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A correction has been published: N Engl J Med 2002;346(5):388.

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Volume 345:1298-1304 November 1, 2001 Number 18
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Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Hip-Fracture Surgery
Bengt I. Eriksson, M.D., Kenneth A. Bauer, M.D., Michael R. Lassen, M.D., Alexander G.G. Turpie, F.R.C.P., for the Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study

 

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ABSTRACT

Background Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.

Methods In a double-blind study, we randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was six weeks.

Results The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding.

Conclusions In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and was equally safe.

Patients undergoing surgery for hip fracture are in the highest category of risk for postoperative venous thromboembolism.1,2 Fatal pulmonary embolism occurs in 3.6 to 12.9 percent of patients who have not received prophylaxis against thromboembolism.1 There are few data on thromboprophylaxis after surgery for hip fracture, and recommendations are based mainly on expert opinion.1 Even with current methods of thromboprophylaxis, the incidence of venographically confirmed deep-vein thrombosis is 24 to 34 percent.1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21

Fondaparinux is a new synthetic pentasaccharide that causes selective inhibition of activated factor X (factor Xa).22,23,24,25 A recent study of patients undergoing major orthopedic procedures suggested that a once-daily subcutaneous injection of fondaparinux reduces the risk of venous thromboembolism more than does low-molecular-weight heparin.26

We conducted a multicenter, randomized, double-blind trial to compare two types of thromboprophylaxis after hip-fracture surgery: a once-daily subcutaneous injection of fondaparinux, initiated postoperatively, and a once-daily subcutaneous injection of enoxaparin, initiated preoperatively.

Methods

Patients

Patients were considered for inclusion if they were at least 18 years of age and were scheduled to undergo standard surgery for fracture of the upper third of the femur, including the femoral head and neck, within 48 hours after admission.

The main reasons for exclusion were multiple trauma affecting more than one organ system; an interval of more than 24 hours between the injury and hospital admission; pregnancy; active bleeding; a documented congenital or acquired bleeding disorder; current ulcerative or angiodysplastic gastrointestinal disease; a history of hemorrhagic stroke or brain, spinal, or ophthalmologic surgery within the previous three months; planned use of an indwelling intrathecal or epidural catheter for more than six hours after surgery; hypersensitivity to heparin, low-molecular-weight heparins, porcine products, or iodinated contrast medium; a contraindication to anticoagulant therapy; a current addictive disorder; a serum creatinine concentration above 2 mg per deciliter (177 µmol per liter) in a well-hydrated patient; and a platelet count below 100,000 per cubic millimeter. Patients who required anticoagulant therapy or received dextran or any type of anticoagulant or fibrinolytic therapy from admission to the time of first administration of the study drug or surgery were also excluded.

Study Design

Within 24 hours after admission and before surgery, patients were randomly assigned to treatment groups in blocks of four, with stratification according to center, with the use of a computer-generated randomization list. Patients were assigned to receive once-daily subcutaneous injections of either 2.5 mg of fondaparinux (Arixtra, Sanofi–Synthelabo, Paris, and NV Organon, Oss, the Netherlands) and a placebo or 40 mg of enoxaparin (Clexane/Lovenox, Aventis Pharmaceuticals, Bridgewater, N.J.) and a placebo. In the enoxaparin group, the first active dose was given 12±2 hours preoperatively and the second 12 to 24 hours postoperatively, according to the recommendation of the manufacturer. Since fondaparinux is a new compound, which differs from enoxaparin in its mechanism of action and pharmacokinetic properties, the starting time after surgery and the dose were determined during the early development of the drug26; the first dose of fondaparinux was administered 6±2 hours postoperatively and the second 12 hours or more after the first. However, if surgery was delayed until 24 to 48 hours after admission, administration of fondaparinux was initiated 12±2 hours before surgery. In both groups, omission of preoperative injections was recommended if spinal or epidural anesthesia or catheterization was planned, and any indwelling intrathecal or epidural catheter was to be removed at least two hours before the first postoperative injection.

Day 1 was defined as the day of surgery. Treatment was scheduled to continue until day 5 to day 9, and the primary efficacy outcome was assessed between day 5 and day 11. Patients were then followed up in person, by mail, or by telephone between day 35 and day 49. During follow-up, patients were instructed to report any symptoms or signs of venous thromboembolism or bleeding and any other clinical event occurring since the completion of treatment. Investigators could extend prophylaxis during follow-up with any currently available therapy, but only after venography had been performed. If venous thromboembolism occurred during the study, treatment was left to the discretion of the investigators.

