Clinical
trial of repeated single dosage administration of Jipailin®(Gensparin
Injection) As an anti-coagulant during haemodialysis
Blood
purifying center No.1 hospital affiliated to zhejiang medical
university
[Astract]
20 patients with chronic renal
failure were randomized to receive treatment of haemodialysis
in two groups, using Jipailin (10 cases) or Fragmin (10
cases) as anti-coagulant agent during haemodialysis respectively.
They were given single intravenous injection and completed
8 continuous haemodialysis course. The efficacy and safety
of the two groups in these haeomdialysis process were observed
and compared.
[Result]
Haemodialysis treatments were
well accomplished for all patients in two groups, and total
anti-coagulation efficacy rate were both 100%. There were
no significant difference of coagulant deposition in dialyzator
and catheter, change of dialyzator capacity between Jipailin
and Fragmin groups(P> 0.05).No bleeding appeared ,and
there were no significant difference of time needed for
pressure at puncture site in internal fistula(P>0.05).
The indexes like anti-Xa factor activity and APTT were all
of no significant difference in haemodialysis courses in
two groups(P>0.05). There were no significant difference
of such indexes as blood routine examination, liver function,
blood lipid checked before haemodialysis between the first
haemodialysis and the eighth course.The results show that
Jipailin has the same curative effect and safety as Fragmin
in repeated use .
[
Background]
Unfractionated
heparin (UFH) is used as a conventional anticoagulant in
haemodialysis, but it can not be regarded as an ideal anticoagulant,
since its is associated with side effects such as an increased
bleeding tendency. In addition, it may lead to osteoporosis
and hyperlipordemia under long-term usage. Produced through
depolymerization and separation of UFH, low molecular weight
heparin has an average molecular weight at about 3000-6000,
has greater ratio of anti-factor Xa/anti-Ⅱa, less effect
on APTT and longer half-life period compared with UFH. It
is also convenient for clinical use and exerts less effect
on platelets and lipid metabolism in long-term use than
UFH.
JIPAILIN,
low molecular weight heparin sodium injection of Hangzhou
Jiuyuan Gene Engineering Co.Ltd., is produced through controlled
nitrous acid depolymerization. It has an average relative
molecular weight at about 3000-5000. The results of former
clinical trials suggested that Jipailin is a safe and effective
anticoagulant in haemodialysis as Fragmin. Now we further
observe the efficacy and safety of Jipailin used repeatedly
and consecutively as an anti-coagulant in haemodialysis.
Materials and Method
1.Patient
1.1 Enrollment
criteria
lWith chronic renal failure, undergoing long-term
haemodialysis, plasma creatinine
Concentration
higher than 500umol/L
lNo-recent use of anticoagulant other than
UFH.
lNo hemorrhagic diseases or severe tendency
of hemorrhage.
1.2 Grouping
characteristic
20
patients are randomly divided into Jipailin group(10 cases)
and Fragmin group(10 cases)
Table 1.Grouping
characteristics
|
Group
|
Case
|
Male/female
ratio
|
Mean
age(years)
|
Body
weight(kg)
|
|
JIPAILIN
|
10
|
6/4
|
50.1±3.35
|
51.5±8.91
|
|
FRAGMIN
|
10
|
5/5
|
51.6±10.46
|
54.8±8.44
|
2. Materials
2.1 Drugs:
2.1.1 JIPAILIN: (Specification:5000 anti-Xa IU/2ml, Batch No:950301)
Hangzhou
Jiuyuan Gene Engineering Co.Ltd
2.1.2 Fragmin:(Specification:10,000 anti-Xa IU/4ml, Batch No:941001/10536A51)
Kabivitrum
Co.Switzerland
2.2 Testing methods and reagents in blood
coagulation
2.2.1 Measurement of anti-Xa activity: STACLOT HEPARIN diagnostic kit (France
Diagnostica),
according to stago coagulation titration method.
