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The clinical evaluation of fondaparinux in the prevention of venous thromboembolism after major orthopaedic surgery
Abstract
Fondaparinux (Arixtra(R)), the first of a new class of antithrombotics - the synthetic selective factor Xa inhibitors - has been developed out of a, necessity for improvements in antithrombotics. In four large, double-blind, randomised studies in orthopaedic surgery, 1-week fondaparinux 2.5 mg showed a major benefit over enoxaparin (>50% risk reduction of venous thromboembolism [VTE]), without increasing clinically relevant bleeding. A recent study, PENTHIFRA Plus, evaluating extended prophylaxis with fondaparinux for 3 weeks after hip fracture surgery, showed a significant improvement in the rate Of total VTE (reduced from 35% to 1.4%), as well as symptomatic VTE (reduced from 2.7% to 0.3%). This VTE risk reduction was achieved without increasing the incidence of clinically relevant bleeding: In summary, 1-week fondaparinux demonstrated superiority over the approved regimens of enoxaparin in prevention of. VTE after major orthopaedic procedures, whereas 4-week fondaparinux showed a major, clinical benefit in patients, undergoing hip fracture surgery.
... Fondaparinux sodium, a synthetic selective factor Xa inhibitor, is one of the newer pharmacological thromboprophylactic agents which is administered subcutaneously and has been used in patients undergoing major orthopaedic surgery. A metaanalysis of four randomised trials involving 7344 patients undergoing major orthopaedic surgery (including hip fracture surgery and elective lower limb arthroplasty) demonstrated an overall risk reduction of venous thromboembolism of greater than 50% when using subcutaneous fondaparinux compared with enoxaparin alone (Turpie et al., 2002). Although major bleeding occurred more frequently in the group receiving fondaparinux, the incidence of clinically relevant bleeding leading to death, reoperation or occurring in a critical organ did not differ between groups (Turpie et al., 2002). ...
... A metaanalysis of four randomised trials involving 7344 patients undergoing major orthopaedic surgery (including hip fracture surgery and elective lower limb arthroplasty) demonstrated an overall risk reduction of venous thromboembolism of greater than 50% when using subcutaneous fondaparinux compared with enoxaparin alone (Turpie et al., 2002). Although major bleeding occurred more frequently in the group receiving fondaparinux, the incidence of clinically relevant bleeding leading to death, reoperation or occurring in a critical organ did not differ between groups (Turpie et al., 2002). The largest study of fondaparinux in patients undergoing hip fracture surgery randomised 1711 patients to receive either fondaparinux (commenced post-operatively) or enoxaparin (started pre-operatively ) (Eriksson et al., 2001). ...
... As concerns exist in the NICE guidelines regarding haemorrhagic complications associated with fondaparinux, LMWH and UFH may be used in favour of fondaparinux in patients with a higher risk of major bleeding (National Collaborating Centre for Acute Care, 2009). A meta-analysis of 7344 patients undergoing major orthopaedic surgery (including hip fracture surgery) receiving either fondaparinux or LMWH demonstrated although major bleeding occurred more frequently in the group receiving fondaparinux, the incidence of clinically relevant bleeding leading to death, reoperation or occurring in a critical organ did not differ between groups (Turpie et al., 2002). As fondaparinux is more effective than LMWH in reducing the incidence of venous thromboembolism in patients undergoing hip fracture surgery, we would still recommend the use of fondaparinux over LMWH in these patients. ...
Patients undergoing hip fracture surgery are at increased risk of deep vein thrombosis. There are limited studies of good quality assessing thromboprophylactic therapies in this patient population. Mechanical pumping devices may have a role in hip fracture patients, especially around the perioperative period, though compliance with these devices is a significant problem. Fondaparinux is the most effective pharmacological thromboprophylactic therapy following hip fracture surgery and can be used for extended prophylaxis after hospital discharge. A number of the recently published recommendations from the National Institute for Health and Clinical Excellence do not take into account the best available evidence specifically in patients undergoing hip fracture surgery, with findings from elective arthroplasty patients being extrapolated. Well-designed randomised trials are needed to determine the role of combined thromboprophylaxis, graduated compression stockings and newer oral anticoagulants so that appropriate recommendations can be made in patients undergoing hip fracture surgery.
Some orthopedic procedures probably carry no material risk of thrombosis (e.g., hand and wrist surgery), whereas others carry a particularly high risk (e.g., hip fracture surgery).
