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Clinical Spotlight on NovelInterventions for Patients withHeart Failure
Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP
Vice-Dean, Diversity & Inclusion
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
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Disclosures
Consultant/speaker/honoraria: none
JAMA Cardiology, Deputy Editor; ; Journal of the American College ofCardiology- associate editor (HF); American Journal of Cardiology -associate editor; : American Heart Journal, Circulation; Circulation-HeartFailure- editorial boards
Guideline writing committees: Chair, ACC/AHA, chronic HF; member,atrial fibrillation; member, Syncope; Chair, Performance Measures,Sudden Cardiac Death
Federal appointments: FDA: Immediate Past Chair, CardiovascularDevice Panel; ad hoc consultant; NIH Scientific Management and
Review Board; AHRQ- adhoc consultant; NHLBI- consultant; PCORI-methodology committee member; IOM- writing group member
Volunteer Appointments: American Heart Association- President,American Heart Association, 2009-2010; American College of Cardiology,Founder- CREDO
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Heart Failure EpidemiologyUS Stat ist ic s
5.7 million persons currently diagnosed with HF
2.7 million males; 3.0 million females
870,000 new HF diagnoses annually
HF with preserved ejection fraction (HFpEF) occursin 55% of symptomatic HF cases
HF incidence is 10 per 1,000 patients older than 65years
1.02 million discharges per year with primary diagnosisof HF
Health care expenditure for HF was $30.7 billion in2012
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
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First Heart Failure Events in the US
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
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Hospital Discharge Rates for HFin the US
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
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A Contemporary Appraisal of theHeart Failure Epidemic
Age- and sex-specific incidence of heart failure has declined
315/100,000 to 219/100,000
Rate reduction of 37.5%
Incidence decline was greater for HFrEF 45.1% vs. HFpEF -27.9%
Risk for CV death was lower for HFpEF but the same for non-CVdeath
Hospitalizations have increased 34% Most hospitalizations, 63%, were due to non-cardiovascular causes
Thus todays epidemic of heart failure is defined by marked
inc rease in hospitalizations, predominance of non -CV death rate,
and persistence and predom inance of HFpEF
JAMA Internal Medicine 2015Roger, Veronique
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HF: Classification of Disease
NYHA
Functional
Classification
ACC/AHA
Stages
Yancy CW et al. Circulation. 2013;128:e240-e327.
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LIFESTYLE ADAPTATIONS:Sod ium and Water Restr ict ion in HF
Sodium Restriction
Discussions should be patient-centered
When considered appropriate,
sodium restriction is deemed aClass IIa recommendation
Sodium restriction is reasonablefor some patients withsymptomatic HF to reducecongestive symptoms. (Level of
Evidence: C) More data are needed to
determine the correct threshold ofsodium restriction
Water restriction
Should be considered but notneeded for all patients; Class IaIrecommendation
Fluid restriction (1.5-2.0 L/d) isreasonable in stage D, especiallyin patients with hyponatremia, toreduce congestive symptoms.(Level of Evidence: C) Arginine vasopressin antagonists may
also be indicated for volume overloadstates associated with profoundhyponatremia
Yancy CW, et al; ACCF/AHA Task Force on Practice Guidelines.Circulation.2013;128:e240-e327.
