Michael Szarek1, Deepak L Bhatt2, Ph Gabriel Steg3, Christopher P Cannon2, Lawrence A Leiter4, Darren K McGuire5, Julia B Lewis6, Matthew C Riddle7, Adriaan A Voors8, Marco Metra9, Lars H Lund10, Michel Komajda11, Jeffrey M Testani12, Christopher S Wilcox13, Piotr Ponikowski14, Renato D Lopes15, Phillip Banks16, Eshetu Tesfaye16, Justin A Ezekowitz17, Subodh Verma4, Bertram Pitt18. 1. CPC Clinical Research and University of Colorado Anschutz Medical Campus, Aurora, Colorado, and State University of New York Downstate School of Public Health, Brooklyn, New York (M.S.). 2. Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts (D.L.B., C.P.C.). 3. Université de Paris, French Alliance for Cardiovascular Trials, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, INSERM Unité 1148, Paris, France (P.G.S.). 4. Li Ka Shing Knowledge Institute, St. Michael's Hospital, and University of Toronto, Toronto, Ontario, Canada (L.A.L., S.V.). 5. University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas, Texas (D.K.M.). 6. Vanderbilt University, Nashville, Tennessee (J.B.L.). 7. Oregon Health & Science University, Portland, Oregon (M.C.R.). 8. University of Groningen-University Medical Center Groningen, Groningen, the Netherlands (A.A.V.). 9. Azienda Socio Sanitaria Territoriale Spedali Civili and University of Brescia, Brescia, Italy (M.M.). 10. Karolinska Institutet, Solna, Sweden (L.H.L.). 11. Paris Sorbonne University and Groupe Hospitalier Paris Saint Joseph, Paris, France (M.K.). 12. Yale University, New Haven, Connecticut (J.M.T.). 13. Georgetown University, Washington, DC (C.S.W.). 14. Wroclaw Medical University, Wroclaw, Poland (P.P.). 15. Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina (R.D.L.). 16. Lexicon Pharmaceuticals, The Woodlands, Texas (P.B., E.T.). 17. University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada (J.A.E.). 18. University of Michigan, Ann Arbor, Michigan (B.P.).
Abstract
BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934). SETTING: 306 sites in 32 countries. PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified. CONCLUSION:Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.
RCT Entities:
BACKGROUND: In the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, sotagliflozin, a sodium-glucose cotransporter-1 and sodium-glucose cotransporter-2 inhibitor, reduced total occurrences of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure relative to placebo by 33%. OBJECTIVE: To determine whether sotagliflozin increased the prespecified efficacy outcome of days alive and out of the hospital (DAOH) in the SOLOIST-WHF trial. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT03521934). SETTING: 306 sites in 32 countries. PARTICIPANTS: 1222 patients with type 2 diabetes and reduced or preserved ejection fraction who were recently hospitalized for worsening heart failure. INTERVENTION: 200 mg of sotagliflozin once daily (with a possible dose increase to 400 mg) or matching placebo. MEASUREMENTS: The primary analysis included hospitalizations for any reason on the basis of investigator-reported incidence and duration of admissions after randomization. Days alive and out of the hospital and its converse (days dead and days in the hospital) were analyzed using prespecified Poisson regression models. RESULTS: Although similar proportions of patients in the sotagliflozin and placebo groups were hospitalized at least once (38.5% vs. 41.4%), fewer patients in the sotagliflozin group were hospitalized more than once (16.3% vs. 22.1%). There were 64 and 76 deaths in the sotagliflozin and placebo groups, respectively. The DAOH rate in the sotagliflozin group was 3% higher than in the placebo group (rate ratio [RR], 1.03 [95% CI, 1.00 to 1.06]; P = 0.027). This difference was primarily driven by a reduction in the rate of days dead (RR, 0.71 [CI, 0.52 to 0.99]; P = 0.041) rather than by a reduction in the rate of days hospitalized for any cause. For every 100 days of follow-up, patients in the sotagliflozin group were alive and out of the hospital for 3% or 2.9 more days than those in the placebo group (91.8 vs. 88.9 days); this difference reflected a 2.6-day difference in days dead (6.3 vs. 8.9 days) and a 0.3-day difference in days in the hospital (1.9 vs. 2.2 days). LIMITATION: Other than heart failure, the primary reason for each hospitalization was unspecified. CONCLUSION:Sotagliflozin increased DAOH, a metric that may provide an additional patient-centered outcome to capture the totality of disease burden. Future studies are needed to quantify the consequences of increasing DAOH in terms of health economics and patient quality of life. PRIMARY FUNDING SOURCE: Sanofi at initiation and Lexicon Pharmaceuticals at completion.