Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure - DELIVER
Contribution To Literature:
Highlighted text has been updated as of October 27, 2023.
The DELIVER trial showed that dapagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable mildly reduced or preserved LVEF (EF >40%), irrespective of diabetes status.
The goal of the trial was to assess the safety and efficacy of dapagliflozin in patients with left ventricular ejection fraction (LVEF) >40%, irrespective of diabetes status.
Patients were randomized in a 1:1 fashion to either dapagliflozin 10 mg (n = 3,131) or matching placebo (n = 3,132). All the patients were receiving appropriate treatments for heart failure (HF).
- Total screened: 10,418
- Total number of enrollees: 6,263
- Duration of follow-up: 2.3 years (median)
- Mean patient age: 71.7 years
- Percentage female: 44%
- Age ≥40 years
- Evidence of structural heart disease
- EF >40%
- Elevated B-type natriuretic peptide (BNP)
Other salient features/characteristics:
- White 71%
- North America: 14%, Asia: 19%, Latin America: 19%
- New York Heart Association functional class II: 75%
- Mean LVEF 54% (≤49%: 34%; 50-59%: 36%)
- Type 2 diabetes mellitus (DM2): 45%
- Estimated glomerular filtration rate: 61 ml/min/1.73 m2
The primary outcome, cardiovascular death or worsening HF for dapagliflozin vs. placebo, was: 16.4% vs. 19.5% (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.73-0.92, p < 0.001).
- Cardiovascular death: 7.4% vs. 8.3% (HR 0.88, 95% CI 0.74-1.05)
- HF hospitalization or urgent visit for HF: 11.8% vs. 14.5% (HR 0.79, 95% CI 0.69-0.91)
For the primary outcome, benefit was similar among patients with or without DM2, and for categories of baseline EF (≤49%, 50-59%, ≥60%).
- All-cause mortality: 15.9% vs. 16.8% (HR 0.94, 95% CI 0.83-1.07, p > 0.05)
- Any amputation: 0.6% vs. 0.8%
- Any major hypoglycemic event: 0.2% vs. 0.2%
Impact of frailty: Frailty was measured using the Rockwood cumulative deficit approach. On this scale, 37.6% had class 1 frailty (not frail); 38.6% had mild-moderate frailty, and 23.8% had severe frailty. The effect of dapagliflozin on the primary endpoint from Frailty Index class 1 to 3 was: 0.85 (95% CI 0.68-1.06); 0.89 (0.74-1.08); and 0.74 (0.61-0.91), respectively (p for interaction = 0.40). Although frailer patients had worse Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline, the improvement with dapagliflozin was greater than in less frail patients (p for interaction = 0.021).
Impact of body mass index (BMI): Mean BMI was 29.8 kg/m2. Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across BMI categories (p for interaction = 0.82). The placebo-corrected change in weight at 12 months for BMI categories was: 18.5-24.9 kg/m2: –0.88; 25-29.9 kg/m2: –0.65; 30-34.9 kg/m2: –1.42; 35.0-39.9 kg/m2: –1.17; ≥40 kg/m2: –2.50 (p for interaction = 0.002). The placebo-corrected change in KCCQ-total symptom score with dapagliflozin at 8 months for the respective BMI categories was: 0.9 vs. 2.5 vs. 1.9 vs. 2.7 vs. 8.6 points (p interaction = 0.03).
Lifetime benefit modeling: Nonparametric age-based methods were used to extrapolate potential gains in survival free from the primary endpoint from long-term use of dapagliflozin. At age 55 years, the estimated survival free from the primary endpoint was 11.8 years with dapagliflozin vs. 9.8 years with placebo (p = 0.14). At age 65 years, the estimated event-free survival was 12.1 years with dapagliflozin and 9.7 years with placebo (p = 0.002). At age 75 years, the estimated event-free survival was 10.6 years with dapagliflozin and 9.4 years with placebo (p = 0.063).
Effect of N-terminal pro–B-type natriuretic peptide (NT-proBNP): The median baseline concentration of NT-proBNP was 716 ng/L and 1,399 ng/L for non–atrial fibrillation/flutter and atrial fibrillation/flutter, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome. The clinical benefit of dapagliflozin was present for the primary outcome (p value for interaction = 0.40 by quartiles) and for HF hospitalizations (p for interaction = 0.86) irrespective of baseline NT-proBNP concentration.
Impact of baseline systolic blood pressure (SBP): Dapagliflozin reduced SBP by 1.8 (95% CI 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and KCCQ total symptom score was consistent across SBP categories (<120, 120-129, 130-139, ≥140 mm Hg; interaction p = 0.15 and p = 0.98, respectively).
Impact of duration of HF: The number of patients in each category was as follows: 1,160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1,569 (>2 to 5 years), and 1,692 (>5 years). Patients with longer-duration HF were older and had more comorbidities and had worse outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI 0.50-0.91); >6 to 12 months, 0.78 (0.55-1.12); >1 to 2 years, 0.81 (0.60-1.09); >2 to 5 years, 0.97 (0.77-1.22); and >5 years, 0.78 (0.64-0.96; p for interaction = 0.41).
