Prophylaxis for thromboembolic complications following total hip replacement (THR) surgery is usually withdrawn when a patient is discharged from the hospital; however, the current trend towards a shorter duration of postoperative hospital care has raised concerns. THR patients are now being discharged while still at risk of postoperative venous thromboembolism. Indeed, although the peak incidence of deep vein thrombosis (DVT) occurs between day 5 and 10 after total hip or knee replacement,1,2 the duration of risk for thrombosis persists for several months beyond the first postoperative week.36 This prolonged duration of risk has even been demonstrated in patients with normal venograms at discharge.7"9 These observations suggest a beneficial role for continued antithrombotic prophylaxis for an extended period after discharge. Consistent with these findings, the European Consensus Statement on the prevention of thromboembolic disease published in 1992 proposed that prospective trials should address the issue of prophylaxis after hospital discharge.10
This is a prospective, single-center, randomized, double-blind trial in THR patients with the aim of better quantifying the risk of developing new DVT after discharge from hospital and assessing the efficacy and tolerability of continued antithrombotic prophylaxis with enoxaparin administered on an outpatient basis. The full results of this study have been published previously.11
PATIENTS AND METHODS
Consecutive patients who had undergone THR surgery at the Clinique Radio-Chirurgicale du Mail were eligible for inclusion in the trial if they met the following criteria: age >45 years; bilateral ascending contrast venography of the legs performed *S5 days before discharge as negative for DVT; and prophylaxis with low-molecularweight heparin (LMWH) for postoperative venous thromboembolism. Patients also had to be able to walk without assistance other than crutches and were required to have had no disorders associated with an increased risk of venous thromboembolism.
Following an initial subcutaneous injection of enoxaparin 40 mg immediately before surgery, eligible patients received routine prophylaxis with enoxaparin 40 mg once daily until hospital discharge (Fig 1). After confirmation of the absence of venographically proven thrombosis of the legs, patients were randomly assigned to receive enoxaparin 40 mg or placebo on an out-patient basis for 21 days after discharge. Contrast venography was repeated at the end of the 21 -day treatment period. Efficacy was analyzed on both an intention-to-treat and per-protocol basis; whereas the analysis of tolerability was by intention-to-treat only. The primary end-point was the total rate of DVT or pulmonary embolism (PE) confirmed by venography and pulmonary angiography or lung scan in each treatment group at day 35 after surgery. The secondary end-point was the rate of proximal or distal DVT.
The size of the study population was determined by assuming a DVT rate of 2% in the enoxaparin group and 13% in the placebo group. Therefore, applying an a error (two-tailed) of 5% and β error of 20%, it was estimated that 80 patients would be required in each treatment group in order to detect an 1 1% intergroup difference in the rate of DVT.
Of the 179 patients enrolled in the trial, 90 were randomized to the enoxaparin group and 89 to the placebo group. The two treatment groups were comparable for baseline demographic and surgery characteristics and risk factors for venous thromboembolism. Although all randomized patients were included in the intention-to-treat analysis of tolerability, six were excluded from the analysis of efficacy because of an unsuccessful second venogram due to withdrawal of consent (N=2) or technical difficulties (N=4).
Intention-to-treat analysis in the 173 evaluable patients who underwent repeat venography revealed a significantly (P=0.018) lower rate of total DVT in the enoxaparin group (7.1%) compared with the placebo group (19.3%), corresponding to an absolute risk reduction in the total incidence of DVT of 12.2% (Fig 2). Although there was no significant intergroup difference in the rate of proximal DVT, the rate of distal DVT was significantly (P=0.006) lower in the enoxaparin group. These results were confirmed by per-protocol analysis in 155 patients that demonstrated a significant (P=0.001) risk reduction in the total incidence of DVT of 17.3% in the enoxaparin group (Fig 3). Patients in the enoxaparin group also experienced a significantly lower rate (P=0.018) of distal DVT and a tendency towards a lower rate of proximal DVT. Based on the incidences of total DVT observed in this study, THR patients who are venogram-negative for DVT may have a risk of developing DVT after discharge from the hospital that is as high as 19%. There were no deaths or episodes of PE during the study period.