The study was conducted according to the ethical principles stated in the Declaration of Helsinki and local regulations. The protocol was approved by independent ethics committees, and written informed consent was obtained from all patients before randomization.

Medications

Study medications were packaged in boxes of identical appearance, each containing 10 prefilled, single-dose syringes of active treatment and 10 prefilled, single-dose syringes of matching placebos. Each syringe contained either 2.5 mg of fondaparinux sodium in 0.25 ml of water for injectable preparations (a concentration of 10 mg per milliliter), 40 mg of enoxaparin sodium in 0.4 ml of water for injectable preparations (a concentration of 100 mg per milliliter), or placebo (0.25 or 0.4 ml of isotonic saline).

Throughout the treatment period, the use of intermittent pneumatic compression, dextran, and thrombolytic, anticoagulant, or antiplatelet agents was prohibited. Centers were advised to avoid giving patients aspirin or nonsteroidal antiinflammatory drugs whenever possible. The use of graduated compression stockings and physiotherapy was recommended.

Outcome Measures

The primary efficacy outcome was assessed by the rate of venous thromboembolism (defined as deep-vein thrombosis, pulmonary embolism, or both) up to day 11. Secondary efficacy outcomes were total, proximal, or distal deep-vein thrombosis or symptomatic venous thromboembolism up to day 11 and symptomatic venous thromboembolism up to day 49. Patients were examined for deep-vein thrombosis by systematic bilateral ascending venography of the legs27 between day 5 and day 11, but no more than two days after the last dose of study drug, or earlier if thrombosis was clinically suspected. Symptomatic pulmonary embolism was confirmed by a lung scan indicating a high probability of pulmonary embolism, by pulmonary angiography,28 by helical computed tomography, or at autopsy.

The primary safety outcome was the incidence of major bleeding, which included fatal bleeding; bleeding that was retroperitoneal, intracranial, or intraspinal or that involved any other critical organ; bleeding leading to reoperation; and overt bleeding with a bleeding index of 2 or more. The bleeding index was calculated as the number of units of packed red cells or whole blood transfused plus the hemoglobin values before the bleeding episode minus the hemoglobin values after the episode (in grams per deciliter). Secondary safety outcomes were death, minor bleeding, a need for transfusion, thrombocytopenia, and any other adverse event. Minor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding.

Efficacy and safety outcomes were adjudicated by a central independent committee whose members were unaware of the treatment assignments and included review of all venograms and reports of bleeding and death.

Statistical Analysis

Assuming an incidence of venous thromboembolism by day 11 of 22 percent in the enoxaparin group7 and a risk reduction of about 30 percent (i.e., an incidence of 15 percent in the fondaparinux group), 600 patients were needed per group to provide the study with a power of 85 percent. The target number of recruited patients was 1700, a number that allowed for failure to obtain primary efficacy data in approximately 30 percent of patients.

The analysis of the primary efficacy outcome included data on all patients who had received at least one dose of study medication, had undergone the appropriate surgery, and had had an adequate assessment for venous thromboembolism by day 11. The analysis of safety included data on patients who had received at least one dose of study medication.

A two-tailed P value of less than 0.05 was considered to indicate statistical significance. The analysis of the primary efficacy outcome was performed with the use of a two-sided Fisher's exact test. Exact 95 percent confidence intervals for the absolute difference between fondaparinux and enoxaparin and the risk ratio were calculated. The treatment effect was also analyzed according to predefined categorical covariates with use of a logistic-regression model.

The study was supervised by a steering committee of 10 people, which included 6 representatives of the sponsor (Sanofi–Synthelabo and NV Organon). The committee designed the study, interpreted the data, and wrote the article. The final statistical analysis was performed by the sponsor. The central adjudication committee and the data-monitoring committee operated independently of the sponsor. One planned interim analysis was conducted when half the projected patient population had been enrolled, for reestimation of the sample size, since the rate of venous thromboembolism in patients undergoing hip-fracture surgery was uncertain. Simulations demonstrated that the predefined procedure did not inflate the type I error. No change in the sample size was found to be necessary, and the study continued as planned.

