TINZAPARIN (INNOHEP ), A LOW-MOLECULAR-WEIGHT HEPARIN, REDUCES COMPLICATIONS OF STANDARD HEPARIN IN HEMODIALYSIS PATIENTS

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1 Original Article 151 TINZAPARIN (INNOHEP ), A LOW-MOLECULAR-WEIGHT HEPARIN, REDUCES COMPLICATIONS OF STANDARD HEPARIN IN HEMODIALYSIS PATIENTS CHENG-HSU CHEN *,***,****, CHI-HUNG CHENG *,**,***, MING-JU WU *,**, KUO-JUNG CHEN *, WEN-CHIN LEE *, KUO-HSIUNG SHU *,** Background: Low-molecular-weight heparin has successfully been used as anticoagulants during hemodialysis and its beneficial effect is well documented. However, the use of this preparation was still very limited in Taiwan. Our study compared tinzaparin (Innohep ), a low-molecular-weight heparin, with conventional heparin (CH) during maintenance hemodialysis for a 12-week period. Methods: Forty patients with chronic renal failure on maintenance hemodialysis for more than 3 months were enrolled in this study. The average duration of dialysis sessions was 12.2±1.4 h/week, the blood flow was more than 250 ml/min, the Kt/V was above 1.2 and bicarbonate dialysate was used. Patients were divided into two groups. For the conventional heparin (CH, n=20) group, heparin was administered as a bolus dose (50 IU/Kg body weight) intravenously into the pre-dialysis arterial line of the extracorporeal blood circuit, followed by a maintenance dose of sodium heparin 500 IU per hour, while for the tinzaparin (IH, n=20) group, 2,000 IU of IH as a bolus was administered without maintenance dose. The dosage of both groups was adjusted according to clinical indications. Clinical adverse effects and laboratory data were collected at Week 0 and Week 12 for analysis. Results: Five patients were excluded for analysis (3 in CH and 2 in IH). There was no significant difference in initial platelet count between the CH group (176.4± /l) and the IH group (193.9± /l, P=0.166) at Week 0, but the platelet count of the IH group (208.5± /l) was higher than that of the CH group (176.4± /l, P=0.028) at Week 12. Comparison of the lipid profiles revealed no significant difference in triglyceride (TG) between the CH group (220.9±154.3 mg/dl) and the IH group (193.9±60.9 mg/dl, P=0.244) at Week 0. However, it was significantly higher in the CH group (211.5±116.6 mg/dl) than in the IH group (155.5±52.0 mg/dl, P=0.036) at Week 12. Similar effect was found for cholesterol. There was no significant difference between the CH group (172.1±28.2 mg/dl) and the IH group (180.9±30.5 mg/dl, P=0.135) at Week 0, but significantly higher level was found in the CH group (187.8±31.4 mg/dl) than the IH group (167.7±33.5 mg/dl, P=0.026) at Week 12. There were no increased incidence of dialyser clotting and bleeding tendency in the IH group. Conclusions: A single dose of IH is effective and safe in chronic hemodialysis patients, with a preferable lipid profile and platelet count as compared with CH. (Acta Nephrologica 2004; 18: ) Key words: Low-Molecular-Weight Heparin; Hemodialysis; Hyperlipidemia; Thrombocytopenia INTRODUCTION In the absence of an anticoagulant, hemodialysis performed with extracorporeal circulation will activate the blood coagulation system to generate fibrin clot and platelet aggregation, resulting in widespread clotting within the dialyser and tubing. This has effectively prevented the use of heparin since the late 1930s. Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan* Division of Nephrology, Chung Shan Medical University Hospital, Taichung, Taiwan** Department of Biotechnology, Hung Kuang University***, Department of Life Science, Tunghai University**** Received: July, 2004 Revised: April, 2005 Accepted: June, 2005 Address reprint requests to Dr. Kuo-Hsiung Shu, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, 160, sec. 3 Chung-Kang Road, Taichung, Taiwan Tel: ext Fax: khshu@vghtc.vghtc.gov.tw

2 152 C. H. CHEN, C. H. CHENG, M. J. WU, K. J. CHEN, W. C. LEE, K. H. SHU Vol. 18, No. 4, 2004 Despite its efficacy and safety, standard unfractionated heparin (UFH) has drawbacks in the lipid profile and platelet count, i.e., hypertriglyceridemia, and thrombocytopenia. Low-molecular-weight heparins (LMWH) are being frequently used as they have several potential advantages over UFH. 1,2 The pharmacokinetics of heparin differs markedly from those of its fractions both in human and in experimental animal models. 3 The bioavailability of heparin fractions has proved to be much greater than heparin after subcutaneous or intraperitoneal administration. Most of the lowmolecular-weight heparin fractions exhibit sustained antiprotease and antithrombotic actions. 