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)
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DGPK Guideline chronic heart failure in Infancy and ... · survival with the use of ACE inhibitors in chronic CHF.1,2,3,4 Paediatric population (structurally normal hearts): no randomized
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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
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:
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.