Myocardial Infarction
Conditions
Keywords
Myocardial Infarction, Angioplasty, Myocardial Ischemia, Myocardial Reperfusion, Stents, Heart Disease
Brief summary
The primary objectives of the trial are: 1. To establish the safety and efficacy of the use of bivalirudin (+ bail-out GP IIb/IIIa inhibitors) compared to the use of unfractionated heparin + GP IIb/IIIa inhibitors in patients with acute myocardial infarction undergoing a primary angioplasty strategy. 2. To establish the safety and efficacy of the slow rate release paclitaxel-eluting TAXUS™ stent compared to an otherwise identical uncoated bare metal EXPRESS2™ stent.
Detailed description
Prospective, 2 x 2 factorial single blind, randomized, multi-center trial of 3400 patients enrolled at up to 200 centers. Patients will be randomized 1:1 in the emergency room to a) anticoagulation with unfractionated heparin plus routine GP IIb/IIIa inhibition vs. b) bivalirudin and bail-out GP IIb/IIIa inhibition. Following angiography, patients with lesions eligible for stenting will then undergo a second randomization (3:1) to stent implantation with either a) a slow rate-release paclitaxel-eluting stent (TAXUS™) or b) an otherwise identical uncoated bare metal stent (EXPRESS2™).
Interventions
DRUGBivalirudin
Bivalirudin bolus of 0.75 mg/kg IV, followed by an infusion of 1.75 mg/kg/h as soon as logistically feasible (ideally in the emergency room).
DRUGUnfractionated heparin
60 U/kg of IV heparin, started as soon as possible (ideally in the emergency room).
DEVICEBare metal stent
Uncoated bare metal stent
DEVICEPaclitaxel-eluting stent
slow rate-release paclitaxel-eluting stent
Sponsors
Boston Scientific Corporation
The Medicines Company
Cardiovascular Research Foundation, New York
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have clinical symptoms consistent with AMI (e.g., angina or anginal equivalent)lasting \>20 minutes but \<12 hours in duration; * ST-segment elevation of \>1 mm in \>2 contiguous leads, or (presumably new) left bundle branch block, or true posterior MI with ST depression of \>1 mm in \>2 contiguous anterior leads; * The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up, and provides informed, written consent.
Exclusion criteria
* The patient has a known hypersensitivity or contraindication to any of the following medications: * Heparin, pork or pork products * Both abciximab and eptifibatide * Aspirin * Both Clopidogrel and Ticlopidine * Bivalirudin * Paclitaxel or Taxol * The polymer components of the TAXUS™ stent (SIBS) * Stainless steel and/or * Contrast media; * Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, low molecular weight heparin or fondaparinux for this admission. Patients receiving prior unfractionated heparin may be enrolled, and treated per randomization; * Current use of coumadin; * Systemic (intravenous) Paclitaxel or Taxol use within 12 months; * Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plans to become pregnant any time after enrollment into this study; * History of bleeding diathesis or known coagulopathy (including heparin-induced thrombocytopenia), or will refuse blood transfusions; * History of intra-cerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic stroke; * Stroke or transient ischemic attack within the past 6 months, or any permanent residual neurologic defect; * Gastrointestinal or genitourinary bleeding within the last 2 months, or major surgery within six weeks; * Recent history or known current platelet count \<100,000 cells/mm3 or Hgb \<10 g/dL; * Extensive peripheral vascular disease, such that emergent angiography and intervention in the opinion of the investigator is likely to be difficult or complicated; * An elective surgical procedure is planned that would necessitate interruption of thienopyridines during the first six months post enrollment; * Non-cardiac