DAPA-HF Trial Summary
Primary Trial Design and Population
The DAPA-HF trial enrolled 4,744 patients with heart failure and reduced ejection fraction (HFrEF ≤40%), NYHA class II-IV symptoms, and elevated NT-proBNP levels, comparing dapagliflozin 10 mg daily to placebo on top of guideline-directed medical therapy. 1, 2
- Mean patient age was 66 years, with 23% women and 55% without diabetes 1
- 94% were on ACE inhibitor/ARB/ARNI, 96% on beta-blocker, and 71% on mineralocorticoid receptor antagonist at baseline 2
- Patients were enrolled from 410 sites across 20 countries between February 2017 and August 2018, with final follow-up in June 2019 1
Primary Outcome Results
Dapagliflozin reduced the primary composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85). 3
- First worsening heart failure events were reduced by 30% 3
- Cardiovascular death was reduced by 18% 3
- All-cause mortality was reduced by 31% 4
Diabetes-Independent Benefits
The treatment effect was completely independent of diabetes status, with identical benefit in patients with and without diabetes. 1
- In patients without diabetes: HR 0.73 (95% CI 0.60-0.88) for the primary outcome 1
- In patients with diabetes: HR 0.75 (95% CI 0.63-0.90) for the primary outcome 1
- Among non-diabetic patients with HbA1c <5.7% (normoglycemic): HR 0.67 (95% CI 0.47-0.96) 1
- Among non-diabetic patients with HbA1c ≥5.7% (pre-diabetes): HR 0.74 (95% CI 0.59-0.94) 1
Age-Related Efficacy
Dapagliflozin demonstrated consistent benefit across all age groups from 22 to 94 years, with no significant interaction by age (P=0.76). 5
- Age <55 years: HR 0.87 (95% CI 0.60-1.28) 5
- Age 55-64 years: HR 0.71 (95% CI 0.55-0.93) 5
- Age 65-74 years: HR 0.76 (95% CI 0.61-0.95) 5
- Age ≥75 years: HR 0.68 (95% CI 0.53-0.88) 5
- 24% of enrolled patients were ≥75 years old 5
Severe Heart Failure Subgroup
Among patients meeting criteria for severe heart failure (NYHA III/IV, recent hospitalization, KCCQ <75), dapagliflozin remained safe and effective. 6
- 296 patients (6.2%) with LVEF ≤40% met severe HF criteria 6
- Treatment effect was consistent regardless of severe HF status (P for interaction = 0.48) 6
- Safety profile remained favorable even in this high-risk population 6
Renal Function Considerations
Dapagliflozin was effective in patients with moderate renal impairment down to eGFR ≥25 mL/min/1.73 m². 7, 8
- The trial included 1,926 patients with eGFR 30-60 mL/min/1.73 m² 8
- A mild, transient eGFR decline may occur after initiation but provides long-term kidney protection 7
- Once enrolled, patients were not required to discontinue if eGFR fell below 30 mL/min/1.73 m² 8
Safety Profile
Dapagliflozin demonstrated a favorable safety profile with minimal adverse events. 1
- Volume depletion: 7.3% with dapagliflozin vs 6.1% with placebo in non-diabetic patients 1
- Kidney adverse events: 4.8% with dapagliflozin vs 6.0% with placebo in non-diabetic patients 1
- Low risk of hypoglycemia, lower limb amputations, bone fracture, and diabetic ketoacidosis 7
- Study drug discontinuation rates were similar between groups across all age ranges 5
Unique Pharmacologic Advantages
SGLT2 inhibitors like dapagliflozin require no dose titration and have minimal effects on blood pressure, heart rate, or potassium levels. 7
- Benefits occur within weeks of drug initiation 7
- Effectiveness is maintained regardless of whether patients received ≥50% of target doses of background HF medications 7
- No dose adjustment needed for age, sex, or background therapy 4
Clinical Implementation Recommendations
Dapagliflozin should be initiated at 10 mg once daily in all eligible HFrEF patients, ideally during hospitalization in stabilized patients. 3, 4
- The American College of Cardiology provides a Class I recommendation for SGLT2 inhibitors in all symptomatic HFrEF patients 3
- Deferring initiation to outpatient follow-up results in many eligible patients never receiving the medication within 1 year 3
- Continue existing guideline-directed medical therapy as dapagliflozin provides additive benefit 9