2.2.2 Measurment of activated partial
thromboplastin time (APTT): Intelligent blood coagulation
instrument, TYXN-91
3. Study Methods
3.1 Haemodialysis Method:
Machine:Ak-100,AK-10(Made
in Sweden)
Dialyzator:
Terumo C12,AM1.2,and Diacap11
Blood
flow:200-250ml/min
Dialysis
time:2-3 times every week,4-5 hours each time
3.2 Usage of anti-coagulant agents
All
patients were studied and observed in 8 consecutive haemodialysis
courses,taken single intravenous injection of Jipailin or
Fragmin before each dialysis, the dosage been 80IU/kg,no
need of maintenance dose.
4. Examination indexes
4.1.Observation
indexes
Observe the change
of physical signs and venous pressure during each dialysis,
and observe coagulant deposition in dialyzator and catheter,
time needed for pressure at puncture site in internal fistula
and the change of dialysizator capacity after each dialysis
a. Grade of coagulant deposition
in catheter
Ⅰ.no coagulant deposition
Ⅱ.a little coagulant deposition
Ⅲ several deposition
Ⅳ coagulation or termination
of haemodialysis
b. Grade of coagulation in dialyzator
Ⅰ no or very little fibrin
Ⅱ several fibrin
Ⅲ fibrin less than 1/5
Ⅳ fibrin more than about 1/3
4.2
Analyzed Indexes
Blood
routine examination before the first and eighth haemodialysis
in each group, including protoheme(Hb), haematocrit (HCT),
blood platelet count (BPC); liver function including glutamic-pyruvic
transaminase (ALT),glutamic-oxalacetic transaminase (AST),
alkaline phospatase (ALP), AG ratio(A/G); blood lipid including
total cholestero(TG), AhE and high density lipoprotein(HDLP);
Dialyzator creatinine and urea nitrogen clearance rate in
dialysis(180 minutes), anti-FⅩa activated partial thromboplastin time(APPT) were
measured
before and during haemodialysis ,at 15,180,300 minutes,
with blood taken from venous end.
5. Judgment grade of efficacy
Efficacy:
Judged by three standards according to the effect of anti-coagulantion.
Ⅰ Apparent effect (coagulant
deposition in dialyzator and catheter withinⅠand Ⅱgrade,
and
haemodialysis course accomplished smoothly)
ⅡEffective (coagulant deposition in dialyzator and catheter in Ⅲ grade, and
haemodialysis course almost accomplished)
Ⅲ Unvalid (coagulant deposition in dialyzator and catheter in Ⅳgrade or
haemodialysis course can not be accomplished)
6.Statistical methods
T-test
analysis was used in comparing with phyical sign, change
fo dialyzator capacity, time needed for pressure at puncture
site, anti-Ⅹa
activity and APTT of plasma and blood routine examination,
liver function, blood lipid and dialyzator clearance rate
in the first and eighth courses.
Ⅹ2 –test analysis was used in comparing with coagulant deposition in dialyzator
and catheter and adverse effects.
There
was not significant difference ,when P <0.05, marked
with *;
when
P <0.01, marked with **;
When P<0.001,marked with ***.
Results
1. Dialysis efficacy
80
Jipailin or Fragmin anti-coagulant haemodialysis course
were taken respectively in
each
groups. All cases smoothly finished 5 hours of haemodialysis
each time, and no physical sign related to anti-coagulant
agents appeared .Cases of haemodialysis termination were
not found due to drug usage, dialysis courses were smooth
and without rising of venous pressure.
The
two groups were similar in coagulant deposition in dialyzator
and catheter, and there were no significant difference (see
Table 1); There were no difference found in dialyzator clearance
rate in 3 hours during the first and eighth dialysis(see
Table 2) in the same group and between the two groups after
T-test (P>0.05).