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Stages, Phenotypes, and Treatment of HF
STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE B
Structural 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 C
Structural heart disease
with prior or current
symptoms of HF
THERAPY
Goals Control symptoms Patient education Prevent hospitalization Prevent mortality
Drugs for routine use Diuretics for fluid retentionACEI or ARB Beta blockersAldosterone antagonists
Drugs for use in selected patients Hydralazine/isosorbide dinitrateACEI and ARB Digoxin
In selected patients CRT ICD Revascularization or valvular
surgery as appropriate
STAGE D
Refractory HF
THERAPY
Goals
Prevent HF symptoms
Prevent further cardiac
remodeling
DrugsACEI 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
THERAPY
Goals Control symptoms Improve HRQOL Reduce hospital
readmissions Establish patients end-
of-life goals
OptionsAdvanced care
measures Heart transplant Chronic inotropes Temporary or permanent
MCS Experimental surgery or
drugs Palliative care and
hospice ICD deactivation
Refractorysymptoms of HF
atrest, despiteGDMT
At Risk for Heart Failure Heart Failure
e.g., Patients with:
Marked HF symptoms at
restRecurrent 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 ofHFStructural heart
disease
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Pharmacologic Treatment forStage C HFrEF
HFrEF Stage C
NYHA Class IIV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+
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Medical Therapy for Stage C HFrEF:Magnitude of Benefit Demonstrated in RCTs
GDMTRR Reduction
in Mortality
NNT for Mortality
Reduction
(Standardized to
36 mo)
RR Reduction
in HF
Hospitalizations
ACE inhibitor orARB
17% 26 31%
Beta blocker 34% 9 41%
Aldosterone
antagonist30% 6 35%
Hydralazine/nitrate 43% 7 33%
Fonarow, G, Yancy C.American Heart Journal, 2012.
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The newest
Paradigms in HF
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The Role of Heart Rate inCardiovascular Disease
Atherosclerosis
Endothelial dysfunction Oxidative stress Plaque stability
Arterial stiffness
Ischemia
Oxygen consumption
Duration of diastole
Coronaryperfusion
Remodeling
Cardiac hypertrophy
Chronic heart failure
Oxygen demand
Ventricular efficiency
Ventricularrelaxation
Elevatedheartrate
+
++
+
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Novel Interventions for Patients with Heart Failure
Ivabradine
+
++
Acts by inhibiting the If channel,present in the cardiac SA node
Reduces persistently elevated
heart rate
Approved by FDA in April 2015 forstable HF pts who have a restingHR of at least 70 bpm, and whoare also taking the highesttolerable dose of a beta blocker
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-1122.
SA node
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SHIFT Trial Inclusion Criteria
Inclusion criteria
Symptomatic chronic heart failure; NYHA class II IV
Admitted to hospital within 12 months before randomization
Left ventricular ejection fraction of 35% or lower
Normal sinus rhythm
Heart rates of 70 bpm or higher
Bohm M, et al. Lancet. 2010;376:886-894.
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Background: Beta-blocker Treatment
Adapted from: Bohm M, et al. Lancet. 2010;376:886-894.Adapted from: Swedberg K, et al. Lancet. 2010;376:875-885.
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SHIFT: Ivabradine ReducesHospitalization for HF
Swedberg K, et al. Lancet. 2010;376:875-885.
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SHIFT: Ivabradine Does Not ReduceCardiovascular Death
Swedberg K, et al. Lancet. 2010;376:875-885.
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PARADIGM HF Trial
McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.
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Simplified Schematic of the ReninAngiotensinAldosterone System
von LuederTG, et al. Circ Heart Fail. 2013;6:594-605.
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Simplified Schematic of the NatriureticPeptide System (NPS)
von Lueder TG, et al. Circ Heart Fail. 2013;6:594-605.
C di A ti d li Eff t f
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Cardiac Antiremodeling Effects ofAngiotensin Receptor Neprilysin Inhibitors(ARNi) in vitro and in vivo
von Lueder TG, et al. Circ Heart Fail. 2013;6:594-605.
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Mechanism of Action of LCZ696
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PARADIGM HF
McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.
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PARADIGM-HF(Prospective Comparison of ARNI with ACEI toDetermine Impact on Global Mortality and Morbidity inHeart Failure trial)
McMurray JJ, Packer M, Desa i AS, et al.N Engl J Med. 2014;371(11):993-1004.
