Published online before print November 5, 2008, doi: 10.1161/CIRCOUTCOMES.108.787176
Original Articles |
Off-Label Use of Cardiovascular Medications in Children Hospitalized With Congenital and Acquired Heart Disease
From the Division of Cardiology (S.K.P.), Department of Pediatrics, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC; Child Health Corporation of America (M.H.), Shawnee Mission, Kan; Departments of Pediatrics and Medicine (A.D.S.), Carilion Medical Center, Roanoke, Va; Department of Cardiology (K.J.J.), Children’s Hospital, Boston, Mass; Divisions of Cardiology and Critical Care, Department of Pediatrics (B.S.M.), Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Cardiology (M.S.C.) and Infectious Diseases (S.S.S.), Department of Pediatrics and Center for Clinical Epidemiology and Biostatistics (S.S.S.), Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pa.
Correspondence to Sara K. Pasquali, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail sara.pasquali{at}duke.edu
Received April 24, 2008; accepted August 27, 2008.
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Abstract |
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Background— Many barriers exist to conducting pediatric cardiovascular (CV) trials, and the majority of therapies used are not evidence based. Recent legislation has aimed to stimulate pediatric research and improve drug labeling. This study describes off-label use of CV medications in children hospitalized with congenital and acquired CV disease.
Methods and Results— The 2005 Pediatric Health Information System database was queried for patients with CV International Classification of Disease, Ninth Revision codes who received CV medications. Off-label use (patient younger than US Food and Drug Administration–approved age) was described. Multivariate analysis used Poisson regression to model the number of CV drugs received off-label. There were 31 432 patients included (median age, 10.4 months; interquartile range, 30 days to 6.8 years). Congenital heart disease (67%) was the most common diagnosis. Other diagnoses included hypertension, arrhythmia, myocarditis/cardiomyopathy, pulmonary hypertension, rheumatic fever/endocarditis, and heart transplant. Seventy-eight percent received 
1 CV medication off-label, and 31% received 3 CV medications off-label. The most commonly used CV medications were furosemide, epinephrine, dopamine, lidocaine, and milrinone. The latter 3 (prescribed in 69% of patients) were used off-label in all cases. Medications studied under recent federal initiatives were prescribed in only 20% of patients, and were still used off-label 62% of the time. In multivariate analysis, heart transplant recipients (odds ratio 1.7; 95% CI 1.5 to 1.9) were most likely to receive a greater number of off-label CV medications.
Conclusions— Despite recent legislation, off-label use of CV medications in the pediatric population is common. These data highlight the need for further study to determine which treatments should be used more frequently and which are unsafe or ineffective in children hospitalized with CV disease.
Key Words: pediatrics • heart defects, congenital • pharmacology
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Introduction |
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During the 1990s, more cardiovascular (CV) clinical trials were published than in the previous 3 decades combined, leading to an era of "evidence-based cardiovascular medicine."1 However, it is known that certain patient populations have been underrepresented in CV research, including women and elderly patients in the adult population.1 In the pediatric population, the majority of medications prescribed have not been formally studied and, as a result, are not labeled for use in children.2 Treatment decisions are often based on clinical experience, observational studies, or extrapolation from adult data, rather than clinical trial evidence. Inadequate information on drug efficacy and safety may deny children potential therapeutic benefits and can also place them at risk for adverse events.
Editorial see p 69
The federal government recently enacted several initiatives to stimulate pediatric research. The Pediatric Exclusivity Provision provides economic incentives involving patent extension to pharmaceutical companies to conduct safety and efficacy studies in children.3 The Best Pharmaceuticals Act extended these incentives and also created a mechanism to study frequently used older or off-patent medications, including several CV medications.4 The National Heart, Lung, and Blood Institute also established the Pediatric Heart Network, a cooperative network of 7 centers specifically designed to develop and apply evidence-based approaches in pediatric CV disease.5
Despite these initiatives, a recent study showed that 79% of hospitalized general pediatric patients received 1 medication off-label.2 The current extent of off-label use of CV medications in children is unknown. The purpose of this study was to describe off-label use of CV medications in children hospitalized with congenital and acquired heart disease using resource-utilization data from a large, multicenter, administrative database. Factors associated with receiving a greater number of off-label CV medications were also evaluated.
