THROMBOSIS RESEARCH 59; 639-650,199O 0049-3848/90 $3.00 + .OO Printed in the USA. Copyright (c) 1990 Pergamon Press pk. All rights reserved.
RANDOMIZED CONTROLLED STUDY OF HEPARIN AND LOW MOLECULAR WEIGHT HEPARIN FOR PREVENTION OF DEEP-VEIN THROMBOSIS IN MEDICAL PATIENTS J. Harenberg, B. Kallenbach, U. Martin, C. E. Dempfle, R. Zimmermann*, W. Ktibler*, D. L. Heene 1st Department of Medicine, Faculty of Clinical Medicine Mannheim, and 3rd Medical Department of Cardiology*, University of Heidelberg, Theodor Kutzer Ufer, 6800 Mannheim, FRG (Received
10.4.1989;
(Received
accepted
in revised form 5.10.1989
in final form by Executive
by Editor A. Henschen)
Editorial Off ice 21.6.1990)
ABSTRACT 166 patients aged 40-80 years were included in a controlled, randomized, doubleblind study to determine the efficacy and safety of a single daily injection of a low molecular weight (LMW) heparin for prevention of deep-vein thrombosis compared to low dose conventional heparin. Patients received 1 x 1.500 aP‘IT units of a LMW heparin fraction (plus 2 x placebo injection) or 3 x 5.000 IU of an unfractionated heparin. During 10 days of treatment, patients underwent repeated clinical investigation, serial impedance plethysmography, and Doppler sonography for detection of thrombosis of the lower limbs. Combined application of these methods revealed evidence of thrombosis in 4.5 % of patients on unfmctionated heparin and 3.6 % of patients on LMW heparin. Subcutaneous hematomas were significantly smaller in diameter upon treatment with LMW heparin @ 200 mm/Hg, diastolic > 120 mm/Hg), cirrhosis of the liver (prothrombin time below 60 %), renal insufficiency (creatinine > 2.5 mg %), increased bleeding risk of the gastrointestinal or urogenital system, acute pancreatitis, disseminated intravascular coagulation, known intolerance to heparin, or if there were indications for therapeutic anticoagulation, fibrinolytic therapy and antiplatelet therapy. On admission to the hospital the following risk factors for DVT were carefully identified: immobilization, obesity, history of thromboembolism, arrhythmia, malignant disease, heart failure, respiratory disease, acute stroke, blood hyperviscosity, and infections. Patients with acute myocardial infarction, acute ischemic stroke and hyperviscosity were excluded because of interference with anticoagulation, fibrinolytic, or antiplatelet therapy. Ethics: The study protocol was accepted by the local ethical committee. All patients gave informed consent prior to entering the study and before randomization. The ethical committee permitted the phlebography only in patients with clinical signs of thrombosis. The suspicion of venous thrombosis based on the results of doppler sonography and impedance plethysmography were no indication to perform phlebography. Treatment: Patients received 3 times daily 5000 IU unfractionated heparin or once daily 1.500 aPIT units LMW heparin and twice daily placebo subcutaneously every 8 hours. LMW heparin has been prepared by amylnitrite-degradation of unfractionated heparin. The mean molecular weight was 3.800 Dalton. The anti-factor Xa activity was 86 IU/mg using the first international LMW heparin standard and the anti aPTI’ activity was 40 U/mg. Placebo contained physiologic saline. LMW heparin did not contain any other additional compounds. All ampules had a volume of 0.7 ml. Substances were provided by Sandoz AG (Niimberg, FRG). Each injection was documented on a protocol by the nurse who performed the injection. Heparin injections were discontinued if patients spent less than 20/24 hrs in bed. Elastic compression stockings were not employed The trial lasted 10 days. Patients with a treatment period less than 7 days were excluded from the final evaluation.
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.
Cllnlcal Patients were investigated on days 1, 3,7 and 10. Each patient was always examined by the same physician. Physical findings were assessed in a standard fashion and results were recorded including leg pain, color tenderness, swelling, increased warms, Homans’ sign or venous engorgement. The presence or absence of clinical events or disorders known to produce results by impedance plethysmography or Doppler ultrasound were also recorded (i.e. peripheral edema). DoDDler The Doppler venous examination was performed using a 8 megahertz, monodirectional, hand-held system Doppler (Parks Medical Electronics Inc., Beverton, USA). The popliteal vein, the superficial vein in the mid thigh and the common femoral vein in the groin were examined. Vein patency, spontaneous flow and variability of flow upon respiration, forward augmentation of flow secondary to distal compression, release augmentation secondary to the Valsalva test, venous mflux, and pulsatility of venous flow all were evaluated (19). The venous flow characteristics of both legs were compared. e aleOcclusive cuff impedance plethysmography (IPG) was performed with Cardio-Dynagraph (KT-C 1100, Diefenbach GmbH, Frankfurt, ERG) using the procedure as described by Wheeler et al (20). Each patient was tested in supine position with the lower limb elevated 25O-300, the knees flexed 10°-200* and slight supination of the feet. A 15 cm wide pneumatic cuff was applied to the mid thigh and inflated to 60 mmHg. After 2 min the cuff was rapidly deflated and the changes in the electrical resistance (impedance) were detected by circumferential calf electrodes and recorded continuously. Electrodes were always put on the same places on the patient’s leg in the following order: the first electrode was put 3 cm proximal to the upper margin of the patella, the second 3 cm distal to the lower margin of the patella, the third 11 cm distal to the second electrode and the fourth electrode 3 cm proximal to the malleoli. Alterations in blood volume distal to the cuff lead to changes in the electrical resistance between the electrodes 2 and 3. The changes in the impedance during cuff inflation and deflation were measured and both the total rise during cuff inflation and the fall occuring in the first 3 seconds of deflation were plotted in mm on the two-way IPG graph. The impedance was measured in mm deflection on the writing paper. The rise/fall index was calculated of each measurement for each leg. Values for rise and fall (in mm) were put in the venous function nomogram of Wheeler et al (20). From this nomogram the venous function index (VFI) was calculated for each measurement. Normal values were 15 to 40 units. Together with changes in Doppler sonography a decrease of the index by more than 50 % was regarded as suspicious for ongoing deep venous thrombosis. The IPGs were repeated 3 times at every examination. The result with the highest fall was taken for the evaluation. Thereby false positive results were minimized and the accuracy of the method increased (21).
