Samuel Hawley

Clinical effectiveness of orthogeriatric and fracture liaison service models of care for hip fracture patients: population-based longitudinal study

Objectives: to evaluate orthogeriatric and nurse-led fracture liaison service (FLS) models of post-hip fracture care in terms of impact on mortality (30 days and 1 year) and second hip fracture (2 years). Setting: Hospital Episode Statistics database linked to Office for National Statistics mortality records for 11 acute hospitals in a region of England. Population: patients aged over 60 years admitted for a primary hip fracture from 2003 to 2013. Methods: each hospital was analysed separately and acted as its own control in a before–after time-series design in which the appointment of an orthogeriatrician or set-up/expansion of an FLS was evaluated. Multivariable Cox regression (mortality) and competing risk survival models (second hip fracture) were used. Fixed effects meta-analysis was used to pool estimates of impact for interventions of the same type. Results: of 33,152 primary hip fracture patients, 1,288 sustained a second hip fracture within 2 years (age and sex standardised proportion of 4.2%). 3,033 primary hip fracture patients died within 30 days and 9,662 died within 1 year (age and sex standardised proportion of 9.5% and 29.8%, respectively). The estimated impact of introducing an orthogeriatrician on 30-day and 1-year mortality was hazard ratio (HR) = 0.73 (95% CI: 0.65–0.82) and HR = 0.81 (CI: 0.75–0.87), respectively. Following an FLS, these associations were as follows: HR = 0.80 (95% CI: 0.71–0.91) and HR = 0.84 (0.77–0.93). There was no significant impact on time to second hip fracture. Conclusions: the introduction and/or expansion of orthogeriatric and FLS models of post-hip fracture care has a beneficial effect on subsequent mortality. No evidence for a reduction in second hip fracture rate was found.

Anti-Osteoporosis medication prescriptions and incidence of subsequent fracture among primary hip fracture patients in England and Wales: an interrupted time-series analysis

In January 2005, the National Institute for Health and Care Excellence (NICE) in England and Wales provided new guidance on the use of antiosteoporosis therapies for the secondary prevention of osteoporotic fractures. This was shortly followed in the same year by market authorization of a generic form of alendronic acid within the UK. We here set out to estimate the actual practice impact of these events among hip fracture patients in terms of antiosteoporosis medication prescribing and subsequent fracture incidence using primary care data (Clinical Practice Research Datalink) from 1999 to 2013. Changes in level and trend of prescribing and subsequent fracture following publication of NICE guidance and availability of generic alendronic acid were estimated using an interrupted time series analysis. Both events were considered in combination within a 1‐year “intervention period.” We identified 10,873 primary hip fracture patients between April 1999 and Sept 2012. Taking into account prior trend, the intervention period was associated with an immediate absolute increase of 14.9% (95% CI, 10.9 to 18.9) for incident antiosteoporosis prescriptions and a significant and clinically important reduction in subsequent major and subsequent hip fracture: –0.19% (95% CI, –0.28 to –0.09) and –0.17% (95% CI, –0.26 to –0.09) per 6 months, respectively. This equated to an approximate 14% (major) and 22% (hip) reduction at 3 years postintervention relative to expected values based solely on preintervention level and trend. We conclude that among hip fracture patients, publication of NICE guidance and availability of generic alendronic acid was temporally associated with increased prescribing and a significant decline in subsequent fractures.

Cost-effectiveness of orthogeriatric and fracture liaison service models of care for hip fracture patients: a population based study

Fracture liaison services are recommended as a model of best practice for organizing patient care and secondary fracture prevention for hip fracture patients, although variation exists in how such services are structured. There is considerable uncertainty as to which model is most cost‐effective and should therefore be mandated. This study evaluated the cost‐ effectiveness of orthogeriatric (OG)‐ and nurse‐led fracture liaison service (FLS) models of post‐hip fracture care compared with usual care. Analyses were conducted from a health care and personal social services payer perspective, using a Markov model to estimate the lifetime impact of the models of care. The base‐case population consisted of men and women aged 83 years with a hip fracture. The risk and costs of hip and non‐hip fractures were derived from large primary and hospital care data sets in the UK. Utilities were informed by a meta‐regression of 32 studies. In the base‐case analysis, the orthogeriatric‐led service was the most effective and cost‐effective model of care at a threshold of £30,000 per quality‐adjusted life years gained (QALY). For women aged 83 years, the OG‐led service was the most cost‐effective at £22,709/QALY. If only health care costs are considered, OG‐led service was cost‐effective at £12,860/QALY and £14,525/QALY for women and men aged 83 years, respectively. Irrespective of how patients were stratified in terms of their age, sex, and Charlson comorbidity score at index hip fracture, our results suggest that introducing an orthogeriatrician‐led or a nurse‐led FLS is cost‐effective when compared with usual care. Although considerable uncertainty remains concerning which of the models of care should be preferred, introducing an orthogeriatrician‐led service seems to be the most cost‐effective service to pursue.