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Methods |
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Data Source
Data for this study were obtained from the Pediatric Health Information System, an administrative database that contains inpatient data from 36 not-for-profit tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Child Health Corporation of America (Shawnee Mission, Kan), a business alliance of children’s hospitals. Data quality and reliability are assured through a joint effort between the Child Health Corporation of America and participating hospitals. The data-warehouse functions for the Pediatric Health Information System database are managed by Thomson Healthcare (Evanston, Ill). For the purposes of external benchmarking, participating hospitals provide discharge data including demographics, diagnoses, and procedures. Thirty-four of these hospitals also submit resource-utilization data (eg, pharmaceuticals, radiologic imaging, and laboratory studies). Data are de-identified at the time of data submission and before data extraction and analysis. For this study, we used medication data from the 34 hospitals that submitted complete resource-utilization data, including the date when a specific drug was given. This study was reviewed and approved by our institutional Committee for the Protection of Human Subjects. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Patient Population
Patients 18 years or younger at the time of hospital discharge between January 1, 2005 and December 31, 2005 who had CV disease and received 1 or more CV medications were included. Patients with CV disease were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes and were classified into the following categories:
- Congenital heart disease
- a. Procedural: includes patients undergoing surgery (ICD-9 procedure codes 35.xx [all], 39.0, 39.21, 38.35, 38.45, 38.85, 39.59, and any one of diagnostic codes under category b below) and cardiac catheterization (any catheterization code [37.21 to 37.23, 88.42 to 88.44, or 88.50 to 88.59], any one of the diagnostic codes under category b below, and no code for cardiopulmonary bypass [39.61])
- b. Medical: ICD-9 diagnostic codes 745.xx (all), 746.xx (all), 747.0x to 747.4x, 424.0 to 424.3, and no procedural code. Infants with an isolated patent ductus arteriosus (defined by ICD-9 diagnosis code 747.0 and age <3 months), or infants undergoing isolated patent ductus arteriosus closure (defined by ICD-9 diagnosis code 747.0, procedure code 38.85, and age <3 months) were excluded.
- b. Medical: ICD-9 diagnostic codes 745.xx (all), 746.xx (all), 747.0x to 747.4x, 424.0 to 424.3, and no procedural code. Infants with an isolated patent ductus arteriosus (defined by ICD-9 diagnosis code 747.0 and age <3 months), or infants undergoing isolated patent ductus arteriosus closure (defined by ICD-9 diagnosis code 747.0, procedure code 38.85, and age <3 months) were excluded.
- a. Procedural: includes patients undergoing surgery (ICD-9 procedure codes 35.xx [all], 39.0, 39.21, 38.35, 38.45, 38.85, 39.59, and any one of diagnostic codes under category b below) and cardiac catheterization (any catheterization code [37.21 to 37.23, 88.42 to 88.44, or 88.50 to 88.59], any one of the diagnostic codes under category b below, and no code for cardiopulmonary bypass [39.61])
- Other CV disease
- a. Rheumatic fever and endocarditis: ICD-9 diagnostic codes 391.xx (all), 393.xx to 398.xx (all), and 421.xx (all)
- b. Hypertension: ICD-9 diagnostic codes 401.xx to 405 xx (all)
- c. Pulmonary hypertension: ICD-9 diagnostic codes 416.xx (all)
- d. Myocarditis and cardiomyopathy: ICD-9 diagnostic codes 422.xx (all) and 425.xx (all)
- b. Hypertension: ICD-9 diagnostic codes 401.xx to 405 xx (all)
- a. Rheumatic fever and endocarditis: ICD-9 diagnostic codes 391.xx (all), 393.xx to 398.xx (all), and 421.xx (all)
- Heart transplant: ICD-9 code 37.51
- Rhythm and conduction disturbances (primary)
- a. Arrhythmia: ICD-9 codes 427.xx (all), 426.7, and 426.8
- b. Conduction disturbances: ICD-9 codes 426.0 to 426.6, 426.9, 746.86
- b. Conduction disturbances: ICD-9 codes 426.0 to 426.6, 426.9, 746.86
- a. Arrhythmia: ICD-9 codes 427.xx (all), 426.7, and 426.8
Medication Data
CV medications prescribed in 0.1% of the study population were included and classified as antiarrhythmics, adrenergic agents, β- and 
-adrenergic blocking agents, vasodilators, calcium channel blockers, antihypertensive agents, angiotensin-converting enzyme inhibitors and receptor blockers, diuretics, and "other" medications (prostaglandin, sildenafil, and milrinone). We excluded drug formulations and methods of administration of drugs not used for a CV indication (ie, subcutaneous lidocaine and racemic epinephrine). Off-label use was defined as use of a specific drug in a patient younger than the US Food and Drug Administration–approved age range for any indication at the time of drug administration. For medications with US Food and Drug Administration–approved ranges for weight, we converted the minimum approved weight to age using the 75th percentile on standard growth curves. We chose the 75th percentile to give conservative estimates of the number of patients in which a drug was considered off-label. Data on the hospital charges associated with medication administration were also collected. Total hospital charges in the Pediatric Health Information System database are adjusted for hospital location using the Centers for Medicare and Medicaid price/wage index.
