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Low molecular weight heparin for the treatment of deep vein thrombosis and pulmonary embolism in patients with chronic kidney disease.

OBJECTIVES

After reading this article, the reader will be able to:

1. Compare and contrast the pharmacokinetics of different low molecular weight heparins (LMWH)

2. Discuss the evidence surrounding the use of LMWH in patients with chronic kidney disease (CKD)

3. Discuss how to monitor a CKD patient who is initiated on LMWH

Venous thromboembolism (VTE) affects approximately 1-2 in 1,000 Canadians each year, with one-third of the patients presenting due to a pulmonary embolism (PE) and the remaining due to deep vein thrombosis (DVT). Up to 10% of these PEs can be fatal within the first hour of symptoms, making prompt diagnosis vital to treatment success (Thrombosis Canada, 2013). Following a thrombotic event, patients are typically initiated on an oral anticoagulant. Although a number of new oral agents exist, warfarin is the only agent that is not contraindicated in end-stage renal disease, making it the treatment of choice in this patient population. If warfarin is not tolerated or there is a contraindication to its use, low molecular weight heparin (LMWH) serves as an alternative option (Hughes, Szeki, Nash, & Thachil, 2014). The use of LMWH in patients with CKD is often cautioned against, as these agents are renally cleared and relatively contraindicated due to concerns surrounding drug accumulation and an increased risk of bleeding (Saltiel, 2010). Although there is some evidence reporting the safe use of LMWH for VTE prevention and preventing circuit thrombosis in hemodialysis patients (Chan, Thadhani, & Maddux, 2013; Lim, Cook, & Crowther, 2004), there remains limited evidence for use in patients with chronic kidney disease (CKD) for VTE treatment. This article will address this issue through reviewing the pharmacokinetics of the different LMWH, as well as the literature evidence.

PHARMACOKINETICS OF LMWH

Although different LMWHs are generally comparable clinically, they have different molecular weights, which affect their kinetic properties. The mechanism by which LMWH causes anticoagulation is through the inhibition of coagulation factors Xa and II (Figure 1). The molecular weight affects the specificity that each LMWH has to binding factor Xa or II, with smaller molecular weights selectively targeting factor Xa compared with factor II. This, in turn, influences the bioavailability and half-life of the LMWH (Table 1). Renal clearance is also indirectly proportional to the molecular weight of the LMWH. Therefore, accumulation may be more pronounced in a LMWH with a smaller molecular weight (Hughes et al., 2014). This article will address three LMWHs: enoxaparin, dalteparin, and tinzaparin.

Enoxaparin

Enoxaparin is the most widely studied LMWH, with most of the data stemming from its use in cardiovascular trials. An analysis of renally-impaired patients (creatinine clearance [CrCl] [less than or equal to] 30ml/min) in two of these major trials showed a significantly higher risk of bleeding compared to patients with normal renal function (Spinler et al., 2003). Enoxaparin also has the smallest molecular weight, making its renal clearance the most prominent of the agents discussed (Table 1). Due to the increased risk of bleeding from potential accumulation in renal impairment, a dose reduction is recommended in all patients with a CrCl <30 ml/min with a recommended dose of 1 mg/kg once daily in the treatment of VTE (Table 2) (Sanofi Canada, 2014).

Dalteparin

Dalteparin has been shown to be safely used for thromboprophylaxis in renally-impaired patients with a CrCl < 30ml/min at a dose of 5,000 units once daily (Douketis et al., 2008), but there have been no trials studying its use in the treatment of VTE. The recommended dose for the treatment of VTE in non-renally-impaired patients is 200 units/kg once daily, but due to the lack of evidence, there are no recommended dose adjustments for this indication in renally-impaired patients. Taking into account its pharmacokinetics, dalteparin has the second largest molecular weight and a clearance that is less dependent on renal function compared with enoxaparin (Table 1).

Tinzaparin

Tinzaparin has been studied in elderly patients with moderate renal impairment (CrCl 20-50ml/min). Patients in these studies were safely administered a standard dose of tinzaparin 175 units/kg once daily for the treatment of VTE with no signs of accumulation or increased risk of bleeding (Mahe et al., 2007; Pautas, Gouin, Bellot, Andreux, & Siguret, 2002; Siguret et al., 2000). There is limited evidence on the use of tinzaparin in end-stage renal disease, but tinzaparin has the largest molecular weight and the least dependency on renal clearance of all the agents (Table 1). Despite limited clinical trial evidence confirming the safety of its use in VTE treatment in patients with end-stage renal disease (including dialysis), tinzaparin appears to be the agent that is least likely to accumulate in CKD.

MONITORING

Anti-Xa Levels

It is evident that information for the use of LMWH in patients with CKD is limited, making monitoring of therapy an important aspect if LMWH is to be used in this patient population. Because LMWH exerts its action through the binding of anti-Xa, a laboratory test assessing anti-Xa factor activity can identify accumulation in a patient. The anti-Xa level can be measured as a peak level, which is drawn four hours after administration of the third dose, or as a trough level taken immediately prior to administration of the fourth dose. The peak anti-Xa target range for treating VTE is 0.5-1.0 units/ml and the trough level should be <0.5 units/ml. It should be noted that this value may change depending on specific laboratory parameters (Hughes et al., 2014).

