Recent Advances in Venous Thromboembolic Prophylaxis in Major Orthopedic Surgery: A Regional Perspective

Abstract

Review ArticleRecent Advances in Venous Thromboembolic Prophylaxis in Major Orthopedic Surgery: A Regional Perspective Hikmat Abdel-RazeqMD Hikmat Abdel-Razeq Address reprint requests and correspondence to Dr. Abdel-Razeq: Department of Medicine, King Fahad Armed Forces Hospital, P.O. Box 9862, Jeddah 21159, Saudi Arabia. From the Department of Medicine, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia. Search for more papers by this author Published Online:1 Jan 2003https://doi.org/10.5144/0256-4947.2003.39SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionVenous thromboembolism (VTE) remains a common but preventable lethal complication following major orthopedic surgery. VTE prophylaxis has witnessed major advances in recent years. Low molecular weight heparin (LMWH) has become the agent of choice in major orthopedic procedures as elective total hip replacement (THR), hip fracture surgery and total knee replacement (TKR). Despite this, there is still some hesitation among local physicians in using MWH since it originates from pork. More recently, the issue of extended out-of-hospital prophylaxis has come up for considerable debate. Now it is widely accepted that the incidence of VTE will be lowered considerably if prophylaxis is extended to about four weeks after the procedure. Efforts to find the ideal antithrombotic agent continued, and pentasaccharides have been introduced as a prophylactic agent for patients undergoing high-risk orthopedic procedures. Multiple studies have shown promise in the superiority of these agents compared to the existing LMWH. One other major advantage of this in our local community is the fact that pentasaccharides are totally synthetic and lack any animal derivatives. In this review, we address the need and the duration for prophylactic therapy and the integration of these new antithrombotic agents in orthopedic surgery.THE RATIONALEVTE is a major health problem worldwide, and pulmonary embolism (PE) is the most feared complication. One study showed that more than 50% of patients who die of PE did not receive prophylaxis despite having major risk factors and absence of contraindications to antithrombotic agents.1 Despite overwhelming evidence of the efficacy of prophylaxis, many survey studies document wide practice variations.2-5 Some studies show that only one-third of high-risk patients receive prophylaxis,6 and that of those who do receive prophylaxis, one-third do not get the appropriate antithrombotic agent.7Orthopedic surgery carries a high risk of VTE. Total hip and knee replacements as well as hip fracture surgeries are among the highest risk procedures. In the absence of prophylaxis, the incidence of venography-proven VTE exceeds 50%.8-12 The incidence of symptomatic VTE is far less.13-15 While the majority of the thrombi detected by venography are asymptomatic and will resolve without treatment, venography remains a credible outcome measure for comparing the efficacy of different prophylactic regimens.16 Also, unrecognized and untreated deep vein thrombosis (DVT) may lead to a long-term morbidity from the postphlebotic syndrome and may predispose patients to future episodes of recurrent VTE.17,18DURATION OF ANTICOAGULATIONIn a recent retrospective cohort study of 19,586 California Medicare patients undergoing THR and 24,059 patients undergoing TKR, the diagnosis of VTE was made after discharge in 76% of THR and 47% of TKR cases. The median time to diagnosis was 17 days for THR and 7 days for TKR.19 This shows that limiting prophylaxis for the inpatient duration is clearly not enough, especially with recent advances in medical care with emphasis on shorter hospital stay.Many studies have addressed the issue of out-of-hospital prophylaxis. In most of these studies, the incidence of venography-proven DVT was reduced by 50%.20-24 In a recent meta-analysis of randomized clinical trials, Cohen et al. showed that the incidence of symptomatic VTE was decreased by 50% following extended out-of-hospital prophylaxis.25PRE-OPERATIVE VS. POSTOPERATIVE PROPHYLAXISThe timing of the first dose of LMWH prophylaxis differs among practitioners. In North America, LMWH is usually given 12-24 hours postoperatively, while in Europe, the first dose is usually given 12 hours prior to surgery. While this issue is still controversial, Hull et al.26 in a metaanalysis showed that preoperative administration of LMWH was more effective than the postoperative approach. This same group addressed this issue in another prospective study in which patients undergoing elective THR were randomized to three groups: one group received Warfarin while the other two received LMWH (Dalteparin) either before or after surgery. Based on pre-discharge venography, the total and proximal DVT rates were similar among the two LMWH groups, however, preoperative LMWH caused non significant trend toward more bleeding.24,27LMWH AND THE RISK