Prevention of deep vein thrombosis by low-molecular-weight heparin and dihydroergotamine in patients undergoing total hip replacement

THROMBOSIS RESEARCH 63; 133-143,199l 0049-3848/91 $3.00 + .OOPrinted in the USA. Copyright (c) 1991 Pergamon Press pk. All rights reserved.

PREVENTION OF DEEP VEIN THROMBOSIS BY LOW-I’IOLECULAR-WEIGHT HEPARINAND DIHYDROERGOTAMINE IN PATIENTSUNDERGOING TOTALHIP REPLACEMENT

H. Freick”, S. Haas” ’ Krankenhaus Bethanien, Dortmund, Germany ‘* Institut fiir Experimentelle Chirurgie Technische UniversitSt hiinchen, Germany

(Received 22.3.1991; accepted in revised form 27.4.1991 by Editor H.A. Vinazzer)

ABSTRACT In 110 high-risk patients undergoing total hip replacement the antithrombotic efficacy and safety of a single daily injection of 1500 aPTT-U low-molecular-weight heparin plus 0,5 mg dihydroergotamine (EmbolexTM) was, in a double-blind study, compared with a twice daily administration of 5000 IU of the heparin-dihydroergotDeep vein thrombosis diagamine combination Heparin-DihydergotTM. nosed with phlebography occurred in 9,6 % in the EmbolexTM-group and in 25 % in the Heparin-DihydergotTH-group. Intraand postoperative blood loss and blood replacement were similar in both and on account of the single daily administragroups. Therefore, tion, EmbolexTM offers at least the advantage of improved compliance of the patients and reduced workload of the nursing staff.

INTRODUCTION In a double-blind study involving 160 patients undergoing elective total hip replacement, Haas et al. (1) compared the efficacy and tolerance of a once-aday subcutaneous administration of a fixed combination of 1500 aPTT-units of low-molecular-weight heparin and 0,5 mg dihydroergotamine (LHWH-DHE, Embolex*M, Sandoz) with that of a twice-a-day treatment with 5000 IU low-dose heparin-DHE (LDH-DHE). Using the radiolabeled fibrinogen uptake test (RFUT), the incidence of deep vein thrombosis (DVT) was found to be 20,5% in each of the groups. Although it can be assumed that the RFUT led to equally distributed false positive results in both groups, an uncertainty remains with regard to the reliability of the RFUT; this is mainly based on the fact that the RFUT is also sensitive to extravascular fibrin depositions in wound hematomas and to smaller thrombi, which may become dissolved in the course of the Key words: thrombosis;

low-molecular-weight heparin; dihydroergotamine; heparin; total hip replacement: postoperative thromboembolism 133

deep vein

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postoperativeperiod and thus have no clinical significance.The comparative trial as reportedin this paper was thus performedto test the above mentioned assumption regarding the specifity of the REUT by using phlebography as screeningmethod for the diagnosis of DVT. The trial comprised 110 patients undergoingelective total hip replacementand receivingin two groups the same prophylactictreatment as describedabove. A supplementaryDoppler ultrasonography was performed to determine the venous and arterial flow parameters, firstly to find out whether venous thrombosiscan be early diagnosedby means of this non-invasivemethod and secondlyto get early hints to the occurrance of arterialangiospasticcomplications.