Venw Ascending venography according to the method of Rabinov and Paulin was performed if clinical signs of DVT occurred (22). : The results of Doppler and IPG were interpreted independently of one another including the knowledge of the patient’s conditions. Clinical examination with the typical signs of DVT, changes in Doppler blood flow, and decrease of rise/fall index in IPG to less than 50 % were regarded as a suspicion for DVT. If two of three clinical examinations gave suspicion for DVT this patient was evaluated as “suspicion for DVT’ and referred to venography. .
Blood for analysis of coagulation parameters was taken 2-4 h after the morning injection on days 1, 5, and 10. Blood was anticoagulated immediately in the plastic syringe containing 1:9 (v/v) 3.8 8 sodium-citrate/blood. The following coagulation parameters were determined: prothrombin time (Quick), activated partial thromboplastin time (aPTT) (PathmmbinR, Behringwerke AG, Marburg, FRG), thrombin clotting time (6 units thrombin/ml,
manalvsis:
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Behringwerke AG, Marburg, FRG), HeptestR (Haemachem, St. Louis, USA) (23),S-2222 chromogenic substrate method using purified bovine factor Xa (reagents from Kabi AB, Stockholm, Sweden), antithrombin III activity (fluorescence substrate, Merz & Dade, Munich, FRG), and thrombelastography using recalcified whole blood (24) calculating the reaction time (rtime), contraction time (k-time), and elasticity of the clot (me). &&&The diameter of local hematomas at the injection site on the abdominal wall were carefully recorded on days 1, 3, 7, and 10. The incidence was expressed in % of patients. The largest hematoma of each patient was used for statistical evaluation. All patients had hematoma during medication. The diameter of each hematoma was classified as follows: below 3 mm, between 3 mm to 3 cm, between 3 and 5 cm, between 5 and 10 cm, and larger than 10 cm. Biological tolerance was recorded by measurements of haemoglcbin, haematocrit, thrombocyte count, SGOT, SGPT, creatinine, urea, and albumin using clinical chemistry routine methods. The clinical tolerance was quantified also by asking the patient, whether he tolerated the daily S.C. injections very well, well, bad, very bad, or no opinion. . . Statlstlcal
All parameters were tested for normal distribution. If they were normally distributed, the 2 way analysis of variance was performed. The difference of incidence of subcutaneous hematomas between the two treatment groups was calculated by the Chi squared test. The level of significance was set as p < 0.001. All data are expressed as mean and standard deviation. RESULTS
200 patients entered the clinical study. 34 patients were treated less than 7 days and were therefore excluded from the evaluation. None of these patients had any sign of incidence of thromboembolism or side effects on the prophylactic regimen. Therefore 166 patients finished the study protocol and entered the statistical evaluation 82 belonging to the heparin group and 84 to the LMW heparin group. The mean treatment period was range 7-12 days on heparin and on LMW heparin including all patients. Male and female patients were equally repesented in both groups. Age, bodyweight, height, systolic and diastolic blood pressure (BP), and heart rate were comparable in both groups (table 1). Table 1: Characteristics of the patients which were included into the study. I
females (n) males (n) age (x + SD) height cm(x + SD) bodyweight kg (x + SD) heart rate/mitt (x 2 SD) BP syst (mmHg, SD) BP diast (mmHg, SD)
Heparin n = 82
LMW Heparil n=84 45
165.8 f. 8.5 69.3 + 12.4 81 + 13.7 135.8 + 19.7 80 + 12.4
66.2 + 2: 165.5 + 8.1 66.5 + 12.9 82 + 15.6 137.6 + 20.8 80.5 + 11.8
The main diagnoses of patients included in the trial are shown in table 2. Secondary diagnoses are shown in table 3. Risk factors were not completely comparable in both groups. Malignancy, previous thromboembolism and smoking was more frequent in the LMW heparin group. Diabetes, cardiac arrhythmias, and arteriosclerosis were more frequent in the heparln group. Drug treatment was similarly distributed in both groups (not shown).
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Table 2: Main diagnosis of the patients which were included in the study (multiple designations possible). .
HeDarrn I
17
malignancy
heart insufficiency coronary heart disease atrial fibrillation cerebral ischemia infections asthma bronchiale 9thet-s sum
+F-
::
23 12 12
:
1
;
9 +
Table 3: Other diagnosis of the patients which were included in the study.
Varicous veins cardiac arrhythmias hypertension diabetes coronary heart disease stenosis A. carotis renal insufficiency peripheral arterial disease smoking cerebral sclerosis cardiomyopathy hyperthyroidism
;!f 28 19 11 9 : 17 4 7 4
DVT was suspected in 4 out of 83 patients in the heparin group and in 3 out of 89 patients in the LMW heparin group. In all patients clinical investigation and impedance plethysmography together resulted in suspicion of venous thrombosis. In addition, in each group one of these patients developed pathological findings in Doppler ultrasound of the vena femoralis. IPG alone was regarded as suspicious in 4 patients of the heparin group and in 4 patients of the LMW heparin group. There were no differences in the venous function index of impedance plethysmography between the right and left leg of patients receiving heparin or LMW heparin (table 4). The number of patients are plotted against percentiles of improvement and impairment of IPG. The incidences of suspicion of DVT were 4.8 % (n = 4) in the heparin group and 3.4 % (n = 3) in the LMW group, respectively.
