Persistence With Growth Hormone Therapy in Pediatric Patients | Page 2
Published Online: February 19, 2014
Bradley S. Miller, MD, PhD; Deborah Rotenstein, MD; Larry C. Deeb, MD; John Germak, MD; and Tami Wisniewski, MPH
An initial total of 944 patients with GHD (IGHD, n = 876; MPHD, n = 68) met the inclusion criteria (Table 1). The mean age at baseline was 11.7 ± 3.48 years and 71.7% of the patients were male (IGHD: 72.9% male; MPHD: 55.9% male). Patients with IGHD were, on average, 2 years older (11.8 ± 3.27 years) than patients with MPHD (9.9 ± 5.22 years; P = .0038), and had a greater average delayed bone age versus chronologic age (IGHD, 1.6 years; MPHD: 0.2 years). The HSDS and target HSDS at baseline differed between patients with IGHD and MPHD (HSDS: −2.1 ± 0.85 and −1.8 ± 1.19, respectively, P = .0213; target HSDS: −0.4 ± 0.83 and 0.1 ± 0.75, respectively, P = .0005). Maximal stimulated serum GH levels (nanograms per milliliter) were significantly higher in patients with IGHD than MPHD (6.0 ± 2.59 and 4.4 ± 3.99, respectively, P = .0125). Baseline Characteristics by Discontinuation Category: Combined IGHD and MPHD Baseline characteristics were analyzed in a reduced subset of 826 patients for whom reason for discontinuation of GH treatment was available. Individuals with IGHD (n = 778) or MPHD (n = 48) were combined and categorized based on reason for discontinuation of GH treatment (Table 2). Baseline characteristics were similar among all discontinuation categories except for chronologic age and bone age. The mean baseline chronologic age (9.9 ± 3.8 years; P <.0001) and the mean baseline bone age (8.8 ± 3.3 years; P <.0001) were lowest in the insurance-issues patient category. No statistically significant differences (P = .4563) occurred in sex distributions among categories (ie, final height achieved, 70.8% male; insurance issues, 75.8% male; patient and caregiver decision, 70.1% male; and other, 69.4% male). The most common reason for discontinuation was final height achieved (34.9%), followed in order by insurance issues (28.0%), other (20.9%), and patient and caregiver decision (16.2%). Nonadherence (3.6%), healthcare provider recommendation (3.3%), adverse events (2.5%), change of physician or patient moved (1.5%), or lack of response (0.1%) were collectively included in the other category. The mean ± SD treatment duration was 46 ± 21 months for final height achieved, followed by patient and caregiver decision (35 ± 15 months), insurance issues (32 ± 21 months), and other (31 ± 18 months). Overall, no difference in treatment duration (mean ± SD) was observed between patients with IGHD (37 ± 19.9 months, n = 778) or MPHD (39 ± 26.7 months, n = 48). However, in patients who discontinued GH due to final height achieved, those with MPHD had a longer duration of treatment (57 ± 35.4 months, n = 13) than patients with IGHD (45 ± 19.6 months, n = 275); this was likely due to the younger age of MPHD patients at treatment start, but may also have been due to delayed entry into puberty of individuals with MPHD. The overall mean duration of GH treatment among all categories was 37 ± 20.3 months (n = 826).
Age- and Sex-Adjusted Persistence With GH Therapy
After adjusting for baseline age and sex, differences in persistence with GH therapy over time among the 4 discontinuation categories were estimated from analysis of survival curve functions (Figure 1A). Category comparisons indicated that patients who discontinued therapy due to final height being achieved were more persistent than patients in the other categories of insurance issues (P <.0001), other (P <.0001), and patient and caregiver decision (P = .0009). Patients who discontinued therapy due to patient and caregiver decision were also more persistent than patients who discontinued therapy due to insurance issues (P = .0086). Thus, patients who discontinued because of insurance issues or other reasons were the least persistent with GH treatment. Patients with either IGHD or MPHD were equally persistent with GH therapy (Figure 1B; P = .6953).
Height Outcome by Reason for Discontinuation
Overall, mean HSDS increased significantly in the combined IGHD and MPHD groups from baseline to the year 3 visit (Table 3) in patients in all discontinuation categories (Figure 2A, P <.0001). Pairwise comparisons showed that mean HSDS at last visit for patients who discontinued due to final height achieved (−0.6 ± 0.91, n = 288) was significantly higher than the mean HSDS for other (−1.3 ± 1.06, n = 173; P <.0001), insurance issues (−1.2 ± 0.90, n = 231; P <.0001), and patient and caregiver decision (−0.9 ± 1.19, n = 134; P = .0222). At year 3, prior to GH discontinuation and the last visit, the mean HSDS for final height achieved (−0.7 ± 0.82, n = 197) was significantly higher than that for other (−1.2 ± 1.06, n = 65; P = .0006) and insurance issues (−1.0 ± 0.83, n = 79; P = .0149), but it was not significantly higher than that for patient and caregiver decision (−1.0 ± 0.95, n = 51; P = .0679).
The mean corrected HSDS in the combined IGHD and MPHD groups also increased significantly from baseline to the year 3 visit (Table 3) in patients in all categories (Figure 2B, P <.0001). Pairwise comparisons showed that mean corrected HSDS at last visit for patients who discontinued due to final height achieved (−0.3 ± 0.98, n = 258) was significantly higher than the mean corrected HSDS for other (−1.0 ± 1.07, n = 139; P <.0001), insurance issues (−0.9 ± 1.03, n = 190; P <.0001), and patient and caregiver decision (−0.5 ± 1.18, n = 110; P = .05). Mean corrected HSDS for final height achieved at year 3 (−0.3 ± 0.90, n = 179) was significantly higher than that for other (−1.0 ± 1.03, n = 55; P = .0006) and insurance issues (−0.6 ± 0.81, n = 63; P = .0269), but it was not significantly higher than that for patient and caregiver decision (−0.5 ± 1.07, n = 39; P = .23).
A higher percentage of children in the fi nal-heightachieved discontinuation category reached HSDS greater than −2 at year 3 (96.4%) compared with children in the other 3 discontinuation categories: patient and caregiver decision (94.1%), insurance issues (88.6%), and other (78.5%). Annualized growth rates for the 6 to 12 months prior to discontinuation showed that children who discontinued due to final height achieved had the lowest HV (3.4 ± 2.06 cm/y, n = 249) compared with children in the other categories (Table 3); this is consistent with children in the final-height-achieved group approaching their fi nal height and fusion of their epiphyseal growth plates.
Persistence and adherence are necessary to ensure that GHD patients who receive GH treatment attain their genetic height potential.8,13 Good adherence to prescribed regimens, including GH therapy, wanes beyond 2 years of treatment.10,13,16,17 Good medication adherence among patients is considered to range from 80% to 95% of prescribed doses taken.16 Objective assessments of poor adherence to GH have included analyses of prescription data; patient/caregiver questionnaires, which were followed up with serial clinical assessments to capture HSDS and HV; and the association between HV SDS and the number of GH vials requested or returned empty.9,11,12 By any measure, outcomes have consistently shown that significantly greater linear growth and attainment of genetic height potential are positively associated with adherence to prescribed GH therapy.9,11,12 Adherence to GH regimens is important, but persistence may be even more critical because gaps in therapy that lead to delayed or missed GH doses over the prescribed duration of time from therapy initiation to discontinuation cause suboptimal response to GH treatment that negatively impacts growth outcomes.8,9,12,13
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