As An Anti-coagulant During Haemodialysis

Abstract

JIPAILIN is a low molecular weight heparin sodium injection manufactured by Hangzhou Jiuyuan Gene Engineering Co. Ltd. To test and verify the efficacy and safety of JIPAILIN, a clinical trial was performed in No. 1 Hospital of Zhejiang Medical University, Beijing Friendship Hospital and Shanghai Changzheng Hospital. JIPAILIN was used as an anticoagulant during haemodialysis by 140 patients with chronic or acute renal failure undergoing haemodialysis, compared with Fragmin of Switzerland and unfractionated heparin (UFH).

The results showed that JIPAILIN has the same anticoagulant efficacy as Fragmin for patients undergoing haemodialysis (P>0.05). There was no difference of haemodialysis efficacy, clotting of blood in dialyzator, coagulant deposition in catheter, change of dialyzator capacity and time needed for pressure at puncture site between JIPAILIN and Fragmin (P>0.05). Whether JIPAILIN was administered continuously or as a single dose, plasma anti-factor Xa activity was maintained above 0.4 anti-Xa IU/ml throughout the dialyses, which differed from Fragmin. A single dose of JIPAILIN gave sufficient anticoagulation for dialysis lasting up to 4-5 hours. APTT, an index related to anti-factor IIa activity, was less prolonged after administration of JIPAILIN than Fragmin during dialyses at 15 minute and 180 minute (P<0.05).

Anticoagulation effects of JIPAILIN and UFH are identical. However, anti-factor Xa activity of plasma with JIPAILIN is higher than that of UFH at 180 and 300 minute (P<0.05). In JIPAILIN group, APTT is less prolonged than UFH group (P<0.001). The effect of JIPAILIN in maintaining high plasma anti-factor Xa activity was relatively stronger than its effect on APTT prolongation, suggesting that there is a relatively low risk of bleeding complications and higher safety with JIPAILIN.

There were not other adverse reactions except two patients having tolerable skin itch in JIPAILIN’ group.

The results of the clinical trial suggest that JIPAILIN is a safe and effective anticoagulant as Fragmin. JIPAILIN’ effects on anticoagulation indexes were superior to that of UFHs. A single injection of JIPAILIN is a convenient method. In conclusion, JIPAILIN can be used in as an haemodialysis anticoagulation therapy, in place of UFH.

Background

UFH (unfractionated heparin) is used as a conventional anticoagulant in haemodialysis, but it can not be regarded as an ideal anticoagulant, since its use is associated with side effects such as an increased bleeding tendency. In addition, it may lead to osteoporosis, hyperlipordemia, and thrombocytopenia. Produced through depolymerization and separation of UFH, low molecular weight heparin has an average relative molecular weight at about 3000-6000, has greater ratio of anti-factor Xa/anti-factor IIa, less effect on APTT and longer half-life period. 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. Its average molecular weight is about 4000. After pre-clinical pharmacological studies, a clinical study of JIPAILIN was performed in No. 1 Hospital of Zhejiang Medical University, Shanghai Changzheng Hospital and Beijing Friendship Hospital. The results of the clinical trial are summarized as follows.

Materials and Method

1. Materials

JIPAILIN: Hangzhou Jiuyuan Gene Engineering Co. Ltd

Specification: 5000 anti-Xa IU/2ml

Batch No.: 950301

( JIPAILIN is LMWH injection )

Fragmin: Kabivitrum Co. Switzerland

Specification: 10,000 anti-Xa IU/4ml

Batch No.: 941001/10556A51

( Fragmin is LMWH injection )

UFH (Heparin sodium): Shanghai Biochemical Pharmaceutical Factory

Specification: 12,500 anti-XaIU/2ml

Batch No.: 950216

l Fragmin has been clinically used for 10 years. It has been proved to be safe, effective and representative.

l UFH is a conventional heparin that has been collected in Chinese Pharmacopoeia, regularly used in haemodialysis.

