|Pharmacotherapeutic group: antithrombotic agents. ATC code: B01AX05|
Pharmacodynamic effectsFondaparinux is a synthetic and selective inhibitor of activated Factor X (Xa). The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII) mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no effects on platelets. At the 2.5 mg dose, fondaparinux does not affect routine coagulation tests such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of aPTT prolongation have been received.Fondaparinux does not cross-react with sera from patients with heparin-induced thrombocytopaenia.
Clinical studiesPrevention of Venous Thromboembolic Events (VTE) in patients undergoing major orthopaedic surgery of the lower limbs treated up to 9 daysThe fondaparinux clinical program was designed to demonstrate the efficacy of fondaparinux for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopaedic surgery of the lower limbs such as hip fracture, major knee surgery or hip replacement surgery. Over 8,000 patients (hip fracture 1,711, hip replacement 5,829, major knee surgery 1,367) were studied in controlled Phase II and III clinical studies. Fondaparinux 2.5 mg once daily started 6-8 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours before surgery, or 30 mg twice daily started 12-24 hours after surgery.In a pooled analysis of these studies, the recommended dose regimen of fondaparinux versus enoxaparin was associated with a significant decrease (54% [95% CI, 44 %; 63%]) in the rate of VTE evaluated up to day 11 after surgery, irrespective of the type of surgery performed. The majority of endpoint events were diagnosed by a prescheduled venography and consisted mainly of distal DVT, but the incidence of proximal DVT was also significantly reduced. The incidence of symptomatic VTE, including PE was not significantly different between treatment groups.In studies versus enoxaparin 40 mg once daily started 12 hours before surgery, major bleeding was observed in 2.8% of fondaparinux patients treated with the recommended dose, compared to 2.6% with enoxaparin.Prevention of Venous Thromboembolic Events (VTE) in patients undergoing hip fracture surgery treated for up to 24 days following an initial prophylaxis of 1 weekIn a randomised double-blind clinical trial, 737 patients were treated with fondaparinux 2.5 mg once daily for 7 +/- 1 days following hip fracture surgery. At the end of this period, 656 patients were randomised to receive fondaparinux 2.5 mg once daily or placebo for an additional 21 +/- 2 days. Fondaparinux provided a significant reduction in the overall rate of VTE compared with placebo [3 patients (1.4%) vs 77 patients (35%), respectively]. The majority (70/80) of the recorded VTE events were venographically detected non-symptomatic cases of DVT. Fondaparinux also provided a significant reduction in the rate of symptomatic VTE (DVT, and / or PE) [1 (0.3%) vs 9 (2.7%) patients, respectively] including two fatal PE reported in the placebo group. Major bleedings, all at surgical site and none fatal, were observed in 8 patients (2.4%) treated with fondaparinux 2.5 mg compared to 2 (0.6%) with placebo.Prevention of Venous Thromboembolic Events (VTE) in patients undergoing abdominal surgery who are judged to be at high risk of thromboembolic complications, such as patients undergoing abdominal cancer surgeryIn a double-blind clinical study, 2,927 patients were randomised to receive fondaparinux 2.5mg once daily or dalteparin 5,000 IU once daily, with one 2,500 IU preoperative injection and a first 2,500 IU post-operative injection, for 7+2 days. The main sites of surgery were colonic/rectal, gastric, hepatic, cholecystectomy or other biliary. Sixty-nine percent of the patients underwent surgery for cancer. Patients under-going urological (other than kidney) or gynaecological surgery, laparoscopic surgery or vascular surgery were not included in the study.In this study, the incidence of total VTE was 4.6% (47/1,027) with fondaparinux, versus 6.1%: (62/1,021) with dalteparin: odds ratio reduction [95%CI] = -25.8% [-49.7%, 9.5%]. The difference in total VTE rates between the treatment groups, which was not statistically significant, was mainly due to a reduction of asymptomatic distal DVT. The incidence of symptomatic DVT was similar between treatment groups: 6 patients (0.4%) in the fondaparinux group vs 5 patients (0.3%) in the dalteparin group. In the large subgroup of patients undergoing cancer surgery (69% of the patient population), the VTE rate was 4.7% in the fondaparinux group, versus 7.7% in the dalteparin group. Major bleeding was observed in 3.4% of the patients in the fondaparinux group and in 2.4% of the dalteparin group. Prevention of Venous Thromboembolic Events (VTE) in medical patients who are at high risk for thromboembolic complications due to restricted mobility during acute illnessIn a randomised double-blind clinical trial, 839 patients were treated with fondaparinux 2.5 mg once daily or placebo for 6 to 14 days. This study included acutely ill medical patients, aged ≥ 60 years, expected to require bed rest for at least four days, and hospitalized for congestive heart failure NYHA class III/IV and/or acute respiratory illness and/or acute infectious or inflammatory disease. Fondaparinux significantly reduced the overall rate of VTE compared to placebo [18 patients (5.6%) vs 34 patients (10.5%), respectively]. The majority of events were asymptomatic distal DVT. Fondaparinux also significantly reduced the rate of adjudicated fatal PE [0 patients (0.0%) vs 5 patients (1.2%), respectively]. Major bleedings were observed in 1 patient (0.2%) of each group.
