Update in Cardiology: American College of Physicians Internal Medicine Meeting 2021: Virtual Experience

American
College of Physicians
Internal Medicine Meeting 2021: Virtual Experience
Update in Cardiology
Faculty and Disclosure Information
Clyde W. Yancy, MD, MSc, MACP
Nothing to Disclose.
Clinical questions to be addressed:
1. Presentation of significant papers published during the past 12‐15 months that, in the view of the
presenter, have made the most difference in the practice or understanding of the subspecialty.
Posted Date: April 20, 2021
©2021 American College of Physicians. All rights reserved. Reproduction of Internal Medicine Meeting 2021: Virtual Experience presentations, or
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Contemporary Heart Failure
Treatment in 2021 or, what’s new in
HF? Clyde W. Yancy, MD, MSc
Professor of Medicine,
Professor, Medical Social Science
Chief, Cardiology
Associate Director, Bluhm CV Institute
&
Vice‐Dean, Diversity & Inclusion
Northwestern University, FSM
&
Deputy Editor, JAMA Cardiology
Disclosure of Financial Relationships
Clyde W. Yancy, MD, MSc
Nothing to disclose.
© 2021 American College of Physicians. All rights reserved. 1

Key Teaching Points
• Review the new universal definition of heart failure
• Identify best uses of new prevention and diagnostic risk
scores
• Appreciate the benefit of optimal guideline directed medical
(& device) therapy for heart failure
• Be aware of evolving treatment options for HFpEF
• Review the evidence substantiating the use of Sodium
Glucose Co‐Transporter inhibitors for the prevention and
treatment of heart failure
What’s new in heart failure?
Universal Definition

Definition of Heart Failure- ACC/AHA
2013
Classification Ejection Description
Fraction
I. Heart Failure with ≤40% Also referred to as systolic HF. Randomized clinical trials have
Reduced Ejection Fraction mainly enrolled patients with HFrEF and it is only in these patients
(HFrEF) that efficacious therapies have been demonstrated to date.
II. Heart Failure with ≥50% Also referred to as diastolic HF. Several different criteria have been
Preserved Ejection used to further define HFpEF. The diagnosis of HFpEF is
Fraction (HFpEF) challenging because it is largely one of excluding other potential
noncardiac causes of symptoms suggestive of HF. To date,
efficacious therapies have not been identified.
a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their
characteristics, treatment patterns, and outcomes appear similar to
those of patient with HFpEF.
b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF
previously had HFrEF. These patients with improvement or recovery
in EF may be clinically distinct from those with persistently
preserved or reduced EF. Further research is needed to better
characterize these patients.
Yancy C et al, JACC 2013
Symptoms and/or signs
of HF caused by a
structural and/or
functional cardiac
abnormality
and corroborated by at least one of the following
Elevated natriuretic
peptide levels
or
Objective evidence of
cardiogenic pulmonary or
systemic congestion

HF with reduced EF (HFrEF):
• HF with LVEF ≤ 40%
HF with mid‐range EF (HFmrEF):
• HF with LVEF 41‐49%
HF with preserved EF (HFpEF):
• HF with LVEF > 50%
HF with improved EF (HFimpEF):
• HF with a baseline LVEF ≤ 40%, a ≥ 10 point increase increase
from baseline LVEF, and a second measurement of LVEF > 40%
AT‐RISK FOR PRE‐HEART HEART FAILURE ADVANCED

HEART FAILURE FAILURE (STAGE C) HEART FAILURE
(STAGE A) (STAGE B) (STAGE D)
Patients at risk for HF Patients without current Patients with current or Severe symptoms and/
but without current or or prior symptoms or prior symptoms and/ or or signs of HF at rest,
prior symptoms or signs of heart failure signs of HF caused by recurrent
signs of HF and but evidence of one of hospitalizations despite
without structural, the following GDMT, refractory or
biomarker, or genetic intolerant to GDMT
markers of heart
disease. Structural Heart Disease: structural and/or requiring advanced
e.g. LVH, chamber
enlargement, wall motion
functional cardiac therapies such as
Patients with HTN, abnormality, myocardial abnormality consideration for
tissue abnormality, valvular
CVD, DM, obesity, heart disease transplant, mechanical
known exposure to circulatory support, or
cardiotoxins, family Abnormal cardiac function: palliative care
history of e.g. reduced LV or RV
Heart Persistent Heart
ventricular systolic function,
cardiomyopathy evidence of increased Failure in Failure
filling pressures or
abnormal diastolic Remission
dysfunction with GDMT and risk factor modification
Elevated natriuretic
peptide levels or elevated
cardiac troponin levels in
the setting of exposure to
cardiotoxins