Results

Study Population

Between November 1998 and October 1999, 1711 patients were enrolled in 99 centers in 21 countries (listed in the Appendix). Thirty-eight patients did not receive either study drug (Table 1). Two patients did not undergo the appropriate surgery, and primary efficacy had not been assessed by day 11 in 421 patients. Thus, 1250 patients (73.1 percent) were included in the primary efficacy analysis, a percentage in line with other large multicenter studies that used venography after orthopedic surgery.29,30,31 The characteristics of patients excluded from the primary efficacy analysis did not differ from those of patients included in the analysis (data not shown).

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  		Table 1. Patients Included in the Analyses and Reasons for Exclusion.

 
Base-line characteristics did not differ significantly between the two groups of patients included in the analysis of safety (Table 2) or primary efficacy (data not shown). A total of 551 and 569 patients underwent surgery within 24 hours after admission in the fondaparinux and enoxaparin groups, respectively. Among the 626 patients in the fondaparinux group who were included in the primary efficacy analysis, fondaparinux was given preoperatively to 68 (10.9 percent) because surgery was delayed until 24 to 48 hours after admission; enoxaparin was given postoperatively, rather than preoperatively, to 464 of 624 patients assigned to that drug (74.4 percent) because of very early surgery after admission or planned regional anesthesia. The median time between surgery and the assessment of primary efficacy was eight days in both groups; most patients were assessed between day 5 and day 11 as planned. The two groups did not differ significantly with regard to the last day of active treatment or the use of concomitant treatments up to day 11 (Table 3).

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  		Table 2. Base-Line Characteristics of the Patients.

 
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  		Table 3. Treatments Received during the Study Period by Patients Assessed for the Primary Efficacy Outcome.

 
Overall, 829 patients treated with fondaparinux and 840 patients treated with enoxaparin returned for the follow-up visit on day 49. The duration of follow-up was similar between the two groups. During follow-up of patients who did not receive treatment for an acute thromboembolic event, 58.5 percent of patients treated with fondaparinux and 55.8 percent of patients treated with enoxaparin received prolonged thromboprophylaxis, primarily with a preparation of heparin or a vitamin K antagonist, after the study treatment.

Incidence of Venous Thromboembolism

The incidence of venous thromboembolism by day 11 was 8.3 percent in the fondaparinux group (52 of 626 patients) and 19.1 percent in the enoxaparin group (119 of 624 patients). This was a decrease of 10.8 percentage points, or a relative reduction in risk of 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent; P<0.001) (Table 4). A similar result was found in sensitivity analyses when patients who had had no primary efficacy assessment by day 11 were included in the primary efficacy analysis (data not shown). The incidence of total, proximal, and distal-only deep-vein thrombosis was significantly lower in the fondaparinux group (P<0.001 for all three comparisons). The incidence of symptomatic venous thromboembolism was low (6.5 percent), with no difference between the two groups.

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  		Table 4. Incidence of Venous Thromboembolic Events by Day 11.

 
The superior efficacy of fondaparinux over enoxaparin was found when patients were grouped according to age, sex, body-mass index (the weight in kilograms divided by the square of the height in meters [<30 vs. >=30]), type of anesthesia (general, regional, or both), type of hip fracture (cervical, trochanteric, or subtrochanteric), type of surgery (implantation of half prosthesis, implantation of total prosthesis, or osteosynthesis), the use or nonuse of cement, or whether or not the patient had had previous venous thromboembolism (data not shown). The number of patients treated by participating physicians for a venous thromboembolic event by day 11 was significantly lower in the fondaparinux group (6.1 percent [43 of 702]) than in the enoxaparin group (11.7 percent [84 of 716], P<0.001).

By day 49, the incidence of symptomatic venous thromboembolism was similar in the fondaparinux group (2.0 percent [17 of 831 patients]) and the enoxaparin group (1.5 percent [13 of 840 patients]). Fatal pulmonary embolism occurred in 8 of 831 patients in the fondaparinux group and 7 of 840 patients in the enoxaparin group; nonfatal pulmonary embolism occurred in 3 of 831 patients and 4 of 840 patients, respectively.