Some orthopaedic procedures probably carry no risk of thrombosis (e.g. upper limb surgery), whereas others carry a particularly high risk (e.g. revision hip surgery). Total hip replacement, total knee replacement and hip fracture have been the most widely studied procedures. The rate of fatal PE, without prophylaxis, is around 0.4% for total hip replacement and total knee replacement, and is probably higher for hip fracture. The symptomatic DVT rate for total hip replacement is around 4%. It may be higher for total knee replacement, although the similarity between postoperative and thrombotic swelling or calf pain confounds diagnosis. The frequency of chronic venous insufficiency, an important longer-term outcome, is unknown but is likely to be raised in those with asymptomatic DVT.
Venous thromboembolic disease (VTE) is a well known risk in orthopaedic and trauma surgery. There is no unified opinion on the best method of prophylaxis and so most orthopaedic departments use very different regimes. We provide an overview of the best prophylactic methods available at present and an insight into the future of VTE prevention.
Hip fractures are becoming increasingly common in the United States as the elderly population grows. In addition to cardiopulmonary and other medical complications, hip fracture patients are at extremely high risk for the development of venous thromboembolism (VTE). Although well-designed clinical studies analyzing the efficacy and safety of a variety of therapeutic modalities has been performed, an ideal prophylactic agent for VTE after hip fracture surgery has yet to be identified. Given the fragility of most patients with hip fractures, the choice of prophylaxis must be made carefully to balance the efficacy of the agent against the risks of postoperative bleeding. The purpose of this review is to summarize the literature regarding diagnosis and treatment of VTE after hip fractures.
Hospitalized medically ill patients are at greater risk for venous thromboembolism (VTE). Although pharmacologic prophylaxis regimens have reduced VTE risk in medically ill patients, associations with early postdischarge adverse clinical outcomes among patients with heart failure are unknown.
We hypothesized that patients receiving pharmacologic VTE prophylaxis during hospitalization for heart failure would have lower rates of postdischarge adverse clinical outcomes than patients not receiving prophylaxis.
Using data from the Acute Decompensated Heart Failure (ADHERE) registry linked to Medicare claims, we estimated 30-day postdischarge outcome rates for patients who received in-hospital subcutaneous heparin compared with patients who did not receive in-hospital VTE prophylaxis. We excluded patients who received warfarin or intravenous heparin. Outcomes included mortality, thromboembolic events, major adverse cardiovascular events, and all-cause readmission. We used propensity-score methods to estimate associations between VTE prophylaxis and each outcome. In a secondary analysis, we compared outcomes of patients receiving pharmacologic prophylaxis with unfractionated heparin (UFH) vs low-molecular-weight heparin (LMWH).
Of 36 799 eligible patients in 265 hospitals, 12 169 (33%) received pharmacologic VTE prophylaxis during the hospitalization. In unadjusted analysis and after weighting by the inverse probability of treatment, VTE prophylaxis was not associated with 30-day postdischarge mortality, thromboembolic events, major adverse cardiovascular events, or all-cause readmission. There were no differences in outcomes between patients receiving UFH and those receiving LMWH.
Pharmacologic VTE prophylaxis is provided to one-third of older patients hospitalized with heart failure. Treatment with LMWH or UFH did not have a statistically significant association with 30-day postdischarge outcomes.
Fondaparinux is a synthetic pentasaccharide belonging to a new group of anticoagulants that inhibit thrombin formation by inhibiting Factor Xa, which is located at the crossing of both the intrinsic and extrinsic pathways. It has a favorable pharmacokinetic profile, and its effect is predictable and the drug does not need platelet monitoring. Current evidence suggest that fondaparinux is as effective as, if not more than, enoxaparin in the prevention of venous thromboembolism in the postoperative period. It has also been found to have similar effectiveness to enoxaparin and unfractionated heparin in the treatment of venous and pulmonary embolism, respectively. In the field of cardiology, studies have demonstrated that in the setting of acute coronary syndromes, treatment with fondaparinux is not inferior to enoxaparin in preventing major cardiac outcomes, but it is associated with lower risk of bleeding complications, irrespective of the use of percutaneous coronary intervention. During percutaneous coronary intervention, there is a slightly increased risk of catheter thrombosis, which is removed when used along with unfractionated heparin. However, in patients with ST-elevation myocardial infarction, the benefit has been shown in those either receiving thrombolysis or not undergoing any revascularization, but not in subjects undergoing primary percutaneous coronary intervention where unfractionated heparin is still preferred.
