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Healio
August 01, 2003
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Improvements in the Prevention of Postoperative Venous Thromboembolism in Hip Fracture Patients

ABSTRACT

Bengt I. Eriksson, MD [photo]Bengt I. Eriksson, MD

Hip fracture surgery carries a high risk of venous thromboembolism and, until recently, was poorly investigated. The efficacy and safety of fondaparinux, a new synthetic antithrombotic, were investigated in two large, thromboprophylaxis studies. Results of the Penthifra study, which was a randomized, double-blind phase III trial, showed that 1 week of fondaparinux, compared with enoxaparin, significantly reduced venous thromboembolic events from 19.1% to 8.3% (relative risk reduction: 56.4%; P<.001) without increasing bleeding risk. Penthifra Plus results showed that extending fondaparinux prophylaxis from 1 to 4 weeks was well tolerated and, compared to placebo, significantly reduced delayed venous thromboembolism events from 35% to 1.4% (relative risk reduction: 95.9%; P<.001). Based on these findings, 4-week fondaparinux treatment may become the standard thromboprophylaxis after hip fracture surgery.




Hip fracture is an increasing public health and economic burden in industrialized countries.1-4 The lifetime risk of hip fracture is about 18% in women and 6% in men5 and its incidence is between 70 and 120 per 100,000 people.4,6 The incidence of hip fracture increases exponentially with age, 90% occurring in patients >50 years old.6,7 Hip fracture occurs in as many as 438 per 100,000 people aged >50 years,7 and 1260 per 100,000 women aged >85 years.5 With the aging of the world’s population, the annual number of hip fractures is projected to double or triple by 2030 to 2040.6,7 For unknown reasons, the age-adjusted incidence of hip fracture is also increasing.7

Hip fracture is a serious event that leads to an overall 12%-20% reduction in life expectancy.7 The mortality rate 1 year after hip fracture ranges from 12% to 35%, with most deaths related to hip fracture occurring within the first year after fracture.8

Venous Thromboembolism

The majority of hip fractures are treated surgically. Hip fracture surgery is a high-risk procedure, and the postoperative complications are more severe than those observed after other types of major orthopedic surgery. In a recent randomized study of 887 patients undergoing lower limb joint arthroplasty, the mortality rate at 6 months postoperatively in the femoral neck fracture group was 14.8%, compared with only 1% and 1.3% respectively for the patients undergoing total hip replacement (THR) or total knee replacement.9

A major postoperative complication is venous thromboembolism. Patients undergoing hip fracture surgery are classified in the highest risk category for venous thromboembolism.10,11 Without thromboprophylaxis, the prevalence of total deep vein thrombosis (DVT) after hip fracture surgery ranges from 36% to 60%. The fatality rates of pulmonary embolism are particularly high, occurring in 3.6%-12.9% of unprotected patients.10

In a population-based autopsy review of 581 patients who died after hip fracture between 1953 and 1992, pulmonary embolism was the third most common individual cause of death, following bronchopneumonia and heart failure/myocardial infarction. Death from pulmonary embolism peaked in the second week after injury and accounted for the majority of late deaths along with bronchopneumonia.12

The high incidence of postoperative venous thromboembolism may be associated with elderly patients with coexisting medical illnesses, prolonged immobilization, and vascular and bone lesions resulting in hypercoagulability.

The time of surgery following admission also appears to influence the rate of thrombotic complications, indicating that delayed surgery is associated with a higher incidence of venous thromboembolism, although co-morbidity might play a role.13,14 Likewise, regional anesthesia compared to general anesthesia seems to be associated with a lower incidence of DVT and mortality.5,15

Efficacy of Current Thromboprophylaxis Methods

Due to the silent nature, high prevalence, and potentially life-threatening consequences of thromboembolic disease, the implementation of appropriate thromboprophylactic measures, including early mobilization,6 is essential.10,11 However, with currently available thromboprophylaxis methods such as intermittent pneumatic compression,16,17 low-dose unfractionated heparin,18-20 low-molecular-weight heparin,19-23 heparinoid,24-27 oral anticoagulant,28-32 and aspirin,33,34 the incidence of venographically proven DVT is between 24% and 34%.10 In addition, the most effective and safe treatment used in hip fracture surgery has been uncertain. Data on thromboprophylaxis in patients had been derived from a small number of randomized studies with few patients and methodologic weaknesses. Choice of the best agent was often based on experience from THR trials, which were larger.

