Prevalence of drug-drug interactions in children with cardiac disorders receiving off-label drugs in a single centre in Pakistan: a cross-sectional study

Abstract

Objectives

This study evaluated the prevalence of clinically significant drug-drug interactions (CSDDIs), off-label (OL) drug use and the associated predictors in paediatric cardiology ward.

Design

A cross-sectional study.

Setting

Hayatabad Medical Complex, Tertiary care hospital in Peshawar, Pakistan.

Patients

250 patients.

Methodology

The Micromedex Drug-Reax tool was used to check the drug-drug interactions (DDI) and interactions of major severity were categorised as CSDDI. Association of various predictors including OL drug use with CSDDIs was evaluated using univariate and multivariate binary logistic regression.

Main outcome measures

Rate of drug-drug interactions, types and classification of DDI, OL prescribing in paediatrics.

Result

Of the total 250 paediatric patients, 127 (28.6%) patients were exposed to at least one clinically significant DDI, while 228 (91.20%) patients received at least one OL prescription. Furosemide was the most frequently prescribed drug involved in CSDDIs, while it was also one of the highly prescribed OL drugs. Multivariate analysis revealed that infant age group (OR 0.256; CI 0.080 to 0.814) with p value 0.02 and patients prescribed >5 drugs (OR 3.544; CI 1.906 to 6.589) were significantly more likely to experience CSDDIs in reference to their corresponding categories.

Conclusion

A high prevalence of CSDDIs and OL prescriptions was observed. OL drug presence was also observed to be a significant predictor associated with an increased risk of CSDDIs. Thus, to improve paediatric pharmacotherapy, suitable medical interventions are required to decrease OL drug use and CSDDIs.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Evidence-based medical interventions have improved outcomes of cardiovascular diseases; however, paediatric therapy is still based on clinical experience and extrapolation of adult data.

• Lack of evidence-based therapy increases the exposure of children to off-label (OL) drugs and clinically significant drug-drug interactions (CSDDIs) ultimately leading to adverse drug reactions.

WHAT THIS STUDY ADDS

• This study, to our knowledge, is the first to be conducted in Pakistan to provide the quantitative data on the prevalence of OL drug use and clinically significant drug-drug interactions in the paediatric population with cardiac disorders.

• OL drugs were significantly associated with CSDDIs, which is a new finding and has not been associated previously.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• This study serves as a foundation for future researchers to explore the impact of OL drugs on the health outcomes of paediatric population in other specialties and hence improve patient safety.

• Current research adds OL drug use as a new output for the CSDDIs. This finding will contribute to the literature and hence encourage policymakers to advocate strict regulations and oversight on the use of OL drugs in paediatrics.

• This study identified common drugs prescribed in paediatric cardiology that are significantly involved in CSDDI and hence inform healthcare providers to be more cautious and emphasise the need for a thorough medications review of the paediatric population with complex disease conditions like cardiovascular disorder.

Introduction

Improvements in the treatment outcomes of cardiovascular diseases can be ascribed mainly to the expanded use of evidence-based medical interventions. However, the research leading to this approach misrepresented certain populations including women, elderly and children.^{1 2} Paediatric population commonly encounters acute diseases, and a relatively smaller population has a chronic condition, causing fewer patients to be enrolled in clinical trials to establish the safety and efficacy of drugs.³ Other factors that hinder pharmaceutical companies from investing in paediatric trials are the high financial expenses and low returns from new paediatric drugs, strict guidelines and ethical concerns to include children in clinical trials.^{4 5} Despite legislations being implemented by Food and Drug Administration Modernization Act and European Union, the paediatric population is still being underrepresented in clinical trials.⁶

Paediatric therapy is mostly based on clinical experience and extrapolation of adult data, rather than clinical trials. Thus, the majority of the drugs prescribed to paediatrics are not well studied and not labelled for use in children,7,9 but this does not imply that a drug is contraindicated for use; rather, it means that inadequate data are available to give approved status to a drug and the risks or benefits of using a drug in a particular condition have not been determined yet.^{6 10} In reference to all the factors, paediatricians face a tough choice to either prescribe a medication despite lack of evidence in the paediatric population or deprive the child of a medication that can potentially be a better therapeutic option.⁷

The off-label (OL) drug use entails inherent risk, particularly when accompanied by polypharmacy.^{8 11 12} As a result, the paediatric population is exposed to a high number of clinically significant drug-drug interactions (CSDDIs).^{13 14} These often lead to serious adverse outcomes like ketorolac when administered with ibuprofen causes gastrointestinal bleeding or perforation, metoclopramide with promethazine can cause extrapyramidal effects, fentanyl with morphine can cause additive respiratory depression and lidocaine with propofol can cause additive hypnotic effect of propofol.^{13 15 16}