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Table 4: Venous function in&x (VFI units) calculated from the results of the impedance plethysmography at day 1 and day 10. xi&t leg
left left
Tag 1
Tag 10
Tag 1
Tag 10
unfractionated heparin (SD)
21.2 & 14.0)
22.5 & 13.9)
20.8 (+ 13.7)
23.5 ti 14.5)
heparin (SD)
19.9 k 11.7)
21.8 & 12.6)
21.4 (+ 13.0)
22.2 & 11.8)
4 patients died during the trial, 1 in the heparin group and 3 in the LMW heparin group. One patient treated with heparin developed gastrointestinal bleeding on day 8 and died of cardiac failure. In the LMW heparin group one patient died on day 2 due to cardiogenic shock with tachyarrhythmia and metastatic carcinoma of the prostate. The second patient died on day 5 due to cardiac failure secondary to pulmonary hypertension and severe coronary artery disease. The third patient died on day 9. Autopsy showed that this patient died of toxic cardiac insufficiency, secondary to decompensated liver cirrhosis and liver carcinoma. No thromboembolism was detected. Two other clinical events occured in the heparin group: one patient developed cerebral infarction and another patient developed local cutaneous allergy, which disappeared after switching to another heparin preparation. The patient refused cutaneous tests to demonstrate origin of the $$e5ytions. In summary, clinical complications or death 6 patients of each treatment group .
Table 5: Incidences of thrombosis and other events during the study. Heparin thrombosis suspicion of thrombosis &ath cerebral embolism n=
0 4
LMW-Heparin ;
:
Local hematomas developed in 57 % of patients receiving heparin. 24 % of patients with LMW heparin developed subcutaneous hematomas (p < 0.001, figure 1). The size of hematomas was significantly smaller in patients on LMW heparin. No patient on LMW heparin developed hematomas larger than 10 cm in contrast to 11% of patients with normal heparin. &fetv m:No significant changes in haemoglobin, haematocrit, thrombocyte count, liver transaminases, creatinine, and albumin were seen in either treatment group. Antithrombin III decreased during prophylaxis with heparin and increased during prophylaxis with LMW heparin. The differences between both treatment groups am statistically significant on day 8- 10 (p c 0.001, table 6 and 7).
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subcutaneous
n lxl >5cmllOcm
Hematomas
500 aPTT U LMW Heparin
03x5000
>3cmI
5cm
>3mmS
3cm
645
NJ Heparin
r3mm no hematoma 0
10
20
30
40 50 Percent
60
Figure 1: Incidences of S.C.hematomas at the injection site in percent of the patients who finished the study. The largest hematoma of each patient was used for calculation.
Table 6: Coagulation parameters measured in the patients on low dose heparin during the study. S-2222 = chromogenic substrate S-2222 method using purified bovine factor Xa, aP’l’T = activated partial thromboplastin time, TCT = thrombin clotting time, R-time and K-time = reaction time and contraction time in thrombelastography using recalcified whole blood. (mean, SD)
r-time (%)
147.98
46.23
150.96
49.50
141.71
46.07
k-time (So)
140.29
85.64
136.84
102.00
121.33
96.76
platelet count
295.40
260.62
320.89
257.42
309.49
141.36
13.29
2.09
13.36
2.01
12.98
1.85
hemoglobin
(g/l)
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Heptest (set)
coagulation a -
60’
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values
1x1500 aPTT U LMW Heparin 3x5000 IU Heparin
50’
u
-
113
4--7
8110
(day)
_
Figure 2: Coagulation times of Heptest in patients receiving unfractionated heparin or LMW heparin (mean, standard deviation).
Table 7: Coagulation parameters which were measured in the patients on LMW heparin during the study. S-2222 = chromogenic substrate S-2222 method using purified bovine factor Xa, a.PlT = activated partial thromboplastin time, TCT = thrombin clotting time, R-time and K-time = reaction and contraction time in thrombelastography with recalcified whole blood.(mean, SD). day 1
day 4-7
SD
mean
SD
d y 8-10
I
SD
Heptest
(U/ml)
0.268
0.250
0.233
0.138
0.17
s-2222
(U/I)
0.157
0.171
0.169
0.174
’ 0.152
0.17
aPTT (set)
34.23
7.91
32.63
4.36
33.79
7.18
TCT (set)
12.63
1.59
12.14
1.08
12.13
0.87
AT III (%)
93.74
18.64
94.11
19.11
97.45
20.36
r-time (%)
140.00
50.38
135.80
35.62
129.93
39.24
k-time (%)
113.53
59.96
99.5 1
36.50
104.73
93.17
platelet count
293.20
104.31
303.86
111.82
316.53
120.65
hemoglobin(g/l)
12.60
1.98
12.53
1.71
12.44
1.71
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.
