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Anticoagulation therapy during haemodialysis: a comparativestudy between two heparin regimensAlaa Sabry, Moammer Taha, Mamdouh Nada, Fawzan Al Fawzanand Khalid Alsaran Low-molecular-weight heparins have been suggested as sodium use (1.40 W 0.28 tinzaparin sodium versus providing well tolerated, efficient, convenient and possibly 1.23 W 0.28 for UFH) without any change in the more cost-effective anticoagulation for haemodialysis than haemodialysis prescription. The total cost of 24-week use of unfractionated heparins (UFHs). A single-bolus dose at the tinzaparin sodium was 23% more expensive compared with start of haemodialysis effectively prevents clot formation in that of UFH. Tinzaparin sodium should be considered as an the dialyser and air trap with fewer side effects and possible effective, well tolerated and may be a superior alternative to benefits on uraemic dyslipidaemia. The safety, clinical conventional heparin anticoagulation in haemodialysis.
efficacy and cost of two anticoagulation regimens in 23 However, at least – on the short term – tinzaparin sodium haemodialysis patients were compared over 12-month therapy did not affect lipid profile in haemodialysis patients.
period. The study comprised two stages: the first stage in Currently, the direct cost in Saudi Arabia is a little more than which UFH was used for 6 months and the second stage in standard heparin by about 23%. Blood Coagul Fibrinolysis which UFH was replaced by tinzaparin sodium. The 20:57 –62 ß 2009 Wolters Kluwer Health | Lippincott relationship between the anticoagulant effect of tinzaparin sodium and clinical clotting during haemodialysis was recorded. Clinical clotting (grades 1– 4) was evaluated byvisual inspection after blood draining of the air trap every Blood Coagulation and Fibrinolysis 2009, 20:57–62 hour and by inspection of the dialyser after each session.
The costs and effects of both anticoagulant protocols on the Keywords: anticoagulation, haemodialysis, lipids, low-molecular-weight lipid profile were also compared. Anticoagulation with tinzaparin sodium resulted in less frequent dialyser and air- Prince Salman Center for Kidney Disease, Riyadh, Saudi Arabia trap clotting compared with UFH (P U 0.001 and 0.04, Correspondence to Dr Alaa Sabry, Prince Salman Center for Kidney Disease, respectively). Over 24 weeks, no changes in standard serum lipid profiles were observed. There was statistically significant improvement in dialysis adequacy – evidenced Received 27 April 2008 Revised 20 July 2008 by improved single-pool Kt/V 6 months after tinzaparin LMWHs do not deplete plasma lipase to the same extent Haemodialysis requires anticoagulation to avoid clotting as UFHs however, their effect on uraemic dyslipi- of the dialyser and extracorporeal circuit. Hitherto, the daemia is controversial with some but not all anticoagulation regimen has consisted of an intravenous (i.v.) bolus dose of unfractionated heparin (UFH) fol-lowed either by i.v. continuous infusion or a new bolus Although there are several reported studies comparing a dose during dialysis. However, low-molecular-weight variety of LMWHs with UFHs in haemodialysis patients, heparins (LMWHs) are being frequently used as they experience with tinzaparin sodium is limited. In this cross- were reported to have several potential advantages over over study, we compared the clinical efficacy, safety and UFHs The risk of bleeding is lower with LMWHs cost effectiveness of tinzaparin sodium with UFH in 23 than with UFHs as LMWHs interact less with platelets chronic renal failure patients stabilized on haemodialysis.
and the vessel wall The risk of heparin-inducedthrombocytopaenia is also less In addition, the admin- istration is practical, and the effect on the blood lipids may be more favourable LMWHs act longer than Twenty-three adult patients (17 men and six women) UFHs and can be given as a single-bolus injection at with end-stage renal disease (ESRD) maintained on the start of the dialysis session. LMWHs are as effective as UFHs in preventing thrombosis in animal models andcause less blood loss than UFHs. However, these findings Patients received haemodialysis thrice weekly for 3–4 h have not been confirmed in clinical studies per session at blood flow rates of 250–350 ml/min, with a 0957-5235 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
polysulphone hollow-fibre filter (F7 HPS; Fresenius, prior to cessation of haemodialysis. Activated coagulation Germany). Vascular access was via a native arteriovenous times were monitored and heparin dose was modified fistula, an artificial graft or permanent permcath, patients accordingly to maintain times around 200 s early in the were older than 18 years and chronic haemodialysis was haemodialysis session and 150 s later in the session.