co-morbid conditions are present with life expectancy \<1 year or that may result in protocol non-compliance; * Patients who are actively participating in another drug or device investigational study, which have not completed the primary endpoint follow-up period; * Previous enrollment in this trial; * Patients who underwent coronary stent implantation within the past 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacology Arm - Major Adverse Ischemic Cardiac Events and Major Bleeding Events | 30 Days | Number of participants with major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke) and major bleeding (bleeding adjudicated as not related to coronary artery bypass grafting). |
| Stent Arm - Ischemic Target Lesion Revascularization | 1 year | Number of Participants With Ischemic Target Lesion Revascularization |
| Stent Arm - Death, Reinfarction, Stroke, or Stent Thrombosis | 1 year | Number of Participants With Death, Reinfarction, Stroke, or Stent Thrombosis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacology Arm - Major Adverse Cardiovascular Events | 30 days | Number of participants with major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke) |
| Pharmacology Arm - Non-Coronary Artery Bypass Grafting-Related Major Bleeding | 30 days | Number of participants with major bleeding (bleeding adjudicated as not related to coronary artery bypass grafting) |
| Stent Arm - Segment Binary Angiographic Restenosis | 13 months | Number of Participants With Segment Binary Angiographic Restenosis (13-month Angiographic Subset). |
Countries
United States
Participant flow
Recruitment details
Between March 25, 2005, and May 7, 2007, 3602 patients with STEMI undergoing primary percutaneous coronary intervention were enrolled at 123 academic or community-based medical centers in 11 countries.
Pre-assignment details
Random, open-label assignment (1:1 ratio) to unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin alone. After emergency angiography and triage to PCI, CABG, or GDMT, eligible patients were randomly assigned (3:1 ratio) to either paclitaxel-eluting stents or uncoated, bare-metal stents.
Participants by arm
| Arm | Count |
|---|---|
| Pharmacology Arm - Bivalirudin To establish the safety and efficacy of the use of bivalirudin in patients with acute myocardial infarction undergoing a primary angioplasty strategy by showing that compared to unfractionated heparin plus routine use of GP IIb/IIIa inhibitors, bivalirudin (with use of GP IIb/IIIa inhibitors reserved for angioplasty complications) results in:
1. reduced rates of major bleeding events at 30 days
2. similar rates of major adverse ischemic cardiac events at 30 days
3. reduced rates of the composite of major adverse ischemic cardiac events + major bleeding at 30 days.
Bivalirudin: Bivalirudin bolus of 0.75 mg/kg IV, followed by an infusion of 1.75 mg/kg/h as soon as logistically feasible (ideally in the emergency room).
Unfractionated heparin: 60 U/kg of IV heparin, started as soon as possible (ideally in the emergency room). | 1,800 |
| Pharmacology Arm - Unfractionated Heparin To establish the safety and efficacy of the use of bivalirudin in patients with acute myocardial infarction undergoing a primary angioplasty strategy by showing that compared to unfractionated heparin plus routine use of GP IIb/IIIa inhibitors, bivalirudin (with use of GP IIb/IIIa inhibitors reserved for angioplasty complications) results in:
1. reduced rates of major bleeding events at 30 days
2. similar rates of major adverse ischemic cardiac events at 30 days
3. reduced rates of the composite of major adverse ischemic cardiac events + major bleeding at 30 days.
Bivalirudin: Bivalirudin bolus of 0.75 mg/kg IV, followed by an infusion of 1.75 mg/kg/h as soon as logistically feasible (ideally in the emergency room).
