This document summarizes recent clinical trials evaluating new treatments for heart failure with reduced ejection fraction (HFrEF). It finds that sodium-glucose cotransporter-2 inhibitors (SGLT2i) like dapagliflozin and empagliflozin are now foundational therapies for HFrEF as they reduce mortality, hospitalizations, and improve outcomes. Two novel agents, vericiguat and omecamtiv mecarbil, are described as well-tolerated therapies that may provide additional benefit by reducing residual risk in select HFrEF patients. Vericiguat is now FDA-approved and recommended by guidelines for recent worsening HF, while omecamtiv me

1. New Treatments in HFrEF
Stephen J. Greene, MD
Assistant Professor
Duke University School of Medicine
Duke Clinical Research Institute
@SJGreene_md
October 8, 2021

2. Disclosures
 Research support from Duke Department of Medicine Chair’s Award
 Research support from American Heart Association, NHLBI, Amgen, AstraZeneca,
Bristol Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer.
 Advisory boards for Amgen, AstraZeneca, Bristol Myer Squibb, Cytokinetics, Sanofi
 Consulting for Amgen, Bayer, Bristol Myers Squibb, Merck, Vifor

3. Select Recent Outcome Trials in HFrEF

4. SGLT2 inhibition for HFrEF

5. SGLT2i in HFrEF: DAPA-HF + EMPEROR-Reduced
CV Death
EMPEROR-Reduced
DAPA-HF
CV Death + HF Hosp
EMPEROR-Reduced
DAPA-HF
HF Hosp
EMPEROR-Reduced
DAPA-HF
All-cause Death
EMPEROR-Reduced
DAPA-HF
↓14%
↓26%
↓31%
↓13%
Zannad F et al. Lancet 2020

6. Sustained Reduction in GFR and Initiation of Dialysis
Renal Composite Endpoint
Packer M et al. N Engl J Med 2020

7. Placebo
Primary composite outcome
HR 0.75 (0.63,0.90)
CV Death/HF hospitalization/Urgent HF visit
Dapagliflozin
Diabetes
Dapagliflozin
Placebo
Dapagliflozin
Placebo
HR 0.73 (0.60,0.88)
No Diabetes
P interaction 0.80 Petrie MC et al. JAMA 2020

8. Clinically meaningful change
(≥5 points) in KCCQ-TSS
Placebo Dapagliflozin
0
10
20
30
40
50
60
%
Improvement
Deterioration
No diabetes
1.12 (1.03, 1.22)
0.88 (0.81, 0.97)
0
10
20
30
40
50
60
%
Improvement
Deterioration
Diabetes
1.20 (1.09, 1.31)
0.78 (0.71, 0.87)
Odds ratio
P interaction 0.74 Petrie MC et al. JAMA 2020

9. Significant Benefits Appear Very Early After Initiation
Berg DD et al. JAMA Cardiol 2021 Packer M et al. Circulation 2021

10. Minimal to No Overall Effect on Systolic Blood Pressure
DAPA-HF
Serenelli M et al. Eur Heart J 2020
EMPEROR-Reduced
Bohm M et al. JACC 2021
SGLT2i “auto-titrate” effect on blood pressure

11. Safety/adverse events (AEs)
Patients exposed to at least
one dose of study drug* Placebo Dapa P-value Placebo Dapa P-value
AE of interest (%)
Volume depletion 7.8 7.8 1.00 6.1 7.3 0.24
Renal AE 8.7 8.5 0.94 6.0 4.8 0.19
Fracture 2.4 2.1 0.66 1.9 2.1 0.78
Amputation 0.8 1.1 0.66 0.2 0.1 N/A
Major hypoglycaemia+ 0.4 0.4 N/A 0 0 N/A
Diabetic ketoacidosis 0 0.3 N/A 0 0 N/A
AE leading to treatment
discontinuation (%)
5.4 4.0 0.15 4.5 5.3 0.41
Any serious AE (incl. death) (%) 48.3 41.7 0.002 36.9 34.6 0.24
*The safety population included patients receiving ≥1 dose of trial medication: dapagliflozin n= 2368 and placebo n=2368. +Major hypoglycemia defined as
hypoglycemia requiring the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective action.
Diabetes No diabetes

