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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.
• 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.
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Patients undergoing major orthopaedic surgery are at high risk for venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) [1, 2]. Pharmacological prophylaxis with low molecular weight heparins (LMWH) reduces VTE rates [3, 4]. Their use, however, is associated with an increased bleeding risk. Other side effects include allergic skin reactions and heparin-induced thrombocytopenia as LMWH are derived from animal sources. The indirect selective factor Xa inhibitor fondaparinux is a synthetic pentasaccharide. It has been developed to provide a selective anticoagulant effect and to overcome some side effects of LMWH such as allergic reactions [5–11].
A meta-analysis of large randomized controlled trials (RCTs) of VTE prophylaxis in major orthopaedic surgery [12, 13] found a 50% risk reduction for any VTE using fondaparinux 2.5 mg once daily compared with the LMWH enoxaparin (at doses of 40 mg once daily or 30 mg twice daily). Overall, the rates of bleeding, surgical complications and mortality were not different .
Based on these data, our institution switched from LMWH to fondaparinux for VTE prophylaxis in patients undergoing major orthopaedic surgery.
Translating results of RCTs into clinical practice is limited by the fact that selected study populations may not be representative for cohorts of unselected every day patients due to selection bias. Only selected institutions, often academic or academia-affiliated, participate in clinical trials and may not be representative for all institutions performing the intervention under investigation. At these sites, patients eligible for study participation are selected from all patients treated for this indication. The motivation of patients to or not to participate in a trial may also contribute to selection bias [14–17]. Finally, patients included in a trial have to fulfil strict inclusion and exclusion criteria and, therefore, are more homogenous than the whole group of patients [16, 18]. Consequently, results of RCTs have to be confirmed in large cohorts of unselected patients.
The objective of this retrospective cohort study was to compare the efficacy and safety of VTE prophylaxis with fondaparinux or LMWH in 3896 consecutive patients undergoing major orthopaedic surgery at our centre.
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Of the 3896 patients undergoing major orthopaedic surgery between January 2006 and December 2009, 2439 patients underwent hip arthroplasty (69.9%), 1278 patients underwent knee arthroplasty (36.6%) and 179 patients underwent surgery for explantation of artificial hip or knee joint (5.1%). During the observational period, all 3896 patients received VTE prophylaxis according to guidelines and hospital standard. Of these, 1495 patients (38.4%) received LMWH prophylaxis (hospital standard 2006–2007), 1994 patients (51.2%) received fondaparinux (hospital standard 2008–2009) and 407 patients (10.4%) received other prophylaxis (study drugs, unfractionated heparin due to renal insufficiency, therapeutic anticoagulation due to underlying disease) (Table 1). In the LMWH group, VTE prophylaxis was with certoparin 3000 IU once daily (62.3%), nadroparin 3000 IU once daily (14.7%), nadroparin 4000–6000 IU once daily (14.4%), enoxaparin 4000 IU once daily (8.5%) or tinzaparin 3500 IU once daily (0.1%). Of note, dose adjustments in the LMWH group were necessary, since certoparin is approved at a dosage of 3000 IU once daily, nadroparin at dosages of 3000, 4000 and 6000 IU day−1 (according to body weight and time after surgery), enoxaparin at 4000 IU once daily and tinzaparin at 3500 IU once daily.
