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

May 03, 2023 155 likes •347 views

Heart Fail ilure: : What are the practical consequences of f curr rrent and ongoing SGLT2i outcome tri rials? Faiez Zannad Universit de Lorraine, Inserm, CHRU Nancy Centre dInvestigations Cliniques 1433 and Inserm U1116, France

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Heart Fail ilure: : What are the practical consequences of f curr rrent and ongoing SGLT2i

  • utcome 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

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Disclosures

2

  • 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

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N patients ~7000 ~10,000 ~17,000 Median follow-up (years) 3.1 2.4 4.2

SGLT2 inhibitor CVOTs in T2D: consistent effect across all outcomes, including HF1–3

3 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; PY, patient-years

  • 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Neal B et al.

Empa Placebo HR (95% CI) Cana Placebo HR (95% CI) Dapa Placebo HR (95% CI) Events/1000 PY Events/1000 PY Events/1000 PY 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)

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Drug

EMPAGLIFLOZIN DAPAGLIFLOZIN

Trial

EMPEROR- Preserved1 EMPEROR-Reduced2 Dapa-HF3

DELIVER

Sample size

5500 3350 4500

4700

Key inclusion criteria

  • Chronic HF†
  • Elevated NT-proBNP
  • eGFR ≥20 ml/min/1.73 m2
  • Symptomatic HFrEF†
  • Elevated NT-proBNP
  • eGFR ≥30 ml/min/1.73 m2
  • Symptomatic HFpEF†
  • Elevated NT-proBNP
  • eGFR ≥25 ml/min/1.73 m2
  • ≥ 40 years of age

HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%) HFpEF (LVEF > 40%)

Primary endpoint

  • Time to first event of adjudicated CV

death

  • r adjudicated HHF
  • Time to first occurrence of CV

death, HHF or urgent HF visit

  • Time to first occurrence of CV death,

HHF or urgent HF visit

Key secondary endpoints

  • Individual components of primary

endpoint

  • All-cause mortality
  • All-cause hospitalisation
  • Time to first occurrence of sustained

reduction of eGFR

  • Change from baseline in KCCQ
  • Total number of CV death or HHF
  • All-cause mortality
  • Composite of ≥50% sustained

eGFR decline, ESRD or renal death

  • Change from baseline in KCCQ
  • Total number of CV death or HHF
  • Time to death from any cause
  • Change from baseline in TSS (total

symptom score) of KCCQ at 8 mos

  • Proportion of patients with

worsened NYHA class from baseline to 8 months

Randomised controlled (outcome) trials of SGLT2 inhibitors in HF

4

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Empagliflozin chronic HFpEF and HFrEF outcomes trials

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

et al. ESC-HF 2018; poster P1755 5

EMPEROR-Preserved1,2 EMPEROR-Reduced3,4

Study drug Empagliflozin 10 mg qd Empagliflozin 10 mg qd Population HFpEF (LVEF >40%) with or without T2D

Elevated NT-proBNP (pg/ml) Patients without AF >300

HFrEF (LVEF ≤40%) with or without T2D Sample size ~5500 ~3350 Primary endpoint Time to first event of adjudicated CV death or adjudicated HHF

EF (%) NT-proBNP (pg/ml) Patients without AF* ≥36 to ≤40 ≥2500 ≥31 to ≤35 ≥1000 ≤30 ≥600 ≤40% + HHF within 12 months ≥600

N

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SLIDE 6

Dapagliflozin chronic HFpEF and HFrEF outcomes trials

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; LVEF, left ventricular ejection fraction

  • 1. ClinicalTrials.gov. NCT03619213 (accessed May 2019); 2.

DELIVER1 DAPA-HF2,3

Study drug Dapagliflozin 10 mg qd Dapagliflozin 5 mg or 10 mg qd Population HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) Sample size 4700 4500 Primary endpoint Time to first occurrence

  • f CV death, HHF or urgent HF visit

N

6

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SOLOIST-WHF trial in patients with worsening HF and T2D

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

accessed May 2019) 7

SOLOIST-WHF1,2

Study drug Sotagliflozin Population Worsening HFpEF or HFrEF in patients with T2D Sample size 6667* Primary endpoints Time to first occurrence of CV death or HHF in patients with LVEF <50% Time to first occurrence of CV death or HHF in total patient population

