Comparison of two low-molecular-weight heparins for the prevention of postoperative venous thromboembolism after elective hip surgery. Reviparin Study Group.

Low-molecular-weight heparins (LMWHs) have been shown to be effective in the prevention of deep vein thrombosis (DVT) after major orthopaedic surgery, such as total hip replacement (THR). The efficacy and safety of two LMWHs, reviparin and enoxaparin, were compared in a prospective, double-blind, double-dummy study involving 498 patients undergoing total hip replacement. Drugs were given preoperatively in doses of 4200 IU anti-Xa for reviparin and 40mg (approximately 4000 IU anti-Xa) for enoxaparin. The endpoint for the assessment of efficacy was venographically confirmed DVT. The endpoint for the assessment of safety was clinically important bleeding during study treatment. There were evaluable venograms for 460 patients (93%). Of these 460 patients only 416 fulfilled the study protocol. A total of 39 DVTs (9%) occurred in this per protocol group of patients, 21 (10%) in the reviparin group, and 18 (9%) in the enoxaparin group. The incidence of proximal DVT was 6% in each group. The two treatments were found to be equivalent in terms of efficacy. For the 460 patients with venograms (intent-to-treat) venous thrombosis occurred in 49 patients (11%). Of the 230 patients randomly assigned to reviparin, 27 had a DVT (12%), whereas 22 of the 230 enoxaparin patients (10%) had a DVT. The incidence of proximal DVT was 6% in both groups. Again, the two treatment groups were clinically equivalent in efficacy. Major bleeding complications occurred in two enoxaparin- and one reviparin-treated patient. Peri- and postoperative blood loss and blood transfusions were similar in both treatment groups. The reviparin-treated patients had fewer haematomas, bruisings and higher red cell counts and lower haemoglobin levels than the enoxaparin-treated patients.

Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo.

BACKGROUND: The risk of deep-vein thrombosis (DVT) and pulmonary embolism after total hip replacement (THR) surgery may persist after hospital discharge, but the extent of the risk is not known. We carried out a single-centre, prospective, randomised, double-blind trial with the aims of quantifying this risk and assessing the efficacy of continued prophylactic treatment. METHODS: At hospital discharge 13-15 days after surgery, we recruited 179 consecutive THR patients who had no DVT visible on bilateral ascending venography of the legs. The patients were randomly assigned subcutaneous enoxaparin (40 mg, once daily; n = 90) or placebo (n = 89) for 21 (19-23) days. The primary endpoint was the occurrence of DVT or pulmonary embolism. Venography was repeated at the end of 21 days' treatment or earlier if necessary. FINDINGS: There were no deaths and no symptomatic pulmonary embolisms during the study or follow-up periods. Of 173 patients with evaluable venograms, intention-to-treat analysis of efficacy showed that the rate of DVT at day 21 after discharge was significantly lower in the enoxaparin group than in the placebo group (6 [7.1%] vs 17 [19.3%], p = 0.018). Distal DVT was detected in one (1.2%) patient in the enoxaparin group and in ten (11.4%) patients in the placebo group (p = 0.006). Proximal DVT was observed in five (5.9%) patients in the enoxaparin group and in seven (7.9%) patients in the placebo group (p = 0.592). A perprotocol analysis of efficacy in 155 patients confirmed these findings. Safety was good; three minor bleeding episodes occurred in the enoxaparin group and one in the placebo group, but none of these episodes necessitated withdrawal from the study. INTERPRETATION: In patients who have undergone THR surgery, are without venogram-proven DVT at hospital discharge, and do not receive antithrombotic prophylaxis after discharge, the risk of late-occurring DVT remains high at least until day 35 after surgery. Continued prophylaxis with enoxaparin is effective and safe in reducing this risk.

Efficacy and safety of postdischarge administration of enoxaparin in the prevention of deep venous thrombosis after total hip replacement. A prospective randomised double-blind placebo-controlled trial.

