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 Mild-to-moderate Renal Impairment

All of the newer anticoagulants currently available for the management of VTE and ACS have FDA-approved labeling for use in patients with mild-to-moderate renal impairment. Prescribing information recommendations regarding the use of these newer anticoagulants in patients with mild-to-moderate renal impairment are summarized in Table 2 .

Enoxaparin, dalteparin, and tinzaparin may be used without dosage adjustment for the prevention of thromboembolic disease, treatment, or both in patients with mild-to-moderate renal impairment.[21,22,23] Although no adjustment in enoxaparin dosage is required for patients with mild-to-moderate renal impairment, the prescribing information for enoxaparin cautions that all such patients should be observed carefully for signs and symptoms of bleeding.[23] In addition, some evidence from a recent population pharmacokinetic and simulation analysis suggests that reductions in enoxaparin dosage may be warranted for patients with moderate renal impairment (CLcr of <50 mL/min).[18] This analysis of 532 patients with ACS found that patients with a CLcr of 30-50 mL/min who were receiving a standard dosing regimen of enoxaparin sodium (1 mg/kg every 12 hours) had a 31% reduction in enoxaparin clearance and significant drug accumulation.[18] Subsequent simulations, though, showed that drug accumulation could be avoided in the majority of patients by using an unadjusted first dose of enoxaparin sodium followed by a regimen of 0.8 mg/kg every 12 hours.[18]

There are limited clinical data on the safety of dalteparin and tinzaparin in patients with renal impairment. A recent pharmacokinetic study in which standard doses of dalteparin prophylaxis (5000 IU daily) were administered to 19 patients in a medical-surgical intensive care unit with a wide range of CLcr values (26-208 mL/min) found no evidence of dalteparin bioaccumulation, as detected by trough anti-factor Xa levels.[44] In one pharmacokinetic study of 30 elderly patients with a CLcr of 20 to >50 mL/min who received standard doses of tinzaparin sodium (175 IU/kg) for the treatment of acute VTE, there was no evidence of tinzaparin bioaccumulation based on anti-factor Xa activity levels.[22,45]

No adjustment in fondaparinux dosage is required in patients with mild-to-moderate renal insufficiency. As with the LMWHs, fondaparinux should be used with caution in patients with moderate renal impairment (CLcr of 30-50 mL/min). In addition, as in all patients with renal impairment who are receiving newer anticoagulants, renal function should be assessed periodically.

In clinical trials of fondaparinux in patients undergoing orthopedic surgery, overall rates of major bleeding with use of fondaparinux in patients with mild and moderate renal impairment were reported to be 2.4% and 3.8%, respectively.[19] However, when the initial dose of fondaparinux was given six to eight hours after surgery, rates of major bleeding decreased to 2.2% and 2.3%, respectively.[19]

Lepirudin may be used for the prevention of thromboembolic complications in patients with HIT with mild-to-moderate renal impairment.[28] In patients with moderate renal impairment, the bolus dose and infusion rate of lepirudin should be reduced to amounts equivalent to 30-50% of the standard lepirudin dosage, according to the manufacturer. However, some experts have demonstrated that the currently approved dosing schedule may be too high for patients with or without renal insufficiency.[46,47] We use an initial rate of 0.1 mg/kg/hr in patients with normal renal function and reduce the dose as follows: If CLcr is 45-60 mL/min, decrease to 0.05 mg/kg/hr; if CLcr is 30-44 mL/min, decrease the dosage to 0.03 mg/kg/hr; and if CLcr is 15-29 mL/min, decrease to 0.01 mg/kg/hr. None of the clinical trials of lepirudin in patients with HIT administered a bolus dose to patients who did not have thrombosis. For this reason, a bolus dose of lepirudin is recommended only for patients with HIT who have an active thromboembolic complication. Some experts also recommend omitting the bolus dose for elderly patients and those with renal impairment.[46] However, this is not consistent with product labeling. In addition, frequent monitoring of the aPTT is highly recommended when lepirudin is used in these patients.

Desirudin has also received FDA-approved labeling for the prophylaxis of deep venous thrombosis in patients undergoing elective hip replacement surgery with mild-to-moderate renal impairment.[27] Desirudin prescribing information recommends a dosage reduction and daily monitoring of aPTT and SCr for patients with moderate renal impairment (CLcr of <60 mL/min). Instructions for interruption and resumption of therapy in patients found to have increased serum desirudin concentrations are also provided by the manufacturer in the prescribing information.

Bivalirudin may be used in ACS patients with mild-to-moderate renal impairment undergoing percutaneous interventions.[32] These patients should generally receive the standard bolus dose of bivalirudin (0.75 mg/kg) and standard bivalirudin infusion rate (1.75 mg/kg/hr). However, anticoagulant status (activated clotting time or aPTT) should be monitored in all patients with renal impairment receiving bivalirudin, and the infusion rate of the drug may need to be reduced in some patients.

The pharmacokinetics and pharmacodynamics of argatroban are not significantly affected by renal dysfunction; therefore, no dosage adjustment is necessary in patients with renal impairment.

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