Another important issue that had not been addressed in hip fracture surgery concerns the duration of thromboprophylaxis. In a number of surgical settings, thrombosis risk was shown to persist beyond the perioperative period.35-37 For example, after hip arthroplasty, the median time of occurrence of symptomatic thromboembolism is 17 days postoperatively38 and a thromboprophylaxis duration of 4 weeks is recommended.10 Moreover, biologic hypercoagulability lasts for at least 6 weeks postoperatively for proximal femoral fracture.39

Fondaparinux

Fondaparinux is the first of a new class of synthetic drugs acting through specific inhibition of factor Xa.40 Factor Xa inhibition is mediated via antithrombin and results in effective inhibition of thrombin generation.41 The efficacy and safety of fondaparinux in the prevention of venous thromboembolism after major orthopedic surgery were studied in six trials, including one dose-ranging phase II study and five randomized, double-blind phase III studies.42-47 These studies, which involved major orthopedic surgery settings, were conducted in approximately 9000 patients.

The dosing regimen of fondaparinux was similar in all of the phase III trials and was determined on the basis of results of the dose-ranging phase II study.42 A subcutaneous regimen of 2.5 mg of fondaparinux, once daily, starting 6 hours postoperatively, was used. Administration began postoperatively to improve convenience and safety when regional anesthesia was planned. Furthermore, the initiation of thromboprophylaxis can be postponed in the event of either excess bleeding during surgery or traumatic spinal/epidural anesthesia.

Postoperative initiation of thromboprophylaxis was made possible by the pharmacokinetics of fondaparinux, characterized by rapid and complete absorption.48

Two of the phase III studies (involving 2367 patients) specifically focused on hip fracture surgery. The double-blind Penthifra trial included 1711 patients and compared the efficacy and safety of 2.5 mg fondaparinux given postoperatively with 40 mg enoxaparin given preoperatively for 1 week.43 Fondaparinux was compared with a low-molecular-weight heparin because this class of compounds was considered the reference treatment.10

The Penthifra-Plus trial examined the benefit of extended-duration prophylaxis. After an initial 1-week prophylaxis with fondaparinux, the efficacy and safety of an additional 3 weeks of fondaparinux therapy were compared in double-blind manner with placebo in 737 patients.47 Fondaparinux was compared with placebo because no reliable data were available on the incidence of late-onset venous thromboembolism after 7 days of highly effective thromboprophylaxis, and no antithrombotic therapy administered for 1 month for the prevention of venous thromboembolism had been adequately tested in patients undergoing surgery for hip fracture.11

Penthifra and Penthifra-Plus trials included patients aged >18 years who underwent standard surgery for fracture of the upper third of the femur within 48 hours after admission. Patients were excluded if they had trauma affecting more than one organ system or if >24 hours had elapsed between the causative trauma and hospital admission. Other reasons for exclusion were planned indwelling intrathecal or epidural catheter for >6 hours postoperatively, contraindication to anticoagulant therapy, or serum creatinine concentration >2 mg/dL.

The primary efficacy endpoint was the incidence of venous thromboembolic events consisting of a composite of DVT detected by mandatory bilateral venography, documented symptomatic DVT, or pulmonary embolism.

