DGPK Guideline

chronic heart failure in Infancy

and Adolescence

Carsten Rickers (UKSK, Kiel)

Stephanie Läer (Pharmacology, Univ. Düsseldorf)

Gerhard-Paul Diller (UKM, Münster)

Jan Janousek (Univ. Hosp. Motol, Prag)

Uta Hoppe (Univ. Salzburg)

Thomas Mir (UHZ, Hamburg)

Jochen Weil (DHM, TU München)

Conflicts of interest

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http://www.awmf.org/leitlinien/detail/ll/023-006.html

Definition of heart failure

Congestive heart failure (CHF) is characterized by the

inability of the heart to pump sufficiently to meet the organs

oxygen demands.

This leads to activation of the sympathetic nervous system

and the renin-angiotensin-aldosteron-system (RAAS),

aggravating heart failure symptoms.

Maladaptive systemic responses – Circulus vitiosus

RM Delgado, Pathophy. Heart failure 1999 4

Cardiac performance

Adrenergic

mediators

Afterload

Renin – Angiotensin – Aldosterone

Myocyte damage

Cytokines

(TNF and Interleukins)

Myocardial injury

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Neurohumoral activation in adults with CHD

Bolger et al Circulation 2002

Historically, (congestive) heart failure is referred to

reduced systolic LV ejection fraction (HFrEF).

but patients with preserved LV function (HFpEF)

can also present with heart failure symptoms due

to impaired ventricular relaxation.

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Terminology

Aetiology

Structural heart disease (ca. 80%1):

Volume loaded ventricle:

• left-to-right shunt lesions (e.g. VSD, PDA)

• Valve insufficiencies (e.g. aortic regurgitation)

Pressure load ventricle:

• Left sided obstructions (e.g. Ao-stenosis)

• Right sided obstructions (e.g. PA-stenosis)

Complex CHD:

• Univentricular hearts (e.g. HLHS)

• Systemic RV (e.g. cc TGA)

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1Hsu et al. Circ Heart failure 2009

Aetiology

Structurally normal heart:

Cardiomyopathies: • Dilated CM

• Hypertrophic CM

• Restrictive CM

• Non-compaction CM

• Arrhythmogenic CM

Myocarditis

Rhythm disturbancies

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Epidemiology

Heart failure: Rare in children, in adults 1-2% of the population.

Incidence: 23 of 1000 children with the diagnosis “cardiac disease.”1

Heart failure from structural defects in children estimated to be

about 0.1% of live births.

Heart failure 3 times more often in infants than age 1 to 10.2

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1Sommers et al. Herz 2005 2Rodeheffer et al. Mayo Clinic proceedings

1993

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Leading symptoms

Common Less common

Infants/Toddler Tachypnea Cyanosis

Tachycardia Palpitations

Feeding difficulties Syncope

Diaphoresis Oedema

Pallor Ascites

Failure to thrive

Children/

Adolescents

Fatique Palpitations

Effort intolerance Chest pain

Dyspnea/Orthopnea Leg Oedema

Abdominal Pain Ascites

Nausea/Vomiting

Scoring

11 Laer et al. Am Heart J 2002

Severity Points

Mild 3 – 6

Moderate 7 – 9

Severe 10 – 12

Diagnostic Investigation

Aims

Confirm the diagnosis

Assess severity of heart failure

Evaluate differential diagnosis

Risk stratification

Evaluate therapeutic options

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First line investigation

Secondary

Echocardiography Cardiopul. Exercise Test

ECG MRI

Chest X-Ray Holter-ECG

Labs Catheterisation

Extended labs

Stress echo

CT/ Others

Diagnostic Tools

Echocardiography

TTE is an indispensible part of the initial evaluation

(should be done immediately by an experienced investigator)

Detection/ exclusion of possible structural disease

Assessment of systolic and diastolic function

Useful for follow-ups (e.g. therapeutic effects?)