Coagulation APTT, thrombin clotting time, r-time, k-time, and elasticity parameter of thrombelastography were not influenced by either treatment. Mean values and standard deviation are given in tables 6 and 7. Heptest coagulation values were slightly prolonged during administration of heparin (normal range of Heptest 13-21 set). During administration of LMW heparin, Heptest prolonged significantly more than during administration with normal heparin (p c 0.001, figure 2). Using the first international standard for LMW heparin values of 0.13 U +. 0.11 IU of LMW heparin per ml blood were measured in patients of the LMW heparin group using Heptest reagents. Similar results were obtained with the S-2222 chromogenic substrate assay (mean value 0.12 III/ml). In the group treated with normal heparin, with both test systems 0.05 & 0.08 III/ml and 0.06 + 0.07 III/ml were detected on day 1, by Heptest and S2222 assay respectively (tables 6 and 7). The differences of the Heptest coagulation values and the S-2222 chromogenic substrate method between the heparin and LMW heparin group are statistically significant (p < 0.001). DISCUSSION The results of this study indicate that small doses of LMW heparin may be as effective as low dose conventional heparin in prevention of thromboembolism in medical inpatients. Recent data have demonstrated that a LMW heparin significantly reduced the incidence of DVT in elderly medical inpatients as compared to placebo. DVT was detected in 9 % of patients of placebo and in 3 % of patients treated with one daily injection of the LMW heparin (15). The data of our study show that the incidences of DVT are similar in patients treated with unfractionated heparin and patients treated with LMWH. The incidences were 4.8 % and 3.4 8, respectively. These figures are similar to those found in the reported study (15). Repeated occlusive cuff impedance plethysmography (IPG), Doppler ultrasound of the femoral and popliteal veins, and repeated clinical examinations were used in our study to identify development of thromboembolism. Repeated IPG has been demonstrated to accurately identify thrombosis of the thigh (25,26). When Doppler findings were compared with phlebography in patients with suspected iliofemoral thrombosis the Doppler technique revealed an accuracy of 92 %, a sensitivity of 94 % and a specificity of 90 % (27). Clinical signs such as pain, edema and temperature differences are sensitive and accurate too, even if they are less specific (28). Radiolabelled fibrinogen and repeated ascending phlebography are associated with a number considerable risk factors. Therefore the repeated non invasive IPG techniques recommended as a screening method for detection of thrombosis (29-31). As demonstrated in our study the repeated performance of three non-invasive methods for detection of developing DVT results in similar values for incidence of DVT as compared to those reported in other studies using iodine-labelled fibrinogen test (15). The coagulation studies demonstrate that aPTT and thrombin clotting time as well as thrombelastography do not sensitively detect effects of heparin or LMW heparin. On the other hand factor Xa inhibition tests as Heptest and chromogenic S-2222 substrate method sensitively measure effects of LMW heparin. In addition, Heptest also determines the anticoagulant effects of normal heparin to some extent. Using coagulation time of Heptest, highly significant differences can be found between normal and LMW heparin. However, there is no relation between prolongation of coagulation times and the clinical outcome in terms of development of thrombosis or bleeding complications (data not shown). Antithrombin III is reported to decrease during low dose heparin administration (9). This has been confirmed in our study. In contrast antithrombin III increased during administration of LMW heparin. These effects on antithrombin III am worthwhile to be analyzed more in detail in further clinical studies. During administration of heparin and LMW heparin no changes of transaminases,
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Less occurrence of haemorrhagic complications has always been supposed using LMW heparin, as compared to normal heparin. However, this benefit has never been proven so far. Our study is the first to demonstrate a lower incidence of local hematomas with LMW heparin. This may be due in part to the lower frequency of injection of the active compound (once versus three times daily). Placebo injections induce some small local hematomas. But if the size of hematomas is analyzed it is evident that large hematomas with a diameter of more than 10 cm occured only after administration of unfractionated heparin. The advantages of LMW heparins over low dose conventional heparin for prophylaxis of thmmboembolism in medical inpatients are reduced frequency of daily injections due to prolonged anti Xa-activity, less effect on platelet aggregation (16), successful use in heparin-induced thrombocytopenia (16, 17), and the safe use in patients with high risk of haemorrhagic complications (18). In agreement with previous studies (15) the present investigation favors the administration of LMW heparin for prophylaxis of thromboembolism in medical inpatients. A larger trial now has to be carried out in order to demonstrate equivalent effects of LMW-heparin and unfractionated heparin in prevention of pulmonary embolism. The careful analysis of the results obtained in our study ascertained for the first time that haemorrhagic complications such as subcutaneous hematomas occur less frequently using LMW heparin, as compared to unfiactionated heparin. REFERENCES 1.
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HIRSH, J. Clinical utility of impedance plethysmography in the diagnosis of recurrent deepvein thrombosis. Arch. Intern. Med. 148.519-520, 1988.
R.M., OCKELFORD, P.A., BULLER, DODD, P.E., GILL, G.J., LECLERC, plethysmography for clinically suspected 1985.