Scoring systems for HFrEF & HFpEF
Sadiya S. Khan et al. JACC 2019;73:2388-2397
2019 American College of Cardiology Foundation
10

A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure
With Preserved Ejection Fraction, Volume: 138, Issue: 9, Pages: 861-870, DOI:
(10.1161/CIRCULATIONAHA.118.034646)
11
Heart Failure Treatment
The Current Paradigm
12

Stages, Phenotypes and Treatment of HF
Yancy C, et al. JACC, 2013

13
Treatment of HFrEF Stage C and D
†Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored.
‡See 2013 HF guideline.
§Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF.
Yancy C, et al. JACC, 2016 ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor-blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BP, blood pressure;
bpm, beats per minute; C/I, contraindication; COR, Class of Recommendation; CrCl, creatinine clearance; CRT-D, cardiac resynchronization therapy–device; Dx,
diagnosis; GDMT, guideline-directed management and therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ICD, implantable
cardioverter-defibrillator; ISDN/HYD, isosorbide dinitrate hydral-nitrates; K+, potassium; LBBB, left bundle-branch block; LVAD, left ventricular assist device;
LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm; and NYHA, New York Heart Association.
14

Heart Failure: Is the Current
Paradigm effective?
15
“Only 1% of eligible patients
were simultaneously treated
with target does of
ACEI/ARB/ARNI, beta‐blocker,
and MRA therapy,
and <25% of patients
simultaneously received
any dose of all 3 medications.”
OPTIMIZE & TITRATE
CURRENT GDMT
16

Longitudinal Titration of Medical Therapy for Heart
Failure with Reduced Ejection Fraction: CHAMP HF
Registry
Greene, Fonarow, DeVore et al. JACC 2019

17
18

Would machine learning address the urgency to
treat HF?
• Machine learning can analyze patterns of GDMT
optimization in flagship multidisciplinary clinics and
reproduce them in other settings. Electronic medical
records in top‐performing clinics could integrate with
machine learning systems and transfer data into deep
learning algorithms (3). Deep learning, a type of machine
learning, can extract complex patterns from medical data
19
Is pragmatism the solution?
• The relatively marginal benefit and increased risks of
higher doses, particularly in combination therapy, may not
convince some clinicians. Maximum approved doses (2)
are based on the target dose employed in single drug
versus placebo heart failure clinical trials, which were
designed to demonstrate maximum efficacy, not optimal
dose. Adverse effects may be problematic in practice, are
generally dose related (3), and are under‐represented in
published clinical trials, because patients with adverse
effects were not recruited or did not progress in the trials.
Doses may only need to match the severity of the heart
20

A polypill!!
21
A different idea…
22

Heart Failure: Does the Paradigm
work for HFpEF?
23
HFpEF in 2021
Lung
Chest wall restriction, reduced vital capacity,
impaired ventilation and diffusion
Obstructive sleep apnea
Pulmonary hypertension
Heart
Direct and indirect myocardial lipotoxicity
Worsened cardiac mechanics
Diastolic dysfunction; increased filling pressures/
volume overload, increased afterload
Liver
Non-alcoholic fatty liver disease
Promotes generalized
inflammatory state
Visceral adiposity
Inflammatory cytokines
Adverse neurohormones
Increased BNP clearance
Kidney
Direct toxic effects of perinephric fat
Glomerulomegaly with
glomerular dysfunction
Skeletal muscle
Increased adipose infiltration
Impaired perfusion
Decreased diffusive O2 transport
Mitochondrial dysfunction Kitzman D, Shah SJ. JACC 2016; Borlaug B. Nat Rev Cardiol 2014
24

25
PARAGON‐HF: Study design
Randomized, double‐blind, active comparator trial testing the hypothesis that sacubitril/valsartan, compared with
valsartan, would reduce the composite outcome of total HF hospitalizations and CV death in patients with HFpEF
Randomization 1:1 Double‐blind treatment period
Active single‐blind run‐in period
Sacubitril/valsartan 97/103 mg BID
Valsartan Sacubitril/valsartan
Eligibility Screening
80 mg BID 49/51 mg BID
Valsartan 160 mg BID
Valsartan On top of optimal background medications for co‐
40 mg BID morbidities (excluding ACEi and ARB)
up to 2 weeks 3–8 weeks ~35 months
Primary Endpoint Secondary Endpoints:
Composite of total (first and recurrent) HF hospitalizations • Improvement in NYHA functional classification at 8 months
and CV death • Changes in KCCQ clinical summary score at 8 months
• Time to first occurrence of worsening renal function
• Time to all‐cause mortality
26

