SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17. NO. 4. 1991

Thromboprophylaxis with Heparin and Low Molecular Weight Heparin in Elective Hip Surgery: Current Status and Perspectives

Orthopedic and trauma surgery involve a high risk of postoperative thromboembolism. Several studies were done in the past to evaluate the risk in orthopedic patients, mostly in those with elective total hip arthroplasty. Thus, the thrombosis risk seems to be well known in this group. Since the results of these studies differed, we compared the study designs and evaluation methods for deep vein thrombosis (DVT) and attempted a metaanalysis of the thrombosis risk and the thromboprophylactic effects of different heparins. In an overview performed by Bergqvist in 1983,1 the estimated risk of DVT in elective hip surgery was 59% when DVT was diagnosed by the radiofibrinogen test (RFT) and 52% when it was assessed phlebographically. Reviewing the studies from the 1970s, we found that only a few fulfilled the above criteria and only those were included in our analysis.2-6 We added the results of some recent comparative trials with placebo-treated or untreated patient groups. 7-11 The astonishing fact was that we could confirm Bergqvist's results (Table 1, Fig. 1). One study in our meta-analysis which applied the RFT as the sole diagnostic procedure showed a DVT rate of 67.2%. Six studies with RFT findings that were confirmed phlebographically showed a DVT rate of only 51.5%, ranging from 35.2 to 55%. The five studies using bilateral phlebography as an endpoint showed a similar DVT rate of 51%, ranging from 44 to 53.6%.

From the Department of Trauma and Reconstructive Surgery, Klinikum Steglitz, Free University of Berlin, Berlin Germany. Reprint requests: Dr. Breyer, Professor for Surgery, Dept. of Trauma and Reconstructive Surgery, Klinikum Steglitz, Free University of Berlin, D-1000 Berlin 45, Germany. 336

We therefore, conclude that the incidence of DVT in patients with total hip arthroplasty is about 50% without thromboprophylaxis. We also examined what is called the "golden standard" in thromboprophylaxis, at least in Europe: The application of unfractionated heparin in fixed doses of 5000 IU three times daily. Analyzing 11 reports, 2,3,4,13-20 we found a DVT reduction of 40% with this prophylaxis. This means that the thrombosis rate can be reduced by low-dose heparin to a level of about 30% of all patients (Table 2). In RFT studies that were controlled phlebographically, the DVT rates varied widely, from 11 to 46% (Fig. 2). This may be due to the small numbers of patients included in some of the studies.

D.V.T. in Elective Hip Surgery (THR) Untreated/ Placebo

FIG. 1. Deep vein thrombosis rates in patients undergoing elective total hip replacement surgery. Mean values and ranges of nontreated or placebo groups from randomized trials (see Table 1).

Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

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HANS GEORG BREYER, M.D.

THROMBOPROP

References

No.

DVT

Proximal/Distal

%

%

Dose

Total No.

Versus

RFT†

Phlebography†

Study Type

Untreated (control) or placebo Bergqvist et al,2 1979

51

62.7

44/56

Ctrl*

148

Dextran/heparin

Yes

No

Random

Morris and Hardy,6 1981

27

55.6

Ctrl

81

DHE/H-DHE†

Yes

No

Random

Morris et al, 1974

32

50

— —

59

Heparin

Yes

(Unilateral)

Random

Hampson et al,3 1974

52

54

43/57

Plac*

100

Heparin

Yes

(Bilateral)

Random, d-blind†

Moskovitz et al, 17 1978

32

59.4

53/47

Plac

67

Heparin

Yes

Unilateral

Random, d-blind

Lassen et al, 1988

97

44

53/47

Plac

316

H-DHE/LMWH-DHE†

(Yes)

(Unilateral)

Random, d-blind

Torholm et al, 11 1989

54

35.2

Plac

112

LMWH

Yes

(Unilateral)

