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Heparins and mechanical methods for thromboprophylaxis in colorectal surgery

 

P Wille-Jørgensen*, MS Rasmussen*, BR Andersen, L Borly.

 

DOI: 10.1002/14651858.CD001217

 

David K. Cundiff, MD


Date received: July 10, 2007

 

Authors' conclusions

Implications for practice

 

Both unfractionated heparin and low molecular weight heparin can be used as effective prophylaxis against postoperative thromboembolic complications after colorectal surgery. The optimal prophylaxis in colorectal surgery seems to be the combination of graded compression stockings and low-dose unfractionated heparin. The unfractionated heparin can likely be replaced with low molecular weight heparin.

 

Implications for research

 

Further effort to retrieve colorectal results from the many studies on general surgery should be continued. Large randomised trials evaluating the use of the combination regime versus monotherapy with fatal pulmonary embolism as outcome should be performed.

The conclusions of this review are based on surrogate endpoints (bilateral venography and noninvasive DVT assessment tests) rather than clinical endpoints (total mortality, pulmonary embolism fatalities, symptomatic venous thromboembolism). The small number of patients involved in the studies (< 2,000) made it impossible to reach meaningful conclusions about safety (e.g., bleeding and heparin induced thrombocytopenia with thrombosis) and efficacy. The called for large randomized trials with fatal pulmonary embolism as outcome will probably never be done. Since fatal pulmonary emboli occurs in only about 1-2 cases per 10,000 hospital discharges,1 it would take over 200,000 subjects to do such a trial.

The closest study to such a mammoth RTC was a retrospective analysis of about 80,000 hospitalized patients reported by Goldhaber and colleagues in 2000. They looked for the development of VTE during the index hospitalization and up to 30 days after discharge. Of the 384 VTE cases found, 201 had received prophylaxis and 183 had not. Twelve of the 13 fatal pulmonary emboli (FPE) cases occurred in patients receiving anticoagulant prophylaxis.1

Goldhaber’s study provides evidence that will never be found in RCTs with n < 20,000 (i.e., all reported RCTs): anticoagulant prophylaxis very likely increases the risk of death. A possible mechanism is rebound hypercoagulation.2, 3

Neither heparin nor LMWHs are evidence-based to be safe or effective as thromboprophylaxis after colorectal surgery.

Undisclosed financial conflict of interest:

 

Dr. Wille-Jørgensen has received research funding from Novartis4 and co-authored a Pfizer-funded dalteparin (Fragmin) thromboprophylaxis trial.5

 

1.         Goldhaber SZ, Dunn K, MacDougall RC. New Onset of Venous Thromboembolism Among Hospitalized Patients at Brigham and Women’s Hospital Is Caused More Often by Prophylaxis Failure Than by Withholding Treatment. Chest. 2000;118:1680-1684.

2.         Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994;72(2):222-226.

3.         Cundiff DK. Commentary - Insufficient Evidence Supporting Low-Intensity Warfarin for Venous Thromboembolism (VTE) Prophylaxis. Medscape General Medicine™. 07/02/2003;http://www.medscape.com/viewarticle/457570.

4.         Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. New England Journal of Medicine. 1997;337(19):1329-1335.

5.         Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4(11):2384-2390.

6.         Kakkar VV. Fibrinogen Uptake Test for Detection of Deep Vein Thrombosis - A review of Current Practice. Sem Nucl Med. 1977;7:229-244.

7.         Wille-Jorgensen P, Jorgensen LN, Crawford M. Asymptomatic postoperative deep vein thrombosis and the development of postthrombotic syndrome. A systematic review and meta-analysis. Thromb Haemost. 2005;93(2):236-241.

8.         Hull RD, Pineo GF, Stein PD, et al. Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis in Patients after Elective Hip Arthroplasty: A Systematic Review. Ann Intern Med. 2001;135:858-869.

9.         Rasmussen MS, Wille-Jorgensen P, Jorgensen LN. Postoperative fatal pulmonary embolism in a general surgical department. Am J Surg. 1995;169(2):214-216.

10.       Lindblad B, Eriksson A, Bergqvist D. Autopsy-verified pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. British Journal of Surgery. 1991;78(7):849-852.

11.       Lindblad B, Sternby NH, Bergqvist D. Incidence of venous thromboembolism verified by necropsy over 30 years. BMJ. 1991;302(6778):709-711.

12.       Kakkar VV, Corrigan TP, Fossard DP, Sutherland I, Thirwell J. Prevention of Fatal Postoperative pulmonary embolism by low doses of heparin. Reappraisal of results of international multicentre trial. Lancet. 1977;1(8011):567-569.

