Use of Newer Anticoagulants in Patients With Chronic Kidney Disease

Bob L. Lobo

Disclosures

Am J Health Syst Pharm. 2007;64(19):2017-2026. 

In This Article

Management of Patients With Severe Renal Impairment

Enoxaparin is approved for use in patients with severe renal impairment (CLcr of <30 mL/min).[23] The findings of a recent population pharmacokinetics study of enoxaparin in patients with ACS have prompted concerns that enoxaparin dosage reductions may result in suboptimal anticoagulation in some patients.[49] This study of 803 patients with ACS found that patients with suboptimal anticoagulation, defined as anti-factor Xa levels of <0.5 IU/mL, had a greater than threefold increase in 30-day mortality, compared with patients with anti-factor Xa levels in the target range of 0.5-1.2 IU/mL (p = 0.004). Anti-factor Xa levels were measured after at least two doses of enoxaparin, 4-6 hours after administration of the last dose. Patients in this study with anti-factor Xa concentrations of <0.5 IU/mL had been given lower doses of enoxaparin than patients with anti-factor Xa values of 0.5-1.2 IU/mL (0.66 mg/kg every 12 hours versus 0.82 mg/kg every 12 hours). Based on these findings, the study investigators suggested that it is necessary to achieve an anti-factor Xa concentration of 0.5 IU/mL with enoxaparin in ACS patients. This target value has not been validated and requires further investigation. Nonetheless, the results of this study do suggest that reducing enoxaparin dosage has the potential to lead to underdosing in some patients and consequently increase the risk of thromboembolic complications.

Monitoring of anti-factor Xa levels may be helpful for dosing LMWHs in patients with severe renal impairment.[25,50] Pharmacokinetic studies have confirmed that the anti-factor Xa activity of enoxaparin is negatively correlated with CLcr.[51,52,53] One multidose study of enoxaparin in 48 patients with varying degrees of renal function found that patients with a CLcr of ≤30 mL/min had a 39% decrease in anti-factor Xa clearance and a 35% increase in anti-factor Xa exposure compared with patients with normal renal function.[53] In a more recent open-label study of enoxaparin in 223 patients with varying degrees of renal function, anti-factor Xa activity decreased by 0.003 IU/mL for each 1-mL/min increase in CLcr.[51]

Dalteparin and tinzaparin are also approved for use in patients with severe renal impairment.[21,22] There are currently no recommendations for dosage adjustment for either of these anticoagulants in patients with severe renal impairment.[21,22] There are comparatively less data available on the relationship between anti-factor Xa activity and renal function for dalteparin and tinzaparin than for enoxaparin.

The minimal levels of anti-factor Xa activity required for treatment with LMWHs to be effective have not been well defined. Target therapeutic ranges of anti-factor Xa activity for LMWHs (1.0-2.0 IU/mL for once-daily administration and approximately 0.5-1.1 IU/mL for twice-daily administration), based mainly on pharmacokinetic parameters, have been proposed by a consensus of experts.[50] These target ranges vary according to the frequency of dose administration and may vary by agent.[25,50] It should be emphasized, though, that proposed therapeutic ranges of anti-factor Xa activity for the various LMWHs have not been validated in randomized clinical trials.[48]

Data on the use of fondaparinux in patients with severe renal impairment are limited. In Phase III clinical trials of fondaparinux for the treatment of VTE, 55 of 2,238 patients had severe renal impairment, 7.3% of whom developed major bleeding.[19] In the recently published OASIS 5 trial of NSTEMI, 265 of 10,057 patients treated with fondaparinux had severe renal impairment, 2.4% of whom developed major bleeding.[33] Patients in these trials received fondaparinux without dosage adjustment for renal impairment.

In a recent pharmacokinetic and simulation study, serum fondaparinux concentrations in patients with severe renal impairment who received fondaparinux sodium 2.5 mg every other day were predicted to be similar to those in patients with mild renal impairment who received fondaparinux sodium 2.5 mg once daily.[54] Therefore, increasing the dosing interval for fondaparinux may be a reasonable strategy for dose adjustment for carefully selected patients with severe renal impairment; however, the use of fondaparinux in this population is contraindicated according to its current prescribing information.[19]

Lepirudin, desirudin, bivalirudin, and argatroban have FDA-approved labeling for use in patients with severe renal impairment.[27,28,29,32] Increased monitoring of anticoagulation parameters and bleeding and dosage reduction are recommended for patients with severe renal impairment treated with lepirudin, desirudin, or bivalirudin. Argatroban is approved for use in patients with severe renal impairment without dosage reductions because of its minimal excretion by the kidneys. Manufacturer recommendations regarding the use of lepirudin and bivalirudin in patients with severe renal impairment are described in Table 2 .

The prescribing information for lepirudin states that the bolus dose should be reduced to 0.2 mg/kg; however, it has been suggested that the bolus dose be omitted in patients with severe renal impairment.[46,47] According to the manufacturer, the infusion rate should be reduced to 15% of the standard initial infusion rate in patients with a CLcr of 15-29 mL/min; if the CLcr is less than 15 mL/min, lepirudin should not be used. However, some experts suggest using an alternative to lepirudin or a greater dosage reduction when renal function is severely impaired.[46,47] An initial rate of 0.01 mg/kg/hr should probably not be exceeded in patients with a CLcr of 15-29 mL/min. The aPTT should also be frequently monitored in these patients. No reduction in the bolus dose is required with bivalirudin.[32] In patients with a CLcr of <30 mL/min, an infusion rate of 1.0 mg/kg/hr should be considered. The infusion rate should be reduced to 0.25 mg/kg/hr in patients receiving hemodialysis. Anticoagulant status should be monitored in these patients.

The prescribing information for desirudin recommends initiating therapy at 1.7 mg twice daily in patients with a CLcr of <31 mL/min. In addition, aPTT should be monitored at least daily. If the aPTT exceeds two times control, therapy should be stopped until the aPTT decreases and further dosage reductions should be considered.

In patients with severe renal impairment, anticoagulation with most of the newer anticoagulants is particularly difficult and requires health care provider expertise as well as ongoing evaluation. Therefore, it is prudent to follow the ACCP recommendation that unfractionated heparin, which is minimally eliminated by the kidneys, be used to provide full therapeutic anticoagulation therapy in patients with severe renal impairment because it is less likely to accumulate in these patients.[24] In patients with severe renal impairment but in whom heparin is contraindicated, argatroban may be an alternative anticoagulant.

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