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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 2  |  Page : 437-441

A comparative study between fondaparinux, a low-molecular-weight heparin, and recombinant hirudin in thromboembolic prophylaxis after major abdominal surgery in the surgical intensive care unit


Department of Anaesthesia and Critical care, Faculty of Medicine, Menoufia University, Menoufia Governorate, Egypt

Date of Submission30-Aug-2014
Date of Acceptance14-Oct-2014
Date of Web Publication31-Aug-2015

Correspondence Address:
Hager H Mohammady
Department of Anaesthesia and Critical Care, Faculty of Medicine, Menoufia University, Shebin El-kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.163898

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  Abstract 

Objective
Evaluation of the safety and the efficacy of different anticoagulants in thromboembolic prophylaxis after major abdominal surgeries.
Background
Thromboembolic events are serious complications after major abdominal surgeries, and there are different modalities to prevent them.
Materials and methods
Sixty patients who underwent major abdominal surgery were assigned in a randomized, double-blinded manner and classified into three groups: group A (n = 20) was started on enoxaparin at a daily dose of 40 mg. Group B (n = 20) was given recombinant hirudin 15 mg twice daily. Group C (n = 20) was given fondaparinux 2.5 mg subcutaneously daily. The duration of treatment was 5-12 days. The efficacy of the three drugs was compared by the occurrence of DVT (assessed by Doppler ultrasound) or fatal and nonfatal pulmonary embolism (by computed tomography). The safety was assessed by postoperative bleeding in terms of the number of transfused whole blood units, plasma expanders, or packed red blood cells and fatal bleeding.
Results
Results showed that enoxparin, fondaparinux, and recombinant hirudin were equally effective in the prevention of thromboembolism. The least risk of postoperative bleeding was noticed in patients receiving enoxparin in comparison with patients receiving fondaparinux or recombinant hirudin.
Conclusion
Enoxaparin, hirudin, and fondaparinux are equally effective in protection against thromboembolic events in patients undergoing major abdominal surgeries; however, enoxaparin is superior to the others regarding safety.

Keywords: enoxaparin, fondaparinux, recombinant hirudin, thromboembolic prophylaxis


How to cite this article:
Yehyia MF, Atalla HA, Ibrahim ES, Sadek SA, Mohammady HH. A comparative study between fondaparinux, a low-molecular-weight heparin, and recombinant hirudin in thromboembolic prophylaxis after major abdominal surgery in the surgical intensive care unit. Menoufia Med J 2015;28:437-41

How to cite this URL:
Yehyia MF, Atalla HA, Ibrahim ES, Sadek SA, Mohammady HH. A comparative study between fondaparinux, a low-molecular-weight heparin, and recombinant hirudin in thromboembolic prophylaxis after major abdominal surgery in the surgical intensive care unit. Menoufia Med J [serial online] 2015 [cited 2020 Sep 20];28:437-41. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/437/163898


  Introduction Top


Major abdominal surgical procedures place patients at risk for venous thromboembolism (VTE), including DVT and pulmonary embolism. Complications of DVT include postphlebitic syndrome or death from pulmonary embolism. Therefore, prophylaxis with anticoagulant medications, and the adjunctive use of mechanical devices, is essential [1] .

Enoxaparin, the first low-molecular-weight heparin, has been shown to be a safe and effective form of thromboprophylaxis, and is recommended as the first-line therapy together with UFH by the latest practice guidelines relevant to major abdominal surgery [2] .

The pentasaccharide fondaparinux is the first drug from a new class of synthetic compounds, which has no components from animals, acts through specific inhibition of factor Xa, and has no direct activity against thrombin. Postoperative fondaparinux improved the risk benefit ratio for VTE prophylaxis significantly [3] .

A specific thrombin inhibitor such as recombinant hirudin stems from its direct action on both free and fibrin-bound thrombin; it requires no plasma cofactor in the inhibition of thrombus growth [4] .


  Aim of the work Top


We used low-molecular-weight heparin as a comparison drug and evaluated the antithrombotic efficacy and safety of fondaparinux and hirudin as compared with those of a standard regimen of enoxparin in patients undergoing major abdominal surgical procedures.


  Materials and methods Top


After obtaining guidance and approval from the Department of Ethics Committee, 60 patients who underwent major abdominal surgeries and were admitted in the surgical ICU were enrolled for the study. Written informed consent was obtained from each patient before his or her enrollment in the trial. Patients of both sexes were eligible if they were between 18 and 60 years old, weighed at least 50 kg, and were scheduled for major abdominal surgical procedures. We excluded patients who had any hemostatic or bleeding disorder, patients with active bleeding (gastrointestinal ulceration, hemorrhagic stroke), intracranial or intraocular bleeding within the previous 3 months, uncontrolled hypertension, or renal impairment, pregnant women, patients who had undergone nephrectomy or kidney transplantation, and patients with known allergy to recombinant hirudin, low-molecular-weight heparin, or fondaparinux.

