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Arixtra Study in Percutaneous Coronary Intervention: A Randomized Evaluation - ASPIRE (Study in PCI)
Description:
The goal of the trial was to evaluate the safety and efficacy of treatment with fondaparinux, a synthetic factor Xa inhibitor, compared with unfractionated heparin (UFH) among patients undergoing percutaneous coronary intervention (PCI).
Study Design
Patients Enrolled: 350
Mean Follow Up: 48 hours post-PCI
Mean Patient Age: Mean age 63 years
Female: 22
Patient Populations:
Age >21 years, undergoing urgent or elective PCI for acute coronary syndrome (including primary PCI) or stable angina.
Exclusions:
Activated clotting time >200 seconds immediately before PCI, use of LMWH within 6 hours of PCI, use of an oral anticoagulant with an international normalized ratio >1.8, thrombolytic therapy for STEMI in prior 24 hours, active internal bleeding or a history of hemorrhagic diathesis, pregnancy, absolute contraindication to anticoagulation, participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days.
Primary Endpoints:
Total bleeding (combined major or minor bleeding) by 48 hours
Secondary Endpoints:
Death, MI, urgent revascularization, and bailout use of a GPIIb/IIIa antagonist.
Drug/Procedures Used:
Patients were randomized to intravenous fondaparinux of 2.5 mg (n=118) or 5.0 mg (n=115) or UFH (n=117). Randomization was stratified by planned glycoprotein (GP) IIb/IIIa inhibitor use. Activated clotting time and activated partial thromboplastin time were not routinely monitored in either arm. Bloods were drawn for serial biomarker analysis (CK, CKMB, troponin, prothrombin fragment F1.2, thrombin-antithrombin complex (TAT), P-selectin, D-dimer, factor VIIa, and anti–factor Xa) at baseline, 6 to 8 hours post-PCI, and 12 to 24 hours post-PCI.
Principal Findings:
The majority of patients underwent PCI for an acute coronary syndrome (79%), with <2% undergoing="" primary="" pci="" for="" st="" elevation="" mi.="" approximately="" one-quarter="" of="" patients="" were="" treated="" with="" a="" drug-eluting="" stent.="" gp="" iib/iiia="" inhibitors="" were="" used="" in="" 58%="" of="" patients.="" angiographic="" complications="" did="" not="" differ="" by="" treatment="" group,="" with="" procedural="" success="" of="" 96-98%.="" total="" bleeding="" did="" not="" differ="" for="" the="" combined="" fondaparinux="" group="" compared="" with="" the="" ufh="" group="" (6.4%="" vs="" 7.7%,="" hazard="" ratio="" [hr]="" 0.81,="" p="0.61)." the="" bleeding="" rate="" in="" the="" 2.5="" mg="" fondaparinux="" group="" was="" lower="" than="" in="" the="" 5.0="" fondaparinux="" group="" (3.4%="" vs="" 9.6%,="" hr="" 0.33,="" p="0.06)." there="" were="" no="" major="" bleeds="" in="" the="" ufh="" group="" and="" 1="" (0.8%)="" and="" 3="" (2.6%)="" in="" the="" 2.5="" mg="" and="" 5.0="" mg="" fondaparinux="" groups,="" respectively.="" minor="" bleeding="" occurred="" in="" 7.7%="" of="" the="" ufh="" group="" and="" 2.5%="" and="" 7.0%="" of="" the="" 2.5="" mg="" and="" 5.0="" mg="" fondaparinux="" groups,="" respectively.="" in="" the="" planned="" gp="" iib/iiia="" inhibitor="" subgroup,="" total="" bleeding="" occurred="" in="" 9.2%="" of="" the="" ufh="" group="" and="" 5.7%="" and="" 13.2%="" of="" the="" fondaparinux="" groups;="" in="" the="" no="" planned="" gp="" iib/iia="" subgroup="" (n="147)," the="" rates="" were="" 5.8%,="" 0%,="" and="" 4.3%,="" respectively.="">br />The composite efficacy endpoint occurred in 6.0% of the combined fondaparinux group and the UFH group (HR 1.01, p=0.97). There was no difference in any component of the composite endpoint by treatment group. The reduction in prothrombin fragment F1.2, a marker of thrombin generation, was greater in the fondaparinux group compared with the UFH group at 6 hours (p=0.02) and 12 hours post-PCI (p=0.01).
Interpretation:
Among patients undergoing elective or urgent PCI, treatment with the synthetic factor Xa inhibitor fondaparinux was associated with similar bleeding rates compared with unfractionated heparin by 48 hours post-PCI. There appeared to be a possible dose escalation bleeding response, with lower bleeding rates in the 2.5 mg group compared with the 5.0 mg group. Clinical efficacy endpoints did not between the UFH and fondaparinux groups, and there was no apparent dose response between the 2.5 mg and 5.0 mg groups. The authors note that fondaparinux selectively binds to antithrombin, resulting in rapid and predictable inhibition of factor Xa, with a half-life of 15 hours and linear pharmacokinetics. This predictable pharmacokinetics eliminates the need for monitoring, unlike UFH. Fondaparinux has been previously been studied for the treatment of venous thrombosis in the setting of orthopedic surgery, as well as in dose-escalation studies in non-ST elevation ACS (the PENTUA trial) and ST elevation MI (the PENTALYSE trial). Two larger efficacy studies are planned to evaluate fondaparinux in the setting of non-ST elevation ACS and ST elevation MI.
References:
Mehta SR, et al. Randomized, Blinded Trial Comparing Fondaparinux With Unfractionated Heparin in Patients Undergoing Contemporary Percutaneous Coronary Intervention. Circulation. 2005;111:1390-1397.
Keywords: Polysaccharides, Acute Coronary Syndrome, Thrombin, Angina, Stable, Heparin, Peptide Hydrolases, Prothrombin, Orthopedics, Platelet Membrane Glycoprotein IIb, Stents, Percutaneous Coronary Intervention, P-Selectin, Half-Life, Partial Thromboplastin Time, Peptide Fragments, Venous Thrombosis, Factor VIIa, Factor Xa, Troponin
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