Fondaparinux for DVT Prevention in Moderate Renal Impairment

What Is the Dose Again?

Bryan P. White, PharmD

Disclosures

April 02, 2015

Question

What is the dose of fondaparinux for thromboprophylaxis in patients with moderate renal insufficiency?

Response from Bryan P. White, PharmD
PGY-1 Pharmacy Resident, Albany Medical Center, Albany, New York

The factor Xa inhibitor fondaparinux (Arixtra®) is approved for prophylaxis of deep vein thrombosis (DVT) after hip fracture, hip or knee replacement, or abdominal surgery and for treatment of venous thromboembolism. Fondaparinux is excreted predominantly unchanged by the kidney and is contraindicated in patients with a creatinine clearance (CrCl) less than 30 mL/min. Approved dosing for DVT prophylaxis is 2.5 mg subcutaneously once daily after establishment of hemostasis.[1]

There are conflicting recommendations about the use of fondaparinux in patients with moderate renal impairment (CrCl 30-50 mL/min). The package insert recommends use with caution in this patient population.[1] In clinical trials of orthopedic and abdominal surgical prophylaxis, patients with moderate renal impairment had more bleeding than patients with normal renal function (Table 1).

Table 1. Overall Incidence of Major Bleeding Associated With Fondaparinux Used for Thromboprophylaxis

Population CrCl ≥ 80 mL/min CrCl 30-49 mL/min CrCl < 30 mL/min
Orthopedic surgery 1.6% 3.8% 4.8%
Abdominal surgery 2.1% 6.7% 7.1%

CrCl = creatinine clearance. Adapted from Arixtra® [package insert].[1]

The most recent guidelines on parenteral anticoagulants from the American College of Chest Physicians have a different recommendation: "In patients with moderate renal insufficiency (ie, CrCl 30-50 mL/min) who require thromboprophylaxis, the dose of fondaparinux should be reduced by 50% or low-dose heparin should be used in place of fondaparinux." The guideline recommendation is not cited.[2]

Two cohort studies of low-dose fondaparinux (1.5 mg) for thromboprophylaxis in medical patients and orthopedic surgery have been published.[3,4]

The multicenter, prospective, cohort FONDAIR study[3] investigated the safety and efficacy of fondaparinux 1.5 mg daily for DVT prophylaxis in medical patients 60 years of age or older with a CrCl between 20 and 50 mL/min (calculated by the Modification of Diet in Renal Disease [MDRD] formula). (The differences between the MDRD equation and the Cockcroft-Gault equation have been well described.[5]) The study included 206 patients with an average age of 82 years and average CrCl of 33 mL/minute who received 6-15 days of prophylaxis. The incidences of major bleeding and symptomatic thromboembolism were 0.49% and 1.46%, respectively. It is important to note that the enrollment for this study did not meet a predetermined power calculation.[3]

The PROPICE study[4] was a multicenter, prospective, cohort study investigating the safety and efficacy of fondaparinux 1.5 mg daily for DVT prophylaxis for 16 ± 12.5 days in 442 orthopedic surgery patients 18 years of age and older with a CrCl between 20 and 50 mL/min (calculated by the Cockcroft-Gault formula). The average age was 81 years, and average CrCl was 39 mL/min. The incidences of major bleeding and symptomatic thromboembolism at postoperative day 10 were 4.5% and 0.5%, respectively.

Pharmacokinetic analysis found that predicted anti-Xa exposure to once-daily 1.5-mg fondaparinux in patients with a CrCl of 20-50 mL/min (Cockcroft Gault formula) undergoing major orthopedic surgery was 10%-15% lower than that attained with 2.5-mg once-daily fondaparinux in patients without renal dysfunction.[6]

Data from the original trials of fondaparinux 2.5 mg are included below in Table 2. It is important to note that in these trials, patients were prospectively scanned for thromboembolism, and all clotting events were included regardless of symptoms. Patients with a serum creatinine over 2 mg/dL were excluded.[7,8]

Table 2. Summary of Fondaparinux in Populations With and Without Renal Impairmenta

Population Fondaparinux Dose (mg) Symptomatic VTE Major Bleeding
Medical[3] 1.5 1.46% 0.49%
Medical[9] 2.5 0% 0.2%
Surgical[4] 1.5 0.5% 4.5%
Surgical[7,8] 2.5 0.5%-1% 1.8%-2.2%

VTE = venous thromboembolism. aThese selected trials have varying populations, differing methods for calculating creatinine clearance, and varying outcomes measures.

It is not clear how to use fondaparinux with caution in patients with CrCl less than 50 mL/min. Fondaparinux-specific anti-Xa assays can be performed; however, they may not be available at all hospital laboratories. The dose should be reduced, but this is difficult logistically because the 1.5-mg dose is not available in the United States. The 2.5-mg syringe is not graduated, making it difficult to accurately deliver doses other than 2.5 mg. If doses less than 2.5 mg are to be given, these doses should be individually drawn up by the pharmacy for patient safety. With limited ability to monitor the efficacy or to reduce the dose, clinicians must weigh the increased risk for bleeding against data of increased efficacy in some populations (eg, orthopedic surgery) for the use of fondaparinux in patients with moderate renal function on an individual patient basis.

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