Patients with known bleeding disorders, anaemia with During this stage, 1656 haemodialysis sessions were haemoglobin (Hb) level below 10 g/dl, recent trauma, carried out, the anticoagulation profile was changed to surgery, infectious disease or haemorrhagic disorders tinzaparin sodium. The starting dose was calculated as (<1 month), receiving oral or other forms of anticoagulant 40–50% of the total UFH previously used during the first therapy (e.g. warfarin, aspirin) or drugs that could affect stage, according to manufacturer’s instruction. The dose heparin activity (e.g. tetracyclines, digitalis and antihis- was modified (increased or decreased) in case of clotting or bleeding in steps of 500 anti-Xa IU until a satisfactorydose is obtained. It was administered 3–4 min before Patients continued their usual medication (including dialysis as a bolus dose, injected into the arterial line lipid-lowering therapy in some) and were treated in predialyser. Anticoagulation was monitored by visual the normal manner. Moreover, the individual diet habit inspection of the arterial air trap every 30–60 min.
was maintained throughout the trial that prevented anysignificant change in the BMI and serum albumin level.
Laboratory estimations and blood sampling Human recombinant erythropoietin dose was given when Blood specimens were taken from the arterial line after necessary to maintain target haemoglobin of 11–12 g/dl.
lowering the blood flow to 100 ml/min for 1 min.
They were subjected to two stages, in each stage, a different anticoagulation regimen during haemodialysis Total cholesterol (TC), high-density lipoprotein choles- was used (each stage was of 6 months duration).
(LDL-c) and triglyceride concentrations were measured on a high-throughput autoanalyser (Dimension X band) During this stage, 1656 haemodialysis sessions were using reagents supplied by Dade Behring (Eschborn, carried out, the anticoagulation regimen consisted of Germany). Complete blood count, single pole Kt/V was UFH (sodium heparin 5000 IU/ml) administered as a also measured before and after each stage of the anti- bolus dose (50 IU/kg body weight) i.v. into the predia- coagulant protocol. The protocol was approved by our lyser arterial line of the extracorporeal blood circuit at the start of haemodialysis, followed by a maintenance dose of1000 IU heparin per hour. Infusion was discontinued 1 h Clinical clottingDuring each stage, clinical clotting was evaluated by Demographic criteria for 23 patients included in our study visual inspection of air trap after blood draining everyhour. Air-trap clotting was graded from 1 to 4 (grade 1, no clotting in the trap; grade 2, fibrinous ring; grade 3, clot formation and grade 4, coagulated system) by visual inspection of the dialyser at the end of each session.
Dialyser clotting was graded from 1 to 4 [grade 1, clean filter; grade 2, a few blood stripes (affecting less than 5% of the fibres seen at the surface of the dialyser); grade 3, many blood stripes (affecting more than 5% of the fibres) Variables are given as mean Æ SD unless otherwise stated. Chi-squared test was used to compare the pre- valence of nonparametric variables, whereas differences between variables were analysed by paired Student’s t test or Mann–Whitney test as deemed appropriate. A P value of less than 0.05 was considered statistically significant. All analysis was performed using the Statis-tical Package for Social Science (SPSS, Inc., Chicago, CHF, congestive heart failure; DM, diabetes mellitus; HTN, hypertension; IHD,ischaemic heart disease.
Illinois, USA) version 10.0 for Windows.
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Anticoagulation therapy during haemodialysis Sabry et al.
Comparison between unfractionated heparin (UFH) and A total of 3312 haemodialysis sessions were studied in 23 tinzaparin regarding air-trap clotting grades patients over a period of 12 months.
Our study included 23 patients (17 men and six women).