PARAGON‐HF: Primary results
Recurrent event analysis of total HF hospitalizations and CV death by the semiparametric LWYY method
55
Total HF hospitalizations and CV death
Mean cumulative events per 100 patients
50
45
Valsartan (n = 2389)
40
1009 events, 14.6 per 100 pt‐years
35
30
25
20 Sacubitril/valsartan (n = 2407)
15 894 events, 12.8 per 100 pt‐years
10
Rate ratio 0.87 (95% CI 0.75, 1.01)
5 p = 0.059
0
0 1 2 3 4
Years
27
HF hospitalizations and CV death
HF hospitalizations CV death
55 0.55
Events Patients
Mean cumulative events
50 0.50
Valsartan 797 Valsartan 212 (8.9%)
45 0.45
per 100 patients
Sacubitril/valsartan 690 Sacubitril/valsartan 204 (8.5%)

Proportion
40 0.40
35 0.35
Rate ratio 0.85 (95% CI 0.72, 1.00) Hazard ratio 0.95 (95% CI 0.79, 1.16)
30 0.30
p = 0.056 p = 0.62
25 0.25
20 0.20
15 0.15
10 0.10
5 0.05
0 0.00
0 1 2 3 4 0 1 2 3 4
Years Years
28

Pre‐specified subgroup analysis
29
A new indication for ARNI?
30

Was this a good decision?
• The U.S. Food and Drug Administration asked its
Cardiovascular and Renal Drugs Advisory Committee
to broadly consider whether new analyses of data
from the PARAGON‐HF trial, combined with other
information, could support use of
sacubitril/valsartan (Entresto, Novartis) in heart
failure with preserved ejection fraction (HFpEF).
• The advisory committee voted 12‐1 on this question,
which can be seen as a marker for an expanded
approval: "Does PARAGON‐HF, perhaps supported by
previous studies, provide sufficient evidence to
support any indication?"
FDA Panel Supports Expanded HF Role for Sacubitril/Valsartan (medscape.com)
31
Heart Failure: Changing the
Paradigm
32

Are the SGLT‐2 inhibitors the
answer?
33
Cardiovascular Outcomes and Death from

Any Cause.
Zinman B et al. N Engl J Med 2015;373:2117-2128
34

SGLT2 Inhibitors Reduce the Risk of Heart
SGLTbitors
Failure Events in Type 2 Diabetes
SGLTbitors
Lancet 2018 Nov (online)
35
Cardiovascular Outcomes.
JJ McMurray et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1911303
36

DAPA-HF: Effect of Dapagliflozin in Heart
Failure, With or Without Diabetes
Effect on Primary Endpoint of Cardiovascular

Death and Serious Heart Failure Events
37
An inflection point in the care of patients with heart failure…
• Benefits seen in those with or without Diabetes
• Once a day therapy; single dose; no need for
titration (N.B. low use of ARNI)
• No episodes of hypoglycemia or diabetic
ketoacidosis
• Negligible incidence of amputations
• NNT= 21; benefits seen even in those >75
• Resolution of mechanism of action is needed
38

July 30, 2020
August 29, 2020
39
Primary Outcome and Total Hospitalizations for Heart Failure.
M Packer et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2022190
40

Changes in the Estimated Glomerular Filtration Rate.
M Packer et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2022190
41
Are the SGLT‐2
inhibitors the
answer?
A new target of intervention‐
the cardio‐renal interface
42

43
Primary and Secondary Outcomes.
The primary outcome: Over a median of 2.4 years,

composite of sustained a primary outcome event
decline in the estimated occurred in 197 of 2152
GFR of at least 50%, (9.2%) in the dapagliflozin
end-stage kidney disease, group & 312/2152 (14.5%)
or death from renal in the placebo group
or cardiovascular causes. (hazard ratio, 0.61; 95%
[CI], 0.51 to 0.72); P<0.001;
number needed to treat
to prevent one primary
outcome event,
19 [95% CI, 15 to 27]).
HJ Heerspink et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2024816
44

Change from Baseline in Estimated GFR.
HJ Heerspink et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2024816
45
46

Matthew Griffin. Circulation. Empagliflozin in Heart Failure, Volume:
142, Issue: 11, Pages: 1028-1039, DOI:
© 2020 American Heart Association, Inc.
47
Matthew Griffin. Circulation. Empagliflozin in Heart Failure, Volume:

142, Issue: 11, Pages: 1028-1039, DOI:
© 2020 American Heart Association, Inc.
48

