Clinical and Hemodynamic Outcomes with Enalapril Orodispersible Minitablets in Young Children with Heart Failure Due to Congenital Heart Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Inclusion/Exclusion Criteria
2.3. Study Drug Administration
2.4. Assessments
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Dosing
3.3. Effects of the ODMT of Enalapril on Clinical, Echocardiographic, and Hemodynamic Parameters
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kairuz, T.E.; Gargiulo, D.; Bunt, C.; Garg, S. Quality, safety and efficacy in the ‘off-label’ use of medicines. Curr. Drug Saf. 2007, 2, 89–95. [Google Scholar] [CrossRef] [PubMed]
- Bajcetic, M. Complexity of Medication Regimens for Children with Heart Failure—Pilot study. In Proceedings of the 56th Annual Meeting of the Association for European Paediatric and Congenital Cardiology (AEPC), Dublin, Ireland, 26–29 April 2023; Cambridge University Press: Cambridge, UK, 2003; p. 349. [Google Scholar]
- Bajcetic, M.; Uzelac, T.V.; Jovanovic, I. Heart failure pharmacotherapy: Differences between adult and paediatric patients. Curr. Med. Chem. 2014, 21, 3108–3120. [Google Scholar] [CrossRef]
- Castro Díez, C.; Khalil, F.; Schwender, H.; Dalinghaus, M.; Jovanovic, I.; Makowski, N.; Male, C.; Bajcetic, M.; van der Meulen, M.; de Wildt, S.N.; et al. Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: A European survey. BMJ Paediatr. Open 2019, 3, e000365. [Google Scholar] [CrossRef]
- Amdani, S.; Conway, J.; George, K.; Martinez, H.R.; Asante-Korang, A.; Goldberg, C.S.; Davies, R.R.; Miyamoto, S.D.; Hsu, D.T.; American Heart Association Council on Lifelong Congenital Heart Disease and Heart Health in the Young; et al. Evaluation and Management of Chronic Heart Failure in Children and Adolescents with Congenital Heart Disease: A Scientific Statement from the American Heart Association. Circulation 2024, 150, e33–e50. [Google Scholar] [CrossRef] [PubMed]
- Hsu, D.T.; Pearson, G.D. Heart failure in children: Part II: Diagnosis, treatment, and future directions. Circ. Heart Fail. 2009, 2, 490–498. [Google Scholar] [CrossRef]
- EMA Committee for Proprietary Medicinal Products (CPMP) Summary Information of Referral Opinion Pursuant to Article 30 of Council Directive 2001/83/EC for Renitec and Associated Names (See Annex I), London. 4 December 2003. Available online: https://www.ema.europa.eu/documents/referral/summary-information-referral-opinion-pursuant-article-30-council-directive-2001/83/ec-renitec-associated-names-see-annex-i-international-non-proprietary-name-inn-enalapril-background_en.pdf (accessed on 10 June 2024).
- Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr.; Drazner, M.H.; Fonarow, G.C.; Geraci, S.A.; Horwich, T.; Januzzi, J.L.; et al. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013, 128, 1810–1852. [Google Scholar] [CrossRef]
- Magalhães, J.; Rodrigues, A.T.; Roque, F.; Figueiras, A.; Falcão, A.; Herdeiro, M.T. Use of off-label and unlicenced drugs in hospitalised paediatric patients: A systematic review. Eur. J. Clin. Pharmacol. 2015, 71, 1–13. [Google Scholar] [CrossRef]
- Bajcetic, M.; de Wildt, S.N.; Dalinghaus, M.; Breitkreutz, J.; Klingmann, I.; Lagler, F.B.; Keatley-Clarke, A.; Breur, J.M.; Male, C.; Jovanovic, I.; et al. Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study. Contemp. Clin. Trials Commun. 2019, 15, 100393. [Google Scholar] [CrossRef] [PubMed]
- Laeer, S.; Cawello, W.; Burckhardt, B.B.; Ablonczy, L.; Bajcetic, M.; Breur, J.M.P.J.; Dalinghaus, M.; Male, C.; de Wildt, S.N.; Breitkreutz, J.; et al. Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies). Pharmaceutics 2022, 14, 1163. [Google Scholar] [CrossRef]
- Computation of Centiles and Z-Scores for Height-for-Age, Weight-for-Age and Bmi-for-Age, WHO. Available online: https://cdn.who.int/media/docs/default-source/child-growth/growth-reference-5-19-years/computation.pdf?sfvrsn=c2ff6a95_4 (accessed on 10 June 2024).
