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A streamlined, multicentre, randomised, parallel group, double-blind placebo-controlled superiority trial to evaluate the effect of EMPAgliflozin on hospitalisation for heart failure and mortality in patients with aCuTe Myocardial Infarction (EMPACT-MI)

A study to evaluate the effect of empagliflozin on the risk of heart failure/mortality in patients with acute myocardial infarction (EMPACT-MI)

6522

Refer to 'Baseline Characteristics' in 2-1 Attachment 1 '21245-0202_ClinicalTrials.gov Study Results.pdf.

Refer to 'Participant Flow' in 2-1 Attachment 1 '21245-0202_ClinicalTrials.gov Study Results.pdf.

In this streamlined trial, the investigators were asked to report SAEs, AESIs (serious or non-serious; including contrast-induced acute kidney injury, ketoacidosis, events leading to lower limb amputation, and hepatic injury), and AEs leading to discontinuation of study medication for at least 7 consecutive days (serious or non-serious). On-treatment assessment of safety laboratory data, physical examination, and vital signs was not performed for the general patient population. Median exposure to study medication was about 16 months in both treatment groups, with 68.7% of patients treated for at least 1 year. The frequencies of patients with any AEs to be reported in this trial as well as AEs leading to permanent discontinuation of study medication, serious AEs and fatal AEs were similar between the empagliflozin and placebo groups. The frequencies of AESIs (ketoacidosis, adverse events leading to lower limb amputation, contrast-induced acute kidney injury, hepatic injury), as well as specific AEs of volume depletion, hypotension, hypoglycemia, acute renal failure to be reported in the trial were low. Overall, empagliflozin was considered to be safe and well-tolerated. No new safety concerns were identified in this trial.

For the primary endpoint, time to the first event of HHF or all-cause mortality, no significant difference was observed between the empagliflozin and the placebo group. While no treatment effect was seen for all-cause mortality, a lower risk for empagliflozin versus placebo was observed for time to first HHF based on exploratory analyses. Subgroup analyses for the primary endpoint showed consistency across demographics, baseline characteristics, and baseline medications. As the analysis of the primary endpoint was not statistically significant and following the hierarchical hypothesis testing, the key secondary endpoints were analysed in an exploratory manner. For the key secondary endpoint of non-elective all-cause hospitalisations or all-cause mortality, the adjusted event rate was lower in the empagliflozin group compared with the placebo group in an exploratory sense. For the key secondary endpoints total number of HHF or all-cause mortality, non-elective CV hospitalisations or all-cause mortality, and total number of hospitalisations for MI or all-cause mortality, the adjusted event rates were comparable between the treatment groups. There was no difference in risk of the secondary endpoint time to CV death between the empagliflozin and placebo group. The effect of empagliflozin on HHF observed in the EMPACT-MI trial is consistent with results of the EMPA-REG OUTCOME trial, the EMPEROR trials, and the EMPA-KIDNEY trial.

This trial investigated the effect of empagliflozin vs. placebo added to standard of care on clinical outcome events in patients hospitalised for acute MI with an elevated risk of HHF and mortality. Analyses of the primary endpoint, time to the first event of HHF or all-cause mortality, did not show a significant treatment difference between the empagliflozin and the placebo group. While no treatment difference was found for all-cause mortality, a lower risk for empagliflozin versus placebo was observed for

April. 06, 2024

https://www.nejm.org/doi/full/10.1056/NEJMoa2314051

Yes

After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed 'Document Sharing Agreement'. Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website. The data shared are the raw clinical study data sets.

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210095

Crisan Ioan

Fortrea Inc.

Str. Anghel Nutu, 18A, Sector 5, Bucharest, Romania

Ioan.Crisan@fortrea.com

Umezawa Daisuke

Fortrea Japan K.K.

Harumi Triton Square Office Tower Y 8F 1-8-11, Harumi, Chuo-ku,Tokyo

+81-90-2705-4005

Daisuke.Umezawa@fortrea.com

Complete

Nov. 19, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial
2. Diagnosis of spontaneous AMI: STEMI or NSTEMI with randomisation to occur no later than 14 calendar days after hospital admission.
Spontaneous AMI is defined as MI with a primary etiology of an acute coronary artery disease pathology (e.g., plaque rupture/erosion, in-stent restenosis, stent thrombosis) rather than MI caused by supply-demand mismatch (e.g., sepsis, arrhythmia, anemia, or other condition).
Under these conditions, the following criteria have to be met for the diagnosis of spontaneous AMI:
Detection of rise and/or fall of cardiac enzymes (cardiac troponin, cTn or the MB fraction of creatinine kinase, CKMB) with at least one value above the 99th percentile of the upper reference limit (URL) or the local laboratory MI diagnosis cut-off value, together with evidence of myocardial ischemia with at least one of the following:
- Ischemic discomfort or other ischemia symptom(s)
- Electrocardiogram (ECG) characteristics of STEMI or NSTEMI including new or presumably new significant ST-segment-T wave (ST-T) changes
- Newly developed pathological Q waves or left bundle branch block (LBBB) in the ECG
- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiologyIdentification of a coronary thrombus by angiography.
3. High risk of heart failure, defined as EITHER
a) Symptoms (e.g. dyspnea; decreased exercise tolerance; fatigue), or signs of congestion (e.g. pulmonary rales, crackles or crepitations; elevated jugular venous pressure; congestion on chest X-ray), that require treatment (e.g. augmentation or initiation of oral diuretic therapy; i.v. diuretic therapy; i.v. vasoactive agent; mechanical intervention etc.) at any time during the hospitalisation.
OR
b) Newly developed LVEF < 45% as measured by echocardiography, etc, during index hospitalisation.
4. In addition at least one of the following risk factors:
- Age >= 65 years
- Newly developed LVEF < 35%
- Prior myocardial infarction
- eGFR < 60 ml/min/1.73m2
- Atrial fibrillation
- Type 2 diabetes mellitus
- NTproBNP >=1,400 pg/mL for patients in sinus rhythm, >=2,800 pg/mL if atrial fibrillation; BNP >=350 pg/mL for patients in sinus rhythm, >=700 pg/mL if atrial fibrillation
- Uric acid >=7.5 mg/dL (>=446 micro-mol/L)
- Pulmonary Artery Systolic Pressure [or right ventricular systolic pressure] >=40 mmHg
- Patient not revascularized (and no planned revascularization) for the myocardial infarction
- 3-vessel coronary artery disease at time of the myocardial infarction
- Diagnosis of peripheral artery disease

1. Diagnosis of chronic heart failure prior to the myocardial infarction
2. Systolic blood pressure <= 90 mmHg at randomisation
3. Cardiogenic shock or use of i.v. inotropes in last 24 hours before randomisation
4. Coronary Artery Bypass Grafting planned at time of randomisation
5. Current diagnosis of Takotsubo cardiomyopathy
6. Any current severe (stenotic or regurgitant) valvular heart disease
7. eGFR < 20 ml/min/1.73m2 or on dialysis
8. Type I diabetes mellitus
9. History of ketoacidosis

Both

Myocardial Infarction

Empagliflozin (BI 10773) 10 mg or placebo corresponding to empagliflozin 10 mg is orally administered once daily.

Composite of time to first HHF(Hospitalisation for heart failure) or all-cause mortality

+81-985-77-9101

July. 16, 2021

Argentina/Australia/Brazil/Bulgaria/Canada/China/Denmark/France/Germany/Hungary/India/Israel/Republic of Korea/Netherlands/Poland/Romania/Russian Federation/Serbia/Spain/Ukraine/USA