SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
Biologic Tolerance of Two Different Low Molecular Weight Heparins
Since 1985, a few studies have reported an increase in serum values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in patients and volunteers treated with low molecular weight (LMW) heparins. 1-6 We present the results of two randomized multicenter studies concerning the biologic tolerance of two different LMW heparin compounds used for thromboprophylaxis in patients undergoing total hip replacement (THR).
PATIENTS AND METHODS Study A7 comprised 210 consecutive patients randomized into two groups: 105 patients received thromboprophylaxis with LMW heparin (Logiparin, NovoNordisk, Copenhagen, Denmark) 50 anti-Xa U/kg body weight injected subcutaneously once daily, and 105 patients received injections of placebo (saline) once daily. Study B 8 comprised 246 consecutive patients randomized into two groups: 120 patients received thromboprophylaxis with LMW heparin (Enoxaparin, RhonePoulenc, Paris, France) 40 mg injected subcutaneously once daily, and 126 patients received dextran 70 (Mac-
rodex, 60 mg/ml in saline, Kabi-Vitrum A/S, Denmark), 500 ml was infused intravenously during operation, second dose was infused later on the day of operation, and the third and fourth doses were infused on the first and third postoperative days. An additional dose was given on the fifth postoperative day, in case the patient was not mobilized. Injections were given subcutaneously and started 2 hours (study A) or 12 hours (study B) before operation and continued for 7 postoperative days. Blood samples were collected preoperatively before the first administration of prophylaxis, and on the seventh postoperative day 3 hours (study A) or 12 hours (study B) after the last injection. In study A, we were specifically interested in AST, alkaline phosphatase (AP), albumin, and bilirubin (Table 1). In study B AST, TABLE 1. Blood Assays Study A
Study B
AST*
x†
X
AP
X
X
Albumin
X
X
Bilirubin
X
X
ALT
— — — — — —
LDH CK CKBB
From the Venous Thrombosis Group, Department of Orthopedics, Aalborg Hospital, Aalborg, Denmark, Århus Municipal Hospital, Århus, Denmark, and The Danish Enoxaparin Study Group. Reprint requests: Dr. Christiansen, The Venous Thrombosis Group, Dept. of Orthopedics, Aalborg Hospital, Aalborg, Denmark. 450
CKMB Complement factor C3 activity * See text for abbreviations. † X: assay performed in the study. ‡ Subgroup analysis (n = 71).
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
X X X X X
X‡
Downloaded by: East Carolina University. Copyrighted material.
HANNE M. CHRISTIANSEN, M.D., MICHAEL R. LASSEN, M.D., LARS C. BORRIS, M.D., JENS V. S0RENSEN, M.D., HANS B. RAHR, M.D., LARS N. J0RGENSEN, M.D., PEER W. J0RGENSEN, M.D., and OLE HAUCH, M.D.
BIOLOGIC TOLERANCE OF HEPARINS—CHRISTIANSEN ET AL
STATISTICS In study A, results were analyzed by Fisher's exact test and an analysis of variance of the difference (postoperative-preoperative value). In study B, results were analyzed by Mann-Whitney test, Wilcoxon test, and an analysis of variance of the difference (postoperative-preoperative value). No treatment by center interaction was found, and analyses were performed on pooled data in both studies. All the tests were at the 5% significance level.
RESULTS In study A, seven patients were excluded due to missing data; thus, 203 patients completed the study, with 103 patients receiving Logiparin and 100 receiving placebo. The preoperative values (mean and range) were comparable in the two groups (Table 4). Patients treated with Logiparin had a significantly higher increase in AST (p < 0.0006), and AP (p < 0.014) compared with patients in the placebo group (Table 5). The number of patients, with normal preoperative values, in whom AST and AP turned to pathologic levels postoperatively, also was significantly higher in the Logiparin group 36 (35%) compared with the placebo group 15 (15%) (p = 0.012 and p = 0.025, respectively) (Table 6). All abnormal values returned to normal within 2 weeks after the last injection. In study B, 27 patients were excluded due to missing data; thus, 219 patients completed the study, with 108 receiving Enoxaparin and 111 receiving dextran 70. The preoperative values were comparable in the groups (Table 7). A significant increase from pre- to postoperative values of AST, ALT, AP, and LDH were seen in
TABLE 2. Demographics, Study A Logiparin (n = 105)
Placebo (n= 105)
66 40-85
67 40-86
Height (cm) Mean Range
167 148-190
168 148-194
Weight (kg) Mean Range
73 40-104
74 48-126
Sex M/F
48/57
48/57
Prosthesis Cement +/—
67/38
74/31
115 55-220
121 50-250
76/29
73/32
Age (yr) Mean Range
Duration of operation (min) Mean Range Anesthesia General/regional*
* Spinal, epidural, or combination of spinal and epidural.
