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Fondaparinux versus enoxaparin for prevention of venous thromboembolism
CORRESPONDENCE
the need for extended out-of-hospital prophylaxis with low-molecular-weight heparins. Compared with placebo, extended out-of-hospital prophylaxis decreased significantly the frequency of all episodes of deep venous thrombosis, proximal venous thrombosis, and symptomatic venous thromboembolism; major bleeding occurred only in one of 862 patients in the placebo group. Total duration of prophylaxis in the six clinical trials they reviewed ranged from 27 to 35 days, and duration of the out-of-hospital prophylaxis ranged from 18 to 29 days. Extended thromboprophylaxis with a low-molecular weight heparin is better than placebo in hip-replacement surgery. Fondaparinux, in Lassen and colleagues’ study, is better than enoxaparin at day 11 but does not differ for symptomatic venous thromboembolism at day 49. Therefore, is a short treatment with fondaparinux better than extended treatment with a low-molecular-weight heparin? Turpie and colleagues mention that lack of power and chance cannot be ruled out as explanations for their results. This is true, but in Lassen and colleagues’ study, the dose of enoxaparin is 40 mg once daily, whereas in that of Turpie and colleagues it is 30 mg twice daily. Better results for enoxaparin 30 mg twice daily than for 40 mg once daily have been shown.5 The rate of venous thromboembolism by day 11 in the enoxaparin group is lower in Turpie and colleagues’ than in Lassen and colleagues’ report (8 vs 9%), although that in the fondaparinux group is lower in Lassen and colleagues’ study. If the rate of venous thromboembolism in the enoxaparin group had been 9% in both studies, the corresponding p value would have been 0·029, despite a venous thromboembolism rate of 6% in the fondaparinux group. It would be interesting to know the clinical risk factors for venous thromboembolism (other than previous venous thromboembolism), such as cancer or major medical illness in each group of patients included in both studies. *Javier Borja, Pere Olivella, Jorge Curto Medical Department, Pharmacia Spain SA, Ctra De Rubí 90–100, 08190 Sant Cugat del Vallés, Barcelona, Spain (e-mail: [email protected]) 1
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised
1604
2
3
4
5
double-blind comparison. Lancet 2002; 359: 1715–20. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hipreplacement surgery: a randomised doubleblind trial. Lancet 2002; 359: 1721–26. Agnelli A. Prevention of venous thromboembolism. Thromb Res 2000; 97: V49–62. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecularweight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135: 858–69. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecularweight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. J Bone Joint Surg 1994; 76A: 3–14.
Sir—Michael Rud Lassen and colleagues1 describe their dosing regimen in patients undergoing elective hip replacement surgery as 2·5 mg fondaparinux starting postoperatively, or 40 mg enoxaparin starting preoperatively. If spinal or epidural anaesthesia or catheterisation was planned, however, preoperative administration of study treatments was omitted. 61% of the fondaparinux group and 58% of the enoxaparin group were excluded by this criterion. Lassen and colleagues postulate that, of the 919 patients receiving enoxaparin who were analysed for primary efficacy, the drug was started preoperatively in 718 (78%) and postoperatively in 201 (22%), mainly because of regional anaesthesia. Were preoperative enoxaparin injections given to 42% or 78% of patients? Was it a violation of the study protocol if patients received enoxaparin preoperatively despite regional anaesthesia? The interaction between surgery and first administration of low-molecularweight heparin is a critical parameter that substantially affects the occurrence of deep venous thrombosis in hiparthroplasty patients.2 The delayed start of thromboprophylaxis with enoxaparin could, therefore, have altered the results.