PATENTS AND METHODS Patients Admitted to this trial were patients with idiopathiccoxarthrosisand undergoing an elective total hip replacementeither with or without cement implantation. Inclusioncriteria: . male and female patients over 40 years of age . general or spinal anesthesia . planned durationof operation> 45 min . mobilizationpossibleafter the second postoperativeday . postoperativeobservationperiod at least 10 days Exclusioncriteria: . bleedingdisorders . contraindications to heparin or DHH . pregnancy . malignantdiseases . metabolicdisorders (excludingdiabetestreated orally or with insulin) . myocardialinfarctionwithinthe last 6 months before operation Patientswere withdrawnfrom further investigationwhen either of the followingendpointsoccurred: . DVT pulmonaryembolism : severe side effects of LMWH-DIEor LDH-DHE Study Design The patients were randomly assigned to either of two groups of equal size and received the medication under double-blind conditions.Thepatients of the first group (Group I) receiveda twice-a-daysubcutaneousinjectionof a fixed combinationof 5000 IU LDH and 0,5mg DHE (Heparin-DihydergotTM). The first injection was given in the morning (on the day of operation two hours before operation),the second one twelve hours thereafter.The patientsof the second group (Group II) received a subcutaneousinjectionof 1500 aPTT LMWH combined with 0,5mg DHE (HmbolexTM,Sandoz AG, Nuremberg,PRG) in the morning and a placebo injected 12 hours later with the same timing on the day of operation as described above. These regimens were constantly followed through days 1 (day of operation)to 10.

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135

Statistics The statistical evaluation was planned like demographic data on the patients, fety parameters such as blood loss and bography were evaluated using Fisher’s Ethical

as exploratory analysis for parameters results of the laboratory tests and sablood replacement. The results of phleexact test.

Considerations

The guidelines of good clinical practice had to be followed. with the Declaration of Helsinki the patients were informed methods of the study and gave informed consent.

In accordance on the aim and

Assessment The assessment

included

the following

procedures:

, On entry into the trial the patients were examined for risk factors of DVT by detailed anamnesis and physical examination. Usual blood parameters were determined and a bilateral Doppler ultra sonography was performed in the legs. . The following blood parameters were determined preoperatively and on the days 1, 5 and 10: hemoglobin, hematocrit, platelet count, aPTT (activated partial thromboplastin time), TT (thrombin time) and functional activity of AT III measured by use of a chromogenic substrate method. . The intra- and postoperative blood loss (blood contained in the suction equipment and drainage volume) had to be noted. . Noting of size and type of wound hematomas as well as of the occurrance of infections. . Doppler-sonographic measurement of the arterial and venous flow, performed on days 2, 4, 6, 8 and 10. . Phlebography of the operated leg on the 10th postoperative day . Recording of adverse side effects of the administered drugs All data had to be noted tending physician.

on standardized

case

record

forms signed

by the at-

RESULTS The study was conducted as a monocentric trial at the Krankenhaus Bethanien, Dortmund, FRG. Basic

from Apri1,1986,

to March,1987,

Data on Patients

A total of 110 patients (81 female and 29 male), divided into two groups of equal size, were included in the study. The mean age was 68 years (68,6 years for female patients, 66,7 years for male patients). The stratification of the age of the patients is shown in Table 1. It should be noted that 72,7% of all patients were between 61 and 89 years old. Table 2 shows, for both groups, the number of patients, their gender and the mean values of their age, height and weight. Type and incidence of the patients’ risk factors are listed in Table 3.

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TABLE1 Age of Patients

TABLE 2 Basic Data on Patients I] Gender (No.) . Hale . Female

Group I Group II M=55 N=55 16 39

13 42

Age (yrs) . Hean . Ilin/Hsx

66,5 45/84

69,7 47/89

Weight (kg) . llean . ?Iin/lIax

73,3 71,4 39/105 51/98

TABLE 3 Incidenceof Risk Factors Risk factors

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Patients

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Remaining for

Statistical

Evaluation

of Phlebography

In the course of the trial 10 patients had to be excluded from further evaluation: Two patients due to an allergy to contrast media, in one patient the phlebography could not be completed due to severe pain, one patient was in a too reduced state of health to undergo phlebography, one patient died after an intraoperative complication, one patient had to undergo laparotomy on the developed pulmonary embolism on the fourth postoperative day, one patient third postoperative day and three patients withdrew their consent to undergo phlebography. Thus, exactly 100 patients (48 in Group I and 52 in Group II) remained for the statistical evaluation of the results of phlebography. Incidence