Treatment of unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) OASIS 5 was a double-blind, randomised, non-inferiority study with fondaparinux 2.5 mg subcutaneously once daily versus enoxaparin 1 mg/kg subcutaneously twice daily in approximately 20,000 patients with UA/NSTEMI. All patients received standard medical treatment for UA/NSTEMI, with 34% of patients undergoing PCI and 9% undergoing CABG. The mean treatment duration was 5.5 days in the fondaparinux group and 5.2 days in the enoxaparin group. If PCI was performed, patients received either intravenous fondaparinux (fondaparinux patients) or weight adjusted intravenous UFH (enoxaparin patients) as adjunctive therapy, dependent on the timing of the last subcutaneous dose and planned use of GP IIb/IIIa inhibitor. The mean age of the patients was 67 years, and approximately 60% were at least 65 years old. Approximately 40% and 17% of patients had mild (creatinine clearance ≥50 to <80 ml/min) or moderate (creatinine clearance ≥30 to <50 ml/min) renal impairment, respectively.The primary adjudicated endpoint was a composite of death, myocardial infarction (MI) and refractory ischaemia (RI) within 9 days of randomisation. Of the patients in the fondaparinux group, 5.8% experienced an event by Day 9 compared to 5.7% for enoxaparin-treated patients (hazard ratio 1.01, 95% CI, 0.90, 1.13, one-sided non-inferiority p value = 0.003). By Day 30, the incidence of all cause mortality was significantly reduced from 3.5% on enoxaparin to 2.9% on fondaparinux (hazard ratio 0.83, 95% CI, 0.71;0.97, p = 0.02). The effects on the incidence of MI and RI were not statistically different between the fondaparinux and enoxaparin treatment groups. At Day 9 the incidence of major bleeding on fondaparinux and enoxaparin was 2.1% and 4.1%, respectively (hazard ratio 0.52, 95% CI, 0.44;0.61, p < 0.001). The efficacy findings and results on major bleeding were consistent across prespecified subgroups such as elderly, renally impaired patients, type of concomitant platelet aggregation inhibitors (aspirin, thienopyridines or GP IIb/IIIa inhibitors).In the subgroup of patients treated with fondaparinux or enoxaparin who underwent PCI, 8.8% and 8.2% of patients respectively, experience death/MI/RI within 9 days of randomisation (hazard ratio 1.08, 95% CI, 0.92;1.27). In this subgroup, the incidence of major bleeding on fondaparinux and enoxaparin at Day 9 was 2.2% and 5.0% respectively (hazard ratio 0.43, 95% CI, 0.33;0.57). In subjects undergoing PCI the incidence of adjudicated guiding catheter thrombus was 1.0% vs. 0.3% in fondaparinux vs. enoxaparin subjects, respectively.
Treatment of unstable angina (UA) or non-ST segment elevation myocardial infarction (NSTEMI) in patients who underwent subsequent PCI with adjunctive UFHIn a study of 3235 high-risk UA/NSTEMI patients scheduled for angiography and treated with open-label fondaparinux (OASIS 8/FUTURA), the 2026 patients indicated for PCI were randomised to receive one of two double-blind dose regimens of adjunctive UFH. All enrolled patients received fondaparinux 2.5 mg subcutaneously, once daily for up to 8 days, or until hospital discharge. Randomised patients received either low dose UFH regimen (50 U/kg irrespective of planned GPIIb/IIIa use; non ACT guided) or standard dose UFH regimen (no GPIIb/IIIa use: 85 U/kg, ACT guided; planned GPIIb/IIIa use: 60 U/kg, ACT guided) immediately prior to the start of the PCI.The baseline characteristics and duration of fondaparinux treatment were comparable in both UFH groups. In subjects randomized to the standard dose UFH or the low dose UFH regimen the median dose of UFH was 85 U/kg and 50 U/kg, respectively.The primary outcome was a composite of peri-PCI (defined as time of randomisation up to 48 hours post-PCI) adjudicated major or minor bleeding, or major vascular access site complications.