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are a major cause of morbidity and mortality, affecting approximately 4 million people each year in the United States. The identification of risk factors for the development of DVT and PE helped to develop a system for risk stratification. The risk to develop a deep vein thrombosis has been estimated to be up to 80% in some populations without prophylaxis. In multiple studies LMWHs demonstrated to be efficient and safe for reduction of DVT of patients in general and visceral surgery, orthopedic surgery, and trauma. Three compounds have been studied best, e.g., dalteparin, enoxaparin, nadroparin, which may help to decide which type of LMWH to use. There is clearly an expanding role for LMWHs in gynecology, cancer, intensive care, patients with acute medical illness and bedridden patients. In summary, LMWHs have chemical, physical, and clinical similarities. They have greater bioavailability, longer half-lifes, more predictable pharmacological response, possible improved safety, and similar or greater efficacy compared with UH. However, the evaluation of clinical trials does not allow the determination of therapeutic equivalence due to different diagnostic methods, drug administration times, dose equivalencies, and outcome measurements The scoring of the quality of clinical trials for meta-analysis is problematic and it has been recommended to assess the methodological aspects individually. Despite clear evidence of effectiveness, deep vein thrombosis prophylaxis is underused. This has been recognized by law firms as evidenced by internet advertisement where patients are informed on the prevention of venous thromboembolism or economy class syndrome. "If you or a family member has been injured, contact a personal injury attorney today. Just fill out Injury.Board.com's on-line questionnaire and have a personal injury lawyer review your potential personal injury claim -- free of charge.". The medico legal implications of antithrombotic prophylaxis and treatment are well recognized.
Deep-vein thrombosis following skeletal trauma is an important yet poorly studied issue. The purpose of the present study was to evaluate the efficacy of two different strategies for prophylaxis against deep-vein thrombosis and pulmonary embolus following blunt skeletal trauma.
Two hundred and twenty-four inpatients were enrolled in a prospective, randomized study investigating venous thromboembolic disease following trauma. Two hundred patients completed the study, which compared two different regimens of prophylaxis. The patients in Group A received enoxaparin (30 mg, administered subcutaneously twice a day) starting twenty-four to forty-eight hours after blunt trauma. The patients in Group B were managed with pulsatile foot pumps at the time of admission combined with enoxaparin on a delayed basis. All patients were screened with magnetic resonance venography and ultrasonography before discharge.
There were ninety-seven patients in Group A and 103 patients in Group B. Twenty-two patients (including thirteen in Group A and nine in Group B) had development of deep-vein thrombosis, with two (both in Group A) also having development of pulmonary embolism. The prevalence of deep-vein thrombosis was 11% for the whole series, 13.4% for Group A, and 8.7% for Group B; the difference between Groups A and B was not significant. There were eleven large or occlusive clots (prevalence, 11.3%) in Group A, compared with only three (prevalence, 2.9%) in Group B (p = 0.025). The prevalence of pulmonary embolism was 2.1% in Group A and 0% in Group B. Wound complications occurred in twenty-one patients in Group A, compared with twenty patients in Group B. Patients who had development of deep-vein thrombosis during the inpatient portion of the study required a mean of 7.4 units of blood during hospitalization, compared with 3.9 units of blood for those who did not (p < 0.05).
Our results indicate that early mechanical prophylaxis with foot pumps and the addition of enoxaparin on a delayed basis is a very successful strategy for prophylaxis against venous thromboembolic disease following serious musculoskeletal injury. The prevalence of large or occlusive deep-vein thromboses among patients who had been managed with this protocol was significantly less than that among patients who had been managed with enoxaparin alone.
LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development.
The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin.
In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint.
Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients.
Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.
The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established.
To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context.
This was a randomized, double-blind, placebo-controlled superiority trial. Patients aged at least 40 years undergoing abdominal surgery were randomized to receive either fondaparinux 2.5 mg or placebo s.c. for 5-9 days, starting 6-8 h postoperatively. All patients received intermittent pneumatic compression. The primary efficacy outcome was venous thromboembolism up to day 10. The main safety outcomes were major bleeding and all-cause mortality. Follow-up lasted 32 days.