Incidence and Predictors of Multiple Fractures Despite High Adherence to Oral Bisphosphonates: A Binational Population-Based Cohort Study.

Oral bisphosphonates (BPs) are highly effective in preventing fractures and are recommended first‐line therapies for patients with osteoporosis. We identified the incidence and predictors of oral BP treatment failure, defined as the incidence of two or more fractures while on treatment (≥2 FWOT) among users with high adherence. Fractures were considered from 6 months after treatment initiation and up to 6 months after discontinuation. Data from computerized records and pharmacy invoices were obtained from Sistema d‘Informació per al Desenvolupament de l‘Investigació en Atenció Primària (SIDIAP; Catalonia, Spain) and Danish Health Registries (Denmark) for all incident users of oral BPs in 2006‐2007 and 2000‐2001, respectively. Fine and Gray survival models using backward‐stepwise selection (p‐entry 0.049; p‐ exit 0.10) and accounting for the competing risk of therapy cessation were used to identify predictors of ≥2 FWOT among patients having persisted with treatment ≥6 months with overall medication possession ratio (MPR) ≥80%. Incidence of ≥2 FWOT was 2.4 (95% confidence interval [CI], 1.8 to 3.2) and 1.7 (95% CI, 1.2 to 2.2) per 1000 patient‐years (PYs) within Catalonia and Denmark, respectively. Older age was predictive of ≥2 FWOT in both Catalonian and Danish cohorts: subhazard ratio (SHR) = 2.28 (95% CI, 1.11 to 4.68) and SHR = 2.61 (95% CI, 0.98 to 6.95), respectively, for 65 to <80 years; and SHR = 3.19 (95% CI, 1.33 to 7.69) and SHR = 4.88 (95% CI, 1.74 to 13.7), respectively, for ≥80 years. Further significant predictors of ≥2 FWOT identified within only one cohort were dementia, SHR = 4.46 (95% CI, 1.02 to 19.4) (SIDIAP); and history of recent or older fracture, SHR = 3.40 (95% CI, 1.50 to 7.68) and SHR = 2.08 (95% CI: 1.04‐4.15), respectively (Denmark). Even among highly adherent users of oral BP therapy, a minority sustain multiple fractures while on treatment. Older age was predictive of increased risk within both study populations, as was history of recent/old fracture and dementia within one but not both populations. Additional and/or alternative strategies should be investigated for these patients.

Incidence of hip and knee replacement in patients with rheumatoid arthritis following the introduction of biological DMARDs: an interrupted time-series analysis using nationwide Danish healthcare registers

Objectives To study the impact of the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and associated rheumatoid arthritis (RA) management guidelines on the incidence of total hip (THR) and knee replacements (TKR) in Denmark. Methods Nationwide register-based cohort and interrupted time-series analysis. Patients with incident RA between 1996 and 2011 were identified in the Danish National Patient Register. Patients with RA were matched on age, sex and municipality with up to 10 general population comparators (GPCs). Standardised 5-year incidence rates of THR and TKR per 1000 person-years were calculated for patients with RA and GPCs in 6-month periods. Levels and trends in the pre-bDMARD (1996–2001) were compared with the bDMARD era (2003–2016) using segmented linear regression interrupted by a 1-year lag period (2002). Results We identified 30 404 patients with incident RA and 297 916 GPCs. In 1996, the incidence rate of THR and TKR was 8.72 and 5.87, respectively, among patients with RA, and 2.89 and 0.42 in GPCs. From 1996 to 2016, the incidence rate of THR decreased among patients with RA, but increased among GPCs. Among patients with RA, the incidence rate of TKR increased from 1996 to 2001, but started to decrease from 2003 and throughout the bDMARD era. The incidence of TKR increased among GPCs from 1996 to 2016. Conclusion We report that the incidence rate of THR and TKR was 3-fold and 14-fold higher, respectively among patients with RA compared with GPCs in 1996. In patients with RA, introduction of bDMARDs was associated with a decreasing incidence rate of TKR, whereas the incidence of THR had started to decrease before bDMARD introduction.