1: Odds ratio: Low Dose/Standard Dose
Note: MI - myocardial infarction. TVR - target vessel revascularization
The incidences of adjudicated guiding catheter thrombus were 0.1% (1/1002) and 0.5% (5/1024), in patients randomised to standard dose and low dose UFH respectively during PCI. Four (0.3%) non-randomised patients experienced thrombus in the diagnostic catheter during coronary angiography. Twelve (0.37%) enrolled patients experienced thrombus in the arterial sheath, of these 7 were reported during angiography and 5 were reported during PCI.
|Low Dose UFH
N = 1024
||Standard Dose UFH
N = 1002
|| || || || |
|Peri-PCI major or minor bleeding, or major vascular access site complications
||0.80 (0.54, 1.19)
|| || || || |
|Peri-PCI major bleeding
||1.14 (0.53, 2.49)
|Peri-PCI minor bleeding
||0.40 (0.16, 0.97)
|Major vascular access site complications
||0.74 (0.47, 1.18)
|Peri-PCI major bleeding or death, MI or TVR at Day 30
||1.51 (1.0, 2.28)
|Death, MI or TVR at Day 30
||1.58 (0.98, 2.53)
Treatment of ST segment elevation myocardial infarction (STEMI)OASIS 6 was a double blind, randomised study assessing the safety and efficacy of fondaparinux 2.5 mg once daily, versus usual care (placebo (47%) or UFH (53%) in approximately 12,000 patients with STEMI. All patients received standard treatments for STEMI, including primary PCI (31%), thrombolytics (45%) or no reperfusion (24%). Of the patients treated with a thrombolytic, 84% were treated with a non-fibrin specific agent (primarily streptokinase). The mean treatment duration was 6.2 days on fondaparinux. The mean age of the patients was 61 years, and approximately 40% were at least 65 years old. Approximately 40% and 14% of patients had mild (creatinine clearance ≥50 to <80 ml/min) or moderate (creatinine clearance ≥30 to <50 ml/min) renal impairment, respectively.The primary adjudicated endpoint was a composite of death and recurrent MI (re-MI) within 30 days of randomisation. The incidence of death/re-MI at Day 30 was significantly reduced from 11.1% for the control group to 9.7% for the fondaparinux group (hazard ratio 0.86, 95% CI, 0.77, 0.96, p = 0.008). In the predefined stratum comparing fondaparinux to placebo (i.e patients treated with non-fibrin specific lytics (77.3%), no reperfusion (22%), fibrin-specific lytics (0.3%), primary PCI (0.4%), the incidence of death/re-MI at Day 30 was significantly reduced from 14.0% on placebo to 11.3% (hazard ratio 0.80, 95% CI, 0.69, 0.93, p = 0.003). In the predefined stratum comparing fondaparinux to UFH (patients treated with primary PCI (58.5%), fibrin-specific lytics (13%), non-fibrin-specific lytics (2.6%) and no reperfusion (25.9%), the effects of fondaparinux and UFH on the incidence of death/re-MI at Day 30 were not statistically different: respectively, 8.3% vs 8.7% (hazard ratio 0.94, 95% CI, 0.79, 1.11 p = 0.460). However, in this stratum, in the subgroup of indicated population undergoing thrombolysis or no reperfusion (i.e patients not undergoing primary PCI), the incidence of death/re-MI at Day 30 was significantly reduced from 14.3% on UFH to 11.5% with fondaparinux (hazard ratio 0.79, 95% CI, 0.64, 0.98, p = 0.03).The incidence of all cause mortality at Day 30 was also significantly reduced from 8.9% for the control group to 7.8% in the fondaparinux group (hazard ratio 0.87, 95% CI, 0.77;0.98, p = 0.02). The difference in mortality was statistically significant in stratum 1 (placebo comparator) but not in stratum 2 (UFH comparator). The mortality benefit shown in the fondaparinux group was maintained until the end of follow-up at Day 180.In patients who were revascularised with a thrombolytic, fondaparinux significantly reduced the incidence of death/re-MI at Day 30 from 13.6% for the control group to 10.9% (hazard ratio 0.79, 95%CI, 0.68;0.93, p = 0.003). Among patients initially not reperfused, the incidence of death/re-MI at