Loss of treatment benefit due to low compliance with bisphosphonate therapy

Summary Among 8,822 new female bisphosphonate users, non-compliant bisphosphonate use was associated with a 45% increased risk of osteoporotic fracture compared to compliant use (MPR ≥80%). Classifying compliance into five categories, fracture risk gradually increased with poorer compliance. These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit. Introduction Bisphosphonates are widely used to treat osteoporosis and reduce fracture risk. Low compliance is frequent and will limit treatment benefit. Methods New female users of alendronate or risedronate between 1999–2004, aged ≥45 years were identified from PHARMO-RLS, including drug-dispensing and hospitalization data of ≥2 million residents of the Netherlands. Patients were followed until first hospitalisation for an osteoporotic fracture, death, or end of study period. Compliance with bisphosphonates during follow-up was measured over 90-day intervals using Medication Possession Ratio (MPR). The association between compliance and fracture risk was analyzed using time-dependent Cox-regression. Results The study cohort included 8,822 new female bisphosphonate users, contributing in total 22,484 person-years of follow-up. During follow-up, 176 osteoporotic fractures occurred (excluding the first six months). Non-compliant bisphosphonate use was associated with a 45% increased fracture risk compared to compliant use (MPR ≥80%). Classifying compliance into five categories, fracture risk gradually increased with poorer compliance (p-value <0.05 for trend). A MPR <20% was associated with an 80% increased fracture risk compared to a MPR ≥90%. Conclusions These results show a statistically significant association between level of compliance with bisphosphonates and level of fracture risk, emphasizing the importance of treatment compliance in obtaining maximal treatment benefit. The study was financially supported by an unrestricted grant from Novartis Pharma AG, Basel, Switzerland.     

Risk of refracture associated with compliance and persistence with bisphosphonate therapy in Taiwan

Summary

Bisphosphonates have been used for the treatment of postmenopausal osteoporosis since the early 1990s and studies show that compliant patients experience a lower fracture rate. This cohort study showed that the compliance of Taiwanese patients was poor and the refracture risk was related to compliance with bisphosphonate therapy.

Introduction

Bisphosphonates are potent inhibitors of osteoclast activity, and reduce bone turnover by inhibiting bone resorption. According to Taiwanese reimbursement guidelines, patients with osteoporosis-related fractures are eligible for bisphosphonate treatment. This study aimed to elucidate the relationship of refracture risk with compliance/persistence with bisphosphonate therapy in Taiwan.

Methods

This was a retrospective, administrative, database analysis measuring the adherence status and impact of poor adherence to bisphosphonate therapy in Taiwan. Study data derived from the National Health Insurance Research Database (NHIRD) were used to assemble a cohort of all osteoporosis patients who initiated bisphosphonate treatment between January 1, 2004, and December 31, 2005. Patients were followed until death, end of registration in NHIRD, or end of study period (December 31, 2006), whichever occurred first. Compliance was calculated as medication possession ratio (MPR; sum of days of supply of osteoporosis medications divided by follow-up duration).

Results

The refracture rates for osteoporosis patients were 5.15 %, 7.36 %, and 8.49 % in the first, second, and third year, respectively, and were significantly lower for patients with >80 % compliance than with <80 % compliance (p?<?0.05). Nearly 50 % patients were noncompliant (MPR?<?80 %) at 3 months, and only around 30 % patients were adherent at 1 year. Refracture risk increased with MPR?<?80 %, age, and co-morbidities like diabetes mellitus or dementia. Patients with concomitant statin medication had significantly lower refracture risk.

Conclusions

The compliance of Taiwanese patients with osteoporosis medication is poor, and refracture risk is related to compliance with bisphosphonate therapy.     

