Acute Myocardial Infarction, Heart Failure
Conditions
Keywords
Myocardial Infarction, Cardiovascular Outcome Trial
Brief summary
This study will evaluate the effect of dapagliflozin versus placebo, given once daily in addition to Standard of Care (SoC) therapies for patients with myocardial infarction (MI), for hospitalisation for heart failure (HHF), cardiovascular (CV) death, and other cardiometabolic outcomes.
Detailed description
This is a multicentre, parallel group double-blind, placebo-controlled phase 3 registry-based randomised controlled trial (R-RCT) in patients without diabetes presenting with myocardial infarction (MI) (ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI)) and evidence of impaired regional or global LV systolic function or definite evidence of Q wave MI on ECG. In the study the effect of dapagliflozin versus placebo, given once daily in addition to SoC therapy will be evaluated for the hospitalisation for HF, CV death, and other cardiometabolic outcomes.
Interventions
DRUGDapagliflozin
Dapagliflozin 10 mg tablets given once daily, per oral use
DRUGPlacebo
Placebo matching dapagliflozin 10 mg tablets given once daily, per oral use
Sponsors
Uppsala University
AstraZeneca
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 130 Years
Healthy volunteers
No
Inclusion criteria
* Participant must be ≥18 at the time of signing the informed consent * Confirmed MI, either STEMI or NSTEMI, according to the fourth universal definition of MI (Thygesen et al 2019), within the preceding 7 days, or 10 days if earlier randomisation is not feasible * Evidence of impaired regional or global LV systolic function at any timepoint during current MI-related hospitalisation (established with echocardiogram, radionuclide ventriculogram, contrast angiography or cardiac MRI) or definitive evidence on ECG of Q wave MI (defined as presence of Q waves in two or more contiguous leads, excluding leads III and aVR, and meeting all the following criteria: at least 1.5 mm in depth; at least 30 ms in duration; and, if R wave present, more than 25% of the size of the subsequent R wave) * Hemodynamically stable at randomization (no episodes of symptomatic hypotension, or arrhythmia with haemodynamic compromise in the last 24 hours). * Male or female * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol * Provision of signed and dated, written informed consent prior to any mandatory study specific procedures, sampling, and analyses
Exclusion criteria
* Known type 1 diabetes mellitus (T1DM) or T2DM at the time for admission. Patients with hyperglycaemia, but without a diagnosis of diabetes mellitus prior to the index event, are eligible at the discretion of the Investigator. Patients who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath should be assessed for ketoacidosis, and if ketoacidosis is confirmed the patient should not be randomized. * Chronic symptomatic HF with a prior HHF within the last year and known reduced ejection fraction (LVEF≤40 %), documented before the current MI hospitalization * Severe (eGFR \<20 mL/min/1.73 m2 by local laboratory), unstable or rapidly progressing renal disease at the time of randomization * Severe hepatic impairment (Child-Pugh class C) at the time of inclusion into the trial * Active malignancy requiring treatment at the time of screening, except for basal cell- or squamous cell carcinoma of the skin, presumed possible to treat successfully * Any non-CV condition, eg malignancy, with a life expectancy of less than two years based on the investigator´s clinical judgement * Currently on treatment, or with an indication for treatment, with a sodium glucose co-transporter 2 inhibitor (SGLT2-inhibitor)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | 29 months | Study participants received dapagliflozin 10 mg or matching placebo, given once daily in addition to SoC. Overall, the mean study duration was 12.0 months (time in study until last visit) with an accumulated 4023.9 participant-years. The maximum study duration for any participant was 29 months. Number of Events for NYHA corresponds to the number of participants with a non-missing value for NYHA functional class at the last visit, and that all participants with a non-missing value take part in the analysis comparing their NYHA class value with all other participants with a NYHA value, according to the win-ratio method. |
Countries
Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapa 10 mg Active, Green, plain, diamond shaped, film coated tablet, 10 mg once daily | 2,019 |
| Placebo Control, Green, plain, diamond shaped, film coated tablets, once daily | 1,998 |
| Total | 4,017 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent Withdrawal | 4 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Dapa 10 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous Age (Years) | 63.0 Years STANDARD_DEVIATION 11.06 | 62.8 Years STANDARD_DEVIATION 10.64 | 62.9 Years STANDARD_DEVIATION 10.85 |
| Age, Customized <=65 years | 1188 Participants | 1199 Participants | 2387 Participants |
| Age, Customized >65 years | 831 Participants | 799 Participants | 1630 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 64 Participants | 52 Participants | 116 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 15 Participants | 23 Participants |
| Race/Ethnicity, Customized MISSING | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 40 Participants | 37 Participants | 77 Participants |
| Race/Ethnicity, Customized White | 1905 Participants | 1893 Participants | 3798 Participants |
| Sex: Female, Male Female | 388 Participants | 419 Participants | 807 Participants |
| Sex: Female, Male Male | 1631 Participants | 1579 Participants | 3210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 2,019 | 33 / 1,998 |
| other Total, other adverse events | 0 / 2,019 | 0 / 1,998 |
| serious Total, serious adverse events | 449 / 2,019 | 404 / 1,998 |
Outcome results
Primary
Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set)
Study participants received dapagliflozin 10 mg or matching placebo, given once daily in addition to SoC. Overall, the mean study duration was 12.0 months (time in study until last visit) with an accumulated 4023.9 participant-years. The maximum study duration for any participant was 29 months. Number of Events for NYHA corresponds to the number of participants with a non-missing value for NYHA functional class at the last visit, and that all participants with a non-missing value take part in the analysis comparing their NYHA class value with all other participants with a NYHA value, according to the win-ratio method.
Time frame: 29 months
Population: All participants are included in the analysis; Each row item displays the number of participants for the given event, and without preceding events defined in the hierarchical order.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | The hierachical composite endpoint of all components | 1990 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Death, adjudicated | 41 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Hospitalisation due to HF | 32 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Non-fatal MI | 29 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | AF/Flutter event | 8 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | New onset of T2DM | 40 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | NYHA Classification at last visit, measuring limitations of physical activity | 1839 Participants |
| Dapa 10 mg | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Body Weight decrease of at least 5% at last visit | 684 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Body Weight decrease of at least 5% at last visit | 468 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | The hierachical composite endpoint of all components | 1970 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | AF/Flutter event | 15 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Death, adjudicated | 33 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | NYHA Classification at last visit, measuring limitations of physical activity | 1773 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Hospitalisation due to HF | 41 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | New onset of T2DM | 74 Participants |
| Placebo | Analysis of the Hierarchical Primary Composite Endpoint (Full Analysis Set) | Non-fatal MI | 32 Participants |
Comparison: The primary objective of the study was to determine if the clinical benefit of dapagliflozin was superior as compared with placebo, utilizing a hierarchical composite endpoint and win-ratio (WR) method. With a presumed WR of 1.20, 4000 patients were provide an 80% statistical power for the primary endpoint, maintaining a 1:1 allocation between treatments. The primary analysis was based on the intention-to-treat principle using the Full Analysis Set.p-value: <0.00195% CI: [1.2, 1.5]Win Ratio Analysis