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1.  Association between Ophthalmic Timolol and Hospitalisation for Bradycardia 
Journal of Ophthalmology  2015;2015:567387.
Introduction. Ophthalmic timolol, a topical nonselective beta-blocker, has the potential to be absorbed systemically which may cause adverse cardiovascular effects. This study was conducted to determine whether initiation of ophthalmic timolol was associated with an increased risk of hospitalisation for bradycardia. Materials and Methods. A self-controlled case-series study was undertaken in patients who were hospitalised for bradycardia and were exposed to timolol. Person-time after timolol initiation was partitioned into risk periods: 1–30 days, 31–180 days, and >180 days. A 30-day risk period prior to initiating timolol was also included. All remaining time was considered unexposed. Results. There were 6,373 patients with at least one hospitalisation for bradycardia during the study period; 267 were exposed to timolol. Risk of bradycardia was significantly increased in the 31–180 days after timolol initiation (incidence rate ratio (IRR) = 1.93; 95% confidence interval (CI) 1.00–1.87). No increased risk was observed in the first 30 days or beyond 180 days of continuous exposure (IRR = 1.40; 95% CI 0.87–2.26 and IRR = 1.21; 95% CI 0.64–2.31, resp.). Conclusion. Bradycardia is a potential adverse event following timolol initiation. Practitioners should consider patient history before choosing a glaucoma regime and closely monitor patients after treatment initiation with topical nonselective beta-blocker eye drops.
PMCID: PMC4385589  PMID: 25874117
2.  Opioid use after total hip arthroplasty surgery is associated with revision surgery 
Pain is an indication for total hip arthroplasty (THA) and it should be resolved post-surgery. Because patients’ pain is typically treated pharmacologically we tested whether opioid use can be used as a surrogate for patient-reported pain and as an indicator for early surgical failure. Specifically, we evaluated whether the amount of opioids taken within the year after THA was associated with one and five years risk of revision surgery.
A cohort of 9943 THAs (01/2001-12/2012) was evaluated. Post-operative opioid use was the exposure of interest and cumulative daily oral morphine equivalent (OME) amounts were calculated. Total OMEs/90-day periods were categorised into quartiles. Revisions within one and five years were the outcomes of interest.
Of the THAs, 2.0 % (N = 200) were revised within one year and 4.2 % (N = 413) within five years. After adjustments for gender, age, surgical indication, co-morbidities, and other analgesics, revision was associated with amount of OMEs in the second quarter after THA (days 91–180 after discharge). Patients on medium-high amounts of OME (400-1119 mg) had higher risk of one (hazard ratio (HR) = 2.22, 95 % CI 1.08-4.56) and five year (HR = 1.66, 95 % CI 1.08-2.56) revision than a patient not taking opioids. During the same period, patients taking the highest amounts of OMEs (≥1120 mg) had a 2.64 (95 % CI 1.03-6.74) times higher risk of one year and a 2.11 (95 % CI 1.13-3.96) times higher risk of five year revision.
Opioid use 91–180 days post-surgery is associated with higher risk of revision surgery and therefore is an early and useful indicator for surgical failure.
PMCID: PMC4785728  PMID: 26965992
Opioids; Total hip arthroplasty; Revision; Analgesic drugs
3.  Comparing co-morbidities in total joint arthroplasty patients using the RxRisk-V, Elixhauser, and Charlson Measures: a cross-sectional evaluation 
Joint arthroplasty patients have a high prevalence of co-morbidities and this impacts their surgical outcomes. There are different ways to ascertain co-morbidities and appropriate measurement is necessary. The purpose of this study was to: (1) describe the prevalence of co-morbidities in a cohort of total hip arthroplasty (THA) and knee arthroplasty (TKA) patients using two diagnoses-based measures (Charlson and Elixhauser) and one prescription-based measure (RxRisk-V); (2) compare the agreement of co-morbidities amongst the measures.
