Persistence With Growth Hormone Therapy in Pediatric Patients
Published Online: February 19, 2014
Bradley S. Miller, MD, PhD; Deborah Rotenstein, MD; Larry C. Deeb, MD; John Germak, MD; and Tami Wisniewski, MPH
Recombinant human growth hormone (GH) is used to treat growth failure in children due to GH deficiency (GHD) caused by either idiopathic growth hormone deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD).1-3 Prepubertal status, height velocity (HV) at 4 months, and baseline body mass index standard deviation score (SDS) have been shown to be positively correlated with change in height SDS (HSDS) over the duration of GH treatment, whereas baseline age, baseline HSDS, and baseline insulin-like growth factor I SDS are negatively correlated with change in HSDS in response to GH.4,5 Attainment of near-adult height or final height in GH-treated pediatric patients is associated with uninterrupted GH treatment regimens started at the earliest possible age to optimize long-term height outcomes.6,7
The International Society for Pharmacoeconomics and Outcomes Research has defined medication persistence as “the duration of time from initiation to discontinuation of therapy” and medication compliance (synonym: adherence) as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen.”8 Together, persistence and adherence ensure an optimal response to GH treatment.9-12 Multiple previous studies of GH treatment have analyzed the role of adherence in the response to GH treatment.9-13 However, only 1 study of GH treatment examined the effect of persistence on the response to GH treatment.13 Nonpersistent patients were defi ned as those who were receiving GH at the beginning of the study but then took breaks from treatment, ranging from periods of less than 1 month to more than 1 year, or former patients who had completely discontinued therapy.13 Nonpersistent patients were identifi ed at all compliance levels, from highly compliant to noncompliant.13 Overall, 22% of adolescents and 15% of children were nonpersistent.13 A lack of GH persistence may be due to physician advice, GH cost, insurance coverage changes, painful injections, patient-parent perception that growth has finished, adverse reactions, lack of expected response, and treatment fatigue.13
The objective of this study was to analyze data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program to determine persistence rates and height outcomes of children with IGHD and MPHD who discontinued GH treatment.14 The ANSWER Program is a noninterventional observational study that collects longterm GH effectiveness and safety information from more than 13,000 patients treated at 175 clinical sites since 2002.
Study Design and Analysis Population
Participating clinics obtained informed consent prior to entry of patient histories and physical examination data abstracted from their medical records into the study using an online data-reporting tool in NovoNet, a Web-based research platform. In order to be enrolled in the ANSWER Program, a child must be receiving GH therapy with Norditropin (somatropin injection). At sites participating in the registry, an attempt is made to enroll all individuals receiving somatropin injection. Subjects receiving somatropin injection had laboratory monitoring, clinical visits, and dose adjustment at intervals according to routine clinical practice. Data were collected from each clinic visit. Data for this study were entered into the database between the beginning of data collection (2002) and the date of data cut (2010). Patients with IGHD or MPHD were 18 years or younger, were previously untreated with GH, and had discontinued GH therapy and enrollment in the ANSWER Program. The patients’ reasons for discontinuing GH were evaluated at their last clinic visit. The treating physician reports the reason for stopping therapy in free text form. The reasons for stopping GH therapy entered by physicians into the free text form were consolidated into 4 categories for analysis: final height achieved, insurance issues, patient/caregiver decision, and other reasons. Final height achieved was expected to represent individuals who had slowing of growth or closure of growth plates. Insurance issues were expected to represent individuals who discontinued somatropin injection because insurance coverage of GH therapy was denied, the cost of the medication exceeded the capability of the family to pay despite insurance coverage, or there was an insurance-mandated change in medication due to formulary specifications. The “patient and caregiver decision” category was expected to include individuals who reached a height in or near the adult normal range and who either chose to discontinue therapy or received a recommendation to discontinue therapy from their healthcare provider. It is possible that this category included individuals who were no longer compliant with therapy. HSDS and corrected HSDS (HSDS minus target HSDS) were evaluated at baseline, year 1, year 2, year 3, and the last visit.4,5 Patients were excluded if their baseline age was younger than 1 year or older than 18 years, or if baseline values were missing, deemed inconsistent, or implausible (ie, baseline height <35 cm or >200 cm; baseline HSDS <−5 or > +2).4,5
Measures and Analyses
Baseline characteristics were obtained according to diagnosis as entered by the clinical site based on the clinical impression of the treating physician. No specific diagnostic criteria were imposed by the ANSWER Program. Variables included sex, age, bone age, HSDS, target HSDS, corrected HSDS, and peak stimulated serum GH (nanograms per milliliter). The HSDS was calculated using formulas from the Centers for Disease Control and Prevention.15 Target height was calculated from mean parental height plus 6.5 cm for males or minus 6.5 cm for females. The HV (centimeters per year) was calculated at last visit by assessing the difference in height between the last visit and the previous visit (ie, at least 6 months prior to the last visit) divided by the number of days between visits and multiplied by 365.25. Corrected HSDS described HSDS relative to genetic height potential. The percentage of patients who reached HSDS >−2 was also determined over time. Analyses were performed to detect differences in persistence between the IGHD and MPHD groups and among the 4 discontinuation categories (ie,final height achieved, insurance issues, patient and caregiver decision, and other).
Demographics and baseline characteristics of patients with IGHD and MPHD, and of patients in each discontinuation category, were summarized using descriptive statistics. Significant differences between patient group baseline characteristics were determined using independent sample t tests. A x2 test evaluated differences in sex proportions among categories. The percentage of patients remaining on therapy over time in each category was determined from Kaplan-Meier survival curves. Adjusted for baseline age and sex, persistence was estimated with a computerized statistical model for survival data using proportional hazards without censoring and the Kolmogorov-Smirnov test for comparisons among categories. The same model was applied to analyze persistence in patients with IGHD or MPHD. The HSDS and corrected HSDS were determined using a last-observation-carried-forward approach and tested for differences between each category using independent sample t tests. All reported values are mean and standard deviation (SD). Differences between means were considered significant at P <.05.
Patient Demographics and Baseline Characteristics by Diagnosis
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