Hospitalization costs of total knee arthroplasty with a continuous femoral nerve block provided only in the hospital versus on an ambulatory basis: a retrospective, case-control, cost-minimization analysis

BACKGROUND AND OBJECTIVES: After total knee arthroplasty (TKA), hospitalization may be shortened by allowing patients to return home with a continuous femoral nerve block (CFNB). This study quantified the hospitalization costs for 10 TKA patients receiving ambulatory CFNB versus a matched cohort of 10 patients who received CFNB only during hospitalization. METHODS: We examined the medical records (n = 125) of patients who underwent a unilateral, primary, tricompartment TKA with a postoperative CFNB by 1 surgeon at one institution in an 18-month period beginning January 2004. Each of the 10 patients discharged home with an ambulatory CFNB (cases) was matched with a patient with a hospital-only CFNB (controls) for age, gender, body mass index, and health status. Financial data were extracted from the hospital microcosting database. RESULTS: Nine patients with ambulatory CFNB (cases) were discharged home on postoperative day (POD) 1 and 1 on POD 4. Of the controls, 3 were discharged home on POD 3, 6 on POD 4, and 1 on POD 5. The median (range) costs of hospitalization (excluding implant and professional fees) was US dollars 5,292 (US dollars 4,326-US dollars 7,929) for ambulatory cases compared with US dollars 7,974 (US dollars 6,931-US dollars 9,979) for inpatient controls (difference = US dollars 2,682, 34% decrease, P < .001). The total charges for hospitalization, the implant, and professional fees was US dollars 33,646 (US dollars 31,816-US dollars 38,468) for cases compared with US dollars 39,100 (US dollars 36,096-US dollars 44,098) for controls (difference = US dollars 5,454, 14% decrease, P < .001). CONCLUSIONS: This study provides evidence that ambulatory CFNB for selected patients undergoing TKA has the potential to reduce hospital length of stay and associated costs and charges. However, the current study has significant inherent limitations based on the study design. Additional research is required to replicate these results in a prospective, randomized, controlled trial and to determine whether any savings exceed additional CFNB costs such as from complications, having caregivers provide care at home, and additional hospital/health care provider visits.     

Compliance with osteoporosis drug therapy and risk of fracture

Introduction Patient compliance with osteoporosis drug therapy is often poor in clinical practice and may be associated with higher risk of fracture. Methods A nested case-control study was undertaken using a US health insurance claims database. The source population included all women aged ≥45 years who began drug therapy for osteoporosis. Cases consisted of those who experienced an osteoporosis-related fracture; they were matched to controls without osteoporosis-related fracture. Compliance with osteoporosis drug treatment was assessed in terms of the number of therapy-days received and medication possession ratio (MPR). Conditional logistic regression was employed to examine the relationship between compliance and fracture risk. Results A total of 453 women with osteoporosis-related fracture were identified and matched to 2,160 controls. Fracture risk was significantly lower for patients with >180 days of therapy [181–360 days: odds ratio (OR) = 0.70, 95% CI = 0.49–0.99; >360 days: OR = 0.65, 95% CI = 0.43–0.99) versus those with ≤30 days. Risk was also lower for patients with MPR ≥90% (OR = 0.70, 95% CI = 0.52–0.93) versus those with MPR <30%. Fracture risk decreased as compliance increased (p_trend < 0.05). Conclusion Among women initiating drug therapy for osteoporosis, better compliance is associated with reduced risk of fracture. Financial Support: Funding for this research was provided by Amgen, Inc., Thousand Oaks, California.     

Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer

PURPOSE: We estimated the cost-effectiveness of zoledronic acid vs placebo for decreasing skeletal complications in men with prostate cancer. MATERIALS AND METHODS: We performed a cost-effectiveness analysis alongside a multinational clinical trial of zoledronic acid. Cost estimation was based on prospectively collected resource use data for 85.3% of enrolled patients. Cost-effectiveness ratios were based on within-trial data on clinical outcomes, quality of life and study medication cost. RESULTS: Patients receiving zoledronic acid experienced fewer hospital days during a mean followup of 9 months (average 5.6 vs 8.0 days; p = 0.1910). Mean direct costs excluding study medication were US dollars 5365 for patients receiving zoledronic acid and US dollars 5689 for patients receiving placebo, a difference of US dollars 324 (95% CI US dollars 1781 to US dollars 1146). The global average cost of zoledronic acid plus its administration during the trial was US dollars 5677 (US dollars 450 per dose). The nominal cost per skeletal complication avoided was US dollars 112300 (95% CI US dollars 6900 to US dollars 48700) and the cost per additional patient free of skeletal complications was US dollars 51400 (95% CI US dollars 26900 to US dollars 243700). Nominal within-trial cost per quality adjusted life-year was US dollars 159200, which varied widely in sensitivity analyses. CONCLUSIONS: The nominal base case estimate of the cost per quality adjusted life-year for zoledronic acid in the prevention of skeletal complications of prostate cancer is consistent with that of bisphosphonates in breast cancer. However, the cost-effectiveness ratios for bisphosphonates are higher than commonly cited thresholds for conferring cost-effectiveness.     