49
SGLT 2 inhibitors and HFpEF
50

51
Kim A. Connelly et al. BTS 2019;4:27-37

2019 The Authors
52

Kim A. Connelly et al. BTS 2019;4:27-37
2019 The Authors
53
Evaluation of the effects of sodium–glucose co-transporter 2 inhibition with empagliflozin on morbidity and
mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the
EMPEROR-Preserved Trial
European Journal of Heart Failure, Volume: 21, Issue: 10, Pages: 1279-1287, First published: 16 September 2019, DOI: (10.1002/ejhf.1596)
54

Heart Failure New trials and new
data: SGLT2 inhibitors‐ the most
recent data
55
Total Number of Deaths from Cardiovascular Causes,

Sotagliflozin in Patients with Diabetes and Chronic Kidney
Disease; Hospitalizations for Heart Failure, and Urgent Visits
for HeartFailure. SCORED Trial
“In patients with diabetes

and chronic kidney disease,
with or without albuminuria,
sotagliflozin resulted in
a lower risk of the composite
of deaths from cardiovascular
causes, hospitalizations for
heart failure, and urgent
visits for heart failure than
placebo but was associated
with adverse events.”
DL Bhatt et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2030186
56

Sotagliflozin in Patients with Diabetes and Chronic Kidney
Disease; First Occurrence of Death from Cardiovascular
Causes, Nonfatal Myocardial Infarction, or Nonfatal Stroke.
57
Sotagliflozin in Patients with Diabetes and Recent Worsening

Heart Failure; SOLOIST WHF Trial: Primary Efficacy End-Point
Events.
“In patients with diabetes
and recent worsening
heart failure,
sotagliflozin therapy,
initiated before or shortly
after discharge, resulted
in a significantly lower
total number of deaths
from cardiovascular
causes and hospitalizations
and urgent visits for heart
failure than placebo.”
58

The Full Portfolio of treatment Choices –SGLT2 I
in heart failure
Heart Failure Phenotype SGLT2i
Not currently supported by HF guidelines; pending 2021 HF
HFrEF Guidelines; BUT multiple positive RCTs:
DAPA HF: HR 0.74; CI 0.65 – 0.85; NNT 21
EMPEROR REDUCED; HR 0.75; CI 0. 65 – 0.86; NNT 19
Awaiting EMPEROR PRESERVED; encouraging animal data
HFpEF
SOLOIST – WHF: HR 0.67; CI 0.52 ‐0.85; NNT 54
Hospitalized HF
DAPA CKD; HR 0.61; CI 0.51 – 0.72; NNT 19

HF and CKD SCORED; (with or without albuminuria)HR 0.74; CI 0.63 – 0.88
59
SLGT2i in HF; now recommended first line
therapy
60

61
Thomas M. Maddox et al. J Am Coll Cardiol 2021; 77:772-810.

2021 Elsevier
62

Heart Failure: The SUMMARY
63
Heart Failure Phenotype ARNI SGLT2i Emerging therapies
HFrEF Class of recommendation Not currently supported Vericiguat‐ post AHF

I by HF guidelines; Omecamtiv mecarbil‐
Level of evidence B/A? pending 2021 HF advanced HF
(pending new HF Guidelines; BUT multiple Ferrous carboxymaltose‐
Guidelines, 2021) positive RCTs‐ DAPA HF; Fe Def
EMPEROR REDUCED
HFpEF Not indicated Awaiting EMPEROR Mavacamten
Borderline RCT PRESERVED; encouraging
Intriguing secondary animal data Tafamdis
outcomes‐ esp., Women
HFiEF Secondary endpoint data: No Data GDMT withdrawal is
LVEF 0.45 – 0.57‐ associated with recurrent
intriguing but not HF (TRED HF)
indicated
64

Cumulative Impact of Evidence-Based
Heart Failure with Reduced EF Medical Therapies
Relative-risk 2 yr Mortality
None -- 35%
ACEI or ARB 23% 27%
Beta Blocker 35% 18%
Aldosterone Ant 30% 13%
ARNI (replacing ACEI/ARB) 16% 10.9%
SGLT2 inhibitor 17% 9.1%
Cumulative risk reduction if all evidence-based medical therapies are used:
Relative risk reduction 74.0%, Absolute risk reduction: 25.9%, NNT = 3.9
Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030 and Lancet 2008;372:1195-1196.
65
Key Teaching Points
• Review the new universal definition of heart failure
• Identify best uses of new prevention and diagnostic risk
scores
• Appreciate the benefit of optimal guideline directed medical
(& device) therapy for heart failure
• Be aware of evolving treatment options for HFpEF
• Review the evidence substantiating the use of Sodium
Glucose Co‐Transporter inhibitors for the prevention and
treatment of heart failure
66
66

