Fondaparinux as a Treatment Option for Heparin-Induced Thrombocytopenia

Stella Papadopoulos, Pharm.D.; Jeremy D. Flynn, Pharm.D.; Daniel A. Lewis, Pharm.D.

Disclosures

Pharmacotherapy. 2007;27(6):921-926. 

In This Article

Fondaparinux

Fondaparinux has received FDA approval for prophylaxis of deep vein thrombosis in patients who have undergone hip fracture, or hip or knee replacement surgeries.[17] It is also approved for prophylactic use after abdominal surgery and for treatment of acute deep vein thrombosis and pulmonary embolism. Fondaparinux has a rapid onset of action, with peak plasma concentrations achieved in 2.2–2.6 hours, and it is 100% bioavailable after subcutaneous administration.[17] As it is administered subcutaneously, fonda-parinux is an appealing alternative to the direct thrombin inhibitors, which are administered by continuous infusion and require close monitoring. Moreover, fondaparinux's half-life of 17–21 hours allows for once-daily administration.

Fondaparinux is renally eliminated and thus contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min).[17] Clinical laboratory monitoring is not routinely necessary; however, monitoring with an antifactor Xa assay is possible, provided the assay is calibrated with fondaparinux.[18] Monitoring the antifactor Xa activity of fondaparinux may be desirable for patients with deep vein thrombosis and/or pulmonary embolism, especially if these patients have impaired renal function (i.e., the elderly).[19]

Fondaparinux is a synthetic polysaccharide whose structure contains the same pentasaccharide sequence found on UFH and LMWH.[1,14,20] Fondaparinux possesses fewer negatively charged sulfate groups than either UFH or LMWH, and it lacks the sugar domain necessary to complex with PF4, making the likelihood of inducing HIT extremely low.[5,7] Data from clinical trials encompassing more than 7500 patients who received fondaparinux did not reveal any cases of HIT.[8,20,21]

No reversal agent is approved for fondaparinux, and excessive dosing may lead to hemorrhage.[17] Blood products such as fresh frozen plasma and cryoprecipitate can be used to control adverse effects such as bleeding. A study in which patients were randomized to receive fondaparinux 10 mg with recombinant factor VIIa (rFVIIa) 90 B5g/kg or placebo with rFVIIa provided evidence that rFVIIa can successfully reverse bleeding complications associated with fondaparinux.[22] As with LMWH and heparinoids, concomitant use of fondaparinux with spinal or epidural anesthesia carries a risk for spinal or epidural hematomas.[17]

Adverse Effects

Adverse effects of fondaparinux have been evaluated in several studies. These include thrombocytopenia (not associated with HIT), elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and major bleeding. Randomized controlled studies involving patients with hip fracture, hip replacement, or knee replacement surgery (fondaparinux vs LMWH) and studies of patients with deep vein thrombosis or pulmonary embolism (fondaparinux vs LMWH and UFH) found fondaparinux to be associated with moderate thrombocytopenia (platelet count 50–100 × 103/mm3) in 0.5–2.9% of patients and with severe thrombocytopenia (platelet count < 50 × 103/mm3) in 0.2–0.4% of patients.[17]

In phase III trials in which fondaparinux was administered for up to 11 days after orthopedic surgery, 2.9% of patients had platelet counts ranging from 50–100 × 103/mm3.[8] Platelet counts below 50 × 103/mm3 occurred in 0.2% of patients. It is important to note that thrombocytopenia observed in these orthopedic clinical trials occurred during the first 3 days of therapy and may have been the result of surgery. Thus, it is difficult to discern the relevance of the platelet count decreases seen in these trials. In addition, most patients received a short course of fondaparinux, making the effects of long-term therapy and the potential for thrombocytopenia less clear.[8,20,21]

In the Pentasaccharide in Hip-Fracture Surgery Plus (Penthifra Plus) trial, no cases of thrombo-cytopenia were reported in patients receiving extended prophylaxis with fondaparinux (postoperatively until days 19–23).[8]

In the above trials of fondaparinux, the frequency of major bleeding ranged from 1.2–2.7%.[17] These data compare favorably with major bleeding rates associated with direct thrombin inhibitors in patients with HIT and HITTS.[2] Studies evaluating the use of direct thrombin inhibitors in patients with HIT without evidence of thrombosis reported major bleeding rates of 3.1–5.3% and 5.9–14.4% in patients who received argatroban and lepirudin, respectively.[2] In prospective and postmarketing studies evaluating patients with HITTS who received the same direct thrombin inhibitors, these rates were 6.1–11.1% and 5.4–20.4%, respectively. However, more studies of fondaparinux in the setting of HIT are needed to assess the true frequency of bleeding with fondaparinux in this context.[2]

Another potential adverse effect of fondaparinux is increases in serum transaminase levels. Increases in serum AST or ALT levels have been reported in 0.7–2.6% of patients.[17]

In Vitro Evidence

Several in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies ( Table 1 ).[23–26] One such study compared UFH, LMWH, danaparoid, and fondaparinux.23 Researchers added these four anticoagulants to separate plasma samples from 25 patients with documented HIT and measured cross-reactivity using PAT. Plasma from all 25 patients displayed platelet aggregation in the presence of UFH. When LMWH was added to the plasma, 19 out of the 25 samples showed platelet aggregation. Conversely, sera from only two of the 25 patients had positive results with danaparoid, and none of the samples was positive for cross-reactivity in the presence of fondaparinux.

