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Thromb Haemost 2005; 94(04): 814-819
DOI: 10.1160/TH02-10-0189
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Prevention of fatal pulmonary embolism and mortality in surgical patients

A randomized double-blind comparison of LMWH with unfractionated heparin
Sylvia Haas
1   Institut für Experimentelle Onkologie und Therapieforschung, Technical University of Munich, Munich, Germany,
,
Helmut Wolf
2   Novartis Pharma GmbH, N2Novartis Pharma GmbH, Nürnberg, Germanyrnberg, Germany
,
Ajay K. Kakkar
3   Centre for Surgical Sciences, Barts and The London, London, UK
,
Jawed Fareed
4   Department of Pathology and Pharmacology, Loyola University Medical Center, Maywood, Illinois, USA
,
Albrecht Encke
5   Zentrum für Chirurgie, University of Frankfurt/Main, Germany
› Author AffiliationsGrant support:This study was supported by a grant from Novartis Pharma GmbH, Nürnberg, Germany.
Further Information

Publication History

Received22 October 2002

Accepted after revision14 July 2005

Publication Date:
07 December 2017 (online)

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Summary

The incidences of fatal pulmonary embolism and death in surgical patients receiving low-molecular-weight heparin thromboprophylaxis have not been previously determined in large, adequately designed clinical trials and information on the relative efficacy and safety of unfractionated and low-molecular-weight heparin in preventing these clinical endpoints is not available. In a double-blind study, 23078 surgical patients randomly received the low-molecular-weight heparin, certoparin (3000 anti Xa IU) subcutaneously once-daily, or unfractionated heparin (5000 IU) subcutaneously three-times daily, for a minimum of 5 days. The primary outcome measure, autopsy-proven fatal pulmonary embolism recorded up to 14 days after the end of prophylaxis, occurred in 0.152% (95% confidence interval (CI) 0.10, 0.20%; 35of 23078 patients) of cases, with no significant difference between the certoparin-treated patients (0.147% (95% CI 0.077, 0.217%; 17 of 11542 patients) and patients treated with unfractionated heparin (0.156% (95% CI 0.084, 0.228%; 18 of 11,536 patients, P=0.868). The autopsy rate was 70.2%. Comparing mortality, there was no significant difference between the groups (1.44% [166 of 11542 certoparin patients] versus 1.27% [146 of 11536 unfractionated heparin patients]; P=0.279). The safety profiles of both treatment groups were similar. Once-daily certoparin and three-times daily unfractionated heparin are equally effective and safe in reducing fatal pulmonary embolism and death to low levels in surgical patients and mirror the findings of comparative efficacy studies using surrogate endpoints.

Keywords

Randomised double-blind trial - low-molecular-weight heparin - unfractionated heparin - surgical thromboprophylaxis - fatal pulmonary embolism
 

