|Year : 2010 | Volume
| Issue : 1 | Page : 43-49
|Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis
Khalid A Al-Saran, Alaa Sabry, Moammer Taha, Mamdouh Abdul Ghafour, Fawzan Al Fawzan
Prince Salman Center for Kidney Disease, Riyadh, Saudi Arabia
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|Date of Web Publication||8-Jan-2010|
| Abstract|| |
Low-molecular-weight heparin (LMWH) has been suggested as providing safe, efficient, convenient, and possibly more cost-effective anticoagulation for hemodialysis (HD) than unfractionated heparin (UFH) with a single bolus dose at the start of hemodialysis effectively prevents clot formation in the dialyzer and bubble trap with fewer side-effects and possible benefits on uremic dyslipidemia. In this study, we compared the safety, clinical efficacy, and cost effectiveness of Tinzaparin sodium (Innohep) with unfractionated heparin (UFH) in 23 chronic HD patients; their extracorporeal anticoagulant protocol-consisted of UFH was switched to Tinzaparin for a period of 6 months. Clinical clotting (grade 1-4) was evaluated by visual inspection after blood draining of the air trap every hour and the dialyzer after each session. Anticoagulation with Tinzaparin sodium resulted in less frequent dialyzer and air-trap clotting compared to UFH (P= 001 and 0.04 respectively). Over 24 weeks, we observed no alteration in the serum lipid profile of the patients. There was a statistically significant improvement in the dialysis single pool Kt/V after 6 months of Tinzaparin use (1.40 ± 0.28 for Tinzaparin versus 1.23 ± 0.28 for heparin) without any modification in the hemodialysis prescription. The total cost for 24 weeks use of Tinzaparin sodium was 23% more expensive compared to that for UFH. We conclude that a single bolus of Tinzaparin sodium injection at the start of the dialysis session was more effective and convenient in our patients than UFH, but at a higher total cost. Furthermore, at least on the short term, there was no observed benefit on the lipid profile.
|How to cite this article:|
Al-Saran KA, Sabry A, Taha M, Ghafour MA, Al Fawzan F. Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis. Saudi J Kidney Dis Transpl 2010;21:43-9
|How to cite this URL:|
Al-Saran KA, Sabry A, Taha M, Ghafour MA, Al Fawzan F. Profile of low molecular weight tinzaparin sodium for anticoagulation during hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jan 29];21:43-9. Available from: http://www.sjkdt.org/text.asp?2010/21/1/43/58706
| Introduction|| |
Hemodialysis (HD) requires anticoagulation to avoid clotting of dialyzers and extracorporeal has consisted of an i.v. bolus dose of unfractionated heparin (UFH) followed either by i.v. continous infusion or a repeated bolus dose during dialysis. However, Low Molecular Weight Heparin (LMWH) is reported to have several potential advantages over UFH.  The risk of bleeding is lower than with UFH, since LMWH interacts less with platelets and walls of vessels;  the risk of heparin-induced thrombocytopenia is also smaller.  In addition, the administration of LMWH is practical, and its effect on the blood lipids may be more favorable.  LMWH has a longer half life than UFH,  so it can be administered as a single bolus injection at the start of the dialysis session. LMWH is as effective as UFH in preventing thrombosis in animal models and may has less bleeding risk than UFH. However, these findings have not been confirmed in clinical studies. 
LMWH does not stimulate plasma lipase to the same extent as UFH  ; however, its effect on uremic dyslipidemia is controversial,  with some ,,, but not all studies  reporting a beneficial effect.
Although there are several studies that compared a variety of LMWH with UFH in hemodialysis patients, experience with Tinzaparin sodium is limited.
We aim in this study to compare the clinical efficacy, safety, and cost effectiveness of Tinzaparin sodium with UFH in our chronic hemodialysis patients.
| Patients and Methods|| |
We studied 23 adult patients (17 male, 6 female) on chronic hemodialysis in Prince Salman Center for Kidney Diseases, Riyadh, Saudi Arabia. Their age, original renal disease, disease duration, hemodialysis duration, comorbid conditions and current medications are given in [Table 1]. The patients received hemodialysis thrice weekly for 3-4 hours per session at blood flow rates of 250-350 mL/min using polysulphone hollow-fiber filter (F7 HPS, Fresenius, Germany). The vascular acesses included native arteriovenous fistulas, artificial grafts or permanent catheters. The study patients were started on chronic hemodialysis for at least 6 months before enrollment to the study.