RANDOMIZED CONTROLLED STUDY OF HEPARIN AND LOW MOLECULAR WEIGHT HEPARIN FOR PREVENTION OF DEEP-VEIN THROMBOSIS IN MEDICAL PATIENTS J. Harenberg, B. Kallenbach, U. Martin, C. E. Dempfle, R. Zimmermann*, W. Ktibler*, D. L. Heene 1st Department of Medicine, Faculty of Clinical Medicine Mannheim, and 3rd Medical Department of Cardiology*, University of Heidelberg, Theodor Kutzer Ufer, 6800 Mannheim, FRG (Received
10.4.1989;
(Received
accepted
in revised form 5.10.1989
in final form by Executive
by Editor A. Henschen)
Editorial Off ice 21.6.1990)
ABSTRACT 166 patients aged 40-80 years were included in a controlled, randomized, doubleblind study to determine the efficacy and safety of a single daily injection of a low molecular weight (LMW) heparin for prevention of deep-vein thrombosis compared to low dose conventional heparin. Patients received 1 x 1.500 aP‘IT units of a LMW heparin fraction (plus 2 x placebo injection) or 3 x 5.000 IU of an unfractionated heparin. During 10 days of treatment, patients underwent repeated clinical investigation, serial impedance plethysmography, and Doppler sonography for detection of thrombosis of the lower limbs. Combined application of these methods revealed evidence of thrombosis in 4.5 % of patients on unfmctionated heparin and 3.6 % of patients on LMW heparin. Subcutaneous hematomas were significantly smaller in diameter upon treatment with LMW heparin @ 200 mm/Hg, diastolic > 120 mm/Hg), cirrhosis of the liver (prothrombin time below 60 %), renal insufficiency (creatinine > 2.5 mg %), increased bleeding risk of the gastrointestinal or urogenital system, acute pancreatitis, disseminated intravascular coagulation, known intolerance to heparin, or if there were indications for therapeutic anticoagulation, fibrinolytic therapy and antiplatelet therapy. On admission to the hospital the following risk factors for DVT were carefully identified: immobilization, obesity, history of thromboembolism, arrhythmia, malignant disease, heart failure, respiratory disease, acute stroke, blood hyperviscosity, and infections. Patients with acute myocardial infarction, acute ischemic stroke and hyperviscosity were excluded because of interference with anticoagulation, fibrinolytic, or antiplatelet therapy. Ethics: The study protocol was accepted by the local ethical committee. All patients gave informed consent prior to entering the study and before randomization. The ethical committee permitted the phlebography only in patients with clinical signs of thrombosis. The suspicion of venous thrombosis based on the results of doppler sonography and impedance plethysmography were no indication to perform phlebography. Treatment: Patients received 3 times daily 5000 IU unfractionated heparin or once daily 1.500 aPIT units LMW heparin and twice daily placebo subcutaneously every 8 hours. LMW heparin has been prepared by amylnitrite-degradation of unfractionated heparin. The mean molecular weight was 3.800 Dalton. The anti-factor Xa activity was 86 IU/mg using the first international LMW heparin standard and the anti aPTI’ activity was 40 U/mg. Placebo contained physiologic saline. LMW heparin did not contain any other additional compounds. All ampules had a volume of 0.7 ml. Substances were provided by Sandoz AG (Niimberg, FRG). Each injection was documented on a protocol by the nurse who performed the injection. Heparin injections were discontinued if patients spent less than 20/24 hrs in bed. Elastic compression stockings were not employed The trial lasted 10 days. Patients with a treatment period less than 7 days were excluded from the final evaluation.
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.
Cllnlcal Patients were investigated on days 1, 3,7 and 10. Each patient was always examined by the same physician. Physical findings were assessed in a standard fashion and results were recorded including leg pain, color tenderness, swelling, increased warms, Homans’ sign or venous engorgement. The presence or absence of clinical events or disorders known to produce results by impedance plethysmography or Doppler ultrasound were also recorded (i.e. peripheral edema). DoDDler The Doppler venous examination was performed using a 8 megahertz, monodirectional, hand-held system Doppler (Parks Medical Electronics Inc., Beverton, USA). The popliteal vein, the superficial vein in the mid thigh and the common femoral vein in the groin were examined. Vein patency, spontaneous flow and variability of flow upon respiration, forward augmentation of flow secondary to distal compression, release augmentation secondary to the Valsalva test, venous mflux, and pulsatility of venous flow all were evaluated (19). The venous flow characteristics of both legs were compared. e aleOcclusive cuff impedance plethysmography (IPG) was performed with Cardio-Dynagraph (KT-C 1100, Diefenbach GmbH, Frankfurt, ERG) using the procedure as described by Wheeler et al (20). Each patient was tested in supine position with the lower limb elevated 25O-300, the knees flexed 10°-200* and slight supination of the feet. A 15 cm wide pneumatic cuff was applied to the mid thigh and inflated to 60 mmHg. After 2 min the cuff was rapidly deflated and the changes in the electrical resistance (impedance) were detected by circumferential calf electrodes and recorded continuously. Electrodes were always put on the same places on the patient’s leg in the following order: the first electrode was put 3 cm proximal to the upper margin of the patella, the second 3 cm distal to the lower margin of the patella, the third 11 cm distal to the second electrode and the fourth electrode 3 cm proximal to the malleoli. Alterations in blood volume distal to the cuff lead to changes in the electrical resistance between the electrodes 2 and 3. The changes in the impedance during cuff inflation and deflation were measured and both the total rise during cuff inflation and the fall occuring in the first 3 seconds of deflation were plotted in mm on the two-way IPG graph. The impedance was measured in mm deflection on the writing paper. The rise/fall index was calculated of each measurement for each leg. Values for rise and fall (in mm) were put in the venous function nomogram of Wheeler et al (20). From this nomogram the venous function index (VFI) was calculated for each measurement. Normal values were 15 to 40 units. Together with changes in Doppler sonography a decrease of the index by more than 50 % was regarded as suspicious for ongoing deep venous thrombosis. The IPGs were repeated 3 times at every examination. The result with the highest fall was taken for the evaluation. Thereby false positive results were minimized and the accuracy of the method increased (21).
Venw Ascending venography according to the method of Rabinov and Paulin was performed if clinical signs of DVT occurred (22). : The results of Doppler and IPG were interpreted independently of one another including the knowledge of the patient’s conditions. Clinical examination with the typical signs of DVT, changes in Doppler blood flow, and decrease of rise/fall index in IPG to less than 50 % were regarded as a suspicion for DVT. If two of three clinical examinations gave suspicion for DVT this patient was evaluated as “suspicion for DVT’ and referred to venography. .
