Assessment and Potential Determinants of Compliance and Persistence to Antiosteoporosis Therapy in Italy
Published Online: May 19, 2014
Manuela Casula, PhD; Alberico Luigi Catapano, PhD; Rossana Piccinelli, PharmD; Enrica Menditto, PhD; Lamberto Manzoli, MD, MPH; Luisa De Fendi, BSc; Valentina Orlando, PharmD; Maria Elena Flacco, MD; Marco Gambera, PharmD; Alessandro Filippi, MD; and Elena Tragni, PhD
Osteoporosis has become a clinical and public health concern because osteoporotic fractures are one of the most common causes of disability and reduced quality of life, and an important contributor to medical costs in many regions of the world.1 Several medications are currently available for the prevention and treatment of osteoporosis.2 However, the effectiveness observed in trials may not be applicable to daily practice, where 50% to 80% of patients discontinue bisphosphonate use in the first year of therapy.3,4 Moreover, noncompliance with bisphosphonates has also been reported to be a frequent issue, with rates varying from 35% to 65% of medication possession ratio.4 The full benefits of medications for osteoporosis cannot be reached if compliance is low: poorly compliant patients have a greater risk for fractures than patients who adhere to their prescribed therapy,5 resulting in higher healthcare use and costs.6
The aim of this study was to investigate compliance and persistence with antiosteoporosis drugs (AODs) in a sample of new users and to assess the influence of potential determinants.
Data used for this retrospective pharmacoepidemiological study were retrieved from the health service databases of the Local Health Units (LHUs)—provincial-level divisions of the Regional Health Authority—of Bergamo (Lombardy Region, Northern Italy), Avezzano-Sulmona, Chieti, Lanciano- Vasto, Teramo (Abruzzo Region, Southern Italy), Avellino, Benevento, Caserta, Napoli Nord, Salerno (Campania Region, Southern Italy), with a total population of about 5.5 million people, entirely covered by the National Health Service (NHS).
Prescription data contain dispensed drug name (commercial and international common denomination), Anatomical Therapeutic Chemical (ATC) classification category, dose, number of packs, and date of dispensation. We used the demographic database to retrieve demographic information about patient (gender and age). In compliance with Italian law on privacy, Health Authorities converted patient personal codes to anonymous codes.
AIFA, which is the Italian Medicines Agency and national authority responsible for drug regulation in Italy, has approved 3 bisphosphonates (alendronate, ibandronate, and risedronate) and 4 other drugs (raloxifene, teriparatide, strontium ranelate, and parathyroid hormone) for the treatment of osteoporosis. Oral bisphosphonates are available for daily (alendronate, risedronate), weekly (alendronate, risedronate), or monthly (ibandronate, risedronate) dosing. The Italian government grants reimbursement for AODs in cases of osteoporosis diagnosed by computerized bone mineralometry (T score less than –4, or less than –3 in high-risk patients), previous vertebral fractures, or chronic therapy with corticosteroids in subjects older than age 50 years.
Patients were included in this analysis if they received a prescription of AODs between January 1 and December 31, 2007. A retrospective analysis covering the period from January to December 2006 was performed to identify new users, excluding subjects who had been prescribed any osteoporosis treatment during the 12-month period prior to the index prescription. The first claim for an AOD during the study period was considered the patient’s index date. We also obtained information about any prescription of corticosteroids during the period of 2006 to 2008. Each patient was followed up prospectively for 1 year. Subjects were classified into treatment groups based on the study drug first received.
To evaluate treatment compliance and persistence in our cohort, according to International Society for Pharmacoeconomics and Outcomes Research (ISPOR) definitions, 7-9 the length time with drug available for each refilled prescription was calculated using specific Defined Daily Doses (DDDs).10 Switching products was not considered an interruption.
Compliance (adherence) was measured as medication possession ratio (MPR), calculated as the total number of days of drug supplied in the observation period divided by the total number of days in the observation period (365), calculated as a percentage. Optimal compliance with therapy was defined by MPR of at least 80%.
