Optimal low-molecular-weight heparin regimen in major orthopaedic surgery. A meta-analysis of randomised trials

Low-molecular-weight heparins (LMWH) are routinely used for thromboprophylaxis in major lower limb orthopaedic surgery. However the optimal LMWH regimen, offering the greatest efficacy with an acceptable risk of bleeding, has not been clearly established with regard to dose and timing of treatment initiation. We performed a meta-analysis of all available randomised trials comparing LMWH to placebo. Relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated. By means of subgroup analysis, we evaluated the consistency of the results according to the timing of treatment initiation (preoperative versus postoperative) and dose of LMWH used (low doses, i.e. 4000 anti-Xa IU or below versus high doses). The possibility of a dose-effect relationship of LMWH was also evaluated by meta-regression. Thirteen studies were included (1925 patients). In four studies, LMWH treatment was started postoperatively. Daily LMWH doses ranged from 3000 anti-Xa IU to over 6000 anti-Xa IU. Compared to placebo, LMWH significantly reduced the risk of asymptomatic deep-vein thrombosis (DVT) (RR=0.51, 95% CI=[0.45-0.59], p<0.001) without significantly increasing the risk of major haemorrhage (RR=0.80 [0.36-1.79], p=0.58). We found no convincing evidence that starting prophylaxis preoperatively was associated with a significantly reduced risk of asymptomatic DVT relative to starting postoperatively. Our results showed a strong correlation between the risk of DVT and LMWH dose (meta-regression, test of slope p=0.03). These findings are tentative because the comparisons are across trials, but nevertheless suggest that the different LMWH regimens currently recommended are effective and safe.