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Issues of low molecular weight heparin use in hemodialysis patients
William E. Dager, Pharm.D., FCSHP
December, 2006
When assessing removal of any drug in renal failure requiring hemodialysis, the type of renal failure should be considered. In acute renal failure (ARF), drug removal may depend on degree of residual renal function and presence of continued kidney metabolic function. In addition, renal function and drug removal may constantly change on a moment-to-moment bases, creating challenges in predicting long-term drug elimination and dosing regimens. The approach to hemodialysis may also change on a daily basis depending on the patients’ presentation, with variable methods utilized including either dialysis or convective properties of the dialysis circuit influencing drug removal. Such may be the case with various continuous renal replacement therapies "CRRT" (i.e. CVVH, CVVHD or CVVHDF). Newer hybrid dialysis approaches including extended duration dialysis are also gaining popularity in critically ill ARF patients. These approaches may not require as much anticoagulation to maintain the circuit during hemodialysis compared to CRRT approaches. The patients’ individual clinical presentation may also influence anticoagulation requirements and risk for bleeding. Uremic platelets, the effect of shear forces against the dialysis membrane or if replacement fluids are added in before or after (hemoconcentrated and increased risk for thrombosis) the filter, are additional factors impacting the risk for thrombosis or bleeding. In chronic renal failure, drug removal and predicted anticoagulant responses may be more consistent on a day-to-day basis. Predictive equations for renal function are easier to utilize in CRF compared to ARF, where none are currently feasible to apply with much certainty, creating additional challenges in developing a dosing regimen. There is also a notable difference in drug removal between a CrCl < 30 ml/min compared to patients requiring hemodialysis. As renal function declines other factors impacting hemostasis, such as tissue factor pathway inhibitor may become significant.
The target goals of anticoagulation therapy and dosing strategies will be another factor. Is anticoagulation being used to maintain the dialysis circuit or for systemic treatment or prevention of thromboembolism in the patient? Most of the data currently available regarding the use of LMWH is for preventing thrombosis of the dialysis circuit in CRF patients requiring intermittent hemodialysis. For systemic anticoagulation, there has been a general suggestion to "monitor anti-Xa activity" as a surrogate marker for determining the dynamic degree of decreased ability for thrombosis formation to guide dosing or monitor for potential accumulation of the drug and potential risks for bleeding over time. Unfortunately, there is little evidence on what "anti-Xa" level will adequately prevent thrombosis while minimizing bleeding. Although it appears that the LMWH Enoxaparin may have a favorable profile compared to heparin in this setting regarding effects on TFPI etc, the optimal dose is not clear, with evidence suggesting it to be lower than the 50% reduction for CrCl < 30 ml/min provided in the prescribing information. Some limited data does exist on the pharmacokinetics of LMWH in this setting using anti-Xa activity, however, recent observations question the validity of anti-Xa as a surrogate marker for hemostasis in this setting. In one analysis by Klingel et al assessing changes in surrogate markers (thrombin-antithrombin complex and D-Dimer values) in various forms of CRRT found marked difference in the drive for thrombosis between approaches (increased procoagulable state as convective clearance increased) despite the same anti-Xa activity. The "Flux" or water permeability of a dialysis membrane may also influence the measured anti-Xa level for a given LMWH dose. Bazinet et al and others that have measured anti-Xa activity in patients with CrCl < 30 ml/min observed considerable variability in reported values. A recent CAP survey of 87 labs observed that reported anti-Xa on LMWH sample with a mean of 1.42 ranged form 0.34 to 2.6 u/ml, further limiting the predictive value of a result. This further identifies a need to standardize methods for measuring anti-Xa activity, noting however that this has not yet been accomplished for the aPTT.
