Robert Mentz, MD Duke University

1. Evolving Pharmacological
Treatment Strategies for HFrEF
Robert J. Mentz, MD
Associate Professor of Medicine
Chief, Heart Failure Section
Duke University Medical Center
Editor-in-Chief, Journal of Cardiac Failure
@robmentz
Robert.mentz@duke.edu

2. Disclosures
• Research support and/or honoraria from Abbott, American
Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife,
Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk,
Pharmacosmos, Pfizer, Relypsa, Respicardia, Roche, Sanofi,
Vifor, Windtree Therapeutics, and Zoll.

3. HF Epidemiology
Bozkurt B, et al. J Card Fail 2023

4. 2022 AHA/ACC/HFSA Guideline for
the Management of Heart Failure
Heidenreich PA, et al. J Card Fail OnlineJCF.com

5. HFrEF Quadruple Therapy
ARNI
Beta-
Blocker
MRA SGLT2i
Felker GM. Circulation 2019
Heidenreich PA, et al. J Card Fail 2022
(Sacubitril / Valsartan)
GDMT for HFrEF includes 4 Medication Classes

6. Residual Risk: Even with Quadtherapy
Cardiovascular Death or
Hospitalization for Heart Failure
EMPEROR-Reduced Trial
Packer M, et al. NEJM 2020

9. VICTORIA: Vericiguat in HFrEF + Recent WHF
Median follow-up
10.8 months
Annualized ARR of 4.2%
CV Death or HF Hosp
Armstrong PW, et al. NEJM 2020
Ezekowitz JA, et al. JACC HF 2020
Lam CS, et al. JAMA Cardiol 2021
Potentially larger effect:
• NT-proBNP ≤8,000
• Further out from recent
WHF Event
Soluble Guanylate Cyclase Stimulator

10. • Vericiguat in HFrEF without recent WHF
• Targeting 6,000 patients
• EF ≤40% with no WHF event < 6 months
• NTproBNP 600 – 6,000 pg/mL
• Primary: CV death or HF Hosp
https://clinicaltrials.gov/ct2/show/NCT05093933
Larger Treatment Effect in
those with lower NT-proBNP
& Without Recent WHF
Lam CS, et al. JAMA Cardiol 2021
Ezekowitz JA, et al. JACC HF 2020
Lower BNP
Out from WHF

11. GALACTIC-HF: Omecamtiv Mecarbil in HFrEF
]
1
Teerlink J, et al. NEJM 2020
Felker GM, et al. JAMA Cardiol 2021
Time to First Heart Failure Event or Cardiovascular Death
Months (30 days) since
randomization
Cumulative
incidence,
%
0 6 12 18 24 30 36
50
40
30
20
10
0
Hazard ratio = 0.92 (95% CI, 0.86–
0.99)
P = 0.0252
Placebo
Omecamtiv
mecarbil
HR = 0.92 (95% CI, 0.86–0.99)
P = 0.025
Potentially larger effect w
more advanced disease
• EF ≤28% & NYHA III/IV
• HF hosp 3 mos
• Higher BNP & Lower BP
Myosin Activator
Not currently FDA approved

12. EF ≤ 30
N = 5842
0.88 (0.81, 0.96);
p=0.002
NYHA III-IV
N = 3864
HR 0.88 (0.80, 0.97);
p=0.007
HF Hosp last 6 mos
N = 6308
HR 0.89 (0.83, 0.97);
p=0.006
Benefit of Omecamtiv Mecarbil
by Severe HF Criteria
Severe HF
N = 2258
HR = 0.80 (0.71, 0.90),
p < 0.001
Absolute risk reduction:
8.3 events/100 pt-years
NNT = 12
Felker GM, et al. JAMA Cardiol.
doi:10.1001/jamacardio.2021.4027.

13. AFFIRM-AHF & IRONMAN: IV Iron
Ponikowski P, et al. Lancet 2020
Total HF Hosp and CV Death
Kalra PR, et al. Lancet 2022
Recurrent HF Hosp and CV Death
Nominal Reduction in
HF Hospitalization

14. HEART-FID: Primary Hierarchical Endpoint
158
131
0
20
40
60
80
100
120
140
160
180
200
Deaths (N, %)
All-cause Mortality
(12 mos)
Placebo FCM
10.3%
8.6%
332
297
0
50
100
150
200
250
300
350
400
450
Total HF Hosp (N)
Total HF Hospitalizations
(12 mos)
Placebo FCM
+4 (59)
+8 (60)
0
5
10
15
Mean Change 6-MWD (m)
Change in 6-MWD
(6 mos)
Placebo FCM
1.7% ARR
(20% more wins)
270 fewer HF
hospitalization days
+4 meter benefit
(11% more wins)
P-value = (target <0.01)
Among
227
patients
(14.8%)
Among
204
patients
(13.3%)
0.019 Win Ratio (99%CI) = 1.10 (0.99, 1.23)
Mentz RJ, et al. NEJM 2023

15. Pre-Specified Subgroup: TSAT
Rate ratio
(95% CI)
Rate ratio (95% CI)
CV Death + CV Hosp
P-
Value
Interaction
P-value
TSAT<20%
Ponikowski P, Mentz RJ, et al. Eur Heart J 2023

