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ORIGINAL ARTICLE Table of Contents   
Year : 2003  |  Volume : 37  |  Issue : 2  |  Page : 4
Thromboprophylaxis by dalteparin sodium in elective major orthopaedic surgery - A multicentric Indian study


Department Of Orthopaedics,St. John's Medical College, Bangalore, India

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   Abstract 

Post-operative deep vein thrombo-embolic disease is a serious and frequent complication after major orthopaedic surgery. A multi-centric prospective study was undertaken in 105 patients with major orthopedic surgery to evaluate the thromboprophylatic efficacy and safety of dalteparin sodium in the prevention of deep vein thrombosis. The age of enrolled patients were 58.1 ± 17.1 years. Dalteparin Sodium 5000 IU SC once a day was given upto 6±1 days. Colour Doppler ultrasound was performed on all patients on post-operative 6±1 day. Deep venous thrombosis (DVT) was diagnosed in 8 (7.8%) patients. No patient developed pulmonary embolism. Dalteparin Sodium offers an effective, safe and easily administered prophylaxis against DVT.

Keywords: Deep vein thrombosis - Thoombo prophylaxis - Fracture femur

How to cite this article:
Rajagopalan N. Thromboprophylaxis by dalteparin sodium in elective major orthopaedic surgery - A multicentric Indian study. Indian J Orthop 2003;37:4

How to cite this URL:
Rajagopalan N. Thromboprophylaxis by dalteparin sodium in elective major orthopaedic surgery - A multicentric Indian study. Indian J Orthop [serial online] 2003 [cited 2019 Dec 6];37:4. Available from: http://www.ijoonline.com/text.asp?2003/37/2/4/48502

   Introduction Top


Post-operative deep vein thrombo-embolic disease is often regarded as uncommon in Indians, but there is no objective evidence to support this view. Venous thromboembolism is a serious and frequent complication after total hip replacement, with venous thrombosis occurring in 40-60% of untreated patients, proximal vein thrombosis in 20-40% and fatal pulmonary embolism in 1-3% of untreated patients. [1],[2],[3],[4] Several prophylactic modalities have been shown to reduce the risk, including the use of warfarin, dextran and several heparin regimens. However, surveys indicate that many orthopaedic surgeons do not routinely provide thromboprophylaxis. [5]

To appropriately target prophylaxis against venous thromboembolism, patients at risk must be identified. Several patient characteristics have been identified as independent risk factors for venous thromboembolism, including age, gender, surgery, trauma, hospital or nursing home confinement, malignant neoplasm (with and without concurrent chemotherapy). Of these risk factors, surgery conveys the greatest risk. Patients with recent surgery have a 22-fold increased risk of venous thromboembolism. Patients receiving total hip replacement or knee replacement surgery are especially at high risk to get postoperative venous thromboembolism. In the absence of prophylaxis, about 50% of hip replacement patients, and over 60% of knee replacement patients, develop deep vein thrombosis. [6]

The development of low-molecular-weight heparin (LMWH) has attracted much scientific and clinical interest due to its longer half-life and higher bioavailability compared to unfractionated heparin. Several studies have shown that LMWHs offer effective and safe thromboprophylaxis in orthopaedic surgery. This is a prospective, open, noncomparative, multicentric study with Dalteparin Sodium (Fragmin®) in patients planned for total hip replacement, total knee replacement and fracture femur interventions. The study was designed to evaluate the thromboprophylactic efficacy and safety of dalteparin sodium when used for thromboprophylaxis.


   Material and Methods Top


This study was conducted at 11 centres in 105 patients from July 2000 to January 2001. Ethics committee approval was taken at all centres prior to initiation of study. Written informed consent was obtained from all patients. Patients more than 18 years, admitted for unilateral total hip or knee replacement surgeries, or fracture femur interventions, were included in the study. Patients underwent surgery under general anaesthesia. Patients on long-term aspirin (e.g. patients of coronary artery disease or chronic arthritis) were also enrolled in this study. However, in these patients aspirin was discontinued 7 days before the administration of first dose of Dalteparin Sodium.