Fig 1: Treatment protocol for assessing the protective efficacy of enoxaparin in total hip replacement patients following discharge; DVT = deep-vein thrombosis.
Fig 2: Intention-to-treat analysis of the incidence of venogram-proven deep-vein thrombosis (DVT) in enoxaparin (N=85) and placebo (N=88) treatment groups. * P=0.018 and ** P<0.006 for enoxaparin vs placebo, Adapted from Planes et al.11
Fig 3: Per-protocol analysis of the incidence of venogram-proven deep-vein thrombosis (DVT) in enoxaparin (N=75) and placebo (N=80) treatment groups. *P=0.001 and **P<0.018 for enoxaparin vs placebo. Adapted from Planes et al.11
Enoxaparin was not associated with any major bleeding episodes. The occurrence of minor bleeding episodes (epistaxis, hematemesis and wound hematoma) was similar in the enoxaparin (N=3) and placebo (N=I) groups. There was a higher rate of bruising at die injection site in the enoxaparin group (N= 14) compared with the placebo group (N=4). Importantly, none of these minor bleeding complications necessitated blood transfusion, surgery, or withdrawal from study treatment.
Maintenance of antithrombotic therapy by LMWH for a prolonged period after hip replacement surgery is theoretically and economically important. Conventionally, prophylaxis is maintained for the duration of hospitalization. With shorter hospital stays, THR patients are discharged with a high risk of thromboembolism. The duration of prophylaxis is shortened and it has been demonstrated venographically that the relative risk reduction afforded by LMWHs was only about 70%. Moreover, all THR patients present reversible risk factors: continued activation of the coagulation cascade12, persistence of femoral vein damage13,14, and a prolonged period of venous stasis that follows hip surgery.15
Studies have demonstrated that the period of postoperative manifestations for thromboembolism may be as long as several months.3"6 For example, Trowbridge et al6 reported a 10.5% incidence of proximal DVT with half of the episodes occurring during the second month after discharge. Similarly, Kase and Sharkey4 reported a 2.3% rate of PE in THR patients 3 months after discharge. Indeed, accumulating evidence of a prolonged post-discharge thromboembolic risk prompted one group of investigators to propose that prophylaxis should be continued for 3 months after surgery.16
The results of the present study confirm that the risk of DVT in patients who were venogram-negative for DVT at discharge remains elevated for at least 1 month after surgery. It has been suggested, however, that the demonstrated 20% incidence of thrombosis is rather high considering the rigid inclusion criteria and that only ambulatory patients with normal venograms prior to randomization were enrolled in this study.17 These authors suggested that the contrast-venography procedure used may have been a contributory factor to the thrombosis. Nevertheless, irrespective of this possible bias factor, a long-term threat of dirombosis after surgery has been confirmed, and as a means of minimizing this risk, enoxaparin administered for 3 weeks after discharge significantly reduced the development of DVT and was not associated with major bleeding complications. This finding is consistent with those of other studies that have demonstrated the prolonged risk of thrombosis and protective efficacy and safety of LMWHs administered for a duration of 1 month after hip surgery.18-20
In a study that complements these findings, Bergqvist et al20 demonstrated an 18% incidence of DVT in THR patients who received prophylaxis with enoxaparin for 1 month after surgery compared with 39% in those who received prophylaxis only during hospitalization, a relative risk reduction of 53%. Thus, there is a considerable risk of developing thromboembolism after discharge. The 39% incidence of thromboembolic events demonstrated by Bergqvist et al20 in their placebo group is almost twice that demonstrated in this study. This higher incidence is at least partially attributable to the design of the study, which excluded patients with DVT at discharge and confirms that contrast-venography induced DVTs in this trial were probably minimal.
The results of this prospective, clinical trial highlight the risk of post-discharge thrombosis after hip arthroplasty and further demonstrate that prolonged prophylaxis with enoxaparin is effective in reducing the frequency of late-onset DVT following surgery.
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