3 The pharmacokinetics of the specific anti-iia and anti-xa actions of heparin and its fractions is dependent on the molecular composition of these agents. Even if the fractions are standardized for identical potencies by the in vitro assays, the elimination rates of anti-xa and anti-iia actions are significantly different for each fraction. The antithrombotic actions of heparin and its fractions also vary widely in the rabbit stasis thrombosis model. Different fractions show variable antithrombotic actions against defined thrombogenic challenges. 13,17 Heparin preparations of low molecular weight have efficient antithrombotic properties and such preparations have successfully been used as anticoagulants during hemodialysis and the beneficial effect of this procedure is well documented. Tinzaparin (Innohep [IH], Leo Pharmaceutical Corp.) is a LMWH with an average molecular weight of 4500 daltons. It is produced through controlled enzymatic depolymerisation of sodium heparin from porcine intestinal mucosa. IH potentiates the inhibition of coagulation factor Xa and affects only slightly thrombin inhibition and clotting time e.g. APTT. The antithrombotic effect of IH is correlated with the inhibition of factor Xa. Peak activity of IH appears at 4 to 6 hours after administration. The half-life after intravenous injection in healthy volunteers is 2 hours compared with 1-2 hours with intravenous injection of heparin. Thus, one rationale for using LMWH, as an alternative to conventional heparin, would be simplified routines for heparinization due to a longer half-life. LMWH has efficient antithrombotic properties and such preparations have successfully been used as anticoagulants during hemodialysis and the beneficial effect of this procedure is well documented, but its use in Taiwan is still limited. Our study compared tinzaparin (IH) with conventional heparin (CH) during maintenance hemodialysis for a 12-week period. The efficacy and safety as well as complications of a single dose of IH were observed. SUBJECTS AND METHODS Patients Forty patients with chronic renal failure on chronic hemodialysis for more than 3 months were enrolled for this study. They were randomly selected into the CH (N=20) and IH group (N=20). The mean age was 58.5±13.2 years (range: years). The average duration of dialysis sessions was 12.2±1.4 h/week (range: h/week). In all the patients, the blood flow was more than 250 ml/min, and the Kt/V was more than 1.2. Bicarbonate dialysate with a calcium concentration of 3.5 mmol/l was used. The exclusion criteria were: pregnancy, breast feeding, known hemorrhagic diathesis, platelet count < /l, known proliferative diabetic retinopathy, abnormal liver function (AST > 40 IU/L, ALT > 44 IU/L), marked hyperlipidemia (cholesterol > 300 mg/dl, triglyceride > 500 mg/dl), known hypersensitivity to heparin or tinzaparin, reluctance to participate in the trial, any clinical condition which in the opinion of the physician-in-charge would not allow safe fulfillment of the protocol, and the dialysis treatment for more than 3 times per week, already included in another study. The antihyperlipidemia agents were discontinued 2 weeks before the enrollment. The erythropoietin (EPO) was administered as usual to keep hematocrit (Hct) in the range of 27 to 36%. Written informed consent was obtained from each patient before enrollment. Method In the CH group, conventional heparin (sodium heparin [CH], 5000 IU/ml, Leo Pharmaceutical Corp.) was administered as a bolus dose (50 IU/Kg body weight) intravenously into the arterial line of the extracorporeal blood circuit, followed by a maintenance dose of 500 IU per hour. Activated coagulation time (ACT) was monitored to maintain at around 150 seconds later in the session. In the IH group, 2,000 IU of IH was given as a bolus through intravenous injection into the patient via the vascular access system at the start of each HD. The dosage was adjusted within 5-10% dosage according to clinical indications. Assessment of clotting Clotting in the dialyser was recorded by visual inspection of fibrin deposits in the venous drip chamber at the end of dialysis when blood had been returned to the patient by flushing the dialyser with normal saline. Visible clotting is estimated and recorded using an arbitrary four-grade scale (0-III), with Grade 0 indicating no clot formation, Grade I with mild clotting, Grade II with moderate clotting and Grade III with total occlusion.