Random, d-blind

Ctrl

106

Dextran

No

Bilateral

Not randon

Plac

100

LMWH

Yes

Bilateral

Random, d-blind

4

8

*Eyarts and Feil,4 1971 Turpie et al,

12

1986 10

56

53.6

— —

50

42

48/52

65

Ctrl

49.2

38/62

Plac

130

H-DHE

No

Bilateral

Random, d-blind

Lassen et al,9 1989

102

44



Plac

192

LMWH

No

Bilateral

Random, d-blind

Hoek et al,7 1989

99

57

45/55

Plac

196

Org 10172

No

Bilateral

Random, d-blind

Sasahara et al,

1987

* Studies on patients with thromboprophylaxis versus untreated patients (Ctrl) or placebo (Plac). †RFT: radiofibrinogen test; RFT (yes): technetium plasminogen test: phlebography (): only in case of positive leg scan; DHE: dihydroergotamine mesylate; H: heparin; LMWH: low molecular weight heparin; d-blind: double-blind.

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TABLE 1. Comparative Trials in Untreated Patients with Deep Vein Thrombosis in Elective Hip Surgery*

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

Leyvraz et al, 22,23 Potron et al, 24 and Dechavanne et al demonstrated that an activated partial thromboplastin time-controlled individual dosage of unfractionated (UF) heparin could reduce DVT rates to about 10%. Although this seemed to be a very interesting therapeutic schedule, the method has not found widespread clinical acceptance. The combination of heparin with dihydroergotamine mesylate (DHE) is thought to be more effective against DVT. We found that RFT assessment only seems to underestimate the thrombosis rate in comparison to assessments performed with phlebography-controlled RFT or bilateral phlebography. A comparison with groups receiving UF heparin revealed the same thrombosis rate of about 30%. 8 , 1 4 , 2 0 , 2 6 - 2 9 As in UF heparin groups, RFT plus phlebography yielded only slightly lower thrombosis rates than bilateral phlebography (Table 2, Figure 2). These results give rise to the question of why it is useful to combine heparin and DHE, as it obviously does not produce a lower thrombosis rate in hip surgery patients than UF heparin. We hoped to find a higher thromboprophylactic efficacy with low molecular weight heparins (LMWH) than with UF heparin, especially in the high-risk groups. Although this seems to be confirmed in single studies, it is difficult to determine an overall mean thrombosis rate with LMWH for the following reasons: 25

1. Only a few studies have been published so far. 2. There is a lack of detailed information in some reports.

3. There is no real standard for the LMWH. Since every LMWH has its distinct characteristics and is individually standardized in units or milligrams, the dosage is not directly comparable. 4. There are no comparative trials of the different LMWH. Mindful of these limitations, we considered the results (Fig. 3): Enoxaparine (PK 10169) has been tested in two trials: at a dose of 60 mg by Turpie et al12 and of 40 mg by Planes, et al. 18 They demonstrated a very low thrombosis rate of about 12%. The results of a further study have been reported by Lassen et al. 9 They demonstrated a DVT rate of 6.7%. A similar low thrombosis rate was found by Zilch et al20 with Embolex NM, which is a combination of LMWH and DHE. The dosage of Embolex NM in this study was twice as high as in other trials. 8,30 The DVT was only controlled by RFT and not confirmed by phlebography, as in one of the other trials. The study of Lassen et al, 8 which was performed with a technetiumplasminogen test on the fifth postoperative day, showed a DVT rate of 30%, which is as high as in the UF heparin treatment groups. Six studies have been published in which Fragmin (Kabi 2165) was given at a dose of 5000 anti-Xa U/day. The first two studies with RFT controlled by phlebography in about 50% revealed DVT rates of 12 and 14.5%. 13,20 There were two other trials with higher phlebographic control rates that showed DVT in about 18% of the patients.24,31 Three trials with bilateral phlebographic assessment, one by Eriksson et al,31 the other by Torholm et al11 and by Dechavanne et al, 25

D.V.T. in Elective Hip Surqery (THR) D.V.T. in Elective Hip Surgery (THR) LMw-Heparins

FIG. 2. Deep vein thrombosis rates in patients undergoing elective total hip replacement surgery. Mean values and ranges from randomized trials with unfractionated (UF) heparin in fixed doses (a), or adjusted doses (b), and with unfractionated heparin in combination with dihydroergotamine mesylate (H-DHE) (c).