Blood for analysis of coagulation parameters was taken 2-4 h after the morning injection on days 1, 5, and 10. Blood was anticoagulated immediately in the plastic syringe containing 1:9 (v/v) 3.8 8 sodium-citrate/blood. The following coagulation parameters were determined: prothrombin time (Quick), activated partial thromboplastin time (aPTT) (PathmmbinR, Behringwerke AG, Marburg, FRG), thrombin clotting time (6 units thrombin/ml,
manalvsis:
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Behringwerke AG, Marburg, FRG), HeptestR (Haemachem, St. Louis, USA) (23),S-2222 chromogenic substrate method using purified bovine factor Xa (reagents from Kabi AB, Stockholm, Sweden), antithrombin III activity (fluorescence substrate, Merz & Dade, Munich, FRG), and thrombelastography using recalcified whole blood (24) calculating the reaction time (rtime), contraction time (k-time), and elasticity of the clot (me). &&&The diameter of local hematomas at the injection site on the abdominal wall were carefully recorded on days 1, 3, 7, and 10. The incidence was expressed in % of patients. The largest hematoma of each patient was used for statistical evaluation. All patients had hematoma during medication. The diameter of each hematoma was classified as follows: below 3 mm, between 3 mm to 3 cm, between 3 and 5 cm, between 5 and 10 cm, and larger than 10 cm. Biological tolerance was recorded by measurements of haemoglcbin, haematocrit, thrombocyte count, SGOT, SGPT, creatinine, urea, and albumin using clinical chemistry routine methods. The clinical tolerance was quantified also by asking the patient, whether he tolerated the daily S.C. injections very well, well, bad, very bad, or no opinion. . . Statlstlcal
All parameters were tested for normal distribution. If they were normally distributed, the 2 way analysis of variance was performed. The difference of incidence of subcutaneous hematomas between the two treatment groups was calculated by the Chi squared test. The level of significance was set as p < 0.001. All data are expressed as mean and standard deviation. RESULTS
200 patients entered the clinical study. 34 patients were treated less than 7 days and were therefore excluded from the evaluation. None of these patients had any sign of incidence of thromboembolism or side effects on the prophylactic regimen. Therefore 166 patients finished the study protocol and entered the statistical evaluation 82 belonging to the heparin group and 84 to the LMW heparin group. The mean treatment period was range 7-12 days on heparin and on LMW heparin including all patients. Male and female patients were equally repesented in both groups. Age, bodyweight, height, systolic and diastolic blood pressure (BP), and heart rate were comparable in both groups (table 1). Table 1: Characteristics of the patients which were included into the study. I
females (n) males (n) age (x + SD) height cm(x + SD) bodyweight kg (x + SD) heart rate/mitt (x 2 SD) BP syst (mmHg, SD) BP diast (mmHg, SD)
Heparin n = 82
LMW Heparil n=84 45
165.8 f. 8.5 69.3 + 12.4 81 + 13.7 135.8 + 19.7 80 + 12.4
66.2 + 2: 165.5 + 8.1 66.5 + 12.9 82 + 15.6 137.6 + 20.8 80.5 + 11.8
The main diagnoses of patients included in the trial are shown in table 2. Secondary diagnoses are shown in table 3. Risk factors were not completely comparable in both groups. Malignancy, previous thromboembolism and smoking was more frequent in the LMW heparin group. Diabetes, cardiac arrhythmias, and arteriosclerosis were more frequent in the heparln group. Drug treatment was similarly distributed in both groups (not shown).
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Table 2: Main diagnosis of the patients which were included in the study (multiple designations possible). .
HeDarrn I
17
malignancy
heart insufficiency coronary heart disease atrial fibrillation cerebral ischemia infections asthma bronchiale 9thet-s sum
+F-
::
23 12 12
:
1
;
9 +
Table 3: Other diagnosis of the patients which were included in the study.
Varicous veins cardiac arrhythmias hypertension diabetes coronary heart disease stenosis A. carotis renal insufficiency peripheral arterial disease smoking cerebral sclerosis cardiomyopathy hyperthyroidism
;!f 28 19 11 9 : 17 4 7 4
DVT was suspected in 4 out of 83 patients in the heparin group and in 3 out of 89 patients in the LMW heparin group. In all patients clinical investigation and impedance plethysmography together resulted in suspicion of venous thrombosis. In addition, in each group one of these patients developed pathological findings in Doppler ultrasound of the vena femoralis. IPG alone was regarded as suspicious in 4 patients of the heparin group and in 4 patients of the LMW heparin group. There were no differences in the venous function index of impedance plethysmography between the right and left leg of patients receiving heparin or LMW heparin (table 4). The number of patients are plotted against percentiles of improvement and impairment of IPG. The incidences of suspicion of DVT were 4.8 % (n = 4) in the heparin group and 3.4 % (n = 3) in the LMW group, respectively.
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Table 4: Venous function in&x (VFI units) calculated from the results of the impedance plethysmography at day 1 and day 10. xi&t leg
left left
Tag 1
Tag 10
Tag 1
Tag 10
unfractionated heparin (SD)
21.2 & 14.0)
22.5 & 13.9)
20.8 (+ 13.7)
23.5 ti 14.5)
heparin (SD)
19.9 k 11.7)
21.8 & 12.6)
21.4 (+ 13.0)
22.2 & 11.8)
4 patients died during the trial, 1 in the heparin group and 3 in the LMW heparin group. One patient treated with heparin developed gastrointestinal bleeding on day 8 and died of cardiac failure. In the LMW heparin group one patient died on day 2 due to cardiogenic shock with tachyarrhythmia and metastatic carcinoma of the prostate. The second patient died on day 5 due to cardiac failure secondary to pulmonary hypertension and severe coronary artery disease. The third patient died on day 9. Autopsy showed that this patient died of toxic cardiac insufficiency, secondary to decompensated liver cirrhosis and liver carcinoma. No thromboembolism was detected. Two other clinical events occured in the heparin group: one patient developed cerebral infarction and another patient developed local cutaneous allergy, which disappeared after switching to another heparin preparation. The patient refused cutaneous tests to demonstrate origin of the $$e5ytions. In summary, clinical complications or death 6 patients of each treatment group .