Comparison of direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate: a population-based study

Summary  This population-based study aimed to compare direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. During a 2-year follow-up period, compared to those with medication possession ratio (MPR) ≥ 80%, women with MPR < 80% incurred significantly higher physician care costs and hospital care costs. Introduction  This study aimed to compare direct health care costs related to the treatment of osteoporosis and osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. Methods  A cohort of 15,027 women having initiated alendronate or risedronate was identified. MPR and direct health care costs (physician care, hospital care, drugs) were assessed during a 2-year period. Regression models were used to estimate mean predicted cost for compliant (MPR ≥ 80%) and noncompliant (MPR < 80%) women. Results  Mean predicted physician care cost (in Canadian dollars) was $51 among women with MPR < 80% and $34 among those with MPR ≥ 80%: mean difference $17, 95% confidence interval (CI) $2–22. Mean predicted hospital care cost was $568 among women with MPR < 80% and $379 among those with MPR ≥ 80%: mean difference $189, 95% CI $56–320. Mean predicted drug cost was $439 among women with MPR < 80% and $1,068 among those with MPR ≥ 80%: mean difference $−639, 95% CI $−649 to −629. Conclusion  Compared to compliant women, noncompliant women incurred significantly higher physician care and hospital care costs. Due to lower drug costs, total direct health care costs were lower among noncompliant women.    This study was funded by a grant from the Canadian Institutes of Health Research (Ottawa, Canada)     

Long‐term impact of adherence to oral bisphosphonates on osteoporotic fracture incidence

Adherence to osteoporosis treatments is a critical parameter resulting in suboptimal effectiveness in real‐life practice. The long‐term effect of adherence on fracture risk has not been assessed. This was a retrospective study using provincial health insurance claims databases to assess the association between adherence to oral bisphosphonates (OBP) and incidence of osteoporotic fractures in all Ontario patients with osteoporosis between April 1996 and December 2009. Multivariate logistic regression models were used to assess the association between OBP adherence and fracture risk. Treatment duration was classified into 2‐year intervals. Compliance was estimated with the medication possession ratio (MPR), and persistence was defined as the length of continuous therapy without a gap in refills >30 days. The study cohort was composed of 636,114 patients, among whom 36.1% were prescribed OBPs for 0 to 2 years, 19.7% for 2 to 4 years, 15.1% for 4 to 6 years, 12% for 6 to 8 years, 9.1% for 8 to 10 years, 6.1% for 10to 12 years, and 1.9% for 12 to 14 years. Overall, the mean (SD) compliance for the cohort was 0.72 (0.30) with 53.5% of the patients having compliance >80% and 24.6% being persistent with treatment during the 14‐year follow‐up period. Significant associations between high adherence and reduced fracture risk over the entire 14‐year period were observed; the overall odds ratio for categorical compliance (MPR >80% or MPR ≤80%), continuous compliance, and persistence were 0.909 (95% confidence interval [CI] 0.893–0.925), 0.918 (95% CI 0.893–0.944), and 0.804 (95% CI 0.787–0.821), respectively. In conclusion, adherence to OBP in osteoporosis management is suboptimal in a real‐life setting. A significant positive association exists between poor adherence and increased risk of osteoporotic fractures, which becomes augmented with longer treatment duration. © 2012 American Society for Bone and Mineral Research     

Primary hip arthroplasty costs are greater in low-volume than in high-volume Canadian hospitals