16. 1196 935 775 541 368 226 155 107 71 43 20
1755 1548 1360 952 680 431 310 214 154 86 30
At Risk
TSAT < 20%
TSAT >= 20%
0 6 12 18 24 30 36 42 48 54 60
Months from Randomization
0
20
40
60
80
100
Percentage
of
Patients
with
Event
(95%
CI)
41% pts had TSAT <20%
90% with ferritin <100
All Cause Death or CV Hospitalization
Stratified by TSAT Level
TSAT≥20
2651 2235 1926 1346 942 584 410 285 199 115 45
300 248 209 147 106 73 55 36 26 14 5
At Risk
(ug/L)
Serum Ferritin < 100
(ug/L)
Serum Ferritin >= 100
0 6 12 18 24 30 36 42 48 54 60
Months from Randomization
0
20
40
60
80
100
Percentage
of
Patients
with
Event
(95%
CI)
TSAT<20
All Cause Death or CV Hospitalization
Stratified by Ferritin Level
Ferritin≥100
Ferritin<100
Lewis GD, et al. ACC Scientific Session 2024

17. Acute HF & WHF (including HFrEF)

18. Pre-Specified PARAGLIDE + PIONEER
Outcome Assessment in Pooled Analysis of All 1,347 Participants
• Primary endpoint was time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8.
• Adjudicated clinical endpoints were analyzed through end of follow-up, adjusting for trial.
N = 881
Sac/Val vs. Enalapril
EF ≤ 40%
In-hospital Initiation
N = 466
Sac/Val vs. Val
EF > 40%
In-hospital (70%) or ≤30 days from event
Morrow D, et al. JACC 2024

19. Cardiovascular Death or HF Hospitalization
HR 0.70; 95% CI 0.54-0.91
p=0.0077
Control
Sac / Val
1 event prevented per
4 patients treated per year
Consistent benefit of
Sac/Val vs. Control:
Acute-on-chronic and
de novo HF
Inpatient vs. early post-
event
Control = enalapril (PIONEER-HF), valsartan (PARAGLIDE-HF)
Morrow D, et al. JACC 2024

20. Hypotension in those with LVEF>60% (PARAGON)
Foa A, et al. JACC 2024
Benefit
Sac/Val
Risk
Val

21. Implementation

22. STRONG-HF: Rapid GDMT Uptitration
HF therapy: combining ACEi/ARB/ARNi & BB & MRA
Usual
care
Randomise
1:1; n = 1800
Hospital
discharge
High
intensity
care
Main inclusion
criteria
• AHF pt ready to
be discharged
• No or sub-
optimal dose of
HF therapies
• Pre-discharge
NT-proBNP
>1500 pg/ml
Introduction
of Half
optimal doses
of
HF therapy
90-day
follow-
up
Full optimal
doses of
HF therapy
Week 6
Safety
Full optimal
doses of
HF therapy
Week 3
Safety
Up-titration
to Full
optimal
doses of
HF therapy
Week 2
Safety
Primary
endpoint
180-day
HF readmission
or all-cause
mortality
Week 1
Safety
Half optimal
doses of
HF therapy
Safety = clinical exam & biology (NT-proBNP, K, Creat, hemoglobin)
Follow-up and therapy
adjustments per physicians
usual practice
Study terminated 23d Sept 2022 by DSMB (n=1069 pt)
- larger than expected difference in primary endpoint
- unethical to keep patients in usual care
Mebazaa A, et al. Lancet 2022

23. https://patientdecisionaid.org/
Patient Decision Aids
EPIC-HF

24. QI Projects: eConsult Intervention
Rao VN, et al. Circ Heart Fail 2022

25. VALUE! 2022 ACCF/AHA/HFSA Guidelines for HF
Dominant = saves money
<$50,000 per QALY
<$50,000 per QALY
>$50,000 per QALY
>$180,000 per QALY

26. Boyd C, Smith CD, Masoudi FA, Blaum CS, Dodson JA, Green AR, Kelley A, Matlock D, Ouellet J, Rich MW, Schoenborn NL, Tinetti ME. Decision Making for Older Adults With Multiple Chronic
Conditions: Executive Summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults With Multimorbidity. J Am Geriatr Soc. 2019 Apr;67(4):665-673.

27. Boyd C, Smith CD, Masoudi FA, Blaum CS, Dodson JA, Green AR, Kelley A, Matlock D, Ouellet J, Rich MW, Schoenborn NL, Tinetti ME. Decision Making for Older Adults With Multiple Chronic
Conditions: Executive Summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults With Multimorbidity. J Am Geriatr Soc. 2019 Apr;67(4):665-673.

28. Boyd C, Smith CD, Masoudi FA, Blaum CS, Dodson JA, Green AR, Kelley A, Matlock D, Ouellet J, Rich MW, Schoenborn NL, Tinetti ME. Decision Making for Older Adults With Multiple Chronic
Conditions: Executive Summary for the American Geriatrics Society Guiding Principles on the Care of Older Adults With Multimorbidity. J Am Geriatr Soc. 2019 Apr;67(4):665-673.

29. Guideline-directed
care
Health priorities-aligned
care
Palliative, symptom-
driven care
35F with PPCM 75F with multi-
morbidity
82F with advanced HF
and dementia
Highest value Rx first,
tailored to patient
Courtesy of Larry Allen with permission

30. Summary
• HF Stats through HFSA
• GDMT – Quad Therapy
• Other Therapies
– Vericiguat & IV iron
• Potential future therapies – omecamtiv mecarbil
• Optimizing therapies like ARNI & SGLT2i – inpatient initiation
• Implementation with Shared Decision Making