Day 30 was significantly reduced from 15% for the control group to 12.1% for the fondaparinux group (hazard ratio 0.79, 95% CI, 0.65;0.97, p = 0.023). In patients treated with primary PCI, the incidence of death/re-MI at Day 30 was not statistically different between the two groups [6.0% in fondaparinux group vs 4.8% in the control group; hazard ratio 1.26, 95% CI, 0.96, 1.66].By Day 9, 1.1% of patients treated with fondaparinux and 1.4% of control patients experienced a severe haemorrhage. In patients given a thrombolytic, severe haemorrhage occurred in 1.3% of the fondaparinux patients and in 2.0% of controls. In patients initially not reperfused, the incidence of severe haemorrhage was 1.2% for fondaparinux vs 1.5% for controls. For patients receiving primary PCI, the incidence of severe haemorrhage was 1.0% for fondaparinux and 0.4% for controls.In subjects undergoing primary PCI the incidence of adjudicated guiding catheter thrombus was 1.2% vs 0% in fondaparinux vs. control subjects, respectively.The efficacy findings and results on severe haemorrhage were consistent across prespecified subgroups such as elderly, renally impaired patients, type of concomitant platelet aggregation inhibitors (aspirin, thienopyridines).
Treatment of patients with acute symptomatic spontaneous superficial-vein thrombosis without concomitant Deep-Vein Thrombosis (DVT)A randomised, double blind, clinical trial (CALISTO) included 3002 patients with acute symptomatic isolated, spontaneous superficial-vein thrombosis of the lower limbs, at least 5 cm long, confirmed by compression ultrasonography. Patients were not included if they had concomitant DVT or superficial-vein thrombosis within 3 cm of the sapheno-femoral junction. Patients were excluded if they had severe hepatic impairment, severe renal impairment (creatinine clearance <30ml/min), low body weight (<50kg), active cancer, symptomatic PE or a recent history of DVT/PE (<6 months) or superficial-vein thrombosis (<90 days), or superficial-vein thrombosis associated with sclerotherapy or a complication of an IV line, or they were at high risk of bleeding. Patients were randomised to receive fondaparinux 2.5 mg once daily or placebo for 45 days in addition to elastic stockings, analgesic and/or topical NSAIDS anti-inflammatory drugs. Follow-up continued up to Day 77. The study population was 64% female, with a median age of 58 years, 4.4% had a creatinine clearance <50ml/min. The primary efficacy outcome, a composite of symptomatic PE, symptomatic DVT, symptomatic superficial-vein thrombosis extension, symptomatic superficial-vein thrombosis reoccurrence, or Death up to Day 47, was significantly reduced from 5.9% in placebo patients to 0.9% in those receiving fondaparinux 2.5 mg (relative risk reduction: 85.2%; 95% CIs, 73.7% to 91.7% [p<0.001]). The incidence of each thromboembolic component of the primary outcome was also significantly reduced in fondaparinux patients as follows: symptomatic PE [0 (0%) vs 5 (0.3%) (p=0.031)], symptomatic DVT [3 (0.2%) vs 18 (1.2%); relative risk reduction 83.4% (p<0.001)], symptomatic superficial-vein thrombosis extension [4 (0.3%) vs 51 (3.4%); relative risk reduction 92.2% (p<0.001)], symptomatic superficial-vein thrombosis reoccurrence [5 (0.3%) vs 24 (1.6%); relative risk reduction 79.2% (p<0.001)]. The mortality rates were low and similar between the treatments groups with 2 (0.1%) deaths in the fondaparinux group versus 1 (0.1%) death in the placebo group. Efficacy was maintained up to Day 77 and was consistent across all predefined subgroups including patients with varicose veins and patients with superficial-vein thrombosis located below the knee. Major bleeding during treatment occurred in 1 (0.1%) fondaparinux patient and in 1 (0.1%) placebo patient. Clinically relevant non major bleeding occurred in 5 (0.3%) fondaparinux patients and 8 (0.5%) placebo patients.