Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction - DAPA-HF
Contribution To Literature:
Highlighted text has been updated as of August 25, 2023.
The DAPA-HF trial showed that dapagliflozin was superior to placebo at preventing cardiovascular deaths and heart failure events among patients with heart failure.
Description:
The goal of the trial was to evaluate dapagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) compared with placebo among patients with heart failure with reduced ejection fraction (HFrEF).
Study Design
- Randomized
- Parallel
- Placebo
Patients with HFrEF (irrespective of diabetes status) were randomized to dapagliflozin 10 mg daily (n = 2,373) versus placebo (n = 2,371).
- Total number of enrollees: 4,744
- Duration of follow-up: 18.2 months
- Mean patient age: 66 years
- Percentage female: 24%
- Percentage with diabetes: 42%
Inclusion criteria:
- Symptomatic heart failure
- Left ventricular ejection fraction (LVEF) ≤40%
- N-terminal pro–B-type natriuretic peptide ≥600 pg/ml (if hospitalized for heart failure within last 12 months ≥400 pg/ml; if atrial fibrillation/flutter ≥900 pg/ml)
Exclusion criteria:
- Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2
- Symptomatic hypotension or systolic blood pressure <95 mm Hg
- Type 1 diabetes mellitus
Principal Findings:
The primary outcome of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit occurred in 16.3% of the dapagliflozin group compared with 21.2% of the placebo group (p < 0.001). The primary outcome was the same in prespecified subgroups, including according to diabetes status.
Secondary outcomes:
- Cardiovascular death: 9.6% with dapagliflozin vs. 11.5% with placebo
- Hospitalization for heart failure: 9.7% with dapagliflozin vs. 13.4% with placebo
- Worsening of renal function: 1.2% with dapagliflozin vs. 1.6% with placebo (p = 0.17)
Decline in GFR and association with adverse events:
- Mean change in eGFR between day 0 and 14: -4.2 mL∙min−1∙1.73 m−2 in the dapagliflozin group vs. -1.1 mL∙min−1∙1.73 m−2 in the placebo group
- Cardiovascular death or worsening heart failure in patients in the dapagliflozin group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR: HR 0.73 (95% CI 0.59-0.91)
- Cardiovascular death or worsening heart failure in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19-1.78) (p for interaction < 0.001)
Results according to baseline risk:
Subjects were risk stratified according to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. Dapagliflozin/placebo hazard ratios for the primary outcome according to MAGGIC risk score quintile (p for interaction = 0.71):
- Quintile 1: 7.6% with dapagliflozin vs. 10.2% with placebo
- Quintile 2: 12.9% with dapagliflozin vs. 17.7% with placebo
- Quintile 3: 13.6% with dapagliflozin vs. 20.6% with placebo
- Quintile 4: 21.9% with dapagliflozin vs. 26.8% with placebo
- Quintile 5: 28.7% with dapagliflozin vs. 32.4% with placebo
Dapagliflozin and ventricular arrhythmias:
- Ventricular arrhythmia, resuscitated cardiac arrest, or sudden death: 5.9% with dapagliflozin vs. 7.4% with placebo (p = 0.037)
- Ventricular arrhythmia: 2.1% with dapagliflozin vs. 2.7% with placebo (p = 0.037)
- Resuscitated cardiac arrest: 0.2% with dapagliflozin vs. 0.1% with placebo (p = 0.037)
- Sudden death: 3.9% with dapagliflozin vs. 4.8% with placebo (p = 0.037)
Serial change of high-sensitivity cardiac troponin T (hsTnT) and effect of dapagliflozin:
- The primary outcome was worse with increasing quartiles of baseline hsTnT. The benefit with dapagliflozin was consistent across quartiles of baseline hsTnT (p for interaction = 0.55), although patients in the top quartile had the greatest absolute risk reduction (absolute risk difference, 7.5%; 95% CI, 1.0%-14.0%).
