Heart Failure: What are the practical consequences of ... · N patients ~7000 ~10,000 ~17,000...
Transcript of Heart Failure: What are the practical consequences of ... · N patients ~7000 ~10,000 ~17,000...
Heart Failure: What are the practical consequences of current and ongoing SGLT2i outcome trials?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
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• 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
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
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Comparison of studies should be interpreted with caution due to differences in study design, populations and
methodologyACM, all-cause mortality; HHF, hospitalisation for heart failure;
PY, patient-years1. 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)
Drug EMPAGLIFLOZIN DAPAGLIFLOZIN
TrialEMPEROR-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
or 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
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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
Dapagliflozin chronic HFpEF and HFrEF outcomes trials
Comparisons of studies should be interpreted with caution due to differences in study design, populations and
methodologyHFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure;
LVEF, left ventricular ejection fraction1. 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 endpointTime to first occurrence
of CV death, HHF or urgent HF visit
N
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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 endpointsTime 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
Target patient populations
Diabetes
HFpEF HFrEF
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 0 28
ACEi or ARB 100 100 94a
𝛽-blocker 93 92 96
MRA 60 37 71
Digitalis 30 32 19
Ivabradine 2 1 5
CRT 7 6 7
ICD 15 15 26
Drug Therapy in HFrEFTraffic 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.
20192019 2020 2021
• Failed WHF AHF trials • Suboptimal use of GDMT• Slow adoption of
Sacubutril Valsartan
DAPA-HFrEFEMPEROR rEF
Guidelines
VICTORIA
SOLOIST WHF
Omecamtiv Mecabril
Need for creative implementation solutions• Disease management programs? • Precision medicine?
HF-REF: The building blocks of therapy
Beta-blocker + ACEi/ARB/ARNI + MRA
ICD
CRT
VADTX
H-ISDN, Ivabradine, Digoxin, CABG
SGLT2 I
Vericiguat?
Disease Management ProgramsRemote monitoring
O Mecabril?
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 cardiacbioenergetics
Inhibition of cardiac sodium–hydrogen exchange
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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
Increase in hematocrit with empagliflozin
16Inzucchi SE et al. Diabetes Care (in press).
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
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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
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