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

Abstract

Background:The accepted "one-size-fits-all" dose strategy for prophylactic enoxaparin may not optimize the medication's risks and benefits after surgical procedures. The authors hypothesized that weight-based administration might improve the pharmacokinetics of prophylactic enoxaparin when compared to fixed-dose administration. Methods: The FIxed or Variable Enoxaparin (FIVE) trial was a randomized, doubleblind trial that compared the pharmacokinetic and clinical outcomes of patients assigned randomly to postoperative venous thromboembolism prophylaxis using enoxaparin 40 mg twice daily or enoxaparin 0.5 mg/kg twice daily. Patients were randomized after surgery and received the first enoxaparin dose at 8 hours after surgery. Primary hypotheses were (1) weight-based administration is noninferior to a fixed dose for avoiding underanticoagulation (anti-factor Xa <0.2 IU/ml) and (2) weight-based administration is superior to fixed-dose administration for avoiding overanticoagulation (anti-factor Xa >0.4 IU/ml). Secondary endpoints were 90-day venous thromboembolism and bleeding. Results: In total, 295 patients were randomized, with 151 assigned to fixed-dose and 144 to weight-based administration of enoxaparin. For avoidance of underanticoagulation, weight-based administration had a greater effectiveness (79.9 percent versus 76.6 percent); the 3.3 percent (95 percent CI, -7.5 to 12.5 percent) greater effectiveness achieved statistically significant noninferiority relative to the a priori specified −12 percent noninferiority margin (p = 0.004). For avoidance of overanticoagulation, weight-based enoxaparin administration was superior to fixed-dose administration (90.6 percent versus 82.2 percent); the 8.4 percent (95 percent CI, 0.1 to 16.6 percent) greater effectiveness showed significant safety superiority (p = 0.046). Ninety-day venous thromboembolism and major bleeding were not different between fixed-dose and weight-based cohorts (0.66 percent versus 0.69 percent, p = 0.98; 3.3 percent versus 4.2 percent, p = 0.72, respectively). Conclusion: Weight-based administration showed superior pharmacokinetics for avoidance of underanticoagulation and overanticoagulation in postoperative patients receiving prophylactic enoxaparin.

Genomic Analysis of Thrombophilia Variants in the General Population for the Creation of an Effective Preoperative Screening Tool

“…A weight-based therapy of 0.5 mg/kg twice daily for 90 days was found to avoid both under- and overanticoagulation. 6…”

A New Approach for Venous Thromboembolism Prevention in Plastic Surgery

“…4,6 Therefore, controlling for median Caprini scores and hospital stays to force a P value under 0.05 is not justified. 4,6 Other examples are widening the eligibility criteria to include upper extremity thromboses, 21 which have a different etiology (central line trauma), or finding a safety advantage for weight-based enoxaparin dosing 22 when controlling for age and central lines—factors not known to affect antifactor Xa levels.…”

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.…”

“…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.…”

“…By controlling for median Caprini scores and hospital stays, the Venous Thromboembolism Prevention Study 7 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 variables 1,7 and expanding eligibility criteria 3 in order to achieve a p value less than 0.05 that conforms to the study hypothesis.…”