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Deep Vein Thrombosis Prophylaxis
The Journal of Arthroplasty Vol. 20 No. 4 Suppl. 2 2005
Deep Vein Thrombosis Prophylaxis Better Living Through Chemistry—In the Affirmative Louis M. Kwong, MD, FACS
Abstract: Venous thromboembolism is a recognized complication of total hip arthroplasty, knee arthroplasty, and hip fracture surgery. Various pharmacological agents have been introduced in orthopedic surgery in an attempt to reduce the mortality as well as the short-term and long-term morbidity associated with the development of deep vein thrombosis and pulmonary embolism. Clinical trials demonstrate the increasing thromboprophylactic efficacy of newer generations of drugs. The most current guidelines of the American College of Chest Physicians regarding thromboprophylaxis after total hip arthroplasty, total knee arthroplasty, and hip fracture surgery give the highest recommendations in support of the use of low-molecular-weight heparin, warfarin, or fondaparinux. Their highest recommendation is also given against the use of aspirin due to its lack of demonstrated efficacy. Key words: arthroplasty, deep vein thrombosis, prophylaxis. n 2005 Elsevier Inc. All rights reserved.
caused by PE is widely recognized, it is important to acknowledge that VTE is also a potential source of significant long-term morbidity from its nonfatal sequelae. Perhaps the greatest risk factor for the development of VTE is any prior history of DVT or PE. After even a single first episode of DVT, there is a 30% cumulative risk of recurrent DVT at 8 years [3]. A significant source of morbidity can also result from the development of post-thrombotic syndrome. This sequela of VTE is characterized by varying degrees of pain, swelling, edema, skin breakdown, and frank ulceration. Even at 8 years after a first episode of DVT, there is also a 30% cumulative risk of developing post-thrombotic syndrome [3]. It is therefore important to reduce the risk of all VTE events, even nonfatal events, because of their potentially significant short-term and long-term impact on the quality of life of patients. In response to the high thrombosis risk in the population of individuals after joint arthroplasty and hip fracture, a number of pharmacological agents have been introduced in orthopedic surgery over the last few decades. The use of chemoprophylaxis began with dextran in the 1960s, followed
Venous thromboembolism (VTE) is the most frequent serious complication after total hip arthroplasty, total knee arthroplasty, and hip fracture surgery [1]. It is a largely clinically silent disorder. Venous thromboembolism can be manifested as deep vein thrombosis (DVT) or as pulmonary embolism (PE), which is associated with a 0.1% to 0.2% rate of fatality [1,2]. In the absence of thromboprophylaxis, approximately 50% of individuals after hip arthroplasty and hip fracture and 60% of individuals after knee arthroplasty will go on to develop DVT [2]. Studies indicate that up to almost 13% of individuals may die of fatal PE after hip fracture surgery [2]. Although the potential for fatal consequences
From the Department of Orthopedic Surgery, Harbor/UCLA Medical Center, Torrance, California. No benefits or funds were received in support of the study. Reprint requests: Louis M. Kwong, MD, FACS, Department of Orthopedic Surgery, Harbor/UCLA Medical Center, 1000 W Carson St, Bin 422, Torrance, CA 90509. n 2005 Elsevier Inc. All rights reserved. 0883-5403/05/2004-2006$30.00/0 doi:10.1016/j.arth.2005.03.013
12
DVT Prophylaxis ! Louis M. Kwong
by unfractionated heparin in the 1970s. Warfarin was introduced in the 1980s, followed by lowmolecular-weight heparin in the 1990s and factor Xa and direct thrombin inhibitors in the past few years. The peer review literature clearly illustrates that with the introduction of each subsequent generation of pharmacological agent, there is a progressive improvement in the efficacy of those agents over the previous generations of agents [4-8]. A metaanalysis of antithrombotic studies after total hip arthroplasty compares the effects of these different agents vs placebo on the VTE rate (Table 1) [1,9]. These data demonstrate that with the use of aspirin, the percentage of DVT is decreased from 54.2% to 41.7%. The use of warfarin lowers this incidence further to 22.3%. Low-molecular-weight heparin reduces the rate to 14.8%. The lowest incidence of DVT is found with the use of fondaparinux at 4.7%. With regard to risk reduction, beginning with the 23% rate with aspirin, it is shown that with each subsequent generation of a drug, there is a progressive