Monitoring Adherence to Treatment for Chronic Diseases ---Using osteoporosis as an example from Taiwan Tzu-Chieh Lin 1 Prof. Yea-Huei Kao Yang 1,2 1 Institute of Clinical Pharmacy and Pharmaceutical Sciences, 2 Health Outcome Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Conflicts of interest Our study was supported in part by grants from the Multidisciplinary Center of Excellence for Clinical Trial and Research (DOH100-TD-B ) Department of Health, Executive Yuan, Taiwan and National Science Council, Taiwan (NSC B MY3)

Background - 1 Osteoporosis is characterized by decreased bone mass, deterioration of bone tissue and disruption of bone architecture –↓ bone strength, ↑fracture risk A major public health burden in developed countries – 10 million people ≥50 years of age have osteoporosis in USA → 1.5 million fractures annually Patients with prior osteoporotic fractures → 2 X higher risk of future fractures – Secondary prevention of osteoporotic fractures → standard practice worldwide

Background - 2 Bisphosphonates are recommended as the primary pharmacological therapy for secondary prevention of osteoporotic hip fractures –↓ the risk of hip fractures by 40–50% Long-term compliance is necessary to ensure optimal therapeutic efficacy – <50% of the patients were compliant during the first year after initiation of treatment Several studies using claims databases have estimated the impact of compliance on preventing further fracture events – 20–60% reduction in overall fracture risk

Background - 3 The reimbursement scheme of the Bureau of National Health Insurance in Taiwan – Osteoporosis drugs → patients who have had osteoporotic vertebral or hip fractures – Provides an invaluable opportunity to assess the impact of compliance on outcome in patients who have already had osteoporotic fractures

Clin Pharmacol Ther (1):

Significance & Objectives Previous studies focusing on treatment compliance and its impact on fracture risks – Mainly in the developed countries The objectives of the our study (i) To describe the first-year treatment compliance of patients initiated on alendronate therapy after osteoporotic vertebral or hip fractures (ii) To assess the impact of compliance on the risks of subsequent hip fracture over a longer period

Method – Data source National Health Insurance Research Database (NHIRD) – Demographic data for enrollees – Information regarding health-care professionals and facilities – Service claims from inpatient, ambulatory care, and contracted pharmacies

Method – Study design and Population A retrospective cohort analysis, – Patients >50 years of age with new osteoporotic vertebral or hip fractures and new to alendronate therapy The index date → the first day on which patients received an alendronate prescription – The baseline period was defined as the year preceding the index date To ensure that the index fracture was related to osteoporosis – Patients had at least one osteoporosis-related claim during the baseline period

Method – Study Population Exclusion criteria – Patients who had experienced any prior osteoporotic vertebral/hip fracture – Patients whose index osteoporotic fracture was associated with car accidents or high-impact trauma – Diagnosis of Paget’s disease or malignant neoplasm Follow-up period – Compliance with alendronate → The 1 st year – Impact of compliance on fracture risk → From the index date to the first date of an incident hip fracture or to the end of the study

Method - Compliance with alendronate treatment Alendronate is currently the only oral bisphosphonate that approved for insurance reimbursement for osteoporotic fracture Refill compliance was defined as the medication possession ratio (MPR) for the follow-up period – Dividing the total number of defined daily doses the patient received by the follow-up period – MPR ≥80% as good compliance – Examined the results by adjusting the cutoff point upward and downward

Outcome and Covariates Incident hip fracture – Retrieved from inpatient claims only Demographic characteristics (age, gender) Index osteoporotic fracture, presence of kyphosis, history of any other fracture (radius/ulna, humerus, and other nonvertebral fractures except hip fracture) Comorbid conditions that could increase fracture risk (Alzhelmer’s disease, asthma, diabetes mellitus, ischemic stroke, history of falls, and rheumatic arthritis) Comedications (antiepileptics, β-blockers, benzodiazepines, glucocorticoids, hormone replacement therapy, COX-2 agents, selective serotonin reuptake inhibitors, thyroid drugs, and sleep/hypnotic agents).

