Systolic Dysfunction — Clinical/Hemodynamic
Guide for Management; New Medical and
Interventional Therapeutic Challenges
Clyde W. Yancy, MD, MSc, FACC, FAHA, MACP
Magerstadt Professor of Medicine
Professor, Department of Medical Social Sciences
Chief of Cardiology
Northwestern University, Feinberg School of Medicine
&
Associate Medical Director
Bluhm Cardiovascular Institute
Chicago, IL
Heart Failure Clinic, Northwestern,
12/11/14; 2 patients • #1 – 59 year old man with known dilated CM and class IIIB
HF; LVEF 0.11. BNP ~ 450 pg/ml; MEDS- Carvedilol (LA) 10
mg qd; lisinopril 2.5 mg QD; spironolactone 25 mg QD. BP
90/74; JVP 12 cm H20; soft S3; no edema
• #2 – 48 year old woman with dilated CM; + family history
(but negative genetic screen); NYHA class I/II HF
symptoms; LVEF 0.30. BNP 125 pg/ml. MEDS – Carvedilol
25 mg BID, Lisinopril 10 mg QD, ICD in place; BP 128/78;
o/w compensated exam
• Which patient is appropriate for LCZ – 696
– #1
– #2
– Both
– Neither
Heart Failure; a new era emerges- the proof:
• Outcomes have improved
• We can prevent heart failure
• Biomarkers are potent aids in the
management of HF
• Guideline Directed Medical Therapy
(GDMT) for HF works
• A new PARADIGM has emerged
Improving HF Outcomes
Improving HF Outcomes
Stages, Phenotypes and Treatment of
HF STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE BStructural heart disease
but without signs or
symptoms of HF
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Prevent hospitalization
· Prevent mortality
Strategies
· Identification of comorbidities
Treatment
· Diuresis to relieve symptoms
of congestion
· Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
· Revascularization or valvular
surgery as appropriate
STAGE CStructural heart disease
with prior or current
symptoms of HF
THERAPYGoals· Control symptoms· Patient education· Prevent hospitalization· Prevent mortality
Drugs for routine use· Diuretics for fluid retention· ACEI or ARB· Beta blockers· Aldosterone antagonists
Drugs for use in selected patients· Hydralazine/isosorbide dinitrate· ACEI and ARB· Digoxin
In selected patients· CRT· ICD· Revascularization or valvular
surgery as appropriate
STAGE DRefractory HF
THERAPY
Goals
· Prevent HF symptoms
· Prevent further cardiac
remodeling
Drugs
· ACEI or ARB as
appropriate
· Beta blockers as
appropriate
In selected patients
· ICD
· Revascularization or
valvular surgery as
appropriate
e.g., Patients with:
· Known structural heart disease and
· HF signs and symptoms
HFpEF HFrEF
THERAPY
Goals
· Heart healthy lifestyle
· Prevent vascular,
coronary disease
· Prevent LV structural
abnormalities
Drugs
· ACEI or ARB in
appropriate patients for
vascular disease or DM
· Statins as appropriate
THERAPYGoals· Control symptoms· Improve HRQOL· Reduce hospital
readmissions· Establish patient’s end-
of-life goals
Options· Advanced care
measures· Heart transplant· Chronic inotropes· Temporary or permanent
MCS· Experimental surgery or
drugs· Palliative care and
hospice· ICD deactivation
Refractory symptoms of HF at rest, despite GDMT
At Risk for Heart Failure Heart Failure
e.g., Patients with:
· Marked HF symptoms at
rest
· Recurrent hospitalizations
despite GDMT
e.g., Patients with:
· Previous MI
· LV remodeling including
LVH and low EF
· Asymptomatic valvular
disease
e.g., Patients with:
· HTN
· Atherosclerotic disease
· DM
· Obesity
· Metabolic syndrome
or
Patients
· Using cardiotoxins
· With family history of
cardiomyopathy
Development of
symptoms of HFStructural heart
disease
Survival (years) Ammar et al. Circulation 2007; 115:1563
Prevalence and prognostic significance of HF Stages
Copyright © 2014 American Medical
Association. All rights reserved.