A cross-sectional study of Australian veterans undergoing THAs (n = 11,848) and TKAs (n = 18,972) between 2001 and 2012 was conducted. Seventeen co-morbidities were identified using the Charlson, 30 using the Elixhauser, and 42 using the RxRisk-V measure. Agreement between co-morbidities was calculated using Kappa (κ) statistics.
Combining measures, 64 conditions were identified, of these 28 were only identified using the RxRisk-V, 11 using the Elixhauser, and 2 using the Charlson. The most prevalent conditions was pain treated with anti-inflammatories (58.7 % THAs, 55.9 % TKAs), pain treated with narcotics (55.0 % THAs, 50.9 % TKAs), hypertension (56.0 % THAs and TKAs), and anticoagulation disorders (53.0 % THAs, 48.6 % TKAs). Diabetes was the only condition with substantial agreement (all κ > 0.6) amongst all measures. When comparing the diagnoses based algorithms, agreement was high for overlapping conditions (all κ > 0.71).
Different measures identified different co-morbidities, provided different estimates for the same co-morbidity, and had different levels of agreement for common co-morbidities. This highlights the importance of understanding co-morbidity measures and using them appropriately in studies and case-mix adjustments analyses.
PMCID: PMC4676184  PMID: 26652166
Co-morbidities; Total joint arthroplasty; Pharmacy data; RxRisk-V; Charlson; Elixhauser
4.  Variation in Association Between Thiazolidinediones and Heart Failure Across Ethnic Groups: Retrospective analysis of Large Healthcare Claims Databases in Six Countries 
Drug Safety  2015;38(9):823-831.
The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of adverse drug events.
The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan.
Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates.
Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone [adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14–1.91] and rosiglitazone (ASR 1.65; 95 % CI 1.58–1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93–1.32 and ASR 1.21; 95 % CI 1.01–1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01–3.5 and ASR 1.25; 95 % CI 0.76–2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations.
The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use.
PMCID: PMC4561996  PMID: 26216600
5.  Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries 
Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings.
Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method.
A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47–4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62–0.93) and 0.98 (95%CI 0.85–1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively.
Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events. © 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.
PMCID: PMC4690514  PMID: 25907076
prescription symmetry analysis; pharmacovigilance; amiodarone; hyperthyroidism; pharmacoepidemiology
6.  Impact on Drug Safety of Variation in Adherence: The Need for Routinely Reporting Measures of Dose Intensity in Medication Safety Studies Using Electronic Health Data 
Drug Safety  2015;38(12):1145-1152.
Randomized controlled trials always report the dose assessed and usually include a measure of adherence. By comparison, observational studies assessing medication safety often fail to report the dose used and rarely report any measure of adherence to therapy. This limits the ability to control for differences in doses used when undertaking meta-analyses. Non-adherence with therapy is common in the practice setting and varies across countries and settings. Inter-country differences in the registration of medicines may also result in different product strengths being available in different countries. These two factors combined means that observational studies undertaken for the same medicine in different settings may be assessing the same medicine but in circumstances where quite different dosages are used. Given that many adverse drug effects are dose dependent, differences in dosages used could be a factor explaining differences in risk estimates observed across studies. We argue that dose intensity, which can be defined as a product of the dose prescribed and adherence to the dose prescribed over the course of treatment, should be routinely reported in observational studies of medication safety. We illustrate the issue with the example of dabigatran. The randomized controlled trial evidence underpinning dabigatran’s marketing authorization resulted in uncertainty about the appropriate dose for efficacy versus safety. As a result, different dosages of dabigatran were registered in the USA and Europe. The USA registered the 150- and 75-mg dabigatran products, while the 150- and 110-mg dabigatran products were registered in Europe. Among five observational studies subsequently undertaken to resolve the safety question concerning dabigatran and risk of bleeding, only one stratified results by dose. None of the US studies stratified results by the 75-mg dabigatran dose, despite this dose not being assessed in the original trial. None of the five studies reported adherence measures, despite three separate observational studies finding between 25 and 40 % of patients were non-adherent to dabigatran. The STROBE and RECORD statements should consider adding the requirement for reporting measures of dose intensity and its component products to improve observational study reports.