Patients were ineligible for enrolment in this study if they had any of the following (rationale for not including patients with these characteristics was largely based on safety or the avoidance of contamination): renal insufficiency (serum creatinine > 1.7 mg/dl); liver insufficiency (abnormal prothrombin time); documented bleeding, e.g. gastrointestinal, within 3 months prior to surgery; defective haemostasis e.g. thrombocytopenia (platelet count<100 x 10 9 /1) or ongoing anticoagulant treatment; cerebral haemorrhage within 3 months prior to surgery; eye, ear or CNS surgery within 1 month prior to surgery; known hypersensitivity to heparin, low molecular weight heparin; severe hypertension (diastolic pressure > 120 mm Hg); septic endocarditis; surgery under regional, spinal or epidural anesthesia; patients on long-term aspirin (eg. patients of coronary artery disease or chronic arthritis), However, such patients can be included provided aspirin is discontinued with a wash-out period of 7 days; weight less than 90 pounds; known pregnancy or breast feeding.

On the day of surgery (Day 0), all enrolled patients received first dose of Dalteparin Sodium 2500 IU subcutaneously in the anterior abdominal region, 2 hours before the start of surgery. The second dose of Dalteparin Sodium 2500 IU was given subcutaneously on the evening of the day of surgery, at least six hours after the preoperative dose. On the first and subsequent postoperative days up to 6±1 days, all patients were administered Dalteparin Sodium 5000 IU, subcutaneously, daily, as a single dose.

During postoperative period all patients were observed closely for the signs of DVT or pulmonary embolism. Colour Doppler ultrasound was performed on all patients on post-operative 6±1 day, or following clinical signs of DVT. Intraoperative blood loss, Haemoglobin level and platelet count preoperative and 1 week postoperatively were recorded.


   Results Top


The age of the enrolled patients were 58.1 ± 17.1 years with a range 21-95 years [Table 1]. Three patients were excluded from the study for the various reason. One patient was withdrawn due to prolongation of surgical procedure. The second patient was withdrawn due to acute renal impairment, and the third patient due to major gastrointestinal bleeding. Hence, a total of 102 patients completed the study. A total of 61(60%) male and 41 (40%) female patients were evaluable at the end of 6 ± 1days

Thirty-eight patients had one or more concomitant illness. The most common concomitant illnesses were hypertension (10.5%) and diabetes mellitus (5.7%). Seventy nine (75.3%) patients underwent fracture femur intervention, 14 (13.3%) patients underwent total hip replacement and 12 (11.4%) patients underwent total knee replacement.

Incidence of deep venous thrombosis

Deep venous thrombosis (DVT) was diagnosed in 8 (7.8%) patients; 5 patients had proximal DVT, and 3 patients had distal DVT. Of the five patients with proximal DVT, 2 patients had proximal DVT also in the opposite leg. Two out of 11 patients who had undergone total knee replacement developed DVT, one out of 14 patients who had undergone total hip replacement, and five out of 77 patients who had undergone fracture femur intervention developed DVT. Six patients were male and 2 patients were female. The mean age of patients who had developed DVT was 60.4±7.4 years, whereas mean age of patients who did not have DVT was 57.6±16.9 years. Out of 8 patients, one patient had hypertension, one patient had hypertension with diabetes mellitus, one patient had COAD and other patients were without any concomitant illness.

Cross tabulation revealed no relationship between DVT and type of intervention, age, sex, concomitant illness, postoperative blood loss, amount of blood transfusion and type of intervention undergone. Out of 102 patients, 9 patients had minor bleeding events and 6 patients had a major bleeding event. These patients with major bleeding had reduction in haemoglobin of more than 2 gm% from the preoperative value associated with bleeding. Out of 9 patients with minor bleeding, 6 patients presented on the day of surgery and 3 presented in the postoperative period. Blood loss was classified into 3 categories; less than 300 ml, 300-600 ml and more than 600 ml. Less than 300 ml blood loss was observed with 28(27.5%) patients, blood loss 300-600 ml was observed in 53(51.9%) patients, and more than 600 ml blood loss was observed in 21 (20.6%) patients.

Two (1.96 %) adverse events were reported, which included one patient with acute renal failure and hyperkalemia and one patient who had a transient rise in serum creatinine. Both these patients were managed conservatively and they showed an eventless recovery.


   Discussion Top


Venous thromboembolism remains an important complication of major orthopaedic surgery, despite the use of preventive measures. Few studies using different modalities of diagnosis of DVT have been reported from Asia. These studies have reported widely varying incidence rates ranging from 2.6% to 53.3%. [8],[9],[10] The challenge is to reduce the incidence of this potentially fatal but preventable disease.

In some past studies, a beneficial effect of various LMWH on the incidence of DVT has been reported in elective hip surgery. [11],[12] It is generally accepted that unfractionated heparin, vitamin K antagonist, polysaccharide plasma expanders, and physical methods to some extent reduce the incidence of DVT. But the frequency of DVT remains unacceptably high, and some of the regimens are associated with an increased risk of haemorrhagic complications.