of DVT

DVT according to clinical symptoms: Although all patients were daily examined for clinical symptoms of DVT like increase in leg circumference, pain in the calf, changes in temperature or color of the skin, fever, pulse enhancement and local swelling, none of them showed signs for DVT during the lo-day trial period and also thereafter. Even the above mentioned patient who developed pulmonary embolism did not show clinical signs for DVT. Results of Phlebography: Of the 100 patients undergoing phlebography, 48 were in Group I (LDH-DHE) and 52 in Group II (LMWH-DHE). DVT was diagnosed in a total of 17 cases - 12 in Group I (=25%) and 5 in Group II (=9,6%). These DVTs were in 12 cases diagnosed in the thigh, in 2 cases in the calf and in 3 cases in the thigh as well as in the calf and popliteal region. In the LDH-DHE-Group DVT occurred in the thigh in 8 cases, whereas for the LMWH-DHE-GroupDVT was noted in the thigh in 4 cases and in the popliteal region in one patient (Table 4). In al 1 cases of DVT diagnosed by phlebography there was a sufficient venous flow and a normalized contrast media pattern proximal of the thrombotic obstruction, thus leading to the assumption that the venous flow was not significantly impaired by the thrombi. This finding would not have been obtained by solely using Doppler ultrasound. Characteristics of the contrast media pattern: Stretched vascular congestion was noted two times in each of the two groups. In the remaining 13 cases of DVT the uniform or intermitted thrombus had a length of 1 to 6 cm. In the majority of the cases (8 in Group I and 3 in Group II) the length of the thrombus was between 3 and 4,5 cm, another thrombus measured only I cm in length and one was 6 cm long. TABLE4 Phlebography-Results

1 I

Phlebography DVT diagnosed Incidence

__-__---performed

i

.--

with phlebography

Location of DVT . Proximal . Distal . Proximal+distal+popliteal region ___- ~--__=

1, %;

4

1

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Results of Doppler ultrasonography: In only one patient (belonging to the LDHDHE-Group) signs for DVT (in the operated leg) were detected by Doppler ultrasonography. This finding was established on the 10th postoperative day - the date of the planned phlebography, which thereafter confirmed this DVT. Very discrete hints for DVT were obtained by Doppler ultrasonography in three more of the remaining 96 patients. In these cases, however, the suspected DVT could not be verified by phlebography. In addition, the blood flow in the major leg arteries and in the arteries of A reduction of the arterial perfusion toes I-V was examined in all patients. (toe IV) was established for merely one female patient. Since in this patient there was a suspicion of DVT, phlebography was suggested, but was unfortunately refused. Thus the patient had to be excluded from the trial. For the remaining patients, a reduction of the arterial perfusion caused by vasospasm could not be established: compared with the preoperative values the arterial perfusion was even better on the 4th postoperative day. Incidence

of Pulmonary Embolism

Clinical signs of pulmonary embolism occurred in one patient of the LDH-group, and the diagnosis was confirmed by scintigraphy. This patient, however, refused to undergo phlebography. Blood Loss and Substitution The intraand postoperative blood loss was determined by measuring the content of the blood suction equipment and by gauging the drainage volume. In Group I the intraoperative blood loss was found as 294,4 t/209,6 ml, in Group II the values were 313,8 t/- 226,3 ml. In Group I packed cells were administered intraoperatively to two patients (220 ml) and postoperatively to 28 to two papatients (583,7 t/181,0 ml), and in Group II intraoperatively tients (565,0 +/- 346,5 ml) and postoperatively to 28 patients (608,5 t/242,6 ml). The intraand postoperative administration of infusions (hydroxyethyl starch and crystalloidal solutions) was necessary in both groups: in most cases the volume was between 500 and 1000 ml, only in one case in each of the two groups the maximum volume of 1500 ml was administered (Table 5). Bleeding

Complications

Severe hemorrhage was registered in two patients of Group I but in none of Group II. Only one major wound hematoma was noted in each of the two groups, in the case of the afflicted patient belonging to Group I a deep hip joint which made it necessary to exchange the prosthesis. Other infection developed, adverse side effects did not occur. Laboratory

Data

determined from blood samples taken preThe evaluation of the blood values, One operatively and on the days 1, 5 and 10, was performed in two versions: analysis comprised only those patients for which a complete set of laboratory values was available, whereas the second version included all patients with no regard whether the laboratory data were completely available or not. These two versions did not result in significant differences in the pattern of the blood difference between Group I and parameters, and, too, there was no significant Group II. Table 6 shows the summarized data on the blood values.