Study drugs

A total of 60 patients were divided into three groups: group A was given enoxparin (clexane; Aventis pharma) 40 mg in 0.4 ml water subcutaneously 12 h postoperatively with a daily dose on a regular basis. Group B was given recombinant hirudin (Thrombex; Novartis pharma) 15 mg subcutaneously twice daily, with the first dose given 30 min before the start of the surgery. Group C was given fondaparinux (Arixtra; GSK pharma) 2.5 mg in 0.25 ml water subcutaneously 6 h postoperatively, and then every 24 h.

Placebo prefilled injections were given to complete the double-blind design. The day of surgery was defined as day 1. Treatment was scheduled to last up to days 5-12, and the primary efficacy outcome was assessed between days 5 and 12.

Outcome measures

The primary efficacy outcome was VTE (DVT, fatal, or nonfatal pulmonary embolism or both) up to day 12. Patients were examined for deep-vein thrombosis by Doppler compression sonography of both legs within 48 h of intensive care unit admission, twice weekly, and if VTE was clinically suspected. Symptomatic pulmonary embolism was confirmed by echocardiography and spiral computed tomography.

Safety

Perioperative blood loss was defined as bleeding recorded up to 12 h after the start of the surgery, and postoperative blood loss as that recorded from 12 h after the start of surgery up to postoperative day 6. Transfusion with whole blood, concentrates of red cells, and plasma expanders was recorded. Serious bleeding episodes were defined as a need for perioperative transfusion of more than 5 U of whole blood or concentrates of red cells, a need for transfusion of 7 U at any time after the start of the surgery, or a total blood loss of more than 3500 ml. Any adverse events such as retroperitoneal, intracranial, or intraspinal hematoma were recorded.

Statistical analysis

It was performed using the statistical package for social science. Descriptive statistical analysis (range, mean, and SD), paired Student's t-test, and analysis of variance (F-test) were performed. Statistical significance was considered when P value was less than 0.05.


  Results Top


Demographic data, characteristics, and the duration of surgery showed no significant difference among the three groups [Table 1]. Regarding the frequency of venous thromboembolic events, there was no significant difference among the three groups [Table 2].
Table 1 Characteristics of the treated patients

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Table 2 The frequency of thromboembolic events

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Postoperative blood loss was significantly more in the fondaparinux and the hirudin groups in comparison with the enoxaparin group [Table 3] and [Figure 1]. Transfusion requirements in the three studied groups showed no significant difference among the three groups [Table 4] and [Table 5].
Figure 1: Distribution of the studied groups regarding the mean and SD of the amount of bleeding

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Table 3 Blood loss in the three groups

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Table 4 Transfusion requirements in the three groups

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Regarding the detected cases of thrombocytopenia, there was no significant statistical difference between the three groups [Table 5], and only one case was found in group A.
Table 5 Distribution of the groups regarding the amount of PRBCs, blood units, and the occurrence of thrombocytopenia

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  Discussion Top


VTE is a common complication in patients undergoing surgery. In patients undergoing general surgery without prophylaxis, the rates of DVT and fatal PE range from 15 to 30% and from 0.2 to 0.9%, respectively [5] . Many trials have evaluated the efficacy and the safety of anticoagulants for prophylaxis after major abdominal surgery [6] . The modalities that have clearly reduced the risk of DVT and PE as per evidence-based studies include LDUH and low-molecular-weight heparin [7] .

In this study, we compared low-molecular-weight heparin (enoxaparin) with a thrombin inhibitor (hirudin) and a specific factor Xa inhibitor (fondaparinux) in patients undergoing major abdominal surgery.

The main efficacy outcome was thromboembolic events (DVT and PE), which showed no significant statistical difference among the three groups (same efficacy) despite the fact that PE occurred in two cases in the enoxparin group (10% of cases) and DVT occurred in two cases (10% of cases) in the same group, whereas one case of DVT (5% of cases) occurred in the fondaparinux group. This may be attributed to our small sample size in comparison with other studies. However, this is consistent with the study by Agnelli et al. [8] , because among the 2048 patients evaluated for efficacy, the rate of VTE was 4.6% (47 of 1027) with fondaparinux compared with 6.1% (62 of 1021) with dalteparin (low-molecular-weight heparin).

Although different results have been reported in the field of orthopedic surgery, fondaparinux has been shown to be highly effective in the prevention of DVT among elective hip replacement patients. Lassen et al. [9] randomly assigned 2309 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to once-daily subcutaneous injections of either 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. They assessed the primary efficacy outcome in 1827 (79%) of the 2309 patients. By day 11, VTEs was recorded in 37 (4%) of the 908 patients assigned to fondaparinux and in 85 (9%) of the 919 patients assigned to enoxaparin. The two groups did not differ in the frequency of death or clinically relevant bleeding. Their conclusion was that drugs that act through the specific inhibition of factor Xa, such as fondaparinux, could be more effective than low-molecular-weight heparins in the prevention of VTE in patients undergoing hip-replacement surgery.

