Therapeutic Efficacy Of Captopril In Children With Heart Failure, Using The 6 Minute Walk Test As Clinical Reference

Heart Failure (HF) in children can be defined broadly as the failure of the heart to supply blood to either systemic or pulmonary circulation at an appropriate rate of flow, or to receive venous return at an appropriate filling pressure, resulting in adverse effects on the heart, the circulation, and the patient. (1) Captopril is an ACE inhibitor drug which has been standardized in the HF treatment in adults; however, recommendations on its use on paediatric patients are largely based on the few available paediatric clinical studies and on extrapolations from studies carried out with adult subjects. Plasma concentrations from 50 to 500 ng/mL are generally considered therapeutic. Many instruments have been implemented in order to evaluate the clinical repercussion of HF, among which the 6 Minute Walk Test (6MWT). This is a submaximal test which assesses the integrated functional capacity of pulmonary, cardiovascular, and muscular systems, making it ideal to monitor the clinical evolution of these patients. This study focuses solely on the distance each patient was able to walk on the follow-up visits. The aim of the study is to correlate plasma levels of captopril with clinical recovery, recorded objectively by means of the 6MWT.

Patients selected for the study met the following characteristics: Hispanic, age 2 to 17 years, diagnosed as with HF, with indicated therapy with captopril, who had never consumed the drug, with no concomitant pulmonary, hepatic, or renal disease. Patients received 1 mg/kg/day captopril doses in 8 h intervals. They were assessed on days 1, 11, and 22 of treatment, when they performed 6MWT as described by the ATS (2), supervised by a competent practitioner. The expected distance to walk was calculated for each patient with the formula described by Priesnitz et al (3) for Latin American children, and considered as 100%; net results were considered as percentages of the expected distance for comparisons among patients. On days 11 and 22, 3 mL blood samples were drawn for plasma captopril determination before the first morning dose of captopril, and 40 minutes thereafter. Captopril concentrations were determined by liquid chromatography coupled to a mass detector (LC-MS/MS). Data were analysed with Spearman’s correlation using JMP 12 software from SAS Institute, Inc. Data are expressed as median (minimum-maximum).

Twenty-three patients participated in the study, with ages ranging from 2 to 16 years. All patients were able to attend all of their follow-up visits, and none presented captopril-related adverse effects. The distance walked by the patients was 67% (30%-107%) on day 1, 77% (38%-114%) on day 11, and 86% (45%-172) on day 22. Plasma captopril concentrations were 1,5 ng/mL (0-173,2 ng/mL) before and 75,9 ng/mL (2,6-506,9 ng/mL) after drug administration on day 11, and 2,55 ng/mL(0-64ng/mL) before and 29,75 ng/mL (3,7-509,7 ng/mL) after drug administration on day 22. There was a statistically significant difference between the metres walked by children on days 1 and 11, and on days 11 and 22 (p<0,01), implying clinical recovery. There was a trend to faster recovery with higher captopril plasma concentrations, albeit not statistically significant, although by day 22 of monitoring all children had reached a similar recovery state. Plasma captopril concentrations between 2,6 and 506,9 ng/mL showed clinical efficacy, reflected in greater functional capacity. These data indicate that concentrations lower than 50 ng/mL could be considered therapeutic in paediatric populations, although further studies with a larger sample size are desirable.

(1) Kantor PF et al. (2013). Canadian Journal of Cardiology. 29: 1535-1552.

(2) ATS Statement. (2002). Am J Crit Care Med. 166: 111-7.

(3) Priesnitz CV et al. (2009). Pediatr Pulmonol. 44:1174-9.