypotensive epidural anesthetic as well as a bolus of intravenous heparin intraoperatively. Another study from the University of Pennsylvania had similar findings after TKA; all patients received a spinal anesthetic, and there was a low readmission rate for pulmonary embolism with aspirin as venous thromboembolic disease prophylaxis. Clearly, anesthetic type matters, and, unless used in combination with regional anesthesia, data supporting the use of aspirin for venous thromboembolic disease prophylaxis are sparse and inconclusive.
With respect to mechanical compression, the 2 sets of guidelines have moved closer in the last iteration with the ACCP endorsement of mechanical compression in settings where bleeding risk is extraordinary and chemoprophylaxis is not suitable. It is important to remember, however, that mechanical compression alone has been shown to result in a much higher prevalence of proximal clots after THA.7 Our data demonstrated a statistically significant four-fold greater proximal clot rate with sequential compression alone after THA, likely because the segmental clots in the femoral vein are due to intimal injury, and pneumatic compression alone does not negate that factor. Similarly, after TKA, our data suggest that the effect of a general anesthetic was much more important than compression, aspirin, or warfarin in the prevalence of pulmonary embolism.
The subject of contemporary chemoprophylaxis has fueled much of the present controversy. The baseline comparator is relative to warfarin, which has an approximately 20% residual clot rate with a general anesthetic and 10% with a regional anesthetic after THA; after TKA, the residual clot rate is closer to 50%. The newer drugs effectively reduce the residual venographic clot rate: fractionated heparin to 10% after THA and fondaparinux to 5%, but the overall bleeding risk with these agents is up to 5%.8 Following TKA, fractionated heparin reduces the residual clot rate to approximately 33%, and fondaparinux is the first drug to result in a residual clot rate <20%, but the bleeding risk is 2 to 3 times greater than observed with warfarin.8
An important question in this debate concerns the optimal endpoint used to measure efficacy. While venographic data are not an ideal surrogate for a clinical endpoint, Eikelboom et al demonstrated that if we minimize venographic clots, a reduction in clinical events will follow.9 Therefore, there is a relationship between venographic clots and clinical events, although one may effectively argue that an actual clinical endpoint is far superior to a venogram surrogate representing asymptomatic events in the context of caring for individual patients.10
In our hands, low-intensity (target international normalized ratio, 2.0) warfarin is the best and most rational compromise based on experience in nearly 3300 patients after both THA and TKA over 2 decades of practice.11-13 During the first decade, no patients received post-discharge warfarin who did not have a venogram. During the second decade, if patients had no venogram, they empirically received continued warfarin prophylaxis at discharge. Ultimately, the relative risk of readmission for pulmonary embolism or symptomatic deep vein thrombosis, when discharged without warfarin on the basis of a clean study, was 7 to 8 times greater than if discharged on warfarin for any reason, including a positive study for a known clot. In the entire group of 3300 patients, no single pulmonary embolism occurred in any patient who received extended outpatient warfarin prophylaxis after discharge.
Nevertheless, the bleeding risk on outpatient warfarin is real. The rate in our series was 0.1%, with 1 fatal intracranial bleed in a patient with an elevated international normalized ratio. While no frequency of untoward bleeding is desirable, it is critical to get to a point where the major bleeding risk and the risk of clinically important pulmonary embolism are comparable in magnitude. As such, a much lower bleeding risk than is presently seen with the newer chemoprophylactic agents is necessary before their routine use can be embraced in preventing clinical pulmonary embolism, which occurs at a much lower rate than bleeding with the newer agents.14 This rationale is underscored by current practice among arthroplasty surgeons in North America; half of them still use warfarin despite its need for monitoring, while only one-third use fractionated heparin.15
A question can be posed to the pharmaceutical industry: Is anybody listening? What is needed is a drug that is comparable in efficacy but safer than the current list of newer agents. Improvement in safety is also needed in new drug development, not greater efficacy, to make living through chemistry even better with respect to pulmonary embolism after total joint arthroplasty.
- Charnley J. Thromboembolic complications. In: Low Friction Arthroplasty of the Hip: Theory and Practice. Berlin, Germany: Springer-Verlag; 1979:308-313.
- Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008; 133(6 Suppl):381S-453S.
- Johanson NA, Lachiewicz PF, Lieberman JR, et al. Prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Am Acad Orthop Surg. 2009; 17(3):183-196.
- Antiplatelet Trialists Collaboration. Collaborative review of randomized trials of antiplatelet therapy. III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ. 1994; (308):235-246.
- Freedman KB, Brookenthal KR, Fitzgerald RH Jr, Williams S, Lonner JH. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg Am. 2000; 82(7):929-938.
- Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000; 355(9212):1295-1302.
- Francis CW, Pellegrini VD Jr, Marder VJ, et al. Comparison of warfarin and external pneumatic compression in prevention of venous thrombosis after total hip replacement. JAMA. 1992; 267(21):2911-2915.
- Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA. 1994; 271(22):1780-1785.
- 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. Lancet. 2001; 358(9275):9-15.
- Lieberman JR, Wollaeger J, Dorey F, et al. The efficacy of prophylaxis with low-dose warfarin for prevention of pulmonary embolism following total hip arthroplasty. J Bone Joint Surg Am. 1997; 79(3):319-325.
- Pellegrini VD Jr, Clement D, Lush-Ehmann C, Keller GS, Evarts CM. The John Charnley Award. Natural history of thromboembolic disease after total hip arthroplasty. Clin Orthop Relat Res. 1996; (333):27-40.
- Pellegrini VD Jr, Donaldson CT, Farber DC, Lehman EB, Evarts CM. The John Charnley Award: prevention of readmission for venous thromboembolic disease after total hip arthroplasty. Clin Orthop Rel Res. 2005; (441):56-62.
- Pellegrini VD Jr, Donaldson CT, Farber DC, Lehman EB, Evarts CM. The Mark Coventry Award: Prevention of readmission for venous thromboembolism after total knee arthroplasty. Clin Orthop Relat Res. 2006; (452):21-27.
- Colwell CW Jr, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am. 1999; 81(7):932-940.
- Markel DC, York S, Liston MJ Jr, et al. Venous thromboembolism: management by American Association of Hip and Knee Surgeons. J Arthroplasty. 2010; 25(1):3-9.e1-2.
Dr Pellegrini is from the Department of Orthopedics, University of Maryland School of Medicine, Baltimore, Maryland.
Dr Pellegrini receives royalties from DePuy/Johnson & Johnson for intellectual property related to a total hip stem, and serves on a medical advisory board to Covidien regarding education of practitioners concerning pneumatic compression devices for prevention of venous thromboembolic disease after total joint replacement.
Presented at Current Concepts in Joint Replacement 2009 Winter Meeting; December 9-12, 2009; Orlando, Florida.
Correspondence should be addressed to: Vincent D. Pellegrini Jr, MD, Department of Orthopedics, University of Maryland School of Medicine, 22 S Greene St, Ste S 11 B, Baltimore, MD 21201 (firstname.lastname@example.org).