Death from CV causes
20% risk reductionHF hospitalization
21% risk reduction
693
558
658
537
P = 0.00008 P = 0.00008
Primary composite outcome
HR: 0.80 (0.73, 0.87) p = 0.0000004
PARADIGM HF
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PARADIGM-HF(Prospective comparison of ARNI with ACEI toDetermine Impact on Global Mortality and morbidity inHeart Failure trial)
Death from any cause
0
10
20
30
40
0 180 360 540 720 900 1080 1260
16% risk reduction
Enalapril
(n=4212)
835
LCZ696
(n=4187)
711
Days after Randomization
CumulativeProportionof
Patients
WhoDiedfromAnyCause(%) HR: 0.84 (0.76, 0.93)
P = 0.0009
McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371(11):993-1004.
K l M i C f h Ti Fi
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KaplanMeier Curve for the Time to FirstHospitalization for Heart Failure During First 30 DaysAfter Randomization, According to Study Group
Death from any cause
Packer M, et al. Circulation. 2015;131(1):54-61.
C l ti N b f H it li ti f
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Cumulative Number of Hospitalizations forHeart Failure in the Enalapril and LCZ696Groups per 100 Patients
Death from any cause
Packer M, et al. Circulation. 2015;131(1):54-61.
M B li Ch t i ti f P ti t ith
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Mean Baseline Characteristics of Patients withHeart Failure and a Reduced Ejection Fraction inFive Trials
Death from any cause
Jessup M. N Engl J Med. 2014. DOI: 10.1056/NEJMe1409898
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Pharmacologic Treatment for Stage C HFrEF
Death from any cause
HFrEF Stage C
NYHA Class I IV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+
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HFpEF:
Heart Failure with PreservedEjection Fraction
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Heart Failure with Preserved LVSystolic Function
About 50% of patients with symptomatic HF havepreserved LVEF
Accounts for 40% of HF hospitalizations
More common in women, elderly, and obese, andthose with concomitant hypertension, LVH, or diabetes
Annual mortality rate is now thought to be similar tothat of patients with systolic HF
Paucity of clinical trial data to guide managementof HFpEF patients
KitzmanDW, et al.Am J Cardiol. 2001;87:413-419.
Redfield MM, et al.JAMA. 2003;289:194-202.
Vasan RS, et al.J Am Coll Cardiol. 1999;33:1948-1955.
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Prevalence of Heart Failure with PreservedSystolic Function in Men and WomenCardiovascular Health Study
LVEF = left ventricular ejection fraction
Kitzman DW, et al. Am J Cardiol. 2001;87:413-419.
Normal (LVEF 55%)
Mild (LVEF 45%-54%)
Mod/severe (LVEF
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Trends in Prevalence of HFpEF
OwanTE, et al. N Engl J Med. 2006;355(3):251-259.
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Survival Outcomes of HFpEF and HFrEF
Number at Risk
Reduced ejection fraction
Preserved ejection fraction
Owan TE, et al. N Engl J Med. 2006;355(3):251-259.
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Treatment of HFpEF
Yancy CW, et al. Circulation.2013;128:e240-e327.
Recommendations COR LOE
Systolic and diastolic blood pressure should be controlled according to
published clinical practice guidelinesI B
Diuretics should be used for relief of symptoms due to volume overload I C
Coronary revascularization for patients with CAD in whom angina or
demonstrable myocardial ischemia is present despite GDMT
IIaC
Management of AF according to published clinical practice guidelines
for HFpEF to improve symptomatic HFIIa C
Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertensionin HFpEF
IIa C
ARBs might be considered to decrease hospitalizations in HFpEF IIb B
Nutritional supplementation is not recommended in HFpEFIII: No
BenefitC
Recommendations COR LOE
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Surgery and Devices
Heart monitoring devices
Implantable monitors
ICD and CRT
Heart replacement therapies
Mechanical circulatory support
Heart Transplantation
Heart valve repair/replacement
Surgery
Transcutaneous
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The future is promising
Greater use of biomarkers
Multiple regenerative therapies
Stem cells (mesenchymal)
Gene transfer
Growth factors
Community engagement
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