outcome tri rials? Faiez Zannad Universit de Lorraine, Inserm, - PowerPoint PPT Presentation

Heart Fail ilure: : What are the practical consequences of f curr rrent and ongoing SGLT2i outcome tri rials? Faiez Zannad Université de Lorraine, Inserm, CHRU Nancy Centre d’Investigations Cliniques 1433 and Inserm U1116, France Currently Eugene Braunwald Scholar, Visiting Professor Harvard Medical School, Brigham and Women’s Hospital, Boston, USA

Disclosures • Consultant; DSMB; steering committee; speaker: • Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cardior, Cereno Scientific, CEVA, Cirius therapeutics, CVRx, G3 Pharmaceuticals, GE Healthcare, J&J, KBP biosciences, LivaNova, Merck, Mitsubishi, Mundipharma, Nestlé Health Science, Novartis, NovoNordisk, Pfizer, Quantum Genomics, Relypsa, ResMed, Vifor Fresenius, ZS Pharma • Founder: • CardioRenal, CVCT, Eshmoun DGOS 2

SGLT2 inhibitor CVOTs in T2D: consistent effect across all outcomes, including HF 1 – 3 N patients ~7000 ~10,000 ~17,000 Median follow-up (years) 3.1 2.4 4.2 Empa Placebo Cana Placebo Dapa Placebo Events/1000 PY Events/1000 PY Events/1000 PY HR (95% CI) HR (95% CI) HR (95% CI) 3P-MACE 37.4 43.9 0.86 (0.74, 0.99) 26.9 31.5 0.86 (0.75, 0.97) 22.6 24.2 0.93 (0.84, 1.03) CV death 12.4 20.2 0.62 (0.49, 0.77) 11.6 12.8 0.87 (0.72, 1.06) 7.0 7.1 0.98 (0.82, 1.17) MI 16.8 19.3 0.87 (0.70, 1.09) 11.2 12.6 0.89 (0.73, 1.09) 11.7 13.2 0.89 (0.77, 1.01) Stroke 12.3 10.5 1.18 (0.89, 1.56) 7.9 9.6 0.87 (0.69, 1.09) 6.9 6.8 1.01 (0.84, 1.21) HHF 9.4 14.5 0.65 (0.50, 0.85) 5.5 8.7 0.67 (0.52, 0.87) 6.2 8.5 0.73 (0.61, 0.88) HHF/CV death 19.7 30.1 0.66 (0.55, 0.79) 16.3 20.8 0.78 (0.67, 0.91) 12.2 14.7 0.83 (0.73, 0.95) ACM 19.4 28.6 0.68 (0.57, 0.82) 17.3 19.5 0.87 (0.74,1.01) 15.1 16.4 0.93 (0.82, 1.04) Comparison of studies should be interpreted with caution due to differences in study design, populations and methodology ACM, all-cause mortality; HHF, hospitalisation for heart failure; 3 PY, patient-years 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Neal B et al.

Randomised controlled (outcome) trials of SGLT2 inhibitors in HF Drug EMPAGLIFLOZIN DAPAGLIFLOZIN EMPEROR- EMPEROR-Reduced 2 Dapa-HF 3 DELIVER Trial Preserved 1 4700 5500 3350 4500 Sample size • Symptomatic HFpEF † • Chronic HF † • Symptomatic HFrEF † • Elevated NT-proBNP • Elevated NT-proBNP • Elevated NT-proBNP • eGFR ≥25 ml/min/1.73 m 2 Key inclusion • eGFR ≥20 ml/min/1.73 m 2 • eGFR ≥30 ml/min/1.73 m 2 criteria • ≥ 40 years of age HFrEF (LVEF HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFpEF (LVEF > 40%) ≤40%) • Time to first event of adjudicated CV • Time to first occurrence of CV • Time to first occurrence of CV death, death Primary endpoint death, HHF or urgent HF visit HHF or urgent HF visit or adjudicated HHF • Individual components of primary • Total number of CV death or HHF • Total number of CV death or HHF endpoint • Time to death from any cause • All-cause mortality • All-cause mortality • Change from baseline in TSS (total • Composite of ≥50% sustained Key secondary • All-cause hospitalisation symptom score) of KCCQ at 8 mos endpoints eGFR decline, ESRD or renal • Time to first occurrence of sustained • Proportion of patients with death reduction of eGFR worsened NYHA class from baseline • Change from baseline in KCCQ • Change from baseline in KCCQ to 8 months 4