3 Acta Nephrologica LMWH reduces complications in HD patients 153 Assessment of bleeding After each dialysis, a gentle manual pressure was applied to the puncture sites, which were inspected every 2, 5, 10, 15 and 20 minutes until bleeding is stopped. The post-hd vascular access compression time until cessation of bleeding was recorded. Bleeding complication was assessed as slight when bleeding was stopped within 15 minutes after initial manipulation (compression and discontinued IH or CH); moderate when bleeding was persistent but no more than 1 hour, and severe when bleeding necessitated the suspension of HD, blood transfusion, surgical intervention or other invasive procedure. The bleeding complication was further classified as intra-dialytic and inter-dialytic according to the time of occurrence. Laboratory assessment Blood samples were drawn before dialysis from the afferent fistula needle at baseline (Week 0) and the end of study (Week 12). These samples were analyzed for hemoglobin, platelet count, triglyceride (TG) and cholesterol (Chol), AST and ALT, albumin (Alb). The adequacy of clearance was evaluated by calculating KT/ V (Lowrie formula). Statistics Analyses were performed with the Statistical Package for Social Sciences statistical software (SPSS standard version 10.0; Chicago, IL). The results of continuous variables were given as mean ± SD (standard deviation). The non-continuous variables were presented as percentage in the groups. A Student s t test was used for comparisons of continuous variables before and at the end of study. The Chi-square test was used for the analysis of non-continuous variables. A value of P < 0.05 was considered to be statistically significant. A forward stepwise multiple regression analysis was used to identify risk factors of hypertriglyceridemia and hypercholesterolemia. Results Five patients were excluded for analysis (3 in CH and 2 in IH) during this study. Two were excluded due to peptic ulcer bleeding (1 in CH and 1 in IH), one due to acute pancreatitis (CH), one received renal transplantation (CH) and one due to anxiety (IH). The demographic data of patients were shown in Table 1. There were no significant differences between these two groups. The heparin dose prior to the study was similar in both groups (IH: ±375.0 units vs CH: ±216.4 units; p=0.122) (Table 1). During the 1260 HD sessions (612 sessions of CH and 648 of IH), no vascular accesses occlusion was observed. According to the hemostatic profile that was shown in Table 2, five (29%) patients and four (22%) patients from the CH group needed to increase and decrease heparin dose, respectively; which are not significantly different from those in the IH group (increase: 4 (22%) and decrease: 5 (28)%; p=0.773). The postdialysis compression time until cessation of bleeding was 9.75±4.13 min (range 5-15 min) in the CH group and 9.25±3.73 min (range 5-15 min) in the IH group (p=0.345). Total occlusion of dialyser (Grade III) was observed in two sessions (0.33 %) of treatment in the CH group and four sessions (0.62%) in the IH group (p=0.503). All of them occurred during the initial titration period. No total occlusion of dialyser occurred beyond Week 4 in both groups. Overall, 72.2% of all Table 1. Demographics of standard heparin (CH) and tinzaparin (IH) groups CH (n=17) IH (n=18) P Age (yrs) 60.9± ± Gender (M/F) 7/10 9/ BMI (kg/m2)a 22.3± ± HD duration (yrs) 5.6± ± Cause of ESRD Diabetic nephropathy (%) 7 (41.2) 7 (38.9) Others (%) 13 (76) 11 (61) Blood flow (ml/min) 283.4± ± EPO (units/week) ± ± Heparin dose before study (IU/session) ± ± Average dose of heparin (IU/ session) ±357.4 Average dose of IH (IU/session) ±276.2 Categorical variables were analyzed by Chi-Square test Continuous variables were analyzed by independent Student s t test a Body mass index (BMI): body weight/height 2 (kg/m 2 )

