Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)
Conditions
Keywords
HFrEF, Heart Failure (HF), Cardiovascular Events (CV), Phase III outcome trial
Brief summary
The purpose of this study is to evaluate the effect of dapagliflozin on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure with reduced ejection fraction
Detailed description
This is an international, multicentre, parallel group, event-driven, randomized, double-blind, placebo-controlled study in patients with chronic heart failure with reduced ejection fraction (HFrEF), evaluating the effect of dapagliflozin versus placebo, given once daily in addition to background regional standard of care therapy, for the prevention of cardiovascular (CV) death or reduction of heart failure (HF) events.
Interventions
DRUGDapagliflozin
10 mg or 5 mg tablets given once daily, per oral use.
DRUGPlacebo
Placebo matching dapagliflozin 10 mg or 5 mg.
Sponsors
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
* Provision of signed informed consent prior to any study specific procedures * Male or female, aged ≥18 years * Established documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least 2 months * LVEF≤40% * Elevated NT-proBNP levels * Patients should receive background standard of care for HFrEF and be treated according to locally recognized guidelines * eGFR ≥30 mL/min/1.73 m\^2 (CKD-EPI formula) at enrolment (visit 1)
Exclusion criteria
* Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor * Type 1 diabetes mellitus * Symptomatic hypotension or systolic BP \<95 mmHg at 2 out of 3 measurements either at visit 1 or visit 2 * Current acute decompensated HF or hospitalization due to decompensated HF \<4 weeks prior to enrolment * MI, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment * Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization * Implantation of a CRT within 12 weeks prior to enrolment or intent to implant a CRT device * Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization * HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease * Symptomatic bradycardia or second or third degree heart block without a pacemaker * Severe (eGFR \<30 mL/min/1.73 m\^2 by CKD-EPI), unstable or rapidly progressing renal disease at the time of randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | Up to 27.8 months. | Primary efficacy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure. | Up to 27.8 months. | Secondary |
| Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death. | Up to 27.8 months. | Secondary |
| Change From Baseline in the KCCQ Total Symptom Score | Baseline and 8 months or death before 8 months | KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ total symptom score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. |
| Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death. | Up to 27.8 months. | Secondary |
| Subjects Included in the Endpoint of All-cause Mortality. | Up to 27.8 months. | Secondary |
Countries
Argentina, Brazil, Bulgaria, Canada, China, Czechia, Denmark, Germany, Hungary, India, Japan, Netherlands, Poland, Russia, Slovakia, Sweden, Taiwan, United Kingdom, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapa 10mg Dapagliflozin 10 mg, given once daily per oral use. | 2,373 |
| Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use. | 2,371 |
| Total | 4,744 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 4 |
Baseline characteristics
| Characteristic | Total | Dapa 10mg | Placebo |
|---|---|---|---|
| Age, Continuous | 66.3 Years STANDARD_DEVIATION 10.9 | 66.2 Years STANDARD_DEVIATION 11 | 66.5 Years STANDARD_DEVIATION 10.8 |
| Age, Customized <=50 | 396 Participants | 208 Participants | 188 Participants |
| Age, Customized >50 | 4348 Participants | 2165 Participants | 2183 Participants |
| Age, Customized <=65 | 2030 Participants | 1032 Participants | 998 Participants |
| Age, Customized >65 | 2714 Participants | 1341 Participants | 1373 Participants |
| Age, Customized 66 - 75 | 1711 Participants | 825 Participants | 886 Participants |
| Age, Customized >75 | 1003 Participants | 516 Participants | 487 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 768 Participants | 381 Participants | 387 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3976 Participants | 1992 Participants | 1984 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| LVEF | 31.1 Percentage of blood leaving the heart STANDARD_DEVIATION 6.8 | 31.2 Percentage of blood leaving the heart STANDARD_DEVIATION 6.7 | 30.9 Percentage of blood leaving the heart STANDARD_DEVIATION 6.9 |
| Main etiology of HF Ischaemic | 2674 Participants | 1316 Participants | 1358 Participants |
| Main etiology of HF Non-Ischaemic | 1687 Participants | 857 Participants | 830 Participants |
| Main etiology of HF Unknown | 383 Participants | 200 Participants | 183 Participants |
| NYHA class at enrollment II | 3203 Participants | 1606 Participants | 1597 Participants |
| NYHA class at enrollment III | 1498 Participants | 747 Participants | 751 Participants |
| NYHA class at enrollment IV | 43 Participants | 20 Participants | 23 Participants |
| Prior HF hospitalization Yes | 2251 Participants | 1124 Participants | 1127 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1116 Participants | 552 Participants | 564 Participants |
| Race/Ethnicity, Customized Black or African American | 226 Participants | 122 Participants | 104 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 63 Participants | 34 Participants | 29 Participants |
| Race/Ethnicity, Customized White | 3333 Participants | 1662 Participants | 1671 Participants |
| Sex: Female, Male Female | 1109 Participants | 564 Participants | 545 Participants |
| Sex: Female, Male Male | 3635 Participants | 1809 Participants | 1826 Participants |
| Type 2 diabetes at baseline No | 2605 Participants | 1298 Participants | 1307 Participants |
| Type 2 diabetes at baseline Yes | 2139 Participants | 1075 Participants | 1064 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 286 / 2,368 | 333 / 2,368 |
| other Total, other adverse events | 299 / 2,368 | 325 / 2,368 |
| serious Total, serious adverse events | 895 / 2,368 | 994 / 2,368 |
Outcome results
Primary
Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure.
Primary efficacy
Time frame: Up to 27.8 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | 386 Participants |
| Placebo | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | 502 Participants |
p-value: <0.000195% CI: [0.65, 0.85]Regression, Cox
Secondary
Change From Baseline in the KCCQ Total Symptom Score
KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ total symptom score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Time frame: Baseline and 8 months or death before 8 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapa 10 mg | Change From Baseline in the KCCQ Total Symptom Score | 6.1 Scores on a scale | Standard Deviation 18.6 |
| Placebo | Change From Baseline in the KCCQ Total Symptom Score | 3.3 Scores on a scale | Standard Deviation 19.2 |
p-value: <0.000195% CI: [1.11, 1.26]Win Ratio
Secondary
Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death.
Secondary
Time frame: Up to 27.8 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapa 10 mg | Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death. | 567 events |
| Placebo | Events Included in the Composite Endpoint of Recurrent Hospitalizations Due to Heart Failure and CV Death. | 742 events |
p-value: 0.000295% CI: [0.65, 0.88]LWYY proportional rates model
Secondary
Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death.
Secondary
Time frame: Up to 27.8 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death. | 28 Participants |
| Placebo | Subjects Included in the Composite Endpoint of ≥50% Sustained Decline in eGFR, ESRD or Renal Death. | 39 Participants |
p-value: 0.168195% CI: [0.44, 1.16]Regression, Cox
Secondary
Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure.
Secondary
Time frame: Up to 27.8 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure. | 382 Participants |
| Placebo | Subjects Included in the Composite Endpoint of CV Death or Hospitalization Due to Heart Failure. | 495 Participants |
p-value: <0.000195% CI: [0.65, 0.85]Regression, Cox
Secondary
Subjects Included in the Endpoint of All-cause Mortality.
Secondary
Time frame: Up to 27.8 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Endpoint of All-cause Mortality. | 276 Participants |
| Placebo | Subjects Included in the Endpoint of All-cause Mortality. | 329 Participants |
p-value: 0.021795% CI: [0.71, 0.97]Regression, Cox