Empagliflozin chronic HFpEF and HFrEF outcomes trials EMPEROR-Preserved 1,2 EMPEROR-Reduced 3,4 Study drug Empagliflozin 10 mg qd Empagliflozin 10 mg qd HFpEF (LVEF >40%) with or without T2D HFrEF (LVEF ≤40%) with or without T2D NT-proBNP (pg/ml) Elevated NT-proBNP (pg/ml) EF (%) Patients without AF* Patients without AF Population ≥36 to ≤40 ≥2500 >300 ≥31 to ≤ 35 ≥1000 ≤30 ≥600 ≤40% + HHF within 12 months ≥600 N Sample size ~5500 ~3350 Primary endpoint Time to first event of adjudicated CV death or adjudicated HHF Comparisons of studies should be interpreted with caution due to differences in study design, populations and methodology *NT-proBNP-based enrichment of the population: patients with a higher EF require a higher NT-proBNP level for inclusion AF, atrial fibrillation; EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N- terminal pro−B -type natriuretic peptide 1. ClinicalTrials.gov. NCT03057951 (accessed May 2019); 2. Butler J et al. ESC-HF 2018 ; poster P972; 3. ClinicalTrials.gov. NCT03057977 (accessed May 2019); 4. Zannad F 5 et al. ESC-HF 2018; poster P1755

Dapagliflozin chronic HFpEF and HFrEF outcomes trials DELIVER 1 DAPA-HF 2,3 Study drug Dapagliflozin 10 mg qd Dapagliflozin 5 mg or 10 mg qd Population HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) N Sample size 4700 4500 Time to first occurrence Primary endpoint of CV death, HHF or urgent HF visit Comparisons of studies should be interpreted with caution due to differences in study design, populations and methodology HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; 6 LVEF, left ventricular ejection fraction 1. ClinicalTrials.gov. NCT03619213 (accessed May 2019); 2.

SOLOIST-WHF trial in patients with worsening HF and T2D SOLOIST-WHF 1,2 Study drug Sotagliflozin Population Worsening HFpEF or HFrEF in patients with T2D N Sample size 6667* Time to first occurrence of CV death or HHF in patients with LVEF <50% Primary endpoints Time to first occurrence of CV death or HHF in total patient population Comparisons of trials should be interpreted with caution due to differences in study design, populations and methodology *Patient numbers differ between CT.gov and EU Clinical Trials Register HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction 1. ClinicalTrials.gov. NCT03521934; 2. EU Clinical Trials Register 2017-003510-16. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003510-16/SE (all websites 7 accessed May 2019)

Target patient populations Diabetes HFpEF HFrEF

PARADIGM ATMOSPHERE DAPAHF (n = 8442) (n = 7063) (n = 4744) 64 63 66 Mean age, years 22 22 23 Female sex, n (%) NYHA II % 70 69 68 24 28 32 NYHA III % 29 28 31 Mean LVEF, % Median NT-proBNP, pg/mL 1615 1198 1437 63 60 47 History of HF hospitalization, % 60 56 56 Ischaemic aetiology, % Median BMI, kg/m 2 28 27 27 PARADIGM-HF ATMOSPHERE DAPAHF (n = 8442) (n = 7063) (n = 4744) 32 27 35 Obese, % Treatment (%) 34 28 42 Diabetes, % Diuretic 80 80 93 71 62 74 Hypertension, % ACEi 78 100 56 43 41 44 MI, % 23 0 28 ARB PCI, % 21 20 34 ACEi or ARB 100 100 94 a 15 14 17 CABG, % 𝛾 -blocker 93 92 96 9 7 10 Stroke, % MRA 60 37 71 Atrial fibrillation/ flutter, % Digitalis 30 32 19 37 34 40 History 2 1 5 Ivabradine 25 23 24 ECG CRT 7 6 7 68 74 66 eGFR, mL/min/1.73 m 2 ICD 15 15 26 37 27 41 eGFR < 60 mL/ min/1.73 m 2 ,%

Drug Therapy in HFrEF Traffic Jam Expected Omecamtiv Mecabril Guidelines DAPA-HFrEF SOLOIST WHF EMPEROR rEF • Failed WHF AHF trials • Suboptimal use of GDMT 2019 2019 2020 2021 • Slow adoption of Sacubutril Valsartan VICTORIA Need for creative implementation solutions • Disease management programs? • Precision medicine? Zannad F. Personal communication. AHF, acute heart failure; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; WHF, worsening heart failure.

HF-REF: The building blocks of therapy TX VAD ICD CRT H-ISDN, Ivabradine, Digoxin, CABG Vericiguat ? O Mecabril? Beta-blocker + ACEi/ARB/ARNI + MRA SGLT2 I Disease Management Programs Remote monitoring

Many mechanisms may contribute to the beneficial effects on heart failure seen with empagliflozin Reduction in Natriuresis interstitial oedema SGLT2i and Improved cardiac Reduction in preload, prevention of bioenergetics afterload and LV wall stress chronic HF Improved kidney function Inhibition of cardiac and cardio – renal physiology sodium – hydrogen exchange LV, left ventricular Adapted from: Farkouh ME & Verma S. J Am Coll Cardiol 14 2018;71:2505

Univariable mediation analysis of risk of CV death with empagliflozin versus placebo: time- dependent covariate analysis adjusting for the change from baseline in each variable Cox proportional hazards regression analysis in patients treated with one or more doses of study drug

Increase in hematocrit with empagliflozin 16 Inzucchi SE et al. Diabetes Care (in press).