Table 1A. Patient characteristics and type of VTE prophylaxis in all patients undergoing major orthopaedic surgery between January 2005 and December 2009
| || Prophylactic LMWH > 3000 aXa once daily mean ± SD || Fondaparinux 2.5 mg once daily mean ± SD || t-test P value || UFH 5000 IU three times daily mean ± SD || Therapeutic LMWH 100–200 aXa kg−1 day−1 mean ± SD || Other pharmacological or mechanical VTE prophylaxis mean ± SD |
| n ||1495||1994|| ||92||284||31|
|Male/Female||667/828||721/1273|| <0.001 (Chi squared) ||47/45||149/135||12/19|
|History of VTE||0.94%||0.95%||>0.999||3.4%||24.6%||6.5%|
|yes/no % (n)||14/1481||19/1975||3/89||70/214||2/31|
|Age (years)||62.3 ± 13.3||66. 8 ± 11.9|| <0.001 ||72.1 ± 11.6||71.3 ± 9.9||67.7 ± 11.5|
|Height (cm)||168.5 ± 9.4||167.0 ± 9.7|| <0.001 ||167.7 ± 10.6||169.1 ± 10.0||168.8 ± 6.4|
|Weight (kg)||79.4 ± 16.5||80.9 ± 18.4|| 0.008 ||80.2 ± 18.3||84.4 ± 17.8||84.2 ± 14.1|
|BMI (kg m–2)||27.9 ± 5.2||29.0 ± 5.8||0.945||28.5 ± 5.9||29.4 ± 5.5||29.5 ± 5.3|
|Platelet count (Gpt l–1)||232.2 ± 83.0||207.1 ± 66.6|| <0.001 ||212.2 ± 120.2||205.7 ± 76.4||250.7 ± 58.0|
|INR||1.07 ± 0.12||1.11 ± 0.12|| <0.001 ||1.1 ± 0.2||1.2 ± 0.4||1.1 ± 0.2|
|aPTT (s)||28.9 ± 4.5||28.6 ± 7.1||0.181||31.6 ± 8.2||30.9 ± 5.1||28.4 ± 3.3|
|Creatinine (µmol l–1)||64.1 ± 23.1||63.1 ± 19.8||0.198||187.8 ± 146.9||72.0 ± 27.2||94.1 ± 108.6|
Table 1B. Patient characteristics and type of VTE prophylaxis in patients receiving LMWH or fondaparinux prophylaxis between January 2005 and December 2009. anova group comparisons using covariate analysis for type of thromboprophylaxis, gender and demographic parameters as variables
| Parameter || Gender || LMWH n= 1495 || Fondaparinux n= 1994 || P value |
| Mean || 95% CI || Mean || 95% CI |
|History of VTE [%]||Male||0.31||0.05, 1.06||0.56||0.19, 1.39||0.751|
|Female||1.46||0.82, 2.48||1.11||0.65, 1.81|
|BMI [kg m−2]||Male||28.0||27.6, 28.3||29.1||28.7, 29.4||<0.001|
|Female||27.8||27.5, 28.2||28.9||28.6, 29.2|
|Platelet count (Gpt l−1)||Male||220.1||215.3, 224.8||195.6||191.0, 200.1||<0.001|
|Female||239.7||235.4, 244.1||215.2||211.4, 219.0|
|INR||Male||1.074||1.07, 1.08||1.117||1.11, 1.12||<0.001|
|Female||1.068||1.06, 1.08||1.11||1.105, 1.12|
|aPTT (s)||Male||29.0||28.6, 29.4||28.6||28.2, 29.0||0.044|
|Female||28.9||28.6, 29.3||28.5||28.2, 28.8|
|Creatinine (µmol l−1)||Male||73.22||71.94, 74.51||72.36||71.13, 73.59||0.211|
|Female||57.99||56.81, 59.17||57.12||56.10, 58.14|
Patients in the fondaparinux group were more often female (63.8 vs. 55.4%), were older (66.8 vs. 62.3 years), had lower platelet counts (207 vs. 232 Gpt l−1) and a higher INR (1.2 vs. 1.1) compared with patients receiving prophylactic LMWH. These differences were statistically significant (Table 1). Of note, the number of patients with a history of VTE was low in both groups, since hospital standard at that time recommended therapeutic dosages of LMWH for these patients (Table 1).
Group differences in age, gender and BMI were regarded as clinically significant and in the following analyses, event rates were adjusted according to these parameters.
The rate of all symptomatic VTE events was 4.1% in the LMWH prophylaxis group (62/1495 patients, 95% CI 0.03, 0.05) and 5.6% in patients receiving fondaparinux (112/1994 patients, 95% CI 0.05, 0.07; P= 0.047). Between both treatment arms, no significant differences in rates for major VTE and death were found (Table 2A). Patients receiving thromboprophylaxis with fondaparinux had a significantly higher rate of distal DVT (3.9%, 95% CI 0.03, 0.05) compared with patients treated with LMWH (2.5%, 95% CI 0.02, 0.03; P= 0.021).
