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Deep Vein Thrombosis—Concepts and Controversy

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The typical patient undergoing a joint replacement procedure is a woman in her mid-60s with hip pain that causes limping and limits physical activity. She has borderline diabetes and hypercholesterolemia, takes a statin drug, and receives hormone replacement therapy. Apparently weight bearing the day after surgery, she is discharged on day 3. A consideration for this patient is what prophylaxis against venous thromboembolism should be provided while she is still at risk of developing a clot after being discharged from the hospital.

When this hypothetical patient was presented to orthopedic specialists attending the American Academy of Orthopaedic Surgeons (AAOS) 2007 symposium, 76% of respondents selected low-molecular-weight heparin (LMWH) (36% for a 14-day regimen and 40% for a 28-day regimen). Approximately 18% of specialists reported a preference for a 14-day regimen of warfarin with an International Normalized Ratio (INR) of 2 to 2.5.

Effective venous thromboembolism (VTE) prophylaxis is an important consideration for any patient undergoing hip or knee replacement surgery. Postoperative venous thromboembolic disease, including proximal or distal blood clots, chronic pulmonary hypertension, or postthrombotic syndrome is a significant complication associated with total hip arthroplasty (THA) and total knee arthroplasty (TKA) that can occur in otherwise healthy patients even after successful surgery (Table).¹

Selecting VTE Prophylactic Therapy

Ideally, VTE prophylaxis should be efficacious, cost-effective, and easy to administer and monitor, with few side effects. Although significant advances have been made toward reaching these therapeutic objectives, the ideal prophylactic agent has yet to be discovered. Among those most widely used is the vitamin K antagonist, warfarin, and fractionated heparins, also known as LMWHs.

Given at a low dose, warfarin has a narrow therapeutic range. Generally administered on the day of surgery, low-dose warfarin requires extremely careful monitoring. As many as 80% of patients taking warfarin are discharged with an INR between 2 and 3. However, this value can increase significantly when patients resume their normal diets. This often necessitates dosage adjustments to prevent either INR decrease, which can increase the risk of VTE, or INR increase, which can increase the risk of bleeding.

Fractionated LMWHs are not identical—an agent with a shorter half-life has the advantage of achieving a more rapid systemic effect, while also reducing platelet activity that can help decrease the associated bleeding profile. A comparative study of enoxaparin versus warfarin has reported the superiority of LMWHs in reducing the relative risk of developing a thrombosis.² However, there was a widespread perception of a bleeding problem after LMWH administration associated with use of Lovenox, the first LMWH approved for use in the United States. According to the data, there was an increase in major bleeding, but this does not translate into important clinical events.³ Nevertheless, this has led to hesitance among some surgeons to prescribe these agents as routine thromboprophylaxis after hip or knee replacement procedures. Unfortunately, there are many cases of bleeding, not all related to the prophylaxis used.

Bleeding Management

A significant limitation in managing a perceived bleeding problem is the absence of a standard definition of bleeding. This has made it difficult for clinicians to accurately assess the actual bleeding risk with the use of varying anticoagulants. For example, the typical appearance of the postsurgical leg may be mistaken for a leg with anticoagulant-related bleeding. However, bleeding is a multifactorial function that may be impacted by factors such as inappropriate anticoagulation dosage and/or timing after closure; use of other medications, eg, ketorolac-associated platelet-inhibiting activity; specific surgical technique used; and watertight wound- closure procedures.

Appropriate LMWH dosing will often prevent the development of bleeding complications. Other techniques should also be used routinely to effectively manage bleeding during all phases of the surgical procedure.

Preoperative Techniques

Discontinue administration of supplements, anti-inflammatory agents, and clopidogrel before surgery so the agents are cleared and platelet production has normalized.⁴ This helps ensure proper clotting during the immediate postoperative period.