FIG. 3. Deep vein thrombosis rates in patients undergoing elective total hip replacement surgery. Mean values and ranges from randomized trials with different low molecular weight heparins (LMWH).

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338

TABLE 2. Effects of Treatment in Patients with Deep Vein Thrombosis in Elective Hip Surgery* No.

References

DVT

Proximal/Distal

%

%

Dose

Total No.

Versus

RFT

Phlebography

Study Type

50

48

20/80

bid†

101

Ctrl

Yes

No

Random

Morris et al,4 1974

27

11

100/0

bid

59

Ctrl

Yes

(Unilateral)

Random

Hampson et al,3 1974

48

46

50/50

tid†

100

Plac

Yes

(Bilateral)

Random, d-blind

Sagar et al,9 1976

25

32

tid

82

Ctrl/H-DHE

Yes

(Unilateral)

Random

Moskovitz et al,17 1978

35

22.9

Plac

Yes

Unilateral

Random, d-blind

Schondorf and Weber,20 1980

55

14.5

— — —

H-DHE/dextran-DHE

Yes

(Unilateral)

Random

Westermann et al,29 1981

63

46

H-DHE/DHE

Yes

(Unilateral)

Random

Binsack et al,13 1986

47

14.8

LMWH

Yes

(Unilateral)

Random

Cade et al,14 1987

65

Planes et al,18 1988

108

Eriksson et al,15 1989 GHATC,

16

1990

65 136

tid

67

tid

162

— —

tid

249

tid

95

22

50/50

tid

126

H-DHE

No

Bilateral

Random, d-blind

25

74/26

tid

237

LMWH

No

Bilateral

Random, d-blind

40.4

42/58

tid

130

LMWH

No

Bilateral

Random, d-blind

34.3

57/43

273

LMWH

No

Bilateral

Random, d-blind

tid

Unfractionated heparin (5000 IU) plus DHE (0.5 mg) Bergqvist et al,26 1980

54

18.5

bid

168

Dextran/PZ68B

Yes

No

Random

Schondorf and Weber,20 1980

53

3.8

tid

162

Dextran-DHE/heparin

Yes

(Unilateral)

Random

25

bid

249

H/DHE

Yes

(Unilateral)

Random

30.4

bid

316

LMWH/placebo

(Yes)

(Unilateral)

Random

Heparin

No

Bilateral

Random, d-blind

No

Bilateral

Random (?)

No

Bilateral

Random

Westermann et al,29 1981 Lassen et al,8 1988 14

61 112

30

50/50

tid

126

Kakkar et al,28 1985

500

26.2

54/46

tid



Estoppey et al,27 1989

130

31.7

20/80

bid

278

Cade et al,

1987

61

Org 10172

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Unfractionated (UF) heparin (5000 IU) Bergqvist et al,2 1979

* Studies on patients with thromboprophylaxis of unfractionated (UF) heparin of UF heparin plus dihydroergotamine (DHE) versus different other thromboprophylaxis. † bid: twice daily; tid: three times daily. For other abbreviations, see Table 1.