Although venous thromboembolism has occasionally been reported after hospital discharge in patients who have undergone total hip replacement (THR), this risk has not been fully quantified and the usefulness of a prophylactic treatment has not been evaluated. We conducted a single-centre prospective randomised double-blind clinical trial in 2 parallel groups of patients who had undergone THR and were free of deep venous thrombosis (DVT) at discharge, as assessed by bilateral ascending venography. During hospitalisation, all patients received a low molecular weight heparin, enoxaparin (enoxaparin sodium), as a prophylactic treatment for venous thromboembolism. Just before hospital discharge (15 +/- 1 days from surgery) 179 consecutive patients were randomly assigned to receive subcutaneous enoxaparin 40mg (n = 90) or placebo (n = 89) once daily for 21 +/- 2 days. The primary efficacy outcome was defined as the occurrence of DVT and/or documented pulmonary embolism (PE). DVT was assessed by ascending bilateral venography performed 21 +/- 2 days after randomisation or earlier if necessary. Secondary efficacy outcomes were the occurrence of proximal and distal DVT. Safety outcomes were defined as the occurrence of major and minor haemorrhage, other adverse events and changes in laboratory parameters. All patients underwent a 3-month follow-up. There were no deaths or cases of clinical PE during the study and the follow-up periods. In 173 patients with evaluable venograms, analysis of efficacy on an intention-to-treat basis showed that the incidence of DVT at day 21 was significantly lower in the enoxaparin group (6 of 85; 7.1%) than in the placebo group (17 of 88; 19.3%; p = 0.018), a risk reduction of 63%. Distal DVT was less frequent in the enoxaparin group than in the placebo group (1.2 vs 11.4%; p = 0.006) but there was no significant difference between groups in the incidence of proximal DVT. A 'per-protocol' analysis of efficacy in 155 patients confirmed the results for total and distal DVT, but also showed a trend in efficacy in favour of enoxaparin with regard to the incidence of proximal DVT (p = 0.064). Enoxaparin was safe in comparison with placebo: only 2 minor bleedings occurred in the enoxaparin group and there was no difference in the incidence of other adverse events between the 2 groups. In patients undergoing THR, the risk of late-occurring DVT remained high during the 21 days after hospital discharge in the placebo group. Prophylactic treatment with enoxaparin reduced the risk and was well tolerated in this context.

Prevention of deep vein thrombosis after total hip replacement. The effect of low-molecular-weight heparin with spinal and general anaesthesia.

Enoxaparin, a low-molecular-weight heparin, has been used together with spinal or general anaesthesia in a prospective, randomised study of 188 consecutive elective hip replacements. Bilateral venography was performed on all patients on day 13 after operation. Group I (65 patients) received spinal anaesthesia and no immediate injection of enoxaparin. Group II (61 patients) received spinal anaesthesia and 20 mg of enoxaparin one hour after the onset of anaesthesia. Group III (62 patients) was operated on under general anaesthesia and received 40 mg of enoxaparin 12 hours prior to surgery. This group acted as the control group. In all three groups, 40 mg of enoxaparin was given 12 hours after the end of surgery and continued on a once-daily basis. Proximal DVT occurred in 6% of group I, 6.7% of group II and 6.5% of group III, not a significant difference. Distal DVT was present in 11% of group I, 5% of group II and 0% of group III; this was a highly significant difference (p = 0.007). Tolerance was good and the incidence of bleeding low in the three groups. Our results confirm the low rate of DVT in patients operated on under general anaesthesia with the standard procedure of 40 mg of enoxaparin on a once-daily basis started pre-operatively. The 40 mg-dose is also safe and effective in association with spinal anaesthesia if half the dose (20 mg) is injected an hour after the lumbar puncture.

Efficacy and safety of a perioperative enoxaparin regimen in total hip replacement under various anesthesias.

