Coronary Artery Disease, Diabetes, Heart Failure, ST Elevation Myocardial Infarction (STEMI)
Conditions
Keywords
Metformin, ST elevation myocardial infarction (STEMI), Coronary artery disease, Heart failure, Diabetes
Brief summary
The investigators will evaluate the effect of metformin therapy during 4 months in non-diabetic patients following ST-elevation myocardial infarction on left ventricular ejection fraction as measured with cardiac magnetic resonance imaging, compared to placebo.
Detailed description
In this trial, the investigators will evaluate the effect of metformin therapy following ST-elevation myocardial infarction (STEMI) in a total of 380 non-diabetic patients. This trial is a randomized, double blind, controlled trial. The intervention, which consist of metformin 500mg twice daily or placebo twice daily, will commence within three hours after the percutaneous coronary intervention, and will be continued for 4 months. The primary endpoint is the difference between the two intervention groups (metformin vs placebo) in left ventricular ejection fraction, as measured with magnetic resonance imaging after 4 months. The investigators hypothesize that metformin therapy results in a significantly higher ejection fraction in this population.
Interventions
DRUGMetformin
Metformin 500mg twice daily during 4 months
DRUGPlacebo
Placebo twice daily during 4 months
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The diagnosis acute MI defined by chest pain suggestive for myocardial ischemia for at least 30 minutes, the time from onset of the symptoms less than 12 hours before hospital admission, and an ECG recording with ST- segment elevation of more than 0.1 mV in 2 or more leads. * Successful primary PCI (post-procedural TIMI 2/3); * At least one stent sized ≥ 3.0 mm; * Eligible for 3T CMR imaging; * Verbal followed by written informed consent.
Exclusion criteria
* rescue PCI after thrombolytic therapy; * need for emergency coronary artery bypass grafting; * creatinin \>177 μmol/L measured pre-PCI; * Younger than 18 years; * Mechanical ventilation; * Diabetes; * Prior myocardial infarction; * Contra-indication to metformin (see safety); * The existence of a life-threatening disease with a life-expectancy of less than 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Left Ventricular Ejection Fraction | 4 months | The primary efficacy parameter of the GIPS-III trial is LVEF measured by cardiac MRI 4 months after randomization, based on an intention-to-treat analysis. It is hypothesized that metformin therapy will result in a higher ejection fraction after 4 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| the Incidence of a Cardiovascular Event | 4 months and longterm follow-up | Cardiovascular events include major cardiac adverse events (MACE; death, recurrent MI, target lesion revascularization), stroke, non-elective hospitalizations for chest pain or heart failure, all recurrent coronary interventions, and internal cardiac defibrillator implantations. Mortality will be divided into cardiac and non-cardiac. Cardiac death will be divided into three categories: heart failure, sudden death and other. A cardiologist will confirm deaths from cardiovascular causes by examining medical records obtained from hospitals and attending physicians or from attending general practitioner if the patient died at home. |
| Markers of Heart Failure and Glycometabolic State | 4 months and longterm follow-up | markers of heart failure: neurohormones (e.g. NT-proBNP), renal function (e.g. MDRD); glycometabolic state: e.g. HbA1c. |
| Myocardial Infarct Size and Transmural Extent of Infarction as Measured With Cardiac Magnetic Resonance Imaging | 4 months after hospitalization | myocardial infarct size and transmural extent of infarction will be measured using Late Gadolinium Enhancement cardiac magnetic imaging |
| Diastolic Function | 4 months | echocardiographic analysis of diastolic function |
| Glycometabolic State | 4 months and long-term follow-up | measured by oral glucose tolerance testing and Glycated Hemoglobin according to current criteria |
| Cardiac MRI After 4 Months, Per Protocol Analysis | 4 months | A per-protocol analysis, excluding patients diagnosed with new onset diabetes and treated with oral antihyperglycemic agents or insulin prior to cardiac MRI, will be performed as a secondary efficacy parameter |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin metformin 500mg twice daily during 4 months
Metformin: Metformin 500mg twice daily during 4 months | 191 |
| Placebo Placebo twice daily during 4 months
Placebo: Placebo twice daily during 4 months | 189 |
| Total | 380 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Metformin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 11.8 | 58.8 years STANDARD_DEVIATION 11.5 | 58.8 years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 47 Participants | 48 Participants | 95 Participants |
| Sex: Female, Male Male | 144 Participants | 141 Participants | 285 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 191 | 1 / 188 |
| other Total, other adverse events | 73 / 191 | 51 / 188 |
| serious Total, serious adverse events | 11 / 191 | 6 / 188 |
Outcome results
Primary
Improvement in Left Ventricular Ejection Fraction
The primary efficacy parameter of the GIPS-III trial is LVEF measured by cardiac MRI 4 months after randomization, based on an intention-to-treat analysis. It is hypothesized that metformin therapy will result in a higher ejection fraction after 4 months.
Time frame: 4 months
Population: patients undergoing primary percutaneous coronary intervention (PCI) for STEMI
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Improvement in Left Ventricular Ejection Fraction | 53.1 % of LVEF |
| Placebo | Improvement in Left Ventricular Ejection Fraction | 54.8 % of LVEF |
Secondary
Cardiac MRI After 4 Months, Per Protocol Analysis
A per-protocol analysis, excluding patients diagnosed with new onset diabetes and treated with oral antihyperglycemic agents or insulin prior to cardiac MRI, will be performed as a secondary efficacy parameter
Time frame: 4 months
Secondary
Diastolic Function
echocardiographic analysis of diastolic function
Time frame: 4 months
Secondary
Glycometabolic State
measured by oral glucose tolerance testing and Glycated Hemoglobin according to current criteria
Time frame: 4 months and long-term follow-up
Secondary
Markers of Heart Failure and Glycometabolic State
markers of heart failure: neurohormones (e.g. NT-proBNP), renal function (e.g. MDRD); glycometabolic state: e.g. HbA1c.
Time frame: 4 months and longterm follow-up
Secondary
Myocardial Infarct Size and Transmural Extent of Infarction as Measured With Cardiac Magnetic Resonance Imaging
myocardial infarct size and transmural extent of infarction will be measured using Late Gadolinium Enhancement cardiac magnetic imaging
Time frame: 4 months after hospitalization
Secondary
the Incidence of a Cardiovascular Event
Cardiovascular events include major cardiac adverse events (MACE; death, recurrent MI, target lesion revascularization), stroke, non-elective hospitalizations for chest pain or heart failure, all recurrent coronary interventions, and internal cardiac defibrillator implantations. Mortality will be divided into cardiac and non-cardiac. Cardiac death will be divided into three categories: heart failure, sudden death and other. A cardiologist will confirm deaths from cardiovascular causes by examining medical records obtained from hospitals and attending physicians or from attending general practitioner if the patient died at home.
Time frame: 4 months and longterm follow-up