Safety Outcomes

Major bleeding occurred by day 11 in 18 of 831 patients treated with fondaparinux and 19 of 842 patients treated with enoxaparin (P=1.00) (Table 5). Most of these episodes occurred at the surgical site (14 of 18 patients in the fondaparinux group and 14 of 19 patients in the enoxaparin group). Minor bleeding occurred more often in the fondaparinux group (P=0.02). By day 49, three patients in the fondaparinux group and six patients in the enoxaparin group underwent reoperation because of bleeding. Transfusion requirements and the incidence of other adverse events during treatment or follow-up did not differ significantly between groups. The platelet count was lower than 100,000 per cubic millimeter in 40 of 822 patients in the fondaparinux group (4.9 percent) and 44 of 831 patients in the enoxaparin group (5.3 percent). No episode of decreased platelet count was reported as a serious adverse event in either group. The incidence of wound infection was low and was the same in both groups (0.7 percent [6 of 831 in the fondaparinux group and 6 of 842 in the enoxaparin group]). By day 49, 38 patients in the fondaparinux group (4.6 percent) and 42 in the enoxaparin group (5.0 percent) had died.

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  		Table 5. Safety Outcomes.

 
Discussion

This large study demonstrates that fondaparinux is significantly more effective than enoxaparin in preventing postoperative venous thromboembolism after surgery for hip fracture. The 19.1 percent incidence of venous thromboembolism in the enoxaparin group by day 11 is consistent with the results of previous studies of enoxaparin after hip-fracture surgery.7,8,9,10 By contrast, 8.3 percent of patients given fondaparinux had postoperative venous thromboembolism. Moreover, proximal deep-vein thrombosis, which is prone to embolize, occurred in 6 of 650 patients in the fondaparinux group and 28 of 646 patients in the enoxaparin group (P<0.001).32,33,34 Three other large studies in patients undergoing elective knee35 or hip-replacement36,37 surgery also showed the superiority of fondaparinux over enoxaparin in preventing venous thromboembolism. The efficacy of fondaparinux may be attributed to its ability to inhibit factor Xa rapidly and selectively, its predictable linear pharmacokinetics, and its relatively long half-life, which permits the drug to achieve an antithrombotic effect for 24 hours.

Physicians have been uncertain about effective and safe thromboprophylaxis after hip-fracture surgery.1,2 Warfarin is moderately effective,1,15,16,17,18,19 and aspirin is not recommended in patients undergoing such surgery.1,20,38,39 Promising results have been reported in small studies of 40 mg of enoxaparin administered once daily, with treatment initiated preoperatively.7,8,9,10 In our study, because of planned regional anesthesia, early surgery after admission, or both, only 25.6 percent of patients received the preoperative injection of enoxaparin. This indicates the difficulty of administering low-molecular-weight heparin preoperatively in emergency situations.

In our study, symptomatic events were rare during the treatment period, with a 0.2 percent incidence of fatal pulmonary embolism — similar to that reported in the large Pulmonary Embolism Prevention trial.20 However, the incidence of symptomatic events in our study should be interpreted with caution. Early detection by venographic screening and prolonged prophylaxis in nearly 60 percent of our patients probably prevented symptomatic venous thromboembolism. The incidence of fatal pulmonary embolism by day 49 was nevertheless nearly 1.0 percent in both groups. The duration of treatment may have been too short for some patients who were still at risk for venous thromboembolism when treatment was discontinued.

Our study demonstrates that prophylactic fondaparinux is more effective than enoxaparin in preventing venous thromboembolism in patients undergoing hip-fracture surgery and does not increase the risk of clinically relevant bleeding.

Supported by NV Organon and Sanofi–Synthelabo. All authors have served as consultants to NV Organon and Sanofi–Synthelabo.

Presented in abstract form at the 42nd Annual Meeting of the American Society of Hematology, San Francisco, December 1–5, 2000 (Blood 2000;9:490A, A2110).

* Participants in the study are listed in the Appendix.


Source Information

From the Department of Orthopedics, Sahlgrenska University Hospital–Östra, Göteborg, Sweden (B.I.E.); the Department of Medicine, Veterans Affairs Boston Healthcare System and Beth Israel Deaconess Medical Center, Boston (K.A.B.); the Department of Orthopedics, Hillerød University, Hillerød, Denmark (M.R.L.); and the Department of Medicine, Hamilton Health Sciences Corporation–General Division, Hamilton, Ont., Canada (A.G.G.T.).

Address reprint requests to Dr. Eriksson at the Orthopedics Department, Sahlgrenska University Hospital–Östra, S-41685 Göteborg, Sweden, or at b.eriksson{at}orthop.gu.se.