PMCID: PMC4659848  PMID: 26384490
7.  Comorbid Diabetes and COPD 
Diabetes Care  2013;36(10):3009-3014.
To identify if there is a dose-dependent risk of diabetes complications in patients treated with corticosteroids who have both diabetes and chronic obstructive pulmonary disorder (COPD).
A retrospective study of administrative claims data from the Australian Government Department of Veterans’ Affairs, from 1 July 2001 to 30 June 2008, of diabetes patients newly initiated on metformin or sulfonylurea. COPD was identified by dispensings of tiotropium or ipratropium in the 6 months preceding study entry. Total corticosteroid use (inhaled and systemic) in the 12 months after study entry was determined. The outcome was time to hospitalization for a diabetes-related complication. Competing risks and Cox proportional hazard regression analyses were conducted with adjustment for a number of covariates.
A total of 18,226 subjects with diabetes were identified, of which 5.9% had COPD. Of those with COPD, 67.2% were dispensed corticosteroids in the 12 months from study entry. Stratification by dose of corticosteroids demonstrated a 94% increased likelihood of hospitalization for a diabetes complication for those who received a total defined daily dose (DDD) of corticosteroids ≥0.83/day (subhazard ratio 1.94 [95% CI 1.14–3.28], P = 0.014), by comparison with those who did not receive a corticosteroid. Lower doses of corticosteroid (<0.83 DDD/day) were not associated with an increased risk of diabetes-related hospitalization.
In patients with diabetes and COPD, an increased risk of diabetes-related hospitalizations was only evident with use of high doses of corticosteroids. This highlights the need for constant revision of corticosteroid dose in those with diabetes and COPD, to ensure that the minimally effective dose is used, together with review of appropriate response to therapy.
PMCID: PMC3781532  PMID: 23735725
8.  Ranibizumab and Risk of Hospitalisation for Ischaemic Stroke and Myocardial Infarction in Patients with Age-Related Macular Degeneration: A Self-Controlled Case-Series Analysis 
Drug Safety  2014;37(12):1021-1027.
Ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, is used in the treatment of age-related macular degeneration. Inhibition of VEGF has an anti-angiogenic action and is associated with thrombogenicity, thus, myocardial infarction and ischaemic stroke are potential side effects of VEGF inhibitors.
Our objective was to assess the association between use of ranibizumab and risk of hospitalisation for ischaemic stroke (IS) and myocardial infarction (MI).
The self-controlled case series design was used, including subjects exposed to ranibizumab (Anatomical Therapeutic Chemical [ATC] code S01LA04) who were hospitalized for IS (International Classification of Diseases, tenth edition [ICD-10] code I63) or the combined endpoint of stroke or transient ischaemic attack (TIA) (ICD-10 code G45) or MI (ICD-10 code I21) were identified between August 2007 and March 2013. Rate ratios in exposed periods compared with unexposed periods were calculated using conditional Poisson regression.
A total of 323 subjects received ranibizumab and were hospitalized for IS, 490 for IS or TIA, and 391 for MI. Median period of exposure was 8–9 months with follow-up times of approximately 2.8 years. No elevated risk of IS was seen in the 1–30 days post initiation (incidence rate ratio [IRR] 1.36; 95 % confidence interval [CI] 0.98–1.88); however, elevated risk was observed for those who received therapy for 31–60 days (IRR 1.91; 95 % CI 1.13–3.24). Sensitivity analyses adjusting for time-varying confounders found elevated risk in both the 1–30 days and 31–60 days periods. Similar results to those for IS were observed for the combined endpoint of IS or TIA. No association was seen for MI in either time period (1–30 days IRR 0.90, 95 % CI 0.65–1.23; 31–60 days IRR 0.98, 95 % CI 0.54–1.79).
This case-series analysis suggests an increased risk of hospitalisation for ischaemic stroke for patients receiving ranibizumab in the 31–60 days risk period. Studies with larger populations are required to confirm the risk in the 1–30 days risk period. No evidence of increased risk of hospitalisation for MI was observed.