Insulin use and Excess Fracture Risk in Patients with Type 2 Diabetes: A Propensity-Matched cohort analysis

Despite normal to high bone mineral density, patients with type 2 diabetes (T2DM) have an increased fracture risk. T2DM medications could partially account for this excess risk. The aim of this study was to assess the association between insulin use and bone fracture risk in T2DM patients. A population-based matched cohort study based on a primary care records database validated for research use (Catalonia, Spain) was performed. Propensity score (PS) for insulin use was calculated using logistic regression including predefined predictors of fractures. A total of 2,979 insulin users and 14,895 non-users were observed for a median of 1.42 and 4.58 years respectively. Major fracture rates were 11.2/1,000 person-years for insulin users, compared with 8.3/1,000 among non-users. Matched models confirmed a significant association, with an adjusted subhazard ratio (adj SHR) of 1.38 [95% CI 1.06 to 1.80] for major fractures. No differences between types of insulin or different regimens were found. Estimated number needed to harm (fracture) was 82 (95% CI 32 to 416). Insulin use appears to be associated with a 38% excess fracture risk among T2DM patients in the early stages of the disease. Fracture risk should be included among the considerations to initiate insulin treatment.

Association between NICE guidance on biologic therapies with rates of hip and knee replacement among rheumatoid arthritis patients in England and Wales: An interrupted time-series analysis

OBJECTIVE To estimate the impact of NICE approval of tumor necrosis factor inhibitor (TNFi) therapies on the incidence of total hip replacement (THR) and total knee replacement (TKR) among rheumatoid arthritis (RA) patients in England and Wales. METHODS Primary care data [Clinical Practice Research Datalink (CPRD)] for the study period (1995-2014) were used to identify incident adult RA patients. The age and sex-standardised 5-year incidence of THR and TKR was calculated separately for RA patients diagnosed in each six-months between 1995-2009. We took a natural experimental approach, using segmented linear regression to estimate changes in level and trend following the publication of NICE TA 36 in March 2002, incorporating a 1-year lag. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend. RESULTS We identified 17,505 incident RA patients of whom 465 and 650 underwent THR and TKR surgery, respectively. The modeled average incidence of THR and TKR over the biologic-era was 6.57/1000 person years (PYs) and 8.51/1000 PYs, respectively, with projected (had pre-NICE TA 36 level and trend continued uninterrupted) figures of 5.63/1000 PYs and 12.92 PYs, respectively. NICE guidance was associated with a significant average decrease in TKR incidence of -4.41/1000 PYs (95% C.I. -6.88 to -1.94), equating to a relative 34% reduction. Overall, no effect was seen on THR rates. CONCLUSIONS Among incident RA patients in England and Wales, NICE guidance on TNFi therapies for RA management was temporally associated with reduced rates of TKR but not THR.

Incidence of Total Hip and Knee Replacement in UK Patients with Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton manifested by back pain and progressive stiffness. However, it is not uncommon for peripheral joints to be involved; the underlying histopathology of which is characterized by subchondral bone inflammation that can result in joint erosion and eventual destruction. There have been emerging data on the need for joint replacement surgery among patients with AS1,2,3, although these data have mainly originated from cohorts of patients under hospital care or registry data and therefore may be more selective of severe disease. Our aim here was to better understand the need for joint replacement surgery in the overall AS population in the United Kingdom by using National Health Service (NHS) primary care electronic medical records to determine the incidence of total hip replacement (THR) and total knee replacement (TKR) following diagnosis of AS. We identified patients in the Clinical Practice Research Datalink (CPRD) with a first diagnosis of AS within the United Kingdom between January 1, 1995, and March 31, 2014. We excluded patients with a diagnosis of > 1 type of inflammatory arthritis. CPRD is a primary … Address correspondence to Dr. D. Prieto-Alhambra, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK. E-mail: daniel.prietoalhambra{at}ndorms.ox.ac.uk