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Appendix

The members of the Pentasaccharide in Hip-Fracture Surgery Study Group were as follows: Steering Committee — A.G.G. Turpie (chair), K.A. Bauer, J. Bouthier, R.G. Cariou, J.F.M. Egberts, B.I. Eriksson, J.A. Hoek, M.R. Lassen, A.W.A. Lensing, H. Magnani; Data Monitoring Committee — D. Bergqvist, G.D. Paiement, A. Planes; Central Independent Adjudication Committee — M. Gent (chair), J.S. Ginsberg, J. Hirsh, C. Kearon, M.N. Levine, J.G. Thomson, A.G.G. Turpie, J. Weitz; Independent Statistical Center — A. Leizorovicz, Lyons, France; Sponsor, Sanofi–Synthelabo Recherche, France — Study Management: R.G. Cariou; Monitoring Coordination: M. Blanchard, A. Denys, A. Pelizza, M.C. Pujol; Statistical Analysis: M. Fournier; Data Management: D. Marin, C. Thetiot; Local Monitors and Clinical Research Associates: Argentina: C. Falcon, M. Rodriguez; Australia: N. Chapman, S. Tjia; Belgium: K. Handelberg, F. Cilli; Czech Republic: J. Nedvedova; France: S. Fontecave, M.J. Casellas, V. Vajou; Germany: M. Decker; Greece: N. Nikitas, V. Konstanta; Hungary: D. Pasztor, O. Fister; Italy: F. Ciffo; Poland: A. Lukasik; Portugal: P. Rebelo; Spain: G. Estrada, S. Guttierez; Sweden: U. Tael, A. Klebbe, A. Svard; Switzerland: S. Pilot, A Kullin; the Netherlands: L. Muller, L. Willemsen; United Kingdom: C. Philips; South Africa: C. Toerien; Investigators — Argentina (46 patients, 6 centers): G. Cardinali, J.M. Ceresetto, H.N. Hendler, L. Palmer, E.D. Ruberto, F.S. Silberman; Australia/New Zealand (222 patients, 9 centers): R. Baker, T. Brighton, J. Cade, B. Chong, A. Gallus, M. Holt, B. Richard, D. Zavataro, H.N. Salem, S. Williams; Austria (15 patients, 1 center): V. Vecsei; Belgium (80 patients, 8 centers): P. Broos, F. Burny, J. Colinet, G. De Brouckere, P. Haentjens, E. Spyropoulos, D. Uyttendaele, F. Van Elst; Czech Republic (212 patients, 7 centers): G. Berlinger, I. Kofranek, K. Koudela, Z. Krska, M. Sir, T. Trc, O. Vlach; Denmark (147 patients, 6 centers): L. Borris, E. Horlyck, M.R. Lassen, S. Mejdahl, J.O. Storm, C. Torholm; Finland (26 patients, 1 center): U. Vaatainen; France (109 patients, 9 centers): J. Barre, J.P. Clarac, J.P. Delagoutte, M. Delecroix, P. Mismetti, L. Pidhorz, J. Puget, P. Simon, J. Tabutin; Germany (53 patients, 3 centers): P. Rommens, M. Schurmann, M. Winkler; Greece (70 patients, 3 centers): J. Pournaras, N. Tiliakos, M. Tyllianakis; Hungary (68 patients, 3 centers): Z. Magyari, E. Santha, K. Szepesi; Italy (67 patients, 4 centers): O. Bruchi, G. Caroli, L. Tessari, V. Zaffarana, F. Poivella; Norway (50 patients, 2 centers): O. Dahl, H. Luhr, E. Mohr; Poland (50 patients, 4 centers): A. Gorecki, K. Kwiatkowski, K. Modrzewski, T. Niedzwiecki; Portugal (65 patients, 6 centers): N.J. Canha, J. Carvalho de Oliveira, J. De Morais Neves, A. Figueiredo, E. Mendes, A. Rodrigues Gomes; South Africa (26 patients, 4 centers): L. Bloem, C. Lombard, W. Prinsloo, R.B. Snowdowne; Spain (78 patients, 5 centers): F. Gomar, M. Monreal, A. Navarro, R. Ramon, C. Resines; Sweden (108 patients, 4 centers): B.I. Eriksson, P. Hansson, B. Malmqvist, J. Milbrink; Switzerland (67 patients, 2 centers): P. Hoffmeyer, P.F. Leyvraz; the Netherlands (100 patients, 10 centers): G.H.R. Albers, D.A. Dartee, W. De Graaf, W.F.M. Fievez, M. Iprenburg, R.K. Marti, J. Van Der Meer, P. Van de Sar, M. Van Marwijk Kooij, A.D. Verburg; United Kingdom (52 patients, 2 centers): A.T. Cohen.


 

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