monitoring adherence to treatment for chronic diseases ---using osteoporosis as an example from...
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Monitoring Adherence to Treatment for Chronic Diseases ---Using osteoporosis as an
example from Taiwan
Tzu-Chieh Lin1
Prof. Yea-Huei Kao Yang1,2
1Institute of Clinical Pharmacy and Pharmaceutical Sciences, 2Health 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-111-002)
• Department of Health, Executive Yuan, Taiwan and National Science Council, Taiwan (NSC 99-2320-B-006-016-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 2011 90(1): 109-116
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, 2003-2006
– 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 1st 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 χ2 → 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, 2006 Arlene M Gallagher et al. 2008 V. Rabenda et al,
2008Our study
Study type Cohort Cohort Cohort Cohort
Database Medstat MarketScan Commercial Claims and Encounters and Medicare databases
GPRD The 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 Primary Secondary Secondary
Fracture type
Traditional osteoporotic fracture sites (vertebrae, humerus, radius, ulna, clavicle, pelvis, femoralneck, 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 fracture Hip
ART Alendronate or Risedronate Alendronate or Risedronate Alendronate Alendronate
Follow-up period
2 year 1 year At least year 4 year
Impact of compliance
0.557 0.78 0.40 0.30
Reference Mayo Clin Proc. 2006;81(8):1013-1022
Journal of Bone & Mineral Research 23(10): 1569-1575
Osteoporosis International 19(6): 811-818
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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