麻豆传媒

A majority (67.9%) of colorectal surgery patients showed inadequate anti-factor Xa (aFXa) levels in response to a once-daily 40-mg dose of the anticoagulant enoxaparin (Lovenox), reported researchers from the University of Utah in Salt Lake City. The findings, the team said, may explain the high rate of breakthrough venous thromboembolism (VTE) observed in many clinical trials.

Christopher J. Pannucci, MD, MS, and colleagues also found an association between elevated weight and lower aFXa levels.

"The adequacy of enoxaparin prophylaxis represents a direction for future research, and future studies should examine the effectiveness and safety of weight-based or twice-daily enoxaparin prophylaxis in patients undergoing colorectal surgery," the team wrote online in .

They noted that 4-12% of colorectal surgery patients on a standard dose of the low-molecular-weight heparin (LMWH) enoxaparin have a postoperative VTE event. Although a recent American Society of Colon & Rectal Surgeons recommended prophylaxis with LMWH, the recommendation did not provide specifics about optimal dosing, Pannucci and co-authors added.

in 55 patients after abdominal surgery showed that only 54.4% had inadequate peak aFXa levels after standard-dose enoxaparin.

Over 16 months in 2017-2018, the Salt Lake City group's non-randomized prospective study evaluated 116 patients undergoing colorectal resection. The cohort's composition was 56.0% women, 85.3% white, 11.2% Hispanic or Latino, and 3.5% Pacific Islander; mean patient age was 52.1 (range 18-85).

Among the 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation, showing an aFXa of <0.3 IU/mL at the daily 40 mg dose. Weight and peak aFXa levels were inversely correlated (r²=0.38), the researchers reported.

Forty-seven patients (77%) had a trough aFXa level that was not detectable, and most of these had no detectable level of anticoagulation for at least 12 hours a day.

With real-time dose adjustment, however, patients were significantly more likely to achieve an in-range peak at the standard dose: 85.4% vs 29.2% (P<0.001). Although enoxaparin prophylaxis is typically provided as a one-size-fits-all daily dose, emerging data show that patients metabolize fixed doses at variable rates, suggesting that a more individualized approach might be better, Pannucci and co-authors explained.

Reflecting this view, the U.K. Royal College of Obstetricians & Gynecologists weight-tiered postoperative enoxaparin dosing. "Patient-centric enoxaparin dosing allows patients to achieve in-range aFXa levels more rapidly and more frequently than unmonitored, fixed-dose prophylaxis strategies. This is important because a delay to adequate chemical prophylaxis is a risk factor for downstream VTE," Pannucci, et al. wrote.

Nonetheless, the number of adverse events with standard dosing was low. Among the 116 participants with 90-day follow-up or confirmed 90-day death, the rate of symptomatic VTE was 2.6% and the rate of clinically relevant bleeding was 3.4%, the team reported. One of three VTE events occurred during enoxaparin prophylaxis and two occurred after cessation. One of three VTE events occurred during enoxaparin prophylaxis and two occurred after cessation. All four bleeding events occurred during enoxaparin prophylaxis.

No significant difference emerged in 90-day VTE when patients with low versus in-range aFXa levels were compared: 2.7% and 2.9%, respectively (P=0.96).

Study limitations, the authors said, included the low rates of 90-day VTE and bleeding, which precluded definitive association of aFXa levels with 90-day outcomes. A larger trial or pooled analysis of multiple trials could better examine this issue, the investigators said.

Another concern was that some patients were discharged before laboratory samples were drawn, but enoxaparin reaches a steady state only after the third dose. Hence, the findings are not generalizable to those with inpatient stays shorter than 3 days, and the effect of enoxaparin on patients discharged before a steady state is reached remains unknown.

Writing in an accompanying , Juan I. Arcelus, MD, PhD, of the University of Granada in Spain, agreed that the current dosing of enoxaparin may be insufficient thromboprophylaxis in many patients undergoing colorectal surgery, particularly for those with obesity.

He argued, however, that the authors' conclusion that standard-dose enoxaparin represents inadequate prophylaxis for most patients is not supported by the findings, since the rate of 90-day VTE did not differ between patients with low and in-range aFXa levels.

Arcelus also pointed out that the mean duration of prophylaxis in the study was 9.1 days, with only 20% receiving prophylaxis after discharge, but supports the use of higher than usual doses of other LMWHs for 30 days after colon cancer surgery.

In a study of for example, using high-dose bemiparin (5,000 I/d) for 30 days, target peak aFXa levels were achieved in 74% of patients, with no association observed between measured levels and thrombosis or bleeding events.

"There is a need for future studies evaluating extended prophylaxis and comparing once- vs twice-daily LMWH and fixed vs weight-adjusted LMWH doses in this surgical population," Arcelus wrote.