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Original Investigation
July 28, 2021

Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis of a Phase 3 Randomized Clinical Trial

Author Affiliations
  • 1British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
  • 2Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3National Institute of Health and Medical Research, Center for Clinical Multidisciplinary Research 1433, INSERM U1116, Nancy, France
  • 4AstraZeneca R&D, Gothenburg, Sweden
  • 5Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
  • 6Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
  • 7Saint Luke's Mid America Heart Institute and University of Missouri–Kansas City
  • 8The George Institute for Global Health, University of New South Wales, Sydney, Australia
  • 9Universidad Nacional de Córdoba, Córdoba, Argentina
  • 10Center for Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
  • 11TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
JAMA Cardiol. Published online July 28, 2021. doi:10.1001/jamacardio.2021.2632
Key Points

Question  Would long-term dapagliflozin therapy prolong survival free from worsening heart failure events and mortality in patients with heart failure and reduced ejection fraction?

Findings  In this exploratory analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure randomized clinical trial that included 4744 patients, extrapolated event-free and overall survival time was longer with dapagliflozin compared with placebo. These findings were generally consistent across the age range studied and in subgroups of patients in the trial.

Meaning  In this study, in patients with heart failure and reduced ejection fraction, the addition of dapagliflozin to standard therapy was estimated to provide clinically meaningful gains in extrapolated long-term, event-free, and overall survival.

Abstract

Importance  Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients.

Objective  To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient’s lifetime.

Design, Setting, and Participants  Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months.

Interventions  Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy.

Main Outcomes and Measures  The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient’s lifetime for the primary outcome and the secondary outcome of death from any cause.

Results  A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival.

Conclusions and Relevance  These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF.

Trial Registration  ClinicalTrials.gov Identifier: NCT03036124

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    1 Comment for this article
    EXPAND ALL
    SGLT2 Calories intake and survival
    Enrique J Sanchez Delgado, MD | Hospital Vivian Pellas, Managua
    The interesting analysis of Kieran F. Docherty et. al (JAMA Cardiol. Published online July 28, 2021. doi:10.1001/jamacardio.2021.2632) which found a prolonged survival in patients with HFrEF receiving Dapaglifozin (SGLT2i) supports, at least indirectly, that the calories reduction prolongs survival (in this case trough glucose/calories renal excretion).

    They also confirm, indirectly, my analysis and findings published over two decades ago, when the SGLT2i were not in clinical use.

    The findings are highly similar (Enrique Sánchez Delgado, LANCET Lifetime risk of developing coronary heart disease - The Lancet MARCH 13, 1999)

    We compared caloric intake with life expectancy
    in the 20 most developed countries and found that, indeed, an ingestion of 280 kcal less every day corresponds to 25 months (2.1 years) longer lifespan.

    Docherty et.al. found that the extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years.

    When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 a gain in survival of 1.7 years with dapagliflozin.

    SGLT2i like Dapaglifozin eliminate as glucose in urine, the equivalent to 280 calories per day in average. As noted before, this could potentially add 2.1 years of survival.

    This corresponds very similar to the findings of Docherty et. al., adding weight to the paramount importance of reducing the calories intake and also emphasizes the mechanism of the positive clinical effects of SGLT2 inhibitors.

    Prof. Enrique Sánchez Delgado, MD
    Internal Medicine – Clinical Pharmacology and Therapeutics
    Hospital Vivian Pellas, Managua
    CONFLICT OF INTEREST: None Reported
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