Angiotensin converting enzyme inhibitors in paediatric cardiac patients – current experience and practice

Summary

Paediatric heart failure is a relatively common and potentially life-threatening complication of various diseases, including congenital heart defects and myocardial diseases (e.g. cardiomyopathy and myocarditis). Angiotensin converting enzyme (ACE) inhibitors are currently accepted part of treatment in paediatric heart failure. Captopril, Enalapril, Lisinopril, and Ramipril are the most frequently used ACE inhibitors in paediatric cardiac patients.

We reviewed published data and our institutional practice related to the use of ACE inhibitors in children with heart failure to assess their indications, dose range, safety profile, and outcome data where available.

Although paediatric large scale randomized trails are rare, the published results of ACE inhibitor therapy in managing paediatric heart failure are encouraging. We recommend early initiation, appropriate choice of medication, adequate dosage, and close follow up for monitoring of potential adverse effects.

Keywords:

heart failure – paediatric – angiotensin-converting enzyme inhibitor

INTRODUCTION

Paediatric heart failure (HF) is most often associated with congenital heart disease, cardiomyopathy and acquired heart disease [1]. The incidence of congenital heart disease appeared relatively stable between 6–8/1000 live births world-wide before the impact of fetal cardiac diagnoses and termination of pregnancy in complex congenital heart defects was present [2, 3]. However, only a small percentage of these defects are severe enough to result in heart failure during childhood, while most of the lesions are diagnosed and corrected at an early age. The incidence of primary cardiomyopathy (CM) in developed countries is 0.8 and 1.3 cases per 100,000 children but the risk is up to 10 times higher among infants <1 year old [4, 5]. The majority (87%) of new-onset heart failure patients are diagnosed in a state of severe decompensation (Table 1) [5], and only less than 50% of these children will survive for 5 years without cardiac transplantation [6]. As a result, cardiomyopathy contributes significantly to the number of paediatric patients who present with the symptoms of cardiac failure.

METHODS

Review of the available published evidence (until October 2019) for paediatric heart failure management was undertaken. Literature searches were done using a variety of search engines including PubMed, Medline, Cochrane Database of Systemic Reviews, BMJ Clinical Evidence, and Google scholar to identify recent literature. We also reviewed our institutional database in a tertiary paediatric cardiac center to assess the contemporary use of ACE inhibitors in children, their indications, dose range, safety profile, and outcome data where available.

RATIONALE FOR THE USE OF ACE INHIBITORS IN PAEDIATRIC HEART FAILURE

Paediatric heart failure relates to abnormal changes in cardiac preload, afterload, and/or myocardial function. It leads to impaired end organ perfusion and neuro-hormonal response [7]. One of the compensatory mechanisms is activation of the renin-angiotensin-aldosterone axis with increase of levels of angiotensin and aldosterone. These contribute to vasoconstriction to maintain end organ perfusion [8, 9]. Angiotensin II, due to its potent vasoconstrictor effect, causes release of norepinephrine and induces myocardial remodeling. This leads to myocardial hypertrophy, apoptosis as well as fibrosis [9–11]. There is a marked decrease in the plasma renin activity even within the initial few days of the ACE inhibitor therapy [12, 13]. The angiotensin II activity as well as the aldosterone level in the plasma decreases significantly with time [14, 15]. There is a linear correlation of the plasma ACE activity with the serum ACE inhibitor concentration [16]. Due to its effect of decreasing angiotensin II and aldosterone levels ACE inhibitors have vasodilatory effect on both arterial and venous beds [17]. Therefore, these drugs have a favourable effect on the systemic afterload by decreasing systemic vascular resistance thereby enhancing stroke volume with positive impact on acute and chronic heart failure [18–21].

ACE inhibitors have a proven direct effect on systemic vascular resistence and aortic pressure in paediatric population [22–24]. More importantly, the drop in systemic vascular resistance occurred only in patients where this resistance was elevated and not in those with low systemic vascular resistence [23]. ACE-inhibitors have somewhat less predictable effect on the pulmonary vascular resistance due to decrease in left atrial pressure. Beneficial effect in heart volume overload related heart failure due to large left-to-right shunt relates to alteration in the ratio between systemic and pulmonary vascular resistance with ensuing reduction of the volume of left-to-right shunt [13, 24, 25].