improvement in efficacy, rising to a 91% relative risk reduction (RRR) with fondaparinux. Similar findings are seen with regard to knee arthroplasty (Table 2) [1,9]. The use of aspirin lowers the DVT rate from 64.3% to 56%. Warfarin lowers the risk to 37%. Low-molecular-weight heparin reduces the rate to 35.1%, and fondaparinux use yields the lowest incidence at a 12.5% DVT rate. Similarly, increasing efficacy can be seen beginning with an RRR of 13% with aspirin, progressively increasing to an RRR of 79.5% with fondaparinux. The American College of Chest Physicians (ACCP), since 1986, has assembled a multidisciplinary panel, including representatives from orthopedic surgery, hematology, and pulmonary medicine, to render recommendations and guidelines regarding thromboprophylaxis after total hip arthroplasty, total knee arthroplasty, and hip
Table 1. Deep Vein Thrombosis After Total Hip Arthroplasty: Decreasing VTE Rate With Better Agents* Regimen Control/placebo Aspirin Adjusted warfarin Low-molecularweight heparin Fondaparinux
Trials (n)
DVT (%)
RRR (%)
12 5 12 33
54.2 41.7 22.3 14.8
– 23 59 73
2
4.7
91
*Pooled DVT rates from randomized clinical trials.
13
Table 2. Deep Vein Thrombosis After Total Knee Arthroplasty: Decreasing VTE Rate With Better Agents* Regimen Control/placebo Aspirin Adjusted warfarin Low-molecularweight heparin Fondaparinux
Trials (n)
DVT (%)
RRR (%)
6 6 12 19
64.3 56 37 35.1
– 13 42.5 45.4
1
12.5
79.5
*Pooled DVT rates from randomized clinical trials.
fracture surgery based on their expert opinion and the strength of supporting data in the peer review literature. The recommendations of the ACCP are now widely viewed as representing a national standard of medical care governing thromboprophylaxis after a major orthopedic surgery. These most recent guidelines from the 2003 ACCP Consensus Conference recommend 1 of 3 strategies as being effective after total hip arthroplasty: the use of (1) low-molecular-weight heparin administered at a fixed dose, unmonitored, and started either preoperatively or postoperatively; (2) warfarin, started preoperatively or postoperatively and dose adjusted to target an international normalized ratio between 2.0 and 3.0; or (3) fondaparinux, started at 6 to 8 hours postoperatively. The recommended duration of drug administration is 28 to 35 days [1]. The ACCP guidelines after knee arthroplasty are similar: the highest recommendations for effective thromboprophylaxis are also given to the use of low-molecular-weight heparin, warfarin, or fondaparinux. But the recommended duration of drug administration is 7 to 10 days [1]. With regard to aspirin’s role in the prevention of thrombosis, aspirin functions in the nonreversible inhibition of platelet aggregation. Because it nonselectively inhibits both cyclooxygenases I and II, there is a potential for upper gastrointestinal bleed due to the obstruction of prostaglandin synthesis. Multiple clinical trials, however, clearly demonstrate the efficacy of aspirin in reducing the risk of arterial thrombosis [10,11]. With regard to VTE, the best trial to date regarding the use of aspirin is the Pulmonary Embolism Prevention trial [12]. Although this study supports the use of aspirin, the study design does not separate mechanical from pharmacological effects. In addition, patients enrolled in this trial are also allowed concurrent use of not only traditional anti-inflammatory drugs but also unfractionated heparin and low-molecular-weight
14 The Journal of Arthroplasty Vol. 20 No. 4 Suppl. 2 June 2005 heparin in conjunction with aspirin use. So, a welldesigned, randomized clinical trial isolating the effects of aspirin continues to be lacking. In fact, with regard to aspirin, the ACCP gives its very highest recommendation against the use of aspirin after joint arthroplasty and hip fracture due to its lack of demonstrated efficacy [1]. In the world of evidence-based medicine, there is no good scientific evidence to support the use of aspirin as a chemoprophylactic agent against VTE after total hip arthroplasty, knee arthroplasty, or hip fracture surgery. In summary, contemporary pharmacological agents demonstrate clear superiority in reducing the risk of VTE compared with earlier generations of drugs. Better studies are needed to define the role of aspirin, if any, in VTE prophylaxis after a major orthopedic surgery. Better chemistry has definitely contributed to better clinical outcomes and improvement in quality of life by reducing the largely preventable short-term and long-term complications of VTE after hip arthroplasty, knee arthroplasty, and hip fracture surgery.