Their age, original renal disease, disease duration, hae-modialysis duration, comorbid conditions and currentmedications are given in patients and grade 3 clotting in seven patients duringUFH (P ¼ 0.001). No episode of grade 4 clotting (coagulated No statistically significant differences were observed filter) was observed in either treatment protocol (as regarding standard serum lipids (TC, LDL-c, triglyceride and HDL-c), Hb, white blood cells count and plateletcount after changing from UFH to tinzaparin sodium Tinzaparin sodium use was accompanied by minorhaemorrhage between dialyses in three patients after the first and second dialysis session. Prolonged bleeding To determine whether the type of anticoagulation had from the arteriovenous fistula (AVF) puncture sites in two any effect on dialyser uraemic solute clearance single- patients that necessitated prolonged compression and pool Kt/V urea values were obtained. There was statisti- protamine sulphate infusion, epistaxis in the third patient cally significant improvement in dialysis adequacy – was managed by anterior nasal pack. These events did evidenced by improved single-pool Kt/V 6 months after tinzaparin sodium use (1.40 Æ 0.28 for tinzaparin sodiumuse versus 1.23 Æ 0.28 6 months after UFH use, P ¼ 0.008) without any change in the haemodialysis pre- The mean cost of use of tinzaparin sodium/patient for 6 months (67.57 Æ 25.42 US$) was significantly higher ascompared with that of UFH (51.2263 Æ 23.91 US$), Air-trap clottingGrade 1 clotting was observed in 10 and 14 patients, whereas grade 2 clotting was observed in only one patient The mean dose of tinzaparin sodium per session remains and grade 3 clotting was observed in 12 and eight patients relatively constant with minor modification over the trial during UFH and tinzaparin sodium use, respectively (P ¼ 0.04). No episode of grade 4 clotting (coagulatedsystem) was observed in either treatment protocol (as LMWHs are derivatives of commercial UFHs preparedby enzymatic or chemical hydrolysis. They have been prepared to have a mean molecular weight of 4000– Grade 1 clotting was observed in 15 and 21 patients, 5000 Da (the mean molecular weight of UFHs ranged whereas grade 2 clotting was observed in one and two from 10 000–16 000 Da). Like UFHs, LMWHs inactivate Biochemical criteria for 23 patients included in our study P1, between starting and 6 months after UFH; P2, 6 months after switching to tinzaparin. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; UFH, unfractionated heparin; WBCs, white blood cells. M Statistically significant.
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Comparison between unfractionated heparin and tinzaparin regarding dialyzer clotting grades Heparin and tinzaparin dose/
session over 6 months
factor Xa, but they have a lesser effect on thrombin session (units mean SD)
because most of the molecules do not contain enough saccharide units to bind to form the ternary complex in which thrombin and anti-thrombin III are bound simul-taneously. LMWHs have been proposed to cause less Doses of tinzaparin and unfractionated heparin/session over 6 months bleeding and less thrombocytopaenia than UFHs. On the contrary, LMWHs were reported to be expensive andhave generally not been found to be superior to UFHs interms of dialysis-related bleeding or other complications.
The annual cardiovascular disease mortality in ESRDpatients on haemodialysis is 9.5%, which is 35 times UFH has been the established anticoagulant for haemo- higher than in the general population . The charac- dialysis for several decades. However, in the past 15 years, teristic perturbations in lipoprotein metabolism are con- many reports on the use of LMWH for anticoagulation in sidered as a risk factor for high cardiovascular mortality general, and for haemodialysis in particular, have been rates in these patients . Common dyslipidemic published There is consistency among these studies changes include increases in triglycerides, very low- regarding their beneficial anticoagulant effects , density lipoproteins (VLDLs), intermediate-density nevertheless there is no consensus on their favourable lipoproteins (IDLs) and remnant lipoproteins, increases effects on the lipid profile in such category of patients.