CHOICE OF ACE INHIBITOR IN THE TREATMENT OF HEART FAILURE

As large randomized trials are rare in paediatric heart failure patients, experience with the use of ACE inhibitors has been and still is mostly derived from the adult cardiac failure studies. The beneficial effects of ACE inhibitors in reducing the mortality in adults with heart failure have been long established by the CONSENSUS and SOLVD trials [26, 27]. The adult studies have shown significant decrease in the symptoms, mortality, and morbidity, mainly with the use of enalapril, lisinopril, and ramipril [28–30]. There is currently no data directly comparing the different ACE inhibitors and their impact on adult heart failure patients.

In the neonatal and paediatric population, majority of the studies have used captopril and enalapril, with modest data for cilazapril, ramipril, lisinopril. Predominantly, these studies have been retrospective and assessed surrogate markers for clinical outcomes. Ramipril and lisinopril were mainly studied for their effects on systemic hypertension. Captopril was proposed for addition to the WHO essential medicine list – in children, however only enalapril is included in the 2019 list for its use in systemic hypertension [31]. Newer generation drugs such as benazepril, fosinopril,moexipril, trandolapril and quinapril are predominantly used in adult population.

EVIDENCE FOR POSITIVE IMPACT OF ACE INHIBITORS ON PAEDIATRIC HEART FAILURE

There is evidence for acute and long term improvement of the left ventricular ejection fraction and stroke volume without a significant change in the heart rate [17, 32] more pronounced in dilated than restrictive cardiomyopathy [12, 33]. Variable effect was present in patients with left-to-right shunt [14, 32, 34]. Children with significant aortic or mitral valvar regurgitation, either native or post-operative, showed improvement in the left ventricular dimensions, regurgitation fraction, and left ventricular mass [15, 35, 36]. Improvement in the postoperative cardiac function with ACE inhibitor therapy has been demonstrated after surgical repair of congenital heart defects [16, 34].

a) Heart failure due to congenital heart defects with volume overload

Congenital heart defects (CHD) are the most common cause of paediatric heart failure and 20% of all patients with a CHD has HF [37, 38]. The worldwide estimate for live births with CHD was one million in the year 2001 [39]. The prevalence of CHDs are ever increasing owing to better diagnostic modalities, survival of preterm neonates and availability of corrective as well as palliative surgical treatment options. Consequently, the number of children with associated complications and morbidities requiring medical treatment will continue to increase [40]. These patients will include those awaiting cardiac surgical treatment or those with residual post-operative lesions in need of medical therapy.

Published evidence on ACE inhibitor use in paediatric population with structural congenital heart disease is summarized in Table 2. Early prospective and retrospective studies suggested clinical improvement with better weight gain, lower respiratory rate, and improved feeding. [14, 41–43]. Smaller studies evaluating the echocardiographic parameters show conflicting outcomes with regards to left ventricular dimensions and function. In the most recent review, Slipszuk et al. concluded that ACE inhibitors are an effective treatment in patients with mitral valve regurgitation without hypertrophic cardiomyopathy or mitral valve prolapse [44]. The International Society for Heart and Lung Transplantation (ISHLT) guidelines recommended routine incorporation of ACE inhibitor therapy for symptomatic chronic systolic heart failure with reduced ejection fraction, unless there is specific contraindication [1]. The advice is to start at a low dose and titrate to a maximum tolerated safe dose. For those remaining asymptomatic, routine use of ACE inhibitors was also advocated.

b) Heart failure due to primary cardiomyopathy

Published evidence on the use of ACE inhibitors in paediatric cardiomyopathy patients is listed in Table 3. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in children [6, 54] with primary myocardial systolic dysfunction. Pharmacotherapy of DCM includes positive inotropic agents, diuretics, and substances decreasing afterload. Most published evidence showed clinical improvement even beyond the first year of therapy and better left ventricular size and systolic function. Invasive quantification techniques provided evidence of improved cardiac index, stroke volume, and a considerable decrease in afterload.

In restrictive cardiomyopathy (RCM), ACE inhibitor treatment could be considered, however systemic vasodilation in the setting of reduced left ventricular diastolic function can have deleterious effect on end organ perfusion [33]. While inhibition of renin-angiotensin-aldosteron system can have a favourable impact on ventricular hypertrophy and diastolic function in secondary myocardial hypertrophy [55] when used in patients with dynamic left ventricular outflow obstruction as seen in hypertrophic cardiomyopathy (HOCM), a deleterious fall in cavity size and worsening outflow gradient along with impaired LV compliance could be observed [56]. Hence vasodilators including ACE inhibitors are usually avoided in severe form of HOCM or late stages of RCM [56, 57].