Comparative anti-fracture effectiveness of different oral anti-osteoporosis therapies based on “real-world” data: a meta-analysis of propensity-matched cohort findings from the UK Clinical Practice Research Database and the Catalan SIDIAP Database

Purpose This paper aims to compare the clinical effectiveness of oral anti-osteoporosis drugs based on the observed risk of fracture while on treatment in primary care actual practice. Materials and methods We investigated two primary care records databases covering UK National Health Service (Clinical Practice Research Datalink, CPRD) and Catalan healthcare (Information System for Research in Primary Care, SIDIAP) patients during 1995–2014 and 2006–2014, respectivey. Treatment-naive incident users of anti-osteoporosis drugs were included and followed until treatment cessation, switching, death, transfer out, or study completion. We considered hip fracture while on treatment as main outcome and major osteoporotic fractures (hip, clinical spine, wrist, and proximal humerus) as secondary outcome. Users of alendronate (reference group) were compared to those of (1) OBP, (2) strontium ranelate (SR), and (3) selective estrogen receptor modulators (SERMs), after matching on baseline characteristics using propensity scores. Multiple imputation was used to handle missing data on confounders and competing risk modelling for the calculation of relative risk according to therapy. Country-specific data were analyzed separately and meta-analyzed. Results A total of 163,950 UK and 145,236 Catalan patients were identified. Hip (sub-hazard ratio [SHR] [95% CI] 1.04 [0.77–1.40]) and major osteoporotic (SHR [95% CI] 1 [0.78–1.27]) fracture risks were similar among OBP compared to alendronate users. Both hip (SHR [95% CI] 1.26 [1.14–1.39]) and major osteoporotic (SHR [95% CI] 1.06 [1.02–1.12]) fracture risk were higher in SR compared to alendronate users. SERM users had a reduced hip (SHR [95% CI] 0.75 [0.60–0.94]) and major osteoporotic (SHR [95% CI] 0.77 [0.72–0.83]) fracture risk compared to alendronate users. Conclusion We found a 26% excess hip fracture risk among SR compared to matched alendronate users, in line with placebo-controlled RCT findings. Conversely, in a lower risk population, SERM users had a 25% reduced hip fracture risk compared to alendronate users. Head-to-head RCTs are needed to confirm these findings.

The impact of different strategies to handle missing data on both precision and bias in a drug safety study: a multidatabase multinational population-based cohort study

Background Missing data are often an issue in electronic medical records (EMRs) research. However, there are many ways that people deal with missing data in drug safety studies. Aim To compare the risk estimates resulting from different strategies for the handling of missing data in the study of venous thromboembolism (VTE) risk associated with antiosteoporotic medications (AOM). Methods New users of AOM (alendronic acid, other bisphosphonates, strontium ranelate, selective estrogen receptor modulators, teriparatide, or denosumab) aged ≥50 years during 1998–2014 were identified in two Spanish (the Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria [BIFAP] and EpiChron cohort) and one UK (Clinical Practice Research Datalink [CPRD]) EMR. Hazard ratios (HRs) according to AOM (with alendronic acid as reference) were calculated adjusting for VTE risk factors, body mass index (that was missing in 61% of patients included in the three databases), and smoking (that was missing in 23% of patients) in the year of AOM therapy initiation. HRs and standard errors obtained using cross-sectional multiple imputation (MI) (reference method) were compared to complete case (CC) analysis – using only patients with complete data – and longitudinal MI – adding to the cross-sectional MI model the body mass index/smoking values as recorded in the year before and after therapy initiation. Results Overall, 422/95,057 (0.4%), 19/12,688 (0.1%), and 2,051/161,202 (1.3%) VTE cases/participants were seen in BIFAP, EpiChron, and CPRD, respectively. HRs moved from 100.00% underestimation to 40.31% overestimation in CC compared with cross-sectional MI, while longitudinal MI methods provided similar risk estimates compared with cross-sectional MI. Precision for HR improved in cross-sectional MI versus CC by up to 160.28%, while longitudinal MI improved precision (compared with cross-sectional) only minimally (up to 0.80%). Conclusion CC may substantially affect relative risk estimation in EMR-based drug safety studies, since missing data are not often completely at random. Little improvement was seen in these data in terms of power with the inclusion of longitudinal MI compared with cross-sectional MI. The strategy for handling missing data in drug safety studies can have a large impact on both risk estimates and precision.