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Low Molecular Weight Heparins For DVT Prophylaxis In Orthopedics

Zahra Esmail, Pharm.D. Candidate, Rubina Sunderji, Pharm.D.
September 1997  Drug & Therapeutics Newsletter
(C) 1997, CSU-Pharmaceutical Sceinces
Vancouver Hospital & Health Sciences Centre

Introduction

Deep-vein thrombosis (DVT) is a major source of morbidity and mortality in high risk orthopedic patients. Approximately 50% of these patients will develop DVT and up to 20% will develop pulmonary embolism (PE) in the absence of prophylaxis.1-3 At VHHSC, two low molecular weight heparins (LMWH), tinzaparin and enoxaparin, were recently approved for DVT prophylaxis in patients with spinal cord injury, knee arthroplasty and major trauma.

Comparative Studies

Several randomized studies assessing the efficacy of LMWHs for DVT prophylaxis in high risk orthopedic patients have been published (Table 4).4-8 An important consideration in the evaluation of these studies is the method of DVT detection employed. The most sensitive and specific method for detection is contrast venography. Bilateral venography provides a more accurate representation than unilateral leg venography which can significantly underestimate DVT incidence. Furthermore, the comparator agent employed is dependent on the patient population studied. With knee arthroplasty, warfarin (INR 2-3) offers the most valid comparison and is recommended in this setting since low-dose heparin has shown inferior results.9 In spinal cord injury and major trauma patients, low-dose heparin (5000 units SC BID-TID) is the comparator for DVT prevention.

In the single study available in spinal cord injury patients, tinzaparin 3500 IU SC daily was compared to heparin 5000 IU SC TID.4 The incidence of total and proximal DVTs was significantly lower in the tinzaparin group as compared to the heparin group.

Of the 3 trials available in the knee arthroplasty population, two involved enoxaparin in a 30 mg SC q12h regimen6,7 while the remaining trial involved tinzaparin 75 IU/kg SC daily.5 In all 3 studies, the incidence of total DVTs was significantly reduced in the LMWH group as compared to the warfarin group. In only one of these studies was there a significant difference in the incidence of proximal DVTs in favour of the LMWH group.7 However, this study employed unilateral venography for DVT detection and is available only in abstract form. There were no differences in the rates of PE among treatment groups in any of these studies.

One study has been published in the major trauma population comparing enoxaparin to heparin.8 In this study, enoxaparin 30 mg SC q12h was significantly more effective than heparin 5000 IU SC q12h in reducing the incidence of total and proximal DVTs.

All of the studies comparing LMWHs to either warfarin or heparin have shown a significant benefit in favour of the LMWHs with regards to development of total DVTs. However, the effects of LMWHs in reducing proximal DVTs, which carry a higher risk of PE, have been inconsistent.

To date, there are no head-to-head trials comparing the various LMWHs. The available evidence in knee arthroplasty patients suggest similar efficacy and bleeding rates with tinzaparin and enoxaparin.

Table 4. Summary of Controlled DVT Prophylaxis Trials in Orthopedics Involving a Valid Comparator

Ref. Design Drug/Dose N Method of DVT

Diagnosis

Total DVT (%) Prox. DVT (%) PE (%) Major Bleed (%)
Spinal Cord

Green 19904

 

P,R,NB

 

H 5000 SC q8h

T 3500 SC daily

 

21

20

 

Symptoms & serial venous flow studies; confirmation by venography

 

14.2

01

 

14.2

01

 

9.5

0

 

9.5

0

Knee Replacement

Hull

19935

 

 

Leclerc 19966

Spiro

19947

 

 

P,R,DB

 

 

P,R,DB

 

P,R,NB

 

 

W (INR 2-3)

T 75 IU/kg SC daily

W (INR 2-3)

E 30mg SC q12h

W (INR 2-3)

E 30mg SC q12h

 

 

324

317

 

334

336

176

173

 

 

Bilateral contrast venography

 

Bilateral contrast venography

Unilateral contrast venography

 

 

54.9

45.01

 

51.7

36.91

45.4

25.41

 

 

12.3

7.8

 

10.4

11.7

11.4

1.71

 

 

n/a

n/a

 

0.9

0.3

0.6

0

 

 

0.9

2.8

 

1.8

2.1

2.3

5.2

Major Trauma

Geerts 19968

 

 

P,R,DB

 

 

H 5000 SC q12h

E 30mg SC q12h

 