The ISHLT recommends initiation of ACE inhibitor therapy in individuals with Duchenne muscular dystrophy unless contraindicated [1]. The appropriate age of initiation of therapy is not specified. The Canadian guidelines on paediatric heart failure management strongly recommended ACE inhibitor therapy in children with primary left ventricular myocardial disease states, though the current level of evidence was moderate [58].

c) Heart failure due to chemotherapy induced cardiotoxicity

Anthracycline is a topoisomerase-interacting agent used in most malignancy treatment protocols. As most of the chemotherapeutic regimens depend on the agents like doxorubicin or daunorubicin with known affinity to cardiolipin, the long term cardiac effects cause considerable concern. The initial results from study of Lipshultz et al. were encouraging as to improved left ventricular shortening fraction and mass in the initial 6 years, followed by deterioration and associated mortality or need for heart transplantation [32]. This could be attributed to the inherent prognosis of the disease and not solely on the ACE inhibitor therapy. Silber et al. reported a lower left ventricular wall stress during the first 5 years of treatment with ACE inhibitors maintained throughout the study period, however there was no parallel improvement in cardiac index, stress-velocity index or fractional shortening [62]. In more recent studies, preservation of left ventricular function or its less significant deterioration were observed. The biomarkers of cardiac failure were also lower in the group receiving ACE inhibitors when compared to placebo [63–65]. When parameters with better sensitivity such as strain analysis with speckle tracking technique was employed, a significant improvement in the cardiac function was appreciated which continued follow up [63–65]. These studies are encouraging the routine use of ACE inhibitors to prevent cardiac deterioration    after anthracycline exposure (Table 4).

d) Prophylactic use in single ventricle congenital heart defect physiology

Initial study focusing on the somatic growth during the inter-stage periods for completion of single ventricle palliation pathway did not show any significant advantage of ACE inhibitor therapy [52]. Also, when non-invasive ventricular functional assessment was done, there was no demonstrable effect with prophylactic ACE inhibitors administration [66]. At the time of invasive assessment of cardiac function during cardiac catheterization, the end diastolic pressure and pulmonary arterial and mean atrial pressures were lower among patients receiving ACE inhibitor therapy [67]. In a large multi-centre retrospective case controlled cohort study extracted from National Pediatric Cardiology Quality Improvement Collaborative database between 2008 and 2015, Doris et al. concluded that there has been no beneficial effect of prophylactic ACE inhibitor therapy to prevent inter-stage heart failure in infants with single ventricle physiology [68].

Prophylactic interstage ACE inhibitor therapy for children undergoing staged surgical palliation for single ventricular congenital heart defects has always shown discouraging evidence with no significant added benefits. The recommendation from the ISHLT guideline is that ACE inhibitor therapy should not be routinely instituted for all patients with single ventricle, however its use could be considered in specific cases such as valvar regurgitation or ventricular dysfunction [1] (Table 5).

e) ACE inhibitor therapy in early paediatric post-operative heart failure

Heart failure, both due to cardiac or extra-cardiac cause is a common diagnosis in paediatric intensive care (PICU). In a cardiac PICU, it is frequently seen immediately following a cardiac surgical procedure. This leads to prolonged hospitalization, significant morbidity as well as mortality [69]. There have been reports of considerable improvement with enalapril in postoperative heart failure [34]. Though no large randomized controlled trails assessing their routine use in PICU have been reported, the consensus statement from the Paediatric Cardiac Intensive Care Society from 2014 has recommended the routine use of ACE inhibitors in these children [70]. This is in line with the Canadian Cardiovascular Society and ISHLT guidelines [1, 58].

PHARMACOKINETICS

Being a heterogeneous group of drugs, ACE inhibitors have varied pharmacokinetic profiles which enables the clinician to choose wisely for a given patient (Table 6). Lisinopril and captopril do not require hepatic activation and hence can be safely prescribed even in severe hepatic failure [71]. Enalapril is the only intravenous preparation available and it is also safe to use in liver disease. Lisinopril is almost exclusively excreted by kidneys. Fosinopril is unique as it does not require dose adjustment in renal disease (all other ACE inhibitors need dose modification) owing to its unique property of compensatory dual routes of elimination [71]. Captopril interacts with food and need spacing after meals.