From: Natriuretic Peptide–Based Screening and Collaborative Care for Heart Failure: The STOP-HF
Randomized Trial
JAMA. 2013;310(1):66-74. doi:10.1001/jama.2013.7588
Kaplan-Meier Analysis of Major Adverse Cardiovascular Events in the Full Study Sample and in Participants With BNP ≥50 pg/mLBNP indicates brain-type natriuretic peptide. Major adverse
cardiovascular events included arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. In the full sample, 51 (7.3%) of 697
patients were admitted for major adverse cardiovascular events in the intervention group and 71 (10.5%) of 677 were admitted in the control group. In participants with BNP ≥50 pg/mL, 35 (13.3%)
of 263 were admitted for major adverse cardiovascular events in the intervention group and 45 (19.1%) of 235 were admitted in the control group.
Figure Legend:
BNP Reflects Ventricular Wall
Stress
Iwananga, JACC 2006
Predischarge BNP Is Strong Predictor of Post-
Discharge Events
0
25
50
75
100
0 30 60 90 120 150 180
De
ath
or
Re
ad
mis
sio
n, %
Follow-up, Days
Hazard Ratios
15.2
5.1
1
p<.0001
p<.0001
BNP >700 ng/L*
(n = 41, events = 38)
BNP 350-700 ng/L*
(n = 50, events = 30)
BNP <350 ng/L*
(n = 111, events = 18)
Logeart D, et al. J Am Coll Cardiol. 2004;43:635-641.
new biomarkers?
Figure 2 CV Events, by Categories of Biomarker Time in Response (A) sST2; (B) GDF-1; and (C) hsTnT. There was a direct relationship
between percentage of time spent below prognostic thresholds ( time in response ) and cardiovascular (CV) event rates...
Hanna K. Gaggin , Jackie Szymonifka , Anju Bhardwaj , Arianna Belcher , Benedetta De Berardinis , Shweta Motiwala ...
Head-to-Head Comparison of Serial Soluble ST2, Growth Differentiation Factor-15, and Highly-Sensitive Troponin T Measurements in
Patients With Chronic Heart Failure
JACC: Heart Failure, Volume 2, Issue 1, 2014, 65 - 72
http://dx.doi.org/10.1016/j.jchf.2013.10.005
Soluble ST2 represents a
cellular response to stress
and is indicative
of LV remodeling and fibrosis
Growth Differentiation Factor [GDF]-15
is a member of the transforming
growth factor-Beta cytokine superfamily
and is strongly induced in response
to metabolic stress and is involved
in cell differentiation and tissue
repair
Pharmacological Treatment for
Stage C HFrEF
Measures listed as Class I recommendations for patients in
stages A and B are recommended where appropriate for
patients in stage C. (Levels of Evidence: A, B, and C as
appropriate)
GDMT as depicted in Figure 1 should be the mainstay of
pharmacological therapy for HFrEF.
I IIa IIb III
I IIa IIb III
See
recommendations
for stages A, B, and
C LOE for LOE
Yancy, C. et al. JACC, 2013
Pharmacologic Treatment for Stage C HFrEF
HFrEF Stage C
NYHA Class I – IV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL
For persistently symptomatic
African Americans,
NYHA class III-IV
Class I, LOE A
ACEI or ARB AND
Beta Blocker
Class I, LOE C
Loop Diuretics
Class I, LOE A
Hydral-Nitrates
Class I, LOE A
Aldosterone
Antagonist
AddAdd Add
For all volume overload,
NYHA class II-IV patients
Yancy, C. et al. JACC, 2013
Medical Therapy for Stage C HFrEF:
Magnitude of Benefit Demonstrated in RCTs
GDMT RR Reduction
in Mortality
NNT for Mortality
Reduction
(Standardized to 36 mo)
RR Reduction
in HF
Hospitalizations
ACE inhibitor or
ARB 17% 26 31%
Beta blocker 34% 9 41%
Aldosterone
antagonist 30% 6 35%
Hydralazine/nitrate 43% 7 33%
Yancy, C. et al. JACC, 2013
The newest “Paradigm” in HF
Simplified schematic of the renin–angiotensin–aldosterone system.
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Copyright © American Heart Association, Inc. All rights reserved.
Simplified schematic of the natriuretic peptide system (NPS).
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Copyright © American Heart Association, Inc. All rights reserved.
Cardiac antiremodeling effects of angiotensin receptor neprilysin inhibitors (ARNi) in vitro and in vivo.
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Copyright © American Heart Association, Inc. All rights reserved.