What’s New in Heart Failure?
SUMMARY:
1. New Universal Definition of Heart Failure
2. More data RE: PREVENTION of Heart Failure; especially in the setting of HTN & DM
3. New validated scoring algorithms aid the prediction of HF and diagnosis of HFpEF
4. Use of GDMT is suboptimal; disruptive innovation is needed
5. Treatment of HFpEF may include: MRA, ARB, ARNI (in LVEF < 0.57)
6. New therapies for amyloidosis & HCM ‐ tafamidis and mavacamten
7. The SGLT2i class is breakthrough therapy for prevention and treatment of heart
failure, treatment of hospitalized heart failure and treatment of CKD
8. Additional new therapies‐ Vericiguat, Omecamtiv, ferric carboxymaltose‐
9. Cannot overlook the importance of health equity in the care of patients with heart
failure
67

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American

© 2021 American College of Physicians. All rights reserved. 1

© 2021 American College of Physicians. All rights reserved. 2

Yancy C et al, JACC 2013

and corroborated by at least one of the following

© 2021 American College of Physicians. All rights reserved. 3

AT‐RISK FOR PRE‐HEART HEART FAILURE ADVANCED

© 2021 American College of Physicians. All rights reserved. 4

Sadiya S. Khan et al. JACC 2019;73:2388-2397

2019 American College of Cardiology Foundation

© 2021 American College of Physicians. All rights reserved. 5

© 2021 American College of Physicians. All rights reserved. 6

Yancy C, et al. JACC, 2013

Treatment of HFrEF Stage C and D

© 2021 American College of Physicians. All rights reserved. 7

© 2021 American College of Physicians. All rights reserved. 8

Greene, Fonarow, DeVore et al. JACC 2019

© 2021 American College of Physicians. All rights reserved. 9

© 2021 American College of Physicians. All rights reserved. 10

© 2021 American College of Physicians. All rights reserved. 11

© 2021 American College of Physicians. All rights reserved. 12

© 2021 American College of Physicians. All rights reserved. 13

Sacubitril/valsartan 690 Sacubitril/valsartan 204 (8.5%)

© 2021 American College of Physicians. All rights reserved. 14

© 2021 American College of Physicians. All rights reserved. 15

FDA Panel Supports Expanded HF Role for Sacubitril/Valsartan (medscape.com)

© 2021 American College of Physicians. All rights reserved. 16

Cardiovascular Outcomes and Death from

Zinman B et al. N Engl J Med 2015;373:2117-2128

© 2021 American College of Physicians. All rights reserved. 17

Lancet 2018 Nov (online)

© 2021 American College of Physicians. All rights reserved. 18

Effect on Primary Endpoint of Cardiovascular

© 2021 American College of Physicians. All rights reserved. 19

Primary Outcome and Total Hospitalizations for Heart Failure.

© 2021 American College of Physicians. All rights reserved. 20

© 2021 American College of Physicians. All rights reserved. 21

Primary and Secondary Outcomes.

The primary outcome: Over a median of 2.4 years,

HJ Heerspink et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2024816

© 2021 American College of Physicians. All rights reserved. 22

© 2021 American College of Physicians. All rights reserved. 23

Matthew Griffin. Circulation. Empagliflozin in Heart Failure, Volume:

© 2021 American College of Physicians. All rights reserved. 24

© 2021 American College of Physicians. All rights reserved. 25

Kim A. Connelly et al. BTS 2019;4:27-37

© 2021 American College of Physicians. All rights reserved. 26

2019 The Authors

© 2021 American College of Physicians. All rights reserved. 27

Total Number of Deaths from Cardiovascular Causes,

“In patients with diabetes

© 2021 American College of Physicians. All rights reserved. 28

Sotagliflozin in Patients with Diabetes and Recent Worsening

© 2021 American College of Physicians. All rights reserved. 29

DAPA CKD; HR 0.61; CI 0.51 – 0.72; NNT 19

© 2021 American College of Physicians. All rights reserved. 30

Thomas M. Maddox et al. J Am Coll Cardiol 2021; 77:772-810.

© 2021 American College of Physicians. All rights reserved. 31

Heart Failure Phenotype ARNI SGLT2i Emerging therapies

HFrEF Class of recommendation Not currently supported Vericiguat‐ post AHF

© 2021 American College of Physicians. All rights reserved. 32

© 2021 American College of Physicians. All rights reserved. 33

© 2021 American College of Physicians. All rights reserved. 34