TABLE 3. Demographics, Study B Enoxaparin (n = 108) Age (yr) Median Range
Placebo (n=lll)
71 33-87
71 53-87
Height (cm) Median Range
167 152-193
165 141-190
Weight (kg) Median Range
71 44-125
71 35-107
Sex M/F
46/62
45/66
Prothesis Cement +/—
79/29
86/25
Duration of operation (min) Median Range
95 60-200
95 50-325
Anesthesia General/regional*
29/79
22/89
* Spinal, epidural, or combination of spinal and epidural.
TABLE 4. Preoperative Values of AST and AP, Study A* Logiparin (n = 103)
Placebo (n = 100)
AST (IU/liter) Mean Range
21 10-59
22 11-211
AP (IU/liter) Mean Range
212 104-767
196 86-412
*AST: aspartate aminotransferase: reference interval; 10 to 40 IU/liter; AP: alkaline phosphatase: reference interval: 70 to 275 IU/liter.
Downloaded by: East Carolina University. Copyrighted material.
ALT, AP, lactate dehydrogenase (LDH), complement factor C3 activity, creatine kinase (CK), CK brain band (CKBB), and CK myocardial band (CKMB) were of most interest (Table 1). When pathologic values were found, blood was repeatedly collected with weekly intervals until the assays returned to normal. Additional analyses in both studies were: hemoglobin, hematocrit, platelets, sodium, potassium, calcium (total and albumin corrected), creatinine, protein, uric acid, urea, prothrombin time, white blood cell count, differential count. Patients were well matched in terms of age, sex, weight, duration of operation, type of anesthesia, and type of prosthesis in both studies (Tables 2, 3). All patients gave informed consent and both studies were approved by the local Ethics Committees and notice was given to The National Health Service of Denmark.
451
452
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
TABLE 5. Mean Increase from Baseline Values of AST and AP, Study A* Logiparin (n = 103)
Placebo (n = 100)
P (Two- Tailed)
AST (IU/liter) 95% confidence interval
30 23.4 to 36.6
13 7.1 to 20.5
Biologic Tolerance of Two Different Low Molecular Weight Heparins
Since 1985, a few studies have reported an increase in serum values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in patients and volunteers treated with low molecular weight (LMW) heparins. 1-6 We present the results of two randomized multicenter studies concerning the biologic tolerance of two different LMW heparin compounds used for thromboprophylaxis in patients undergoing total hip replacement (THR).
PATIENTS AND METHODS Study A7 comprised 210 consecutive patients randomized into two groups: 105 patients received thromboprophylaxis with LMW heparin (Logiparin, NovoNordisk, Copenhagen, Denmark) 50 anti-Xa U/kg body weight injected subcutaneously once daily, and 105 patients received injections of placebo (saline) once daily. Study B 8 comprised 246 consecutive patients randomized into two groups: 120 patients received thromboprophylaxis with LMW heparin (Enoxaparin, RhonePoulenc, Paris, France) 40 mg injected subcutaneously once daily, and 126 patients received dextran 70 (Mac-
rodex, 60 mg/ml in saline, Kabi-Vitrum A/S, Denmark), 500 ml was infused intravenously during operation, second dose was infused later on the day of operation, and the third and fourth doses were infused on the first and third postoperative days. An additional dose was given on the fifth postoperative day, in case the patient was not mobilized. Injections were given subcutaneously and started 2 hours (study A) or 12 hours (study B) before operation and continued for 7 postoperative days. Blood samples were collected preoperatively before the first administration of prophylaxis, and on the seventh postoperative day 3 hours (study A) or 12 hours (study B) after the last injection. In study A, we were specifically interested in AST, alkaline phosphatase (AP), albumin, and bilirubin (Table 1). In study B AST, TABLE 1. Blood Assays Study A
Study B
AST*
x†
X
AP
X
X
Albumin
X
X
Bilirubin
X
X
ALT
— — — — — —
LDH CK CKBB
From the Venous Thrombosis Group, Department of Orthopedics, Aalborg Hospital, Aalborg, Denmark, Århus Municipal Hospital, Århus, Denmark, and The Danish Enoxaparin Study Group. Reprint requests: Dr. Christiansen, The Venous Thrombosis Group, Dept. of Orthopedics, Aalborg Hospital, Aalborg, Denmark. 450
CKMB Complement factor C3 activity * See text for abbreviations. † X: assay performed in the study. ‡ Subgroup analysis (n = 71).
