DAPA-HF

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McMurray JV, et al. "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction". The New England Journal of Medicine. 2019. ePub ahead of print.

Clinical Question

Does the addition of dapagliflozin (SGLT-2 inhibitor) onto existing medical therapy reduce cardiovascular death and HF hospitalization in patients with HF with reduced ejection fraction?

Bottom Line

The addition of SGLT-2 inhibitor onto guideline-directed medical therapy reduced cardiovascular death and HF hospitalization in HF patients with and without diabetes.

Major Points

In 2008, the US Food and Drug Administration began requiring every new drug for diabetes to be tested in a cardiovascular outcomes trial. Because of this, the development of three new sodium-glucose cotransporter 2 inhibitors (SGLT2i) for diabetic patients was accompanied by three cardiovascular outcomes trials (CANVAS[1], EMPA-REG[2], and DECLARE-TIMI 58 [3]). EMPA-REG and CANVAS studies showed reductions in composite primary outcomes of CV mortality, nonfatal MI, or nonfatal stroke as well notable secondary outcomes of reductions in heart failure hospitalization with in diabetic patients. Though mechanisms of cardiovascular benefit remains unclear, it is likely that benefit was driven in part to be due to reduction in heart failure death given that rates of myocardial infarction remained similar between treatment arms. In the more recent trial, DECLARE-TIMI 58, dapagliflozin did not show statistically significant reduction in the primary outcome of major adverse cardiovascular events but did show a lower rate of the composite of CV death or hospitalization for heart failure hospitalization. Previous studies were not powered for examining this class of medications in the setting of heart failure with reduced ejection fraction as well in patients without diabetes


Because of this, the DAPA-HF trial was conducted to study whether the addition of an SGLT-2 inhibitor could benefit patients with HF with reduced ejection fraction and whether the benefit extended to patients without diabetes. Only 50% of the patients enrolled had diabetes. The results of DAPA-HF show that the addition of dapagliflozin reduced the risk of cardiovascular death and worsening HF event (HF hospitalization or urgent HF visit) by 26%. This benefit was also shown in the subgroup of patients who did not have type 2 diabetes. Additionally, adverse events were higher in the placebo group. Only 2 patients with pre-existing diabetes had a DKA episode, and no patient without diabetes had DKA. No patient in the intervention arm had Fournier's gangrene. All-cause death was also reduced by 17%. This landmark trial was the first RCT to show a benefit of SGLT2i’s in patients with HFrEF, regardless of whether they had diabetes.

Guidelines

As of September 2019, no major cardiology or diabetes guidelines have been changed to reflect this specific trial.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=4744
    • Intensive (n=5,128)
    • Standard (n=5,123)
  • Setting: Patients from 20 countries, 14% from North America
  • Enrollment: February 2017 to August 2018
  • Mean follow-up: 18.2 months
  • Analysis: Intention-to-treat
  • Primary outcome: composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death

Population

Inclusion Criteria

Patients were included if they met all of the following criteria:

  • Age of at least 18 years
  • Ejection fraction of ≤40%
  • NYHA Class II, III, or IV symptoms
  • Plasma NT-proBNP level of:
    • ≥ 600pg/mL OR
    • ≥ 400pg/mL if they were hospitalized for HF within the past 12 months OR
    • ≥ 900pg/mL if patient had atrial fibrillation/flutter on baseline ECG.

Additionally, all patients were required to receive standard heart-failure device therapy (ICD, CRT or both) and standard drug therapy (ACEi/ARB/ARNI + beta-blocker unless contraindicated or resulting in unacceptable side effects). MRA (mineralocorticoid receptor antagonism) use was encouraged. All drug doses were individually tailored, and dosing of anti-hyperglycemics including insulin was titratable as seen fit by the prescribing physician.

Exclusion Criteria

  • Unacceptable side effects associated with SGLT2i
  • Type 1 Diabetes
  • Hypotension/ sBP <95 mm HG
  • Estimated glomerular filtration rate (eGFR) ≤30 ml/m/1.73m2

  • Current decompensated HF or HF hospitalization <4 weeks prior
  • MI, unstable angina, stroke, or TIA within 3 months to enrolment

Baseline Characteristics

Baseline characteristics were well balanced. Below is reported baseline characteristics from the intervention group (dapagliflozin).

  • Mean age: 66.5 years
  • Mean BMI: 28.2 kg/m2
  • Female: 23.8%
  • Mean Ejection Fraction: 31.2%
  • Mean eGFR: 66.0 ml/min/1.73 m2
  • NYHA Classification

    • NYHA II: 67.7%
    • NYHA III: 31.5%
    • NYHA IV 0.8%
  • HF medication
    • ACEi/ARB/ARNI: 93%
    • Beta-blocker: 96%
    • MRA: 71%
    • Diuretics: 93%
    • ICD: 26%

Interventions

After a 14-day screening period, patients were randomly assigned to receive either:


  • Intervention: dapagliflozin 10mg once daily
  • Control: placebo

Outcomes

Comparisons are intervention (dapagliflozin) vs. control (placebo).

Primary Outcomes

Composite outcome of worsening heart failure (hospitalization or urgent visit resulting in IV therapy for HF) or cardiovascular death
16.3% vs. 21.2%% (HR 0.74; 95% CI 0.65-0.85; P<0.001)

Components of the primary composite outcome:

Hospitalization/urgent visit for heart failure
10.0% vs. 13.7% (HR 0.70; 95% CI 0.59-0.83; P=n/a)
Cardiovascular death
9.6% vs. 11.5%% (HR 0.82; 95% CI 0.69-0.98; P=n/a)

Secondary Outcomes

Cardiovascular death or heart-failure hospitalization
16.1% vs 20.9% (HR 0.75; 95% CI 0.65-0.85; P<0.001)
Changes in KCCQ (Kansas City Cardiomyopathy Questionnaire) total symptom score at 8 months
6.1±18.6 vs 3.3±19.2 (HR 1.1; 95% CI 1.11-1.26; P<0.001)


Worsening renal function
1.2% vs 1.6% (HR 0.71; 95% CI 0.44-1.16; P=n/a)
Death from any cause
11.6% vs 13.9% (HR 0.83; 95% CI 0.71-0.97; P=n/a)


Subgroup Analysis

Adverse Events

Discontinuation due to adverse event
4.7% vs 4.9% (P=0.79)
Renal adverse event
6.5% vs 7.2% (P=0.36)
Fracture
2.1% vs 2.1% (P=0.36)
Amputation
0.5% vs 0.5% (P=1.00)
Major hypoglycaemia (requiring intervention of another person)
0.2% vs 0.2% (P=n/a; only occurred in patients with pre-existing diabetes)
DKA
0.1% vs 0% (P=n/a; only occured in patients with pre-existing diabetes
Fournier’s Gangrene
0 vs <0.1 (P=N/A; only occurred in 1 patient in the placebo group)

Criticisms

  • Patient’s were largely those with moderate heart failure, thus further study in patients with severe HF will be needed.
  • Background use of ARNI was limited. The combination of the two will need to be studied more closely.
  • Individual doses of background HF therapies were not reported - if intervention group had been treated with higher doses of HF medications, then the effect might be attenuated.

Funding

AstraZeneca (producers of dapagliflozin)

Further Reading

  1. Neal B et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017. 377:644-657.
  2. Zinman B et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015. 373:2117-28.
  3. Wiviott SD et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019. 380:347-357.