Acute Coronary Syndrome
Conditions
Keywords
EUROMAX, STEMI, STE-ACS, UFH, bivalirudin, PCI, ambulance study, STE-MI participants
Brief summary
To show that the early administration of bivalirudin improves 30 day outcomes when compared to the current standard of care in participants with ST segment elevation acute coronary syndrome (STE-ACS), intended for a primary percutaneous coronary intervention (PCI) management strategy, presenting either via ambulance or to centers where PCI is not performed.
Detailed description
The purpose of the trial is to show that the early administration of bivalirudin improves 30-day outcomes when compared to the current standard of care in participants with STE-ACS, with an onset of symptoms of \>20 minutes and \<12 hours, intended for a primary PCI management strategy, presenting either via ambulance or to centers where PCI is not performed. All participants are to receive treatment with aspirin (150-325 milligrams \[mg\] administered orally or 250-500 mg intravenously \[IV\]), followed by 75-100 milligrams/day (mg/day) for at least 1 year and a loading dose of an approved P2Y12 receptor blocker, such as clopidogrel, prasugrel, or ticagrelor, that was to be continued as per European Society of Cardiology guidelines (preferably for 1 year) in all participants. The primary objectives of the trial are to show that, when compared with standard anti-thrombotic therapies other than bivalirudin (which includes treatment with unfractionated heparin \[UFH\] and optional glycoprotein IIb/IIIa inhibitor \[GPI\]) that at 30 days: • Bivalirudin is superior to control at reducing a composite of death and non-coronary artery bypass graft (CABG)-related protocol major bleeding.
Interventions
DRUGBivalirudin
DRUGHeparin
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The decision to randomize participants was made by a qualified physician or paramedic who was present at the time. Participants were included in the study if they presented either via ambulance or to a center where PCI was not performed and met all of the following criteria: 1. Provided written informed consent before initiation of any study related procedures. Participants randomized in the ambulance may initially have signed an abridged version. 2. Aged ≥18 years at the time of randomization. 3. Had a presumed diagnosis of STE-ACS with onset of symptoms of \>20 minutes and \<12 hours with one or more of the following: * ST segment elevation of ≥1 millimeters (mm) in ≥2 contiguous leads * Presumably new left bundle branch block * An infero-lateral myocardial infarction with ST segment depression of ≥1 mm in ≥2 of leads V1-3 with a positive terminal T wave 4. All participants would proceed with emergent angiography and primary PCI if indicated \<2 hours after first medical contact
Exclusion criteria
Participants were excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Composite Incidence of Death and Non-coronary Artery Bypass Graft (CABG) Major Bleeding | Within 30 days | A participant was defined to have had a composite event if the participant experienced at least 1 of the 2 components (death or non-CABG major bleeding) of the composite. Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time. Non-CABG major bleeding was defined as any 1 of the following: intra-cranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in hemoglobin (Hb) concentration of \>4 grams/deciliter (g/dL) without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding; re-intervention for bleeding, or use of any blood product transfusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Within 30 days | Incidence=number of participants to experience the event/total number of at risk participants x 100. Death from any cause at any time. Re-infarction was a positive diagnosis of re-infarction not associated with index PCI. Non-CABG major bleeding was any 1 of: intracranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in Hb concentration of \>4 g/dL without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding, re-intervention for bleeding, use of any blood product transfusion. IDR was any refractory ischemia-driven repeat percutaneous intervention or bypass graft surgery involving any native coronary or pre-existing bypass graft vessel. In the absence of pain, new ST segment changes indicative of ischemia, acute pulmonary edema, ventricular arrhythmias, or hemodynamic instability presumed to be ischemic in origin, will constitute sufficient evidence of ischemia. |