 

136

129

 

 

Bilateral contrast venography

 

 

44

311

 

 

15

61

 

 

n/a

n/a

 

 

0.6

2.9

N=number of patients; P=prospective; R=randomized; NB=non-blinded; DB=double-blinded; H=unfractionated heparin; T=tinzaparin; W=warfarin; E=enoxaparin; n/a = not available

1 p<0.05

Adverse Effects

The risk of bleeding was not statistically different between the LMWH group and the comparator agent in any of the above studies. In one trial involving knee arthroplasty patients, the risk of major bleeding with enoxaparin was more than two-fold higher than with warfarin (5.2% vs 2.3%).7 This incidence of major bleeding with enoxaparin was similar to the 5.0% incidence reported by Knudson et al in major trauma patients treated with this agent.10 LMWHs may also cause thrombocytopenia with a reported incidence of <3%. Although the optimal frequency of monitoring the complete blood count (CBC) is unknown, the current recommendation is for twice weekly CBC monitoring for all patients receiving LMWHs.

Comparative Costs

As there is no scientific evidence to support superior efficacy and safety of one LMWH over another, cost considerations in the choice of a LMWH become imperative (Table 5). The annual cost savings associated with prescribing tinzaparin versus enoxaparin averages approximately $100,000 in this high risk population.

Table 5. Cost Analysis for DVT Prophylaxis

Drug Tinzaparin Tinzaparin Enoxaparin
Regimen 3500 IU SC dailyb 5250 IU SC dailyc 30mg SC BID
Costa

($/day)

5.60 8.40 12.07
Cost

($/7 days)

39.20 58.80 84.49
Costa

($/90 days)

504.00 756.00 1086.30

aAcquisition cost quotes provided by the manufacturers to the Logistics Department at VHHSC in May 1997
b Dose of 50 IU/kg for a 70kg patient
c Dose of 75 IU/kg for a 70kg patient

 

Formulary Recommendation

Tinzaparin is currently the only formulary LMWH agent at VHHSC approved for the treatment of established DVT. Based on the available scientific evidence and cost considerations, the Drugs and Therapeutics Committee recommended expansion of the current hospital-approved indication for tinzaparin to include DVT prophylaxis in spinal cord injury and knee arthroplasty patients. In recognition of the lack of published data involving tinzaparin in major trauma, this Committee recommended approval of the addition of enoxaparin to the formulary restricted to DVT prophylaxis for patients with major orthopedic trauma (non-spine).

The Medical Advisory Committee has requested that an external analysis be performed by the Pharmacoeconomic Initiative Scientific Committee (PISC) and BC Office of Health Technology Assessment (BCOHTA). This report is expected to be available by the Fall of 1997. Until then, both LMWHs will be available for DVT prophylaxis for major orthopedic sugery, spinal cord injury, and total knee arthroplasty. Preprinted order forms have been created to facilitate prescribing of the LMWHs pending the decision of the PISC/BCOHTA review.

References

1. Myllynen P et al. Deep vein thrombosis and pulmonary embolism in patients with acute spinal cord injury: a comparison with non-paralyzed patients immobilized due to spinal fractures. J Trauma 1985;25:541-6.

2. Stulberg BN et al. Deep-vein thrombosis following total knee replacement. An analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg (Am) 1984;66:194-201.

3. Shackford SR et al. Venous thromboembolism in patients with major trauma. Am J Surg 1990;159:365.

4. Green D et al. Prevention of thromboembolism after spinal cord injury using low-molecular-weight-heparin. Ann Int Med 1990;113:571-4.

5. Hull R et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. NEJM 1993;329:1370-6.

6. Leclerc JR et al. Prevention of venous thromboembolism after knee arthroplasty: a randomized, double-blind trial comparing enoxaparin with warfarin. Ann Int Med 1996;124:619-26.

7. Spiro TE et al. Enoxaparin a low molecular weight heparin and warfarin for the prevention of venous thromboembolic disease after elective knee replacement surgery. Blood 1994;84(Suppl 1):246a.

8. Geerts WH et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. NEJM 1996;335(10):701-7.

9. Prandoni P et al. Prevention of Venous Thromboembolism in Major Orthopedic Surgery. Clin Appl Thrombosis/Hemostasis 1996;2(3):153-7.

10. Knudson MM et al. Use of low molecular weight heparin in preventing thromboembolism in trauma patients. J Trauma 1996;41(3):446-59.