Low molecular weight heparin is produced by controlled enzymatic or chemical depolymerisation of unfractionated heparin. Compared with unfractionated heparin, LMWH has longer half-life and an almost complete bioavailability after subcutaneous injection. As a result of these properties, a predictable anticoagulant effect can be achieved, which allows subcutaneous administration of LMWH once or twice a day, without the need for laboratory monitoring.

The preparation of low molecular weight heparin-Dalteparin Sodium (Fragmin) that was used in this study was previously demonstrated to have a favourable antithrombotic effect in a placebo-controlled trial in elective total hip replacement. [13] This preparation has also been shown to be superior to Dextran 70 for the prevention of deep vein thrombosis after elective operation on the hip. [11] The efficacy of a fixed dose of Fragmin was equivalent to that of a dose of standard heparin, which had been individually adjusted to the activated partial thromboplastin time. [14] In a placebo controlled study a highly significant reduction in the incidence of deep vein thrombosis has been demonstrated when prophylaxis with low molecular weight heparin was started after hip replacement. [12] .

Other studies of orthopaedic patients undergoing surgery for proximal femoral fractures or total hip replacement used venography to diagnose thrombosis. The incidences of DVT in these studies were 53.1% (Hong Kong), 4% (Thailand), 10% (Korea), and 9.7% (Singapore). [15],[16],[17] The incidence of DVT in patients with total hip replacement has been reported to be 10-16%. [11],[13] in patients who received low molecular weight heparin (Fragmin).

Color Doppler ultrasound allows the examiner to view blood flow or lack thereof in vessels in addition to identifying thrombosis of vein. The test has been reported to 92% to 95% sensitive and 100% specific for proximal venous thrombosis. The test has been reported to be anywhere from 79% to 93% sensitive and from 80% to 100% specific for the diagnosis of all venous thromboses in lower extremity. Color Doppler ultrasound is safe, well tolerated, and relatively easy to performand thus was used to diagnose DVT. The test affords excellent reliability in the assessment of proximal veins of lower extremity.{18] No patient developed pulmonary embolism. Cross tabulation revealed no relationship between DVT and type of intervention, age, sex, concomitant illness, postoperative blood loss, amount of blood transfusion, and type of intervention undergone.

In our study incidence of proximal DVT was high as compared with distal DVT, also it is more commonly observed in male patients. DVT was observed more frequently in the limb that had been operated on than in the contralateral limb. This might be explained by a combination of stasis, changes in blood element, and injury of the venous endothelium. In a limb that has been operated on, the flow of the blood is reduced due to the angulation and narrowing of the proximal part of femoral vein that are caused due to flexion of the hip during preparation of the femoral canal.[19]

This study has proved that DVT occurs in Indian patients in spite of prophylaxis therapy with low molecular weight heparin (Dalteparin sodium). Postoperative thromboembolism is a significant cause of morbidity and probably mortality after unprotected orthopaedic surgery. Fragmin given once daily to patients undergoing major orthopaedic surgery offers an effective, safe and easily administered prophylaxis against DVT.

Study centers (Responsible investigators):Dr. Agarwal Vineet, Avadh Hospital & Heart Center, Lucknow; Dr.. Chandak R.M, Chandak Nursing Home, Nagpur; Dr. Govindaraj A.B., Apollo Speciality Hospital, Chennai; Dr. Nagi O.N. & Dr. Batra Y.K., Post Graduate Institute of Medical Education & Research, Chandigarh; Dr. Rajgopalan, St. John's Medical College & Hospital, Bangalore; Dr. Sancheti Parag, Sancheti Institute for Orthopaedic & Rehabilitation, Pune; Dr. Seth Ajay & Dr. Abhay Srivastava , Jabalpur Hospital & Research Centre, Jabalpur; Dr. Sharma U.C., Down Town Hospital, Guwahati; Dr. Shetty Naresh, M.S. Ramiah Medical Teaching Hospital, Bangalore; Dr. Subbarao Venkat, Vijaya Health Centre, Chennai; Dr. Thomas Joseph, Medical Trust Hospital; Cochin

Acknowledgments:Dr. Sutinder Bindra, MD, Regional Medical Director, Pharmacia Asia Pacific, designed, organised, monitored, and provided technical support throughout the entire project. Dr. Anil Shinde, MD, Manager, Medical Services, Pharmacia India Pvt. Ltd helped for preparing manuscript. Dr. Sanjukta Sircar and Ms. Ekta Garg, Clinical Research Associate of Pharmacia India Pvt. Ltd., supervised the conduct and monitoring of the study.