5.
6.
7.
8.
9.
References 1. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004;126:338S. 2. Gallus AS. Applying risk assessment models in orthopedic surgery: overview of our clinical experience. Blood Coagul Fibrinolysis 1999;10(Suppl 2):S53. 3. Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein thrombosis. Prospective longterm follow-up of 528 symptomatic patients. Haematologica 1997;82:423. 4. Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by
10.
11.
12.
peri-operative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988;318:1162. Harris WH, Salzman EW, Athansoulis C, et al. Comparison of warfarin, low-molecular weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement. J Bone Joint Surg Am 1974;56:1552. Colwell CW, 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;81:932. Hull RD, Pineo GF. Heparin and low-molecularweight heparin therapy for venous thromboembolism: will unfractionated heparin survive? Semin Thromb Hemost 2004;30(Suppl 1):11. Turpie AGG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopaedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest 2001;119:39S. Cohen AT, Skinner JA, Kakkar VV. Antiplatelet treatment for thromboprophylaxis: a step forward or backwards? BMJ 1994;309:1213. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) Trial. Lancet 2000;355:1295.
Deep Vein Thrombosis Prophylaxis Better Living Through Chemistry—In the Affirmative Louis M. Kwong, MD, FACS
Abstract: Venous thromboembolism is a recognized complication of total hip arthroplasty, knee arthroplasty, and hip fracture surgery. Various pharmacological agents have been introduced in orthopedic surgery in an attempt to reduce the mortality as well as the short-term and long-term morbidity associated with the development of deep vein thrombosis and pulmonary embolism. Clinical trials demonstrate the increasing thromboprophylactic efficacy of newer generations of drugs. The most current guidelines of the American College of Chest Physicians regarding thromboprophylaxis after total hip arthroplasty, total knee arthroplasty, and hip fracture surgery give the highest recommendations in support of the use of low-molecular-weight heparin, warfarin, or fondaparinux. Their highest recommendation is also given against the use of aspirin due to its lack of demonstrated efficacy. Key words: arthroplasty, deep vein thrombosis, prophylaxis. n 2005 Elsevier Inc. All rights reserved.