Table 2A. Efficacy endpoints in all patients receiving prophylactic LMWH or fondaparinux for thromboprophylaxis after major orthopaedic surgery (95% Blyth-Still-Casella confidence intervals)
| Efficacy endpoints || LMWH n= 1495 || Fondaparinux n= 1994 || P value |
| % (n) || 95% CI || % (n) || 95% CI |
| All VTE ||4.15 (62)||3.19–5.23||5.62 (112)||4.67–6.68|| 0.047 |
| Proximal DVT||1.07 (16)||0.64–1.69||1.30 (26)||0.85–1.87||0.639|
| PE||0.54 (8)||0.23–1.03||0.50 (10)||0.27–0.89||0.999|
| Distal VTE||2.47 (37)||1.78–3.37||3.91 (78)||3.10–4.83|| 0.021 |
The safety of fondaparinux prophylaxis was comparable with LMWH prophylaxis with regard to the primary safety endpoint of severe bleeding as well as for the secondary safety endpoints, transfusions of units of RBCs, platelets or plasma concentrates (Table 2B). However, patients receiving LMWH prophylaxis had significantly more surgical complications leading to revision surgery (3.7%, 95% CI 0.03, 0.05 vs. 1.6%, 95% CI 0.01, 0.02; P < 0.001; Table 2B).
Table 2B. Safety endpoints in all patients receiving prophylactic LMWH or fondaparinux for thromboprophylaxis after major orthopaedic surgery (95% Blyth-Still-Casella confidence intervals)
| Safety endpoints || LMWH n= 1495 || Fondaparinux n= 1994 || P value |
| % (n) || 95% CI || % (n) || 95% CI |
| Severe bleeding ||12.58 (188)||10.94, 14.35||11.13 (222)||9.80, 12.59||0.202|
| Transfusion > 2 RBC concentrates||11.57 (173)||9.99, 13.27||10.58 (211)||9.27, 11.97||0.547|
| Surgical revisions due to bleeding complications||1.34 (20)||0.85, 2.03||1.10 (22)||0.69, 1.65||0.535|
| Bleeding into critical site||0.07 (1)||0.001, 0.37||0.05 (1)||0.001, 0.28||0.999|
|Any surgical revision||3.68 (55)||2.81, 4.75||1.61 (32)||1.10, 2.23|| <0.001 |
|Transfusion of plasma concentrates||7.09 (106)||5.84, 8.49||5.97 (119)||4.97, 7.06||0.186|
|Transfusion of platelet concentrates||1.34 (20)||0.85, 2.03||0.70 (14)||0.41, 1.14||0.080|
|Any death||0.07 (1)||0.001, 0.37||0.10 (2)||0.02, 0.35||0.999|
|Length of hospital stay (days)||11.1||10.6, 11.3||9.3||9.1, 9.5|| <0.001 |
|Length of hospital stay (days) Median (25th and 75th percentile)||9 (8, 11)||9 (8, 9)|| <0.001 |
Interestingly, efficacy and safety of LMWH and fondaparinux thromboprophylaxis differed in subgroups of patients according to the length of hospital stay (Table 3). Rates of VTE, bleeding and surgical complication events increased with prolonged hospitalization, indicating a causal relationship. However, significant differences between LMWH and fondaparinux prophylaxis were only seen in subgroups of patients. While VTE event rates were only numerically higher in fondaparinux patients discharged up until day 9, this difference became more pronounced and statistically significant in patients discharged later than day 9. On the other hand, bleeding complications were significantly more common in fondaparinux patients discharged before day 9 compared with LMWH prophylaxis. Finally, surgical revisions were more often seen in patients receiving LMWH prophylaxis and discharged after day 9.
Table 3. Event rates for VTE, bleeding complications and surgical revisions according to type of thromboprophylaxis and length of hospital stay. Rates of events increased in all groups according to duration of hospitalization, indicating causal relationship. Of note, significant differences between LMWH and fondaparinux prophylaxis were only seen in subgroups of patients
| Event || Length of hospital stay (days) || Type of thromboprophylaxis || P value |
| LMWH (n= 1474) || Fondaparinux (n= 1973) |
| n || % || 95% CI || n || % || 95% CI |
|Any VTE||0–8||6/502||1.20||0.4, 2.6||13/903||1.44||0.8, 2.4||0.813|
|9||19/487||3.90||2.4, 6.0||30/583||5.15||3.5, 7.3||0.380|
|>9||35/485||7.22||5.1, 9.9||65/487||13.35||10.5, 16.7|| 0.002 |
|Severe bleeding||0–8||11/502||2.19||1.1, 3.9||41/903||4.54||3.3, 6.1|| 0.027 |
|9||20/487||4.11||2.5, 6.3||38/583||6.52||4.7, 8.8||0.103|
|>9||150/485||30.93||26.8, 35.3||140/487||28.75||24.8, 33.0||0.483|
|Surgical revision||0–8||2/502||0.40||0.0, 1.4||3/903||0.33||0.1, 1.0||0.999|
|9||1/487||0.21||0.0, 1.1||3/583||0.51||0.1, 1.5||0.630|
|>9||50/485||10.31||7.7, 13.4||26/487||5.34||3.5, 7.7|| 0.004 |
Three patients died during hospital stay (one treated with LMWH and two treated with fondaparinux). All deaths were caused by septic complications leading to multi-organ failure. One of the two patients treated with fondaparinux who died, was a 74-year-old lady with Alzheimer's disease and septic hip infection who developed relevant wound haematoma as well as proximal DVT after surgery, both of which which did not cause death.