THROMBOPROPH

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

yielded DVT rates of between 4.9 and 30.7%. To sum up, the six studies with Fragmin demonstrated a mean DVT rate of about 20%. There is only one study with Logiparin, which has been published by Lassen et al. 8 There was a DVT rate of 30%. In a recently completed German multicenter trial in which we took part using Fraxiparine (CY 216), fixed doses of 10,000 IU were applied daily.16 DVT was assessed by bilateral phlebography. There was a rate of 33%. Besides this fixed dose, there was a very interesting approach to reduce DVT rates by body-weight-adapted doses of Fraxiparine. Simon et al32 and Leyvraz et al23 have demonstrated a reduction of the DVT rate to about 13%. Since there have thus far only been a few studies with the different LMWH, it is not yet possible to estimate which of the LMWH might have a higher efficacy. It can be concluded that they are at least as effective as UF heparin. To find out whether one of the LMWH is more effective, we need some methodologically and statistically improved individual comparative LMWH trials. Future study designs for clinical trials should comprise: 1. Statistical planning for sufficiently comparable groups. 2. Drug application for at least 10 days. 3. Endpoint bilateral phlebography or at least RFT controlled by uni- or bilateral phlebography when RFT is positive. 4. Documentation of localization and extension of DVT. 5. Monitoring of pulmonary embolism by lung scanning, arteriography, and autopsy. 6. Monitoring of all intra- and postoperative blood loss as well as transfusion and infusion requirements. There is another aspect of LMWH that needs some attention. Some trials indicate that LMWH application reduces proximal deep vein thrombosis, which may lower the incidence of pulmonary embolism. However, the small numbers of patients included in all studies render it impossible to determine whether the rate of pulmonary embolism is actually lower or not. Only a few reports document the ratio of proximal to distal DVT. Findings from seven studies with untreated or placebo patient groups suggest a relationship of 45 to 55% (Fig. 4). The methods of assessment may influence the relationship, since the RFT in hip surgery is limited to the calf and popliteal region. There is only a slight difference between untreated or placebo patients and patients treated with UF heparin.

D.V.T. in Elective Hip Surgery (THR) Proximal/Distal DVT Untreated/Placebo

FIG. 4. Ratio of proximal to distal deep vein thrombosis in untreated or placebo-treated patients undergoing elective total hip replacement surgery.

In the latter, the phlebographically assessed relationship of proximal to distal DVT is 55 to 45% (Fig. 5). Most LMWH studies indicate a distal shift in the relationship of proximal to distal DVT to about 30 to 70% (Fig. 6). It is probably one of the most important effects of LMWH in hip surgery. Although this phenomenon cannot as yet be explained, it will require further attention in the future. The overview of DVT in elective total hip replace-

D.V.T. in Elective Hip Surgery (THR) Proximal/Distal DVT UF-Heparin

FIG. 5. Ratio of proximal to distal deep vein thrombosis in patients undergoing elective total hip replacement surgery treated with unfractionated (UF) heparin.

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340

D.V.T. in Elective Hip Surgery (THR) Proximal/Distal DVT LMW-Heparins

FIG. 6. Ratio of proximal to distal DVT in patients undergoing elective total hip replacement surgery treated with different low molecular weight heparin (LMWH).

ment can be summarized as follows: 1. Total hip arthroplasty is associated with a DVT rate of 50% in untreated patients. 2. UF heparin at a dose of 5000 IU three times daily reduces the DVT rate to about 30%. 3. No advantage is gained by combining UF heparin with DHE. 4. LMWH in single daily doses is at least as effective as UF heparin three times daily. 5. There is an indication that LMWH may reduce proximal DVT. 6. A better antithrombotic effect may be achieved with LMWH by applying individual doses.

REFERENCES 1. Bergqvist D: Postoperative Thromboembolism. Frequency, Etiology, Prophylaxis. Springer, Berlin, 1983. 2. Bergqvist D, O Efsing, T Hallböök, T Hedlund: Thromboembolism after elective and post-traumatic hip surgery—a controlled prophylactic trial with dextran 70 and low-dose heparin. Acta Chir Scand 145:213-218, 1979. 3. Hampson WGF, FC Harris, H Keith Lucas, PH Roberts: Failure of low-dose heparin to prevent deep-vein thrombosis after hip replacement arthroplasty. Lancet 2:795-797, 1974. 4. Morris GK, APJ Henry, BJ Preston: Prevention of deep-vein thrombosis by low-dose heparin in patients undergoing total hip replacement. Lancet 1:797-799, 1974. 5. Evarts Feil 6. Morris WT, AE Hardy: The effect of dihydroergotamine and heparin on the incidence of thromboembolic complications following total hip replacement: A randomized controlled clinical trial. Br J Surg 68:301-303, 1981.

