Novel Rx Heart Failure

7/25/2019 Novel Rx Heart Failure

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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



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Hospital Discharge Rates for HFin the US



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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


Marked HF symptoms at

restRecurrent hospitalizations

despite GDMT


Previous MI

LV remodeling including

LVH and low EF

Asymptomatic valvular

disease


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



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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


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


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


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


Jessup M. N Engl J Med. 2014. DOI: 10.1056/NEJMe1409898


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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+


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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

Novel Rx Heart Failure

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