We excluded from the study patients with known bleeding disorders, anemia with hemoglobin levels less than 10 g/dL, recent trauma, surgery, infectious disease or hemorrhagic disorder (< 1 month) in addition to those receiving oral or other forms of anticoagulant therapy (e.g. warfarin, aspirin), or drugs that could affect heparin activity (e.g. tetracyclines, digitalis, and antihis-tamines).
Subjects continued their regular medications including lipid-lowering therapy and their diets were maintained throughout the trial. Body mass index (BMI) and serum albumin levels remained stable during the study. Human recombinant erythropoietin dose was administered where necessary to maintain target hemoglobin of 11-12 g/dL.
The patients were subjected to the following stages each lasted for 6 months duration:
The extracorporeal circuits were anticoagulated with UFH (sodium heparin 5000 IU/mL) administered as a bolus dose (50 IU/kg body weight) intravenously into the pre-dialyzer arterial line of the extracorporeal blood circuit, followed by a maintenance dose of 1000 IU heparin per hour. Infusion was discontinued 1 hour prior to cessation of HD. Activated coagulation times were monitored and maintained around 200 s early in the HD session and 150 s later in the session, and UFH dose was adjusted accordingly.
During this stage, the UFH was switched to Tinzaparin sodium (anti-Xa). The starting dose was 40-50% of the total UFH previously used according to manufacturer's instructions. The dose was modified in case of clotting or bleeding in steps of 500 IU until a satisfactory dose was obtained, and it was administered 3-4 min before dialysis as a bolus dose injected into the pre-dialyzer arterial line.
During each stage clinical clotting was evaluated by visual inspection after blood draining of the air trap every hour (1, no clotting in the trap; 2, fibrinous ring; 3, clot formation and 4, coagulated system) and by visual inspection of the dialyzer at the end of each session (1, clean filter; 2, a few blood stripes (affecting less than 5% of the fibers seen at the surface of the dialyzer); 3, many blood stripes (affecting more than 5% of the fibers) and 4, coagulated filter).
Blood specimens were obtained from the arterial line after lowering the blood flow to 100 mL/min for 1 min. Laboratory investigations for each patient included fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDL), Low-density lipoprotein cholesterol (LDL) and triglyceride concentrations (TG), which were measured on a high-throughput auto-analyser (Dimension X band) using reagents supplied by Dade Behring (Germany). Complete blood count, Kt/V was also measured before and after each stage of the anticoagulant protocols. The protocol was approved by the local ethical committee.
| Statistical Analysis|| |
All analysis was performed using the Statistical Package for Social Science (SPSS, Chicago) version 10.0 for windows. Variables are displayed as mean ± standard deviation (SD) unless otherwise stated. Chi-squared test was used to compare the prevalence of non-parametric variables, while differences between variables were analyzed by paired Student's t test or MannWhitney test as deemed appropriate. A P of < 0.05 was considered statistically significant.
| Results|| |
A total of 3312 HD sessions were studied in 23 patients over a period of 12 months. No changes in standard serum lipids (Total cholesterol, LDL, TG and HD lipoprotein), hemoglobin, WBCs count, and platelet count after changing from UFH to Tinzaparin sodium. However, there was statistically significant improvement in dialysis efficiency-evidenced by improved single pool Kt/V 6 months after switching to Tinzaparin (1.40 ± 0.28 for Tinzaparin versus 1.23 ± 0.28 for heparin, P= 0.008) without any change in the hemodialysis prescription [Table 2].
No clotting was observed in the air trap chamber in 10 and 14 patients, moderate clotting was observed in 12 and 8 patients, and mild clotting in 1 and zero patients during UFH and Tinzaparin stages respectively, (P= 0.04). No episodes of grade 4 (coagulated system) were observed in either treatment protocol [Table 3].
No clotting was observed in the dialyzers in 15 and 21 patients, moderate clotting in 1 and 2 patients, and mild clotting in 7 and no patients during UFH and Tinzaparin stages respectively (P= 0.001). No episode of grade 4 (coagulated filter) was observed in either treatment protocol [Table 4].
Tinzaparin use was accompanied by minor hemorrhage between dialyses in 3 patients after the first and second dialysis sessions of conversion from UFH, which was easily managed with dose reduction. The dose of Tinzaparin/ session (mean ± Sd) remained relatively constant with minor modification over the trial period [Figure 1].