12. In-hospital or Early Post-discharge Initiation –
Sotagliflozin in SOLOIST-WHF
0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18
0
10
20
30
40
50
60
70
80
90
100
HR=0.67 (95% CI, 0.52–0.85)
P<0.001
Primary endpoint
Total number of CV deaths and hospitalisations and
urgent visits for HF (first and subsequent events)
First occurrence of either
CV death or HFH
No. at risk
Placebo
Sotagliflozin
614
608
524
540
416
430
305
310
195
209
100
97
25
29
Events
per
100
patients
Months since randomisation
HR=0.71 (95% CI, 0.56–0.89)
No. at risk
Placebo
Sotagliflozin
614
608
461
498
345
374
241
266
144
171
66
76
14
25
Cumulative
incidence
(%)
Months since randomisation
Placebo
Sotagliflozin
Placebo
Sotagliflozin
Bhatt DL et al. NEJM 2021

13. Foundational therapy in HFrEF
to reduce mortality
ARNI
(Superior
to ACEi)
MRA
Beta-
blocker SGLT2i
Where Are We With Medical Therapy for HFrEF in 2021?

14. Residual Risk in HFrEF Remains Despite GDMT
0
2
4
6
8
10
12
14
16
Annualized
CV
death
events
per
100
patient-years
Diuretic
Digoxin
Beta blocker
MRA
ACEi
Diuretic
Digoxin
Beta blocker
MRA
ARNI
SOC
SOC + new therapy
PARADIGM-HF (2014)1,2
RRR = 20%
Median follow-up:
27 months
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Dapagliflozin
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
DAPA-HF (2019)2,3
RRR = 18%
Median follow-up:
18.2 months
EMPEROR-Reduced
(2020)2,4
RRR = 8%
Median follow-up:
16 months
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Diuretic
ACEi or ARB
Beta blocker
MRA
ARNI
Empagliflozin
GALACTIC-HF (2020)5
RRR = –1%
Median follow-up:
21.8 months
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Omecamtiv
mecarbil
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Diuretic
Digoxin
ACEi or ARB
Beta blocker
MRA
ARNI
Vericiguat
VICTORIA (2020)2,6
RRR = 7%
Median follow-up:
10.8 months
1. McMurray JJ, et al. N Engl J Med. 2014;371:993-1004; 2. Butler J, et al. Eur J Heart Fail. 2020;22:1991-1993; 3. McMurray JJV, et al. N Engl J Med. 2019;381:1995-2008;
4. Packer M, et al. N Engl J Med. 2020;383:1413-1424; 5. Teerlink JR, et al. N Engl J Med. 2021;384(2):105-116; 6. Armstrong PW, et al. N Engl J Med. 2020;382:1883-1893.

15. Vericiguat for HFrEF

16. Extracellular
cGMP
sGC
Intracellular
↓ Arterial constriction
↓ Vascular stiffness
Heart
↓ Progressive myocardial stiffening
↓ Myocardial thickening
↓ Ventricular remodeling
↓ Fibrosis
Vasculature
Increases
sGCactivity
Increased
cGMP production
Low NO availability
VERICIGUAT INCREASES sGC ACTIVITY TO IMPROVE
MYOCARDIAL AND VASCULAR FUNCTION
Decreased NO
Decreased sGC activity
cGMP=cyclic guanosine monophosphate; HF=heart failure; NO=nitric oxide; sGC=soluble guanylatecyclase.
Heart Fail Rev. 2013;18:123-34.; Braunwald’s Heart Disease 2015; Handb Exp Pharmacol. 2009;191:485-506; Handb Exp Pharmacol. 2017;243:225-47; Heart Failure: A Companion to Braunwald’s Heart Disease 2020.
Oxidative stress
Nitric oxide
Endothelial dysfunction

17. VICTORIA Trial – Inclusion Criteria
“Worsening event”
“Chronic HF” after
Patients may have been randomized as an inpatient or outpatient but must have met
criteria for clinical stability (e.g., SBP ≥ 100 mmHg, off IV treatments ≥ 24 hours)
• NYHA class II–IV
• LVEF < 45%
• Guideline based HF
therapies
• Recent HFH or IV diuretic use
• With very elevated natriuretic
peptides (BNP or NT-proBNP)
BNP ≥ 300 & pro-BNP ≥ 1000 pg/ml NSR
BNP ≥ 500 & pro-BNP ≥ 1600pg/ml AF
Armstrong PW et al. NEJM 2020