Bilateral venography is the standard method for the evaluation of new antithrombotic drugs in patients undergoing major orthopedic procedures due to its accuracy and reliability for detecting DVT in asymptomatic patients.49,50 Moreover, bilateral venography is widely accepted as an appropriate surrogate for important clinical outcomes: meta-analyses of trials on prophylaxis of similar duration with low-molecular-weight heparin in elective joint replacement surgery have shown that, compared with placebo, reduction in venographically detected DVT and symptomatic venous thromboembolism were of the same order of magnitude.35,36,51,52

The main safety endpoint was major bleeding. Major bleeding was a composite of fatal bleeding, nonfatal bleeding in a critical organ, bleeding requiring reoperation, or overt bleeding with a bleeding index of >2. The bleeding index was calculated as the number of units of packed red blood cells or whole blood transfused in addition to the difference between pre- and postbleeding hemoglobin values in grams per deciliter. All efficacy and safety outcomes were adjudicated by a central independent committee, the members of which were unaware of the patients’ treatment assignment.

Table 1

Penthifra: Short-Term Thromboprophylaxis

A total of 1711 patients were randomized in 99 centers in 21 countries between November 1998 and October 1999 to receive fondaparinux or enoxaparin for 5-9 days postoperatively. Thirty-eight patients did not receive any study drug, leaving 1673 (97.8%) available for safety analysis. Baseline characteristics did not differ significantly between the two patient groups (Table 1). Patients aged 17-101 years and weighing 30-125 kg were included.

In the fondaparinux group, the first injection in the study occurred 6±2 hours postoperatively, and the second injection 12 hours later. In accordance with the protocol when surgery was delayed 24-48 hours after admission, fondaparinux was started 12±2 hours before surgery in 10.9% of patients.

Enoxaparin was given at the approved dose of 40 mg once daily. In accordance with the manufacturer’s recommendation, the first dose was given 12±2 hours preoperatively and the second dose 12-24 hours postoperatively. However, due to early surgery after admission and planned regional anesthesia, enoxaparin was given preoperatively in 25.6% of patients (160/624). This reflects usual clinical practice where it is difficult to administer antithrombotic agents preoperatively in emergency situations. The two groups did not differ in the median (range) number of treatment days up to the qualifying examination for venous thromboembolism: 7 (range: 1-11) and 7 (range: 1-10) days in the fondaparinux and enoxaparin groups, respectively.

Efficacy Outcomes

The primary efficacy outcome was assessed between days 5 and 11 postoperatively in 1250 patients (74.7%). Two patients did not undergo appropriate surgery and venography could not be performed and therefore was not evaluated in 421 patients (Table 2). Fondaparinux significantly reduced the incidence of venous thromboembolism (8.3%) compared with enoxaparin (19.1%) with a relative risk reduction of 56.4% (95% CI: 39%-70.3%, P<.001). The 19.1% incidence of venous thromboembolic events in the enoxaparin group is consistent with the 10.4%-21.6% range reported in previous studies with 40 mg enoxaparin in hip fracture surgery.20-23

The reduction included total, proximal, and distal-only DVT. The incidence of symptomatic venous thromboembolism was low, with no difference between groups. The efficacy of fondaparinux was influenced by the duration of its administration: the incidence of venous thromboembolism was higher in patients treated for <5 days (11.3%) than in patients treated for >5 days (7.9%). The optimal duration of thromboprophylaxis beyond 10 days postoperatively was further addressed in the Penthifra-Plus study.47

Overall, the superiority of fondaparinux over enoxaparin in terms of primary efficacy was consistent regardless of age, gender, body mass index (BMI) (above/below 30 kg/m2), type of anesthesia (general/regional only), hip fracture (cervical only/trochanteric/sub-trochanteric), surgery (half prosthesis/total prosthesis/osteosynthesis), or the use of cement.