| The Incidence of Death at 1 Year | Within 1 Year | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time. |
| The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) | Within 30 days | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Major bleeding based on TIMI criteria was defined as any intra-cranial bleeding, or any bleeding associated with clinically overt signs associated with a drop in Hb of \>5 g/dL (or, when Hb was not available, an absolute drop in hematocrit \[Hct\] \>15%). Major bleeding based on GUSTO criteria was defined as severe/life-threatening: intra-cranial hemorrhage or resulting in substantial hemodynamic compromise requiring treatment. |
| The Composite Incidence of Death, Re-infarction (MI), or Non-CABG Major Bleeding | Within 30 days | A participant had a composite event if the participant experienced at least 1 of the 3 components (death, re-infarction \[MI\], or non-CABG major bleeding) of the composite. Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time. Non-CABG major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in Hb concentration of \>4 g/dL without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding, re-intervention for bleeding, use of any blood product transfusion. MI was defined as a positive diagnosis of re-infarction (new event) not associated with index PCI. |
| The Incidence of Stent Thrombosis (Academic Research Consortium [ARC Definition]) | Within 30 days | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Stent thrombosis, based on the ARC definition, was defined as angiographic confirmation of stent thrombosis, non-occlusive thrombus, occlusive thrombus, or pathological confirmation of stent thrombosis. |
| The Incidence of Thrombocytopenia | Within 30 days | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Thrombocytopenia was defined as a post-procedural platelet count \<100,000 cells/millimeter cubed (cells/mm\^3) in a participant with a baseline or pre-procedural platelet count \>100,000 cells/mm\^3. |
| The Incidence of Stroke | Within 30 days | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Stroke was defined as a sudden, focal neurological defect resulting from a cerebrovascular cause, resulting in death or lasting greater than 24 hours that was not due to a readily identifiable cause, such as a tumor, infection, or trauma. |
| The Incidence of Minor Bleeding: TIMI and GUSTO | Within 30 days | Incidence=the number of participants to experience the event/total number of at risk participants x 100. Minor bleeding based on TIMI criteria was defined as any clinically overt sign of bleeding (including observation by imaging techniques) that was associated with a fall in Hb of ≥3 g/dL and ≤5 g/dL (or, when Hb was not available, an absolute drop in Hct of ≥9% and ≤15%). Minor bleeding based on GUSTO criteria was defined as other bleed not requiring blood transfusion or causing hemodynamic compromise. |
Countries
Austria, Czechia, Denmark, France, Germany, Italy, Netherlands, Poland, Slovenia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bivalirudin Given immediately upon enrollment as an IV bolus of 0.75 mg/kg, followed immediately by an infusion of 1.75 mg/kg/h. This infusion was to be run continuously until completion of PCI, at which time the infusion was reduced to 0.25 mg/kg/h for at least 4 hours. An optional PCI-dose infusion of 1.75 mg/kg/h was also permitted for up to 4 hours at the discretion of the operator. | 1,089 |
| Standard of Care: Heparins With Optional GPI Standard-of-care anti-thrombotic therapy as outlined in the European Society of Cardiology Dosing Guidelines for Management of STE-ACS, not including bivalirudin: UFH (100 international IU/kg without GPI and 60 IU/kg with GPI). Any of the following approved GPIs were used either as a routine strategy or as a bail out: eptifibatide (two 180-μg/kg IV boluses with a 10-min interval followed by an infusion of 2.0 μg/kg/min for 72-96 hours); tirofiban (25 μg/kg followed by an infusion of 0.15 μg/kg/min for 18-24 hours); or abciximab (bolus of 0.25 mg/kg followed by an infusion of 0.125 μg/kg/min for 12-24 hours \[maximum dose of 10 μg/min\]).