PMCID: PMC4242979  PMID: 25260802
9.  Early discontinuation of endocrine therapy for breast cancer: who is at risk in clinical practice? 
SpringerPlus  2014;3:282.
Despite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice.
We identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003–2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation.
Initial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95% CI = 1.3–3.3), not undergoing chemotherapy (HR = 1.4, 95% CI = 1.1–1.8) and not undergoing mastectomy (HR = 1.5, 95% CI = 1.2–1.8).
Less than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice.
PMCID: PMC4058005  PMID: 24936397
Persistence; Adherence; Tamoxifen; Aromatase inhibitors; 45 and up study
10.  Association Between Use of Multiple Psychoactive Medicines and Hospitalization for Falls: Retrospective Analysis of a Large Healthcare Claim Database 
Drug Safety  2014;37(7):529-535.
Little is known about the impact of taking multiple psychoactive medicines on the risk of hospitalization for falls.
To identify the association between multiple psychoactive medicine use and hospitalization for falls.
A retrospective cohort study was conducted between July 2011 and June 2012 in the Australian veteran population who had been dispensed at least one psychoactive medicine within the previous year. Psychoactive medicines with sedative properties included antipsychotics, anxiolytics, hypnotics, antidepressants, opioids, anti-epileptics, anti-Parkinson medicines and medicines for migraine. The associations between falls and the number of psychoactive medicines used or the number of doses were analysed in comparison with falls that occurred when no psychoactive medicine was used.
The adjusted results showed a significantly increased risk of falls when patients were on one or more psychoactive medicines or were receiving 0.1–0.9 defined daily dose (DDD) or more per day. The incident rate ratios (IRRs) were 1.22 (95 % confidence interval [CI] 1.08–1.38) for those on one psychoactive medicine, 1.70 (95 % CI 1.45–1.99) for those on two, 1.96 (95 % CI 1.58–2.43) for those on three or four, and 3.15 (95 % CI 1.90–5.23) for those on five or more. A similar result was observed when the data were analysed by dose, with the highest risk being found for those taking three or more DDD per day (adjusted IRR 4.26, 95 % CI 2.75–6.58).
Increased numbers or increased doses of psychoactive medicines are associated with an increased risk of hospitalization for falls in older adults. Strategies to reduce the psychoactive medicine burden are likely to translate into significant health benefits.
PMCID: PMC4077245  PMID: 24872015
11.  The performance of sequence symmetry analysis as a tool for post-market surveillance of newly marketed medicines: a simulation study 
Sequence symmetry analysis (SSA) is a potential tool for rapid detection of adverse drug events (ADRs) associated with newly marketed medicines utilizing computerized claims data. SSA is robust to patient specific confounders but it is sensitive to the underlying utilization trends in the medicines of interest. Methods to adjust for utilisation trends have been developed, however, there has been no systematic investigation to assess the performance of SSA when variable prescribing trends occur. The objective of this study was to evaluate the validity of SSA as a signal detection tool for newly marketed medicines.
Randomly simulated prescription supplies for a population of 1 million were generated for two medicines, DrugA (medicine of interest) and DrugB (medicine indicative of an adverse event). Scenarios were created by varying medicine utilization trends for a newly marketed medicine (DrugA). In addition, the magnitude of association between DrugA and DrugB was varied. For each scenario 1000 simulations were generated. Average Adjusted Sequence Ratios (ASR), bootstrapped 95% confidence intervals (CIs), percentage of CI's which covered the expected ASR and percent relative bias were calculated.
When no association was simulated between DrugA and DrugB, over 95% of SSA CI's covered the expected ASR (ASR = 1) and relative bias was 1% or less irrespective of medicine utilization trends. In scenarios where DrugA and DrugB were associated (ASR = 2), unadjusted SR's were underestimated by between 11.7 and 15.3%. After adjustment for trend, ASR estimates were close to expected with relative bias less than 1%. Power was over 80% in all scenarios except for one scenario in which medicine uptake was gradual and the effect of interest was weak (ASR = 1.2).