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
X X X X X
X‡
Downloaded by: East Carolina University. Copyrighted material.
HANNE M. CHRISTIANSEN, M.D., MICHAEL R. LASSEN, M.D., LARS C. BORRIS, M.D., JENS V. S0RENSEN, M.D., HANS B. RAHR, M.D., LARS N. J0RGENSEN, M.D., PEER W. J0RGENSEN, M.D., and OLE HAUCH, M.D.
BIOLOGIC TOLERANCE OF HEPARINS—CHRISTIANSEN ET AL
STATISTICS In study A, results were analyzed by Fisher's exact test and an analysis of variance of the difference (postoperative-preoperative value). In study B, results were analyzed by Mann-Whitney test, Wilcoxon test, and an analysis of variance of the difference (postoperative-preoperative value). No treatment by center interaction was found, and analyses were performed on pooled data in both studies. All the tests were at the 5% significance level.
RESULTS In study A, seven patients were excluded due to missing data; thus, 203 patients completed the study, with 103 patients receiving Logiparin and 100 receiving placebo. The preoperative values (mean and range) were comparable in the two groups (Table 4). Patients treated with Logiparin had a significantly higher increase in AST (p < 0.0006), and AP (p < 0.014) compared with patients in the placebo group (Table 5). The number of patients, with normal preoperative values, in whom AST and AP turned to pathologic levels postoperatively, also was significantly higher in the Logiparin group 36 (35%) compared with the placebo group 15 (15%) (p = 0.012 and p = 0.025, respectively) (Table 6). All abnormal values returned to normal within 2 weeks after the last injection. In study B, 27 patients were excluded due to missing data; thus, 219 patients completed the study, with 108 receiving Enoxaparin and 111 receiving dextran 70. The preoperative values were comparable in the groups (Table 7). A significant increase from pre- to postoperative values of AST, ALT, AP, and LDH were seen in
TABLE 2. Demographics, Study A Logiparin (n = 105)
Placebo (n= 105)
66 40-85
67 40-86
Height (cm) Mean Range
167 148-190
168 148-194
Weight (kg) Mean Range
73 40-104
74 48-126
Sex M/F
48/57
48/57
Prosthesis Cement +/—
67/38
74/31
115 55-220
121 50-250
76/29
73/32
Age (yr) Mean Range
Duration of operation (min) Mean Range Anesthesia General/regional*
* Spinal, epidural, or combination of spinal and epidural.
TABLE 3. Demographics, Study B Enoxaparin (n = 108) Age (yr) Median Range
Placebo (n=lll)
71 33-87
71 53-87
Height (cm) Median Range
167 152-193
165 141-190
Weight (kg) Median Range
71 44-125
71 35-107
Sex M/F
46/62
45/66
Prothesis Cement +/—
79/29
86/25
Duration of operation (min) Median Range
95 60-200
95 50-325
Anesthesia General/regional*
29/79
22/89
* Spinal, epidural, or combination of spinal and epidural.
TABLE 4. Preoperative Values of AST and AP, Study A* Logiparin (n = 103)
Placebo (n = 100)
AST (IU/liter) Mean Range
21 10-59
22 11-211
AP (IU/liter) Mean Range
212 104-767
196 86-412
*AST: aspartate aminotransferase: reference interval; 10 to 40 IU/liter; AP: alkaline phosphatase: reference interval: 70 to 275 IU/liter.
Downloaded by: East Carolina University. Copyrighted material.
ALT, AP, lactate dehydrogenase (LDH), complement factor C3 activity, creatine kinase (CK), CK brain band (CKBB), and CK myocardial band (CKMB) were of most interest (Table 1). When pathologic values were found, blood was repeatedly collected with weekly intervals until the assays returned to normal. Additional analyses in both studies were: hemoglobin, hematocrit, platelets, sodium, potassium, calcium (total and albumin corrected), creatinine, protein, uric acid, urea, prothrombin time, white blood cell count, differential count. Patients were well matched in terms of age, sex, weight, duration of operation, type of anesthesia, and type of prosthesis in both studies (Tables 2, 3). All patients gave informed consent and both studies were approved by the local Ethics Committees and notice was given to The National Health Service of Denmark.
451
452
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
TABLE 5. Mean Increase from Baseline Values of AST and AP, Study A* Logiparin (n = 103)
Placebo (n = 100)
P (Two- Tailed)
AST (IU/liter) 95% confidence interval
30 23.4 to 36.6
13 7.1 to 20.5