Table
1.Comparison of coagulant deposition in dialyzator and catheter
|
Group
|
Case
|
Coagulant deposition
in dialyzator
|
Coagulant
deposition in catheter
|
|
Ⅰn(%)
|
Ⅱn(%)
|
Ⅲn(%)
|
Ⅰn(%)
|
Ⅱn(%)
|
Ⅲn(%)
|
|
JIPAILIN
|
80
|
52(65.0)
|
26(32.5)
|
2(2.5)
|
56(70.0)
|
24(30.0)
|
0(0)
|
|
FRAGMIN
|
80
|
54(67.5)
|
25(31.3)
|
1(1.25)
|
55(68.7)
|
24(30.0)
|
1(1.2)
|
Table
2 Comparison of dialyzator clearance rate(ml/min) in 3 hours(X±SD)
|
Index
|
Case
|
Jipailin
|
Fragmin
|
|
No.1st
|
No.8th
|
No.1st
|
No.8th
|
|
Urea
Nitrogen
|
10
|
132.2±55.1
|
161.6±20.1
|
160.6±8.64
|
158.0±8.23
|
|
Creatinine
|
10
|
112.3±41.8
|
123.4±20.9
|
105.2±58.5
|
117.1±41.6
|
Judged
according to efficacy grade: apparent effective rate for
Jipailin group was 98% and effect rate 2%; apparent effective
rate of Fragmin was 99% and effective rate 1%, total effective
rate 100%, there were no significant difference between
the two groups.
2. Adverse effects
During
haemodialysis in Jipailin group,one patient observed puff
and pant,two patients observed nasal haemorrhage after returning
home; In Fragmin group, two patients observed nausea, one
observed oozing blood at the puncture site of the internal
fistula and one patient gum bleeding. The occurrence rate
of side effects was respectively 3.75% and 5.0%, and there
was no significant difference(P>0.05)
3.
Influence on time needed for pressure at puncture site in
artery and dialysis capacity
After
dialysis ,time needed for pressure at puncture site in artery
:Jipailin group 8.0±3.13 minutes, Fragmin group:6.9±2.02 minutes, there were no significant differences(P>0.05). The
decline rate of dialyzator capacity: Jipailin group 4.55±2.61%,Fragmin
group 5.57±0.70%, there
were no significant differences(P>0.05).
.
4.
Influence on anti-factor Xa activity of plasma and APTT.
The
change of anti-factor Xa activity of plasma and APTT during
dialysis in Jipailin and Fragmin group were recorded (see
table3 and table4). In Jipailin group there were no significant
differences of anti-factor Xa activity of plasma at different
time during No.1st and No 8th dialysis
course. In Fragmin group, after No.8th course
(300mins), anti-factor Xa activity of plasma was higher
than No.1st course of Fragmin and No.8th
course of Jipailin and there were significant difference.
In other correspondent time, there was no significant difference
between two groups and No.1st and No.8th
course in the same group. There was no obvious difference
of plasma value of APTT prolongation between two groups
and in the same group at correspondent time .
Table
3 Anti-Xa factor activity( anti-Xa IU/ml) of plasma(X±SD) during dialysis
|
Time
(min)
|
Jipailin(n=10)
|
Fragmin(n=10)
|
|
No.1st
|
No.8th
|
No.1st
|
No.8th
|
|
15
|
0.87±0.18
|
0.94±0.12
|
0.93±0.14
|
0.95±0.10
|
|
180
|
0.67±0.16
|
0.74±0.15
|
0.75±0.10
|
0.77±0.18
|
|
300
|
0.43±0.16
|
0.41±0.14
|
0.42±0.10
|
0.58±0.19#*
|
*P<0.05:compared with No.1st
course of Fragmin group;
#P<0.05:compared
with No.8th course of Jipailin group.
