Systolic Dysfunction Clinical/Hemodynamic Guide for...

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

[email protected]

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

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


· Marked HF symptoms at

rest

· Recurrent 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 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


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%


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).



Cardiac antiremodeling effects of angiotensin receptor neprilysin inhibitors (ARNi) in vitro and in vivo.



Cardiac antiremodeling effects of angiotensin

receptor neprilysin inhibitors (ARNi) in vitro and in

vivo.


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


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


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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