Another in vitro study evaluated the cross-reactivity of fondaparinux with HIT antibodies in 49 patients with HIT who had positive PATs in the presence of heparin.[24] Using the ELISA test, this study produced findings similar to those in the in vitro study described above.[23] All patients with clinical HIT exhibited an increase in antibody binding when PF4 was complexed with unfractionated heparin. No cross-reactivity was observed between fondaparinux and heparin-PF4 complexes.

A third in vitro study evaluated the potential of fondaparinux, idraparinux (not yet approved by the FDA), LMWH, and UFH to cross-react with sera from 30 patients with HIT.[25] The researchers used SRA, PAT, ELISA, and flow cytometry assays. They observed HIT antibody platelet activation with UFH and LMWH but not with fondaparinux or idraparinux.

Finally, a blinded, multicenter, in vitro study used sera from 39 patients with confirmed HIT and 15 controls to evaluate the cross-reactivity of fondaparinux to HIT antibodies.[26] The functional tests used in this study were the heparin-induced platelet agglutination (HIPA) test, SRA, and PAT. Sera were sent to one of three laboratories that specialized in these functional assays. In the presence of control sera, two (2.4%) of 82 assays and two (4.9%) of 41 assays were positive with UFH, whereas 75 (79.8%) of 94 assays were positive when UFH was used in the presence of HIT sera. The positive activity of fondaparinux was significantly less than that of UFH in that only three (3.3%) of 91 assays and none of 41 assays were positive in the presence of HIT and control sera, respectively.

Collectively, these in vitro studies demonstrate the limited ability of fondaparinux to cross-react with HIT antibodies. Limitations to consider include the in vitro study design and small sample sizes.

Clinical Experience

In vivo data on the use of fondaparinux in patients with HIT are limited. Most of the published information is in abstract form with few details of the patients studied. Two reports describe the use of fondaparinux in patients with subacute HIT.[27,28] One of these reports was a retrospective review of 20 patients who received fondaparinux for longer than 5 days.[27] Fondaparinux was tolerated without thrombotic complications or continued thrombocytopenia, and platelet counts recovered in a mean of 3.7 days. The other report describes management of a thrombus in the left femoral vein of a 3-month-old girl.[28] On day 23 after surgery, the patient was transitioned from warfarin to fondaparinux 0.15 mg/kg every 24 hours. Antifactor Xa levels were monitored 2, 4, and 8 hours after injection and then at prespecified intervals on days 2, 3, 4, and 7. By discharge (day 30 after surgery) the patient showed no evidence of bleeding or decreased platelet count, and the thrombus had resolved. Fondaparinux was continued for 3 months with stable platelet counts and no bleeding or thrombosis.

Fondaparinux has also been used in the setting of acute HIT. A study describes its use in five patients who developed acute HITTS after receiving UFH for 6–10 days.[29] Heparin was discontinued, and all five patients received fondaparinux 7.5 mg/day. Platelet counts recovered within 2–9 days. Once a platelet count exceeding 100 × 103/mm3 was reached, warfarin was started and overlapped with fondaparinux until the INR was at least 2.0 for 2 consecutive days. Another published report describes the use of fondaparinux in a patient with renal failure.[30] In this patient, antifactor Xa activity was monitored and platelet counts recovered on day 5, at which time fondaparinux was replaced by warfarin.

Two reports describe the use of fondaparinux in patients with a history of HIT. One of these reports describes the use of fondaparinux in eight patients—six who required anticoagulation and two patients who developed thrombocytopenia after treatment with LMWH.[31] All eight patients received fondaparinux 2.5 mg/day for 7–14 days with no evidence of thrombocytopenia, thrombotic complications, or bleeding. A related report describes administration of fondaparinux to a patient with a recurrent pulmonary embolus.[32] This patient received a lepirudin infusion for 5 days and was then transitioned to fondaparinux 2.5 mg/day. Once lepirudin was discontinued, the patient received a daily regimen of fonda-parinux 2.5 mg alternating with 5 mg for 8 months with no reported adverse effects.

Finally, a report describes the use of fonda-parinux in a patient with HITTS who received hemodialysis.[33] Fondaparinux 2.5 mg was administered into the dialysis circuit every other day. Therapy was continued for 10 weeks with no adverse effects reported.

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