Stephen Greene, MD Duke University

1. Contemporary Principles for the
Management of Heart Failure
Disclosures: Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb,
Corteria, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Novartis, Novo Nordisk, PharmaIN, Pfizer,
Roche Diagnostics, Sanofi, scPharma, Tricog Health, and Urovant
Stephen J. Greene, MD
Duke University School of Medicine
Duke Clinical Research Institute
@SJGreene_md
May 4, 2024

2. Contemporary GDMT Principle #1
Speed of initiation and optimization
matters

3. Clinical Benefits Appear Within Days to Weeks Following GDMT Initiation
Beta
blocker1
ARNI3 SGLT2i4
Delayed initiation of any of these 4 drugs in eligible patient = needless exposure to excess clinical risk5
ARNi, angiotensin receptor-neprilysin inhibitor; CI, confidence interval; CV; cardiovascular; DAPA, dapagliflozin; HF, heart failure; HR, hazard ratio; GDMT, guideline-directed medical therapy;
MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor; WHF, worsening heart failure.
1. Krum H, et al. JAMA. 2003;289(6):712-718. 2. Zannad F, et al. N Engl J Med. 2011;364(1):11-21. 3. Morrow DA, et al. Circulation. 2019;139(19):2285-2288. 4. Berg DD, et al. JAMA Cardiol. 2021;6(5):499-507. 5. Greene SJ, et al. JAMA Cardiol. 2021;6(7):743-744.
PIONEER-HF:
CV Death or HF
Rehospitalization
Days from Randomization
Cumulative
Incidence
of
CV
Death
Of
Rehospitalization
for
HF
(%)
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
0 7 14 21 28 35 42 49 56
Sacubitril/Valsartan
Enalapril
9.2%
15.2%
Effect through Week 8
HR 0.58 (95% CI: 0.39, 0.87)
P=0.007
Significant Clinical
Benefits within 30 Days
0 2 4 6 8
0
1
2
3
Weeks After Randomization
Placebo
(n=1,133)
Carvedilol
(n=1,156)
%
of
Patients
With
Event
HR (95% CI),
0.75 (0.41-1.35)
Early Mortality Reduction
6.4
11.4
5.1
8.8
0
5
10
15
All Patients Highest-Risk Subgroup
Placebo
Carvedilol
Lower Risk for Worsening HF
n=1,133 n=1,158 n=316 n=308
Early Benefits
and Early Safety of
Carvedilol
Even in Severe
HF:COPERNICUS
Eplerenone in
Patients with
Systolic Heart
Failure and
Mild Symptoms:
EMPHASIS HF
Primary Endpoint:
CV Mortality and
HF Hospitalization
MRA2
No.
at Risk
Placebo 1373 848 512 199
Eplerenone 1364 925 562 232
Primary
Endpoint
Cumulative
K-Mrate
(%)
10
20
30
40
50
0
0 1 2 3
Placebo
Eplerenone
Years from Randomization
HR=0.63 (0.54-0.74), P<0.001
356 (25.9%)
249 (18.3%)
Significant Clinical
Benefits within 30 Days
Early Benefit of
Dapagliflozin on
CV Death
or WHF
0
0.5
1.0
1.5
HR=0.51
(0.28-0.94)
P=0.03
20 40 60 80 100
28
Day
Hazard
Ratio
(DAPA
vs
Placebo)
Hazard
Ratio
(DAPA
vs
Placebo)
0
0.4
0.6
0.8
1.0
First 100 days
Reproduced with permission
from JAMA. 2003. Volume
289(6): 712-718. Copyright ©
2022 American Medical
Association. All rights reserved
From New England Journal of Medicine, Zannad F, et al. Eplerenone in patients with systolic heart failure and mild symptoms, Volume 364, 11-21,
Copyright© 2010 Massachusetts Medical Society.
Morrow DA, et al. Clinical
Outcomes in Patients With Acute
Decompensated Heart Failure
Randomly Assigned to
Sacubitril/Valsartan or Enalapril
in the PIONEER-HF Trial,
Circulation, 139(19), 2285-2288.

4. Contemporary GDMT Principle #2
In-hospital initiation matters

5. Deferring Initiation = Never Initiating (or Substantial Delay)
93.1%
80.5%
85.5%
30.5%
7.7%
22.3%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Beta-Blocker ARNi MRA
Proportion
With
Postdischarge
Medication
Fill
Postdischarge Use of GDMT by Prescription Status at Hospital Discharge
Prescribed at Hospital
Discharge
Not Prescribed at Hospital
Discharge
Don’t “consider prescribing GDMT” ... actually prescribe it
ARNi, angiotensin receptor-neprilysin inhibitor; GDMT, guideline-directed medical therapy; MRA, mineralocorticoid receptor antagonist.
Rao VN, et al. J Am Coll Cardiol. 2021;78(20):2004-2012.
60- to 90-day follow-up 12-month follow-up

6. Placebo
SOLOIST-WHF:
CV Death and HF-Related Events 30 Days Post Discharge
Treatments at 30 Days:
HR (95% CI) = 0.49
(0.27-0.91), P = 0.023
Sotagliflozin
Pitt B et al. JACC Heart Fail. 2023 Aug;11(8):879-889.