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TABLE 5 Blood Loss and Replacement

Packed cells . No. Pat. . Median (ml) . min (ml) . max (ml) Infusions . No. Pat. . Volume 100 ml 500 ml 1000 ml 1500 ml

2 220 220 220

28 520 360 1130

2 565 320 810

28 500 210 1200

54

27

51

20

27

34 16 1

19 1

1 30 22 1

Blood volume in suction system . No. Pat. . Median (ml) . min/max

55 250 o/1200

Drainagevolume . No. Pat. . Median (ml) . min/max

55 250 o/1150 54 1467 535/2795

54 1237 460/3660 _-

TABLE 6 Blood Parameters

-

T

Admission GI GII =

DaY 1 GI GII

DaY 5 GI GII

Day 10 GI GII

Hemoglobin .No. Pat. .Hean (g%) .SD

54 53 52 53 53 52 50 54 13,4 13,3 10,8 10,9 11,3 10,9 11,4 11,9 1,2 1,2 1,l 1,2 1,2 1,l 1,l 1,6

Hematocrit .No. Pat. .Hean (%) .SD

54 54 51 51 53 52 52 49 44,5 44,l 35,7 36,6 37,6 36,5 38,l 38,7 486 3,7 3,4 3,8 3,8 3,7 3,5 3,2

Prothrombintime .No. Pat. 53 54 45 46 53 52 51 50 3112,21116,3 69,3 72,6 94,l 96,9 97,9 97,0 .I¶ean(%) .SD 21,0 21,6 13,8 19,9 18,6 17,7 19,3 15,l -

.I__ -

140

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PREVENTION OF DEEP VEIN THROMBOSIS

TAHLE6 cont. Thrombintime .No. Pat. .Mean (set) .SD

53 17,6 2,4

53 17,8 1,7

46 18,7 9,8

45 16,3 1,9

53 18,9 3,9

52 17,9 1,7

51 18,3 2,l

50 18,6 2,4

aPTT .No. Pat. .Mean (set) .SD

53 30,2 2,6

53 30,3 2,6

45 31,0 5,5

45 33,8 9,l

53 29,7 3,3

52 30,6 2,2

50 29,5 6,9

48 30,l 2,8

AT III .No. Pat. .Mean (%I .SD

53 53 LOO,2 103,9 14,l 18,3

46 81,6 14,2

46 79,8 15,2

51 95,5 14,4

53 98,3 17,0

50 93,5 14,5

47 97,4 12,8

Platelets .No. Pat. .Mean (*lo3 .SD /ml)

54 52 38 38 51 52 50 47 237,4 220,4 185,l 191,9 239,5 233,6 333,0 337,7 69,0 59,l 44,3 64,l 61,3 62,5 94,l 94,0

SD=Standard Deviation DISCUSSION Total hip replacement is associated with a high risk of thromboembolic complications. This may be due to the following reasons: . Most of the patients are of older age and usually have further concomitant diseases, especially cardiovascular and pulmonary failures . Severe tissue trauma leads to the release of large quantities of substances activating the coagulation cascade . The femoral vein and its branches are torqued and congested due to the rotation maneuvers necessary during the implantation of the prosthesis . Surgical instruments may lead to a damage of the blood vessels the polymerisation process produces . In case of using methylacrylat-cement temperatures up to 90° C (4,5) proved that the postoperaNakkar et al. (2,3) and other investigators tive risk of thromboembololism can be considerably reduced by low-dosemerely for high risk patients undergoing major bone surheparin-prophylaxis; gery, low-dose-heparin is not sufficiently effective (6-8) and a combination of LDIi and DHE should be preferred (9). The development of low-molecularweight heparin with its higher affinity to the Factor Xa consequently led to the question, whether a combination of this drug with DHE would have an equivalent or even better antithrombotic efficacy without inducing more hemorrhagic complications. This was investigated for the first time in a trial performed by Haas et al. (l), involving patients undergoing total hip replacement and comparing the efficacy of a single daily dosage of a low-molecularweight heparin combined with DHE (Wolex*k) with that of a twice daily administration of LDH-DHE. In this study the incidence of DVT, diagnosed by NFUT, was found to be 20,5% in both groups. So far, 16 further trials with other