Of the 1309 patients randomized, 842 (64.3%) were evaluable for efficacy. The venous thromboembolism rate was 1.7% (7/424) in the fondaparinux-treated patients and 5.3% (22/418) in the placebo-treated patients (odds ratio reduction 69.8%; 95% confidence interval 27.9-87.3; P = 0.004). Fondaparinux significantly reduced the proximal deep vein thrombosis rate from 1.7% (7/417) to 0.2% (1/424; P = 0.037). Major bleeds occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux-treated and placebo-treated patients, respectively (P = 0.006), none being fatal or involving a critical organ. By day 32, eight patients (1.3%) receiving fondaparinux and five (0.8%) receiving placebo had died.
In patients undergoing abdominal surgery and receiving intermittent pneumatic compression, fondaparinux 2.5 mg reduced the venous thromboembolism rate by 69.8% as compared to pneumatic compression alone, with a low bleeding risk as compared to placebo.
Patients with lower limb and pelvic trauma, or undergoing major orthopaedic surgery represent one of the highest risk groups for the development of venous thromboembolism (VTE). A significant number of pharmacological and mechanical agents have been used for the prophylaxis and treatment of VTE. Fondaparinux is a relative new pharmacological agent that selectively binds to antithrombin, and represents a new class of synthetic selective inhibitors of activated factor X. Eleven percent of the fondaparinux-related English language literature, between 2001 and 2007, refers to orthopaedic trauma, and was the sample assessed for this critical analysis review. The clinical studies evaluating the safety, efficacy, and financial implications associated with lower limb orthopaedic trauma show that fondaparinux has comparable results with the well-established use of enoxaparin. However, the scientific community has raised several issues regarding mostly fondaparinux's safety, timing of its 1(st) dose, bleeding side effects, duration of administration and lack of a reliable reversing agent. Further trials are necessary focusing on the safety and efficacy of this drug mostly in relation to clinical relevant outcomes and to different fields of trauma surgery (pelvis, long bone fractures and polytrauma patients).
The optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events.
We identified randomised trials comparing extended-duration prophylaxis using heparin or warfarin with placebo or untreated control in patients undergoing elective total hip or knee replacement by searching electronic databases (MEDLINE, EMBASE), references from retrieved articles, and abstracts from conference proceedings, and by contact with pharmaceutical companies and investigators. Two reviewers independently extracted data on study design, symptomatic and symptomless venographic venous thromboembolism, death, and bleeding outcomes. Results from individual trials were combined with the Mantel-Haenszel method.
Nine studies met our inclusion criteria (3999 patients), eight with low molecular weight heparin, and one with unfractionated heparin. Extended-duration prophylaxis for 30-42 days significantly reduced the frequency of symptomatic venous thromboembolism (1.3% vs 3.3%, OR 0.38; 95% CI 0.24-0.61, numbers needed to treat [NNT]=50), with no statistical evidence of heterogeneity (x(2) test, p=0.69). There was a greater risk reduction in patients undergoing hip replacement (1.4% vs 4.3%, 0.33; 0.19-0.56, 34) compared with knee replacement (1.0% vs 1.4%, 0.74; 0.26-2.15, 250). A significant reduction in symptomless venographic deep vein thrombosis was also observed (9.6% vs 19.6%, 0.48; 0.36-0.63, 10). There was no increase in major bleeding but extended-duration prophylaxis was associated with excess minor bleeding (3.7% vs 2.5%, 1.56; 1.08-2.26, numbers needed to harm [NNH]=83).
Among patients undergoing total hip or knee replacement, extended-duration prophylaxis significantly reduces the frequency of symptomatic venous thromboembolism. The reduction in risk is equivalent to about 20 symptomatic events per 1000 patients treated.
Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk.
In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding.
The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.
In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.
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.
In a double-blind study, were 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.
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.
In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and equally safe.
Venous thromboembolism is a frequent complication of total hip replacement. The pentasaccharide Org31540/SR90107A, a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents. To determine the optimal dose for phase 3 studies, we conducted a dose-ranging study in which Org31540/SR90107A was compared with a low-molecular-weight heparin, enoxaparin, in patients undergoing total hip replacement.
In a double-blind study, patients were randomly assigned to postoperative administration of one of five daily doses of Org31540/SR90107A, given once daily, or to 30 mg of enoxaparin, given every 12 hours. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days.
