Erythropoiesis-Stimulating Agents in Trauma Patients Associated With Significantly Increased Risk for Venous Thromboembolism

Emma Hitt, PhD

February 05, 2008

February 5, 2008 (Honolulu) — Use of erythropoiesis-stimulating agents (ESAs) in trauma patients appears to be associated with a significantly increased risk for venous thromboembolism (VTE), and anticoagulants do not protect against this risk, a new study has found.

Keith A. Hecht, PharmD, from the University of Southern Nevada College of Pharmacy, Henderson, presented the findings here at the Society of Critical Care Medicine 37th Critical Care Congress.

According to Dr. Hecht and colleagues, recent clinical studies have demonstrated an increased risk for VTEs in patients receiving ESAs for various indications. Trauma patients, especially those with an Abbreviated Injury Score (AIS)-Head or AIS-Extremities of 3 or more (ie, a high degree of trauma severity) may be at increased risk for VTEs after the use of erythropoietin.

To evaluate this issue further, the researchers conducted a retrospective cohort study at a level 1 trauma center, comparing patients who had and patients who had not received ESAs. All patients were admitted for trauma-related injuries between August 1, 2002, and August 31, 2007. Patients were all 18 years of age or older and had survived for 24 or more hours. Patients assigned to the cohort group (n = 1565) had all received ESAs (for various indications excluding renal), and patients in the control group (n = 8419) had not received ESAs. Of the patients receiving ESAs, 97% received erythropoietin and 3% received darbepoetin.

The primary outcome was occurrence of VTEs as indicated by discharge coding (International Statistical Classification of Diseases and Related Health Problems 9 code for pulmonary embolism [PE] or deep vein thrombosis [DVT]). Secondary outcomes were VTE rates in patients with AIS-Head and AIS-Extremities of 3 or more. VTE rates in patients receiving prophylaxis with anticoagulants were also determined.

As expected, several differences existed at baseline between the cohort group receiving ESAs and the control group. Patients requiring ESAs had a significantly higher length of stay in the hospital and in the intensive care unit. In addition, Glasgow Coma scores, Injury Severity scores, and AIS were higher in the ESA cohort compared with the control group.

Among patients receiving ESAs, rates of VTE were nearly 7 times higher: 3.96% had VTE compared with 0.57% in control group (P < .001). The rate of DVT was 2.49% vs 0.32% (P < .001), and the rate of PE was 1.66% vs 0.29% (P < .001).

To overcome the differences at baseline between the cohort and control groups, the researchers compared results in patients with the most severe injuries only (AIS ≥ 3). According to Dr. Hecht, the baseline characteristics between these 2 groups were much more comparable, but the risk for VTE remained elevated with ESA use. In patients with AIS-Head of 3 or more, the VTE rates were 1.04% and 5.51% in the control and cohort groups, respectively (P < .001); in patients with AIS-Extremities of 3 or more, the VTE rates were 0.99% and 3.27%, respectively (P < .001).

Notably, VTE prophylaxis with anticoagulants, used in about two thirds of patients receiving ESAs, did not appear to reduce the risk for VTEs overall, although prophylaxis reduced the rate of VTE in the subgroup of patients receiving ESAs with AIS-Extremities of 3 or more compared with those not receiving prophylaxis (2.60% vs 6.31%; P = .05), although Dr. Hecht pointed out that "this population wasn't large enough to say with confidence that prophylaxis reduced risk significantly."

He told Medscape Critical Care, "ESAs used to be considered a relatively benign group of drugs, but more data have come out showing the risk of VTEs, and these results definitely support those findings. Once hemoglobin [Hb] levels have exceeded 12 g/dL, patients receiving ESAs are at higher risk of VTE. Clinicians need to be monitoring patients carefully.

"We were also concerned that prophylaxis with anticoagulants seemed to provide little benefit, probably because the risk with ESAs was so dramatic," he added.

Dr. Hecht also pointed out that his study only included patients with symptomatic VTE, so many more cases of asymptomatic VTE also may have occurred.

"This study highlights the importance of withholding ESAs for many patients when possible," said Raymond Wedderburn, MD, from St. Luke's Roosevelt Hospital Center, New York, who moderated the poster discussion session. "At our institution, we rarely give ESAs unless a patient has dropped to a Hb level much lower than 10 g/dL — sometimes as low as 7 g/dL," he said, "especially in trauma patients who are younger and who may be able to tolerate lower Hb levels."

The study was performed with no outside support. Dr. Hecht and Dr. Wedderburn have disclosed no relevant financial relationships.

Society of Critical Care Medicine 37th Critical Care Congress: Abstract 251. Presented February 3, 2008.

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