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

Safety in Patients With Renal Impairment

Currently available LMWHs, factor Xa inhibitors, and DTIs (excluding argatroban) are eliminated primarily by the kidneys. Therefore, the clearance of all of these agents is reduced in patients with renal impairment.[1,24,34] In patients with severe renal impairment, the clearances of enoxaparin and fondaparinux, for example, are reported to be reduced by about 44% and 55%, respectively.[18,19]

On the other hand, renal clearance of unfractionated heparin is minimal.[24] Unfractionated heparin may therefore be an attractive anticoagulant option for patients with renal impairment. Unfractionated heparin has long been used as an anticoagulant for the prevention and treatment of arterial and venous thromboembolic disease.[1] Nevertheless, its highly variable pharmacokinetic properties complicate its use.[24,25] In addition, some evidence suggests that the risk of bleeding with unfractionated heparin increases with dosage and age (>70 years).[3] Close monitoring of aPTT values is generally recommended when the drug is administered at therapeutic or high doses to the elderly or those with renal insufficiency, although there is a poor correlation between aPTT values and bleeding complications.[1]

Renal elimination of argatroban is minimal, and its pharmacokinetics and pharmacodynamics are not significantly affected by renal dysfunction.[29,35,36] Hence, argatroban may be the DTI of choice in patients with renal impairment.[37] The efficacy of argatroban anticoagulation during dialysis has been investigated in patients with and without HIT.[37,38,39] Dialysis was effective with argatroban, as evidenced by urea reduction rates of 64-73%. Bleeding rates ranged between 0% during therapy and 6.0% with continued anticoagulation and at follow-up at 37 days.[37,38] In clinical studies of argatroban therapy for the prophylaxis or treatment of thrombosis in patients with HIT, the major bleeding rate at 37 days was 5.3%, irrespective of their renal function (6.7% in historical control patients).[29]

Clinical data on the safety of newer anticoagulants in patients with severe renal impairment have been slow to emerge, as these patients are often excluded from clinical trials.[1,25] To clarify the bleeding risk with LMWHs in patients with severe renal impairment, a meta-analysis was conducted on data from 18 studies of LMWHs (15 studies of enoxaparin, 2 of tinzaparin, and 1 of dalteparin) for various indications, including the prevention of VTE, treatment of VTE, and management of ACS.[40] Use of LMWHs in patients with a CLcr of ≤30 mL/min was associated with a twofold increased risk for major bleeding (5.0%), compared with patients with a CLcr of >30 mL/min (2.4%) (odds ratio, 2.25; p = 0.013).[40]

Major bleeding rates have also been reported to increase when fondaparinux is used in patients with severe renal impairment.[19] In patients who underwent orthopedic surgery, the frequency of major bleeding increased from 1.6% in those with normal renal function to 4.8% in those with severe renal impairment.[19] Likewise, when fondaparinux was used in patients undergoing abdominal surgery, major bleeding increased from 2.1% in those with normal renal function to 7.1% in patients with severe renal impairment.[19] In clinical trials of fondaparinux for the treatment of VTE, major bleeding rates increased from 0.4% in patients with normal renal function (4 of 1132 patients) to 7.3% in patients with severe renal impairment (4 of 55 patients).[19]

The risk of bleeding with fondaparinux and enoxaparin in ACS patients with varying degrees of renal impairment was compared in a recent analysis of data from the OASIS-5 study.[41] In this study, 20,078 patients with unstable angina or NSTEMI were randomized to receive fondaparinux sodium (2.5 mg once daily) or enoxaparin sodium (1 mg/kg twice daily) for a mean of five days.[33] In the 535 patients with severe renal impairment (CLcr of <30 mL/min), the dosage of enoxaparin sodium was reduced to 1 mg/kg once daily, while the dosage of fondaparinux sodium was maintained at 2.5 mg once daily (note that, per FDA-approved labeling, fondaparinux is contraindicated in patients with a CLcr of <30 mL/min).[33] In the overall study population, rates of major bleeding were found to increase with respective quartiles of SCr (2.7%, 2.5%, 2.4%, and 4.8%, respectively).[41] However, for each quartile of creatinine, the hazard ratio for bleeding was consistently lower with fondaparinux than with enoxaparin (0.54, 0.56, 0.54, and 0.48, respectively) (p < 0.01 for each).[41] These findings are notable given that the enoxaparin dosage was adjusted in this study for patients with severe renal impairment but the fondaparinux dosage was not adjusted.[41]

Another large analysis using data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials also examined bleeding rates with enoxaparin in ACS patients with severe renal impairment.[42] In both of these trials, patients with NSTEMI were randomized to receive enoxaparin or unfractionated heparin.[42] Overall, 2% of patients (143 of 7081 patients) in the combined study populations had severe renal impairment.[42] Patients with severe renal impairment had significantly more major hemorrhages than patients without renal impairment (6.6% versus 1.1%, respectively) (p < 0.0001), regardless of whether they were treated with enoxaparin (7.5% versus 1.2%, respectively) or unfractionated heparin (5.8% versus 1.0, respectively).[42]

It appears that although patients with severe renal impairment comprise a relatively small percentage of patients with ACS, they account for a disproportionate number of those who will experience major bleeding. In a retrospective chart review that reflected a real-world clinical practice assessment of 208 ACS patients treated with enoxaparin at a tertiary care teaching hospital, severe renal impairment, when defined as a CLcr of <25 mL/min, was reported in only 3% of all patients treated for ACS but in 25% of all patients with major bleeding.[11]

The safety of bivalirudin in patients with ACS and renal impairment was also examined in a large clinical database analysis.[43] Data from two Phase III trials involving 4312 patients with unstable angina undergoing PTCA who were treated with either bivalirudin or unfractionated heparin showed that rates of major bleeding were strongly correlated with renal function for both anticoagulants. Rates of major bleeding with bivalirudin increased from 1.2% in patients with normal renal function to 6.0% in patients with moderate renal impairment. Although no patients with severe renal impairment who used bivalirudin had major bleeding, patients with severe renal impairment comprised only 1% of patients treated with bivalirudin in the analysis (18 of 1914 patients), so the rate of major bleeding in this population was likely underestimated.

Argatroban is not eliminated by the kidneys, and data on the safety of argatroban in patients with ACS with renal impairment have not been published. However, major bleeding was reported in 1.8% of patients undergoing PCI who were treated with argatroban versus 3.1% of historical controls.[29]

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