 

Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Author's reply

Submitted by contact author Peer Wille-Jørgensen, July 17, 2007

The discussion on surrogate end-points in research on thrombosis prophylaxis has been long. In my opinion there is overwhelming evidence, that if you lower the incidence of subclinical DVT, you will also lower the incidence of clinical DVT and Fatal PE (1) - but for statistical reasons it might be difficult to lower the total postoperative mortality. Also an indirect proof of the relation between subclinical DVT and later postphlebitic syndrome has been established (2) Latest evidence is seen in the research on the efficacy of long-term postoperative prophylaxis, in which the same trials the extended prophylaxis lower the incidence of both subclinical and clinical DVT (3;4).
As the diagnosis of pulmonary embolism very seldom is established before death (5) retrospective analysis of incidences of postoperative fatal PE is of very little value even thoug the number of patients is large. Another investigation from one department found although an association between fatal PE and omission of prophylaxis(6).
I agree, that a prospective randomised trial with total mortality as endpoint is unfeasible. We must not althoug forget that the efficacy of heparin prophylaxis against fatal Postoperative PE was established in a methodologically correctly performed trial more than 30 years ago(7).
Taken these facts in mind I still mean that the use of postoperative prophylaxis is evidence based, and for comparing different methods the use of venography for detecting subclinical DVT as endpoint is scientifically acceptable.

Concerning my conflict of interest. I have participtated in several partly industry-sponsored trials on thrombosis prophylaxis, but never have gained any personal financial benefits from it.

Peer Wille-Jørgensen

Reference List

(1) Kakkar VV. Fibrinogen Uptake Test for Detection of Deep Vein Thrombosis - A review of Current Practice. Sem Nucl Med 1977; 7:229-244.
(2) Wille-Jorgensen P, Jorgensen LN, Crawford M. Asymptomatic postoperative deep vein thrombosis and the development of postthrombotic syndrome. A systematic review and meta-analysis. Thromb Haemost 2005; 93(2):236-241.
(3) Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: A systematic review. Ann Int Med 2001; 135(10):858-869.
(4) Dahl OE. Continuing out-of-hospital prophylaxis following major orthopaedic surgery: what now? Haemostasis 2000; 30 Suppl 2:101-105.
(5) Hauch O, Jorgensen LN, Khattar SC, Teglbjaerg CS, Wahlin AB, Rathenborg P et al. Fatal pulmonary embolism associated with surgery. An autopsy study. Acta Chir Scand 1990; 156(11-12):747-749.
(6) Rasmussen MS, Wille-Jorgensen P, Jorgensen LN. Postoperative fatal pulmonary embolism in a general surgical department. Am J Surg 1995; 169(2):214-216.
(7) Kakkar VV, Corrigan TP, Fossard DP, Sutherland I, Thiewell J. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Reappraissal of Results of International Multicenter Trial. Lancet 1977; i:567-569.

Contributors

David Cundiff and Peer Wille-Jørgensen

My Rebuttal

 

I thank Dr. Wille-Jørgensen for the reply.

 

The clinical relevance of the surrogate endpoint of asymptomatic DVT prevention with anticoagulants correlating with a lower incidence of clinical DVT and fatal PE is hardly settled by Kakkar’s 1977 article in the Seminars of Nuclear Medicine, ‘Fibrinogen Uptake Test for Detection of Deep Vein Thrombosis’ review’6 (reference 1 of the reply).

 

While you have demonstrated a positive correlation between asymptomatic post operative DVT with later postphlebitic syndrome,7 this does not prove that post phlebitic syndrome is prevented by prophylactic anticoagulants. It may be that rebound hypercoagulation related DVT after stopping heparin increases VTE and subsequently the post phlebitic syndrome.

 

Regarding the efficacy of long-term postoperative prophylaxis with orthopaedic procedures, RCTs comparing heparins for 6-10 days post op versus extending the prophylaxis for an additional 3-4 weeks at home generally do not have data on outcomes after the completion of the extended prophylaxis. This misses outcome events due to post heparin rebound hypercoagulability. In the six RCTs reviewed by Hull and colleagues,8 none had an unanticoagulated arm to see the effect of short term prophylaxis itself. This meta-analysis included only 1953 patients and fatal PE occurred in only 2/862 placebo-treated patients (possibly due to rebound hypercoagulability) versus 0/1091 who received extended prophylaxis. This makes the Goldhaber study,1 about which Dr. Wille-Jorgensen had no comment, particularly relevant. Out of about 80,000 hospitalizations of patients followed for at least 2 months (i.e., capturing rebound hypercoagulability events), 12/13 cases of fatal PE occurred in patients given prophylaxic anticoagulants.

 

Regarding the reference to the data on the association between fatal PE and omission of prophylaxis from the Bispebjerg Hospital, University of Copenhagen, Denmark,9 despite the statistical significance of the data (p < .05), little can be concluded from an observational study with 20 cases of post operative fatal PE out of 4881 surgeries. The abstract of this study states, ‘Antithrombotic prophylaxis was applied routinely according to standard instructions.’ At least some of those not given antithrombotic prophylaxis may have had contraindications. In a much larger study of autopsy verified fatal PE cases of all surgical patients in Malmo, Sweden, during the period from 1951 to 1988 in whom pulmonary emboli were found at autopsy (391 cases),10 the incidence of previous prophylaxis with anticoagulants in people with autopsy-proven FPE increased from 50% in 1971-1975 to 76% in 1976-1980, 85% in 1979-1983, and 94% in 1984-1988. The overall incidence of venous thromboembolism in this hospital had not changed from 1957 to 1987.11 Again, these data suggest the possibility of rebound hypercoagulability causing FPE.

 

While methodologically correct for its time, the ‘International Multicentre Trial’12 was before the era of early mobilization and mechanical VTE prophylaxis. The followup period was only until discharge from hospital, so the deaths due to rebound hypercoagulation on stopping the heparin were missed.