4 154 C. H. CHEN, C. H. CHENG, M. J. WU, K. J. CHEN, W. C. LEE, K. H. SHU Vol. 18, No. 4, 2004 dialysis sessions with IH and 70.6% of sessions with CH had no visible clots in the dialysers (Fig. 1). The final dosage of heparin was ±357.4 IU/session for the CH group, and ±276.2 IU/session for the IH group. Both pre- and post-study laboratory data were shown in Table 3. While there was no significant difference at the beginning between the two groups, a significantly lower platelet count (176.4± /l vs ± /l, p=0.028, CH vs IH), higher serum triglyceride (211.5±116.6 mg/dl vs 155.5±52.0 mg/dl, P= 0.036) and higher serum cholesterol (187.8±31.4 mg/ dl vs 167.7±33.5 mg/dl, P=0.026) were found in the CH group at the end of the study (Table 2). In multiple regression analysis, hypertriglyceridemia showed no correlation with age, gender, HD duration and BMI. Instead, it was related to diabetes (r 2 =0.759, P<0.05) and use of CH (r 2 =0.757, P<0.05). Hypercholesterolemia was also correlated with diabetes (r 2 =0.528, P<0.05) and use of CH (r 2 =0.856, P<0.05). DISCUSSION Heparin is a mucopolysacccharide comprising D- glucuronic acid and D-glucosamine, both suphated, in 1,4-linkage, with a spread of molecular weights of between 6000 and daltons (mean daltons). Although standard heparin can be safely and effectively used on HD patients for decades, it is still associated with complications of platelet dysfunction, thrombocytopenia, lipid abnormalities, allergic reactions, osteoporosis and increased risk of hemorrhage following long-term use The LMWH have molecular weights in the range (mean daltons), depending on the preparation. Because different LMWHs have different size profiles, the activities with respect to plasma antithrombin III, Factors Xa and Factor IXa were also different. The various preparations available on market are thus not exactly interchangeable. In this study, we found that a single dose of IH was as effective as standard sodium heparin with similar hemostatic profile and side effects. Similar results have been obtained in previous reports The initial dose of IH was 2000 IU, which was equivalent to approximately 37 IU/Kg. This dose is far below 75 IU/ Kg that had been reported in a previous study. 4 Similarly, the average dosage of sodium heparin (3008.3±357.4 IU/session) was also lower than that suggested in western countries. 16,17,18 It is likely that such difference can be attributed to ethnic factor. One of our patients in the IH group developed peptic ulcer bleeding at Day 5 of the study with a dose of 2000 IU/session despite an acceptable ACT (118 seconds). Therefore, caution should be taken in patients with previous history of peptic ulcer disease, even with an average dose of IH. In our study, we found that the platelet count was significantly higher in the IH group than in the CH group at Week 12. Among patients who received therapeutic courses of heparin, 1-3% would develop anti- Fig. 1. requency of clot formation (%) in dialyser, Grade 0 (clot-free) and Grade I (mild clotting) were more common in the IH group, but there was no significant difference between the two groups.

5 Acta Nephrologica LMWH reduces complications in HD patients 155 Table 2. Hemostatic profile, side effects and dosage adjustment. CH (n=17) Tinzaparin (n = 18) P value Bleeding Intradialytic period Slight 1 (5.9) 2 (11.1) Moderate 1 (5.9) 1 (5.5) Severe 0 (0.0) 0 (0.0) Interdialytic period Slight 1 (5.9) 1 (5.5) Moderate 1 (5.9) 0 (0.0) Severe 0 (0.0) 0 (0.0) Initial Hct (mg/dl) 30.1 ± ± Final Hct (mg/dl) 30.9 ± ± Episodes of total occlusion (%) (Grade III) 2 (0.33) 4 (0.62) Post-dialysis compression (min) 9.25 ± ± Dose adjustment Increased 4 (22%) 5 (29%) Decreased 5 (28%) 4 (22%) Pruritus 0 (0.0) 1 (5.5) Figures in parentheses are percentage. Table 3. Laboratory data analysis at Week 0 and Week 12 between standard heparin (CH) and Innohep (IH) groups Week 0 Week 12 CH (n=17) IH (n=18) P CH (n=17) IH (n=18) P WBC (10 3 cumm -1 ) 6.20± ± ± ± Hb (mg%) 9.9± ± ± ± Hct (%) 30.1± ± ± ± Platelet (10 9 /l) 176.4± ± ± ± Albumin (mg/dl) 4.1± ± ± ± GOT (IU/L) 20.0± ± ± ± GPT (IU/L) 20.4± ± ± ± Cholesterol (mg/dl) 172.1± ± ± ± Triglyceride (mg/dl) 220.9± ± ± ± KT/V 1.45± ± ± ± URR 0.76± ± ± ± TACurea (mg/dl) 44.6± ± ± ± body-mediated thrombocytopenia, 19,20 and 30-70% of these patients will develop potentially life-threatening bleeding. These patients usually developed antibodies that recognize complexes formed by platelet factor 4 and heparin LMWH binds less to plasma proteins, platelets, and the endothelium as compared with standard heparin, which may improve their bioavailability and reduce the extent of thrombocytopenia. 4 Uremia per se is associated with dyslipidemia, which is a potential risk factor of atherosclerosis in hemodialysis patients. LMWH does not stimulate plasma lipase activity to the same extent as unfractionated heparin. 5 However, their effect on uremic dyslipidemia is still controversial, 6 with some 7-10 but not all studies noting a beneficial effect. Our study revealed that both triglyceride and cholesterol were significantly lower in the IH group. Whether this may be extrapolated to a reduction in cardiovascular complications remains to be tested in a long-term follow-up. In conclusion, a single dose of IH appears to be effective and safe in patients on maintenance hemodialysis. The procedure of anticoagulation with IH is simple and easy. The beneficial effect on platelet count and lipid profile makes it a better drug of choice

