Correspondence
Prevention of Venous Thromboembolism with Fondaparinux
N Engl J Med 2002; 346:940-942March 21, 2002
- Article
To the Editor:
Eriksson et al. (Nov. 1 issue)1 report that fondaparinux was more effective than enoxaparin and equally safe in preventing venous thromboembolism after hip-fracture surgery. In their study, the first dose of enoxaparin was to be administered 12±2 hours preoperatively and the second dose 12 to 24 hours postoperatively, according to the recommendation of the manufacturer. However, enoxaparin was first given postoperatively in as many as 74.4 percent of the patients in the enoxaparin group. The delay in the initiation of enoxaparin may have resulted in an underestimation of its preventive effects against thromboembolism and its hemorrhagic risks, thus obscuring the relative effects of fondaparinux. Since significant unrecognized bias may exist, the results must be interpreted with caution. A better explanation of why the treatment of the majority of the patients did not conform to the study protocol would be beneficial for readers.
1 ReferencesNaoko Murashige, M.D.
Beth Israel Medical Center, New York, NY 10003
nmurashige@hotmail.com Masahiro Kami, M.D.
National Cancer Center Hospital, Tokyo 104-0045, Japan1
Eriksson BI ,Bauer KA ,Lassen MR ,Turpie AGG . Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345:1298-1304
Full Text | Web of Science | Medline
To the Editor:
Several methodologic issues have to be considered in interpreting the results reported by Eriksson et al. Other investigators have found that the initiation of antithrombotic prophylaxis close to the time of surgery is more effective than delaying prophylaxis and that the efficacy of fondaparinux is dose-dependent.1-4 It is therefore apparent that the superiority of the pentasaccharide reported by Eriksson et al. reflects the timing of the initiation of treatment in the early postoperative period, the doubling of the dose within 24 hours after surgery, and the administration of one additional dose during the study period.
4 ReferencesStefan Marlovits, M.D.
University of Vienna, A-1090 Vienna, Austria
stefan.marlovits@akh-wien. ac. at 1
Jorgensen PS ,Strandberg C ,Wille-Jorgensen P , et al. Early preoperative thromboprophylaxis with Klexane in hip fracture surgery: a placebo-controlled study. Clin Appl Thromb Hemost 1998;4:140-142
CrossRef | Web of Science2
Hull RD ,Pineo GF ,Francis C , et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. Arch Intern Med 2000;160:2199-2207
CrossRef | Web of Science | Medline3
Francis CW ,Pellegrini VD Jr ,Totterman S , et al. Prevention of deep-vein thrombosis after total hip arthroplasty: comparison of warfarin and dalteparin. J Bone Joint Surg Am 1997;79:1365-1372
Web of Science | Medline4
Turpie AGG ,Gallus AS ,Hoek JA . A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001;344:619-625
Full Text | Web of Science | Medline
To the Editor:
In his editorial, Diuguid1 suggests that low-molecular-weight heparins need to be administered preoperatively to provide maximal benefit. The timing of the commencement of treatment with heparin and low-molecular-weight heparins has been long debated; a recent study suggests that there is no difference in efficacy.2 This absence of a difference weakens the editorialist's suggestion that fondaparinux “may find its initial niche in patients undergoing regional anesthesia” because of the fact that it can be commenced postoperatively. The pharmacologic profile of fondaparinux does not make it more suitable than other agents to use in combination with regional anesthesia. On the contrary, it is long acting and its effects are difficult to monitor or reverse, so that the precautions required when spinal or epidural anesthesia is combined with perioperative fondaparinux would need to be as stringent as those for low-molecular-weight heparins, if not more so. At present, there appears to be no reason to commence fondaparinux therapy any earlier or later after surgery than treatment with any of the low-molecular-weight heparins is begun, and in my opinion, a fair comparison of the efficacy of these agents has not yet been performed.
2 ReferencesMark Priestley, M.B., B.S.
Westmead Hospital, Westmead 2145, Sydney, Australia
mark_priestley@wsahs.nsw. gov. au 1
Diuguid DL . Choosing a parenteral anticoagulant agent. N Engl J Med 2001;345:1340-1342
Full Text | Web of Science | Medline2
Hull RD ,Pineo GF ,Francis C , et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. Arch Intern Med 2000;160:2208-2215
CrossRef | Web of Science | Medline
To the Editor:
After reading Dr. Diuguid's editorial, I still have a question concerning the choice of low-molecular-weight heparins for the treatment of venous thromboembolism. Is it permissible to recommend dalteparin instead of enoxaparin for the treatment of venous thromboembolism, especially if there are major differences in cost? Are we taking a leap of faith to use these low-molecular-weight heparins interchangeably, or should this be the standard of care?
Rick Scacewater, M.D.
1531 W. 32nd St., Suite 201, Joplin, MO 64804Author/Editor Response
Dr. Eriksson replies:
To the Editor: Drs. Murashige and Kami and Dr. Marlovits comment on the timing of the first doses of enoxaparin and fondaparinux in our study. According to the study protocol, the first dose of enoxaparin was to be given 12±2 hours preoperatively, except that omission of the preoperative injection was recommended if the use of regional anesthesia or epidural catheterization was planned. This approach is in line with the recommendations of health authorities in Europe. Because in many cases, surgery was performed soon after admission and the use of regional anesthesia was planned, only 25.6 percent of patients received this injection. This outcome reflects the usual situation in clinical practice, in which it is difficult to administer antithrombotic agents preoperatively in emergency situations. My colleagues and I think that this practice did not result in an underestimation of the prophylactic effect of enoxaparin. Furthermore, in one study, treatment with enoxaparin (40 mg) was initiated preoperatively in 78.1 percent of patients who were undergoing elective hip surgery, and this approach was significantly less effective in preventing deep-vein thrombosis than was the postoperative initiation of fondaparinux.1
The regimen of fondaparinux was selected from a large, phase 2 trial.2 A post hoc logistic-regression analysis of all phase 3 studies involving patients who first received fondaparinux between three and nine hours after orthopedic surgery showed that there was no significant relation between the timing of the first injection and efficacy.3 The hypothesis that administering low-molecular-weight heparins close to the time of surgery may increase efficacy has not been tested in a direct comparison.