  • References

  • 1 Geerts WH, Pineo GF, Heit J A. et al. Prevention of venous thromboembolism: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126 (Suppl) 338S-400S.
    CrossrefPubMedSearch in Google Scholar
  • 2 Nicolaides AN, Breddin HK, Fareed J. et al. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001; 20: 1-37.
    PubMedSearch in Google Scholar
  • 3 Prevention of fatal postoperative pulmonary embolism by low doses of heparin – An international multicentre trial. Lancet 1975; 2: 145-51.
    PubMedSearch in Google Scholar
  • 4 Kakkar VV, Corrigan TP, Fossard D P. et al. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Reappraisal of results of international multicentre trial. Lancet 1977; 1: 567-9.
    PubMedSearch in Google Scholar
  • 5 Gruber UF, Duckert F, Fridrich R. et al. Prevention of fatal postoperative pulmonary embolism by dextran 40, low doses of heparin or xantinol nicotinate. Lancet 1977; 1: 207-10.
    CrossrefPubMedSearch in Google Scholar
  • 6 Adolf J, Knee H, Roder J D. et al. Thromboembolism prophylaxis with low molecular weight heparin in abdominal surgery. Dtsch Med Wochenschr 1989; 114: 48-53.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Bergqvist D, Burmark US, Frisell J. et al. Low molecular weight heparin once daily compared with conventional low-dose heparin twice daily. A prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J Surg 1986; 73: 204-8.
    CrossrefPubMedSearch in Google Scholar
  • 8 Bergqvist D, Matzsch T, Burmark U S. et al. Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis. Br J Surg 1988; 75: 888-91.
    CrossrefPubMedSearch in Google Scholar
  • 9 Bounameaux H, Huber O, Khabiri E. et al. Unexpectedly high rate of phlebographic deep venous thrombosis following elective general abdominal surgery among patients given prophylaxis with lowmolecular-weight heparin. Arch Surg 1993; 128: 326-8.
    CrossrefPubMedSearch in Google Scholar
  • 10 Caen JP. A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery. A French multicenter trial. Thromb Haemost 1988; 59: 216-20.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 ENOXACAN Study Group.. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84: 1099-103.
    CrossrefPubMedSearch in Google Scholar
  • 12 European Fraxiparin Study (EFS) Group.. Comparison of a low molecular weight heparin and unfractionated heparin for the prevention of deep vein thrombosis in patients undergoing abdominal surgery. Br J Surg 1988; 75: 1058-63.
    CrossrefPubMedSearch in Google Scholar
  • 13 Kakkar VV, Murray WJ. Efficacy and safety of lowmolecular-weight heparin (CY216) in preventing postoperative venous thromboembolism: a co-operative study. Br J Surg 1985; 72: 786-91.
    CrossrefPubMedSearch in Google Scholar
  • 14 Kakkar VV, Boeckl O, Boneu B. et al. Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial. World J Surg 1997; 21: 2-8.
    CrossrefPubMedSearch in Google Scholar
  • 15 Koppenhagen K, Adolf J, Matthes M. et al. Low molecular weight heparin and prevention of postoperative thrombosis in abdominal surgery. Thromb Haemost 1992; 67: 627-30.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Nurmohamed MT, Verhaeghe R, Haas S. et al. A comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery. Am J Surg 1995; 169: 567-71.
    CrossrefPubMedSearch in Google Scholar
  • 17 Ockelford PA, Patterson J, Johns AS. A doubleblind randomized placebo controlled trial of thromboprophylaxis in major elective general surgery using once daily injections of a low molecular weight heparin fragment (Fragmin). Thromb Haemost 1989; 62: 1046-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Sasahara AA, Koppenhagen K, Haring R. et al. Low molecular weight heparin plus dihydroergotamine for prophylaxis of postoperative deep vein thrombosis. Br J Surg 1986; 73: 697-700.
    CrossrefPubMedSearch in Google Scholar
  • 19 Wiig JN, Solhaug JH, Bilberg T. et al. Prophylaxis of venographically diagnosed deep vein thrombosis in gastrointestinal surgery. Multicentre trials 20 mg and 40 mg enoxaparin versus dextran. Eur J Surg 1995; 161: 663-8.
    PubMedSearch in Google Scholar
