Fondaparinux Trial With Unfractionated Heparin (UFH) During Revascularization in Acute Coronary Syndromes (ACS)

Phase 4

Completed

Conditions: Acute Coronary Syndrome

Interventions: Drug: fondaparinux background and standard dose UFH
Drug: Fondaparinux background and low dose heparin
Drug: Open label fondaparinux

Registration Number: NCT00790907

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to compare the safety of two different dose regimens of unfractionated heparin (UFH) during a percutaneous coronary intervention (PCI) procedure in patients with UA (unstable angina)/NSTEMI (non ST segment elevation myocardial infarction) who have been initially treated with fondaparinux.

Detailed Description: Subjects presenting at hospital with suspected UA or NSTEMI and who are likely to undergo angiography (ideally within 72 hours) will be assessed for eligibility and consented. Suitable subjects will be enrolled and commence treatment with open-label fondaparinux, 2.5 milligram (mg), subcutaneous (s.c.), once daily. Following angiography subjects indicated for PCI and meeting the additional requirements for randomization will be randomised to receive one of two dose regimens of UFH either standard dose or low dose immediately prior to the PCI procedure. Post-PCI, therapy with fondaparinux (2.5 mg, s.c.) may be resumed at the investigator's discretion for up to a maximum of 8 days or hospital discharge, whichever is earlier.

Subjects not indicated for PCI, will continue treatment with fondaparinux, 2.5mg, s.c, once daily for up to 8 days or hospital discharge, whichever is earlier.

All subjects will be followed up for 30 days after randomization/angiography.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3235

Inclusion Criteria

Presenting or admitted to hospital with symptoms suspected to represent UA or NSTEMI, i.e., clinical history consistent with new onset, or a worsening pattern of, characteristic ischemic chest pain or ischemic symptoms occurring at rest or with minimal activity (lasting longer than 5 minutes or requiring sublingual nitro-glycerine for relief of the pain).
Available to be enrolled within 48 hours of the onset of the most recent episode of symptoms.
Planned coronary angiography, with PCI if indicated, within 72 hours of enrollment where possible.
At least two of the three following additional criteria:
Age greater than or equal to 60 years
Troponin T or I or CK-MB above the upper limit of normal for the local institution;
Electrocardiogram (ECG) changes compatible with ischemia, i.e., ST depression at least 1 mm in 2 contiguous leads or T wave inversion > 3 mm or any dynamic ST shift or transient ST elevation.
Written informed consent dated and signed

Exclusion Criteria

Age < 21 years.
Any contraindication to UFH or fondaparinux
Contraindication for angiography or PCI at baseline
Subjects requiring urgent (<120 minutes) coronary angiography as characterized by those with:
refractory or recurrent angina associated with dynamic ST-deviation
heart failure
life-threatening arrhythmias
hemodynamic instability
Subjects already receiving treatment with enoxaparin (or other LMWH), bivalirudin or UFH for treatment of the qualifying events unless the last administered (intravenous(i.v.) or s.c.) dose was:
≥ 8 hours for low molecular weight heparin (LMWH)
≥60 minutes for bivalirudin
≥90 minutes for unfractionated heparin (UFH)
Hemorrhagic stroke within the last 12 months.
Indication for anti-coagulation other than acute coronary syndrome (ACS) during the index hospitalization.
Pregnancy or women of childbearing potential who are not using an effective method of contraception.
Co-morbid condition with life expectancy less than 6 months.
Currently receiving an experimental pharmacological agent.
Revascularization procedure already performed for the qualifying event.
Severe renal insufficiency (i.e., estimated creatinine clearance <20 ml/min)

Following angiography and confirmation that the subject is to undergo PCI, the subject must also meet all of the following additional criteria in order to be randomised:

Subjects will have received at least 1 dose of open-label fondaparinux
The most recent dose of open-label fondaparinux will not have been more than 24 hours before the start of the PCI procedure.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Open label fondaparinux background and standard dose UFH	fondaparinux background and standard dose UFH	Subjects indicated for PCI and randomized to receive standard dose UFH
Open label fondaparinux background and low dose UFH	Fondaparinux background and low dose heparin	Subjects indicated for PCI and randomized to receive low dose UFH
Open label fondapaparinux	Open label fondaparinux	Subjects not indicated for PCI and not randomized

Primary Outcome Measures

Name	Time	Method
Number of Participants With Composite of Major Bleeding, Minor Bleeding, or Major Vascular Access Site Complications During the Peri-PCI Period	Peri-PCI Period: occurred at randomization (from randomization to 48 hours after end of PCI procedure, typically 49 hours total)	The peri-percutaneous coronary intervention (peri-PCI) period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Major and minor bleeding events were adjudicated by a blinded central independent adjudication committee (CIAC). Major vascular access site complications comprised large hematoma, pseudoaneurysm requiring treatment, aterio-venous fistula, or other vascular procedures related to the access site.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Major Bleeding During the Peri-PCI Period	Peri-PCI Period: occurred at randomization (from randomization to 48 hours after end of PCI procedure, typically 49 hours total)	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Major bleeding, MI and TVR were adjudicated by a blinded CIAC.
Number of Participants Experiencing Death, MI, TVR, Definite/Probable Stent Thrombosis, or Stroke, Assessed Separately During the Peri-PCI Period and at Day 30	Peri-PCI (during the time from randomization up to 48 hours after the end of PCI, typically 49 hours total) and from randomization up to Day 30	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Assessment of death, MI, TVR, definite/probable stent thrombosis, or stroke was performed during the peri-PCI period and at Day 30. MI, TVR, definite/probable stent thrombosis, and stroke events were adjudicated by a blinded CIAC.
Number of Participants With Composite of Death, MI or TVR During the Peri-PCI Period and at Day 30	Peri-PCI (during the time from randomization up to 48 hours after the end of PCI, typically 49 hours total) and from randomization up to Day 30	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Assessment of composite of death, MI, or TVR was performed both during the peri-PCI period and at Day 30. MI and TVR events were adjudicated by a blinded CIAC.
Number of Participants With Minor Bleeding During the Peri-PCI Period	Peri-PCI Period: occurred at randomization (from randomization to 48 hours after end of PCI procedure, typically 49 hours total)	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Minor bleeding events were adjudicated by a blinded CIAC.
Number of Participants With Major Vascular Access Site Complications During the Peri-PCI Period	Peri-PCI Period: occurred at randomization (from randomization to 48 hours after end of PCI procedure, typically 49 hours total)	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Major vascular access site complications included: large hematoma, pseudoaneurysm requiring treatment, arterio-venous fistula, or other vascular procedures related to the access site.
Number of Participants With Major PCI-related Procedural Complications	During PCI procedure: immediately after randomization (approximately 10-75 minutes)	Major PCI-related procedural complications included: abrupt vessel closure, a new angiographic filling defect representing either angiographic thrombus or major dissection with reduced flow, no-reflow phenomenon, or catheter-related thrombus. Investigator reports of catheter-related thrombus were defined as suspected catheter-related thrombus events, and were adjudicated by a blinded CIAC.
Number of Participants With Composite of Major Bleeding During the Peri-PCI Period, With Death, MI, or TVR at Day 30	Peri-PCI period for major bleeding (during the time from randomization up to 48 hours after the end of PCI [typically 49 hours total] ) and from randomization up to Day 30 for death, MI, or TVR	The peri-PCI period was defined as the period during the time from randomization up to 48 hours after the end of the PCI procedure, typically 49 hours total. Assessment of death, myocardial infarction (MI) and target vessel revascularisation (TVR) was performed at Day 30. Major bleeding, MI and TVR were adjudicated by a blinded CIAC.