Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey

Abstract

Objective: To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting.

Methods: A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology.

Results: Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination.

Conclusions: Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children.

Keywords: cardiology; paediatric practice; pharmacology; therapeutics.

Figure 1

Survey participation/response rate by country and region. Hospitals were eligible if contact data of one clinician dedicated to the field of paediatric cardiology were available. We were able to find contact data of physicians from 204 different hospitals in 39 European countries. Four were excluded from analysis: one physician contacted expressed his wish not to participate, one did not feel able to participate because of limited experience, one was retired and one returned the completed questionnaire after the pre-established deadline. If more than one physician in a hospital answered, only the first questionnaire received was taken into consideration for analysis. Response rate was calculated as the number of different hospitals from which at least one physician submitted a completed or partially completed questionnaire divided by the number of different hospitals from which a physician was sent the invitation with questionnaire link. Criteria of the United Nations statistical division for Europe were followed for the classification of countries by European region. Four of the countries referred to are not considered as being European in this classification. Armenia and Azerbaijan were assigned here to Eastern Europe, Cyprus and Turkey to Southern Europe.

Figure 2

ACE-I use for the management of congenital heart defects. This question was applicable to 97 participants (n total for percentage calculation). Most of those 97 participants agreed on the usefulness of the therapy with ACE-I in patients with LRS lesions (80/97=82%) single ventricle lesions (84/97=87%) and/or valve regurgitation (92/97=95%). A marked division of opinions existed among the physicians asked with regard to pressure overloading lesions (44/97=45% yes vs 51% no). Twelve participants reported using ACE-I for other CHD (mainly systemic right ventricle, Marfan syndrome, postsurgical correction of aortic coarctation, complex CHD). ACE-I, angiotensin-converting enzyme inhibitors; CHD, congenital heart defect; LRS, left-to-right shunt.

Figure 3

First-choice ACE-I by age group. Age groups were defined according to age classification for paediatric patients proposed by the EMA. 72% of the participants reported prescribing ACE-I in all age groups. ACE-I, angiotensin-converting enzyme inhibitor.

Figure 4

Starting dose (mg/kg/dose) and maintenance/target daily dose (mg(kg/day) in use reported by survey participants for captopril and enalapril by age group. Opacity of each point is proportional to the number of participants that entered that dose. Diamonds (◊) indicate median values. Thick horizontal lines indicate ranges of paediatric dosage recommendations that have been published. Detailed results corresponding to these figures are provided in online supplementary tables S8 and S9. Age groups were defined as follows: newborns 0–27 days, infants and toddlers 28 days to 23 months, children 2–11 years and adolescents 12–18 years. Mean of starting doses reported for captopril was: 0.22 mg/kg/dose for newborns, 0.26 mg/kg/dose for infants and toddlers, 0.33 mg/kg/dose for children and 0.18 mg/kg/dose for adolescents. The mean of enalapril reported staring doses was: 0.06 mg/kg/dose for newborns and infants and toddlers, 0.08 mg/kg/dose for children and 0.09 mg/kg/dose for adolescents. SD values are provided in online supplementary table S6. The reported captopril mean maintenance doses were 1.58, 1.99, 2.30 and 1.75 mg/kg/day for each age group, respectively, in order of increasing age. Mean of maintenance doses reported for enalapril was 0.27 mg/kg/day for newborns and 0.41, 0.42 and 0.43 mg/kg/day for infants and toddlers, children and adolescents, respectively. SD values are provided in online supplementary table S7.

Figure 5

Dosing frequency of ACE-I maintenance dose reported for ACE-I of choice selected for each age group. Age groups were defined as follows: newborns 0–27 days, infants and toddlers 28 days to 23 months, children 2–11 years and adolescents 12–18 years. Captopril appeared to be most commonly prescribed three times per day and enalapril two times a day in all paediatric age groups except for adolescents. In this age group, the prevalence of prescribing enalapril once a day was similar to two times a day prescribing. Similarly, the percentage of clinicians reporting captopril administration two times and three times a day for adolescents was as high. Participants who reported using lisinopril, perindopril, ramipril and/or trandolapril prescribe these ACE-Is in single daily doses in virtually all cases. Answer option ‘4 times per day’ was also provided, but this was not selected in any case. One of the 30 participants that reported using captopril for children did not specify any dosing frequency. ACE-I, angiotensin-converting enzyme inhibitor.

Figure 6

Attitude towards deterioration of renal function in terms of baseline serum creatinine level increase in the context of ACE-I therapy. The thresholds of baseline serum creatinine levels increase were based on the KDIGO proposed staging for acute kidney injury. Participants were requested to select the answer option that most reflected their practice. When considering deterioration of renal function in patients under ACE-I therapy, 25% of the participants claimed not to base treatment decisions on any formal cut-off value. A rise of 1.5 to 1.9-times in serum creatinine level was the most frequently selected limit as the criterion to stop increasing dose by those that reported being guided by formal limits (61%, 44 out of 72), while an increase of 2.0–2.9 times creatinine was the most frequently selected option for therapy withdrawal (51%, 36 out of 71). ACE-I, angiotensin-converting enzyme inhibitor.