N

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Target patient populations

Diabetes HFpEF HFrEF

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PARADIGM (n = 8442) ATMOSPHERE (n = 7063) DAPAHF (n = 4744)

Mean age, years

64 63 66

Female sex, n (%)

22 22 23

NYHA II %

70 69 68

NYHA III %

24 28 32

Mean LVEF, %

29 28 31

Median NT-proBNP, pg/mL

1615 1198 1437

History of HF hospitalization, %

63 60 47

Ischaemic aetiology, %

60 56 56

Median BMI, kg/m2

28 27 27

Obese, %

32 27 35

Diabetes, %

34 28 42

Hypertension, %

71 62 74

MI, %

43 41 44

PCI, %

21 20 34

CABG, %

15 14 17

Stroke, %

9 7 10

Atrial fibrillation/ flutter, % History

37 34 40

ECG

25 23 24

eGFR, mL/min/1.73 m2

68 74 66

eGFR < 60 mL/ min/1.73 m2,%

37 27 41

PARADIGM-HF (n = 8442) ATMOSPHERE (n = 7063) DAPAHF (n = 4744)

Treatment (%) Diuretic

80 80 93

ACEi

78 100 56

ARB

23 28

ACEi or ARB

100 100 94a

𝛾-blocker

93 92 96

MRA

60 37 71

Digitalis

30 32 19

Ivabradine

2 1 5

CRT

7 6 7

ICD

15 15 26

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SLIDE 10
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SLIDE 11
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SLIDE 12

Drug Therapy in HFrEF Traffic Jam Expected

AHF, acute heart failure; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; WHF, worsening heart failure.

Zannad F. Personal communication.

2019

2019 2020 2021

  • Failed WHF AHF trials
  • Suboptimal use of GDMT
  • Slow adoption of

Sacubutril Valsartan

DAPA-HFrEF EMPEROR rEF

Guidelines

VICTORIA

SOLOIST WHF Omecamtiv Mecabril

Need for creative implementation solutions

  • Disease management programs?
  • Precision medicine?
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SLIDE 13

HF-REF: The building blocks of therapy

Beta-blocker + ACEi/ARB/ARNI + MRA ICD CRT VAD TX H-ISDN, Ivabradine, Digoxin, CABG SGLT2 I

Vericiguat?

Disease Management Programs Remote monitoring

O Mecabril?

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SLIDE 14

Many mechanisms may contribute to the beneficial effects on heart failure seen with empagliflozin

LV, left ventricular Adapted from: Farkouh ME & Verma S. J Am Coll Cardiol 2018;71:2505

SGLT2i and prevention of chronic HF

Reduction in interstitial oedema Reduction in preload, afterload and LV wall stress Improved kidney function and cardio–renal physiology Natriuresis Improved cardiac bioenergetics Inhibition of cardiac sodium–hydrogen exchange

14

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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

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Increase in hematocrit with empagliflozin

16

Inzucchi SE et al. Diabetes Care (in press).

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What is unique about the diuretic effect of SGLT2 inhibitors?

  • 1. Verma S & McMurray J. Diabetologia 2018;61:2108; 2. Hallow KM et al. Diabetes Obes Metab 2018;20:479; 3. Heise T et al. Clin Ther 2016;38:2248;
  • 4. Rehman A et al. Diabetes Spectrum 2011;24:234; 5. Zinman B et al. N Engl J Med 2015;373:2117; 6. Scheen AJ. Diabetes Metab 2016;42:224;
  • 7. Wanner C et al. N Engl J Med 2016;375:323

✓ Selectively reduces interstitial volume with minimal change in blood volume1 ✓ NO counter-regulatory stimulation of the RAAS2–4 ✓ NO hypokalaemia (unlike loop diuretics)5,6 ✓ NO effect on uric acid (unlike loop diuretics)6 ✓ NO hyperglycaemic effect (unlike thiazides)4,5 ✓ AND improved renal function!5,7

17

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Heart failure with preserved ejection fraction (HFpEF) LVEF >40%1 Heart failure with reduced ejection fraction (HFrEF) LVEF ≤40%4

The empagliflozin chronic heart failure program

LVEF, left ventricular ejection fraction See slide notes for references

Outcomes trial with planned recruitment:

3350 patients3,4

Outcomes trial with planned recruitment:

5500 patients1,2 Functional capacity study 300 patients5,6 Functional capacity study 300 patients7,8 Mechanistic study 86 patients9

18

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