Myocardial Infarction, Segment Elevation Myocardial Infarction (STEMI)
Conditions
Keywords
Heart attack, heart disease, cardiovascular disease, stroke, reperfusion, pre hospital settings, ticagrelor, Percutaneous Coronary Intervention
Brief summary
The aim of this study is to determine whether initiation of ticagrelor as early as in the ambulance setting leads to a rapid reperfusion of the infarct-related artery therefore facilitating the Percutaneous Coronary Intervention (PCI) and optimizing the outcome for the patient. The study will assess the efficacy and safety of pre-hospital compared to in-hospital administration of ticagrelor in co-administration with aspirin, on restoring the blood flow in the occluded heart artery and improving the myocardial perfusion in patients suffering from myocardial infarction and planned to have a PCI. Patients can be randomised in either one of the 2 arms: re-hospital ticagrelor arm: Patients will receive a loading dose of 180 mg ticagrelor for the pre-hospital administration and placebo for in-hospital administration. or In-hospital ticagrelor arm: Patients will receive a placebo for pre-hospital administration and 180 mg ticagrelor loading dose for in-hospital administration. Patients are initially managed by ambulance physician/personnel in pre hospital settings. They are then transferred into a Catheterization room to undergo a PCI. After the administration of the loading dose of ticagrelor (double blind), patients will continue on ticagrelor 90 mg bid and be followed in study for 30 days post randomisation.
Interventions
DRUGTicagrelor
Oral Ticagrelor loading dose (180 mg) followed by matching placebo
DRUGPlacebo
Placebo followed by oral Ticagrelor loading dose (180 mg)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women must not be of child-bearing potential (1 year post-menopausal or surgically sterile). * Symptoms of acute MI of more than 30 min but less than 6 hours * New persistent ST-segment elevation ≥ 1 mm in two or more contiguous electrocardiogram (ECG) leads.
Exclusion criteria
* Expected time to 1st PCI balloon inflation in the hospital, from the qualifying ECG is more than 120 minutes * Contraindication to ticagrelor (refer to SmPC) * Concomitant medication that may increase the risk of bleeding \[e.g non steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulant and / or fibrinolytics, planned or administered 24 hours before randomization\] * Any of the following conditions in the absence of a functioning implanted pacemaker: known SSS, second or third degree AVB, or documented syncope of suspected bradycardic origin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Thrombolysis In Myocardial Infarction (TIMI) Flow Grade 3 of MI Culprit Vessel at Initial Angiography (Co-primary Endpoint) | At initial angiography, pre PCI | (TIMI) flow grade classification is used to assess coronary blood flow in acute coronary syndromes. grade 0:no reperfusion, grade 1: penetration without perfusion, grade 2: Partial reperfusion, grade 3: complete perfusion. |
| ST-segment Elevation Resolution Pre PCI ≥70% (Co-primary Endpoint) | Between baseline and PCI | ST segment elevation resolution is the mean ST elevation pre-hospital minus the mean STelevation pre-PCI divided by the mean ST elevation pre-hospital. It is expressed as a percentage and split in 2 categories , complete (≥70%) versus incomplete (\<70%) resolution. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Definite Stent Thrombosis | during 30 days of treatment | Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation. It is an adjudicated endpoint |
| TIMI Flow Grade 3 Post -PCI | at coroangiography post-PCI | TIMI) flow grade 3 is complete perfusion post-PCI. |
| ST Segment Elevation Resolution Post-PCI >= 70% | Between baseline and ECG 60 mn post-PCI | ST segment elevation resolution post PCI \>=70% is defined as complete resolution |
| Thrombotic Bail-out With GPIIb/IIIa Inhibitors at Initial PCI | during PCI | Glycoprotein (GP) IIb/IIIa inhibitors are often used as a rescue or bailout therapy to manage complications arising during percutaneous coronary intervention. |
| 1st Composite Clinical Endpoint | during the 30 days of treatment | death/MI/stroke/urgent revascularization/stent thrombosis. Adjudicated events except death |