Despite the widespread success of total hip arthroplasties for treatment of arthritis of the hip, the procedure continues to be targeted for cost control. Our objective was to compare the total in-hospital cost of primary total hip arthroplasties in high-volume and low-volume hospitals. Data concerning the patient-level in-hospital costs of 940 consecutive primary total hip arthroplasties were extracted from the cost accounting system of three Canadian hospitals. Mean in-hospital costs for patients having total hip arthroplasties in a high-volume institution (> or = 300 total hip arthroplasties/year) compared with two low-volume Canadian institutions (< 300 total hip arthroplasties/year) were: overhead costs 1380 US dollars +/- 35 US dollars versus 2432 US dollars +/- 49 US dollars; direct costs 3023 US dollars +/- 93 US dollars versus 4952 US dollars +/- 91 US dollars and total costs 4403 US dollars +/- 117 US dollars versus 7385 US dollars +/- 1 US dollar 38, respectively (all comparisons in US dollars). Lower overhead and direct and total costs were found for primary total hip arthroplasties done in a high-volume Canadian hospital compared with the low-volume centers. Differences in direct costs, made up in large part by the implant cost, accounted for most of the disparity. As total hip arthroplasties continue to be scrutinized for cost containment, doing the procedure in a high-volume center seems to be an effective method of controlling costs.     

Potential Clinical and Economic Impact of Nonadherence with Osteoporosis Medications

This study aims to estimate the potential clinical and economic implications of therapeutic adherence to bisphosphonate therapy. A validated Markov microsimulation model was used to estimate the impact of varying adherence to bisphosphonate therapy on outcomes (the number of fractures and the quality-adjusted life-years [QALYs]), health-care costs, and the cost-effectiveness of therapy compared with no treatment. Adherence was divided into persistence and compliance, and multiple scenarios were considered for both concepts. Analyses were performed for women aged 65 years with a bone mineral density T-score of −2.5. Health outcomes and the cost-effectiveness of therapy improved significantly with increasing compliance and/or persistence. In the case of real-world persistence and with a medical possession ratio (MPR; i.e., the number of doses taken divided by the number of doses prescribed) of 100%, the QALY gain and the number of fractures prevented represented only 48 and 42% of the values estimated assuming full persistence, respectively. These proportions fell to 27 and 23% with an MPR value of 80%. The costs per QALY gained, for branded bisphosphonates (and generic alendronate), were estimated at €19,069 (€4,871), €32,278 (€11,985), and €64,052 (€30,181) for MPR values of 100, 80, and 60%, respectively, assuming real-world persistence. These values were €16,997 (€2,215), €24,401 (€6,179), and €51,750 (€20,569), respectively, assuming full persistence. In conclusion, poor compliance and failure to persist with osteoporosis medications results not only in deteriorating health outcomes, but also in a decreased cost-effectiveness of drug therapy. Adherence therefore remains an important challenge for health-care professionals treating osteoporosis.     

Adherence and profile of non-persistence in patients treated for osteoporosis—a large-scale, long-term retrospective study in The Netherlands

Summary  

We analyzed 12-month compliance for all ten oral osteoporosis drugs in the Netherlands by medication possession ratio (MPR ≥ 80%) in 105,506 patients, and persistence in 8,626 starters indicated high MPR (91%), low persistence (43%), and no restart in 78% of the stoppers after 18 months.     