Intraoperative Techniques

Institute optimal surgical technique and achieve hemostasis (eg, inject lidocaine and epinephrine along the arthrotomy site, into the fat pad) to enable patients to better tolerate the anticoagulation therapy that accompanies the surgical procedure.

Postoperative Techniques

Use the appropriate drain. Experience has shown that decreasing bleeding that may otherwise occur during TKA can dramatically improve the appearance of the knee and, ultimately, the surgical outcome.

Other Prophylactic Treatment Approaches

Aspirin

Substantial clinical evidence reported over the past 3 decades has documented that aspirin, or acetylsalicylic acid, is no more effective than standard warfarin in preventing deep venous thrombosis (DVT).⁵ Nonetheless, recent study results support this prophylactic approach.^5,6

Although interest in aspirin use has grown within the orthopedic community, it should be noted that the incidence of DVT in aspirin-treated patients ranges from 55% to 79%.⁵

One argument often used in support of aspirin use is the absence of scientific evidence of an increased rate of fatal PE in patients treated with aspirin compared with other therapeutic agents. However, given the low (0.1%) frequency of PE in patients who have not received DVT prophylaxis, it is not surprising that no significant difference in fatal PE incidence is readily apparent.

Thus, from the data, it can be reasonably concluded that aspirin and warfarin are equally ineffective in preventing thrombosis and are associated with DVT rates comparable with those seen in untreated patients.^7-10

Compression Devices

As with LMWHs, sequential compression devices vary widely in prophylactic effectiveness. Some of these devices are associated with a higher peak velocity flow, and some lower. Conclusions from Westrich and colleagues indicate that sequential compression devices must be used for 19.2 ± 5.1 hours per day to be effective, with sharply reduced efficacy observed when daily use time was below 15.6 hours.¹¹

It is unlikely that sequential compression devices will be used for sufficient periods beyond the first postoperative day. This supports the use of a “stacked modality” approach to treatment, beginning with a sequential compression device and then initiating pharmacotherapy 18 to 24 hours after surgery. It is also important to note that with earlier hospital discharge, eg, 3 to 5 days postoperatively, patients will have no access to compression device treatment at home.

7th ACCP Conference on Antithrombotic and Thrombolytic Therapy

Guidelines

In 2004, the American College of Chest Physicians convened a panel on DVT prevention with substantial representation and input from the orthopedics community. The panel members reviewed a range of well-designed, English-language venographic studies to formulate their recommendations.⁵

The ACCP panel concluded that patients undergoing elective THA or TKA should receive either LMWH (grade 1A), fondaparinux (grade 1A), or a vitamin K antagonist to a target INR of 2 to 2.5 (grade 1A). For patients undergoing hip fracture surgery, the ACCP panel recommended fondaparinux (grade 1A), LMWH (grade 1C+), a vitamin K antagonist to a target INR of 2.5 (grade 2B), or low-dose unfractionated heparin (grade 1B). The recommended duration of thromboprophylaxis is at least 10 days for TKA, extended to 28 to 35 days for higher-risk patients undergoing THA or hip fracture surgery.

A randomized, double-blind, placebo-controlled study examined the effect of extended (21 day) prophylaxis on DVT in patients who had a THA or TKA.¹² The investigators reported that in 435 patients undergoing THA, LMWH, 40 mg daily, reduced the incidence of DVT determined by venography to 8%, compared with 23% for placebo (P<.001). Proximal clots occurred in 13% of the placebo group vs 3% of the LMWH group (P<.001). However, in 438 patients undergoing TKA, the rate of DVT did not differ significantly between the placebo and LMWH groups (21% and 17.5%, respectively). These findings provide additional support for the ACCP guidelines relative to the duration of treatment, although the decision to extend prophylactic therapy will depend on the individual patient’s risk factors as well as on the ability of anticoagulation to reduce the risk (Figure).