- Ross, R.D. The Ross classification for heart failure in children after 25 years: A review and an age-stratified revision. Pediatr. Cardiol. 2012, 33, 1295–1300. [Google Scholar] [CrossRef]
- Sluysmans, T.; Colan, S.D. Theoretical and empirical derivation of cardiovascular allometric relationships in children. J. Appl. Physiol. 2005, 99, 445–457. [Google Scholar] [CrossRef] [PubMed]
- National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004, 114, 555–576. [Google Scholar] [CrossRef]
- Wong, D.T.; George, K.; Wilson, J.; Manlhiot, C.; McCrindle, B.W. Effectiveness of serial increases in amino-terminal pro-B-type natriuretic peptide levels to indicate the need for mechanical circulatory support in children with acute decompensated heart failure. Am. J. Cardiol. 2011, 107, 573–578. [Google Scholar] [CrossRef] [PubMed]
- Sluysmans, T.; Styns-Cailteux, M.; Tremouroux-Wattiez, M.; de Lame, P.A.; Lintermans, J.; Rubay, J.; Vliers, A. Intravenous enalaprilat and oral enalapril in congestive heart failure secondary to ventricular septal defect in infancy. Am. J. Cardiol. 1992, 70, 959–962. [Google Scholar] [CrossRef]
- Nakamura, H.; Ishii, M.; Sugimura, T.; Chiba, K.; Kato, H.; Ishizaki, T. The kinetic profiles of enalapril and enalaprilat and their possible developmental changes in pediatric patients with congestive heart failure. Clin. Pharmacol. Ther. 1994, 56, 160–168. [Google Scholar] [CrossRef]
- Seguchi, M.; Nkazawa, M.; Momma, K. Effect of enalapril on infants and children with congestive heart failure. Cardiol. Young 1992, 2, 14–19. [Google Scholar] [CrossRef]
- Shaddy, R.E.; Teitel, D.F.; Brett, C. Short-term hemodynamic effects of captopril in infants with congestive heart failure. Am. J. Dis. Child. 1988, 142, 100–105. [Google Scholar] [CrossRef]
- Mori, Y.; Nakazawa, M.; Tomimatsu, H.; Momma, K. Long-term effect of angiotensin-converting enzyme inhibitor in volume overloaded heart during growth: A controlled pilot study. J. Am. Coll. Cardiol. 2000, 36, 270–275. [Google Scholar] [CrossRef] [PubMed]
- Alehan, D.; Ozkutlu, S. Beneficial effects of 1-year captopril therapy in children with chronic aortic regurgitation who have no symptoms. Am. Heart J. 1998, 135, 598–603. [Google Scholar] [CrossRef]
- Leversha, A.M.; Wilson, N.J.; Clarkson, P.M.; Calder, A.L.; Ramage, M.C.; Neutze, J.M. Efficacy and dosage of enalapril in congenital and acquired heart disease. Arch. Dis. Child. 1994, 70, 35–39. [Google Scholar] [CrossRef]
- Kouatli, A.A.; Garcia, J.A.; Zellers, T.M.; Weinstein, E.M.; Mahony, L. Enalapril does not enhance exercise capacity in patients after Fontan procedure. Circulation 1997, 96, 1507–1512. [Google Scholar] [CrossRef] [PubMed]
- Hsu, D.T.; Zak, V.; Mahony, L.; Sleeper, L.A.; Atz, A.M.; Levine, J.C.; Barker, P.C.; Ravishankar, C.; McCrindle, B.W.; Williams, R.V.; et al. Pediatric Heart Network Investigators. Enalapril in infants with single ventricle: Results of a multicenter randomized trial. Circulation 2010, 122, 333–340. [Google Scholar] [CrossRef] [PubMed]