2. Dialysis condition

Dialysis machine: AK-100, AK-10

Dialyzator: Terumo C12, AM1.2, and Diacap110

Blood flow: 200-250ml/min

Dialysis time: 2-3 times every week, 4-5 hours every time

3. Patients

3.1 Selected criteria

l With acute or chronic renal failure, undergoing haemodialysis, plasma creatinine concentration higher than 500mmol/l.

l Non-recent use of anticoagulants other than UFH.

l No hemorrhagic diseases or severe tendency of hemorrhage.

3.2 Superseded criteria

Patients didn't finish haemodialysis because of mechanical failure of dialysis appliance, operation trouble or patient’ primary affection.

3.3 Terminated criteria

Patients didn't finish haemodialysis because of adverse reactions. Record causes of failure, time of failure and evaluate drug effects at termination.

3.4 Clinical characteristic

Patients are randomly divided into JIPAILIN group (100 cases), Fragmin group (50 cases) and UFH group (40 cases).

Table 1. Clinical characteristics

There was no significant difference among 3 groups (P>0.05).

4. Method and dosage

In JIPAILIN group, 70 patients received a single I.V. bolus injection of 70-80 anti-Xa IU/kg of JIPAILIN at the beginning of haemodialysis ( in which 50 later on also received a single I.V. bolus injection of Fragmin at same dosage for self-control observation ); 30 received an I.V. bolus injection of 30 anti-Xa IU/kg of JIPAILIN at the beginning of haemodialysis followed by an infusion of 10 anti-Xa IU/kg/hr of JIPAILIN till half hour prior to the end of haemodialysis.

In Fragmin group, 50 patients received a single I.V. bolus injection of 70-80 anti-Xa IU/kg Fragmin at the beginning of haemodialysis.

In UFH group, 40 patients received an I.V. bolus injection of 30-50 anti-Xa IU/kg UFH at the beginning of haemodialysis, followed by an infusion of 10-30 anti-Xa IU/kg/hr UFH till half an hour prior to the end of haemodialysis.

5. Observation indexes

5.1 Physical sign

Major complained symptom, self-sense; Change of breath, pulse, blood pressure, and body temperature.

5.2 Clotting of blood in dialyzator

I. no clotting of blood

II. a little clotting of blood

III. some clotting of blood

IV. a lot of clotting of blood

5.3 Coagulation deposition in catheter

I. no coagulation deposition

II. a little coagulation deposition

III. some coagulation deposition

IV. a lot of coagulation deposition

5.4 Chance of dialyzator capacity before the start to the end of dialysis

5.5 Time needed for pressure at puncture site of internal fistula to stop bleeding

5.6 Anti-factor Xa activity and APTT of plasma

Before connecting the dialysis tube to dialyzator, blood sample was taken from fistula needle at the start of dialysis. When the dialysis took place at 15, 180, 300 minutes, blood was taken from the arterial and venous tubing. The concentration of anti-Xa activity of plasma was measured using a Staclot Heparin Kit (France, Diagnostica, Stago), according to coagulated titration method. Activated partial thromboplastin time (APTT) of plasma was measured with automatic assay instrument.

5.7 Synthesized index

5.7.1 Anti-coagulation efficacy

I. coagulation deposition in catheter and clotting of blood in dialyzator I-II, successfully finished dialysis course

II. coagulation deposition in catheter and clotting of blood in dialyzator III, successfully finished dialysis course

III. coagulation deposition in catheter and clotting of blood in dialyzator IV, successfully finished dialysis course

5.7.2 Anti-coagulation safety

Synthesize patients bleeding tendency, time needed for pressure at puncture site, adverse effect to judge safety.

6. Statistical methods

t-test analysis was used in comparing with physical sign, change of dialyzator capacity, time needed for pressure at puncture site, anti-Xa activity and APTT of plasma.

X²-test analysis was used in comparing with clotting of blood in dialyzator, coagulation deposition in catheter and adverse effects.

There was not significant difference, when P>0.05;

There was significant difference, when P<0.05, marked with *;

P<0.01, marked with **;

P<0.001, marked with ***.

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