341 7. Hoek J, MT Nurmohamed, H ten Cate, JW ten Cate, HR Büller: Prevention of deep-vein thrombosis (DVT) following total hip replacement by a low molecular weight heparinoid (ORG 10172). (Abst.) Thromb Haemost 58:510, 1987. 8. Lassen MR, LC Borris, HM Christiansen, F Moller-Larsen, VE Knudsen, P Boris, AM Nehen, A de Carvalho, AG Jurik, BW Neilsen, U Lucht: Heparin/dihydroergotamine for venous thrombosis prophylaxis: Comparison of low-dose heparin and low molecular weight heparin in hip surgery. Br J Surg 75:686-689, 1988. 9. Lassen MR, LC Borris, HM Christiansen, AD Olsen, P Schott, S Eiskjaer, KL Boll, BW Neilsen, JC Rodenberg, U Lucht: Low molecular weight heparin in the prevention of thromboembolism in elective total hip replacement. (Abst.) Thromb Haemost 62:126, 1989. 10. Sasahara AA, FJ DiSerio, and the Multicenter Investigators: Dihydroergotamine-heparin prophylaxis of DVT in total hip replacement patients: A multicenter trial. (Abst.) Thromb Haemost 58:240, 1987. 11. Torholm C, JB Knudsen, PS Jorgensen, P Bjerregaard, PK Jorgensen, K Hagen, L Broeng, L Josefson: Thromboprophylactic effect of a low molecular weight heparin (Fragmin) in elective hip surgery. A placebo controlled study. Thromb Haemost (Abst) 62:488, 1989. 12. Turpie AGG, MN Levine, J Hirsh, CJ Carter, RM Jay, PJ Powers, M Andrew, RD Hull, M Gent: A randomized controlled trial of a low molecular weight heparin (Enoxaparin) to prevent deep vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 315:925-929, 1986. 13. Binsack T, M Zellner, I Schimming, C Wirth, E Moser, H Riess, E Hiller: Thrombosis prophylaxis with LMW heparin and sodium heparin in patients with total hip replacement. Thromb Res 44(Suppl VI):83, 1986. 14. Cade JF, KW Mills, AS Gallus, W Murphy: Preventing venous thrombosis (VT) with heparin alone or with heparin/ dihydroergotamine after elective hip replacement. A double-blind, randomized, venogram end-point comparison. (Abst.) Thromb Haemost 58:240, 1987. 15. Eriksson BI, E Eriksson, H Wadenvik, L Tengborn, B Risberg: Comparison of low molecular weight heparin and unfractionated heparin in prophylaxis of deep vein thrombosis and pulmonary embolism in total hip replacement. (Abst.) Thromb Haemost 62:470, 1989. 16. German Hip Arthroplasty Trial Group (GHATG): Prevention of deep-vein thrombosis with low molecular weight heparin (CY 216) versus low dose heparin in patients with elective total hip arthroplasty. In press. 17. Moskovitz PA, SS Ellenberg, HL Feffer, PI Kenmore, R Neviaser, BE Rubin, VM Varma: Low dose heparin for prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures. J Bone Joint Surg 60A: 1065-1070, 1978. 18. Planes A, N Vochelle, F Mazas, C Mansat, J Zucman, A Landais, JC Pasciarello, D Weill, J Butel: Prevention of postoperative venous thrombosis: A randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 60:407-410, 1988. 19. Sagar S, D Nairn, JD Stamatakis, FH Maffei, AF Higgins, DP Thomas, VV Kakkar: Efficacy of low dose heparin in prevention of extensive deep vein thrombosis in patients undergoing total hip replacement. Lancet 2:1151-1154, 1976. 20. Schondorf TH, U Weber: Prevention of deep vein thrombosis in orthopedic surgery with the combination of low dose heparin plus either dihydroergotamine or dextran. Scand J Haematol 25:126— 134, 1980. 21. Zilch H: Personal communication.

