Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery – findings from the ORTHO‐TEP registry

Abstract

WHAT IS ALREADY KNOWN ABOUT THE TOPIC• Patients undergoing major orthopaedic surgery are at high risk of venous thromboembolism.• Medical thromboprophylaxis is effective to reduce this risk and in large trials, fondaparinux proved superiority over low molecular weight heparin (LMWH) in this indication with the downside of higher complication rates.• Patients in clinical trials are a selected subpopulation and efficacy and safety results need to be confirmed in large cohorts of unselected patients.WHAT THIS STUDY ADDS• In unselected patients undergoing major orthopaedic surgery, thromboprophylaxis with fondaparinux was equally effective to prevent major venous thromboembolism (VTE), but inferior to prevent distal deep vein thrombosis (DVT) compared with low molecular weight heparin.• The rates of bleeding complications or blood transfusions were similar for patients receiving fondaparinux and LMWH, but use of fondaparinux was associated with significantly lower rates of surgical complications, which contributed to a shorter hospital stay.• Overall, we found much higher rates of symptomatic VTE and bleeding events in our large cohort of unselected patient in daily care compared with results of large phase III trials evaluating anticoagulants in this indication, indicating a selection bias in these prospective trials.AIMS In large randomized trials, thromboprophylaxis with fondaparinux in major orthopaedic surgery (MOS) has been shown to be superior to low molecular weight heparin (LMWH) prophylaxis with comparable safety. However, patients treated under trial conditions are different from unselected patients and efficacy and safety outcomes may be different in unselected patients in daily practice. We performed a retrospective cohort study to compare the efficacy and safety of venous thromboembolism (VTE) prophylaxis with fondaparinux or LMWH in 3896 consecutive patients undergoing major orthopaedic surgery at our centre.METHODS All patients undergoing MOS between January 2006 and December 2009 were retrospectively analyzed using patient charts, hospital admission and discharge database, quality management database, transfusion unit database and VTE event documentation. VTE standard prophylaxis at our institution was LMWH (3000–6000 aXa units once daily) from January 2006 to December 2007 or fondaparinux 2.5 mg from January 2008 to December 2009. In these two large cohorts of unselected consecutive patients, in‐hospital incidences of VTE, surgical complications, severe bleeding and death were evaluated.RESULTS Symptomatic VTE was found in 4.1% of patients in the LMWH group (62/1495 patients; 95% CI 0.032, 0.052) compared with 5.6% of patients receiving fondaparinux (112/1994 patients, 95% CI 0.047, 0.067; P= 0.047). Distal deep vein thrombosis (DVT) was significantly more frequent in the fondaparinux group (3.9%, 95% CI 0.031, 0.048; vs. 2.5%; 95% CI 0.018, 0.034; P= 0.021). No significant differences in the rates of major VTE or death were found. Rates of severe bleeding, transfusion of RBC concentrates, plasma and platelet concentrates were comparable between both treatment groups. However, patients receiving fondaparinux had significantly lower rates of surgical revisions (1.6%, 95% CI 0.011, 0.022 vs. 3.7%, 95% CI 0.028, 0.047; P < 0.001). Multivariate analysis revealed previous VTE (HR 18.2, 95% CI 11.6, 28.5; P < 0.001) and female gender (HR 1.9, 95% CI 1.3, 2.7; P < 0.001), but not fondaparinux prophylaxis (HR1.3, 95% CI 0.9, 1.7; P= 0.184) to be associated with significantly increased VTE risk.DISCUSSION Thromboprophylaxis with fondaparinux is less effective to prevent distal VTE than LMWH in unselected patients undergoing MOS, but is equally effective with regard to rates of major VTE and death. However, differences in efficacy of LMWH or fondaparinux are of little relevance compared with a history of VTE or female gender, which were found to be the main VTE risk factors in MOS. The safety profile of fondaparinux was comparable with LMWH with regard to rates of severe bleeding complications, but patients receiving fondaparinux had significantly less surgical complications requiring surgical revisions. Both our efficacy and safety findings differ from data derived from large phase III trials testing fondaparinux against LMWH in MOS, where overall rates of symptomatic VTE were lower and the safety profile of fondaparinux was different.CONCLUSION We conclude that the strict patient selection and surveillance in phase‐III trials results in lower VTE and bleeding event rates compared with unselected routine patients. Consequently, the efficacy and safety profile of thromboprophylaxis regimens needs to be confirmed in large registries or phase IV trials of unselected patients.

Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO‐TEP registry

“…All patients undergoing MOS at the Orthopaedic Department of the University Hospital in Dresden, Germany, between January 2006 and June 2011, were included in the ORTHO‐TEP registry. A detailed description of the registry design has previously been published [12]. In brief, all patients undergoing major orthopedic surgery are prospectively entered in a quality management database.…”

Pharmacology of Heparin and Related Drugs

“…Fondaparinux can be used as an alternative to UH or LMWH in the majority of indications for antithrombotic treatment or prophylaxis, in patients with competent renal function, by once-daily subcutaneous delivery without the need for laboratory monitoring (Garcia et al, 2012). For example, efficacy and safety of fondaparinux have been found to be comparable with intravenous UH in the treatment of PE (Büller et al, 2003), LMWH in VTE prophylaxis after major orthopedic surgery (Donath et al, 2012), and LMWH in non-STEMI, whereby bleeding risk was found to be lower with fondaparinux (Szummer et al, 2015). Fondaparinux is reported to have been used successfully during pregnancy in the case of hypersensitivity to heparin (Elsaigh et al, 2015), but it is not currently recommended because of the lack of safety data in this setting .…”

“…Nonetheless, risk of death from VTE was found to be very low in patients managed with modern anticoagulant regimens, including enoxaparin, in the trials analyzed in a recent systematic review (Chan et al, 2015), and routine pharmacological thromboprophylaxis is recommended in the majority of patients undergoing major orthopedic procedures (Falck-Ytter et al, 2012). While presenting a considerable risk in itself, the presence of additional risk factors in patients undergoing major surgery may further increase the likelihood of significant thrombosis; a large retrospective cohort study of patients who had undergone major orthopedic surgery found that female sex and a previous history of VTE were the major determinants of thrombosis risk in this setting (Donath et al, 2012). …”

Prophylaxis of Venous Thromboembolism in Knee Replacement Surgery

“…ORTHO-TEP registry compared the efficacy and safety of fondaparinux and LMWH in 3819 patients undergoing major orthopaedic surgery [16]. The main limitation of the study was its retrospective nature and the comparison of two different periods, the first in which LMWH ( 3000-6000 aX U) and in the second with fondaparinux 2.5 mg used as thromboprophylaxis ,.…”

“…Female sex and previous DVT were the more relevant risk factors for DVT independently from the drug used for pharmacological prophylaxis in the ORTHO-TEP study [16] . In a study by Kang et al [17] DVT was detected by B-mode ultrasonography performed 7 days after TKR in 175/1025 patents aged >75 years.…”