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
2
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
46
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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