7. Placebo
Sotagliflozin
Pitt B et al. JACC Heart Fail. 2023 Aug;11(8):879-889.
SOLOIST-WHF:
CV Death and HF-Related Events 90 Days Post Discharge
Treatments at 90 Days:
HR (95% CI) = 0.54
(0.35-0.82), P = 0.004

8. Contemporary GDMT Principle #3
Absolute benefits of GDMT are generally
greater among patients who are older,
frail, and with common comorbidities

9. Of 4,744 patients with HFrEF, 34% moderately frail, and 16% “very frail”
Relative benefits of dapagliflozin consistent, irrespective of patient frailty
Absolute risk reduction largest, and number needed to treat lowest,
among very frail patients
Butt J et al. Annals Intern Med. 2022
Not frail 3.5%
Moderately frail 3.6%
Very frail 7.9%
Absolute Risk Reduction
Efficacy and Safety of Dapagliflozin According to Frailty in HFrEF
FI, Frailty Index

10. Contemporary GDMT Principle #4
Among eligible patients, GDMT has a
favorable safety and tolerability profile,
across the spectrum of age, frailty, and
comorbidities

11. Harrington J et al. JACC Heart Fail 2023
High Rates of Adverse Events Happen to HF Patients
Treated with Placebo

12. SGLT2i Placebo
Adverse event category n (%) n (%)
DAPA-HF (HFrEF)
UTI 11 (0.5) 17 (0.7)
Sepsis 13 (0.5) 14 (0.6)
EMPEROR-Reduced (HFrEF)
UTI 91 (4.9) 83 (4.5)
EMPULSE (in-hospital initiation HFrEF/HFpEF)
UTI 11 (4.2) 17 (6.4)
EMPA-Reg (Type 2 DM)
UTI 426 (18.2) 423 (18.1%)
Complicated UTI 34 (1.4) 41 (1.8)
…whether or not they are treated with SGLT2i
No convincing evidence that SGLT2i increases risk of UTI
Distinguish from genital mycotic infections
Patients with HF and Comorbidities Get UTIs….

13. Contemporary GDMT Principle #5
Recognize the risks of omission

14. The Unintended Harms of “First, Do No Harm”
Risks of
Commission
Risks of
Omission
Shared decision-making critical…but consider the risks of omission
Greene SJ et al. JACC 2023; Greene SJ, Fonarow GC. Eur J Heart Fail. 2021

15. Risks of Delaying or Omitting GDMT
HF with EF ≤40%
HF with EF >40%
ARNI
~25% relative risk of all-cause mortality vs putative
placebo
~30% relative risk of CV mortality or HF hospitalization vs
putative placebo
MRA
24-35% relative risk of all-cause mortality
35-42% relative risk of HF hospitalization
SGLT2i
20% relative risk of CV mortality or HF hospitalization
26% relative risk of HF hospitalization
Beta-Blocker
34-35% relative risk of all-cause mortality
19-24% relative risk of all-cause mortality or
hospitalization
SGLT2i
13% relative risk of all-cause mortality
31% relative risk of HF hospitalization
Lack of initiation, titration, or persistence of:
Lack of initiation or persistence of:
Fonarow GC, Greene SJ. JACC 2023

16. “But GDMT is just too expensive”
GWTG-HF 2021-2022: Gaps in GDMT for HFrEF in the United States
at Hospital Discharge Among Medically Eligible Patients
<33% of eligible patients received
“triple therapy” with 3 generic drugs
(ACEI/ARB + BB + MRA)
Median cost of generic triple therapy
for HFrEF = ~$160/year
Median cost of newly approved cancer
drug = $283,000/year
Pierce JB…Greene SJ. JAMA Cardiol 2023; Furlow B. Lancet Onc 2021

17. Give patients the opportunity to benefit from proven medications.
Barring absolute contraindications, prescribe 4 pillars simultaneously
or in rapid sequence.
Yes, some patients may not tolerate this approach…but large majority will…
…and consider that many more patients will “not tolerate” serial/slow/selective
approach (i.e., deaths and hospitalizations that could have been prevented).
Summary
Many patients with HF are dying or being hospitalized every day, without ever
receiving medications proven to prevent these events, despite being eligible.
Grim Reality: <10% of eligible HFrEF patients receive quad therapy