Previous studies conducted in paediatric settings in Pakistan have primarily focused on drug-drug interaction (DDI) regarding various diseases.^{17 18} However, research specifically addressing DDI among paediatric patients admitted to the cardiology ward is scarce. These studies identified the number of prescribed drugs and age groups as a common predictor for CSDDI.^{16 19 20}-To date, OL drug use has never been considered as a predictor for the occurrence of CSDDIs. The objectives of the study were to report the prevalence of CSDDIs and its predictors at a paediatric cardiology ward in a tertiary care hospital of Peshawar, Pakistan.

Methods

Study design and clinical setting

A prospective cross-sectional study was conducted at the paediatric cardiology ward in Hayatabad Medical Complex (HMC), a government tertiary care setup in Peshawar, Pakistan. The data were collected from 250 paediatric patients admitted to the cardiology ward between 01 January 2023 and 30 June 2023.

The HMC encompasses the largest cardiology centre in the Khaybar Pakhtunkhwa province, with a total capacity of 1280 beds, of which 124 are allocated to the cardiology department. Paediatric patients from the rural, urban and suburban areas of the northwestern region of Pakistan and Afghanistan visit HMC for treatment.

Ethical consent

The study was approved by the ethical committees of the hospital through letter number 8075–79/HMC. Ethical principles under the declaration of Helsinki were followed.²¹ Protected Health Information of patients were coded and stored in a secured location.

Sample size

Sample size was calculated using the Danial formula for known populations,²² which resulted in a sample of 250 patients. The following is the sample size formula: n= NZ² P(1-P)/ d²(N-1)+Z² P(1-P)

Where n=required sample size

N=population size (710)

Z=Confidence interval (for 95% confidence level, Z=1.96)

P=expected prevalence (0.5)

d=margin of error (0.05)

Patient selection

Patients with a stay of 24 hours in the paediatric cardiology ward were included in the study. Patients’ drug profiles lacking relevant information required for the study were excluded. The patients who undergo any surgical procedure were also excluded from the study. Standard electrolyte solutions, oxygen therapy and topical medicines were also excluded. Simple random sampling was employed to collect patient data from the cohort. A predesigned proforma was used to collect patient demographics and clinical profiles which included details about diagnosis, stay, prescribed drugs, dose, frequency and duration of regimen. All the data were collected manually from clinical drug profiles of patients. Patient data were evaluated using Thomson healthcare Micromedex DrugDex and DrugReax (Watson health, IBM Corporation).

Information bias was addressed by excluding the patients with incomplete medical records. Observational bias was addressed by the extraction of data by two independent raters and their agreement strengthened the reliability of data. Drug-drug interactions were identified and classified by the MICROMEDEX drug interaction database, a validated tool and widely used in clinical decision support. The use of this standardised database enhances the reliability of DDI assessment.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plan of this research as this study was an anonymised prospective cross-sectional study and the data were collected from patients medical and clinical records.

Definition of variables

Paediatrics age was categorised according to WHO classification as infants (age 0–2 years), children (2–12 years) and adolescents (12 to 18 years).²³ OL drug use was defined as the use of a drug outside information labelled on the product licence. Categories for OL drug use were (1) the drug not approved for specific age of paediatric, (2) use of a drug for a specific indication not approved, (3) dose administered not mentioned in labelled information and (4) dosage form used other than approved ones.^{8 24} DDIs were screened using Micromedex Drug Reax which classifies DDIs based on severity, documentation and onset DDIs with a major severity were considered to be CSDDIs and included in the regression analyses.²⁵ Severe drug-drug interactions were defined as those which have the potential to cause life-threatening outcomes to patients’ health and require intervention to prevent or minimise the adverse effects.^{26 27}

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows, V.20 (Armonk, NY: IBM Corp.). Descriptive analysis of patient characteristics and clinical outcomes was performed. Univariate binary logistic regression was employed to calculate OR with 95% CI for predictors of CSDDIs, including age, number of prescribed drugs, hospital stay and OL drugs. Predictors with a significant association were further included in a multivariate binary logistic regression model.