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Ten were open or double-blind controlled LMWH-preparations have been reported: the optimum LMWHdosage scheme both for effectistudies aimed at determining veness and tolerance (10-19). Four were randomized, controlled studies on DVT prevention with various LMWHs, published as abstracts (20-23). Two were well designed randomized double-blind controlled clinical trials published as full papers in which the low-molecular-weight heparin Enoxaparin was tested against placebo and LDH (24,25); they provide firm evidence that this LMWHis effective and safe in the prevention of DVT in patients undergoing hip surgery. In cur study the incidence of phlebographically verified DVT was markedly lower in the LMWH-Group (9,5%) than in the LDH-DHE-Group (25%), yet it must be noted that this difference in the incidence rates is not statistically signiof these DVT were located in the ficant (2p<=O,16, p<=O,O9). The majority thigh of the operated leg and the thrombi were of about equal extent and the common assumption that DVT following hip operashape, which contradicts tions is mainly located in the calf. From this finding it may be concluded that most DVT were caused by damaging the veins in or near the site of operation and that the RFUT does not correctly reflect the postoperative thrombotic The administration of heparin obviously prevents the formation of situation. an extensive and completely occluding thrombus; in the majority of DVT the length of the thrombus was between only 3 and 4,5 cm. None of the patients showed clinical signs of DVT. This finding confirms the common opinion that clinical symptoms are very unreliable and that about 80% of DVT are clinically inapparent. In only one patient DVT was clearly diagnosed by Doppler ultrasonography, which was performed every second day. In three more cases discrete hints for DVT were provided by this technique, the following phlebography, however, could not confirm these findings. Thus, Doppler ultrasonography proved to be not sensitive enough to be used as a screening method for diagnosis of postoperative DVT. In order to assess the arterial flow, Doppler ultrasonography however proved to be a very useful method. In one patient, the arterial flow was slightly reduced in toe IV, what, however, was not of clinical significance. In general, the arterial flow measured on the fourth postoperative day was even better than that determined preoperatively. This may be due to the improved fluidity induced by the administered infusions. No difference between the two groups could be established with regard to blood loss, bleeding complications and substitution volume. It should be kept in mind, however, that the intraoperative blood loss depends on various parameters (e.g. experience of the surgeon, vascular situation at site of operation, method of stanching the blood) and may be overestimated in its significance when comparing the side effects of drugs. The variation over the time of the laboratory values was also equivalent between the two groups. Neither subjective nor objective signs for a reduced perfusion in the coronary arteries as well as other adverse side effects were established. Thus, it can be concluded that a single daily injection of EmbolexTM is at least as safe and efficacious as LDH-DHEadministered twice a day. Comparing the incidence of DVT in the two groups, the results of this study provide firm evidence that the antithrombotic efficacy of EmbolexTM might even be superior to LDH-DHEwithout causing more bleeding complications.