Table 5: Incidences of thrombosis and other events during the study. Heparin thrombosis suspicion of thrombosis &ath cerebral embolism n=
0 4
LMW-Heparin ;
:
Local hematomas developed in 57 % of patients receiving heparin. 24 % of patients with LMW heparin developed subcutaneous hematomas (p < 0.001, figure 1). The size of hematomas was significantly smaller in patients on LMW heparin. No patient on LMW heparin developed hematomas larger than 10 cm in contrast to 11% of patients with normal heparin. &fetv m:No significant changes in haemoglobin, haematocrit, thrombocyte count, liver transaminases, creatinine, and albumin were seen in either treatment group. Antithrombin III decreased during prophylaxis with heparin and increased during prophylaxis with LMW heparin. The differences between both treatment groups am statistically significant on day 8- 10 (p c 0.001, table 6 and 7).
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subcutaneous
n lxl >5cmllOcm
Hematomas
500 aPTT U LMW Heparin
03x5000
>3cmI
5cm
>3mmS
3cm
645
NJ Heparin
r3mm no hematoma 0
10
20
30
40 50 Percent
60
Figure 1: Incidences of S.C.hematomas at the injection site in percent of the patients who finished the study. The largest hematoma of each patient was used for calculation.
Table 6: Coagulation parameters measured in the patients on low dose heparin during the study. S-2222 = chromogenic substrate S-2222 method using purified bovine factor Xa, aP’l’T = activated partial thromboplastin time, TCT = thrombin clotting time, R-time and K-time = reaction time and contraction time in thrombelastography using recalcified whole blood. (mean, SD)
r-time (%)
147.98
46.23
150.96
49.50
141.71
46.07
k-time (So)
140.29
85.64
136.84
102.00
121.33
96.76
platelet count
295.40
260.62
320.89
257.42
309.49
141.36
13.29
2.09
13.36
2.01
12.98
1.85
hemoglobin
(g/l)
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Heptest (set)
coagulation a -
60’
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values
1x1500 aPTT U LMW Heparin 3x5000 IU Heparin
50’
u
-
113
4--7
8110
(day)
_
Figure 2: Coagulation times of Heptest in patients receiving unfractionated heparin or LMW heparin (mean, standard deviation).
Table 7: Coagulation parameters which were measured in the patients on LMW heparin during the study. S-2222 = chromogenic substrate S-2222 method using purified bovine factor Xa, a.PlT = activated partial thromboplastin time, TCT = thrombin clotting time, R-time and K-time = reaction and contraction time in thrombelastography with recalcified whole blood.(mean, SD). day 1
day 4-7
SD
mean
SD
d y 8-10
I
SD
Heptest
(U/ml)
0.268
0.250
0.233
0.138
0.17
s-2222
(U/I)
0.157
0.171
0.169
0.174
’ 0.152
0.17
aPTT (set)
34.23
7.91
32.63
4.36
33.79
7.18
TCT (set)
12.63
1.59
12.14
1.08
12.13
0.87
AT III (%)
93.74
18.64
94.11
19.11
97.45
20.36
r-time (%)
140.00
50.38
135.80
35.62
129.93
39.24
k-time (%)
113.53
59.96
99.5 1
36.50
104.73
93.17
platelet count
293.20
104.31
303.86
111.82
316.53
120.65
hemoglobin(g/l)
12.60
1.98
12.53
1.71
12.44
1.71
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.
Coagulation APTT, thrombin clotting time, r-time, k-time, and elasticity parameter of thrombelastography were not influenced by either treatment. Mean values and standard deviation are given in tables 6 and 7. Heptest coagulation values were slightly prolonged during administration of heparin (normal range of Heptest 13-21 set). During administration of LMW heparin, Heptest prolonged significantly more than during administration with normal heparin (p c 0.001, figure 2). Using the first international standard for LMW heparin values of 0.13 U +. 0.11 IU of LMW heparin per ml blood were measured in patients of the LMW heparin group using Heptest reagents. Similar results were obtained with the S-2222 chromogenic substrate assay (mean value 0.12 III/ml). In the group treated with normal heparin, with both test systems 0.05 & 0.08 III/ml and 0.06 + 0.07 III/ml were detected on day 1, by Heptest and S2222 assay respectively (tables 6 and 7). The differences of the Heptest coagulation values and the S-2222 chromogenic substrate method between the heparin and LMW heparin group are statistically significant (p < 0.001). DISCUSSION The results of this study indicate that small doses of LMW heparin may be as effective as low dose conventional heparin in prevention of thromboembolism in medical inpatients. Recent data have demonstrated that a LMW heparin significantly reduced the incidence of DVT in elderly medical inpatients as compared to placebo. DVT was detected in 9 % of patients of placebo and in 3 % of patients treated with one daily injection of the LMW heparin (15). The data of our study show that the incidences of DVT are similar in patients treated with unfractionated heparin and patients treated with LMWH. The incidences were 4.8 % and 3.4 8, respectively. These figures are similar to those found in the reported study (15). Repeated occlusive cuff impedance plethysmography (IPG), Doppler ultrasound of the femoral and popliteal veins, and repeated clinical examinations were used in our study to identify development of thromboembolism. Repeated IPG has been demonstrated to accurately identify thrombosis of the thigh (25,26). When Doppler findings were compared with phlebography in patients with suspected iliofemoral thrombosis the Doppler technique revealed an accuracy of 92 %, a sensitivity of 94 % and a specificity of 90 % (27). Clinical signs such as pain, edema and temperature differences are sensitive and accurate too, even if they are less specific (28). Radiolabelled fibrinogen and repeated ascending phlebography are associated with a number considerable risk factors. Therefore the repeated non invasive IPG techniques recommended as a screening method for detection of thrombosis (29-31). As demonstrated