The Future of DVT Prophylaxis

Many orthopedists were anticipating the approval of ximelagatran, an oral direct thrombin inhibitor, and were surprised when the FDA denied approval owing to risk for liver toxicities and cardiac events. Despite this setback, there are several new oral agents in phase 3 trials that look promising—direct Factor Xa inhibitors (DFa) and another direct thrombin inhibitor. These agents can be distinguished by how they affect clotting factors. Direct thrombin inhibitors directly inhibit thrombin, whereas Direct Factor Xa inhibitors do not directly inhibit thrombin or Factor IIa, which is essential for hemostasis. Direct Factor Xa agents also provide the benefits of oral administration without requiring routine monitoring.

Representative of these pharmacologic agents is rivaroxaban, a Direct Factor Xa inhibitor with once-daily oral administration currently in phase 3 studies for patients undergoing THA or TKA. Rivaroxaban requires no monitoring, is highly bioavailable, and has a rapid onset of action, achieving high plasma concentrations within 3 to 4 hours after oral dosing with no evidence of accumulation. Its short half-life of 5 to 9 hours ensures that the drug is rapidly eliminated from the system after discontinuation of dosing.

In phase 2 studies, rivaroxaban showed similar efficacy to enoxaparin at a dose of 5 mg twice daily and 10 mg once daily, with a comparable safety profile and predictable pharmacokinetics.¹³ Recruitment of more than 11,000 patients for phase 3 studies is underway.

The future availability of targeted pharmacologic agents will enable more effective DVT prophylaxis after total joint replacement surgery. This will permit the orthopedic community to improve the care of patients who undergo these common surgical procedures and help hospitals meet the regulatory initiatives designed to ensure the provision of effective DVT prophylaxis.

References

1. 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-400S.
2. Fitzgerald RH, Spiro TE, Trowbridge AA, et al. Enoxaparin vs. warfarin prophylaxis after total knee replacement. J Bone Joint Surg Am. 2001; 83A:900-906.
3. 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: 932– 940.
4. Adusumilli PS, Ben-Portat L, Pereira M, Roesler D, Leitman IM. The prevalence and predictors of herbal medicine use in surgical patients. J Am Coll Surg. 2004; 198(4):583-590.
5. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001; 119:132S-175S.
6. Larson CM, MacMillan DP, Lachiewicz PF. Thromboembolism after total knee arthroplasty: intermittent pneumatic compression and aspirin prophylaxis. J South Orthop Assoc. 2001; 10(3):155-163.
7. Lotke PA, Ecker ML, Alavi A, Berkowitz H. Indications for the treatment of deep venous thrombosis following total knee replacement. J Bone Joint Surg Am. 1984; 66(2):202-208.
8. Haas SB, Insall JN, Scuderi GR, Windsor RE, Ghelman B. Pneumatic sequential-compression boots compared with aspirin prophylaxis of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg Am. 1990; 72(1):27-31.
9. Haas SB, Tribus CB, Insall JN, Becker MW, Windsor RE. The significance of calf thrombi after total knee arthroplasty. J Bone Joint Surg Br. 1992; 74(6):799-802.
10. Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone. J Bone Joint Surg Am. 1996; 78(6):826-834.
11. Westrich GH, Specht LM, Sharrock NE, et al. Venous haemodynamics after total knee arthroplasty: evaluation of active dorsal to plantar flexion and several mechanical compression devices. J Bone Joint Surg Br. 1998; 80(6):1057-1066.
12. Comp PC, Spiro TE, Friedman RJ, et al; Enoxaparin Clinical Trial Group. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am. 2001; 83-A(3):336-345.
13. Eriksson BI, Borris LC, Dahl OE, et al; ODIXa-HIP Study Investigators. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006; 114(22):2374-2381.

Author

Dr Cushner is director of the Insall Scott Kelly Institute, chief of the Department of Orthopedic Surgery in Southside Hospital, and assistant clinical professor at the Albert Einstein College of Medicine, New York, New York.

Dr Cushner is a consultant for Zimmer, Sanofi-Aventis, and Scios Inc. Dr Cushner is a speaker for ConMed.