A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement.

BACKGROUND: Patients who undergo total hip replacement have a high risk of thromboembolic complications. Recombinant hirudin (desirudin), a specific inhibitor of thrombin, represents a new development in antithrombotic therapy. We compared the efficacy and safety of desirudin with those of a low-molecular-weight heparin (enoxaparin) for the prevention of thromboembolic complications in patients undergoing primary total hip replacement. METHODS: Both treatments, which were assigned in a randomized, double-blind manner, were started preoperatively: enoxaparin on the evening before surgery, and desirudin within 30 minutes before the start of surgery. The dose of desirudin was 15 mg subcutaneously twice daily, and the dose of enoxaparin was 40 mg subcutaneously once daily. The duration of treatment was 8 to 12 days. Deep-vein thrombosis was verified by bilateral venography performed at the end of the treatment period or earlier, if there were clinical signs of deep-vein thrombosis. RESULTS: At 31 centers in 10 European countries, 2079 eligible patients were randomly assigned to receive desirudin or enoxaparin. A total of 1587 patients were included in the primary analysis of efficacy. In the desirudin group, as compared with the enoxaparin group, there was a significantly lower rate of proximal deep-vein thrombosis (4.5 vs. 7.5 percent, P=0.01; relative reduction in risk, 40.3 percent) and a lower overall rate of deep-vein thrombosis (18.4 vs. 25.5 percent, P=0.001; relative reduction in risk, 28.0 percent). The safety profiles were similar in the two treatment groups. CONCLUSIONS: When administered 30 minutes before total hip replacement surgery, desirudin is more effective than enoxaparin in preventing deep-vein thrombosis.

Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement.

Specific inhibition of thrombin is a new method for the prevention of postoperative deep-vein thrombosis. The objective of this multicenter, randomized, double-blind study was to compare the efficacy and safety of desirudin (Revasc, CGP 39393; fifteen milligrams two times a day) with that of unfractionated heparin (5000 international units three times a day) in patients having a primary elective total hip replacement. The medications were administered subcutaneously, starting preoperatively and continuing for eight to eleven days. The primary end point was a confirmed thromboembolic event during the treatment period. The presence of deep-vein thrombosis was evaluated with bilateral venograms, which were centrally assessed by two independent radiologists. A total of 445 eligible patients were randomized: 220, to management with heparin, and 225, to management with desirudin. A per-protocol analysis of efficacy was performed for the 351 patients (79 per cent) for whom an adequate bilateral venogram had been made within eight to eleven days after the operation or who had had a proved thromboembolic event. The prevalence of confirmed deep-vein thrombosis was thirteen (7 per cent) of 174 patients who had received desirudin and forty-one (23 per cent) of 177 patients who had received heparin, a significant difference (p < 0.0001). The prevalence of proximal deep-vein thrombosis was also significantly reduced (p < 0.0001), by 79 per cent, in the group that had received desirudin (six [3 per cent] of 174 patients) compared with in the group that had received heparin (twenty-nine [16 per cent] of 177). There were no confirmed pulmonary embolisms or deaths during the period of prophylaxis. During a six-week follow-up period, pulmonary embolism was confirmed in four patients, all of whom had received heparin. There was no significant difference between the treatment groups with respect to bleeding variables or bleeding complications. These data demonstrate that a fixed dose of fifteen milligrams of desirudin, started preoperatively and administered subcutaneously twice daily for at least eight days, provided effective, safe prevention of thromboembolic complications, with no specific requirements for laboratory monitoring, in patients who had a total hip replacement.

Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment.

This study examines inadequacy rates for phlebography in two multicenter trials for the prevention of post-operative DVT and determines inter-and intra-observer variability in evaluating phlebograms. A total of 991 (I) and 385 (II) patients underwent bilateral phlebography in two studies of thromboprophylaxis. Phlebography was performed using a standard method designed to visualize and assess all deep veins. Each vein was scored as normal, DVT or inadequate by both local and central assessment. The study showed low inadequacy rates for phlebograms of 12.2% (121/991) and 6.5% (25/385). Inter-observer agreement (local vs. central assessment) was moderate in both studies (I: 74.8%, Kappa-value 0.41; II: 82.6%, Kappa-value 0.51). Good intra-observer agreement (within the central assessment group) was observed (I:88.8%, Kappa-value 0.75). This study demonstrates low inadequacy rates for phlebograms using a standardized methodology and superior intra-observer agreement compared to inter-observer agreement and supports the importance of central assessment of phlebograms in thromboprophylactic multicenter trials to reduce observer variability.

Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement.

Hirudin is an anticoagulant originally extracted from the leech Hirudo medicinalis. Using recombinant DNA technology a new compound, recombinant desulphato hirudin CGP 39393 has now been produced. The aim of this study was to determine the maximum tolerated dose in patients undergoing elective hip replacement. This open safety trial represents, to our knowledge, the first experience of recombinant hirudin in orthopedic patients. In this study 48 patients undergoing primary total hip replacement were included and the safety of subcutaneous injections of 10, 15, 20 and 40 mg CGP 39393 twice daily, was evaluated. Prophylaxis was started immediately pre-operatively and continued for 8-10 days. A mandatory bilateral phlebography was performed at the end of the prophylactic treatment period and a clinical follow-up was done 6 weeks after surgery. A major bleeding event occurred in the first 3 patients receiving 40 mg CGP 39393 b.i.d. and the prophylaxis regimen at this dosage level was therefore discontinued. Median values of total blood loss and requirements of blood transfusion in the patients receiving 10-20 mg CGP 39393 were similar to those reported in previous studies on total hip replacement performed at the same centre, using other prophylactic drugs. Deep vein thrombosis (DVT) was confirmed by phlebography in 5 out of 12 patients in the 10 mg group (41.7%, 95% confidence limits [CL]: 15.2-72.3%), 1 out of 11 patients in the 15 mg group (9.1%, CL: 0.23-41.3%) and 2 out of 20 patients in the 20 mg group (10.0%, CL: 1.2-31.7%) during the prophylaxis period. CGP 39393 was safe and well tolerated, when administered as subcutaneous injections of 10-20 mg twice daily. The dose level of 40 mg CGP 39393 twice daily resulted in serious disturbance of the hemostasis in patients after hip prosthesis surgery.