Results according to age:
Dapagliflozin/placebo hazard ratios (HRs) of the primary outcome for various age groups:
- <55 years: HR 0.87 (95% confidence interval [CI] 0.60-1.28)
- 55-64 years: HR 0.71 (95% CI 0.55-0.93)
- 65-74 years: HR 0.76 (95% CI 0.61-0.95)
- ≥75 years: HR 0.68 (95% CI 0.53-0.88) (p for interaction = 0.76)
Results according to diuretic use:
Dapagliflozin/placebo hazard ratios (HRs) of the primary outcome for various age groups:
- No diuretic use: HR 0.57 (95% CI 0.36-0.92)
- Furosemide equivalent dose <40 mg daily: HR 0.83 (95% CI 0.63-1.10)
- Furosemide equivalent dose 40 mg daily: HR 0.77 (95% CI 0.60-0.99)
- Furosemide equivalent dose >40 mg daily: HR 0.78 (95% CI 0.63-0.97) (p for interaction = 0.61)
Dapagliflozin and health status:
Dapagliflozin/placebo HRs of the primary outcome according to Kansas City Cardiomyopathy Questionnaire (KCCQ) health status (tertiles):
- Lowest tertile: HR 0.70 (95% CI 0.57-0.86)
- Middle tertile: HR 0.77 (95% CI 0.61-0.98)
- Highest tertile: HR 0.62 (95% CI 0.46-0.83) (p for heterogeneity = 0.52)
Dapagliflozin vs. placebo was associated with a 2.3-point increase in KCCQ overall summary score from baseline to 8 months (p < 0.0001).
Results according to diabetes status:
Dapagliflozin/placebo HRs of the primary outcome according to diabetes:
- Diabetes: HR 0.75 (95% CI 0.63-0.90)
- No diabetes: HR 0.73 (95% CI 0.60-0.88) (p for interaction = 0.80)
Dapagliflozin and baseline medication use:
- Angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) target dose <50%: HR 0.78
- ACE inhibitor/ARB target dose ≥50%: HR 0.64 (p for interaction = 0.21)
- Beta-blocker target dose <50%: HR 0.71
- Beta-blocker target dose ≥50%: HR 0.44 (p for interaction = 0.76)
- Mineralocorticoid receptor antagonist (MRA) target dose <50%: HR 0.71
- MRA target dose ≥50%: HR 0.74 (p for interaction = 0.82)
Dapagliflozin and recurrent events (instead of time-to-first events):
- Dapagliflozin vs. placebo, time-to-first event (Cox model): HR 0.75 (p < 0.0001)
- Dapagliflozin vs. placebo, recurrent events (LWYY model): HR 0.75 (p = 0.0002)
- Dapagliflozin vs. placebo, total heart failure hospitalization (joint frailty model): HR 0.71 (p < 0.0001)
- Dapagliflozin vs. placebo, cardiovascular death (joint frailty model): HR 0.81 (p = 0.0282)
Dapagliflozin and outpatient worsening of heart failure:
- Outpatient intensification of heart failure therapy: 11.1% in the dapagliflozin group vs. 14.3% of the placebo group (p = 0.0003)
Results in patients treated with sacubitril/valsartan:
Efficacy of dapagliflozin vs. placebo for the primary outcome according to use of sacubitril/valsartan:
- Taking sacubitril/valsartan: HR 0.75 (95% CI 0.50-1.13)
- Not taking sacubitril/valsartan: HR 0.74 (95% CI 0.65-0.86) (p for interaction = 1.0)
Efficacy of dapagliflozin vs. placebo for the primary outcome according to use of an MRA:
- Taking an MRA: HR 0.74 (95% CI 0.63-0.87)
- Not taking an MRA: HR 0.74 (95% CI 0.57-0.95) (p for interaction = 0.97)
IGFBP-7 and outcomes in heart failure:
- Insulin-like growth factor–binding protein-7 (IGFBP-7) is a potential prognostic marker in heart failure.
- Adjusted hazard ratio for the primary endpoint for tertile 3 vs. tertile 1: 1.48 (95% CI 1.17-1.88). There was no modification of the benefit of dapagliflozin according to IGFBP-7 (p for interaction = 0.34).
Effect of dapagliflozin according to endothelin-1 level:
- Primary outcome for tertile 3 vs. tertile 1 of baseline endothelin-1 level: adjusted hazard ratio (aHR) 1.95 (95% CI 1.53-2.50). Primary outcome for tertile 2 vs. tertile 1 of baseline endothelin-1 level: aHR 1.36 (95% CI 1.06-1.75).
- Estimated glomerular filtration rate (eGFR) slope for tertile 3 of baseline endothelin-1 level: -3.19 (95% CI -3.66 to -2.72); eGFR slope for tertile 2 of baseline endothelin-1 level: -2.08 (95% CI -2.52 to -1.63); eGFR slope for tertile 1 of baseline endothelin-1 level: -2.35 (95% CI -2.79 to -1.91); p = 0.002.