An additional factor is the increased risk for hemorrhagic complications in renal insufficiency irrespective of what form of anticoagulation therapy is used. Some recent data on the use of LMWHs in this setting suggests a higher overall bleeding rate compared to heparin. In a recent retrospective analysis by Thorevska et al evaluating the use of enoxaparin or heparin in individuals with a serum creatinine of 2.5mg/dl or more, the incidence of major bleeding was similar (37% vs 31% respectively), but a higher incidence of minor bleeding with enoxaparin (68% vs 27%), correlating with the degree of renal insufficiency (p<0.0001). Because of the lack of a sufficient means to easily monitor LMWH, dose adjustments to reduce the risk for bleeding that may be difficult to provide. As such, LMWHs have tended to be second line agents in this setting. Given mixed observations in analysis of trials comparing LMWH vs heparin, mostly in the non-dialysis population, the true risk factors for bleeding may not yet be clear.
However, in cases where phlebotomy cannot be done to monitor heparin a LMWH may be considered. When this occurs, consider frequent assessment of the patient for bleeding, presence of thrombosis (patient and the hemodialysis circuit). Although the LMWH dosing in such situations is not clear, a lower starting dose of Enoxaparin, such as 0.5-0.6mg/kg once daily may be considered. There is also data on the dosing of Tinzaparin and Dalteparin in this setting as well.
Given the variability in reported anti-Xa and lack of proven benefits with measuring and adjusting the dose of LMWH in this setting, caution should be considered. If continued low anti-Xa levels drive the dose upwards, the potential risk of bleeding may increase. In contrast, high anti-Xa levels resulting in lower doses may increase the risk for thromboembolism. One consideration is if it is elected to monitor the anti-Xa level, there should be a plan on how to respond to the result.
Some References of interest:
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Farooq V, Hegarty J, Chandrasekar T, Lamerton EH, Mitra S, Houghton JB et al. Serious adverse incidents with the use of low molecular weight heparins in patients with chronic kidney disease. Am J Kidney Dis 2004;43:531-7.
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Nagge J, Crowther M, Hirsh J. Is impaired renal function a contraindication to the use of low-molecular-weight heparin? Arch Intern Med 2002;162:2605-2609.
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Bazinet A, et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 2005;116:41-50.
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Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, et al Anticoagulation in hospitalized patients with renal insufficiency. A comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest 2004;125:856-863.
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Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta analysis of randomized trials. J Am Soc Nephrol 2004;15:3192-206.
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Naumnik B, Borawski J, Mysliwiec M. Different effects of enoxapairn and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study. Nephrol Dial Transplant 2003;18:1376-82.
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Klingel R, Schaefer M, Schwarting A, Himmelsbach F, Altes U, Uhlenbusch-Korwer I et al. Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodialfiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation. Nephrol Dial Transplant 2004;19:164-70.
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McMahon LP, Chester K, Walker RG. Effects of different membranes in serum concentrations of epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose during dialysis. Am J Kidney Dis 2004;44:509-16.
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Brophy DF, Martin EJ, Gehr TWB, Carr ME. Enhanced anticoagulant activity of enoxaparin in patients with ESRD as measured by thrombin generation time. Am J Kidney Dis. 2004 Aug;44(2):270-7.
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Hainer JW, Sherrard DJ, Swan SK, Barrett SJ, Assaid CA, Fossler MJ, et al. Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal patients undergoing chronic hemodialysis. Am J Kidney Dis 2002;40:531-538.
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Al-Arrayed S, Seshadri R. Use of low molecular weight heparin for hemodialysis: A short term study. Saudi J Kidney Dis Transplant 13: 146-150, 2002.
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Apsner R, Buchmayer H, Lang T, Unver B, Speiser W, Sunder-Plassmann G, et al. Simplified citrate anticoagulation for high-flux hemodialysis. Am J Kidney Dis 38: 979-987, 2001.
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Bambauer R, Rucker S, Weber U, Kohler M. Comparison of low molecular weight heparin and standard heparin in hemodialysis. ASAIO Trans 36: M646-M649, 1990.
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Beijering RJR, ten Cate H, Stevens P, Vanholder R, Van Dorp WT, Van Olden RW, et al. Randomised long-term comparison of tinzaparin and dalteparin in haemodialysis. Clin Drug Invest 23: 85-97, 2003.
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Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC. The clinical use and laboratory monitoring of low-molecular-weight-heparin, danaparoid, hirudin and related compounds, and argatroban: College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy. Arch Pathol Lab Med 122: 799-807, 1998.
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