With limited number of pharmacokinetic studies in paediatric population, it has been shown that in infants the peak serum concentration of enalaprilat occurs at 8 hours and the serum half-life (T ½) ranged from 6 to 10 hours [72]. In infants with heart failure, it was concluded that the enalapril was less bioavailable with shorter duration of action. It was suggested that the dose of enalapril needs to be calculated based on body surface area rather than the body weight in paediatric heart failure patients. The area under the curve (AUC) was similar both in children and adults when a dose of 1 mg/m² of enalapril was used instead of body weight directed dosing. However, this was not true for preterm neonates who showed much higher AUC with delayed peak and delayed decline [73]. For cilazapril, a dose of 0.04 mg/kg demonstrated sufficient inhibition of plasma ACE activity and hemodynamic effects [16].

DOSE INITIATION AND TITRATION

The general consensus on ACE inhibitor therapy is to begin with a smaller ‘test’ dose and follow it up with gradual increase of doses as tolerated in order to avoid potential hypotension [70]. As the neonatal age group seems to react significantly differently, dosage needs to be markedly reduced in the setting of heart failure. Patients developing acute renal failure due to prolonged persistent inhibition of renin-angiotensin-aldosterone may benefit from either a short acting ACE inhibitor or a lower dose of long acting alternative. Appropriate choice of drug as well as tailored dosage needs to be prescribed in patients with hepatic or renal impairment.

The Paediatric Cardiac Intensive Care consensus document suggests a well-structured drug dosage for initiation and continuation therapy [70]. Our hospital guidelines for paediatric patients are listed in Table 7.

SAFETY PROFILE AND ADVERSE EFFECTS

Common adverse effects due to direct inhibition of renin-angiotensin-aldosterone axis include systemic hypotension, hyperkalemia, renal failure, and possible fetal anomalies (Table 9). As ACE inhibitors increase the bradykinin levels in the body, the resulting cough can be a significant problem [74]. As captopril contains a sulfhydryl group, it can lead to adverse effects like neutropenia and proteinuria. Systemic hypotension is reported in up to 19% of patients, necessitating dose modification, and rarely transient inotropic support [75]. Hyperkalemia has been reported but none resulting in cardiac arrhythmia.

Nephrotoxicity of ACE inhibitors was predominantly seen in younger age and lower weight patients [34]. Neonates had a greater risk of renal functional impairment associated with ACE inhibitor treatment than older children [79]. When compared to term neonates, preterm neonates are at a significantly higher risk of similar treatment complications. This is probably owing to the renal immaturity, reduced glomerular filtration rate with impaired renal autoregulation [78]. Renal failure has been described even with the initial doses of ACE inhibitors [34] with a dramatic rise in serum urea, creatinine as well as development of oliguria [15]. Fortunately these adverse effects were short-lived and resolved within a few days of treatment cessation [15]. Most importantly, the coexistent conditions leading to dehydration such as gastroenteritis, poor oral fluid intake and/
/or concomitant use of diuretics can pre-dispose to higher incidence of acute kidney injury [81]. Spironolactone and chlorothiazide administration have been described as an independent risk factor for nephrotoxicity with ACE inhibitor therapy [78, 79]. Mortality has been reported in two studies involving patients treated with ACE inhibitors, however, no direct association with the ACE inhibitor administration was proven [34, 75] (Table 8).

Our own institutional experience relates to audit of the use of ACE inhibitor in 124 paediatric patients between January and December 2018. The most common indications for this type of treatment was myocardial dysfunction in 38% of the patients. Apart from a mild and transient reduction in systemic blood pressure associated with the initial doses of ACE inhibitors, we have not encountered any significant side effects.

CONCLUSIONS

Although paediatric large scale randomized trails are rare, the published experience with ACE inhibitor therapy in managing paediatric heart failure is encouraging. We recommend their early initiation in carefully selected patients, appropriate choice of medication, adequate dosage, and close follow up for early diagnosis of potential adverse effects. Careful monitoring of blood pressure, serum electrolytes, and renal function is essential in paediatric patients treated with ACE inhibitors.

Došlo: 6. 3. 2020

Přijato: 13. 5. 2020

Corresponding author:

Zdeněk Slavik, MD, FRCPCH

Royal Brompton and Harefield

NHS Foundation Trust

Sydney Street

London, SW3 6NP

United Kingdom

e-mail: z.slavik@rbht.nhs.uk