Results

Patient demographics

The profiles of 250 patients were screened, of which male patients 139 (55.60%) and the infant age group 144 (57.60%) were prevalent. Median number of prescribed drugs and hospital stay was 5, while 61.5% patients were prescribed ≥5 drugs, and 129 (51.6 %) had a hospital stay of ≥5 days. Out of a total of 228 patients who received at least one OL drug, 82 (38.5%) patients were exposed to CSDDIs as shown in table 1. Adolescent age group (p<0.00), prescribed drugs ≥5 (p<0.00) and OL drug use (p<0.03) were significantly associated with the occurrence of clinically significant DDI.

Table 1. General characteristics of patients in paediatric cardiology ward.

Variables		Clinically significant		Total	P value
		Clinically significant	Clinically insignificant
Gender	Male	96	43	139	0.252
	Female	69	42	111
	Total	165	85	250
Age groups	Infants	106	38	144	0.000***
	Children	55	33	88
	Adolescent	4	14	18
	Total	165	85	250
Prescribed drugs	≤ 5 drugs	120	33	153	0.000***
	< 5 drugs	45	52	97
	Total	165	85	250
Hospital stays	≤ 5 days	90	39	129	0.194*
	< 5 days	75	46	121
	Total	165	85	250
Patients receiving at least one off-label drug	Yes	146	82	228	0.035**
	No	19	3	22
	Total	165	85	250

*Significant at p<0.1 **significant at p<0.05 ***significant at p<0.01.

^*All categories’ values were calculated for 250 patients.

International statistical classification of disease and related health problems system was used to categorise diagnosis. Cardiomyopathy 39 (15.60%) was the most frequent diagnosis, followed by ventricular septal defect 35 (14.00%), tetralogy of Fallot 20 (8.00%), patent ductus arteriosus 15 (6.00%), secundum atrial septal defect 12 (4.80%), dilated dysfunction left ventricle 9 (3.60%), pulmonary hypertension of newborn 9 (3.60%), pulmonary valve stenosis 8 (3.20%), atrioventricular septal defect 7 (2.80%) and rheumatic heart disease 7 (2.80%). Other diagnoses included pneumonia 23 (9.20%) and lower respiratory tract infections 7 (2.8%).

Prescribed drugs and dosing

Drugs were categorised according to Anatomical Therapeutic Chemical (ATC) Classification system. Anti-bacterials (27.21%), diuretics (25.35%), ACE inhibitors (7.64%), anti-anaemic (7.07%) and anti-coagulants (6.94%) were frequently prescribed drug classes in the paediatric cardiology unit.

A total of 64 different drugs were prescribed 1232 times. Commonly prescribed drugs included furosemide (13.97%), spironolactone (11.29%), co-amoxiclav (10.32%), captopril (9.34%), cefazolin (5.69%), aspirin (4.87%), paracetamol (4.31%), iron (3.82%), folic acid (2.92%) and ceftriaxone (2.68%).

Of the total patients, 17.12% were prescribed drugs in sub-therapeutic doses and 0.97% in overdoses. Intravenous drugs prescribed frequently in sub-therapeutic doses included furosemide (163 times) and co-amoxiclav (116 times), while oral drugs included captopril (134 times) and spironolactone (124 times). Frequently prescribed intravenous drug in overdoses included furosemide (11 times) and cefazolin (10 times), while oral drugs included captopril (13 times) and spironolactone (eight times),

clinically significant drug-drug interactions (CSDDIs)

A total of 71 drug pairs were prescribed which resulted in a total of 444 potential DDIs. Of these, 127 (28.60%) were CSDDIs. Out of 10 frequently observed DDIs, nine were clinically significant DDI. The clinically significant DDI pairs included pharmacodynamics interactions: captopril+furosemide 90 (20.27%), spironolactone+captopril 64 (14.41%), aspirin+furosemide 50 (11.26%), aspirin+spironolactone 25 (5.63%) and aspirin+ibuprofen 5 (1.12%). Pharmacodynamic interactions include artemether+metronidazole 38 (8.55%), digoxin+spironolactone 34 (7.65%), diazepam+phenytoin 33 (7.43%) and aspirin+prednisolone 6 (1.35%). Of all the CSDDIs, infant (41.26%) and children (39.68%) age groups were frequently exposed to these DDIs as compared with adolescents.

Off-label (drug use

At least one OL drug was prescribed to 228 (91.2%) patients corresponding to a total of 44.59% OL drugs in total prescribed drugs. Dose (43.35%) and indication (22.22%) were the most common categories for OL- drug use. Other observed reasons for OL use were indication dose (12.02%), age (7.83%), administration form (5.28%), different dose administration form (3.64%), age administration form dose (2.73%), age dose (2.55%) and age administration form (0.36%). Most frequently prescribed OL drugs and their OL categories which also contributed to CSDDI in paediatric cardiology ward are listed in table 2.