Patient follow-up was conducted between days 35 and 49. Incidence of symptomatic venous thromboembolism by day 49 was comparable in the fondaparinux and enoxaparin groups, 2% (17/831) and 1.5% (13/840), respectively. The incidence of fatal pulmonary embolism was 1% (8/831) and 0.8% (7/840), and that of nonfatal pulmonary embolism was 0.4% (3/831) and 0.5% (4/840) in the fondaparinux and enoxaparin groups, respectively. However, the trials were not designed or powered to detect a difference in symptomatic events. In addition, two therapeutic interventions are likely to have prevented the subsequent occurrence of symptomatic events.

First, based on the local site assessment, the majority of patients with positive venography at screening received anticoagulant therapy in therapeutic doses. By day 11, fewer patients were being treated for a venous thromboembolic event in the fondaparinux (6.1%) than in the enoxaparin (11.7%) group (P<.0001). Second, during follow-up of patients who did not receive treatment for an acute thromboembolic event, 58.5% of fondaparinux-treated patients and 55.8% of enoxaparin-treated patients received prolonged thromboprophylaxis with any currently available therapy. It is also noteworthy that, overall, 22 of the 30 symptomatic venous thromboembolic events and 11 of the 15 fatal pulmonary embolism episodes occurred during follow-up between days 11 and 49, suggesting that the thrombogenic risk persists beyond the perioperative period.

Table 2

Safety Outcomes

Application of effective prophylaxis in patients undergoing hip fracture surgery is of particular concern due to the increased risk of bleeding in elderly patients with recent trauma.

Within the Penthifra trial, the risk of major bleeding by day 11 was low and did not differ between the two groups; 2.2% (18/831) in fondaparinux-treated patients and 2.3% (19/842) in enoxaparin-treated patients (P=1) (Table 2). One patient’s bleeding was fatal in the enoxaparin group and no critical organ bleeding occurred in either group. Three episodes of bleeding were associated with reoperation in the fondaparinux group and two episodes of bleeding in the enoxaparin group. Most major patient bleeding occurred at the surgical site; 14/18 patients in the fondaparinux group and 14/19 patients in the enoxaparin group. Minor bleedings occurred in 4.1% (34/831) of fondaparinux-treated patients and 2.1% (18/842) of enoxaparin-treated patients (P=.024).

A post-hoc analysis showed that the incidence of major bleeding was significantly lower when the first fondaparinux injection was given at >6 hours after skin closure (1.6%, 7/435) rather than earlier (2.8%, 11/396). In patients who received the first injection of fondaparinux at >6 hours after skin closure, the efficacy of the drug was maintained and the incidence of venous thromboembolism (7.6%, 25/328) was at least as low as that observed in patients who received this injection <6 hours after skin closure (9.1%, 27/298).

Similar findings were observed in other trials of fondaparinux in major orthopedic surgery.53 Based on these observations, health authorities recommend initiating fondaparinux treatment at least 6 hours postoperatively. Interestingly, the influence of the timing of the first administration of low-molecular-weight heparins relative to the surgical procedure on their benefit-to-risk ratio is still debated.54

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 any other adverse events during treatment or follow-up did not differ between groups. No episode of decreased platelet count was reported as a serious adverse event in either group. By day 49, the incidence of wound infection was low and similar in both groups (0.7%). A total of 38 (4.6%) patients in the fondaparinux and 42 (5%) patients in the enoxaparin group died.

Penthifra Plus, a Trial of Long-Term Thromboprophylaxis

A total of 737 patients were enrolled in 57 centers in 16 countries between June 2001 and February 2002 to receive fondaparinux or placebo. Both treatments were administered in double-blind manner for 3 weeks after initial 1-week prophylaxis with fondaparinux. Eighty-one patients were not randomized in the double-blind period due to, among other reasons, confirmed symptomatic venous thromboembolism in five patients and bleeding complications in eight patients. Thus, 656 patients met the selection criteria for randomization and constituted the safety population. Baseline characteristics did not differ significantly between the two groups of patients (Table 1). These characteristics were similar to those of patients included in the Penthifra trial.