Patient and Hospital Data
Variables collected for each institution included geographic location and hospital volume (total annual discharges). Patient variables collected included age, gender, race (non-Hispanic white, non-Hispanic black, Hispanic, Asian, other), genetic or chromosomal abnormality (ICD-9 diagnosis codes 758.0 to 758.9, 553.3, 756.6 to 756.7, 759.7 to 759.9), noncardiac operative procedures performed during the hospitalization,6 primary payer (private insurance, government insurance, other), length of stay, and disposition at discharge (home, died, other).
Statistical Analysis
Demographic and diagnostic variables, and off-label drug use were summarized using frequencies and percentages for categorical variables and medians and interquartile ranges for continuous variables. Within each drug category, we compared demographic and diagnostic variables of patients receiving a drug off-label using 
2 tests. Accounting for hospital clustering, we used Poisson regression to model the number of cardiac drugs received off-label. 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). All analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC), and statistical significance was considered when P<0.05.
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Results |
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There were 31 432 patients included. Demographic information is shown in Table 1. Median age was 10.4 months (interquartile range 30 days to 6.8 years), and 55.7% were male. Our study population comprised patients from a diverse ethnic/racial background, included those with government and private insurance, and represented a wide range of hospital size and geographic location. CV diagnoses are shown in Table 2. Patients with congenital heart disease (67%) comprised the largest proportion of our study population (35% procedural [congenital heart surgery or a catheter-based intervention] and 32% medical). Of note, 26% in the congenital heart disease medical group underwent a noncardiac operative procedure during their hospitalization. In the group that underwent heart transplant during the hospitalization, underlying diagnoses included cardiomyopathy/myocarditis (n=64), congenital heart disease (n=24), repeat transplant (n=13), neoplasm (n=2), and unknown (n=2). Evaluation of median age for each diagnosis group showed that patients with congenital heart disease were the youngest group (median age 4.3 months; interquartile range 3 days to 2.1 years). Congenital heart disease was by far the most common diagnosis (94.1%; 51.5% medical and 42.6% procedural) in neonates (
28 days of age).
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CV medications (n=65) prescribed in our study population are shown in Table 3
. Sixty percent of medications were used off-label in all cases, and 69% of medications were used off-label >50% of the time. Off-label use accounted for more than half of the hospital charges for CV medication prescribed in our population ($42 754 219; 54.5%). The 5 most commonly used CV medications were furosemide (prescribed in 49.6%), dopamine (prescribed in 26.6%), lidocaine (prescribed in 22.7%), epinephrine (prescribed in 22.4%), and milrinone (prescribed in 19.1%). Of these, dopamine, lidocaine, and milrinone (prescribed in 68.4% of patients) were used off-label in all cases. Furosemide and epinephrine are approved for pediatric use. Six CV medications included in our study (enalapril, sotalol, lisinopril, amlodipine, losartan, and fenoldopam) were evaluated under the Pediatric Exclusivity Provision before our study period.7 These 6 medications combined were prescribed in 19.9% of patients and were used off-label 62.1% of the time (Table 3).
