J A Hoek

Perioperative anticoagulant prophylaxis for postoperative venous thromboembolism (VTE) in neurosurgical patients has not gained wide acceptance due to the fear of intracranial bleeding. Physical methods give a worthwhile reduction of postoperative VTE but there still remains a substantial residual incidence. In other clinical indications, low molecular weight heparins have proven to be effective for prophylaxis of VTE when administered postoperatively, with the advantage of no bleeding enhancement during surgery. Therefore, we performed a multicentre, randomized, double-blind trial in neurosurgical patients to investigate the efficacy and safety of adding a low molecular weight heparin (LMWH), nadroparin, initiated postoperatively, to graduated compression stockings in the prevention of VTE. Deep-vein thrombosis was detected by mandatory venography. Bleeding was determined according to pre-defined objective criteria for major and minor episodes. An adequate bilateral venogram was obtained in 166 of 241 LMWH patients (68.9%) and 179 of 244 control patients (73.4%). A total of 31 of 166 LMWH patients (18.7%) and 47 of 179 controls patients (26.3) had VTE up to Day 10 postoperatively (p = 0.047). The relative risk reduction (RRR) was 28.9%. The rates for proximal deep-vein thrombosis/pulmonary embolism were 6.9% and 11.5% for the two groups, respectively (RRR: 40.2%; p = 0.065). Secondary analyses involved all VTE up to day 56 post-surgery which was detected in 33 patients of 241 in the LMWH group (13.7%) and 51 of 244 control patients (20.9%; RRR 34.5%; p = 0.018). The corresponding percentages for proximal deep-vein thrombosis/pulmonary embolism were 5.8% and 10.2% for the two groups, respectively, giving a RRR of 43.3%; p = 0.36. Major bleeding complications, during the treatment period, occurred in six low molecular weight heparin treated patients (2.5%) and in two control patients (0.8%); p = 0.87. A higher mortality was observed in the low molecular weight heparin group over the 56-day follow-up period (22 versus 10; p = 0.026). However, none of these deaths was judged by a blinded adjudication committee to be related to the study drug. In conclusion, this study demonstrates that the low molecular weight heparin, nadroparin, added to graduated compression stockings results in a clinically significant decrease in VTE without inducing any significant increase of major bleeding.

OBJECTIVE: To evaluate the efficacy and safety of two subcutaneous prophylactic regimens for postoperative deep vein thrombosis after total hip replacement. DESIGN: Prospective open randomised multicentre trial. SETTING: 28 European departments of orthopaedic surgery. INTERVENTION: All patients had bilateral phlebography 10 days after surgery. 31 patients receiving low molecular weight heparin and 29 receiving unfractionated heparin were excluded from the efficacy analysis for various reasons. PATIENTS: 349 patients undergoing total hip replacement between September 1988 and May 1989. 174 patients received subcutaneously a low molecular weight heparin (Fraxiparine) with anti-factor Xa activity of 41 IU/kg/day for three days, then 62 IU/kg/day from day 4 to day 10. 175 patients received subcutaneous unfractionated heparin at intervals of eight hours; doses were adjusted to maintain the activated thromboplastin time at two to five seconds above control values. MAIN OUTCOME MEASURE: Total incidence of deep vein thrombosis and incidence of proximal deep vein thrombosis on bilateral phlebography. RESULTS: The total incidence of deep vein thrombosis was 16% in patients receiving unfractionated heparin and 12.6% in patients receiving low molecular weight heparin (p = 0.45), and the incidence of thrombosis of the proximal veins was 13.1% and 2.9% respectively (p less than 0.001). Four patients receiving unfractionated heparin and one receiving low molecular weight heparin developed pulmonary embolism. The incidence of bleeding complications was low and comparable in the two groups. CONCLUSION: Low molecular weight heparin is at least as effective as unfractionated heparin in preventing deep vein thrombosis and is more effective at preventing thrombosis of the proximal veins in patients undergoing hip replacement. Low molecular weight heparin is not more likely to cause bleeding complications and is simpler to give than unfractionated heparin.

We assessed the safety and efficacy of the novel low molecular weight heparinoid Lomoparan (Org 10172) for the prevention of deep-vein thrombosis in patients undergoing elective total hip replacement in a randomized, placebo-controlled, double-blind trial in 197 consecutive patients. The heparinoid (750 anti-factor Xa-units, s.c., b.i.d.) was administered to 97 patients and 99 patients received placebo. Study medication was started preoperatively and continued for 10 days. Efficacy was assessed by bilateral phlebography at day 10, postoperatively. The incidence of deep-vein thrombosis was 56.6% and 15.5% respectively in the placebo and heparinoid treated patients (incidence reduction: 74%; P less than 0.001). This reduction was observed both for proximal-vein thrombosis (25% to 8%; P less than 0.005) and isolated calf-vein thrombosis (31% to 7%; P less than 0.001). No major hemorrhage was observed. The number of red-cell units transfused and drain-fluid loss were comparable for the two study groups. Six patients in the heparinoid group and none in the control group developed minor wound hematomas (P less than 0.05). During an 8-week post-discharge follow-up period three patients with a normal venogram at day 10 developed clinically apparent venous thromboembolism, which was confirmed by objective testing. All three patients belonged to the heparinoid-treated group. We conclude that 750 anti-factor Xa units Org 10172 s.c. twice daily starting preoperatively is safe and effectively reduces early deep-vein thrombosis following elective total hip replacement. Further studies on the incidence of post-discharge thromboembolism are required.

We evaluated a recently developed commercial assay for quantifying thrombin-antithrombin III (TAT) complexes in human plasma. The assay is precise (within-assay CV less than 10%, between-assay CV less than 13%), and sensitive (detection limit 0.7 micrograms of TAT per liter of plasma). Measurements for healthy volunteers yielded a normal reference (95 percentile) interval of 0.8 to 5.0 micrograms/L (n = 50, mean 2.1 micrograms/L, range 1.1 to 7.5 micrograms/L). TAT concentrations were increased in 25 of the 41 patients who fulfilled the clinical criteria of disseminated intravascular coagulation (DIC, overall mean 15.8 micrograms/L) and in 30 of the 35 patients with deep-vein thrombosis of the leg (overall mean 9.4 micrograms/L). We assessed the accuracy of the TAT assay by comparison with established criteria for the laboratory diagnosis of DIC involving various cutoff values for antithrombin III, factor V, fibrinogen, platelet count, fibrin/fibrinogen degradation products, and activated partial thromboplastin time. The low specificity of the TAT assay with regard to some of these criteria indicates that the latter are probably insensitive.