Screening for pts at risk (e.g. oncology)

normal diastolic dysfunction normal

Echocardiography

Syst. heart failure in children is currently defined as:

SF<25% and/or EF <50%.1

1Lang et al. J Am Soc Echocardiogr 2005 2 Kantor et al. JACC 2010

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Diagnostic Tools - Baseline

Cardiomegalý: CTR >50%

ECG: Nonspecific but frequently

abnormal in heart failure

NT-proBNP:

- Significant relationship with

symptoms and LV-function.1

- Might be associated with worse

outcome in heart failue.2

1Kocharian et al. Cardiol Young 2009 2Sugimoto et al. Circ J 2010

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Diagnostic Tools - MRI

MRI is showing increasing diagnostic

potential in cardiomyopathies and myocarditis.1

MRI is superior to echocardiography to

assess LV and RV function.2

In adult DCM prognostic value.3

Dilated cardiomyopathy

(♂ 15 y/o)

D-TGA, status post Senning

(♂ 35 y/o)

1Grun et al. JACC 2012 2Lai et al. Int J Cardiovasc Imaging 2008 3Grothues et al.Am J Cardiol 2002

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Diagnostic Tools - MRI

MRI is showing increasing diagnostic

potential in cardiomyopathies and myocarditis.1

MRI is superior to echocardiography to

assess LV and RV function.2

In adult DCM prognostic value.3

Dilated cardiomyopathy

(♂ 15 y/o)

D-TGA, status post Senning

(♂ 35 y/o)

1Grun et al. JACC 2012 2Lai et al. Int J Cardiovasc Imaging 2008 3Grothues et al.Am J Cardiol 2002

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Diagnostic Tools - Catheterization

Pressure volume loop in

congestive heart failure

No general indication in paediatric heart failure.

Indicated if non-invasive diagnostics not sufficient.

Indicated: • to assess pulmonary vascular resistance and pressure prior to operation

• to assess coronary abnormalities

• to assess haemodynamics and anatomy in complex CHD (e.g. TCPC)

• Prior to HTX

Cardiopulmonary exercise test (CPET)

Rationale for CPET

Objective evaluation of exercise capacity and

exertional symptoms.

To differentiate between cardiac and respiratory causes of

dyspnoea.

To evaluate asymptomatic patients

To detect stress induced ischemia

Evaluation before heart transplantation

Recommendations for sport

Assess prognosis but poor correlation between exercise

capacity and hemodynamic measures (e.g. EF)

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Therapy - General

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Surgical or interventional treatment of shunt or

valve lesions (e.g. PDA closure)

Bridging medical heart failure therapy

Therapy - General

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Arrhythmias: Pacemaker, Ablation, Medication

Arterial Hypertension: antihypertensive Therapie

Coronary anomalies (e.g. ALCAPA): surgical correction

Other diseases (Thalassämia, Thyroid, Beri-Beri): appropriate therapy

Therapy - Pharmacotherapy

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General Consideration

Pharmacokinetic is age dependent

(e.g. slower excretion rate in new borns)

Pharmacodynamics is age dependent

Few randomized controlled trials (RCT)

EU Kinderverordnung: (EG) Nr. 1901/2006:

- Approval only if results from paed.

studies are included.

- results must be listed in

product information.

Pharmacotherapy – General Considerations

Principles of medical therapy

Normally structured heart:

- According to the recent adult guidelines.

Congenital heart disease:

- Shunt lesions: bridging medical therapy (ß-Blocker, Diuretics)

- Systemic RV: According to failing LV, but no evidence!

Dosing:

- Max. dose for chronical heart failure: in principle not different from

pharmacotherapy for arterial hypertension!

- But, lower starting dose (1/4 or 1/2 as for hypertension)

- Usually doubling after 1 to 3 weeks (until max. dose or side-effects)

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Pharmacotherapy – RAAS

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Angiotensinogen

Angiotensin I

Angiotensin II

Vasoconstriction Aldosterone

-secretion

Renin

Drugs

Converting

-enzym

Bradykinin

Inactive

degradation products

// //

ACE inhibitors

AT1-receptor antagonists

Aldosterone antagonists

First line therapy: neurohumoral antagonists

ACE/AT1 – Inhibitors as first line therapy in all patients (NYHA I-IV)

ß-Blocker in all symptomatic patients (in hemodynamic stable pts)

Mineralocorticoid rezeptor antagonists (caveat: kidney failure)

Survival benefit: Evidence derived from large adult studies

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Pharmacotherapy

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Major adult studies (> 7,000 pts) have shown improved

survival with the use of ACE inhibitors in chronic CHF.1,2,3,4

Paediatric population (structurally normal hearts): no

randomized controlled trials (RCT).

Approval status for children in Germany: Captopril from 1.

day of life, Enalapril > 20 kg.

