Faiez Zannad1, João Pedro Ferreira2, Stuart J Pocock3, Stefan D Anker4, Javed Butler5, Gerasimos Filippatos6, Martina Brueckmann7, Anne Pernille Ofstad8, Egon Pfarr9, Waheed Jamal9, Milton Packer10. 1. Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Institut National de la Santé et de la Recherche Médicale 1116, Centre Hospitalier Régional Universitaire de Nancy, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France. Electronic address: f.zannad@chru-nancy.fr. 2. Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Institut National de la Santé et de la Recherche Médicale 1116, Centre Hospitalier Régional Universitaire de Nancy, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France. 3. Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK. 4. Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany. 5. Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA. 6. National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece. 7. Boehringer Ingelheim International, Ingelheim, Germany; Faculty of Medicine, University of Heidelberg, Mannheim, Germany. 8. Medical Department, Boehringer Ingelheim Norway KS, Asker, Norway. 9. Boehringer Ingelheim International, Ingelheim, Germany. 10. Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; Imperial College London, London, UK.
Abstract
BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.
BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.
Authors: Fabiana G Marcondes-Braga; Lídia Ana Zytynski Moura; Victor Sarli Issa; Jefferson Luis Vieira; Luis Eduardo Rohde; Marcus Vinícius Simões; Miguel Morita Fernandes-Silva; Salvador Rassi; Silvia Marinho Martins Alves; Denilson Campos de Albuquerque; Dirceu Rodrigues de Almeida; Edimar Alcides Bocchi; Felix José Alvarez Ramires; Fernando Bacal; João Manoel Rossi Neto; Luiz Claudio Danzmann; Marcelo Westerlund Montera; Mucio Tavares de Oliveira Junior; Nadine Clausell; Odilson Marcos Silvestre; Reinaldo Bulgarelli Bestetti; Sabrina Bernadez-Pereira; Aguinaldo F Freitas; Andréia Biolo; Antonio Carlos Pereira Barretto; Antônio José Lagoeiro Jorge; Bruno Biselli; Carlos Eduardo Lucena Montenegro; Edval Gomes Dos Santos Júnior; Estêvão Lanna Figueiredo; Fábio Fernandes; Fabio Serra Silveira; Fernando Antibas Atik; Flávio de Souza Brito; Germano Emílio Conceição Souza; Gustavo Calado de Aguiar Ribeiro; Humberto Villacorta; João David de Souza Neto; Livia Adams Goldraich; Luís Beck-da-Silva; Manoel Fernandes Canesin; Marcelo Imbroinise Bittencourt; Marcely Gimenes Bonatto; Maria da Consolação Vieira Moreira; Mônica Samuel Avila; Otavio Rizzi Coelho Filho; Pedro Vellosa Schwartzmann; Ricardo Mourilhe-Rocha; Sandrigo Mangini; Silvia Moreira Ayub Ferreira; José Albuquerque de Figueiredo Neto; Evandro Tinoco Mesquita Journal: Arq Bras Cardiol Date: 2021-06 Impact factor: 2.000
Authors: Muthiah Vaduganathan; Stephen J Greene; Shuaiqi Zhang; Maria Grau-Sepulveda; Adam D DeVore; Javed Butler; Paul A Heidenreich; Joanna C Huang; Michelle M Kittleson; Karen E Joynt Maddox; James J McDermott; Anjali Tiku Owens; Pamela N Peterson; Scott D Solomon; Orly Vardeny; Clyde W Yancy; Gregg C Fonarow Journal: JAMA Cardiol Date: 2020-11-13 Impact factor: 14.676