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THROMBOPROPHYLAXIS IN HIP SURGERY—BREYER

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991

22. Leyvraz PF, J Richard, F Bachmann, G van Melle, JM Treyvaud, JJ Livio, G Candarjis: Adjusted versus fixed dose subcutaneous heparin in the prevention of deep vein thrombosis after total hip replacement. N Engl J Med 309:954-958, 1983. 23. Leyvraz PF, F Bachmann: Prophylaxie thromboembolique souscutanee en chirurgie de la hanche (heparin standard en doses adjustees versus Fraxiparine). (Abst.) Schweiz Med Wochenschr 120 (Suppl 32/I):58, 1990. 24. Potron G, J Barre, C Droulle, JC Baudrillard, P Barbier, A Kher: Thrombosis prophylaxis with low molecular weight heparin (Kabi 2165) and calcium heparin in patients with total hip replacement. (Abst.) Thromb Haemost 58:118, 1987. 25. Dechavanne M, D Ville, M Berruyer, F Trepo, F Dalery, N Clermont, JL Lerat, B Moyen, LP Fischer, A Kher, P Barbier: Randomized trial of a low molecular weight heparin (Kabi 2165) versus adjusted dose subcutaneous standard heparin in the prophylaxis of deep vein thrombosis after elective hip surgery. Haemostasis 1:5-12, 1989. 26. Bergqvist D, O Efsing, T Hallböök, B Lindblad: Prevention of postoperative thromboembolic complications. Acta Chir Scand 146:559-568, 1980. 27. Estoppey D, J Hochreiter, HG Breyer, H Jakubek, PF Leyvraz, S

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Haas, JCJ Stiekema: Org 10172 (Lomoparan) versus heparin-DHE in prevention of thromboembolism in total hip replacement. A multicentre trial. (Abst.) Thromb Haemost 62:356, 1989. Kakkar VV, PJ Fok, WJG Murray, P Paes, D Merenstein, R Dodds, R Farrell, RQ Crellin, EM Thomas, TR Morley, AJ Price: Heparin and dihydroergotamine prophylaxis against thromboembolism after hip arthroplasty. J Bone Joint Surg 67B:538-542, 1985. Westermann F, O Trentz, P Pretschner, J Mellmann: Thromboembolism after hip surgery. Int Orthop 4:253-257, 1981. Haas S, HM Fritsche, H Ritter, F Hasner, F Lechner, G Blümel: Thromboembolieprophylaxe mit niedermolekularem Heparin bei Patienten mit totalem Hüftgelenksersatz. In: Rahmanzadeh HG: Unfallheilkunde. Schnetztor, Konstanz, 1989, pp 303-308. Eriksson B, et al. Comparison of Fragmin with dextran in elective hip replacement surgery. In: Fragmin. The New Generation Antithrombotic Agent. The Medicine Group (UK), Oxford, 1987, pp 17-18. Simon P, A Kindermans, JF Kempf, M Postel: Efficaciteé et tolérance d'une thromboses veineuses profondes lors des arthroplasties totales de hance réglées. Essal prospectif, multicentrique. J Chir (Paris) 127:252-257, 1990.

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Thromboprophylaxis with heparin and low molecular weight heparin in elective hip surgery: current status and perspectives.

SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17. NO. 4. 1991 Thromboprophylaxis with Heparin and Low Molecular Weight Heparin in Elective Hip Surgery...
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