Of 933 patients treated, 593 were eligible for the efficacy analysis. With Org31540/SR90107A a dose effect was observed (P=0.002), with rates of venous thromboembolism of 11.8 percent, 6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for the groups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg of the drug, respectively, as compared with a rate of 9.4 percent in the enoxaparin group. The reduction in the risk of venous thromboembolism was 82 percent for the 3.0-mg Org31540/SR90107A group (P=0.01) and 29 percent for the 1.5-mg group (P=0.51). Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groups was discontinued because of bleeding complications. Major bleeding occurred 3.5 percent less frequently in the 0.75-mg group (P=0.01) and 3.0 percent less frequently in the 1.5-mg group (P=0.05) than in the enoxaparin group (in which the rate was similar to that in the 3.0-mg group).
A synthetic pentasaccharide, Org31540/SR90107A, has the potential to improve significantly the risk-benefit ratio for the prevention of venous thromboembolism, as compared with low-molecular-weight heparin.
Elective hip-replacement surgery carries significant risk of venous thromboembolism, despite use of thromboprophylaxis. We aimed to see whether the pentasaccharide fondaparinux, the first drug of a new class of synthetic antithrombotic agents, could reduce this risk to a greater extent than other available treatments.
In a double-blind study, we randomly assigned 2275 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to receive postoperative subcutaneous injections of either 2.5 mg fondaparinux once daily or 30 mg enoxaparin twice daily. The primary efficacy outcome was venous thromboembolism to day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks.
We assessed venous thromboembolism to day 11 in 1584 (70%) of 2275 patients. By day 11, venous thromboembolisms were recorded in 48 (6%) of 787 patients on fondaparinux and in 66 (8%) of 797 patients on enoxaparin. The relative reduction in risk was 26.3% (95% CI -10.8 to 52.8, p=0.099). The two groups did not differ in the number of patients who died or in the number who had clinically relevant bleeding.
In patients undergoing elective hip-replacement surgery, 2.5 mg fondaparinux once daily was not significantly more effective than 30 mg enoxaparin twice daily in reducing risk of venous thromboembolism. However, the lower risk recorded with fondaparinux than enoxaparin was clinically important, with no increase in clinically relevant bleeding.
Despite use of thromboprophylaxis, elective hip-replacement surgery carries a high risk of venous thromboembolic complications. We aimed to assess the ability of the pentasaccharide fondaparinux, the first of a new class of synthetic antithrombotic agents, to further reduce this risk.
In a double-blind study, we randomly assigned 2309 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to once daily, subcutaneous injections of either 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. The primary efficacy outcome was venous thromboembolism up to day 11, 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 bleeding and death. The duration of follow-up was 6 weeks. Analysis was per protocol.
We assessed the primary efficacy outcome in 1827 (79%) of 2309 patients. By day 11, venous thromboembolisms were recorded in 37 (4%) of 908 patients assigned to fondaparinux and in 85 (9%) of 919 assigned to enoxaparin (difference -5.2% [95% CI -8.1 to -2.7], p<0.0001). The relative reduction in risk was 55.9% (95% CI 33.1-72.8). The two groups did not differ in frequency of death or clinically relevant bleeding.
Drugs that act through specific inhibition of factor Xa, such as fondaparinux, could be more effective than low molecular weight heparins in prevention of venous thromboembolism in patients undergoing hip-replacement surgery.
Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments.
A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding.
Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups.
In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.
The benefit of thromboprophylaxis for 1 month has never been evaluated in patients undergoing hip fracture surgery, a setting in the highest risk category for postoperative venous thromboembolism (VTE).
In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with a once-daily subcutaneous injection of either 2.5 mg of fondaparinux sodium or placebo for 19 to 23 days. Before randomization, all patients had received fondaparinux for 6 to 8 days. The primary efficacy outcome was VTE occurring during the double-blind period (deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism). The main safety outcome was major bleeding.
The primary efficacy outcome was assessed in 428 patients. Fondaparinux reduced the incidence of VTE compared with placebo from 35.0% (77/220) to 1.4% (3/208), with a relative reduction in risk of 95.9% (95% confidence interval, 87.2%-99.7%; P<.001). Similarly, the incidence of symptomatic VTE was significantly lower with fondaparinux (1/326; 0.3%) than with placebo (9/330; 2.7%). The relative reduction in risk was 88.8% (P =.02). Although there was a trend toward more major bleeding in the fondaparinux group than in the placebo group (P =.06), there were no differences between the 2 groups in the incidence of clinically relevant bleeding (leading to death, reoperation, or critical organ bleeding).
Extended prophylaxis with fondaparinux for 3 weeks after hip fracture surgery reduced the risk of VTE by 96% and was well tolerated.