Statistical analysis Student’s t-test or χ 2 → Primary analysis Time-to-event analysis → Impact of compliance – A time-dependent covariate for compliance – Multivariate Cox proportional hazard models with time-dependent covariates – Determined whether covariates fitted a proportional hazards assumption Sensitivity analyses – Different thresholds of good compliance, MPR as a continuous variable – Female patients only, types of index osteoporotic fracture, patients with/without any other fracture 1 year before treatment initiation, stratified patient age groups with 65 years as a cutoff point, and patients not on hormone replacement therapy – Excluding the data for patients who had an incident hip-fracture event within 6 months after treatment initiation

Discussion This retrospective analysis of Taiwanese patients with osteoporotic vertebral or hip fractures who were new to alendronate found : – Only 38% of patients to be compliant during the first year – Compliant patients had significantly lower hip-fracture risk as compared with noncompliant patients – The results were consistent through various sensitivity analyses

Discussion It is difficult to make a direct comparison of compliance rates among published studies because of their use of different covariates for adjustment – Age, sex, fracture history, and medications of interest Several studies have used claims databases to assess patients’ compliance – MPR: 61-74% in the States, Canada or UK – In our study: 60.2% in Taiwan

Discussion – Impact of compliance ETHEL S. SIRIS et al, 2006Arlene M Gallagher et al. 2008V. Rabenda et al, 2008 Our study Study type Cohort Database Medstat MarketScan Commercial Claims and Encounters and Medicare databases GPRDThe Belgian national database NHIRD Patient population Patients ≥45 yr with claims for BP Women or men ≥18 yr of age who received a prescription for alendronate or risedronate. Postmenopausal women aged>45 years, and were new users with previous vertebral fractures Postmenopausal women aged above 50yrs, with prior vertebral or hip fracture Prevention Primary Secondary Fracture type Traditional osteoporotic fracture sites (vertebrae, humerus, radius, ulna, clavicle, pelvis, femoral neck, and femur), as well as the patella, tibia, fibula, and ankle Osteoporotic fracture (defined as a hip/femur, vertebral, radius/ulna, humerus, rib, or pelvis fracture), hip/femur fracture, radius/ulna fracture Hip fractureHip ART Alendronate or Risedronate Alendronate Follow-up period 2 year1 yearAt least year4 year Impact of compliance Reference Mayo Clin Proc. 2006;81(8): Journal of Bone & Mineral Research 23(10): Osteoporosis International 19(6):

Discussion – Sensitivity analysis Most studies using MPR ≥80% as the threshold for good compliance – We varied the threshold for good compliance in steps from 70 to 100% The benefit of compliance was pronounced even when the alendronate treatment was for secondary prevention – Adjusted HR, 0.28; 95% CI 0.18–0.51 The most pronounced reduction in patients with no history of fracture prior to the index osteoporotic fracture

Discussion - Strength The first large-scale one in Asia to assess the association between treatment compliance and fracture risk Demonstrated a pronounced benefit of compliance in preventing secondary hip fracture The duration of follow-up – Most published compliance studies → 1–2 years – Up to 4 years in our study Included various covariates – Age, comorbidities, and co-medications that were thought to be related to osteoporotic fractures

Discussion - Limitations The inherent weakness of an observational study and the administrative database → residual confounders – Lack of socioeconomic covariates → confounding by lifestyle – Body mass index, smoking status, and caffeine intake Misclassification of compliance – Comprehensively captured prescription claims from inpatient, outpatient, and contracted pharmacies Patients who received HRT may have benefited from its protective effect – Consistent results were found even after excluding data for those kinds of patients

Discussion – Clinical implications The main policy of Taiwan’s Bureau of National Health Insurance regarding osteoporotic fractures was secondary prevention – Fracture sites other than vertebra/hip (e.g., radius and ulna) ↑ 2 X incident hip-fracture risk – Higher fracture risk in older patients

Summary The compliance status among Taiwanese osteoporotic patients new to alendronate was suboptimal within the first year after treatment initiation Compliant patients had a significantly lower incident hip- fracture risk as compared with noncompliant patients In real-world setting → osteoporosis drugs will not work optimally unless patients actually take them – Every effort should be made to gain greater insight into the factors associated with poor compliance and to initiate interventions to improve patient adherence.

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