Cardiac antiremodeling effects of angiotensin
receptor neprilysin inhibitors (ARNi) in vitro and in
vivo.
von Lueder T G et al. Circ Heart Fail. 2013;6:594-605
Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure
by Milton Packer, Robert M. Califf, Marvin A. Konstam, Henry Krum, John J. McMurray,
Jean-Lucien Rouleau, and Karl Swedberg
Circulation
Volume 106(8):920-926
August 20, 2002
Copyright © American Heart Association, Inc. All rights reserved.
Figure 1. Kaplan-Meier analysis of time to death or hospitalization for heart failure requiring intravenous
treatment in the omapatrilat and enalapril groups.
Packer M et al. Circulation. 2002;106:920-926
Copyright © American Heart Association, Inc. All rights reserved.
Natriuretic peptides BK, ADM
Subs-P, VIP, CGRP
Angiotensin II
• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy
Degradation
products
Neprilysin AT1 Receptor
Angiotensin Receptor Neprilysin
Inhibition (ARNI): LCZ696
• Vasodilation
• Natriuresis
• Diuresis
• Inhibition of pathologic
growth/fibrosis
LCZ696
sacubitril valsartan
PARADIGM HF
Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.
McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077
Adverse Events during Randomized Treatment.
McMurray JJ et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1409077
Mean Baseline Characteristics of Patients with Heart Failure and a Reduced Ejection Fraction in Five Trials.
Jessup M. N Engl J Med 2014. DOI: 10.1056/NEJMe1409898
New data: Pre-specified exploratory outcomes
Selected outcomes – reflecting disease
progression
Summary and conclusions
Compared with enalapril, patients on LCZ696: · Are less likely to show symptomatic deterioration
· Are less likely to need intensification of oral therapy/addition of iv therapy
· Are less likely to visit the emergency department
· Are less likely to be admitted to hospital
· When admitted, are less likely to go to the ICU and less likely to need iv inotropic therapy
· Are less likely to require devices/surgery for worsening/ end-stage heart failure (not statistically significant)
· Are less likely to die prematurely (either suddenly or from worsening HF)
· Less likely to show biomarker evidence of cardiac wall-stress and myocyte injury (data not shown – see Circulation)
Compared with enalapril, LCZ696 slows progression of heart failure, delaying/preventing non-fatal and fatal worsening.
The Critical Question
Pharmacologic Treatment for Stage C HFrEF
HFrEF Stage C
NYHA Class I – IV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL
For persistently symptomatic
African Americans,
NYHA class III-IV
Class I, LOE A
ACEI or ARB AND
Beta Blocker
Class I, LOE C
Loop Diuretics
Class I, LOE A
Hydral-Nitrates
Class I, LOE A
Aldosterone
Antagonist
AddAdd Add
For all volume overload,
NYHA class II-IV patients
ARNI
Next Steps?
Efficacy and Safety of LCZ696 Compared to Valsartan, on
Morbidity and Mortality in Heart Failure Patients With
Preserved Ejection Fraction (PARAGON-HF)
• The primary objective compare LCZ696 to valsartan in reducing the rate
of the composite endpoint of CV death and total (first and recurrent) HF
hospitalizations, in HF patients (New York Heart Association [NYHA]
Class II-IV) with preserved ejection fraction (left ventricular ejection
fraction [LVEF] ≥45%).
• Inclusion Criteria:
• Left ventricular ejection fraction (LVEF) ≥45% prior to study entry.
• Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF
≥30 days prior to study entry
• Current symptom(s) of HF
• Structural heart disease (left atrial enlargement or left ventricular hypertrophy)
documented by echocardiogram
• At least one of the following: a HF hospitalization within 9 months prior to study
entry and/or an elevated NT-proBNP.
Heart Failure Clinic, Northwestern,
12/11/14; 2 patients • #1 – 59 year old man with known dilated CM and class IIIB
HF; LVEF 0.11. BNP ~ 450 pg/ml; MEDS- Carvedilol (LA) 10
mg qd; lisinopril 2.5 mg QD; spironolactone 25 mg QD. BP
90/74; JVP 12 cm H20; soft S3; no edema
• #2 – 48 year old woman with dilated CM; + family history
(but negative genetic screen); NYHA class I/II HF
symptoms; LVEF 0.30. BNP 125 pg/ml. MEDS – Carvedilol
25 mg BID, Lisinopril 10 mg QD, ICD in place; BP 128/78;
o/w compensated exam
• Which patient is appropriate for LCZ – 696
– #1
– #2
– Both
– Neither
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