In contrast, Bauer et al. [10] showed that patients undergoing knee surgery receiving fondaparinux achieved equal reduction in the risk of VTE compared with enoxaparin. Many other orthopedic studies [9],[11] proved that fondaparinux showed better efficacy than enoxaparin. They concluded that the unique mechanism of action of fondaparinux, its rapid onset of action, and its highly reproducible and predictable linear pharmacokinetics are important reasons for its better efficacy compared with enoxaparin. Two other studies by Eriksson and colleagues [12],[13] showed a controversial result and found that recombinant hirudin was superior to enoxaparin in its efficacy in preventing thromboembolic complications. They explained the better effect of hirudin to be due to its administration immediately before surgery and two times daily thereafter. The mode of action of this specific inhibitor of thrombin may also have accounted for its superiority to enoxaparin.

Regarding the safety in using enoxaparin, fondaparinux, and hirudin, our results showed that enoxaparin was the best, with the least postoperative bleeding compared with hirudin and fondaparinux.

In contrast, the results of trials on patients undergoing hip surgery [9, 11, 14] showed that fondaparinux did not increase the risk and the amount of bleeding in comparison with enoxaparin. Eriksson et al. [11] conducted a double-blinded study, wherein 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur were randomly assigned to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily initiated postoperatively or 40 mg of enoxaparin once daily initiated preoperatively, for at least 5 days. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was 6 weeks. There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding.

Our results did not match with those of Eriksson et al. [12] regarding the treatment regimens by enoxaparin and hirudin as they were equally safe without any significant difference in relation to the amount of blood loss and did not require specific laboratory monitoring.

Our study showed that there were no significant statistical differences among the three groups with regard to the type and the number of blood products given. These results are contradictory to those of Lassen et al. [9] Eriksson et al. [11] , and Turpie et al. [14] who studied patients undergoing hip surgery, and found that the fondaparinux group showed a lesser number of blood products transfused in comparison with the enoxaparin group.


  Conclusion Top


Enoxaparin, hirudin, and fondaparinux were equally effective in protection against thromboembolic events in patients undergoing major abdominal surgeries; however, enoxaparin is superior to fondaparinux or hirudin in relation to safety, due to the lesser amount of postoperative bleeding.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest..



 
  References Top

1.
Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G, Balzarotti R, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg 2014; 259 :665-669.  Back to cited text no. 1
    
2.
Comp PC, Spiro TE, Friedman RJ, Whitsett TL, Johnson GJ, Gardiner GA Jr, et al. Enoxaparin Clinical Trial Group Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83 -A):336-345.  Back to cited text no. 2
    
3.
Turpie AG, Gallus AS, Hoek JA. Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344 :619-625.  Back to cited text no. 3
    
4.
Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86 :385-391.  Back to cited text no. 4
    
5.
Agnelli G. Prevention of venous thromboembolism in surgical patients. Circulation 2004; 110 :4-12.  Back to cited text no. 5
    
6.
Leonardi MJ, McGory ML, Ko CY. A systematic review of deep venous thrombosis prophylaxis in cancer patients: implications for improving quality. Ann Surg Oncol 2007; 14 :929-936.  Back to cited text no. 6
    
7.
Lijfering WM, Meer JV. Pharmacological prevention of venous thromboembolism. In: van Beek ER, Buller HR, Oudkerkeds M eds. Deep vein thrombosis and pulmonary embolism. 1st ed. UK: John Wiley & Sons; 2009. 435-461.  Back to cited text no. 7
    
8.
Agnelli G, Bergqvist D, Cohen AT, Gallus AS. Gent MPEGASUS investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92 :1212-1220  Back to cited text no. 8
    
9.
Lassen MR, Bauer KA, Eriksson BI, Turpie AG. European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359 :1715-1720.  Back to cited text no. 9
    
10.
Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345 :1305-1310.  Back to cited text no. 10
    
11.
Eriksson BI, Bauer KA, Lassen MR, Turpie AG. Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345 :1298-1304.  Back to cited text no. 11
    
12.
Eriksson BI, Wille-Jørgensen P, Kälebo P, Mouret P, Rosencher N, Bösch P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337 :1329-1335.  Back to cited text no. 12
    
13.
Eriksson BI, Ekman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347 :635-639.  Back to cited text no. 13
    
14.
Turpie AG, Bauer KA, Eriksson BI. Lassen MRPENTATHALON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 35:1721-1726.  Back to cited text no. 14
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Introduction
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