Dr. Marlovits suggests that the superior efficacy of fondaparinux may reflect a disparity between the number of fondaparinux and enoxaparin injections. This is unlikely because a median of 7 injections of fondaparinux (range, 1 to 11) and of enoxaparin (range, 2 to 10) were administered up to the time of the qualifying examination for venous thromboembolism. Furthermore, in a companion study of patients undergoing elective knee surgery,4 30 mg of enoxaparin administered twice daily was significantly less effective in preventing deep-vein thrombosis than was fondaparinux administered in the same dose regimen that we used.
We believe that factors other than the timing of the initial dose contributed to the superior efficacy of fondaparinux, such as the ability of this agent to inhibit activated factor X selectively and the rapid onset of action and optimal half-life of this agent.
4 ReferencesBengt I. Eriksson, M.D., Ph.D.
Sahlgrenska University Hospital–Östra, SE-41685 Göteborg, Sweden
b.eriksson@orthop. gu. se 1
Lassen MR . The EPHESUS Study: comparison of the first synthetic factor Xa inhibitor with low molecular weight heparin (LMWH) in the prevention of venous thromboembolism (VTE) after elective hip replacement. Blood 2000;96:490A-490A abstract.
Web of Science2
Turpie AGG ,Gallus AS ,Hoek JA . A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001;344:619-625
Full Text | Web of Science | Medline3
Turpie AGG ,Bauer KA ,Eriksson BI ,Lassen MR . Effect on efficacy and safety of the timing of the first pentasaccharide (fondaparinux, Arixtra) administration in the prevention of venous thromboembolism after major orthopedic surgery. Blood 2001;98:266A-266A abstract.
CrossRef | Web of Science4
Bauer KA ,Eriksson BI ,Lassen MR ,Turpie AGG . Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-1310
Full Text | Web of Science | Medline
Author/Editor Response
The editorialist replies:
To the Editor: Priestley cites a study by Hull et al. to bolster his argument that there is no difference between preoperative and postoperative administration of dalteparin in terms of the prevention of venous thromboembolism after hip surgery. However, Hull et al.1 reported an incidence of venous thromboembolism of 19.7 percent, which was virtually identical to the rate of 19.1 percent reported by Eriksson et al. in the enoxaparin group in their trial and considerably higher than the incidence of 8.3 percent reported in the fondaparinux group.2 Several earlier studies of preoperatively administered low-molecular-weight heparins have reported rates of venous thromboembolism similar to that associated with fondaparinux therapy, but the preoperative administration of these drugs is contraindicated in patients who receive regional anesthesia.
I share Priestley's concern about the pharmacologic profile of fondaparinux, especially since the problems with low-molecular-weight heparins became apparent only after the drugs had been on the market for several years. I agree that the precautions for the use of fondaparinux should be similar to those for the use of low-molecular-weight heparins. However, I think that the current data support strong consideration of the use of fondaparinux as prophylaxis against venous thromboembolism in high-risk patients, especially those who receive regional anesthesia, since such patients cannot receive low-molecular-weight heparins preoperatively.
Scacewater raises a legitimate question about the interchangeability of low-molecular-weight heparins in the treatment of venous thromboembolism. These drugs have clear differences in their pharmacologic profiles. It is not clear, however, that these differences result in clinically significant differences in efficacy. All the studies conducted to date have compared low-molecular-weight heparin with unfractionated heparin, and they have shown that dalteparin, enoxaparin, and tinzaparin, given in appropriate anticoagulant doses, are equivalent to unfractionated heparin in terms of both safety and efficacy. Although a head-to-head trial of the low-molecular-weight heparins would be ideal, from the data available it follows that these agents are equivalent in the treatment of venous thromboembolism and that the choice can be based on the preference of the physician, patient, or institution.
2 ReferencesDavid L. Diuguid, M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 10032
dld6@columbia.edu 1
Hull RD ,Pineo GF ,Francis C , et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized trial. Arch Intern Med 2000;160:2208-2215
CrossRef | Web of Science | Medline2
Eriksson BI ,Bauer KA ,Lassen MR ,Turpie AGG . Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345:1298-1304
Full Text | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Bruno Tribout, Florence Colin-Mercier. (2007) New versus Established Drugs in Venous Thromboprophylaxis. American Journal of Cardiovascular Drugs 7:1, 1-15
CrossRef2
A.G.G. Turpie. (2004) The design of venous thromboembolism prophylaxis trials: Fondaparinux is definitely more effective than enoxaparin in orthopaedic surgery. International Journal of Clinical Practice 58:5, 483-493
CrossRef3
Gordon DO Lowe, Peter AG Sandercock, Frits R Rosendaal. (2003) Prevention of venous thromboembolism after major orthopaedic surgery: is fondaparinux an advance?. The Lancet 362:9383, 504-505
CrossRef