- The efficacy of dapagliflozin in preventing the primary endpoint was consistent regardless of baseline endothelin-1 concentration (p for interaction = 0.47).
Deterioration in estimated glomerular filtration rate (eGFR) <25ml/min/1.73m2 (pooled analysis of DELIVER and DAPA-HF): 3.2% experienced a deterioration in eGFR to <25 at least once during follow-up. The median time to deterioration in kidney function to eGFR <25ml/min/1.73m2 was 121 days. The risk of the primary outcome was lower with dapagliflozin compared with placebo both among patients who did (HR 0.53, 95% CI 0.33-0.83) and did not (HR 0.78, 95% CI 0.72-0.86) experience deterioration in kidney function below eGFR 25ml/min/1.73m2 (p for interaction = 0.17). Rates of drug discontinuation were similar.
Interpretation:
Among patients with symptomatic HFrEF, dapagliflozin was beneficial. Dapagliflozin vs. placebo was associated with a reduction in cardiovascular deaths and heart failure events. Dapagliflozin vs. placebo was associated with a reduction in recurrent heart failure events and also associated with improvement in symptoms. Dapagliflozin vs. placebo was associated with a reduction in ventricular arrhythmias. Benefit was consistent across the age spectrum, risk spectrum, baseline diuretic use, baseline use of sacubitril/valsartan, in diabetics/nondiabetics, across the range of baseline health status, and baseline medication use (for example, sacubitril/valsartan and MRAs). There was no sign of adverse safety events. The baseline use of sacubitril/valsartan was low. Decline in eGFR was common with dapagliflozin; however, this was actually associated with better clinical outcomes. Dapagliflozin is an important medication in the treatment of patients with HFrEF.
Current US Food and Drug Administration labeling does not recommend initiation of dapagliflozin in patients with eGFR <25ml/min/1.73m2. The clinical benefits of SGLT2 inhibitors have been previously reported in the subgroup of patients with stage IV chronic kidney disease (eGFR <30ml/min/1.73m2 at baseline); however, these studies were not conducted in populations of HF. The pooled data analysis suggests a preserved benefit among patients who had a decline in eGFR to <25 during follow-up.
References:
Chatur S, Vaduganathan M, Claggett BL, et al. Dapagliflozin in Patients With Heart Failure and Deterioration in Estimated Glomerular Filtration Rate to <25ml/min/1.73m2. J Am Coll Cardiol 2023;Aug 25:[Epub ahead of print].
Presented by Dr. Scott Solomon at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.
Yeoh SE, Docherty KF, Campbell RT, et al. Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin: Findings From DAPA-HF. Circulation 2023;147:1670-83.
Adamson C, Welsh P, Docherty KF, et al. IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction: Findings From DAPA-HF. JACC Clin Heart Fail 2023;11:291-304.
Editorial Comment: Bayes-Genis A, Núñez J. Is Dapagliflozin a Cardiac Anti-Aging Drug? JACC Clin Heart Fail 2023;11:305-6.
Adamson C, Docherty KF, Heerspink HJ, et al. Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights From DAPA-HF. Circulation 2022;146:438-49.
Docherty KF, Simpson J, Jhund PS, et al. Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF. JACC Heart Fail 2022;10:104-18.
Berg DD, Docherty KF, Sattar N, et al. Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of the DAPA-HF Trial. Circulation 2022;145:158-69.
Presented by Dr. David D. Berg at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 2021.
Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J 2021;42:3727-38.
Editorial: Light PE. Decoding the effects of SGLT2 inhibitors on cardiac arrhythmias in heart failure. Eur Heart J 2021;42:3739-40.
Presented by Dr. James Curtain at the European Society of Cardiology Virtual Congress, August 27, 2021.
Jhund PS, Ponikowski P, Docherty KF, et al. Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure With Reduced Ejection Fraction: An Analysis of DAPA-HF. Circulation 2021;143:1962-72.
Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists: An Analysis of DAPA-HF. JACC Heart Fail 2021;9:254-64.
Editorial Comment: Zannad F, Rossignol P. Mineralocorticoid Receptor Antagonists and SGLT2 Inhibitor Therapy: The Best of Both Worlds in HFrEF. JACC Heart Fail 2021;9:265-7.
Docherty KF, Jhund PS, Anand I, et al. Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. Circulation 2020;142:1623-32.
Solomon SD, Jhund PS, Claggett BL, et al. Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial. JACC Heart Fail 2020;8:811-8.
Editorial Comment: Ahmad T, Desai NR. Quadruple Therapy Is the New Standard of Care for HFrEF. JACC Heart Fail 2020;8:819-21.
Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation 2020;142:1040-54.
Presented by Dr. Piotr Ponikowski at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.
Docherty KF, Jhund PS, Inzucchi SE, et al. Effects of Dapagliflozin in DAPA-HF According to Background Heart Failure Therapy. Eur Heart J 2020;41:2379-92.
Martinez FA, Serenelli M, Nicolau JC, et al. Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to Age: Insights From DAPA-HF. Circulation 2020;141:100-11.
Kosiborod MN, Jhund P, Docherty KF, et al. Effects of Dapagliflozin on Symptoms, Function and Quality of Life in Patients with Heart Failure and Reduced Ejection Fraction: Results from the DAPA-HF Trial. Circulation 2020;141:90-9.
Presented by Dr. Filipe Martinez at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.
Presented by Dr. John J. McMurray at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16 and 17, 2019.
McMurray JJ, Solomon SD, Inzucchi SE, et al., on behalf of the DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381:1995-2008.
Editorial: Fang JC. Heart-Failure Therapy — New Drugs but Old Habits? N Engl J Med 2019;381:2032-42.
Presented by Dr. John McMurray at the European Society of Cardiology Congress, Paris, France, September 1, 2019.
Docherty KF, Simpson J, Jhund PS, et al. Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF. JACC Heart Fail 2022;10:104-18.
Berg DD, Docherty KF, Sattar N, et al. Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of the DAPA-HF Trial. Circulation 2022;145:158-69.
Presented by Dr. David D. Berg at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 2021.
Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J 2021;42:3727-38.
Editorial: Light PE. Decoding the effects of SGLT2 inhibitors on cardiac arrhythmias in heart failure. Eur Heart J 2021;42:3739-40.
Presented by Dr. James Curtain at the European Society of Cardiology Virtual Congress, August 27, 2021.
Jhund PS, Ponikowski P, Docherty KF, et al. Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure With Reduced Ejection Fraction: An Analysis of DAPA-HF. Circulation 2021;143:1962-72.
Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists: An Analysis of DAPA-HF. JACC Heart Fail 2021;9:254-64.
Editorial Comment: Zannad F, Rossignol P. Mineralocorticoid Receptor Antagonists and SGLT2 Inhibitor Therapy: The Best of Both Worlds in HFrEF. JACC Heart Fail 2021;9:265-7.
Docherty KF, Jhund PS, Anand I, et al. Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. Circulation 2020;142:1623-32.
Solomon SD, Jhund PS, Claggett BL, et al. Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial. JACC Heart Fail 2020;8:811-8.
Editorial Comment: Ahmad T, Desai NR. Quadruple Therapy Is the New Standard of Care for HFrEF. JACC Heart Fail 2020;8:819-21.
Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation 2020;142:1040-54.
Presented by Dr. Piotr Ponikowski at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.
Docherty KF, Jhund PS, Inzucchi SE, et al. Effects of Dapagliflozin in DAPA-HF According to Background Heart Failure Therapy. Eur Heart J 2020;41:2379-92.
Martinez FA, Serenelli M, Nicolau JC, et al. Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to Age: Insights From DAPA-HF. Circulation 2020;141:100-11.
Kosiborod MN, Jhund P, Docherty KF, et al. Effects of Dapagliflozin on Symptoms, Function and Quality of Life in Patients with Heart Failure and Reduced Ejection Fraction: Results from the DAPA-HF Trial. Circulation 2020;141:90-9.
Presented by Dr. Filipe Martinez at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.
Presented by Dr. John J. McMurray at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16 and 17, 2019.
McMurray JJ, Solomon SD, Inzucchi SE, et al., on behalf of the DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019;381:1995-2008.
Editorial: Heart-Failure Therapy — New Drugs but Old Habits? N Engl J Med 2019;381:2032-42.
Presented by Dr. John McMurray at the European Society of Cardiology Congress, Paris, France, September 1, 2019.
Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: AHA Annual Scientific Sessions, AHA21, AHA19, ACC Annual Scientific Session, acc20, Endothelin-1, ESC Congress, ESC23, ESC21, ESC 19, Benzhydryl Compounds, Glomerular Filtration Rate, Glucosides, Heart Failure, Hospitalization, Hypotension, Natriuretic Peptide, Brain, Peptide Fragments, Renal Insufficiency, Sodium-Glucose Transporter 2, Stroke Volume, Diabetes Mellitus, Diuretics, Furosemide, Troponin
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