Adverse Events

Bleeding is the major risk associated with the use of LMWH in patients with CKD. While anti-Xa levels should be closely followed, patients should also be monitored for early clinical signs of bleeding. This is especially important because patients with CKD are at an increased risk of bleeding in general compared to the non-CKD population (Schmid, Fischer, & Wuillemin, 2009). Clinical signs of bleeding may include episodes of epistaxis, hematuria, or melena, but bleeding may occur at any site. It can be difficult to detect in certain situations such as retroperitoneal bleeding, therefore hemoglobin levels should be closely followed to monitor for potential decrease that can signify undetected bleeding (Sanofi Canada, 2014).

SUMMARY

The use of LMWH in patients with CKD requires caution and careful monitoring due to the risk of accumulation and bleeding. Evidence supporting its use in treating VTE in this patient population is quite limited, and selection and dosing of specific agents requires consideration of the current evidence available, as well as pharmacokinetic properties. Taking into account these factors, tinzaparin is the agent least likely to accumulate in renal failure due to its larger molecular weight, making it less dependent on renal elimination. Regardless of which agent is used, monitoring of anti-Xa levels plays an important role in ensuring that patients are being appropriately anticoagulated and that the risk of accumulation and potential bleeding is minimized.

REFERENCES

Chan, K. E., Thadhani, R. I., & Maddux, F. W. (2013). No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal disease. Kidney International, 84(3), 555-561.

Douketis, J., Cook, D., Meade, M., Guyatt, G., Geerts, W., Skrobik, Y., ... Crowther, M. (2008). Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: An assessment of safety and pharmacodynamics: the DIRECT study. Archives of Internal Medicine, 168(16), 1805-1812.

Hughes, S., Szeki, I., Nash, M. J., & Thachil, J. (2014). Anticoagulation in chronic kidney disease patients - The practical aspects. Clinical Kidney Journal, 7, 442-449.

Lim, W., Cook, D. J., & Crowther, M. A. (2004). Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: A meta-analysis of randomized trials. Journal of the American Society of Nephrology, 15, 3192-3206.

Mahe, I., Aghassarian, M., Drouet, L., Bal, D. C., Lacut, K., Heilman, J. J. ... Bergman, J. F. (2007). Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function. A comparative pharmacokinetic study. Thrombosis and Haemostasis, 97(4), 581-586.

Merli, G. J., & Groce, J. B. (2010). Pharmacological and clinical differences between low-molecular-weight heparins: Implications for prescribing practice and therapeutic interchange. Pharmacy and Therapeutics, 35(2), 95-105.

Pallister, C. J., & Watson, M.vS. (2010). Haematology (2nd ed., pp, 336-347). Banbury, UK: Scion Publishing, Ltd.

Pautas, E., Gouin, I., Bellot, O., Andreux, J., & Siguret, V. (2002). Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients. Drug Safety, 25(10), 725-733.

Saltiel, M. (2010). Dosing low molecular weight heparins in kidney disease. Journal of Pharmacy Practice, 23(3), 205-209.

Sanofi Canada (2014). Lovenox product monograph. Retrieved from http://products.sanofi.ca/en/lovenox.pdf.

Schmid, P., Fischer, A. G., & Wuillemin, W. A. (2009) Low molecular weight heparin in patients with renal insufficiency. Swiss Medical Weekly, 139(31-32), 438-452.

Siguret, V., Pautas, E., Fevrier, M., Wipff, C., Durand-Gasselin, B., Laurent, M., ... Gaussem, P. (2000). Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): Anti-Xa and anti-IIa activities over 10 days. Thrombosis and Haemostasis, 84(5), 800-804.

Spinler, S. A., Inverso, S. M., Cohen, M., Goodman, S. G., Stringer, K. A., & Antman, E. M. (2003). Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: Analysis from the ESSENCE and TIMI 11b studies. American Heart Journal, 146, 33-41.

Thrombosis Canada (2013). Pulmonary embolism: Diagnosis and management. Retrieved from http://thrombosiscanada.ca/ guides/pdfs/PE.pdf

Jennifer Ma, BScPhm, PharmD, Pharmacy Resident, University Health Network, Toronto, ON

Marisa Battistella, BScPhm, PharmD, ACPR, Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Clinical Pharmacist - Nephrology, University Health Network, Toronto, ON

Table 1: Properties of LMWH

                      Enoxaparin   Dalteparin   Tinzaparin

Half-life (hours)        4.5          4.0          3.4

Bioavailability (%)       91           87           87

Anti-Xa/anti-IIa         3.8          2.7          2.8
ratio

Average Molecular        4500         5000      5500-7500
Weight (daltons)

Relative Renal           +++           ++           +
Elimination

(Hughes et al., 2014; Merli et al., 2010)

Table 2: Dosing of LMWH

             Enoxaparin    Dalteparin         Tinzaparin

Dose for     1 mg/kg       200 units/kg       175 units/kg
treatment    twice daily   once daily         once daily
of VTE

Dose         CrCl>30 ml/   CrCl>30ml/min:     CrCl>20 ml/
adjustment   min: No       No adjustment      min: No
in CKD       adjustment    required           adjustment
             required                         required

             CrCl<30 ml/   CrCl<30ml/min:     CrCl<20 ml/
             min: 1 mg/    Dose adjust as     min: Dose
             kg once       needed based       adjust as
             daily         on anti-Xa level   needed
                                              based on
                                              anti-Xa level

(Hughes et al., 2014)
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Title Annotation:CONTINUING EDUCATION SERIES: CONTACT HOUR: 2.0 HRS
Author:Ma, Jennifer; Battistella, Marisa
Publication:CANNT Journal
Geographic Code:1CANA
Date:Jul 1, 2016
Words:1738
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