The mean cost for the use of Tinzaparin/patient/6 months (67.57 ± 25.42 USD) was significantly higher compared to that for UFH (51.23 ± 23.91 UDS), P= 0.001 [Table 5].
| Discussion|| |
In our study, Tinzaparin was more effective than UFH over 1656 HD sessions evidenced by significantly less air trap and dialyzer clotting. This is in agreement with the observations of several investigators who have noticed similar beneficial effect of LMWH compared with UFH. ,,,
The annual cardiovascular disease mortality in end-stage renal disease (ESRD) patients on HD is 9.5%, which is 35 times higher than in the general population.  The characteristic perturbations in lipoprotein metabolism are considered as a cardiovascular risk factor in these patients.  Common dyslipidemic changes include increased in triglycerides levels, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), remnant lipoproteins, and lipoprotein-(a) besides decreased high density lipoprotein (HDL) cholesterol. 
The primary cause for the accumulation of triglyceride-enriched lipoproteins in patients on HD is a defective catabolism of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) and hepatic lipase (HL). LPL activity in post-heparin plasma of uremic patients was found to be lower than in healthy individuals,  probably due to reduced enzyme synthesis by the parenchymal cell secondary to peripheral insulin resistance and hyperparathyroidism, which both down-regulate synthesis of LPL;  decreased LPL activity may largely contribute to the generation of atherogenic dense LDL. 
Repeated administration of heparin for anticoagulation during HD causes depletion of LPL and may exhaust lipolytic capacity. LMWH was reported to release LPL from the vessel wall to a lesser extent.  Accordingly, the lipolytic potential will increase gradually over months if patients are switched from UFH to LMWH  .
Preliminary studies on LMWH suggested beneficial effects on the lipid metabolism in hemodialysis patients, but this has not been supported by later larger studies, at least in the short term. , In our study, we did not observe any significant improvement of any element of lipid profile 6 months after Tinzaparin therapy, which is in concordant with other studies. Kronenberg et al 1995  failed to observe any benefit on lipids in 153 HD patients treated with three different LMWH preparations (dalterparin, sandoparin and enoxaparin) and a similar number on UFH over at least 6 months, even after allowing for gender, age, and diabetes mellitus. In another study involving 36 patients using three LMWH preparations for 6 months, no effects on cholesterol or triglyceride concentrations were found.  A long-term study of Spaia et al 1994  of 30 HD patients switched from UFH to enoxaparin found significantly lower HDL and higher triglyceride concentrations after 33 months of the LMWH treatment. Noticeably, the lipid parameters returned to baseline in the 10 patients switched back to UFH for 6 months.
Furthermore, the beneficial effect of LMWH was reported not to occur with all preparations of LMW heparin, since heparin preparations with a relatively large heparin molecules do not appear to have an LPL activity.  In our study, values of Kt/V urea were significantly better 6 months after the use of Tinzaparin compared to UFH; To our knowledge this finding was not reported previously and can be explained by less microthrombi formation in the dialyzer that allows better blood flow and solute clearance.
Previous pharmacokinetic studies suggested that HD patients receiving LMWH during dialysis are at risk of bleeding up to 10 hours after the injection. In our study, no severe hemorrhagic complications were observed with the use of either heparin preparation, however moderate hemorrhagic events occurred in 3 patients early after switch to Tinzaparin therapy, which was easily managed with dose modification.
The total mean cost of Tinzaparin use as anticoagulant during HD in our study was 23%higher than that of UFH, which is in agreement with what was reported previously. 
Finally, limitations of our study included a relatively small study population, a short duration, and lack of a control group. Furthermore, it was not a specifically a dose-finding study. This study was performed with Tinzaparin and any generalization to other LMWH should be inferred with caution as the pharmacology of each LMWH is unique.
In conclusion, Tinzaparin should be considered as an effective, safe and may be a superior alternative to conventional heparin anticoagulation in hemodialysis patients. However, during the short-term Tinzaparin therapy, we did not observe any affect on lipid profile in these patients. Currently, the direct cost in KSA is a little more than standard heparin by about 23%. However, with more widespread usage, the price of Tinzaparin is likely to decrease and the small extra cost will be counterbalanced by the convenience of administration.
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Khalid A Al-Saran
Prince Salman Center for Kidney Disease, Riyadh
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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