The fracture and osteoporosis clinic: 1-year results and 3-month compliance

INTRODUCTION: A Fracture and Osteoporosis (F&O) clinic started in two major general hospitals in the South of the Netherlands on April 1st 2004. Its objectives were to perform easy and complete assessment of female and male patients aged 50 years and over, initially treated for a low-energy trauma fracture, and to evaluate its effectiveness for early diagnosis and treatment of osteoporosis. METHODS: All eligible patients were selected from the digital X-ray system of the Emergency Department. DXA-scans and, if indicated, spinal radiographs were made. If osteoporosis was diagnosed, the F&O nurse explained the treatment strategy. Treatment advice was sent to the general practitioner (GP), who prescribed medication and provided further support. After 3 months, all osteoporosis patients received a compliance and side effects follow-up questionnaire. RESULTS: Up to June 1st 2005, 1058 patients followed the diagnostic procedure; 584 patients did not. Three times more women (804) than men (254) suffered a fracture. Osteoporosis occurred 10% more often in women. Overall, 37.1% had osteoporosis, based on DXA-scan only, and 39.6% when spinal radiographs were added. Spinal radiographs of the thoracic and or lumbar spine were made in 166 patients, radiographs of the thorax in 114 patients. Overall, fractures of the wrist were most common, with fractures of the hand occurring most frequently in men (20.0%). All fracture sites, except foot and clavicula, were associated with a higher frequency of osteoporosis than in the Dutch population. The response rate to the 3-month compliance questionnaire was 73% increasing to 96% after telephone contact. 86% visited their GP; 11% did not because they already received anti-osteoporotic medication prior to the fracture. Bisphosphonates were prescribed to 84% and discontinued by 7%. 13% reported side effects of bisphosphonates. Only half of the patients received the recommended calcium supplementation. CONCLUSIONS: The F&O clinic with its digital X-ray system facilitated easy, complete identification of fracture patients and early treatment of osteoporosis, which was frequently diagnosed. Self-reported compliance was high.     

Benefit of Adherence With Bisphosphonates Depends on Age and Fracture Type: Results From an Analysis of 101,038 New Bisphosphonate Users

The relationship between high adherence to oral bisphosphonates and the risk of different types of fractures has not been well studied among adults of different ages. Using claims data from a large U.S. health care organization, we quantified adherence after initiating bisphosphonate therapy using the medication possession ratio (MPR) and identified fractures. Cox proportional hazards models were used to evaluate the rate of fracture among nonadherent persons (MPR < 50%) compared with highly adherent persons (MPR ≥ 80%) across several age strata and a variety of types of clinical fractures. In conjunction with fracture incidence rates among the nonadherent, these estimates were used to compute the number needed to treat with high adherence to prevent one fracture, by age and fracture type. Among 101,038 new bisphosphonate users, the proportion of persons with high adherence at 1, 2, and 3 yr was 44%, 39%, and 35%, respectively. Among 65‐ to 78‐yr‐old persons with a physician diagnosis of osteoporosis, the crude and adjusted rate of hip fracture among the nonadherent was 1.96 (95% CI, 1.48–2.60) and 1.74 (95% CI, 1.30–2.31), respectively, resulting in a number needed to treat with high adherence to prevent one hip fracture of 107. The impact of high adherence was substantially less for other types of fractures and for younger persons. Analysis of adherence in a non–time‐dependent fashion artifactually magnified differences in fracture rates between adherent and nonadherent persons. The antifracture effectiveness associated with high adherence to oral bisphosphonates varied substantially by age and fracture type. These results provide estimates of absolute fracture effectiveness across age subgroups and fracture types that have been minimally evaluated in clinical trials and may be useful for future cost‐effectiveness studies.     

Emergency and elective coronary artery bypass grafting: comparisons of risk profiles, postoperative outcomes, and resource requirements

OBJECTIVE: To investigate the association between preoperative risk factors and postoperative outcomes in emergency and elective coronary artery bypass graft (CABG) patients and to quantify resource requirements. DESIGN: Retrospective database review. SETTING: New York State SPARCS database. PARTICIPANTS: Data from 4,001 emergency and 7,489 elective CABG patients were evaluated retrospectively. INTERVENTIONS: Data were compared between groups using chi-squares, t tests, and logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: Preoperatively, 47.1% of patients in the emergency group had unstable angina and 34.1% had acute myocardial infarction compared with 33.9% and 15.2% in the elective group, respectively (p < 0.0001). There were no marked differences in the preoperative noncardiac risk factors between groups. The mortality rate was 4.7% in the emergency group and 2.6% in the elective group (p < 0.0001). The emergency group had more postoperative cardiac complications (18.3% v 8.3%, p < 0.0001). The length of hospital stay in the emergency group was 17.5 +/- 15.8 days (median 14 days) compared with 12.9 +/- 15.1 days (median 9 days) in the elective group (p < 0.00001). Total hospital charges in the emergency and elective groups were 46,700 US dollars +/- 42,400 US dollars (median 35,600 US dollars ) and 34,800 US dollars +/- 36,400 US dollars (median 26,500 US dollars) (p < 0.00001), respectively. The median total cost was 26,300 US dollars for emergency and 19,600 US dollars for elective group (p < 0.00001). CONCLUSION: Patients undergoing emergency CABG had greater postoperative morbidity and mortality, longer LOS, and higher total costs than patients undergoing elective surgery. This difference is predictable on the basis of preoperative cardiac risk factors. Emergency operations have a major impact on the rates of morbidity, mortality, and use of resources.     