1 HAAS, s., STEMBERGER, A., FRITSCHE, H.-M., WELZEL, D., WOLF, H., LECHNER,F. and BLiiMEL, G. Prophylaxis of deep vein thrombosis in high risk patients undergoing total hip replacement with low-molecular-weight heparin plus dihydroergotanine. 9 Res. _37, 839-843, 1987 __

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2 KAKKAR, V.V. The current status of low-doseheparin in the prophylaxisof thrombophlebitis and pulmonaryembolism.World J. Surg. 2, 3-18, 1978 -3 KAKKAR, V.V., CORRIGAN,T.P., SPINDLER,J., FOSSARD,D.P., FLUTE, P.T., CRELLIN,R.Q., WESSLER, S. and YIN, E.T. Efficacyof low doses of heparin in preventionof deep-veinthrombosisafter major surgery - A double-blind, randomisedtrial. Lancet ___- II, 101-106,1972 4 GALLUS, A.S., HIRSH, J., O'BRIAN,S.E., MCBRIDE,J.A., TUTTLE, R.J. and GENT, M. Preventionof venous thrombosiswith small, subcutaneousdoses of heparin.JAMA -__ 235, 1980-1982,1976 5 KAKKAR, V.V. Preventionof fatal postoperativepulmonaryembolism by low doses of heparin:An internationalmulticentertrial. Lancet ___- II, 45-51, 1975 6 KAKKAR, V.V. Use of heparin in the preventionof venous thromboembolism.In: Blutgerinnunqund Fibrinolyse.Gross, R. and Holtmeier,H.-J. (Eds.) Stuttgart-New-York: Thieme-Verlag,1981, p.p. 33-34 7 HAMPSON,W., HARRIS, F.C., LUCAS, H.K., ROBERTS,P.H., MCCALL, I.W., JACKSON,P.C., POWELL, N.L. and STADDON,G.E. Failure of low-doseheparinto prevent deep-veinthrombosisafter hip-replacementarthroplasty.Lancet II, 795-799,1974 8 KAKKAR, V.V., STAMATAKIS,J.D., BENTLEY,P.G., LAWRENCE,D., de HAAS, H.A. and WARD, V.P. Prophylaxisfor postoperativedeep-veinthrombosis. Synergisticeffect of heparin and dihydroergotamine. JAMA 241, 39-42, 1979 -__ 9 SAGAR, S., NAIRN, D., STAMATAKIS,J.D., MAFFEI, F.H., HIGGINS,A.F., THOMAS, D.P. and KAKKAR, V.V. Efficacy of low-doseheparin in preventionof extensive deep-veinthrombosisin patientsundergoingtotal hip replacement.Lancet, 1151-1154,1976 10 PLANES, A., VOCHELLE,N., FERRU, J., PRYZYROWSKI,D., CLERC, J., FAGOLA,M. and PLANES, H. Enoxaparinelow molecularweight heparin: its use in the preventionof deep venous thrombosisfollowingtotal hip replacement. Haemostasis 16, 152-153,1986 -11 PLANES, A., VOCHELLE,N. and MANSAT, C. Preventionof deep vein thrombosis (DVT) after total hip replacement(THR) by Enoxaparine(LovenoxR):one daily injectionof 40 mg versus two daily injectionsof 20 mg. Thromb.Haemost.2, 415 (abst),1987 12 BARSOTTI,J., DABO, B., ANDREAU,J., ALISON,D., LEROY, L. and DELAHOUSSE,V.B. Preventionof deep vein thrombosis(DVT) by Enoxaparine (Lovenoxa)after surgery for fractureof femoralneck. One daily injectionof 40 mg versus two daily injectionsof 20 mg. Thromb. Haemost.511,891 (abst), -___ 1987 13 BANSILLON,V., DEJOUR, H., BESSON, L., DAVIDAS,J.L., RONDELFP,B., AZZAR, D. and MASSIGNON,D. PrOventiondes thrombosesveineusesprofondesen chirurgieorthopediquepour mise en place d'une prothesetotale de hanche. Essai randomisede determinationde la posologieoptimale.Ann. Chir. 41, 5765, 1987