caused by PE is widely recognized, it is important to acknowledge that VTE is also a potential source of significant long-term morbidity from its nonfatal sequelae. Perhaps the greatest risk factor for the development of VTE is any prior history of DVT or PE. After even a single first episode of DVT, there is a 30% cumulative risk of recurrent DVT at 8 years [3]. A significant source of morbidity can also result from the development of post-thrombotic syndrome. This sequela of VTE is characterized by varying degrees of pain, swelling, edema, skin breakdown, and frank ulceration. Even at 8 years after a first episode of DVT, there is also a 30% cumulative risk of developing post-thrombotic syndrome [3]. It is therefore important to reduce the risk of all VTE events, even nonfatal events, because of their potentially significant short-term and long-term impact on the quality of life of patients. In response to the high thrombosis risk in the population of individuals after joint arthroplasty and hip fracture, a number of pharmacological agents have been introduced in orthopedic surgery over the last few decades. The use of chemoprophylaxis began with dextran in the 1960s, followed
Venous thromboembolism (VTE) is the most frequent serious complication after total hip arthroplasty, total knee arthroplasty, and hip fracture surgery [1]. It is a largely clinically silent disorder. Venous thromboembolism can be manifested as deep vein thrombosis (DVT) or as pulmonary embolism (PE), which is associated with a 0.1% to 0.2% rate of fatality [1,2]. In the absence of thromboprophylaxis, approximately 50% of individuals after hip arthroplasty and hip fracture and 60% of individuals after knee arthroplasty will go on to develop DVT [2]. Studies indicate that up to almost 13% of individuals may die of fatal PE after hip fracture surgery [2]. Although the potential for fatal consequences
From the Department of Orthopedic Surgery, Harbor/UCLA Medical Center, Torrance, California. No benefits or funds were received in support of the study. Reprint requests: Louis M. Kwong, MD, FACS, Department of Orthopedic Surgery, Harbor/UCLA Medical Center, 1000 W Carson St, Bin 422, Torrance, CA 90509. n 2005 Elsevier Inc. All rights reserved. 0883-5403/05/2004-2006$30.00/0 doi:10.1016/j.arth.2005.03.013
12
DVT Prophylaxis ! Louis M. Kwong
by unfractionated heparin in the 1970s. Warfarin was introduced in the 1980s, followed by lowmolecular-weight heparin in the 1990s and factor Xa and direct thrombin inhibitors in the past few years. The peer review literature clearly illustrates that with the introduction of each subsequent generation of pharmacological agent, there is a progressive improvement in the efficacy of those agents over the previous generations of agents [4-8]. A metaanalysis of antithrombotic studies after total hip arthroplasty compares the effects of these different agents vs placebo on the VTE rate (Table 1) [1,9]. These data demonstrate that with the use of aspirin, the percentage of DVT is decreased from 54.2% to 41.7%. The use of warfarin lowers this incidence further to 22.3%. Low-molecular-weight heparin reduces the rate to 14.8%. The lowest incidence of DVT is found with the use of fondaparinux at 4.7%. With regard to risk reduction, beginning with the 23% rate with aspirin, it is shown that with each subsequent generation of a drug, there is a progressive improvement in efficacy, rising to a 91% relative risk reduction (RRR) with fondaparinux. Similar findings are seen with regard to knee arthroplasty (Table 2) [1,9]. The use of aspirin lowers the DVT rate from 64.3% to 56%. Warfarin lowers the risk to 37%. Low-molecular-weight heparin reduces the rate to 35.1%, and fondaparinux use yields the lowest incidence at a 12.5% DVT rate. Similarly, increasing efficacy can be seen beginning with an RRR of 13% with aspirin, progressively increasing to an RRR of 79.5% with fondaparinux. The American College of Chest Physicians (ACCP), since 1986, has assembled a multidisciplinary panel, including representatives from orthopedic surgery, hematology, and pulmonary medicine, to render recommendations and guidelines regarding thromboprophylaxis after total hip arthroplasty, total knee arthroplasty, and hip
Table 1. Deep Vein Thrombosis After Total Hip Arthroplasty: Decreasing VTE Rate With Better Agents* Regimen Control/placebo Aspirin Adjusted warfarin Low-molecularweight heparin Fondaparinux
Trials (n)
DVT (%)
RRR (%)
12 5 12 33
54.2 41.7 22.3 14.8
– 23 59 73
2
4.7
91
*Pooled DVT rates from randomized clinical trials.