For this study, the control consisted of treatment with UFH or LMWH with or without GPI and is referred to as heparins with optional GPI. | 1,109 |
| Total | 2,198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 1 Year Visit Too Early (<335 days) | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Reason Not Specified | 1 | 2 |
| Overall Study | Withdrawal by Subject | 10 | 13 |
Baseline characteristics
| Characteristic | Total | Standard of Care: Heparins With Optional GPI | Bivalirudin |
|---|---|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 13 | 62.0 years STANDARD_DEVIATION 13.1 | 61.4 years STANDARD_DEVIATION 12.8 |
| Medical history: Participant Has Diabetes | 296 participants | 169 participants | 127 participants |
| Medical history: Participant Has Had Previous myocardial infarction (MI) | 493 participants | 113 participants | 380 participants |
| Medical history: Participant Has Hyperlipidemia | 815 participants | 417 participants | 398 participants |
| Medical history: Participant Has Hypertension | 963 participants | 504 participants | 459 participants |
| Medical history: Participant Is a Current smoker (within past 30 days) | 925 participants | 472 participants | 453 participants |
| Region of Enrollment Austria | 9 participants | 5 participants | 4 participants |
| Region of Enrollment Czech Republic | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Denmark | 150 participants | 72 participants | 78 participants |
| Region of Enrollment France | 795 participants | 397 participants | 398 participants |
| Region of Enrollment Germany | 279 participants | 140 participants | 139 participants |
| Region of Enrollment Italy | 72 participants | 41 participants | 31 participants |
| Region of Enrollment Netherlands | 768 participants | 391 participants | 377 participants |
| Region of Enrollment Poland | 111 participants | 56 participants | 55 participants |
| Region of Enrollment Slovenia | 13 participants | 6 participants | 7 participants |
| Sex: Female, Male Female | 523 Participants | 248 Participants | 275 Participants |
| Sex: Female, Male Male | 1675 Participants | 861 Participants | 814 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 134 / 1,099 | 119 / 1,094 |
| serious Total, serious adverse events | 145 / 1,099 | 129 / 1,094 |
Outcome results
Primary
The Composite Incidence of Death and Non-coronary Artery Bypass Graft (CABG) Major Bleeding
A participant was defined to have had a composite event if the participant experienced at least 1 of the 2 components (death or non-CABG major bleeding) of the composite. Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time. Non-CABG major bleeding was defined as any 1 of the following: intra-cranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in hemoglobin (Hb) concentration of \>4 grams/deciliter (g/dL) without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding; re-intervention for bleeding, or use of any blood product transfusion.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Composite Incidence of Death and Non-coronary Artery Bypass Graft (CABG) Major Bleeding | 5.1 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Composite Incidence of Death and Non-coronary Artery Bypass Graft (CABG) Major Bleeding | 8.5 percentage of participants |
p-value: 0.001495% CI: [0.43, 0.82]Chi-squared
Secondary
The Composite Incidence of Death, Re-infarction (MI), or Non-CABG Major Bleeding
A participant had a composite event if the participant experienced at least 1 of the 3 components (death, re-infarction \[MI\], or non-CABG major bleeding) of the composite. Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time. Non-CABG major bleeding was defined as any one of the following: intracranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in Hb concentration of \>4 g/dL without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding, re-intervention for bleeding, use of any blood product transfusion. MI was defined as a positive diagnosis of re-infarction (new event) not associated with index PCI.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Composite Incidence of Death, Re-infarction (MI), or Non-CABG Major Bleeding | 6.6 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Composite Incidence of Death, Re-infarction (MI), or Non-CABG Major Bleeding | 9.2 percentage of participants |
Secondary
The Incidence of Death at 1 Year
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Death was defined as death from any cause at any time.