Four trials in which enoxaparin, a low-molecular-weight heparin, was used in patients having hip surgery are reported. In the first two trials, enoxaparin was given before general anesthesia. The protocol consisted of 40 mg of enoxaparin, 4,000 anti-factor Xa IU, subcutaneously 12 hours before surgery, followed by the same dose 12 hours after surgery and then once daily. In the third trial, this protocol was compared with unfractionated heparin calcium given in a standardized manner and appeared to be significantly superior both in efficacy and tolerance. In the fourth trial, the protocol was adapted for use in spinal subarachnoidal anesthesia; 20 mg of enoxaparin, 2,000 anti-factor Xa IU, was given subcutaneously 1 hour after anesthesia and 40 mg 12 hours later. In all these trials tolerance was good. Excessive bleeding did not occur with the 40 mg once daily regimen. Efficacy was good and compared favorably with other protocols in use.

Total hip replacement and deep vein thrombosis. A venographic and necropsy study.

Bilateral venography was performed between 12 and 15 days after total hip replacement in 745 consecutive patients, all of whom had heparin prophylaxis. Of these, 81 patients (10.8%) showed evidence of recent deep vein thrombosis: 23 (3%) distal, 44 (5.9%) isolated proximal, five (0.7%) both proximal and distal, and nine (1.2%) extensive thrombosis from calf to thigh. Compared with previous reports heparin appeared to have reduced the number of distal and contralateral thromboses, but was far less effective in reducing proximal femoral thrombosis. In a cadaver study, the femoral veins were inspected during simulated total hip replacement by either an anterior or a posterior approach. In every case the femoral vein became kinked or folded in the thigh position imposed during the preparation of the femur. Local damage appears to be an important factor in proximal thrombosis; care at operation could help to minimise trauma to the femoral veins and reduce the number of such cases.

Once-daily dosing of enoxaparin (a low molecular weight heparin) in prevention of deep vein thrombosis after total hip replacement.

The main results of three successive prospective clinical trials which represent the successive steps in the definition of once-daily dosing of enoxaparin in elective hip surgery are demonstrated. In the first trial, a dose of 40 mg/day (4000 anti-Factor Xa IU), in one or two subcutaneous injections, was preferred to a dose of 60 mg because it gave the same efficacy with a better tolerance. In a second, randomized double-blind trial, the two modes of administration of a dose of 40 mg, in one or two injections daily, were found to be equivalent with regard to tolerance and efficacy. In a third prospective, controlled, randomized, double-blind multicentre trial, once-daily dosing of enoxaparin at the dose of 40 mg was found superior to 5000 IU of unfractionated heparin tds with regard to tolerance and efficacy. It is concluded that the dose of 40 mg/day, begun 12 h pre-operatively, gives the best benefit:risk ratio in elective hip surgery.

Enoxaparine low molecular weight heparin: its use in the prevention of deep venous thrombosis following total hip replacement.

UNLABELLED: The effect of Enoxaparin in the prevention of thromboembolism after total hip prosthesis has been controlled by phlebography. 228 consecutives patients were studied with 4 dose regimens: 60 mg once a day, 40 mg once a day, and 30 and 20 mg twice a day. CONCLUSIONS: a total dose of 40 mg once a day or twice a day gives a rate of postoperative thrombosis of 8%.

[Phlebography after total prosthesis. Action of subcutaneous sodium heparin in the prevention of thromboembolism. Results of therapeutic research with subcutaneous sodium heparin using 2 protocols in 250 patients monitored with phlebography]. / Phlébographie après prothèse totale. Action de l'héparine sodique sous-cutanée dans la prévention de la maladie thrombo-embolique. Résultats d'une recherche thérapeutique par l'héparine sodique sous-cutanée, selon 2 protocoles, chez 250 patients contrôlés par phlébographies.

Two series of patients on which total hip or knee prostheses had been inserted were studied. In the first series (150 cases), the patients were treated with low molecular Dextran and subcutaneous sodium heparin at a constant dosage. The Howell test was done every 3 days. The rate of post-operative thrombosis was 14 p. 100. In the second series (100 cases), the patients were treated with low molecular Dextran and subcutaneous sodium heparin with a variable dose adapted to the type of patient. The rate of post-operative thrombosis was only 7 p. 100. The insertion of a knee prosthesis was much more thrombogenic than hip prostheses. In the second series the rate of thrombosis after hip surgery was only 2 p. 100. However a number of complications relating to anticoagulation were a limiting factor of the method.