Table 2. Frequencies of OL categories of prevalently prescribed OL drugs and their contribution to clinically significant DDIs.

Drugs	Age	Indication	Dose	Administration form	Age, dose	Indication, dose	Administration form, dose	Total	Frequency in contribution to CSDDIs
Furosemide	–	80	195	–	11	43	–	329	(81)
Spironolactone	18	69	156	–	3	31	–	277	(79)
Co-amoxiclav	–	52	133	26	–	33	18	262	(45)
Captopril	–	51	162	–	–	28	–	241	(73)
Cefazolin	–	26	102	–	–	8	–	136	(49)
Aspirin	–	31	74	–	–	8	–	113	(48)
Paracetamol	29	–	60	7	12	–	8	116	(10)
Iron	–	–	57	–	–	–	–	57	(16)
Folic acid	–	19	49	–	–	38	–	106	(12)
Propranolol	4	15	17	–	1	22	–	59	(03)

CSDDIs, clinically significant drug-drug interactions; DDI, drug-drug interaction; OL, off label.

Inappropriate dose was also prevalent reason for OL drug use in all the age groups as shown in figure 1.

Figure 1. Distribution of off-label categories according to paediatric age groups.

The drugs which were frequently prescribed and also attributed to CSDDIs are shown in figure 2.

Figure 2. Frequency of 10 common drugs which were attributed to both CSDDIs and off-label prescriptions. CSDDIs, clinically significant drug-drug interaction.

Regression analysis

Regression analysis reported that the infant age group (OR 0.256; 95% CI 0.080 to 0.814) with p value 0.02 was more likely to experience a CSDDI as compared with other categories. Similarly, patients prescribed >5 drugs were also (OR 0.146; 95% CI 0.084 to 0.254) with p value 0.00 more likely to experience a clinically significant DDI. However, patients who did not receive OL drugs were significantly less likely (OR 0.234; 95% CI 0.083 to 0.656) to experience a clinically significant DDI as presented in table 3. The visualisation of odds ratios is illustrated in figure 3.

Table 3. Predictors for drug interactions in paediatric cardiology ward.

Variables	Unadjusted odds ratio		Adjusted odds ratio
	P value	OR (CI)	P value	OR (CI)
Gender
Male	0.25	1.359 (0.803–2.299)	0.42	0.787 (0.439–1.411)
Female	Reference		Reference
Age groups
Infants	0.02**	0.256 (0.080–0.814)	0.04**	0.223 (0.053–0.931)
Children	0.1	0.376 (0.115–1.234)	0.14	0.338 (0.078–1.462)
Adolescent	Reference		Reference
Prescribed drugs
< 5 drugs	0.00***	0.146 (0.084–0.254)	0.00***	0.165 (0.090–0.302)
≥ 5 drugs	Reference		Reference
Hospital stay
< 4 days	0.02**	0.553 (0.330–0.926)	0.89	1.042 (0.565–1.923)
≥ 4 days	Reference		Reference
Off label
Absent	0.00**	0.234 (0.083–0.656)	0.08*	0.356 (0.112–1.135)
Present	Reference		Reference

*Significant at p <0.05 **significant at p < 0.01 ***significant at p < 0.001.

Figure 3. Graph to visualise the predictor effects on DDI in paediatric patients. DDI, drug-drug interaction.

Discussion

Multiple factors are involved in the paediatric population being under-represented in clinical trials.⁶ Thus, therapy is based on clinical experience of the physician and extrapolation of adult data, leading to the use of drugs not labelled for use in paediatrics.⁷ Additionally, they are also exposed to a high number of CSDDIs. Studies have reported multiple risk factors for DDIs,^{24 28} but to the best of our knowledge, OL drug use has not been used as a risk factor for CSDDIs. Drugs that contributed to CSDDIs as well as those prescribed in an OL manner could lead to an increased risk of adverse events (AEs), deteriorate the condition of the patient and increase the length of hospital stay.^{29 30}

The current study reported the prevalence of OL drugs and CSDDIs to be 44.5% and 25.6%, respectively. A total of 91.2% patients were prescribed at least one OL drug. The results are congruent with a Serbian study which was conducted in a cardiology setting and reported 47% of all the drugs prescribed were OL.³¹ Another study performed in France reported OL drug prescription to be 37.6%.³² A German study where 417 paediatric patients were assessed for OL prescriptions reported 31% OL prescriptions, and among them, 60% of anti-hypertensive drugs prescribed as OL in children.³³ The variation among different countries in prevalence of OL prescriptions is possibly due to the different design and method of studies.