The mean duration (±SD) of open-label fondaparinux prophylaxis was 7±0.8 days for patients randomized to fondaparinux and 7±0.9 days for patients randomized to placebo. The two groups did not differ in the median (range) number of treatment days up to the qualifying examination for venous thromboembolism during the extended period; 21 (3-24) days in the fondaparinux group and 21 (4-24) days in the placebo group. A high level of compliance was achieved with treatment compliance verified for 94.2% (307/326) who were assigned to fondaparinux and 92.4% (305/330) assigned to placebo.

Efficacy Outcomes

Patients were examined for DVT by systematic ascending bilateral contrast venography of the legs between 25 and 32 days postoperatively. In contrast to some previous trials investigating optimal prophylaxis duration in hip replacement surgery patients,55-57 venography at the time of hospital discharge was not systematically performed; consequently, patients with asymptomatic DVT 7 days postoperatively were not excluded, and the natural history of the disease was not altered. By day 32, 428 patients (65.2%) had an adequate venous thromboembolism assessment, a percentage close to that recently reported in another 4-week prophylaxis study,37 and were included in the primary efficacy analysis.

Fondaparinux significantly reduced the incidence of venous thromboembolism compared with placebo, from 35% to 1.4%, which is a relative risk reduction of 95.9% (95% CI: 87.2-99.7%, P<.001) (Table 3). The 35% incidence of events observed 1 month postoperatively in our placebo group after an initial 7-day period of open-label treatment with fondaparinux was close to that reported in the placebo group of another study with a similar duration of prophylaxis after an initial 7-day period of open-label treatment with enoxaparin in hip replacement surgery (39%).58 This indicates that the risk of venous thromboembolism associated with hip fracture surgery is high and persists longer than 11 days, even though short-term fondaparinux already provided effective protection against venous thromboembolism.43

There was a significant (P<.001) reduction in the incidence of total, proximal, and distal-only DVT with fondaparinux compared with placebo. The percentage of patients treated for a venous thromboembolic event during the double-blind period based on the local site assessment was 4.6% (12/261) in the fondaparinux group and 22.3% (59/264) in the placebo group.

Fondaparinux significantly reduced the incidence of symptomatic venous thromboembolism compared with placebo, from 2.7% to 0.3%, a relative risk reduction of 88.8% (95% CI: 67.7%-100%, P=.021). This significant reduction in symptomatic events observed with fondaparinux is consistent with an important clinical benefit.

Venographically detected DVT and clinically symptomatic venous thromboembolism were reduced by the same order of magnitude. This confirms that venographically detected DVT is a valid surrogate endpoint for symptomatic events. Symptomatic pulmonary embolism occurred in three placebo-treated patients (one of which was fatal) but did not occur in fondaparinux-treated patients. The single symptomatic venous thromboembolic event in the fondaparinux group occurred 18 days postoperatively. The nine symptomatic events in the placebo group occurred throughout the study period, between days 11 and 24 postoperatively, confirming the persistence of the thrombogenic risk for at least 4 weeks postoperatively.

The superior efficacy of fondaparinux was observed in all patient subgroups. In hip fracture patients undergoing hip arthroplasty (either or total prosthesis) the incidence of venous thromboembolism was 1.5% (1/66) in the fondaparinux group and 35.7% (25/70) in the placebo group (P<.001). Furthermore, no particular subgroup at lower risk for venous thromboembolism was identified, indicating that all patients with hip fracture surgery, and not only high-risk targeted patients, should benefit from 1-month treatment with fondaparinux.

Eriksson

Safety Outcomes

There was no fatal bleeding or bleeding in a critical organ in either treatment group (Table 3). Bleeding was associated with a need for reoperation in two patients from each group. In both the fondaparinux and placebo groups, one of these episodes led to the discontinuation of study treatment. Six patients experienced overt bleeding associated with a bleeding index of >2 in the fondaparinux group, all occurring at the surgical site.