18. Primary Composite Endpoint: CV Death or First HF
Hospitalization
HR 0.90 (95% CI 0.82–0.98)
P-value 0.019
Absolute event reduction 4.2 / 100 pt-yrs
Armstrong PW et al. NEJM 2020

19. Cardiovascular Death
HR 0.93 (95% CI 0.81–1.06)
P-value 0.269
First HF Hospitalization
HR 0.90 (95% CI 0.81–1.00)
P-value 0.048
Armstrong PW et al. NEJM 2020

20. Patients with Adverse Events of Clinical Interest
Vericiguat Placebo Difference in % vs. Placebo
No. (%) No. (%) Estimate (95% CI)* P-value
Patients in population 2519 2515
Symptomatic hypotension 229 (9.1) 198 (7.9) 1.2 (-0.3 to 2.8) 0.121
Syncope 101 (4.0) 87 (3.5) 0.6 (-0.5 to 1.6) 0.303
*Based on the Miettinen & Nurminen method.
Note: Includes events/measurements from the day of first dose of study drug to 14 days after the last dose of study drug.
Based on data up to the primary analysis cutoff date (18Jun2019).
CI indicates confidence interval.
Armstrong PW et al. NEJM 2020

21. McDonagh TA et al. Eur Heart J 2021

22. Omecamtiv Mecarbil for HFrEF

23. Omecamtiv Mecarbil (OM):
A Novel Selective Cardiac Myosin Activator
Malik FI, et al. Science 2011; 331:1439-43; Shen YT, et al. Circ Heart Fail. 2010;3:522-7; Planelles-Herrero VJ, et al. Nat Commun. 2017;8:190;
Teerlink JR, et al. JACC Heart Fail. 2020;8:329-340.
Increases duration of systole
Increases stroke volume
No increase in myocyte calcium
No change in dP/dtmax
No increase in MVO2
OM stabilizes myosin in the
Pre-Powerstroke State, increasing the entry rate of
myosin into the tightly-bound, force-producing
state with actin
“More hands pulling on the rope”
Mechanochemical Cycle of Myosin

24. Primary Composite Endpoint
Time to First Heart Failure Event or Cardiovascular Death
Placebo 4112 3310 2889 2102 1349 647 141
Omecamtiv mecarbil 4120 3391 2953 2158 1430 700 164
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
Teerlink JR et al. NEJM 2020

25. Treatment Effect of OM by Baseline Ejection Fraction
Treatment Effect
Teerlink JR et al. J Am Coll Cardiol 2020

26. Adverse event
Omecamtiv
Mecarbil
(N=4110)
Placebo
(N=4101)
Relative Risk
(95% CI)
Any serious AE, n (%) 2373 (57.7) 2435 (59.4) 0.97 (0.94, 1.01)
Drug discontinuation due to AE, n (%) 371 (9.0) 382 (9.3) 0.97 (0.85, 1.11)
Adverse events of interest
Ventricular tachyarrhythmias 290 (7.1) 304 (7.4) 0.95 (0.82, 1.11)
Torsade de pointes/QT prolongation 176 (4.3) 195 (4.8) 0.90 (0.74, 1.10)
SAE of ventricular arrhythmia requiring
treatment 119 (2.9) 127 (3.1) 0.93 (0.73, 1.20)
Adjudicated major cardiac ischemic events, n
(%) 200 (4.9) 188 (4.6) 1.06 (0.87, 1.29)
Myocardial infarction 122 (3.0) 118 (2.9) --
Hospitalized for unstable angina 25 (0.6) 12 (0.3) --
Coronary revascularization 115 (2.8) 117 (2.9) --
Adjudicated Strokes 76 (1.8) 112 (2.7) 0.68 (0.51, 0.91)
26
No imbalance of AEs/SAEs (including cardiac ischemia and arrhythmias)
Adverse Events
Teerlink JR et al. NEJM 2020

27. Conclusions
 SGLT2i are now foundational therapy for HFrEF.
– reduce mortality
– reduce HF and all-cause hospitalization
– improve renal outcomes
– improve patient-reported quality of life
– strong safety and tolerability profile
 Vericiguat and omecamtiv mecarbil are novel therapies that are well tolerated and
may reduce residual clinical risk in select patients with HFrEF.
– Vericiguat now FDA approved and in ESC HF guidelines for patients with HFrEF and
recent worsening HF event
– Omecamtiv mecarbil reduces risk of worsening HF, particularly in patients with lower EF
and more severe HFrEF.