Purpose

to evaluate the safety and efficacy of dapagliflozin, an SGLT2 inhibitor, in patients with HFrEF with and without T2DM.

Trial Design

Phase 3 randomized, double-blinded, parallel comparison of dapagliflozin 10 mg./day + standard therapy versus placebo + standard therapy in 4744 HFrEF patients with and without T2DM. N=4744. 20 countries. Median 18.2 months follow-up.

Primary Endpoints

Composite of first worsening of HF or CV death.

Results

In those with and without T2DM, dapagliflozin + standard therapy reduced the risk of the composite primary endpoint.

Recommended

• DAPA-HF Abstract
• John J V McMurray's presentation slides (PDF)
• Discussant slides (PDF)
• DAPA-HF - Circulation
• Efficacy and Safety of Dapagliflozin in HFrEF According to Age: Insights From DAPA-HF
• 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
• Editorial: Building the Foundation for a New Era of Quadruple Therapy in Heart Failure

Primary Endpoints Results:

Composite outcome of a first episode of worsening HF (hospitalization for HF or an urgent HF visit requiring intravenous therapy) or death from cardiovascular causes when split across diabetics and non-diabetics were the following:

• No diabetes: Hazard’s ratio of 0.73 ( 0.60 , 0.88)
• Diabetes: Hazard’s ratio of 0.75 (0.63, 0.90)

Secondary Endpoints Results:

1. The composite of HF hospitalization or cardiovascular death for non-diabetics was a hazard’s ratio of 0.73 ( 0.60 , 0.89)
2. Total number of recurrent HF hospitalizations (including repeat admissions) and cardiovascular deaths was significantly reduced in the active arm in both diabetics and non-diabetics (Rate Ratio 0.77, (0.63 – 0.94) and Rate Ratio 0.73 (0.59 – 0.91)
3. Clinically meaningful change (=5 points) in the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) showed Odds ratio of 1.12 (1.03, 1.22) with P interaction of 0.74
4. Worsening renal function was seen in 0.8% of the active arm and 1.2 % of the placebo arm amongst non-diabetics (Hazard’s ratio of 0.67 [0.30, 1.49] 95% CI)

Key Findings

The composite outcome of heart failure hospitalization, urgent heart failure visit or death from cardiovascular causes was improved, with an absolute risk reduction of 5% over 18 months. All components were improved including all-cause death, quality of life and renal function. The findings were independent of the patient’s HbA1c level. The drug was generally well-tolerated, and the side effect profile was minimal.

Impression

Though initially developed for the treatment of diabetes, the SGLT2i dapagliflozin when added to guideline-directed medical therapy has proven efficacy in HFrEF irrespective of whether the patient had diabetes or not.

Related Science

• 2017/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America – Circulation, April 2017

Trial Design — An international, multi-center, parallel group, event-driven, randomized, double-blind, placebo-controlled study in patients with chronic HFrEF, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background standard of care therapy, for the prevention of CV death or reduction of HF events.

Trial Population — 4,744 patients aged 18years or more with symptomatic HFrEF (EF ≤40%) (NYHA functional class II-IV), which has been present for at least 2 months, on standard of care treatment, with elevated NT-proBNP levels and eGFR ≥30 mL/min/1.73 m^2 (CKD-EPI formula) at enrolment. Type 1 diabetics were excluded.

Primary Endpoints

• Time to the first occurrence of any of the components of the composite: CV death or hospitalization for HF or an urgent HF visit. [Time?Frame:?From randomization visit (day 0) up to approximately 3 years]

Secondary Endpoints

1. Time to the first occurrence of either of the components of the composite: CV death or hospitalization for HF. [Time?Frame:?From randomization visit (day 0) up to approximately 3 years]
2. Total number of (first and recurrent) HF hospitalizations and CV death. [Time?Frame:?From randomization visit (day 0) up to approximately 3 years]
3. Change from baseline measured at 8 months in the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ), a specific HF patient reported outcome questionnaire. [Time?Frame:?From randomization visit (day 0) up to 8 months (day 240)]
4. Time to the first occurrence of any of the components of the composite: ≥50% sustained decline in eGFR or reaching End Stage Renal Disease (ESRD) or renal death. [Time?Frame:?From randomization visit (day 0) up to approximately 3 years]
   End Stage Renal Disease (ESRD) is defined as:
• Sustained eGFR <15 mL/min/1.73m^2 or,
• Chronic dialysis treatment or,
• Receiving a renal transplant
5. Time to death from any cause. [?Time?Frame:?From randomization visit (day 0) up to approximately 3 years]

Sponsor

Astra-Zeneca

HFrEF, Heart failure, Heart disease, 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol, Sodium-Glucose Transporter 2 Inhibitors

• Heart Failure with Reduced Ejection Fraction
• Non-Cardiac Drugs with Cardiovascular Benefits
• Diabetes and Cardiovascular Complications