 
   References Top

1.Harris WH, Salzman EW, Athanasoulis C, Waltman AC, Baum S, DeSanctis RW. Comparison of warfarin, low-molecular-weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement. J Bone Joint Surg [Am] 1974; 56-A: 1552-1562.  Back to cited text no. 1    
2.Rogers PH, Walsh PN, Marder VJ, et al. Controlled trial of low-dose heparin and sulfinpyrazone to prevent venous thromboembolism after operation on the hip. J Bone Joint Surg [Am] 1978; 60-A: 758-762.  Back to cited text no. 2    
3.Sautter RD, Koch EL, Myers WO, et al. Aspirin-sulfinpyrazone in prophylaxis of deep venous thrombosis in total hip replacement. J Am Med Assoc 1983; 250: 2649-2654.  Back to cited text no. 3    
4.Collins R, Scrimgeour A, Yusef S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by peroperative administration of subcutaneous heparin. N Engl J Med 1988; 18:1162-1173.  Back to cited text no. 4    
5.Paiement GD, Wessinger SJ, Harris WH. Survery of prophylaxis against venous thromboembolism in adults undergoing hip surgery. Clin Orthop 1987; 232:188-193.  Back to cited text no. 5    
6.Heit J. Low molecular weight heparin: The optimal duration of prophylaxis against postoperative venous thromboembolism after total hip or knee replacemnt. Thrombosis research 2001; 101:163-173.  Back to cited text no. 6    
7.Bratt G et al. A human pharmacological study comparing conventional heparin and low molecular weight heparin fragment. Thromb Haemost 1985; 53:208-211.  Back to cited text no. 7    
8.Cunningham IGE, Young NK. The incidence of postoperative deep vein thrombosis in Malaysia. Br J Surg 1974; 61; 482-83.   Back to cited text no. 8    
9.Inada K et al. Postoperative deep venous thrombosis in Japan-Incidence and Prophylaxis. Am J Sur 1983; 145; 775-779   Back to cited text no. 9    
10.Nandi et al. Incidence of postoperative deep vein thrombosis in Hong Kong Chinese. Br J Surg 1980; 67; 251-253, 1980.   Back to cited text no. 10    
11.Eriksson BI, Zachrisson BE, Teger-Nilsson AC. Thrombosis prophylaxis with low molecular weight heparin in total hip replacement. Br J Surg 1988; 75:1053.  Back to cited text no. 11    
12.Turpie A, Levine GG, Hirsh MN, et al. A randomised controlled trial of a low molecular weight heparin (Enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery. New Eng J Med 1986; 315:925.  Back to cited text no. 12    
13.Torholm C, Knudsen JB, Jorgensen PS, et al. Thromboprophylatic effect of a low molecular weight heparin (Fragmin) in elective hip surgery. A placebo controlled study. Thromb Haemostas 1989; 62: 488.  Back to cited text no. 13    
14.Dechavanne M, Ville D, Berruyer M, et al. Randomised trial of low molecular weight heparin( Kabi 2165) versus adjusted dose subcutaneous standard heparin in the prophylaxis of deep vein thrombosis after elective hip surgery. Hemostasis 1989; 19:5-12.  Back to cited text no. 14    
15.Mok CK et al. The incidence of deep vein thrombosis in Hong Kong Chinese after hip surgery for fracture of the proximal femur. Br J Surg 1979; 66: 640-642.  Back to cited text no. 15    
16.Atichartakarn V et al. Deep vein thrombosis after hip surgery among Thai. Arch Intern Med 1988; 148, 1349-1353.  Back to cited text no. 16    
17.Kim YH, Suh JS. Low incidence of deep vein thrombosis after cementless total hip replacement. J Bone Joint Surg 1988; 70, 878-82.  Back to cited text no. 17    
18.Davis J. Prevention, diagnosis, and treatment of venous thromboembolic complications of gynaecologic surgery. Am J Obstet Gynaecol 2001; 184(4): 759-775  Back to cited text no. 18    
19.Stamatakis JD, Kakkar VV, Sagar S, et al. Femoral vein thrombosis and total hip replacement. Br Med J 1977; 2: 223-225.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]

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Correspondence Address:
N Rajagopalan
Professor and Head of the Dept. Of Orthopaedics,St. John's Medical College, Bangalore - 560034.
India
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Source of Support: None, Conflict of Interest: None


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