2
Sir—Despite Michael Rud Lassen and colleagues1 and Alexander Turpie and colleagues2 finding the safety profile of fondaparinux and enoxaparin to be comparable and acceptable, major bleeding did occur in both studies. Bounameaux and Perneger3 summarised the data from 4 phase III trials comparing fondaparinux and enoxaparin and an association between fondaparinux and major bleeding in 2·7% of cases and enoxaparin in 1·7% of cases. Although no patients died from bleeding, risk-benefit analyses must also take into account that only one patient in Turpie and colleagues’ and no patients in Lassen and colleagues’ studies died from venous thromboembolic disease. In all environments mistakes happen. Makris and co-workers4 reported a patient who was accidentally given a therapeutic rather than prophylactic dose of enoxaparin before neurosurgery. Protamine could not fully reverse the coagulopathy, and notable clinical implications ensued. Fondaparinux is not reversed by protamine5 or any other reliable reversal agent. In addition, the half-life of fondaparinux (15–20 h) is substantially longer than that of unfractionated and most lowmolecular-weight heparins.5 In assessment of the usefulness of newer anticoagulant agents, serious consideration must be given to the reversibility of anticoagulant effects before their widespread introduction into clinical practice. Edward Morris Department of Haematology, Canterbury Health Laboratories, PO Box 151, Christchurch, New Zealand (e-mail: [email protected]) 1
*Heinrich Thaler, Ernst Sim Unfallkrankenhaus Meidling, 1120 Vienna, Austria (e-mail: [email protected]) 1
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hipreplacement surgery: a randomised doubleblind comparison. Lancet 2002; 359: 1715–20.
Hull R, Pineo G, Stein P, et al. Timing of the initial administration of low-molecular weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. J Thromb Haemost 2001; 86 (suppl): 86/1736.
2
3
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hipreplacement surgery: a randomised doubleblind comparison. Lancet 2002; 359: 1715–20. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee. Post-operative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hipreplacement surgery: a randomised doubleblind trial. Lancet 2002; 359: 1721–26. Bounameaux H, Perneger T. Fondaparinux: a new synthetic pentasaccharide for thrombosis prevention. Lancet 2002; 359: 1710.
THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
the need for extended out-of-hospital prophylaxis with low-molecular-weight heparins. Compared with placebo, extended out-of-hospital prophylaxis decreased significantly the frequency of all episodes of deep venous thrombosis, proximal venous thrombosis, and symptomatic venous thromboembolism; major bleeding occurred only in one of 862 patients in the placebo group. Total duration of prophylaxis in the six clinical trials they reviewed ranged from 27 to 35 days, and duration of the out-of-hospital prophylaxis ranged from 18 to 29 days. Extended thromboprophylaxis with a low-molecular weight heparin is better than placebo in hip-replacement surgery. Fondaparinux, in Lassen and colleagues’ study, is better than enoxaparin at day 11 but does not differ for symptomatic venous thromboembolism at day 49. Therefore, is a short treatment with fondaparinux better than extended treatment with a low-molecular-weight heparin? Turpie and colleagues mention that lack of power and chance cannot be ruled out as explanations for their results. This is true, but in Lassen and colleagues’ study, the dose of enoxaparin is 40 mg once daily, whereas in that of Turpie and colleagues it is 30 mg twice daily. Better results for enoxaparin 30 mg twice daily than for 40 mg once daily have been shown.5 The rate of venous thromboembolism by day 11 in the enoxaparin group is lower in Turpie and colleagues’ than in Lassen and colleagues’ report (8 vs 9%), although that in the fondaparinux group is lower in Lassen and colleagues’ study. If the rate of venous thromboembolism in the enoxaparin group had been 9% in both studies, the corresponding p value would have been 0·029, despite a venous thromboembolism rate of 6% in the fondaparinux group. It would be interesting to know the clinical risk factors for venous thromboembolism (other than previous venous thromboembolism), such as cancer or major medical illness in each group of patients included in both studies. *Javier Borja, Pere Olivella, Jorge Curto Medical Department, Pharmacia Spain SA, Ctra De Rubí 90–100, 08190 Sant Cugat del Vallés, Barcelona, Spain (e-mail: [email protected]) 1
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised
1604
2
3
4
5
double-blind comparison. Lancet 2002; 359: 1715–20. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hipreplacement surgery: a randomised doubleblind trial. Lancet 2002; 359: 1721–26. Agnelli A. Prevention of venous thromboembolism. Thromb Res 2000; 97: V49–62. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecularweight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135: 858–69. Colwell CW, Spiro TE, Trowbridge AA, et al. Use of enoxaparin, a low-molecularweight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement. J Bone Joint Surg 1994; 76A: 3–14.
