Most medications are not labeled for use in the pediatric population because they have not been formally studied in children. Data on off-label use of cardiovascular (CV) drugs in the home therapy of children with CV disease are scanty. The study included 325 pediatric patients with CV disease and on ≥1 CV medication who underwent ≥1 visit during 2019 at the Pediatric Cardiology outpatient clinic of Giovanni XXIII Pediatric Hospital in Bari, Italy. A total of 287 patients (88.3%) received ≥1 off-label medication, whereas 113 patients (34.7%) received ≥2 off-label medications, and 22 patients (6.7%) ≥3 off-label medications. In CV medications (n = 27) 85% were used off-label in all cases, and 92.5% were used off-label in ≥50% of patients. Adverse events occurred in 8 patients, leading to drug discontinuation in 2 of them. In all 8 cases, medications were used off-label. In multivariate analysis, congenital heart disease patients with single-ventricle physiology (odds ratio 8.4, 95% confidence interval 2.25 to 54.4) and those with heart failure (odds ratio 2.0, 95% confidence interval 1.1 to 3.6) were at higher risk for receiving ≥2 off-label drugs. The off-label use of CV drugs in the home therapy of children with congenital or acquired heart disease is common and adverse events may occur. Patients with congenital heart disease with single-ventricle physiology and those with heart failure have a higher probability to receive ≥2 off-label medications. This study highlights the need for larger safety and efficacy trials in this specific cohort of pediatric patients.
Prescribing drugs for pediatric patients has always been a clinical and ethical problem mainly because of the limited number of clinical trials available in patients under the age of 18. The lack of controlled clinical trials in the pediatric population is mainly because of ethics, parent distrust, low economic interest by drug companies, and low funds for specific age-related studies. , It means that most medications are prescribed and dispensed off-label to pediatric patients. Off-label use refers to unapproved use of a licensed medication, such as a different indication, age group, dosage, or route of administration. Inadequate information on drug efficacy and safety can also involve serious risk for adverse events. It is particularly true for patients receiving multiple drugs with insufficient knowledge of their pharmacokinetic and pharmacodynamic data. Hence, physicians could be involved in legal claims when prescribing medication for off-label use. The present study aims to describe the off-label use of cardiovascular (CV) medications in the home therapy of pediatric patients with congenital or acquired heart disease during 1 year of observation in a Pediatric Cardiology outpatient clinic.
Methods
The local Institutional Ethics Committee approved this study. We performed a retrospective cohort study identifying all patients younger than 18 years who underwent ≥1 visit at the Pediatric Cardiology outpatient clinic from January 2019 to December 2019. All patients who had a CV disease and ≥1 home therapy CV medication were included.
The following demographic and clinical data were retrospectively abstracted from the patient’s medical records: age, gender, CV diagnosis, main comorbidities, age at therapy start, cause and date of therapy suspension, adverse events. The age of the patient was defined as age on the date of the first visit of the year. It was identified as a primary CV diagnosis as the diagnosis for which the therapy had started. The primary CV diagnosis was classified into 6 different groups: arrhythmia, heart failure, arterial systemic hypertension, pulmonary hypertension, pulmonary infundibular stenosis, others. The diagnosis of congenital heart disease (CHD) was noted and classified in: left-to-right shunt lesion, cyanotic CHD, left heart obstructive CHD, single-ventricle physiology, others. Transcatheter and/or surgical interventions were noted for patients with CHD. The cause of therapy suspension was classified as disease resolution, inefficacy, or adverse event. Written informed consent was obtained for each off-label drug prescription.
All prescribed medications were recorded and classified into the following categories: antiarrhythmics, β-adrenergic blocking agents, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, diuretics, mineralocorticoid receptor antagonist, anticoagulants, antiplatelets, pulmonary hypertension medications, gastrointestinal medications, and others. Off-label use was defined as the use of a specific drug in a patient younger than the European Medicines Agency approved age range for any indication at the time of drug administration. In off-label prescriptions, we noted all drugs with a special authorization by Act number (Act No.) 648/1996 of the Italian Law. It regulates the use of nonauthorized medical agents, allowing their prescription in case of positive safety and efficacy evaluations in phase II or a phase III clinical trial.
Categorical data are presented as counts (percentages). Fischer’s exact test and chi-square test were used for proportions. The normality of distributions was tested using the Shapiro-Wilk test. Because continuous variables were not normally distributed, they are presented as medians and interquartile ranges. Continuous variables were compared using Wilcoxon rank sum testing. Categorical variables were compared using chi-square or Fisher’s exact testing as appropriate. Patients were stratified by the number of off-label drugs received (greater than the median vs less than or equal to the median). The median number of off-label drugs received was 2. We used logistic regression to look for predictors of therapy with >2 off-label medications. Significant factors from bivariate analyses were included in a multivariable model, and the model was reduced using backward elimination. From this model, we provide unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Statistical significance was assumed when a 2-sided p <0.05 was considered. All the analyses were performed using R statistical software, version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).