OF SPINAL HEMATOMAIn December 1997, the FDA called attention to safety reports describing 43 patients who developed epidural, or spinal hematoma, or bleeding after receiving Enoxaparin.28 Regional anesthesia should be avoided in patients at high risk for bleeding, and the insertion of spinal needle should be delayed for 10-12 hours after the initial LMWH injection. The whole regional anesthesia should be aborted if the aspirate was a bloody one.THE SOURCEAll LMWH originate from pork, a fact which has resulted in delayed application of these products in our daily practice. Despite multiple randomized studies showing superior efficacy compared to unfractionated heparin, some local physicians are still reluctant to prescribe them.PENTASACCHARIDESFondaparinux (AriXtra, Sanofi-Synthelab, France) is the first agent of a new class of selective factor Xa inhibitors (pentasaccharides). This new synthetic compound with no animal-sourced components, has been designed to bind selectively to a single target in the plasma, Antithrombin III, which inactivates factor Xa, thus resulting in strong inhibition of thrombin generation and clot formation.29,30Figure 1 (Figure 1. Mechanism of action for Fondaparinux. Fondaparinux {1} binds with high affinity to its binding site on antithrombin (AT). This results in {2} irreversible conformational changes, which, {3} enables it to bind and inhibit activated factor X (Xa), which is needed to activate factor 11 (prothrombin) to thrombin.) shows the site and mechanism of action of pentasaccharides.Figure 1. Mechanism of action for Fondaparinux. Fondaparinux {1} binds with high affinity to its binding site on antithrombin (AT). This results in {2} irreversible conformational changes, which, {3} enables it to bind and inhibit activated factor X (Xa), which is needed to activate factor II (prothrombin) to thrombin.Download FigureThe results of a large phase II dose-finding study suggested that a once-daily subcutaneous injection of 2.5 mg of Fondaparinux started postoperatively had the potential to significantly decrease the incidence of VTE in patients undergoing major orthopedic surgery.31 In four multi-center, randomized, double-blinded clinical trials in patients undergoing major orthopedic surgery,32-35 Fondaparinux was given at a dose of 2.5 mg sub-cutaneously once a day. The first dose was started 4-8 hours postoperatively, and the second dose was given at least 12 hours after the first one, but not more than 24 hours after the surgical procedure. In all four studies, the primary assessment for efficacy was based on a mandatory bilateral venography of the legs between day 5 and 11 or earlier if thrombosis was clinically suspected.In patients undergoing hip fracture surgery or elective total hip replacement, PENTHIFRA32 and EPHESUS33, studies respectively, Fondaparinux at the above dose and schedule was compared to 40 mg of Enoxaparin once daily, started 12 hours preoperatively; a regimen widely used in Europe. While in PENTAMAKS34 (major knee surgery) and PENTATHALON 200035 (elective THR) studies, Fondaparinux was compared to Enoxaparin given at 30 mg twice daily, started 12 hours postoperatively; a regimen commonly used in North America. The results of the individual studies are shown in Figure 2.Figure 2. Primary efficacy results: reduction in VTE rate.Download FigureIn a meta-analysis of the four studies with a total of 7344 randomized patients in more than 300 centers worldwide, the superior efficacy of Fondaparinux over Enoxaparin was demonstrated in all types of surgery (Table 1), with a reduction of 61.6%, 63.1% and 45.3% in hip fracture, major knee, and hip replacement surgery respectively (Figure 3). The superior efficacy of Fondaparinux over Enoxaparin was achieved without significant increase in the risk of bleeding.37Table 2 shows the difference in bleeding in both agents.Table 1. Efficacy outcomes.Table 1. Efficacy outcomes.Figure 3. Fondaparinux’s superior efficacy over Enoxaparin in all orthopedic indications (modified with permission from: Turpie et al.).Download FigureTable 2. Safety outcomes in orthopedic studies.Table 2. Safety outcomes in orthopedic studies.These promising results encouraged investigators to further investigate the efficacy and safety of the pentasaccharide Fondaparinux in extended out-of-hospital prophylaxis (PENTATHALON 2000 Plus Study). The initial presentation of the results were outstanding. Using venography as an end-point, the incidence of VTE was reduced from 35% to 1.4%, while clinically detected VTE was reduced from 2.7% to 0.3% (data presented at the 12th World Congress of the International Society of Orthopedic Surgery and Traumatology in San Diego, USA, August 2002).Ongoing multiple studies are currently testing pentasaccharides in other therapeutic and prophylactic indications. The PENTALYSE study is testing the use of pentasaccharides in acute myocardial infarction, while the PENTUA study is testing it in unstable angina. 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