Diuretic utilization: 10.9% were on no diuretic, 12.3% were on a non-loop diuretic, and 76.8% were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (p for interaction = 0.64) or loop diuretic dose (p for interaction = 0.57). Dapagliflozin reduced new initiation of loop diuretics by 32% (hazard ratio [HR] 0.68, 95% CI 0.55-0.84, p < 0.001) but did not influence discontinuations/disruptions (HR 0.98, 95% CI, 0.86–1.13, p = 0.83).
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.
Worsening of HF: Over the duration of follow-up, 72% of patients experienced no worsening HF event, while 13% had outpatient oral diuretic intensification, 1% required an urgent HF visit, 9% had a HF hospitalization, and 4% died of cardiovascular causes as a first presentation. All-cause mortality: no worsening HF: 4/100 patient-years (PY), outpatient oral diuretic intensification: 10/100 PY, urgent HF visit: 10/100 PY, HF hospitalization: 35/100 PY. Dapagliflozin relative to placebo consistently reduced the occurrence of first nonfatal worsening HF events including outpatient oral diuretic intensification (HR 0.72, 95% CI 0.64-0.82) and HF hospitalization (HR 0.77, 95% CI 0.67-0.89).
Apparent treatment-resistant hypertension: 11.5% of patients had apparent treatment-resistant hypertension at baseline (defined as BP ≥140/90 mm Hg [≥130/80 mm Hg if diabetes]) despite treatment with three antihypertensive drugs including a diuretic). The primary outcome for controlled BP vs. nonresistant hypertension group vs. apparent treatment-resistant hypertension: 8.7 vs. 8.5 vs. 9.5 per 100 patient-years. The relative benefits of dapagliflozin on the primary composite outcome were consistent irrespective of baseline BP category (HR 0.91 [95% CI 0.78–1.05] for controlled BP; HR 0.73 [95% CI 0.58–0.91] for nonresistant hypertension; HR 0.67 [95% CI 0.48–0.94] for apparent treatment-resistant HTN; p for interaction = 0.114). Similar findings were observed for individual components of the primary endpoint and across key secondary endpoints. Mean SBP reduction was 1-3 mm Hg with dapagliflozin vs. placebo.
The results of this trial indicate that dapagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable mildly reduced or preserved LVEF (EF >40%), irrespective of diabetes status, duration of HF baseline diuretic use, baseline NT-proBNP levels, and among patients with apparent treatment-resistant hypertension. Benefit is primarily driven by a reduction in HF hospitalizations, not mortality. The benefit of dapagliflozin was consistent across the range of frailty, baseline SBP, and BMI categories studied. Worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin compared with placebo.
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. The improvement in health-related quality of life with dapagliflozin occurred early and was greater among patients with greater frailty and higher BMI. Absolute gains in event-free survival appeared to be meaningful, although statistically significant only among the subgroup of patients aged 65 years at randomization. This is helpful since many HF trials have a short span of follow-up (1-3 years).
Even though the sodium–glucose cotransporter 2 (SGLT2) inhibitors were introduced as DM2 management drugs, results of EMPA-REG OUTCOME, EMPEROR-Reduced, DAPA-HF, SCORED, SOLOIST, and other trials indicated a clear benefit in HF management. Similar to EMPEROR-Preserved, this trial enrolled patients with near normal or normal EFs, and shows a benefit in this patient population, irrespective of diabetes status. The recent American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines designate SGLT2 inhibitor use in patients with HF with preserved EF (HFpEF) a Class IIA, Level B recommendation. In the current trial, an attenuation of benefit among patients with EF >60% was not observed, as was noted in EMPEROR-Preserved, although they are both subgroup analyses. Most routinely used drugs for HF with reduced EF (HFrEF) have not shown to be effective among patients with HFpEF, and some drugs such as candesartan, spironolactone, and sacubitril/valsartan appear to mostly have a benefit among patients with EF between 40-49% rather than true HFpEF. The exact mechanism of benefit is unclear.
Ostrominski JW, Vaduganathan M, Selvaraj S, et al. Dapagliflozin and Apparent Treatment-Resistant Hypertension in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The DELIVER Trial. Circulation 2023;Oct 13:[Epub ahead of print].
Chatur S, Vaduganathan M, Claggett BL, et al. Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial. Circulation 2023;Aug 26:[Epub ahead of print].
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.
Chatur S, Vaduganathan M, Claggett B, et al. Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial. Eur Heart J 2023;44:2930-43.
Kondo T, Jering KS, Willem Borleffs CJ, et al. Patient Characteristics, Outcomes, and Effects of Dapagliflozin According to the Duration of Heart Failure: A Prespecified Analysis of the DELIVER Trial. Circulation 2023;147:1067-78.
Adamson C, Kondo T, Jhund PS, et al. Dapagliflozin for heart failure according to body mass index: the DELIVER trial. Eur Heart J 2022;43:4406-17.
Solomon SD, McMurray JJV, Claggett B, et al., on behalf of the DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. N Engl J Med 2022;387:1089-98.
Butt JH, Jhund PS, Belohlávek J, et al. Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial. Circulation 2022;146:1210-24.
Presented by Dr. Scott Solomon at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 27, 2022.
Keywords: Cardiometabolic Diseases, Heart Failure, Heart Failure, Preserved Ejection Fraction
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