Correspondence
Enoxaparin in Neurosurgical Patients
N Engl J Med 1998; 339:1639-1640November 26, 1998
- Article
To the Editor:
The study by Agnelli et al. (July 9 issue)1 of the efficacy of enoxaparin (a low-molecular-weight heparin) plus graded compression stockings as prophylaxis against deep-vein thrombosis in neurosurgical patients is both sound and timely. Unfortunately, their conclusion that this combination “should be the method of choice for prophylaxis against venous thromboembolism in the majority of patients undergoing elective neurosurgery” may be premature. Such a statement would require this combination to be superior to all alternatives with respect to efficacy, safety, and cost. Although Agnelli et al. showed that the combination of enoxaparin and compression stockings is as safe as and more efficacious than compression stockings alone, they present no data on whether low-dose unfractionated heparin plus compression stockings may be just as efficacious. The use of such an alternative would clearly save money and might even be safer. Studies examining low-dose unfractionated heparin and low-molecular-weight heparin have demonstrated that the two are equally effective or only slightly different.2,3 In addition, although Agnelli et al. found no increase in bleeding in the enoxaparin group, there is sufficient evidence in the literature to suggest that bleeding is a concern, particularly in neurosurgical patients. Nurmohamed et al. found a nonsignificant difference in the number of major hemorrhages between neurosurgical patients in the low-molecular-weight–heparin group and those in the control group (six vs. two events), but closer inspection reveals that all six of the bleeding episodes in the low-molecular-weight–heparin group were intracranial, whereas only one of those in the control group was intracranial (the other was gastric).4 Thus, the incidence of intracranial bleeding was significantly greater with low-molecular-weight heparin. Studies in patients who have had trauma or have undergone abdominal surgery have also aroused concern that low-molecular-weight heparin is associated with a higher risk of hemorrhagic complications than is low-dose unfractionated heparin.2,5 In addition, there are questions whether protamine can neutralize low-molecular-weight heparin as effectively as it can low-dose unfractionated heparin; no studies of these questions have been conducted in humans.3
5 ReferencesE. Sander Connolly, M.D.
J Mocco, B.S.
Columbia University College of Physicians and Surgeons, New York, NY 100321
Agnelli G ,Piovella F ,Buoncristiani P , et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998;339:80-85
Full Text | Web of Science | Medline2
Bergqvist D ,Burmark US ,Frisell J , et al. Thromboprophylactic effect of low molecular weight heparin started in the evening before elective general abdominal surgery: a comparison with low-dose heparin. Semin Thromb Hemost 1990;16:Suppl:19-24
Web of Science | Medline3
Weitz JI . Low-molecular-weight heparins. N Engl J Med 1997;337:688-698
Full Text | Web of Science | Medline4
Nurmohamed MT ,van Riel AM ,Henkens CM , et al. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost 1996;75:233-238
Web of Science | Medline5
Geerts WH ,Jay RM ,Code KI , et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701-707
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We appreciate the concern expressed by Connolly and Mocco about whether treatment with enoxaparin and compression stockings should be regarded as the method of choice to prevent venous thromboembolism in neurosurgical patients. Their concern is based on two major issues: the absence of a comparison trial with unfractionated heparin and the fear of bleeding complications.
The relative advantage of enoxaparin over unfractionated heparin with respect to efficacy and safety in this setting remains to be defined in a comparison trial. However, our understanding of meta-analyses of the comparative efficacy of low-molecular-weight heparins and unfractionated heparin in the prevention of venous thromboembolism differs from that of Connolly and Mocco. Indeed, whereas for low-risk surgical procedures, low-molecular-weight heparins have few if any advantages over unfractionated heparin, low-molecular-weight heparins appear to be more effective than unfractionated heparin for high-risk procedures,1 a category that we believe should include elective neurosurgery.
Bleeding complications in neurosurgical patients who are receiving an antithrombotic agent to prevent venous thromboembolism remain a crucial issue. Our study was not large enough to address differences in the risk of bleeding between the two groups. To obtain a more accurate estimation of the risk of bleeding, we performed an overview of four randomized studies (total, 1022 patients) comparing low-dose unfractionated heparin or low-molecular-weight heparins with placebo in this clinical setting.2-5 Major bleeding was observed in 12 patients who received heparin or low-molecular-weight heparin (2.4 percent) and 7 patients who received placebo (1.4 percent). All but one of the episodes in each group were intracranial, but none were fatal. The number needed to harm — the number of patients who would have to receive the experimental treatment as compared with the control treatment in order for 1 additional patient to be harmed — is 103. In our study, nine patients in the placebo group (6 percent) and one in the enoxaparin group (1 percent) had clinically overt thromboembolic events confirmed by objective testing (P=0.002). The thromboembolic event was fatal in two patients in the placebo group. The number needed to treat — the number of patients who need to be treated in order to have one additional favorable clinical outcome — is 20.
We believe that these data reinforce the concept of the clinical value of treatment with enoxaparin and compression stockings in the prevention of venous thromboembolism in neurosurgical patients. However, a large study of clinical outcomes (symptomatic venous thromboembolism and major bleeding) would be necessary before this strategy of prophylaxis could be recommended for patients who are undergoing elective neurosurgery.
5 ReferencesGiancarlo Agnelli, M.D.
Alfonso Iorio, M.D.
Università di Perugia, 06123 Perugia, Italy1
Weitz JI . Low-molecular-weight heparins. N Engl J Med 1997;337:688-698
Full Text | Web of Science | Medline2
Agnelli G ,Piovella F ,Buoncristiani P , et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998;339:80-85
Full Text | Web of Science | Medline3
Nurmohamed MT ,van Riel AM ,Henkens CM , et al. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost 1996;75:233-238
Web of Science | Medline4
Melon E, Keravel Y, Gaston A, Huet Y, Combes S, Neuronox Group 5
Cerrato D ,Ariano C ,Fiacchino F . Deep vein thrombosis and low-dose heparin prophylaxis in neurosurgical patients. J Neurosurg 1978;49:378-381
CrossRef | Web of Science | Medline