| Minor and Major Bleedings Within 48 Hours | within 48 hours of first dose | non CABG related bleeds (PLATO definition) |
| Major Bleeds After 48 Hours | after 48hours post-first dose | non CABG related bleeds (PLATO definition) include life threatening and other major bleedings |
| Minor and Major Bleeds After 48 Hours | after 48 hours post first dose | non CABG related bleeds (PLATO definition) |
| Major Bleeds Within 48 Hours | within 48 hours of first dose | non CABG related bleeds, (PLATO definition) include Life threatening and other major bleeds |
| 2nd Composite Clinical Endpoint | within 30 days of study | Death/MI/urgent revascularization. Adjudicated events except death |
Countries
Algeria, Australia, Austria, Canada, Denmark, France, Germany, Hungary, Italy, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
Patients were randomized in pre-hospital settings at 102 Emergency Medical Services between September 2011 and October 2013. 1875 patients were recruited in the study, 1862 consented patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Pre-hospital Ticagrelor Loading dose of Ticagrelor (180 mg) followed by matching placebo. After the loading dose the patient will receive Ticagrelor (90 mg bid) for 30 days. | 909 |
| In-hospital Ticagrelor Placebo followed by a loading dose of Ticagrelor (180 mg). After the loading dose the patient will receive Ticagrelor (90 mg bid) for 30 days. | 953 |
| Total | 1,862 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 30 | 19 |
| Overall Study | Had other reason | 9 | 6 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Protocol Violation | 10 | 7 |
| Overall Study | Withdrawal by Subject | 13 | 23 |
Baseline characteristics
| Characteristic | Pre-hospital Ticagrelor | In-hospital Ticagrelor | Total |
|---|---|---|---|
| Age, Continuous Years | 60.6 Years STANDARD_DEVIATION 12.38 | 61.0 Years STANDARD_DEVIATION 12.49 | 60.8 Years STANDARD_DEVIATION 12.43 |
| Diabetes mellitus no/unknown | 794 patients | 815 patients | 1609 patients |
| Diabetes mellitus yes | 115 patients | 138 patients | 253 patients |
| First medical contact in ambulance | 689 patients | 723 patients | 1412 patients |
| First medical contact in emergency department | 220 patients | 230 patients | 450 patients |
| Killip class I | 819 patients | 862 patients | 1681 patients |
| Killip class II, III, IV | 51 patients | 43 patients | 94 patients |
| Killip class unknown | 39 patients | 48 patients | 87 patients |
| PCI no | 109 Patients | 123 Patients | 232 Patients |
| PCI yes | 800 Patients | 830 Patients | 1630 Patients |
| Sex: Female, Male Female | 173 Participants | 196 Participants | 369 Participants |
| Sex: Female, Male Male | 736 Participants | 757 Participants | 1493 Participants |
| Time between the 2 loading doses | 32 minutes | 30 minutes | 31 minutes |
| TIMI risk score 0-2 | 552 patients | 573 patients | 1125 patients |
| TIMI risk score 3-6 | 337 patients | 365 patients | 702 patients |
| TIMI risk score >6 | 20 patients | 15 patients | 35 patients |
| type of PCI without stent | 40 patients | 54 patients | 94 patients |
| type of PCI with stent | 760 patients | 776 patients | 1536 patients |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 529 / 950 | 469 / 908 |
| serious Total, serious adverse events | 143 / 950 | 140 / 908 |
Outcome results
Primary
ST-segment Elevation Resolution Pre PCI ≥70% (Co-primary Endpoint)
ST segment elevation resolution is the mean ST elevation pre-hospital minus the mean STelevation pre-PCI divided by the mean ST elevation pre-hospital. It is expressed as a percentage and split in 2 categories , complete (≥70%) versus incomplete (\<70%) resolution.
Time frame: Between baseline and PCI
Population: mITT, on patients with non missing values
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | ST-segment Elevation Resolution Pre PCI ≥70% (Co-primary Endpoint) | 102 patients |
| In-hospital Ticagrelor | ST-segment Elevation Resolution Pre PCI ≥70% (Co-primary Endpoint) | 102 patients |
p-value: 0.632295% CI: [0.801, 1.441]Regression, Logistic
Primary
Thrombolysis In Myocardial Infarction (TIMI) Flow Grade 3 of MI Culprit Vessel at Initial Angiography (Co-primary Endpoint)
(TIMI) flow grade classification is used to assess coronary blood flow in acute coronary syndromes. grade 0:no reperfusion, grade 1: penetration without perfusion, grade 2: Partial reperfusion, grade 3: complete perfusion.