in our study the repeated performance of three non-invasive methods for detection of developing DVT results in similar values for incidence of DVT as compared to those reported in other studies using iodine-labelled fibrinogen test (15). The coagulation studies demonstrate that aPTT and thrombin clotting time as well as thrombelastography do not sensitively detect effects of heparin or LMW heparin. On the other hand factor Xa inhibition tests as Heptest and chromogenic S-2222 substrate method sensitively measure effects of LMW heparin. In addition, Heptest also determines the anticoagulant effects of normal heparin to some extent. Using coagulation time of Heptest, highly significant differences can be found between normal and LMW heparin. However, there is no relation between prolongation of coagulation times and the clinical outcome in terms of development of thrombosis or bleeding complications (data not shown). Antithrombin III is reported to decrease during low dose heparin administration (9). This has been confirmed in our study. In contrast antithrombin III increased during administration of LMW heparin. These effects on antithrombin III am worthwhile to be analyzed more in detail in further clinical studies. During administration of heparin and LMW heparin no changes of transaminases,
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Less occurrence of haemorrhagic complications has always been supposed using LMW heparin, as compared to normal heparin. However, this benefit has never been proven so far. Our study is the first to demonstrate a lower incidence of local hematomas with LMW heparin. This may be due in part to the lower frequency of injection of the active compound (once versus three times daily). Placebo injections induce some small local hematomas. But if the size of hematomas is analyzed it is evident that large hematomas with a diameter of more than 10 cm occured only after administration of unfractionated heparin. The advantages of LMW heparins over low dose conventional heparin for prophylaxis of thmmboembolism in medical inpatients are reduced frequency of daily injections due to prolonged anti Xa-activity, less effect on platelet aggregation (16), successful use in heparin-induced thrombocytopenia (16, 17), and the safe use in patients with high risk of haemorrhagic complications (18). In agreement with previous studies (15) the present investigation favors the administration of LMW heparin for prophylaxis of thromboembolism in medical inpatients. A larger trial now has to be carried out in order to demonstrate equivalent effects of LMW-heparin and unfractionated heparin in prevention of pulmonary embolism. The careful analysis of the results obtained in our study ascertained for the first time that haemorrhagic complications such as subcutaneous hematomas occur less frequently using LMW heparin, as compared to unfiactionated heparin. REFERENCES 1.
GALLUS, A.S., HIRSH, J., TUTTLE, R.J., TREBILOCK, R., O’BRIAN, S.E., CARROLL, J.J., MINDEN, J.H., HUDECKI, S.M. Small subcutaneous doses of heparin in prevention of venous thrombosis. New. EngL J. Med. 288.545-549,1978.
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WARLOW, C.H., BEATTIE, A.G., TERRY, G., OGSTON, D., KENMURE, C.F., DOUGLAS, A.S. A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet 934-937,1973.
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WHEELER, H.B., ANDERSON, F.A. Jr. The diagnosis of venous thrombosis by occlusive impedance plethysmography. In: Yao I S T, Enmczinski R F (eds). Noninvasive diagnostic techniques in vascular disease. 2nd ed. CV Mosby carp. St. Louis, 482-496, 1982.
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HULL, R., TAYLOR, W., HIRSH, J., SACKETT, D.L., POWERS, P., TURPIE, A.G.G., WALKER, I. Impedance plethysmography: the relationship between venous filling and sensitivity and specificity for proximal vein thrombosis. circulation 898~902,1987.
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HARTERT, H. Die Thrombelastographie. Eine Methode zur physikalischen Analyse des Blutgerinnungsvorganges. atschr. Ges. EXD.Med. 117,189-203, 1951.
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HULL, R.D., HIRSH, J., CARTER, C.J., JAY, H.R., TURPIE, G., POWERS, P., KINCH, D., J.R., GENT, M. Diagnostic efficacy of impedance deep-vein thrombosis. Ann. Int. Med. 102.21-28,
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HUISMAN, M.V., BULLER, H.R., TEN CATE, J., VREEKEN, J. Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. N. Enzl. J. Med, X823-828, 1986.
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SUMNER, D.S., LAMBETH, A. Reliability of Doppler Ultrasound in the diagnosis of acute venous thrombosis both above and below the knee. Am. J. Sure. 138.205-210, 1979.
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SANDLER, D.A., MARTIN, J.F., DUNCAN, J.S., BLAKE, G.M., WARD, P., RAMSAY, L.E., LAMONT, A.C., ROSS, B., SHERRIF’F, S., WALTON, L. Diagnosis of deep-vein thrombosis: comparison of clinical evaluation, ultrasound, plethysmography, and venoscan with x-ray venogram. Lancet I, 7 16-7 19,1984.
29.
CURLEY, F.J., PRATTER, M.R., IRWIN, R.S., ANDERSON, F.A., PHILIPS, D.A., DOHERTY, P.W., WHELLER, B., DALEN, J.E. The clinical implications of bilaterally abnormal impedance plethysmography. Arch. Intern. Med. 147.125-129,1987.
30.
HUISMAN, M.V., BULLER, H.R., TEN CATE, J.W. Utility of impedance pletbysmography in the diagnosis of recurrent deep-vein thrombosis. -Intern. Me& 14& 68 l-683, 1988.
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HIRSH, J. Clinical utility of impedance plethysmography in the diagnosis of recurrent deepvein thrombosis. Arch. Intern. Med. 148.519-520, 1988.
R.M., OCKELFORD, P.A., BULLER, DODD, P.E., GILL, G.J., LECLERC, plethysmography for clinically suspected 1985.