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14 DROUET,J.C., BOURRELI,B., BERNARD,J.M., GUNST, J.P. and BAINVEL,J.V. Preventionde la maladie thrombo-embolique en chirurgieorthopediquepar la Fraxiparine.Presse Med. 16, 1331-1332, 1987 ~15 HAAS, S., FRITSCHE,H.-M., RITTER, H., STEMBERGER,A., WENDT, P., ZEISEL,H.J., LECHNFR,F. and BLUMEL,G. Thrombosisprophylaxiswith low molecularweight heparin in total hip replacement.Thromb.Haemost.54, 5596 (abst),1985 16 BREYER,H.G., RAHMANZADEH,R., BACHER,P. and WERNER, B. LMW-heparinversus Haemost.58, 890 (abst),1987 heparin-DHEin orthopedicsurgery.Thromb. ____ 17 ERIKSSON,B., ZACHRISSON,B., TEGER-NISSON,A.C., RISBERG,B. and LUNDMARK,S. Thrombosisprophylaxiswith low molecularweight heparin in Thromb.Res. 22 (Suppl.7),1987 total hip replacement.Fragminversus dextran.__-18 POTRON,G., BARRE, J., DROULLE,C., BAUDRILLARD,J.C., BARBIER,P. and KHER, A. Thrombosisprophylaxiswith low molecularweight heparin (KABI 2165) and calciumheparin in patientswith total hip replacement.Thromb. Haemost. 58, 421 (abst),1987 19 BINSACK,T., ZELLNER,M., SCHIMMING,I., WIRTH, C., MOSER, E., RIES, H. and HILLER, E. Thrombosisprophylaxiswith LMW heparinand sodium heparin in patientswith total hip replacement.Thromb.Res. Sup& IV: A165, 1986 20 LEYVRAZ,P. and POSTEL, M. Preventionof postoperativedeep vein thrombosis in electivetotal hip replacementby LMW heparinCY 216. A controlled, randomized,collaborativetrial. TwelfthCongress-__ of the InternationalSociety on Thrombosisand Haemostasis.SatelliteSymposium.Tokyo, August 26, 1989 21 BERGQUIST,D., KETTUNEN,K., SUOMALAINEN,O., SIUMAKALLIO,S., KARJALAINEN,P., FREDIN, H., CEDERHOLM,C., FAUNO, P., JENSEN,L.J., JUSTESEN,T., VISSINGER,H. and STIEKEMA,J.C.J. A prospectiverandomized comparisonbetweenORG 10172 and Dextran 70 in hip fracturepatientsThromboprophylaxis and safety.Thromb.Haemost.62, 355 (abst. 1105), I989 22 ESTOPPEY,D., HOCHREITER,J., BREYFR,H.G., JAKUBEK,H., LEYVRAZ,P.F., STIEKEMA,J.C.J. and HAAS, S. ORG 10172 (Lomoparan)versus heparin-DHEin preventionof thromboembolismin total hip replacement- A multicentretrial. Thromb. 62, 126 (abst. 1107), 1989 _- Haemost. -~ 23 LASSEN,M.L., BORRIS,L.C., CHRISTIANSEN,H.M., OLSEN, A.D., SCHOTT,P., EISKJAER,S., BOLL, K.L., NIELSEN,B.W., RODENBERG,J.C. and LUCHT, U. Low molecularweight heparin in the preventionof thromboembolismin elective total hip replacement.Thromb. Haemost.62, 126 (abst.398), 1989 __24 TURPIE, A.G.G., LEVINE,M.N., HIRSH, J., CARTER,C.J., JAY, R.M., POWERS, P.J., ANDREW,M., HULL, R.D. and GENT, M.A. A randomizedcontrolled trial of a low-molecular-weight heparin (Enoxaparin)to prevent deep-vein thrombosisin patientsundergoingelectivehip surgery.N. Engl. J. Med. 315, 925-929,1986 25 PLANES, A., VOCHELLE,N., MAZAS, F., MANSAT,C., ZUCMAN,J., LANDAIS,A., PASCARIELLO,J.C., WEILL, D. and BUTEL, J. Preventionof postoperativevenous thrombosis:a randomizedtrial comparingunfractionatedheparinwith lowmolecular-weight heparin in patientsundergoingtotal hip replacement. Thromb.---_ Haemost._60, 407-410,1988