Although the benefits of LMWH over standard UFH in The primary cause for the accumulation of triglyceride- the treatment and prophylaxis of venous thromboembo- enriched lipoproteins and atherogenic-dense LDLs in lism are well established, the relative merits of LMWH patients on haemodialysis is not fully understood. In for haemodialysis coagulation are less clear. The ease ESRD patients, decreased lipoprotein lipase (LPL) administration of LMWH (single-bolus predialysis) activity may largely contribute to the generation of and lack of laboratory monitoring would seem clear atherogenic-dense LDLs . Repeated administration of heparin for anticoagulation during haemodialysiscauses depletion of LPL and may exhaust lipolytic The primary purpose of anticoagulation during haemo- capacity, whereas LMWH was reported to release LPL dialysis is of course the prevention of thrombosis in the from the vessel wall to a lesser extent . As a result, extracorporeal circuit, and in this respect, in our study lipolytic potential are expected to increase gradually over tinzaparin sodium was more effective than UFH – over months with subsequent beneficial effects on atherogenic 1656 haemodialysis sessions – evidenced by significantly lipid particles if patients are switched from UFH to less air trap and dialyser clotting. This is in agreement with the observations of several investigators who havenoticed similar beneficial anticoagulant effect of LMWH Preliminary studies with LMWH suggested beneficial effects on the lipid metabolism of haemodialysis patients,but this has not been supported by later larger studies, atleast in the short term Comparison between unfractionated heparin and tinzaparin regarding cost, air-trap and dialyzer clotting In our study, we did not observe significant improvement on lipid metabolism of any element of lipid profile6 months after tinzaparin sodium therapy, which is in agreement with other studies. Kronenberg et al. failed to observe any beneficial effects on lipid profile in 153 haemodialysis patients treated with three different LMWH preparations (dalteparin, sandoparin and enox- a Values are given in mean Æ SD. M Statistically significant.
aparin) compared with a similar number of patients Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anticoagulation therapy during haemodialysis Sabry et al.
treated with UFH over at least 6 months, even after lysis in our study was 23% higher than that of UFH, allowing for sex, age and diabetes mellitus.
which is in agreement with previous reports Hombrouckx et al. reported no beneficial effects on The major limitations of our study include the relatively cholesterol or triglyceride concentrations using three small study population, the short duration, it was not LMWH preparations in a month study that included specifically a dose-finding study and including also 36 patients. Furthermore, in a longer term study carried patients with diabetes mellitus, as well as the lack of a out by Spaia et al. including 30 haemodialysis control group, and finally the lack of factor X level assay patients who switched from UFH to enoxaparin, a sig- during the second stage of the study.
nificantly lower HDL and higher triglyceride concen-trations after 33 months of the LMWH treatment was The present study was performed with tinzaparin sodium observed. Of note is that the lipid parameters returned and any generalization to other LMWH should be to baseline in the 10 patients switched back to UFH for inferred with caution as the pharmacology of each 6 months. In the latter two studies mentioned above, enoxaparin was given both as an initial bolusand as a continuous infusion during the haemodialysis session. It is therefore possible that differences in Tinzaparin sodium should be considered as effective and the mode of administration may have a bearing on well tolerated and may be a superior alternative to differences found between studies In our study, conventional heparin anticoagulation in haemodialysis.
tinzaparin sodium was administered as a bolus dose However, at least – on the short term – tinzaparin sodium prior to haemodialysis. An important point in relation therapy did not improve lipid profile in haemodialysis to our lipid findings should be noted; care was taken not patients. Currently, the direct cost in Saudi Arabia is a to alter any of the patients’ lipid-lowering therapies or little more than standard heparin by about 23%. How- ever, with more widespread usage, the price of tinzaparinsodium is likely to reduce and the small extra cost is However, it should be noted that the beneficial effect of counterbalanced by the convenience of administration.
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“HEARTLESS EXPLOITATION OF THE POOR AND SUFFERING”? Note: Center Discussion Papers are preliminary materials circulated to stimulate Abstract The decision to require that countries grant product patents for pharmaceutical innovations as a condition of membership in the World Trade Organization was verycontentious. Almost fifty developing countries were not granting patent monopolies for

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English books 1. Kaku K, Matsuda M, Kaneko T, Permutt MA: Genetic analysis of diabetic susceptibility in inbred mouse strains. In Tai Hee Lee (Ed) Recent advances in insulin therapy pp.127㹼 130, Springer International (Heidelberg, Germany), 1990. 2. Matsuda M, DeFronzo RA : In vivo Measurement of Insulin Sensitivity in Human Clinical Research in Diabetes and Obesity In Draznin B, Rizza R (Ed)

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