Sir—Michael Rud Lassen and colleagues1 describe their dosing regimen in patients undergoing elective hip replacement surgery as 2·5 mg fondaparinux starting postoperatively, or 40 mg enoxaparin starting preoperatively. If spinal or epidural anaesthesia or catheterisation was planned, however, preoperative administration of study treatments was omitted. 61% of the fondaparinux group and 58% of the enoxaparin group were excluded by this criterion. Lassen and colleagues postulate that, of the 919 patients receiving enoxaparin who were analysed for primary efficacy, the drug was started preoperatively in 718 (78%) and postoperatively in 201 (22%), mainly because of regional anaesthesia. Were preoperative enoxaparin injections given to 42% or 78% of patients? Was it a violation of the study protocol if patients received enoxaparin preoperatively despite regional anaesthesia? The interaction between surgery and first administration of low-molecularweight heparin is a critical parameter that substantially affects the occurrence of deep venous thrombosis in hiparthroplasty patients.2 The delayed start of thromboprophylaxis with enoxaparin could, therefore, have altered the results.
2
Sir—Despite Michael Rud Lassen and colleagues1 and Alexander Turpie and colleagues2 finding the safety profile of fondaparinux and enoxaparin to be comparable and acceptable, major bleeding did occur in both studies. Bounameaux and Perneger3 summarised the data from 4 phase III trials comparing fondaparinux and enoxaparin and an association between fondaparinux and major bleeding in 2·7% of cases and enoxaparin in 1·7% of cases. Although no patients died from bleeding, risk-benefit analyses must also take into account that only one patient in Turpie and colleagues’ and no patients in Lassen and colleagues’ studies died from venous thromboembolic disease. In all environments mistakes happen. Makris and co-workers4 reported a patient who was accidentally given a therapeutic rather than prophylactic dose of enoxaparin before neurosurgery. Protamine could not fully reverse the coagulopathy, and notable clinical implications ensued. Fondaparinux is not reversed by protamine5 or any other reliable reversal agent. In addition, the half-life of fondaparinux (15–20 h) is substantially longer than that of unfractionated and most lowmolecular-weight heparins.5 In assessment of the usefulness of newer anticoagulant agents, serious consideration must be given to the reversibility of anticoagulant effects before their widespread introduction into clinical practice. Edward Morris Department of Haematology, Canterbury Health Laboratories, PO Box 151, Christchurch, New Zealand (e-mail: [email protected]) 1
*Heinrich Thaler, Ernst Sim Unfallkrankenhaus Meidling, 1120 Vienna, Austria (e-mail: [email protected]) 1
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hipreplacement surgery: a randomised doubleblind comparison. Lancet 2002; 359: 1715–20.
Hull R, Pineo G, Stein P, et al. Timing of the initial administration of low-molecular weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. J Thromb Haemost 2001; 86 (suppl): 86/1736.
2
3
Lassen MR, Bauer KA, Eriksson BI, Turpie AGG, for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hipreplacement surgery: a randomised doubleblind comparison. Lancet 2002; 359: 1715–20. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee. Post-operative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hipreplacement surgery: a randomised doubleblind trial. Lancet 2002; 359: 1721–26. Bounameaux H, Perneger T. Fondaparinux: a new synthetic pentasaccharide for thrombosis prevention. Lancet 2002; 359: 1710.
THE LANCET • Vol 360 • November 16, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.