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Metformin to Reduce Heart Failure After Myocardial Infarction (GIPS-III)

Primary Purpose

ST Elevation Myocardial Infarction (STEMI), Coronary Artery Disease, Heart Failure

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ST Elevation Myocardial Infarction (STEMI) focused on measuring Metformin, ST elevation myocardial infarction (STEMI), Coronary artery disease, Heart failure, Diabetes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University Medical Center Groningen

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Metformin

Placebo

Arm Description

metformin 500mg twice daily during 4 months

Placebo twice daily during 4 months

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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
Diastolic Function
echocardiographic analysis of diastolic function
Glycometabolic State
measured by oral glucose tolerance testing and Glycated Hemoglobin according to current criteria
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

Full Information

First Posted
October 7, 2010
Last Updated
July 31, 2017
Sponsor
University Medical Center Groningen
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT01217307
Brief Title
Metformin to Reduce Heart Failure After Myocardial Infarction
Acronym
GIPS-III
Official Title
Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
January 2011 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ST Elevation Myocardial Infarction (STEMI), Coronary Artery Disease, Heart Failure, Diabetes
Keywords
Metformin, ST elevation myocardial infarction (STEMI), Coronary artery disease, Heart failure, Diabetes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
380 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Metformin
Arm Type
Experimental
Arm Description
metformin 500mg twice daily during 4 months
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo twice daily during 4 months
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Intervention Description
Metformin 500mg twice daily during 4 months
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo twice daily during 4 months
Primary Outcome Measure Information:
Title
Improvement in Left Ventricular Ejection Fraction
Description
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
Secondary Outcome Measure Information:
Title
the Incidence of a Cardiovascular Event
Description
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
Title
Markers of Heart Failure and Glycometabolic State
Description
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
Title
Myocardial Infarct Size and Transmural Extent of Infarction as Measured With Cardiac Magnetic Resonance Imaging
Description
myocardial infarct size and transmural extent of infarction will be measured using Late Gadolinium Enhancement cardiac magnetic imaging
Time Frame
4 months after hospitalization
Title
Diastolic Function
Description
echocardiographic analysis of diastolic function
Time Frame
4 months
Title
Glycometabolic State
Description
measured by oral glucose tolerance testing and Glycated Hemoglobin according to current criteria
Time Frame
4 months and long-term follow-up
Title
Cardiac MRI After 4 Months, Per Protocol Analysis
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Iwan CC van der Horst, MD, PhD
Organizational Affiliation
Thorax Centre, University Medical Centre Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center Groningen
City
Groningen
ZIP/Postal Code
9700RB
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
34593124
Citation
de Koning MLY, Westenbrink BD, Assa S, Garcia E, Connelly MA, van Veldhuisen DJ, Dullaart RPF, Lipsic E, van der Harst P. Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol. 2021 Oct 5;78(14):1421-1432. doi: 10.1016/j.jacc.2021.07.054.
Results Reference
derived
PubMed Identifier
28755285
Citation
Hartman MHT, Prins JKB, Schurer RAJ, Lipsic E, Lexis CPH, van der Horst-Schrivers ANA, van Veldhuisen DJ, van der Horst ICC, van der Harst P. Two-year follow-up of 4 months metformin treatment vs. placebo in ST-elevation myocardial infarction: data from the GIPS-III RCT. Clin Res Cardiol. 2017 Dec;106(12):939-946. doi: 10.1007/s00392-017-1140-z. Epub 2017 Jul 28.
Results Reference
derived
PubMed Identifier
28100626
Citation
Eppinga RN, Kofink D, Dullaart RP, Dalmeijer GW, Lipsic E, van Veldhuisen DJ, van der Horst IC, Asselbergs FW, van der Harst P. Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction. Circ Cardiovasc Genet. 2017 Feb;10(1):e001564. doi: 10.1161/CIRCGENETICS.116.001564.
Results Reference
derived
PubMed Identifier
26808474
Citation
Eppinga RN, Hartman MH, van Veldhuisen DJ, Lexis CP, Connelly MA, Lipsic E, van der Horst IC, van der Harst P, Dullaart RP. Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial. PLoS One. 2016 Jan 25;11(1):e0145719. doi: 10.1371/journal.pone.0145719. eCollection 2016.
Results Reference
derived
PubMed Identifier
26688733
Citation
Lexis CP, van der Horst-Schrivers AN, Lipsic E, Valente MA, Muller Kobold AC, de Boer RA, van Veldhuisen DJ, van der Harst P, van der Horst IC. The effect of metformin on cardiovascular risk profile in patients without diabetes presenting with acute myocardial infarction: data from the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) trial. BMJ Open Diabetes Res Care. 2015 Dec 11;3(1):e000090. doi: 10.1136/bmjdrc-2015-000090. eCollection 2015.
Results Reference
derived
PubMed Identifier
24687169
Citation
Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, de Boer RA, van den Heuvel AF, van der Werf HW, Schurer RA, Pundziute G, Tan ES, Nieuwland W, Willemsen HM, Dorhout B, Molmans BH, van der Horst-Schrivers AN, Wolffenbuttel BH, ter Horst GJ, van Rossum AC, Tijssen JG, Hillege HL, de Smet BJ, van der Harst P, van Veldhuisen DJ; GIPS-III Investigators. Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA. 2014 Apr 16;311(15):1526-35. doi: 10.1001/jama.2014.3315.
Results Reference
derived
PubMed Identifier
22968678
Citation
Lexis CP, van der Horst IC, Lipsic E, van der Harst P, van der Horst-Schrivers AN, Wolffenbuttel BH, de Boer RA, van Rossum AC, van Veldhuisen DJ, de Smet BJ; GIPS-III Investigators. Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther. 2012 Oct;26(5):417-26. doi: 10.1007/s10557-012-6413-1.
Results Reference
derived

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Metformin to Reduce Heart Failure After Myocardial Infarction

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