- Lloyd, T.R.; Mahoney, L.T.; Knoedel, D.; Marvin, W.J., Jr.; Robillard, J.E.; Lauer, R.M. Orally administered enalapril for infants with congestive heart failure: A dose-finding study. J. Pediatr. 1989, 114, 650–654. [Google Scholar] [CrossRef] [PubMed]
- Park, M.K.; Salamat, M. Left-to-right shunt lesions. In Park’s Pediatric Cardiology for Practitioners, 7th ed.; Elsevier: Amsterdam, The Netherlands, 2020; pp. 129–131. ISBN 9780323681070. [Google Scholar]
Patient Group | N | Gender (m) | Gender (f) | Age (years) | Body Weight (kg) | Height (cm) |
---|---|---|---|---|---|---|
Total | 53 | 26 (49.10%) | 27 (50.90%) | 0.49 (0.05–4.80) | 5.45 (2.51–21.00) | 61.31 (48–101) |
1 day to 3 months | 21 (39.60%) | 11 (42.30%) | 10 (37.00%) | 0.12 (0.05–0.22) | 3.80 (2.51–5.26) | 54.76 (48.00–61.00) |
3 months to 6 months | 19 (35.80%) | 10 (38.50%) | 9 (33.30%) | 0.34 (0.26–0.50) | 4.78 (3.29–7.20) | 59.28 (51.50–68.50) |
6 months to 12 months | 9 (17%) | 3 (11.50%) | 6 (22.20%) | 0.61 (0.50–0.70) | 6.90 (5.48–8.70) | 68.92 (64.00–78.00) |
12 months to 6 years | 4 (7.50%) | 2 (7.70%) | 2 (7.40%) | 2.78 (1.03–4.80) | 13.97 (7.30–21.00) | 88.12 (67.50–101.00) |
Prior enalapril | 6 (11.30%) | 4 (15.40%) | 2 (7.40%) | 0.276 (0.07–0.40) | 4.75 (3.10–6.70) | 60.83 (52.00–67.00) |
Prior captopril | 18 (34.00%) | 8 (30.80%) | 10 (37.00%) | 0.91 (0.10–4.80) | 7.11 (3.40–21.00) | 67.66 (53.00–101.00) |
Treatment-naïve | 29 (54.70%) | 14 (53.80%) | 15 (55.60%) | 0.26 (0.04–0.70) | 4.56 (2.51–7.22) | 57.45 (48.00–71.00) |
Screening Visit | Initial Dose Visit | Titration Visit 1 | Titration Visit 2 | ||||
---|---|---|---|---|---|---|---|
Diagnosis | Age (days) | Weight (kg) | Pretreatment Dose (mg/kg) | NT-ProBNP (pmol/L) | ODMT Dose (mg) | ODMT Dose (mg) | ODMT Dose (mg) |
VSD | 85 | 4.01 | Enalapril 0.15 | 2322 | 1 × 0.25 | 2 × 0.25 | – |
VSD + ASD | 213 | 5.48 | Naïve | 1090 | 2 × 0.25 | 2 × 0.5 | – |
VSD + ASD | 55 | 4.05 | Naïve | 811 | 1 × 0.25 | 2 × 0.25 | – |
VSD + ASD; Down sy | 132 | 4.07 | Captopril 0.25 | 756 | 2 × 0.25 | 2 × 0.5 | – |
VSD + ASD | 117 | 4.02 | Captopril 0.22 | 611 | 2 × 0.25 | 2 × 0.5 | – |
AVSD; Down sy | 251 | 7 | Naïve | 1111 | 2 × 0.25 | 2 × 0.5 | 2 × 1 |
VSD + ASD | 109 | 4.21 | Naïve | 2376 | 1 × 0.25 | 2 × 0.25 | – |
Screening Visit | End-of-Study Visit | p-Value | |||||
---|---|---|---|---|---|---|---|
Mean ± SD | Median | IQR | Mean ± SD | Median | IQR | ||
Ross score | |||||||
All patients | 4.33 ± 2.94 | 5 | 2–7 | 2.02 ± 2.03 | 2 | 0–3 | <0.001 |
Pretreated | 3.08 ± 3.02 | 2.5 | 0–5.7 | 1.37 ± 1.73 | 0.50 | 0–3 | <0.005 |
Naïve | 5.45 ± 2.42 | 6 | 3.5–7 | 2.62 ± 2.11 | 2 | 1–4 | <0.001 |
Weight-for-age z-score | −1.79 ± 1.81 | −1.86 | −2.80–(−0.76) | −1.75 ± 1.65 | −2.00 | −2.85–(−0.69) | 0.841 |