The mean length of hospital stay was significantly shorter in the fondaparinux group (9.3 days, 95% CI 9.1, 9.5 vs. 10.9 days, 95% CI 10.6, 11.3; P < 0.001). This finding was caused by a statistically significant difference in the 75th percentile (Table 2B) between both treatment groups, who had the same 25th and 50th percentile for length of hospitalization. Furthermore, subgroup analyses were carried out describing the influence of complications or type of thromboprophylaxis on length of hospitalization (Figure 2). Of note, due to the interference of confounding factors such as early discharge policy, the Kaplan–Meier curves in Figure 2 are of descriptive nature only and were not statistically tested for significance. A difference in length of hospitalization was found in patients without any VTE, bleeding or surgical complications (Figure 2A), indicating that the existing trend to early discharge due to economic considerations contributed to this finding. Interestingly, the occurrence of VTE complications contributed to a comparable prolongation of hospitalization in both treatment groups (Figure 2B).
Figure 2. Kaplan–Meier analysis of hospital discharge (length of hospital stay in days) according to treatment group (A), subgroups with and without VTE (B), subgroups with and without severe bleeding (C) and subgroups with and without surgical revisions (D). , LMWH; , fondaparinux; , LMWH without symptomatic VTE; , LMWH with symptomatic VTE; , fondaparinux without symptomatic VTE; , fondaparinux with symptomatic VTE; , LMWH without severe bleeding; , LMWH with severe bleeding; , fondaparinux without severe bleeding; , fondaparinux with severe bleeding; , LMWH without revision; , LMWH with revision; , fondaparinux without revision; , fondaparinux with revision
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In contrast, in cases of bleeding or surgical complications, our analysis indicated that these patients had longer hospitalizations with LMWH than with fondaparinux prophylaxis (Figure 2C,D), which also contributed to the finding of a shorter hospital stay in the fondaparinux group.
Risk factors for VTE
Using the type of thromboprophylaxis as co-variables, a multivariate analysis using a Cox logistic regression model was used to evaluate potential risk factors for the occurrence of VTE complications. A total number of 3447 patients had complete data for this analysis (1474 LMWH and 1973 fondaparinux), who experienced a total of 168 VTE events (60 and 108, respectively).
The first step of the risk analysis included type of thromboprophylaxis only and found the use fondaparinux to be related to an increased risk for VTE (HR 2.29, 95% CI 1.66, 3.16). After adjustment for age- and gender-related differences, the HR decreased to 1.80 (95% CI 0.52, 6.24), which failed to reach statistical significance.
The third step included ‘platelet count’, ‘positive history of VTE’ and ‘BMI’, which improved analysis. The last step excluded group-specific age- and gender-corrections from analysis. The results of multivariate analysis are given in Table 4.
Table 4. Multivariate analysis using Cox logistic regression model to evaluate potential risk factors for the occurrence of VTE in patients receiving prophylactic LMWH or fondaparinux for thromboprophylaxis after major orthopaedic surgery (n= 3447)
| || Patients with/without VTE |
| HR || 95% CI || P value |
|Use of fondaparinux||1.25||0.90, 1.75||0.184|
|Female gender||1.89||1.30, 2.75|| 0.001 |
|Age (per year)||1.03||1.01, 1.04|| <0.001 |
|Platelet count||0.99||0.99, 1.00|| 0.024 |
|Previous VTE||18.21||11.64, 28.48|| <0.001 |
|BMI (per unit)||1.05||1.02, 1.08|| <0.001 |
A positive history of VTE (HR 18.3) followed by female gender (HR 1.9) were found to be the most relevant independent risk factors for VTE in our cohort. In contrast, fondaparinux use (HR 1.3) was not an independent VTE risk factor.