Time frame: At initial angiography, pre PCI
Population: mITT, on patients with non missing values
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Thrombolysis In Myocardial Infarction (TIMI) Flow Grade 3 of MI Culprit Vessel at Initial Angiography (Co-primary Endpoint) | 143 patients |
| In-hospital Ticagrelor | Thrombolysis In Myocardial Infarction (TIMI) Flow Grade 3 of MI Culprit Vessel at Initial Angiography (Co-primary Endpoint) | 145 patients |
p-value: 0.821495% CI: [0.799, 1.327]Regression, Logistic
Secondary
1st Composite Clinical Endpoint
death/MI/stroke/urgent revascularization/stent thrombosis. Adjudicated events except death
Time frame: during the 30 days of treatment
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | 1st Composite Clinical Endpoint | 41 patients |
| In-hospital Ticagrelor | 1st Composite Clinical Endpoint | 42 patients |
p-value: 0.905695% CI: [0.661, 1.595]Regression, Logistic
Secondary
2nd Composite Clinical Endpoint
Death/MI/urgent revascularization. Adjudicated events except death
Time frame: within 30 days of study
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | 2nd Composite Clinical Endpoint | 39 patients |
| In-hospital Ticagrelor | 2nd Composite Clinical Endpoint | 34 patients |
p-value: 0.416895% CI: [0.76, 1.942]Regression, Logistic
Secondary
Definite Stent Thrombosis
Definite stent thrombosis is considered to have occurred by either angiographic or pathologic confirmation. It is an adjudicated endpoint
Time frame: during 30 days of treatment
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Definite Stent Thrombosis | 2 patients |
| In-hospital Ticagrelor | Definite Stent Thrombosis | 11 patients |
p-value: 0.030795% CI: [0.042, 0.856]Regression, Logistic
Secondary
Major Bleeds After 48 Hours
non CABG related bleeds (PLATO definition) include life threatening and other major bleedings
Time frame: after 48hours post-first dose
Population: safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Major Bleeds After 48 Hours | 11 patients |
| In-hospital Ticagrelor | Major Bleeds After 48 Hours | 11 patients |
Secondary
Major Bleeds Within 48 Hours
non CABG related bleeds, (PLATO definition) include Life threatening and other major bleeds
Time frame: within 48 hours of first dose
Population: Safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Major Bleeds Within 48 Hours | 16 patients |
| In-hospital Ticagrelor | Major Bleeds Within 48 Hours | 15 patients |
Secondary
Minor and Major Bleedings Within 48 Hours
non CABG related bleeds (PLATO definition)
Time frame: within 48 hours of first dose
Population: Safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Minor and Major Bleedings Within 48 Hours | 24 patients |
| In-hospital Ticagrelor | Minor and Major Bleedings Within 48 Hours | 24 patients |
Secondary
Minor and Major Bleeds After 48 Hours
non CABG related bleeds (PLATO definition)
Time frame: after 48 hours post first dose
Population: safety
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Minor and Major Bleeds After 48 Hours | 18 patients |
| In-hospital Ticagrelor | Minor and Major Bleeds After 48 Hours | 16 patients |
Secondary
ST Segment Elevation Resolution Post-PCI >= 70%
ST segment elevation resolution post PCI \>=70% is defined as complete resolution
Time frame: Between baseline and ECG 60 mn post-PCI
Population: mITT on patients with non missing ECG values
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | ST Segment Elevation Resolution Post-PCI >= 70% | 410 patients |
| In-hospital Ticagrelor | ST Segment Elevation Resolution Post-PCI >= 70% | 390 patients |
p-value: 0.054795% CI: [0.996, 1.506]Regression, Logistic
Secondary
Thrombotic Bail-out With GPIIb/IIIa Inhibitors at Initial PCI
Glycoprotein (GP) IIb/IIIa inhibitors are often used as a rescue or bailout therapy to manage complications arising during percutaneous coronary intervention.
Time frame: during PCI
Population: mITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | Thrombotic Bail-out With GPIIb/IIIa Inhibitors at Initial PCI | 78 patients |
| In-hospital Ticagrelor | Thrombotic Bail-out With GPIIb/IIIa Inhibitors at Initial PCI | 100 patients |
p-value: 0.16695% CI: [0.588, 1.096]Regression, Logistic
Secondary
TIMI Flow Grade 3 Post -PCI
TIMI) flow grade 3 is complete perfusion post-PCI.
Time frame: at coroangiography post-PCI
Population: mITT, on patients with non missing TIMI flow grade values
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-hospital Ticagrelor | TIMI Flow Grade 3 Post -PCI | 625 patients |
| In-hospital Ticagrelor | TIMI Flow Grade 3 Post -PCI | 630 patients |
p-value: 0.34495% CI: [0.876, 1.462]Regression, Logistic