Height-for-age z-score | −0.92 ± 1.87 | −0.91 | −1.66–(−0.34) | −0.24 ± 1.91 | −0.48 | −1.72–1.04 | 0.008 |
LVD z-score | |||||||
All patients | 1.95 ± 1.68 | 2.05 | 1.14–3.20 | 1.27 ± 1.36 | 1.30 | 0.52–2.01 | <0.001 |
Pretreated | 2.2 ± 1.65 | 2.44 | 1.11–3.40 | 1.46 ± 1.33 | 1.47 | 0.78–2.42 | 0.004 |
Naïve | 1.75 ± 1.70 | 1.79 | 1.11–2.81 | 1.11 ± 1.39 | 1.23 | 0.29–2.01 | 0.001 |
Pretreated non-operated | 1.91 ± 1.73 | 1.86 | 0.28–3.05 | 1.50 ± 1.49 | 1.49 | 0.20–2.19 | 0.071 |
Naïve non-operated | 1.72 ± 1.77 | 1.78 | 1.30–2.85 | 1.12 ± 1.50 | 1.50 | 0.58–2.13 | 0.008 |
LVS z-score | 1.09 ± 1.55 | 1.40 | 0.16–2.23 | 0.74 ± 1.27 | 1.04 | −0.55–1.5 | 0.038 |
Shortening fraction% | 41.45 ± 5.28 | 41 | 37–45 | 39.81 ± 4.71 | 40 | 36–44 | 0.062 |
Parameter (Mean ± SD) | Screening Visit | Dose-Confirmation Visit | Study Control Visit 1 | Study Control Visit 2 | Study Control Visit 3 | End-of-Study Visit | p-Value |
---|---|---|---|---|---|---|---|
SBP z-score | 1.19 ± 1.25 | 0.81 ± 1.11 | 0.52 ± 1.07 | 0.72 ± 1.07 | 0.67 ± 1.21 | 0.84 ± 1.22 | 0.066 |
DBP z-score | 1.18 ± 1.24 | 1.23 ± 1.11 | 0.91 ± 0.92 | 1.08 ± 0.96 | 1.06 ± 0.95 | 0.93 ± 0.82 | 0.242 |
Heart rate | 140.59 ± 19.47 | 137.71 ± 17.65 | 139.27 ± 19.22 | 138.73 ± 20.26 | 135.29 ± 16.72 | 135.19 ± 18.31 | 0.146 |
Screening Visit | End-of-Study Visit | ||||||
---|---|---|---|---|---|---|---|
Mean | Median | Min–Max | Mean | Median | Min–Max | p-Value | |
All patients | 2549.8 ± 3099.3 | 1111 | 8–11,056 | 906.2 ± 1058.9 | 484 | 41–5348 | <0.005 |
ACEI-naïve non-operated | 3043.2 ± 2057.5 | 2057.5 | 8–10,511 | 931.9 ± 887.5 | 596 | 41–2630 | 0.001 |
ACEI-pretreated non-operated | 2030.5 ± 2901.1 | 711 | 45–11,056 | 879.15 ± 1238.7 | 383 | 68–5348 | 0.002 |
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Bijelic, M.; Djukic, M.; Vukomanovic, V.; Parezanovic, V.; Lazic, M.; Pavlovic, A.; Popovic, S.; Parezanovic, M.; Stefanovic, I.; Djordjevic, S.; et al. Clinical and Hemodynamic Outcomes with Enalapril Orodispersible Minitablets in Young Children with Heart Failure Due to Congenital Heart Disease. J. Clin. Med. 2024, 13, 4976. https://doi.org/10.3390/jcm13174976
Bijelic M, Djukic M, Vukomanovic V, Parezanovic V, Lazic M, Pavlovic A, Popovic S, Parezanovic M, Stefanovic I, Djordjevic S, et al. Clinical and Hemodynamic Outcomes with Enalapril Orodispersible Minitablets in Young Children with Heart Failure Due to Congenital Heart Disease. Journal of Clinical Medicine. 2024; 13(17):4976. https://doi.org/10.3390/jcm13174976
Chicago/Turabian StyleBijelic, Maja, Milan Djukic, Vladislav Vukomanovic, Vojislav Parezanovic, Milica Lazic, Andrija Pavlovic, Sasa Popovic, Miro Parezanovic, Igor Stefanovic, Stefan Djordjevic, and et al. 2024. "Clinical and Hemodynamic Outcomes with Enalapril Orodispersible Minitablets in Young Children with Heart Failure Due to Congenital Heart Disease" Journal of Clinical Medicine 13, no. 17: 4976. https://doi.org/10.3390/jcm13174976