Is Differential Activity of Enoxaparin and Unfractionated Heparin According to the Location of Deep-Vein Thrombosis in Acute Ischemic Stroke Patients Driven by Different Pathogenic Mechanisms?.
Authors: Drouet Ludovic , Sherman David G. , Albers Gregory W. , Bladin Christopher , Fieschi Cesare , Gabbai Alberto A. , Kase Carlos S. , O’Riordan William , Pineo Graham F. 
Published: October 2019

Introduction Studies of patients undergoing hip surgery have shown that approximately two-thirds of subsequent deep-vein thromboses (DVT) were ipsilateral to the surgery and that not all thromboprophylactic agents were equally effective in reducing DVT on both sides of the body. This suggests a possible difference in the mechanisms of action of these agents. In PREVAIL, a study of VTE prophylaxis in acute ischemic stroke patients, we assessed the relationship between the side of the body affected by motor impairment, the side on which a DVT occurred, and the comparative effects of enoxaparin and UFH on the incidence of ipsilateral and contralateral DVT.

Methods Patients with acute ischemic stroke (confirmed by CT scan or MRI) and unable to walk unassisted due to motor impairment of the leg were randomized, within 48h of symptom onset, to receive enoxaparin 40mg subcutaneously once-daily or UFH 5000 IU subcutaneously every 12h for 10±4 days. DVT was confirmed by venography, or ultrasonography when venography was not practical. Pulmonary embolism (PE) was confirmed by VQ or CT scan, or angiography. We conducted a post hoc analysis to test:

the correlation between side of motor impairment and side of subsequent DVT; the relative risk reduction for DVT, associated with enoxaparin versus UFH when DVT and motor impairment were ipsilateral or contralateral. Differences between the sides of motor impairment and VTE were tested using the McNemar test.

Results The PREVAIL study reported a 43% relative reduction in the risk of symptomatic or asymptomatic DVT, symptomatic PE, or fatal PE with enoxaparin compared with UFH in acute ischemic stroke patients (10.2% versus 18.1%, p=0.0001), with no increase in clinically important bleeding. The current analyses, investigating the incidence of unilateral DVT, demonstrated a good concordance between the side of the motor impairment and subsequent DVT (McNemar test, p=0.47 suggesting strong correlation). The benefit of enoxaparin compared with UFH for reducing the risk of DVT was significant for ipsilateral DVT, but not contralateral DVT (see Table).

Table: DVT incidence in acute ischemic stroke patients relative to the side of motor impairment Side of DVT relative to motor impairment Enoxaparin (N=613) UFH (N=609) Relative Risk [95% CI] P value* *Chi-squared test Ipsilateral, n (%) 33 (5.4) 60 (9.9) 0.55 [0.36–0.82] 0.003 Contralateral, n (%) 21 (3.4) 26 (4.3) 0.80 [0.46–1.41] 0.44

Conclusion Our observations in this post hoc analysis of PREVAIL study data are consistent with the hypothesis that the relative effectiveness of enoxaparin compared with UFH may be more important for flow-dependent thrombogenic factors (ipsilateral side of DVT) than for inflammation (hypercoagulability)-dependent thrombogenic factors (contralateral side of DVT). Further research is warranted to confirm this hypothesis.