Results
The study included 325 patients. Demographic information is listed in Table 1 . Figure 1 displays the number of medications that patients received off-label. A total of 287 patients (88.3%) received ≥1 off-label medication, whereas 113 patients (34.7%) received ≥2 off-label medications, and 22 (6.7%) ≥3 off-label medications. Medications prescribed in our study population are listed in Table 2 . In CV medications (n = 27), 85% were used off-label in all cases, and 92.5% were used off-label in ≥50% of patients. A total of 12 off-label CV medications (44.4%) were prescribed out of Act No. 648/1996 of the Italian Law authorization in all cases.
| Male | 179 (55.1 %) |
| Female | 146 (44.9 %) |
| Age (years, [IQR]) | 4.0 (0.8 – 11.0) |
| Age groups | |
| ≤ 28 days | 29 (8.9 %) |
| 29 days – 1 year | 81 (24.9 %) |
| 2 – 5 years | 69 (21.3 %) |
| 6 – 12 years | 81 (24.9 %) |
| 13 – 18 years | 65 (20.0 %) |
| Congenital heart Disease | 216 (67.1 %) |
| Native | 85/216 (39.4 %) |
| Post procedural | 131/216 (60.6 %) |
| Catheter based | 37/131 (29.0 %) |
| Surgery | 93/131 (70.9 %) |
| Cardiomyopathy | 28 (8.7 %) |
| Dilated | 17/28 (65.4 %) |
| Hypertrophic | 9/28 (34.6 %) |
| Drugs | N. patients receiving the drug | N. patients receiving drug off-label ⁎ | 648/96 Law authorization † | |
|---|---|---|---|---|
| Anti-arrhythmic agents | 73 (21.8%) | 73 (100%) | 63 (86.3%) | |
| Flecainide | 53 (16.5%) | 53 (100%) | 53 (100%) | |
| Amiodarone | 9 (2.8%) | 9 (100%) | 9 (100%) | |
| Sotalol | 7 (2.2%) | 7 (100%) | 0 | |
| Verapamil | 2 (0.6%) | 1 (50%) | 0 | |
| Mexiletine | 1 (0.3%) | 1 (100%) | 0 | |
| Propafenone | 1 (0.3%) | 1 (100%) | 1 (100%) | |
| ACE-I/ARBs | 109 (33.5%) | 108 (99.1%) | 94 (87%) | |
| Captopril | 59 (18.1%) | 58 (98.3%) | 58 (100%) | |
| Enalapril | 32 (9.9%) | 32 (100%) | 32 (100%) | |
| Ramipril | 14 (4.3%) | 14 (100%) | 0 | |
| Losartan | 4 (1.2%) | 4 (100%) | 4 (100%) | |
| Beta-blockers | 96 (29.2%) | 96 (100%) | 78 (81.2%) | |
| Carvedilol | 38 (11.7%) | 38 (100%) | 35 (92%) | |
| Propranolol | 23 (7%) | 23 (100%) | 23 (100%) | |
| Nadolol | 16 (4.9%) | 16 (100%) | 16 (100%) | |
| Bisoprolol | 13 (4%) | 13 (100%) | 0 | |
| Metoprolol | 4 (1.2%) | 4 (100%) | 4 (100%) | |
| Atenolol | 1 (0.3%) | 1 (0.3%) | 0 | |
| Nebivolol | 1 (0.3%) | 1 (0.3%) | 0 | |
| Other anti-hypertensive agents | 4 (1.2%) | 4 (100%) | 2 (50%) | |
| Amlodipine | 2 (0.6%) | 2 (100%) | 2 (100%) | |
| Clonidine | 2 (0.6%) | 2 (100%) | 0 | |
| Diuretics | 104 (32.5%) | 0 | ||
| Furosemide | 97 (30.3%) | 0 | ||
| Spironolactone | 7 (2.2%) | 0 | ||
| Canrenoate | 5 (1.5%) | 5 (100%) | 0 | |
| Pulmonary vasodilators | 13 (4%) | 13 (100%) | 12 (92.3%) | |
| Sildenafil | 7 (2.2%) | 7 (100%) | 7 (100%) | |
| Bosentan | 5 (1.5%) | 5 (100%) | 5 (100%) | |
| Macitentan | 1 (0.3%) | 1 (100%) | 0 | |
| Antiplatelets | 62 (19.1%) | 7(11.2%) | 0 | |
| Aspirin | 62 (19.1%) | 7 (11.2%) | 0 | |
| Anticoagulant | 3 (0.9%) | 0 | ||
| Warfarin | 3 (0.9%) | 0 | ||
| Non CV medications | 20 (6.1%) | 4 (80%) | 0 | |
| PPIs | 10 (3%) | 3 (30%) | 0 | |
| Steroids | 4 (1.2%) | 0 | ||
| NSAIDs | 4 (1.2%) | 0 | ||
| Colchicine | 2 (0.6%) | 1 (50%) | 0 | |
| Anakinra | 1 (0.3%) | 0 | ||
| Valproate | 1 (0.3%) | 0 | ||
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