Pharmacotherapy – ACE Inhibitors

1Enalapril on mortality - The CONSENSUS Trial Study Group. N Engl J Med 1987 2Enalapril on survival - The SOLVD Investigators. N Engl J Med 1991 3ACE inhibitors on mortality and morbidity. ACE Inhibitor Trials. JAMA 1995. 4Packer M, Lisinopril on morbidity and mortality. ATLAS Study. Circulation 1999

Pharmacotherapy – AT1-Receptor Antagonists

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Important adult studies show improved symptoms and survival.1,2,3

AT1-receptor antagonists: can be considered as alternative in

patients intolerant of an ACE inhibitor.

Paediatric population: no randomized controlled trials (RCT).

Approval status for children in Germany: not approved for heart

failure but >6 year for arterial hypertension (Valsartan, Candesartan,

Losatan).

1Maggioni et al. Valsartan on morbidity and mortality. J Am Coll Cardiol 2002. 2Cohn JN et al. Valsartan in chronic heart failure. N Engl J Med 2001. 3McMurray et al. Effects of candesartan . The CHARM-Added trial. Lancet 2003.

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Three key trials randomized nearly 9000 patients and showed

reduced mortality and hospitalization rate.1,2,3

Paediatric population (structurally normal hearts): no RCTs.

Approval status for children in Germany: not approved for heart

failure but arterial hypertension (Metoprolol: >6 years, Propanolol: all ages) .

Pharmacotherapy – Beta-Blocker

1Bisoprolol Study II (CIBIS-II). Lancet 1999. 2Effect of Metoprolol (MERIT-HF). Lancet 1999. 3Packer et al. Carvedilol on the morbidity (COPERNICUS). Circulation 2002.

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Aldosterone antagonists: Survival benefit in adult heart failure trials.1,2

Paediatric population (structurally normal hearts): no RCTs.

Approval status for children in Germany: not approved for heart

failure but for oedema due to secondary hyperaldosteronism

(Spironolactone from first day of life).

Reduced dose for heart failure therapy.

Pharmacotherapy – Aldosterone antagonists

1Pitt et al. Spironolactone on mortality. Aldactone Evaluation Study. NEJM 1999. 2Zannad et al. Eplerenone in systolic heart failure. NEJM 2011.

Pharmacotherapy – Diuretics

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Additional therapy: diuretics

Improve clinical symptoms in heart failure with congestion*

The effects of diuretics on mortality and morbidity have not

been studied in patients with heart failure.

No RCTs in adults or children!

Approval status for children in Germany: Furosemide from

infancy, Torasemide >12 y/o.

Caveat:Chronic diuretics may aggravate RAAS activation.

Therefore, indicated to achieve euvolaemia

with the lowest achievable dose!

*McMurray et al.; Eur Heart J 2012

Pharmacotherapy – Digitalis glycosides

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Additional therapy: digoxin

Digoxin did not alter all-cause mortality1,2

Can improve symptoms and prevent deterioration1,2

To be considered for rate control in atrial fibrillation

Paediatric population: no randomized controlled trials (RCT)

Approval status for children in Germany: Digoxin from first

day of life.

Target plasma level: 0,5 – 0,9 ng/ml

Not recommended in shunt lesions (e.g. VSD)

1Digitalis Investigation Group. NEJM 1997 2Hoos WB et al.; J Card Fail 2004

Pharmacotherapy – New drugs

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Additional therapy: ivabradine

May be considered in patients with sinus tachycardia (as alternative to

digoxin) despite treatment with an evidence based dose of beta-blocker.

Showed significant risk reduction in heart failure hospitalization in adults1

Paediatric population (structurally normal hearts): RCT in preparation2

Approval status for children in Germany: Expected for >6 months of age.

1Swedberg et al. Ivabradine and outcomes (SHIFT). Lancet 2010. 2Paediatric Investigation Plan for ivabradine (Procoralan). EMA/203739/2013

Pharmacotherapy – New drugs

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Additional therapy: Levosimendan

Calcium sensitiser used in acutely decompensated heart failure.

Should usually be reserved for patients with such severe reduction in

cardiac output (i.v. interval therapy).

Paediatric population: few cases with congestive heart failure1,2

Approval status for children in Germany: not approved

1Swedberg et al. Early experience with Levosimendan in children. Pediatr Crit Care Med 2006.

2Ryerson LM et al. Inotrope therapy in a pediatric population. Pediatr Crit Care Med 2011.

Pharmacotherapy – Anticoagulation

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Increased risk for thromboembolic events in children with dilated

cardiomyopathy1,2

Paediatric population: no RCTs, only small studies

Vitamin K antagonists or heparin in pts with EF <25%, A-Fib. or

with a history of thromboembolic events (expert consensus)

1Arola et al. Idiopathic dilated cardiomyopathy in children. Pediatrics 1998.