Persistence was quantified by the number of days covered by a drug from initiation to discontinuation of therapy. Discontinuation occurred when the period between the end of the coverage of a prescription and the date of the refill was longer than the permissible gap of 30 days.11,12 Patients with at least 1 discontinuation episode were considered nonpersistent, even if they subsequently restarted treatment. A sensitivity analysis was performed in order to determine the influence of the duration of the permissible gap on the results.
MPR was described by mean values and by distribution of patients across MPR classes. Persistence rates were evaluated using Kaplan-Meier survival analysis. Heterogeneity tests across groups were undertaken using the unpaired student’s t test or a 1-way analysis of variance (ANOVA) for continuous variables, and χ² test for categorical measures, as appropriate. The impact of some sociodemographic and clinical variables on MPR was estimated using multivariate Poisson regression analysis (dependent variable: MPR <80%). As persistence can change over time, we used a Cox proportional hazards model (dependent variable: nonpersistence). Both regression analyses were adjusted for LHUs. All analyses were performed using SPSS 19.0 (SPSS Inc, an IBM Company, Chicago, Illinois).
We identified 40,004 new users of AODs in 2007: 35,956 women (89.9%, mean age [standard deviation] 69.8 years [11.2]), 4048 men (mean age [SD] 69.6 years [13.9]). Of those, 1792 subjects were 50 years or older and on chronic corticosteroid therapy: 1403 women (3.9%) and 389 men (9.6%).
Characteristics of prescriptions are reported in Table 1. Alendronic acid was the most commonly prescribed drug (with or without colecalciferol, 45.8% women and 53.2% men), followed by risedronic acid and strontium ranelate. Antiosteoporosis therapy was mainly administered weekly (97.2% of all prescriptions of only alendronic acid and 96.6% of all prescriptions of risedronic acid). Generics were used by 6.1% of both women and men. The switch to another drug was more frequent than the change of administration regimen (10.0% vs 6.3%).
Compliance is reported in Table 2. Although suboptimal in 75.1% of our total sample, compliance was better for women. More than 70% of subjects had already interrupted their treatment after 6 months (Figure).
At 1 year, persistent women and men were 15.9% and 10.1%, respectively. In these groups, mean compliance was about 100%. Of the nonpersistent population, females (87.7%) and males (92.8%) had suboptimal compliance; about one-third of nonpersistent women and half of nonpersistent men had only 1 prescription in the study period (Table 3). Excluding these subjects, mean MPR levels were 64.3% in women and 58.1% in men. On the other hand, 46.2% and 29.2% of nonpersistent women and men, respectively, showed at least 1 prescription after the interruption (Table 3). The sensitivity analysis with a permissible gap of 60 days showed a persistence rate of 40.5%.
Table 4 reports adjusted risk ratios for suboptimal compliance and shows that female subjects younger than 50 years and those 75 years or older were at higher risk of suboptimal compliance, while weekly or monthly administrations (women only), change of drug or of frequency of administration, and concomitant use of corticosteroids were associated with a lower risk of noncompliance. Similar patterns can be seen in the adjusted hazard ratios for nonpersistence (Table 4).
Osteoporotic fractures represent one of the most common causes of disability and are associated with enormous healthcare expenditure. Although several specific therapies are available, accumulating evidence suggests that these agents are underused in clinical practice.13 Moreover, even in subjects undergoing therapy, the management of osteoporosis is difficult because of poor compliance.5
Several studies showed that a significant proportion of female patients stopped their treatment within 6 months of initiation and more than half did so within 1 year.4,14 In addition, observational studies, although showing wide variations, reported high rates of suboptimal adherence. 15-18 McCombs and colleagues reported a mean MPR of 68%, 1-year persistence rates of 24.2%, and mean lengths of persistence of 170 days for bisphosphonates.19 Downey and colleagues observed a 12-month prevalence of optimally compliant patients (MPR ≥80%) of less than 60%, with persistence rates of 20%.15 Results of previous studies are not always directly comparable to ours due to a number of methodological differences such as the population selected, the definition of compliance and persistence, the duration of follow-up, analytical techniques used, and differences in settings (populations, practices, and healthcare systems).20 Nonetheless, our findings are consistent with data from other studies, highlighting the widespread problem of poor adherence to antiosteoporosis therapy.
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