Unfractionated heparin: 60 U/kg of IV heparin, started as soon as possible (ideally in the emergency room). | 1,802 |
| Total | 3,602 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Pharmacology Intervention/Randomization | Lost to Follow-up | 97 | 103 | 0 | 0 |
| Pharmacology Intervention/Randomization | Not true myocardial infarction | 29 | 28 | 0 | 0 |
| Pharmacology Intervention/Randomization | Withdrawal by Subject | 40 | 43 | 0 | 0 |
| Stent Intervention/Randomization | Lost to Follow-up | 0 | 0 | 113 | 47 |
| Stent Intervention/Randomization | Withdrawal by Subject | 0 | 0 | 41 | 15 |
Baseline characteristics
| Characteristic | Pharmacology Arm - Bivalirudin | Pharmacology Arm - Unfractionated Heparin | Total |
|---|---|---|---|
| Age, Continuous | 59.8 years | 60.7 years | 60.2 years |
| Sex: Female, Male Female | 412 Participants | 430 Participants | 842 Participants |
| Sex: Female, Male Male | 1388 Participants | 1372 Participants | 2760 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 102 / 1,800 | 134 / 1,802 | 123 / 2,257 | 48 / 749 |
| other Total, other adverse events | 81 / 1,800 | 132 / 1,802 | 122 / 2,257 | 32 / 749 |
| serious Total, serious adverse events | 397 / 1,800 | 439 / 1,802 | 473 / 2,257 | 185 / 749 |
Outcome results
Primary
Pharmacology Arm - Major Adverse Ischemic Cardiac Events and Major Bleeding Events
Number of participants with major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke) and major bleeding (bleeding adjudicated as not related to coronary artery bypass grafting).
Time frame: 30 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Pharmacology Arm - Major Adverse Ischemic Cardiac Events and Major Bleeding Events | 166 Participants |
| Pharmacology Arm - Unfractionated Heparin | Pharmacology Arm - Major Adverse Ischemic Cardiac Events and Major Bleeding Events | 218 Participants |
Primary
Stent Arm - Death, Reinfarction, Stroke, or Stent Thrombosis
Number of Participants With Death, Reinfarction, Stroke, or Stent Thrombosis
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Stent Arm - Death, Reinfarction, Stroke, or Stent Thrombosis | 181 Participants |
| Pharmacology Arm - Unfractionated Heparin | Stent Arm - Death, Reinfarction, Stroke, or Stent Thrombosis | 59 Participants |
Primary
Stent Arm - Ischemic Target Lesion Revascularization
Number of Participants With Ischemic Target Lesion Revascularization
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Stent Arm - Ischemic Target Lesion Revascularization | 98 Participants |
| Pharmacology Arm - Unfractionated Heparin | Stent Arm - Ischemic Target Lesion Revascularization | 54 Participants |
Secondary
Pharmacology Arm - Major Adverse Cardiovascular Events
Number of participants with major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke)
Time frame: 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Pharmacology Arm - Major Adverse Cardiovascular Events | 379 Participants |
| Pharmacology Arm - Unfractionated Heparin | Pharmacology Arm - Major Adverse Cardiovascular Events | 377 Participants |
Secondary
Pharmacology Arm - Major Adverse Cardiovascular Events
Number of participants with major adverse cardiovascular events (death, reinfarction, target-vessel revascularization for ischemia, and stroke)
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Pharmacology Arm - Major Adverse Cardiovascular Events | 98 Participants |
| Pharmacology Arm - Unfractionated Heparin | Pharmacology Arm - Major Adverse Cardiovascular Events | 99 Participants |
Secondary
Pharmacology Arm - Non-Coronary Artery Bypass Grafting-Related Major Bleeding
Number of participants with major bleeding (bleeding adjudicated as not related to coronary artery bypass grafting)
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Pharmacology Arm - Non-Coronary Artery Bypass Grafting-Related Major Bleeding | 89 Participants |
| Pharmacology Arm - Unfractionated Heparin | Pharmacology Arm - Non-Coronary Artery Bypass Grafting-Related Major Bleeding | 149 Participants |
Secondary
Stent Arm - Segment Binary Angiographic Restenosis
Number of Participants With Segment Binary Angiographic Restenosis (13-month Angiographic Subset).
Time frame: 13 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pharmacology Arm - Bivalirudin | Stent Arm - Segment Binary Angiographic Restenosis | 102 Participants |
| Pharmacology Arm - Unfractionated Heparin | Stent Arm - Segment Binary Angiographic Restenosis | 76 Participants |