Optimal Dosing of Prophylactic Enoxaparin after Surgical Procedures: Results of the Double-Blind, Randomized, Controlled FIxed or Variable Enoxaparin (FIVE) Trial

Pannucci et al.1 conclude that prescribing enoxaparin 0.5 mg/kg twice daily is effective and safe for venous thromboembolism prevention.1 The authors measure anti-factor Xa levels. These levels reflect enoxaparin activity, not the anticoagulation effect.2 Weight-based dosing was found to be superior to fixed doses in avoiding overdoses (9.4 percent versus 17.8 percent, p = 0.046) when controlling for patient age and central lines. The effect of either variable on anti-factor Xa levels is unexplained. The authors reference an earlier study3 suggesting that patients with low anti-factor Xa levels are more likely (p = 0.041) to develop venous thromboembolism. Three of the five cases of venous thromboembolism in that underpowered study (n = 94) represented upper extremity thromboses in patients with central catheters.3 Such thromboses have a different etiology (i.e., intimal trauma rather than venous stasis). Patients with low anti-factor Xa levels who developed venous thromboembolism also received extra doses of enoxaparin, which would theoretically remedy the low anti-factor Xa levels. Pannucci et al.4 previously reported a 6.8 percent risk of clinically relevant bleeding in patients who received enoxaparin 40 mg twice daily. Importantly, enoxaparin is unapproved for venous thromboembolism prophylaxis in plastic surgery patients.5 Moreover, prescribing 80 mg daily, plus supplemental 10-mg doses, exceeds the 40-mg dose recommended for venous thromboembolism prophylaxis in general surgery and orthopedic patients.5 Risks include frequent (30 percent) overdoses, more bleeding, more returns to the operating room, more blood transfusions, and death.6 Venous thromboembolism persists (0.7 percent).1 By controlling for median Caprini scores and hospital stays, the Venous Thromboembolism Prevention Study7 found an advantage (p = 0.042) for chemoprophylaxis, despite equal (1.2 percent) venous thromboembolism rates in anticoagulated and control patients. Caution is needed when selectively controlling for variables1,7 and expanding eligibility criteria3 in order to achieve a p value less than 0.05 that conforms to the study hypothesis. Subsequent studies have failed to reproduce a beneficial effect of chemoprophylaxis. Counterintuitively, a large study (n = 1598) by Jeong et al.8 found more venous thromboembolism cases among plastic surgery patients who received chemoprophylaxis than those who did not (3.3 percent versus 0.5 percent, p < 0.00001). A 2017 meta-analysis also reported more venous thromboembolism cases among anticoagulated patients (4.37 percent versus 2.45 percent, p < 0.0001).9 In their 2016 meta-analysis, Pannucci et al.10 recommend against chemoprophylaxis without risk stratification. Nevertheless, the senior author does not reserve anticoagulation for patients with high Caprini scores.1,11,12 Recognizing that enoxaparin “has an unfavorable risk/benefit relationship among patients at low risk for [venous thromboembolism],” a new “de-implementation” trial by Pannucci randomized cancer patients into two groups, one of which received no chemoprophylaxis.13 The trial was scheduled to begin in July of 2021. The treatment group will receive a fixed dose (not weight-based) of enoxaparin, 40 mg daily. Logically, if the data do not support chemoprophylaxis, or even show a reverse relationship with venous thromboembolism,8,9 then this practice should be discontinued. No discussion of bleeding risk is needed. Major hemorrhage is the most common adverse effect of enoxaparin (1 percent to 10 percent).14 Twelve patients (8.3 percent) receiving weight-adjusted enoxaparin doses developed bleeds.1 The number of blood transfusions and the cause of two deaths are unreported. Chemoprophylaxis likely is ineffective because the anticoagulation course is too early and too brief.15 A safe and effective alternative is available, using ultrasound screening to select affected patients for a therapeutic course of anticoagulation.15 Unnecessary bleeding is avoided. DISCLOSURE Dr. Swanson receives royalties from Springer Nature (Cham, Switzerland). Eric Swanson, M.D.Swanson CenterLeawood, Kan.