2Hsu et al. Acute pulmonary embolism in pediatric pts awaiting heart transplantation. JACC 1991.

Structural heart disease – ACE/ AT1-Antagonists

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No effect of Enalapril in a cohort of unselected Fontan-patients1

No effect of Enalapril in single ventricles prior to palliation. (Hsu et

al überprüfen !!!!

No benefit from AT1-Receptor Antagonists in systemic RV2,3

1Kouatli et al. Enalapril does not enhance exercise capacity in Fontan. Circulation 1997

2Dore A et al. AT1-Antagonist and exercise capacity in systemic RV. Circulation. 2005 3van der Bom T et al. Effect of valsartan on systemic RV function. Circulation. 2013

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1Buchhorn et al. CHF PRO INFANT Studie. Int J Cardiol. 2001

2Buchhorn et al. Cardiol Young 2003

3 Shaddy et al. Carvedilol for children and adolescents with heart failure:

a randomized controlled trial. Jama 2007

Pharmacotherapy – Beta-Blocker

Propanolol: Improved heart failure symptoms (Ross score)

and neurohormonal activation in left-to-right shunt lesions.1,2

Carvedilol vs Placebo: No significant improvement in clinical

heart failure outcomes, but subgroup analysis showed a

beneficial trend for patients with systemic LV.3

Pharmacotherapy – Drugs

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Structural heart disease – Vasoactive substances

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Hypothesis: Lowering the PA-pressure in Fontan-patients may

be beneficial.

Phosphodiesterase-5-Inhibitors and Endothelin-Receptor-

Antagonists showed improved exercise capacity1,2

1Giardini et al. Effect of Sildenafil on exercise capacity in Fontan. Eur heart J 2008. 2Hebert A et al. Bosentan in Fontan: TEMPO RCT. Circulation 2014.

Pharmacotherapy – dosages

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Pharmacotherapy – dosages*

41 *www.kinderkardiologie.org/dgpkLeitlinien.shtml

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Therapy – Outlook

Entresto®

(Sacubitril und Valsartan)

Electromechanical dyssynchrony

Regional heterogeneity of function and loading

Structural and cellular remodeling

Dyssynchronous cardiomyopathy

Pathophysiology of

dyssynchronous cardiomyopathy

Therapy – CRT

Kass et al,. Mechanical dyssynchrony amenable to CRT

(as caused by an electrical activation delay. JACC 2008 Courtesy J. Janousek

0

20

40

60

80

100

120

Dubin et al. Cecchin et al. Janousek et al.

N pts.

Electrical dyssynchrony

Unknown

Non-specific

RBBB/syst RV

LBBB/syst LV

Conv. pacing

Types of electrical dyssynchrony

in pediatric/CHD CRT studies

Dubin AM et al. J Am Coll Cardiol 2005

Cecchin F et al. JCE 2009

Janousek J et al. Heart 2009

Therapy – CRT

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CRT is resonable in all symptomatic patients with pacemaker

induced dyssynchrony/ cardiomyopathy

In symptomatic patients (NYHA II-IV) with systemic LV, SR,

QRS ≥150 ms and LBBB.

Therapy – CRT

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Khairy P et al. Expert Consensus Statement on the Management of Arrhythmias

in Adult Congenital Heart Disease. Heart Rhythm J 2014

Therapy – Other options

May be considered for selected patients:

VAD/ HTX1,2

ICD3

PA-Banding (experimental)4

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1Kirk R et al. The International Society for Heart and Lung Transplantation (ISHLT) Guidelines:

Executive summary. J heart and lung transplant 2014. 2Miera et al. Akute Herzinsuffizienz und Ventrikulärer Assist Device (VAD)/Extrakorporale

Membranoxygenierung (ECMO). DGPK guideline 2015. 3Paul et al. Tachykarde ventrikuläre Herzrhythmusstörungen-Indikationen zur ICD Therapie.

DGPK guideline 2010. 4 Schranz et al. Pulmonary artery banding in infants and young children with cardiomyopathy: a novel

therapeutic strategy before heart transplantation. J Heart Lung Transplant. 2013.

Summary

In structurally normal heart, paed. heart failure

pharmacotherapy follows largely adult principles.

In structural heart disease, study results were

mostly disappointing (also under-powered).

More RCT are warranted and exspected due to

current legislation (effective 2006) .

CRT is a promising approach for selected patients.

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