  • 20 Collins R, Scrimgeour A, Yusuf S. et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162-73.
    CrossrefPubMedSearch in Google Scholar
  • 21 Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg 1988; 208: 227-40.
    CrossrefPubMedSearch in Google Scholar
  • 22 Bulstrode CJ. Commentary on thromboprophylaxis in hip replacement surgery (Dahl O E. Acta Orthop Scand 1998; 69: 339-42 Acta Orthop Scand 1998; 69: 343–4.
    CrossrefPubMedSearch in Google Scholar
  • 23 Prentice CR. Are symptomatic endpoints acceptable in venous thromboprophylactic studies?. Haemostasis 1998; 28 (Suppl. 03) 109-12.
    PubMedSearch in Google Scholar
  • 24 Mismetti P, Laporte S, Darmon J Y. et al. Metaanalysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 2001; 88: 913-30.
    CrossrefPubMedSearch in Google Scholar
  • 25 Adolf J, Fritsche HM, Haas S. et al. Comparison of 3,000 IU aXa of the low molecular weight heparin certoparin with 5,000 IU aXa in prevention of deep vein thrombosis after total hip replacement. German Thrombosis Study Group. Int Angiol 1999; 18: 122-6.
    PubMedSearch in Google Scholar
  • 26 Kakkar VV, Kadziola Z, Mertes R. Does efficacy and safety of LMWH prophylaxis after total hip replacement depend upon body weight. Thromb Haemost 1999; 82: 61 (abstract).
    PubMedSearch in Google Scholar
  • 27 Silverstein MD, Heit JA, Mohr D N. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-93.
    CrossrefPubMedSearch in Google Scholar
  • 28 Mulloy B, Gray E, Barrowcliffe TW. Characterization of unfractionated heparin: comparison of materials from the last 50 years. Thromb Haemost 2000; 84: 1052-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Haake DA, Berkman SA. Venous thromboembolic disease after hip surgery. Risk factors, prophylaxis, and diagnosis. Clin Orthop 1989; 242: 212-31.
    CrossrefPubMedSearch in Google Scholar
  • 30 Perez JV, Warwick DJ, Case C P. et al. Death after proximal femoral fracture – an autopsy study. Injury 1995; 26: 237-40.
    CrossrefPubMedSearch in Google Scholar
  • 31 Todd CJ, Freeman CJ, Camilleri-Ferrante C. et al. Differences in mortality after fracture of hip: the East Anglian Audit. BMJ 1995; 310: 904-8.
    CrossrefPubMedSearch in Google Scholar
  • 32 PEP Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295-302.
    CrossrefPubMedSearch in Google Scholar
  • 33 Eriksson BI, Bauer KA, Lassen M R. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip fracture surgery. N Engl J Med 2001; 345: 1298-304.
    CrossrefPubMedSearch in Google Scholar
  • 34 Walker N, Norton R, Vander H S. et al. Mortality after hip fracture: regional variations in New Zealand. N Z Med J 1999; 112: 269-71.
    PubMedSearch in Google Scholar
  • 35 Boereboom FT, Raymakers JA, Duursma SA. Mortality and causes of death after hip fractures in The Netherlands. Neth J Med 1992; 41: 4-10.
    PubMedSearch in Google Scholar
  • 36 Eriksson BI, Kalebo P, Anthymyr B A. et al. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement. Comparison of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg [Am] 1991; 73: 484-93.
    CrossrefPubMedSearch in Google Scholar
  • 37 Mohr DN, Silverstein MD, Ilstrup D M. et al. Venous thromboembolism associated with hip and knee arthroplasty: current prophylactic practices and outcomes. Mayo Clin Proc 1992; 67: 861-70.
    CrossrefPubMedSearch in Google Scholar
  • 38 Moskovitz PA, Ellenberg SS, Feffer H L. et al. Lowdose heparin for prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures. J Bone Joint Surg [Am] 1978; 60: 1065-70.
    CrossrefPubMedSearch in Google Scholar
  • 39 Stulberg BN, Insall JN, Williams G W. et al. Deepvein thrombosis following total knee replacement. An analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg [Am] 1984; 66: 194-201.
    CrossrefPubMedSearch in Google Scholar
  • 40 Stringer MD, Steadman CA, Hedges A R. et al. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients. J Bone Joint Surg [Br] 1989; 71: 492-7.
    CrossrefPubMedSearch in Google Scholar
  • 41 Kakkar AK, Haas S, Walsh D. et al. Evaluation of perioperative heparin prophylaxis and clinical outcome after cancer surgery. Thromb Haemost 2005; 94: 867-71.
    Thieme ConnectPubMedSearch in Google Scholar