Table
4 Plasma value of APTT(X±SD) during
dialysis
|
Time
(min)
|
Jipailin(n=10)
|
Fragmin
(n=10)
|
|
No.1st
|
No.8th
|
No.1st
|
No.8th
|
|
0
|
44.3±1.90
|
44.9±13.4
|
47.5±7.05
|
46.2±8.64
|
|
15
|
79.5±22.0
|
68.3±11.8
|
86.2±24.6
|
85.6±31.01
|
|
180
|
52.3±15.2
|
51.8±11.3
|
59.3±9.14
|
52.5±9.85
|
|
300
|
40.9±3.27
|
43.6±8.48
|
50.7±7.36
|
51.9±23.5
|
5. Impact on blood platelet cell
(BPC) and blood lipid
Blood
routine examination,liver function and blood lipid
before No.1st and No.8th of Jipailin
group and Fragmin group were shown in table 5. In Fragmin
group, the HDLP value of the first haemodialysis course
was lower than No.8th course in the same group
and No.1st haemodialysis in Jipailin group (P<0.05).There
were no significant differences of other indexes between
two groups and No.1st and No.8th haemodialysis
course in the same group.
Table
5 Blood routine examination,liver function and blood lipid
before dialysis
|
Items
|
Jipailin(n=10)
|
Fragmin
(n=10)
|
|
No.1st
|
No.8th
|
No.1st
|
No.8th
|
|
Blood
Routin
Examination
|
Hb(g/l)
|
7.34±1.23
|
7.36±1.39
|
6.10±2.10
|
5.90±1.71
|
|
Hct
(%)
|
23.2±5.50
|
23.2±4.11
|
17.
±5.838
|
18.0±5.25
|
|
BPC(109/l)
|
131.9±49.6
|
137.1±55.3
|
122.9±90.1
|
128.0±477.7
|
|
Liver
Function
Blood
lipid
|
ALT
(μ/l)
|
23.0±17.0
|
20.6±9.5
|
29.5±20.5
|
28.8±26.5
|
|
AST
(μ/l)
|
38.7±34.2
|
26.0±8.56
|
34.6±17.2
|
34.0±22.6
|
|
ALP
(μ/l)
|
84.3±62.5
|
79.9±70.8
|
85.6±36.8
|
83.4±56.0
|
|
A/G
|
1.40±0.48
|
1.10±0.47
|
1.36±0.16
|
1.36±0.15
|
|
Blood
lipid
|
TG(mM)
|
1.69±0.73
|
1.96±0.51
|
1.53±0.65
|
1.77±0.46
|
|
CHE(mM)
|
4.81±1.08
|
4.36±1.27
|
4.42±1.53
|
1.77±0.46
|
| |
1.04±0.43
|
1.11±0.41
|
0.61±0.18#*
|
1.11±0.24
|
|
HDLP(mM)
|
*P<0.05:compared
with No.8th in Fragmin group;
#P<0.05:compared
with No.1st in Jipailin group
Result and discussion
As
UFH has short half-life period, it must be administered
by continuous i.v. infusion during haemodialysis . Also,
there was adverse reaction such as bleeding, therefore requiring
laboratory monitoring. Also platelet and lipid metabolism
can be influenced by long-term usage of UFH. Low Molecular
Weight Heparin can overcome these shortcomings. It has been
widely used in clinic and will gradually replace UFH.
Jipailin
is the first low molecular weight heparin injection produced
by a domestic company and marketed in Chinese. The result
demonstrated that the efficacy of Jipailin is stable during
8 consecutive dialysis .A single injection of Jipailin can
maintain the whole dialysis with a efficacy rate of 100%.There
were no significant difference between Jipailin and Fragmin
.The plasma anti-factor Xa activity was maintained above
0.4IU/ml through 5 hours’ dialysis, which is the same as
Fragmin. APTT was less prolonged after administration of
Jipailin than Fragmin , but there was no significant difference.
The results of the clinical trial suggest that Jipailin
has long half-life, low bleeding risk and convenient usage,
and can replace UFH to be used as an anti-coagulant during
haemodialysis. Abnormality for exceptional values of anti-Xa
activity and HDLP in Fragmin group may relate to relatively
small trial cases, and enlarged further study is to be performed.
In
usage of Jipailin during 8 consecutive haemodialysis , no
significant changes of BPC and blood lipid level appeared
in plasma showed that Jipailin had no impact on BPC and
lipid metabolism, and this point should be further verified
through additional trials and time of usage in clinics.
Current
verified results show that Jipailin has the same efficacy
and safety as Fragmin under consecutive usage.