The clinical relevance of such bleedings is questionable: bleedings were not associated with wound infection, did not result in reoperation, and led to permanent cessation of study treatment in only one patient. Overall, there were eight adjudicated major bleeds in the fondaparinux group (2.4%), compared with two in the placebo group (0.6%, P=.063). In the fondaparinux group, four major bleeding episodes started before randomization but were not considered by the investigators of sufficient clinical relevance to prevent randomization and continued study treatment.

No patient experienced a platelet count below 100 X 109/L, and the number of patients presenting a decrease in platelet count of >40% because randomization was similar in the two groups. In addition, no cases of white clot syndrome or type II immunoallergic thrombocytopenia were reported. In previous major orthopedic surgery studies in which fondaparinux was administered for up to 7±2 days postoperatively, no episode of decreased platelet count was reported as a serious adverse event.53 However, due to the short duration of administration, the risk of type II thrombocytopenia was limited.

The Penthifra-Plus study further confirms the safety of prolonged administration of fondaparinux regarding immunoallergic thrombocytopenia. Similarly, in vitro studies evidenced no cross-reactivity between fondaparinux and the antibodies responsible for type II thrombocytopenia, ie, antiplatelet factor 4/heparin antibodies.59,60

No differences were noted between the two groups in the overall incidence of adverse events, despite the vulnerability of this patient group. Similarly, no difference was noted in overall mortality, although our study was not designed to detect mortality differences.

Conclusion

Reducing the number of venous thromboembolic complications in patients undergoing hip fracture surgery is an important objective. Even with the best current agents, significant risk of fatal pulmonary embolism still exists. Aspirin is inexpensive and does not require monitoring but is not recommended in patients due to lack of efficacy.10

Vitamin K antagonists achieve a moderate reduction in relative risk10 but have limitations such as drug and diet interactions and a narrow therapeutic index, resulting in the need for laboratory monitoring and dose adjustment. Promising results have been reported in small studies with enoxaparin 40 mg, once daily, starting preoperatively.20-23

At the Consensus Conference on Antithrombotic Therapy in 2001, before the Penthifra and Penthifra-Plus trials, the American College of Chest Physicians recommended low-molecular-weight heparins or warfarin in patients undergoing hip fracture surgery.10

Penthifra and Penthifra-Plus were the largest thromboprophylaxis studies conducted in hip fracture surgery using the recommended objective screening test for DVT.49

Penthifra results demonstrated that 2.5 mg of fondaparinux once daily, beginning 6 hours postoperatively, significantly reduced the rate of venous thromboembolism by 56.4% compared with 40 mg of enoxaparin once daily. Moreover, fondaparinux reduced the rate of proximal DVT by 78.7%, the more prone to embolize.61,62 These findings indicate a major clinical benefit over currently available antithrombotic agents and are consistent with those of three other large studies in patients undergoing elective knee44 or hip replacement45,46 surgery, in which fondaparinux achieved an overall risk reduction of >50% for venous thromboembolism compared with enoxaparin.53

Penthifra-Plus results showed that extending fondaparinux prophylaxis from 1 to 4 weeks was effective in reducing the occurrence of delayed venous thromboembolic episodes to a low absolute incidence of 1.4%. Compared to placebo, such extended thromboprophylaxis also significantly reduced symptomatic venous thromboembolism.

Due to advanced age, frailness, and high frequency of comorbidities, patients undergoing hip fracture surgery have a high risk of postoperative general complications.6 Nevertheless, fondaparinux given up to 4 weeks postoperatively was well tolerated and reduced the risk of venous thromboembolism without increasing the risk of clinically relevant bleeding.

Special care should be given to patients with indwelling epidural or intrathecal catheters, severe renal impairment, and patients with low body weight, due to potential risk of serious bleeding complications. These results indicate that fondaparinux could now become the standard thromboprophylaxis after hip fracture surgery. Four-week therapy seems to be advantageous.

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Authors

From the Department of Orthopedics, Sahlgrenska University Hospital/ÖSTRA, S-41685 Göteborg, Sweden.