6 156 C. H. CHEN, C. H. CHENG, M. J. WU, K. J. CHEN, W. C. LEE, K. H. SHU Vol. 18, No. 4, 2004 for anticoagulation during hemodialysis. ACKNOWLEDGEMENTS We wish to thank Leo Pharmaceutical Corp. who supports this clinical trial of tinzaparin (Innohep ). The author is grateful to the Biostatistics Task Force of Taichung Veterans General Hospital for their assistance in statistical analysis. REFERENCES 1.Ljungberg B, Jacobson SH, Lins LE, Pejler G: Effective anticoagulation by a low molecular weight heparin (Fragmin) in hemodialysis with a highly permeable polysulfone membrane. Clin Nephrol 1992; 38: Suzuki T, Ota K, Naganuma S, et al: Clinical application of Fragmin (FR-860) in hemodialysis: multicenter cooperative study in Japan. Semin Thromb Hemost 1990; 16: S Harenberg J, de Vries JX, Weber E, Zimmermann R: Effect of low-molecular heparin on blood coagulation. Dtsch Med Wochenschr. 1984; 109: Bates SM, Weitz JI: The new heparins. Coron Artery Dis 1998; 9: Persson E, Nordenstrom J, Nilsson-Ehle P, Hagenfeldt L: Lipolytic and anticoagulant activities of a low molecular weight fragment of heparin. Eur J Clin Invest 1985; 15: Stenvinkel P: Low molecular weight heparin does it favourably affect lipid levels? Nephrol Dial Transplant 1995; 10: Schrader J, Stibbe W, Armstrong VW, et al: Comparison of low molecular weight heparin to standard heparin in hemodialysis/hemofiltration. Kidney Int 1988; 33: Deuber HJ, Schulz W: Reduced lipid concentrations during four years of dialysis with low molecular weight heparin. Kidney Int 1991; 40: Yang C, Wu T, Huang C: Low molecular weight heparin reduces triglyceride, VLDL and cholesterol/hdl levels in hyperlipidemic diabetic patients on hemodialysis. Am J Nephrol 1998; 18: Schmitt Y, Schneider H: Low-molecular-weight heparin (LMWH): influence on blood lipids in patients on chronic haemodialysis. Nephrol Dial Transplant 1993; 8: Stefoni S, Cianciolo G, Donati G, et al: Standard heparin versus low-molecular-weight heparin. A medium-term comparison in hemodialysis. Nephron 2002; 92: Kronenberg F, Konig P, Lhotta K, Steinmetz A, Dieplinger H: Low molecular weight heparin does not necessarily reduce lipids and lipoproteins in hemodialysis patients. Clin Nephrol 1995; 43: Kronenberg F, Konig P, Neyer U, et al: Influence of various heparin preparations on lipoproteins in hemodialysis patients: a multicentre study. Thromb Haemost 1995; 74: Ryan KE, Lane DA, Flynn A, Shepperd J, Ireland HA, Curtis JR: Dose finding study of a low molecular weight heparin, Innohep, in haemodialysis. Thromb Haemost 1991; 66: Simpson HK, Baird J, Allison M, et al: Long-term use of the low molecular weight heparin tinzaparin in haemodialysis. Haemostasis 1996; 26: Egfjord M, Rosenlund L, Hedegaard B, et al: Dose titration study of tinzaparin, a low molecular weight heparin, in patients on chronic hemodialysis. Artif Organs 1998; 22: Pedersen PC, Ostergaard PB, Hedner U, Bergqvist D, Matzsch T: Pharmacokinetics of a low molecular weight heparin, logiparin, after intravenous and subcutaneous administration to healthy volunteers. Thromb Res 1991; 61: Hainer JW, Sherrard DJ, Swan SK, et al: Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis. Am J Kidney Dis 2002; 40: Schmitt BP, Adelman B: Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci 1993; 305: Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: Amiral J, Bridey F, Dreyfus M, Vissoc AM, Fressinaud E, Wolf M, Meyer D: Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: Pouplard C, Amiral J, Borg JY, Laporte-Simitsidis S, Delahousse B, Gruel Y: Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1999; 111: Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C: Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: Arepally G, Reynolds C, Tomaski A, Amiral J, Jawad A, Poncz M, Cines DB: Comparison of PF4/heparin ELISA assay with the 14C-serotonin release assay in the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1995; 104: