DAPA-HF & DEFINE-HF: Dapagliflozin in heart failure with reduced ejection fraction

Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF), the SGTL2 inhibitor dapagliflozin reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 21), death (NNT 44) & HF hospitalizations (NNT 28) at 1.5 years in patients with OR WITHOUT diabetes.
Dapagliflozin also improves quality of life beyond the clinically important difference as early as 12 weeks (NNT 10-14), without any differences in adverse effects (e.g. hypovolemia, kidney injury, severe hypoglycemia).

From Feb 2017-Aug 2018, 8134 screened -> 4744 randomized
Included
- HF with ejection fraction of 40% or less (HF with reduced ejection fraction [HFrEF])
- NYHA functional class 2-4
- NT-proBNP
  - >900 pg/mL if AF/atrial flutter
  - >400 pg/mL if HF hospitalization within 1 year
  - >600 pg/mL if neither of the above
- +/- type 2 diabetes
- Stable doses (at least 4 weeks) of standard HF medications (ACEI/ARB/ARNI + beta-blocker as tolerated, + MRA)
Key exclusion criteria: Type 1 diabetes, symptomatic hypotension or SBP <95, eGFR <30
Baseline (average/proportions)
- 66 y/o
- Female 23%
- White 70%, Asian 24%, Black 5%
- North America 14%
- HF characteristics
  - Etiology: Ischemic (56%), non-ischemic (36%), unknown (8%)
  - Prior HF hospitalization 47%
  - NYHA 2 (68%), 3 (32%), 4 (<1%)
  - LVEF 31%
  - NT-proBNP ~1400
- PMHx: Diabetes 42%, AF 38%
- Clinical variables: SBP 122, eGFR 66
- Therapies
  - Diuretic 93%, digitalis 19%
  - ACEI 56%, ARB 27%, ARNI 11%
  - Beta-blocker 96%
  - MRA 71%
  - ICD 26%, CRT 7%
  - Antihyperglycemics (% of those with T2DM): Metformin (51%), sulfonylurea (22%), DPP4i (16%), GLP1RA (1%), insulin (27%)

Intervention: Dapagliflozin 10 mg daily
- Dose reduced to 5 mg/d or temporary discontinuation if acute, unexpected decline in eGFR, volume depletion, or hypotension (or to avoid these)
Control: Matching placebo
Standardized monitoring: Follow-up at 14 days & 60 days (focus on HF/volume assessment, adverse events, & evaluation of renal function & potassium), then q4 months

CV outcomes @ median 18 months

Primary outcome (CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): Dapagliflozin 16.3% vs placebo 21.2%
- Hazard ratio (HR) 0.74 (95% confidence interval 0.65-0.85); Absolute difference 4.9%, NNT 21
- CV death: 9.6% vs 11.5%; HR 0.82 (0.69-0.98)
- HF hospitalization: 9.7% vs 13.4%; HR 0.70 (0.59-0.83)
- Consistent across subgroups (HR 0.75 for type 2 diabetes, HR 0.73 for those without diabetes)
All-cause mortality: Dapagliflozin 11.6% vs placebo 13.9%; HR 0.83 (0.71-0.97)

Quality of life (QoL) @ month 8

Measured using Kansas City Cardiomyopathy Questionnaire [KCCQ] total symptom score, range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)
Mean change: +6.1 vs +3.3 (/100); “win ratio” 1.18 (1.11-1.26)
Improvement 5+ points: Dapagliflozin 58.3% vs placebo 50.9%, odds ratio (OR) 1.15 (1.08-1.23)
Deterioration 5+ points: Dapagliflozin 25.3% vs placebo 32.9%, OR 0.84 (0.78-0.90)

Safety @ median 18 months (none statistically significant vs placebo)

Discontinuation due to adverse events: 4.7% vs 4.9%
Volume depletion: 7.5% vs 6.8% (p=0.4); serious in 1.2% vs 1.7%
Worsening renal function (sustained eGFR reduction >50%, ESRD [eGFR <15 >28 days], or death from renal disease): 1.2% vs 1.6%
Amputations: 0.5% in both groups
Fournier’s gangrene: 0 vs <0.1%
Bone fractures: 2.1% in both groups
Major hypoglycemia: 0.2% in both groups
DKA: 0.1% vs 0

Lab changes (difference vs placebo)