Fondaparinux and idraparinux

Comparative studies

There have been two double-blind, randomized comparisons of fondaparinux 2.5 mg/day or enoxaparin 40 mg/day after hip fracture surgery [ ], or elective major knee surgery [ ]. Fondaparinux reduced the risk of thromboembolism by 56% in the first study (n = 1250) and by 55% in the second (n = 724). There were no significant differences between the two groups in the first study in the incidence of death or clinically important bleeding. In the second study, major bleeding occurred more often with fondaparinux, but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation, or occurring in a critical organ.

In a double-blind, randomized study of 2309 consecutive patients undergoing elective hip replacement, postoperative subcutaneous fondaparinux 2.5 mg/day was compared with preoperative enoxaparin 40 mg/day [ ]. By day 11, venous thromboembolism had occurred in 85 (9%) of 919 patients assigned to enoxaparin and in 37 (4%) of 908 patients assigned to fondaparinux, a relative risk reduction of 56% (95% CI = 33, 73). In a similar comparison of postoperative fondaparinux 2.5 mg/day and enoxaparin 30 mg bd in 2275 consecutive patients undergoing elective hip replacement, by day 11 venous thromboembolism had occurred in 48 (6%) of 787 patients assigned to fondaparinux and in 66 (8%) of 797 patients assigned to enoxaparin, a relative risk reduction of 26% (95% CI = 11, 53) [ ].

In a meta-analysis of these studies, bleeding was slightly, but not significantly, more frequent with fondaparinux than with enoxaparin [ , ].

In the OASIS-6 study 12 092 patients with ST-segment elevation myocardial infarction were randomized to subcutaneous fondaparinux 2.5 mg/day for up to 8 days or standard care with either placebo intravenous unfractionated heparin for 48 hours [ ]. The rate of bleeding was not increased by fondaparinux compared with controls (1.8% versus 2.1%). There was no difference in the numbers of total strokes (0.9% versus 1.1%) or hemorrhagic strokes (11 versus 10 events). Among patients who underwent primary percutaneous coronary intervention, there was an excess of catheter thrombosis in patients treated with fondaparinux and there was a non-significant excess of ischemic outcomes and bleeding. There were no episodes of catheter thrombosis in patients who received unfractionated heparin.

In two randomized, open, non-inferiority comparisons of idraparinux and heparin followed by a coumarin for either 3 or 6 months bleeding rates at 6 months were similar [ ]. In patients with deep venous thrombosis efficacy was similar, but in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. In an extension study in 1215 patients, major bleeding occurred in 11 (1.9%) of those who were given idraparinux and in none in the placebo group; of the 11 episodes, three were fatal intracranial hemorrhages [ ].

A randomized comparison of subcutaneous idraparinux 2.5 mg/week and a coumarin (target INR 2–3) was stopped after 4576 patients had been randomized at a mean follow-up period of 11 months because of excess clinically relevant bleeding with idraparinux (346 cases versus 226 cases; 20 versus 11 per 100 patient-years) [ ]. There were 21 instances of intracranial bleeding with idraparinux and nine with coumarins (1.1 versus 0.4 per 100 patient-years); elderly patients and those with renal impairment were at greater risk.

Hematologic

Of 1103 patients randomly assigned to receive fondaparinux 42 (3.8%) had recurrent thromboembolic events, compared with 56 of 1110 patients randomly assigned to receive unfractionated heparin (5.0%), an absolute difference of − 1.2% in favor of fondaparinux (95%CI = − 3.0, 0.5) [ ]. There was major bleeding in 1.3% of those treated with fondaparinux and 1.1% of those treated with unfractionated heparin. Mortality rates at 3 months were similar in the two groups.

In four phase III multicenter, randomized, parallel-group, double-blind trials in 375 centers in Argentina, Australia and New Zealand, Europe, North America, and South Africa, 7344 patients (mean age 68 years, 60% women) undergoing elective total hip arthroplasty (two studies), elective knee arthroplasty (one study), or hip fracture surgery (one study) were given either subcutaneous fondaparinux (n = 3668) 2.5 mg once daily, beginning 6 hours after surgery or subcutaneous enoxaparin (n = 3676) 30 mg bd beginning 12 hours before surgery; 7237 received at least one dose of the study drug and 5385 completed the study [ ]. The incidence of venous thromboembolism was significantly lower with fondaparinux (182/2682) than enoxaparin (371/2703). However, major bleeding events were significantly more frequent with fondaparinux (96/3616) than enoxaparin (63/3621). The incidences of death, minor bleeding, and other adverse events did not differ between the two groups.

In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with once-daily subcutaneous fondaparinux sodium 2.5 mg of placebo for 19–23 days [ ]. Before randomization, all had received fondaparinux for 6–8 days. Fondaparinux reduced the incidence of venous thromboembolism from 35% (77/220) to 1.4% (3/208), with a relative risk reduction of 96% (95% CI = 87, 100%). Although there was a trend towards more major bleeding with fondaparinux than with placebo, there were no differences between the two groups in the incidence of clinically relevant bleeding (leading to death, re-operation, or critical organ bleeding).

Fondaparinux shares many of the advantages of danaparoid, without the potential disadvantage of cross-reactivity in vitro with antibodies that are found in patients with heparin-induced thrombocytopenia [ ]. Three patients were successfully treated for thromboembolic events with fondaparinux after developing heparin-induced thrombocytopenia during therapy with unfractionated heparin or low-molecular-weight heparin [ ].

• A 39-year-old pregnant woman with protein S deficiency and previous severe skin reactions to heparin was initially treated with subcutaneous danaparoid sodium [ ] However, she soon developed severe skin reactions at injection sites. Danaparoid was withdrawn and she was given subcutaneous fondaparinux 2.5 mg/day uneventfully for 150 days until delivery. No adverse reactions were observed in the neonate.

In two case series of patients with heparin-induced thrombocytopenia, fondaparinux did not alter platelet counts [ ]. Finally, a retrospective review has shown that fondaparinux prevented thromboembolic events or recurrent thrombocytopenia in patients with prior heparin-induced thrombocytopenia [ ]. Questions remain regarding efficacy, safety, optimal doses, treatment duration, and incidence of thromboembolic events when fondaparinux is used in this setting. Prospective trials of the efficacy and safety of fondaparinux in this population need to be conducted.

Fondaparinux has been successfully used in patients with heparin-induced thrombocytopenia [ ]. However, cross-reactivity has been reported [ ].

Bleeding with fondaparinux is uncommon but can be serious when it occurs, as has been illustrated by a case of spontaneous retroperitoneal bleeding from a ruptured lumbar artery in a 78-year-old man with only one kidney [ ].