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Figure 1 displays the number of CV medications patients received off-label. Seventy-eight percent of patients received
1 CV medication off-label, 48% received 2 CV medications off-label, and 31% received 3 CV medications off-label.
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Off-label CV medication use by demographic and diagnostic classification is displayed in Tables 4 and 5
. Of note, antihypertensive agents (in patients >12 years of age) and angiotensin-converting enzyme inhibitors and receptor blockers (in patients 6 years of age) were least likely to be prescribed off-label (P<0.001). We also evaluated the number of off-label drugs received in each CV diagnosis category (Figure 2). Transplant patients (median 6 off-label CV medications; interquartile range 5 to 9), and the surgical congenital heart disease group (median 3 off-label CV medications; interquartile range 2 to 5) received the greatest number of CV medications off-label.
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Predictors of off-label CV medication use are shown in Table 6
. In multivariate analysis, heart transplant recipients (OR 1.67; 95% CI 1.47 to 1.90) were most likely to receive a greater number of off-label CV medications compared with the other CV diagnosis groups. Neonates (OR 1.11; 95% CI 1.06 to 1.18), patients undergoing a noncardiac surgical procedure during the hospitalization (OR 1.15; 95% CI 1.12 to 1.18), those who received a greater number of CV medications overall (OR 11.26; 95% CI 10.29 to 12.34 for 7 CV medications), and patients who died in-hospital (OR 1.16; 95% CI 1.12 to 1.20) were also at risk for receiving a greater number of off-label CV medications.
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Discussion |
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Despite recent government initiatives, off-label use of CV medications in pediatric patients hospitalized with congenital and acquired heart disease is common. Sixty percent of the CV medications in our study were used off-label in all cases, and 78% of patients received
1 CV drug off-label. Use of multiple off-label medications per patient was also common, with nearly one-third of patients receiving 3 CV medications off-label. CV medications studied under recent federal initiatives were prescribed in only 20% of patients and were still used off-label 62% of the time. Many barriers exist to conducting clinical trials in pediatric CV medicine, including the relative rarity of disease compared with adult CV disease, disease heterogeneity, lack of research infrastructure, ethical issues concerning pediatric research, and difficulty in identifying valid clinical end points.5,8 For example, in a recent clinical trial investigating the use of perindopril in children with Duchenne muscular dystrophy, investigators screened patients from 10 different centers in France to recruit 57 patients for the trial.9 In addition, investigators followed study subjects for 5 years before they were able to identify a difference in progression of left ventricular dysfunction.9 Recruiting a larger number of study subjects and increasing follow-up by several additional years would likely be necessary to evaluate "hard" end points, such as mortality, that are traditionally used in adult CV trials.
As a result of these difficulties in conducting pediatric CV research, the majority of treatments used in this population are not evidence based. Treatment decisions are most often based on observational data, extrapolation from adult studies, or clinician experience. However, several recent pediatric studies have highlighted some potential pitfalls in relying on this type of data. A recent study of dopamine in neonates after the Norwood procedure showed adverse effects on oxygen transport and hemodynamic status, contrary to traditional thinking.10 In a randomized trial of carvedilol in children with heart failure, Shaddy et al11 showed that carvedilol did not improve heart failure outcomes in children and adolescents with symptomatic heart failure. This is in contrast with the beneficial effects of β-blockers demonstrated in multiple adult heart failure studies.12 Finally, Li et al13 showed that the optimal dose of clopidogrel in infants and young children with a cardiac condition at risk for arterial thrombosis was found to be only one-fifth of what would be given if extrapolating from adult data. However, it should be noted that investigators conducting these studies faced similar difficulties to those mentioned above, including small sample size, heterogeneity of the study population, and difficulty in identifying relevant clinical end points.