Cost-effectiveness of vertebral fracture assessment to detect prevalent vertebral deformity and select postmenopausal women with a femoral neck T-score>-2.5 for alendronate therapy: a modeling study.

Most fractures occur in postmenopausal women who do not have osteoporosis by bone density criteria (T-score>-2.5). Prevalent vertebral deformity is a strong risk factor for incident fractures independent of bone mineral density, yet the majority of these deformities are clinically unapparent. Spine imaging on a dual-energy densitometer, called vertebral fracture assessment (VFA), can accurately detect these deformities. The purpose of this modeling study was to estimate the lifetime societal costs and health benefits of VFA and confirmatory follow-up radiography to detect prevalent vertebral deformity in osteopenic (T-score -1.5, -2.0, or -2.4) postmenopausal women, followed by anti-resorptive drug therapy for those with one or more deformities. We compared three strategies; no initial drug therapy, 5 yr of initial alendronate therapy, or VFA followed by 5 yr of alendronate therapy in those with one or more vertebral deformities confirmed on radiography (VFA strategy). Results for the base-case analyses showed that the cost per quality adjusted life year (QALY) gained for the VFA strategy relative to no initial drug therapy ranged from 18,000 US dollars (for a 60-yr-old with a femoral neck T-score of -2.4) to 77,000 US dollars (for an 80-yr-old with a T-score of -1.5). VFA with selective confirmatory radiography is cost-effective, assuming a societal willingness to pay per QALY gained of 50,000 US dollars, for postmenopausal women aged 60 to 80 yr with femoral neck T-scores between -2.0 and -2.4, and for women age 60 or 70 yr with a T-score of -1.5. Assuming a societal willingness to pay of 100,000 US dollars per QALY gained, VFA is also cost-effective for women age 80 yr with a T-score of -1.5. These conclusions are robust to reasonable changes in fracture rates, assumed fracture disutility, discount rates, relative risk of fracture attributable to vertebral deformity, alendronate cost, and drug adherence.     

Assessment of adherence to treatment of postmenopausal osteoporosis with raloxifene and/or alfacalcidol in postmenopausal Japanese women

Patients who are diagnosed with osteoporosis and beginning treatment often discontinue their osteoporosis medication relatively early after the start of treatment because of their poor recognition of fracture risk and the asymptomatic nature of osteoporosis. In this study we aimed to assess adherence to treatment with 1 μg alfacalcidol (D), 60 mg raloxifene (R) or a combination of both (D + R) for 1 year in postmenopausal Japanese women with osteoporosis or osteopenia. We defined persistence of D and R as continuing to take tablets for more than 7 of any 14 days immediately before the 1-year visit. A total of 137 subjects aged 49–81 years [64.9 ± 7.0 years, 16.0 ± 12.7 years since menopause (YSM)] were randomly assigned to each treatment group. The proportions persisting with each treatment group at 1 year were 61.4, 65.3, 55.1% for D, R and D + R groups, respectively whereas the compliance to each therapy as judged by the medical possession ratio (MPR) at 1 year were 77.5, 93.8, 78.4%, respectively. There were no significant differences in persistence, compliance and the number of subjects who discontinued treatment due to adverse events among each group. We found significant inverse correlations in percent changes at 1 year between compliance and serum BAP in R and D + R groups or urinary (u-) CTX in the R group. The changes in the level of serum BAP and u-CTX were significantly higher in high-compliance patients (MPR > 80%) treated with raloxifene alone or concomitantly with alfacalcidol compared to those in low-compliance patients.