13
Table 2. Deep Vein Thrombosis After Total Knee Arthroplasty: Decreasing VTE Rate With Better Agents* Regimen Control/placebo Aspirin Adjusted warfarin Low-molecularweight heparin Fondaparinux
Trials (n)
DVT (%)
RRR (%)
6 6 12 19
64.3 56 37 35.1
– 13 42.5 45.4
1
12.5
79.5
*Pooled DVT rates from randomized clinical trials.
fracture surgery based on their expert opinion and the strength of supporting data in the peer review literature. The recommendations of the ACCP are now widely viewed as representing a national standard of medical care governing thromboprophylaxis after a major orthopedic surgery. These most recent guidelines from the 2003 ACCP Consensus Conference recommend 1 of 3 strategies as being effective after total hip arthroplasty: the use of (1) low-molecular-weight heparin administered at a fixed dose, unmonitored, and started either preoperatively or postoperatively; (2) warfarin, started preoperatively or postoperatively and dose adjusted to target an international normalized ratio between 2.0 and 3.0; or (3) fondaparinux, started at 6 to 8 hours postoperatively. The recommended duration of drug administration is 28 to 35 days [1]. The ACCP guidelines after knee arthroplasty are similar: the highest recommendations for effective thromboprophylaxis are also given to the use of low-molecular-weight heparin, warfarin, or fondaparinux. But the recommended duration of drug administration is 7 to 10 days [1]. With regard to aspirin’s role in the prevention of thrombosis, aspirin functions in the nonreversible inhibition of platelet aggregation. Because it nonselectively inhibits both cyclooxygenases I and II, there is a potential for upper gastrointestinal bleed due to the obstruction of prostaglandin synthesis. Multiple clinical trials, however, clearly demonstrate the efficacy of aspirin in reducing the risk of arterial thrombosis [10,11]. With regard to VTE, the best trial to date regarding the use of aspirin is the Pulmonary Embolism Prevention trial [12]. Although this study supports the use of aspirin, the study design does not separate mechanical from pharmacological effects. In addition, patients enrolled in this trial are also allowed concurrent use of not only traditional anti-inflammatory drugs but also unfractionated heparin and low-molecular-weight
14 The Journal of Arthroplasty Vol. 20 No. 4 Suppl. 2 June 2005 heparin in conjunction with aspirin use. So, a welldesigned, randomized clinical trial isolating the effects of aspirin continues to be lacking. In fact, with regard to aspirin, the ACCP gives its very highest recommendation against the use of aspirin after joint arthroplasty and hip fracture due to its lack of demonstrated efficacy [1]. In the world of evidence-based medicine, there is no good scientific evidence to support the use of aspirin as a chemoprophylactic agent against VTE after total hip arthroplasty, knee arthroplasty, or hip fracture surgery. In summary, contemporary pharmacological agents demonstrate clear superiority in reducing the risk of VTE compared with earlier generations of drugs. Better studies are needed to define the role of aspirin, if any, in VTE prophylaxis after a major orthopedic surgery. Better chemistry has definitely contributed to better clinical outcomes and improvement in quality of life by reducing the largely preventable short-term and long-term complications of VTE after hip arthroplasty, knee arthroplasty, and hip fracture surgery.
5.
6.
7.
8.
9.
References 1. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004;126:338S. 2. Gallus AS. Applying risk assessment models in orthopedic surgery: overview of our clinical experience. Blood Coagul Fibrinolysis 1999;10(Suppl 2):S53. 3. Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein thrombosis. Prospective longterm follow-up of 528 symptomatic patients. Haematologica 1997;82:423. 4. Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by
10.
11.
12.
peri-operative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988;318:1162. Harris WH, Salzman EW, Athansoulis C, et al. Comparison of warfarin, low-molecular weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement. J Bone Joint Surg Am 1974;56:1552. Colwell CW, 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;81:932. Hull RD, Pineo GF. Heparin and low-molecularweight heparin therapy for venous thromboembolism: will unfractionated heparin survive? Semin Thromb Hemost 2004;30(Suppl 1):11. Turpie AGG, Bauer KA, Eriksson BI, et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopaedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest 2001;119:39S. Cohen AT, Skinner JA, Kakkar VV. Antiplatelet treatment for thromboprophylaxis: a step forward or backwards? BMJ 1994;309:1213. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) Trial. Lancet 2000;355:1295.