Our study shows that off-label use of CV medications is common in children hospitalized with congenital or acquired CV disease, with 78% receiving 1 CV drug off-label. A recent study by Shah et al2 found a similar proportion of hospitalized general pediatric patients received off-label medications. Interestingly, this extent of off-label drug use is not found across all pediatric subspecialties. Data from the Shah et al2 study showed that only 4.5% of pediatric oncology patients received an antineoplastic medication off-label. This is likely because many more clinical trials are performed in pediatric oncology patients. For example, the Children’s Oncology Group, a network of >200 participating institutions, currently has 89 active research protocols.14
We also found that use of multiple off-label drugs per patient was common, with nearly one-third of patients receiving 3 CV medications off-label. Heart transplant recipients and patients undergoing congenital heart surgery received the greatest number of off-label CV medications. Patients in these 2 groups are often the most critically ill and may have few US Food and Drug Administration–approved therapeutic options. Alternatively, those with a high severity of disease may have already failed approved therapies. We also found that neonates were more likely to receive a greater number of off-label CV medications in multivariate analysis, as demonstrated by others studying the general pediatric population.15 This is likely due to fewer studies evaluating medications in this youngest, most vulnerable population. Because neonates are known to have important differences in drug absorption, distribution, metabolism, and elimination compared with older children, the use of medications with limited safety and efficacy data in this population is particularly concerning and warrants further study.16 Presently, no studies have evaluated the association between off-label CV medication use and adverse events. However, we speculate that patients receiving multiple CV drugs with inadequate dosing and safety information and those with significant variation in drug pharmacokinetics, such as neonatal patients, may be at greatest risk, as suggested with respect to other classes of medications.17
To our knowledge, this is the first study to evaluate off-label medication use in pediatric patients hospitalized with CV disease in the United States. A European study of 544 pediatric cardiology inpatients over a 2-year period performed at the Children’s Hospital in Belgrade found that 76% received off-label or unlicensed medications.18 CV medications made up the highest proportion of off-label/unlicensed medications prescribed (69%).
The Pediatric Exclusivity Provision and Best Pharmaceuticals Act have done much to stimulate pediatric research, with >300 pediatric studies performed and >100 labeling changes.7 In our study, we found that few patients over age 6 received angiotensin-converting enzyme inhibitors and receptor blockers off-label. This can likely be attributed to the recent labeling changes for enalapril, lisinopril, and losartan.7 A total of 6 CV medications included in our study were evaluated under the Pediatric Exclusivity Provision before our study period.7 However, we found that these 6 CV medications were prescribed in only 19.9% of patients and were still used off-label 62.1% of the time. Thus, under the present program, CV medications used in only a minority of the population with CV disease have been studied, and even those medications that have been studied are still used off-label more than half of the time.
Additional federal programs have been initiated recently to further the study of other CV medications in children. The Best Pharmaceuticals Act awards contracts to study older medications with expired patents.5 Under this program, a study of sodium nitroprusside is being conducted.19 In addition, through creation of the Pediatric Heart Network, support now exists to conduct studies in important subgroups of patients that may not be studied by pharmaceutical companies. Presently, a study evaluating atenolol versus losartan in patients with Marfan syndrome is under way, as well as a study of angiotensin-converting enzyme inhibitors in single-ventricle patients.20 Changes in the pediatric drug-approval process may also be necessary so that drugs that have been studied in certain patient populations are appropriately labeled. For example, milrinone has been studied in the past in patients undergoing congenital heart surgery.21 In a multicenter, randomized, double-blind, placebo-controlled trial, Hoffman et al21 showed that milrinone was safe and effective in preventing low cardiac output syndrome in patients of age 2 days to 6.9 years undergoing biventricular repair of congenital heart disease. However, milrinone is currently not labeled for use in pediatric patients of any age.
Limitations
This study was limited to inpatient resource-utilization data; data from our study may not be generalizable to outpatient use of off-label CV medications. In addition, we defined off-label medication use solely based on age. We were unable to evaluate the use of these medications for reasons other than the approved indications, which also constitutes off-label use. Thus, our results likely represent an underestimate of off-label CV medication use in this population. Although we found that heart transplant recipients received the greatest number of CV medications off-label, the relatively small number of patients in this group precluded further subanalysis to evaluate whether particular underlying diagnoses in transplant patients are associated with more risk. Finally, we limited our analysis to CV medications only. Medications such as antiplatelet, anticoagulation, and immunosuppressive agents are also used frequently in patients with CV disease and require additional study.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Despite recent legislation, off-label use of CV medications in children hospitalized with congenital and acquired heart disease is common. This study highlights the need for additional investigation to determine which treatments should be used more frequently and which are unsafe or ineffective in children hospitalized with CV disease. Changes in the mechanisms of pediatric research support and the pediatric drug-approval process may also be necessary to reverse this trend.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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Presented at the 2008 American College of Cardiology Scientific Sessions Young Investigators Competition.
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References |
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11. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY; Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007; 12: 1171–1179.
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