Time frame: Within 1 Year
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Incidence of Death at 1 Year | 5.4 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Death at 1 Year | 5.3 percentage of participants |
Secondary
The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR)
Incidence=number of participants to experience the event/total number of at risk participants x 100. Death from any cause at any time. Re-infarction was a positive diagnosis of re-infarction not associated with index PCI. Non-CABG major bleeding was any 1 of: intracranial, retroperitoneal, intraocular, access site hemorrhage requiring radiological or surgical intervention, reduction in Hb concentration of \>4 g/dL without an overt source of bleeding, reduction in hemoglobin concentration of \>3 g/dL with an overt source of bleeding, re-intervention for bleeding, use of any blood product transfusion. IDR was any refractory ischemia-driven repeat percutaneous intervention or bypass graft surgery involving any native coronary or pre-existing bypass graft vessel. In the absence of pain, new ST segment changes indicative of ischemia, acute pulmonary edema, ventricular arrhythmias, or hemodynamic instability presumed to be ischemic in origin, will constitute sufficient evidence of ischemia.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bivalirudin | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Death | 2.9 percentage of participants |
| Bivalirudin | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Re-infarction | 1.7 percentage of participants |
| Bivalirudin | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Non-CABG-related major bleeding | 2.6 percentage of participants |
| Bivalirudin | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | IDR | 2.2 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | IDR | 1.5 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Death | 3.1 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Non-CABG-related major bleeding | 6.0 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Death, Re-infarction, Non-CABG-related Major Bleeding, or Ischemia-driven Revascularization (IDR) | Re-infarction | 0.9 percentage of participants |
Secondary
The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO)
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Major bleeding based on TIMI criteria was defined as any intra-cranial bleeding, or any bleeding associated with clinically overt signs associated with a drop in Hb of \>5 g/dL (or, when Hb was not available, an absolute drop in hematocrit \[Hct\] \>15%). Major bleeding based on GUSTO criteria was defined as severe/life-threatening: intra-cranial hemorrhage or resulting in substantial hemodynamic compromise requiring treatment.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bivalirudin | The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) | Major bleeding: TIMI | 1.3 percentage of participants |
| Bivalirudin | The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) | Major bleeding: GUSTO | 1.3 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) | Major bleeding: TIMI | 2.1 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Major Bleeding: Thrombolysis in MI (TIMI) and Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) | Major bleeding: GUSTO | 2.3 percentage of participants |
Secondary
The Incidence of Minor Bleeding: TIMI and GUSTO
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Minor bleeding based on TIMI criteria was defined as any clinically overt sign of bleeding (including observation by imaging techniques) that was associated with a fall in Hb of ≥3 g/dL and ≤5 g/dL (or, when Hb was not available, an absolute drop in Hct of ≥9% and ≤15%). Minor bleeding based on GUSTO criteria was defined as other bleed not requiring blood transfusion or causing hemodynamic compromise.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bivalirudin | The Incidence of Minor Bleeding: TIMI and GUSTO | Minor bleeding: TIMI | 6.5 percentage of participants |
| Bivalirudin | The Incidence of Minor Bleeding: TIMI and GUSTO | Minor bleeding: GUSTO | 6.5 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Minor Bleeding: TIMI and GUSTO | Minor bleeding: TIMI | 11.2 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Minor Bleeding: TIMI and GUSTO | Minor bleeding: GUSTO | 11.0 percentage of participants |
Secondary
The Incidence of Stent Thrombosis (Academic Research Consortium [ARC Definition])
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Stent thrombosis, based on the ARC definition, was defined as angiographic confirmation of stent thrombosis, non-occlusive thrombus, occlusive thrombus, or pathological confirmation of stent thrombosis.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Incidence of Stent Thrombosis (Academic Research Consortium [ARC Definition]) | 1.6 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Stent Thrombosis (Academic Research Consortium [ARC Definition]) | 0.5 percentage of participants |
Secondary
The Incidence of Stroke
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Stroke was defined as a sudden, focal neurological defect resulting from a cerebrovascular cause, resulting in death or lasting greater than 24 hours that was not due to a readily identifiable cause, such as a tumor, infection, or trauma.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Incidence of Stroke | 0.6 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Stroke | 1.0 percentage of participants |
Secondary
The Incidence of Thrombocytopenia
Incidence=the number of participants to experience the event/total number of at risk participants x 100. Thrombocytopenia was defined as a post-procedural platelet count \<100,000 cells/millimeter cubed (cells/mm\^3) in a participant with a baseline or pre-procedural platelet count \>100,000 cells/mm\^3.
Time frame: Within 30 days
Population: Participants who were randomized and signed an ICF; ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | The Incidence of Thrombocytopenia | 0.7 percentage of participants |
| Standard of Care: Heparins With Optional GPI | The Incidence of Thrombocytopenia | 1.4 percentage of participants |