According to a study conducted in Saudi Arabia, the prevalence of major DDIs in paediatric patients was observed to be 52.8%.³⁴ Another study conducted at the paediatric intensive care unit of a tertiary care centre of Pakistan in 2017 reported 59% DDIs. Out of the total DDIs, 34% were CSDDIs.¹⁶ Similarly, a study in the USA reported 49% of the hospitalised children had DDIs and 41% of these were clinically significant.¹⁵ Difference in the study population and drugs may be the reason for the differences in the prevalence of CSDDIs.

Anti-bacterial was the most prevalent therapeutic category in the cardiology ward. The reason for the high prevalence of anti-bacterial drug class may be the high prevalence of respiratory infectious disease (pneumonia) present in the study population. Aspirin was the most frequently reported drug involved in CSDDIs and was also one of the frequently prescribed OL drugs. Drugs that are prescribed as OL or are involved in a clinically significant DDI pose greater risk of AEs. Various studies reported an increased risk of AEs when a patient is exposed to OL prescriptions.^{30 35 36} Similarly, the presence of clinically significant drug interactions also poses a higher risk of an AE. A research revealed significant difference between the children who had AEs with the presence of DDIs to children without the AEs in absence of DDIs.³⁷ A Croatian study also validated this significant relationship.³⁸

Dose (43.35%) and indication (22.22%) were the prevalent reasons for OL drug use while a prospective study conducted in a paediatric cardiology ward in Serbia also observed dose (26%) and age (21%) as the most common reason for OL drug use.³¹ The major problem in the treatment of paediatric cardiac disorders was lack of paediatric pharmaceutical formulations of cardiovascular drugs. In paediatrics, 75% of the prescribed drugs were prepared from adult dosage forms.³⁹

Age group, number of prescribed drugs and OL use of drugs were found to be significant for drug interactions in the univariate model, while only age group and number of prescribed drugs were significantly associated with CSDDIs in the multivariate model. A similar relationship has also been reported by other paediatric studies.^{13 40 41} OL drug use was also found to be a significant output for DDIs in the univariate model and is also known to be associated with AEs; however, it became insignificant in the multivariate model. This may be because of the inclusion of a single cardiology ward, not having sufficient patients to display a significant association. The relationship could be tested in a multicentre study in the future for better insight.

Lack of paediatric pharmaceutical formulations of cardiovascular drugs and previously mentioned notable facts emphasise that some interventions must be performed, like monitoring of plasma concentrations, laboratory tests and dose adjustments. Many problems exist which restrict clinical trials in cardiovascular drugs for paediatrics, including low prevalence of paediatric cardiovascular diseases as compared with adult cardiovascular disease, disease heterogeneity, lack of research infrastructure, ethical consideration in paediatric research and difficulty in identifying appropriate clinical end points.⁴²

Therefore, conducting research at the paediatric cardiology ward is difficult, as the majority of regimens used in this population are not well documented. The decisions regarding the therapy are most often based on extrapolation from adult studies, observational data or clinician experience. A drug used as OL and has also contributed to drug interaction should be replaced by a safer one, while suitable strategies should be introduced during the usage of these drugs.

Current research adds a new output for the CSDDIs especially for paediatric population. Furthermore, the study also identified common drugs prescribed in paediatric cardiology, significantly involved in CSDDIs.

Future strategies to reduce drug-drug interactions

The clinical pharmacist can play a vital role in preventing adverse outcomes caused by DDIs in paediatric ward.⁴³ Moreover, the use of advanced technologies such as artificial intelligence can significantly enhance the prediction and prevention of potential DDIs in paediatric therapy, particularly in the case of OL drug use.⁴⁴

Limitations

The study was conducted at a single centre and limited to paediatric cardiology ward, which may affect the generalisability of the study. Another limitation is the exclusion of standard electrolyte solutions, despite their known potential to interact with cardiovascular drugs. The reason to exclude them was to focus specifically on DDI among therapeutically prescribed drugs. The future studies should include electrolyte solutions to provide a more comprehensive assessment of clinically relevant interactions.

Conclusion

Our study highlights the high prevalence of OL prescribing and CSDDIs. OL drugs were significantly associated with CSDDIs in univariate analysis but did not remain significant in multivariate analysis. Nonetheless, this preliminary finding is novel and warrants further investigation. Appropriate guidelines must be developed and implemented by health regulatory agencies to avoid the complexities caused in pharmacotherapy of cardiac disorders in children.

Data availability statement

Data are available upon reasonable request.