Adjustment for underlying medicine utilization patterns effectively overcomes potential under-ascertainment bias in SSA analyses. SSA may be effectively applied as a safety signal detection tool for newly marketed medicines where sufficiently large health claim data are available.
PMCID: PMC4035856  PMID: 24886247
12.  Trends over 5 years in cardiovascular medicine use in Australian veterans with diabetes 
What is already known about this subject
Previous cross-sectional studies have demonstrated underuse of cardiovascular medicines in the population with diabetes.
What this study adds
Trends are changing over 5 years with increasing use of medicines affecting the angiotensin–renin system, lipid-lowering medicines and antiplatelets in the Australian veteran population, in line with recommended practice.
To determine trends over 5 years in cardiovascular medicine use in the Australian veteran population with diabetes
An observational study. All veterans dispensed medicines indicative of diabetes between 2000 and 2005 were identified from the Veterans Affairs pharmacy claims dataset. Concurrent dispensings of angiotensin-converting enzyme inhibitor (ACEI), lipid-lowering medicines and antiplatelets were assessed.
ACEI/angiotensin II receptor blocker use has risen from 46% to 67% in the veteran population dispensed medicines indicative of diabetes. Lipid-lowering medicines have increased from 33% to 58% and antiplatelets from 28% to 50%.
The increasing use of cardiovascular medicines in the diabetes population is suggestive of improved treatment practices over time, consistent with guidelines and quality use of medicines initiatives.
PMCID: PMC2000620  PMID: 17298476
ACE inhibitors; antiplatelet; cardiovascular; diabetes; drug utilisation; lipid lowering therapy
13.  Women Commencing Anastrozole, Letrozole or Tamoxifen for Early Breast Cancer: The Impact of Comorbidity and Demographics on Initial Choice 
PLoS ONE  2014;9(1):e84835.
Australian clinical guidelines recommend endocrine therapy for all women with hormone-dependent early breast cancer. Guidelines specify tamoxifen as first-line therapy for pre-menopausal women, and tamoxifen or an aromatase inhibitor (AI) for post-menopausal women depending on the risk of recurrence based on tumour characteristics including size. Therapies have different side effect profiles; therefore comorbidity may also influence choice. We examined comorbidity, and the clinical and demographic characteristics of women commencing different therapies.
Patients and Methods
We identified the first dispensing of tamoxifen, anastrozole or letrozole for women diagnosed with invasive breast cancer in the 45 and Up Study from 2004–2009 (N = 1266). Unit-level pharmacy and medical service claims, hospital, Cancer Registry, and self-reported data were linked to determine menopause status at diagnosis, tumour size, age, comorbidities, and change in subsidy restrictions. Chi-square tests and generalised regression models were used to compare the characteristics of women commencing different therapies.
Most pre-menopausal women commenced therapy with tamoxifen (91%). Anastrozole was the predominant therapy for post-menopausal women (57%), followed by tamoxifen (28%). Women with osteoporosis were less likely to commence anastrozole compared with tamoxifen (anastrozole RR = 0.7, 95% CI = 0.5–0.9). Women with arthritis were 1.6-times more likely to commence letrozole than anastrozole (95% CI = 1.1–2.1). Tamoxifen was more often initiated in women with tumours >1 cm, who were also ≥75 years. Subsidy restriction changes were associated with substantial increases in the proportion of women commencing AIs (anastrozole RR = 4.3, letrozole RR = 8.3).
The findings indicate interplay of comorbidity and therapy choice for women with invasive breast cancer. Most post-menopausal women commenced therapy with anastrozole; however, letrozole and tamoxifen were more often initiated for women with comorbid arthritis and osteoporosis, respectively. Tamoxifen was also more common for women with tumours >1 cm and aged ≥75 years. Subsidy restrictions appear to have strongly influenced therapy choice.
PMCID: PMC3879327  PMID: 24392158
14.  Bridging evidence-practice gaps: improving use of medicines in elderly Australian veterans 
The Australian Government Department of Veterans’ Affairs (DVA) funds an ongoing health promotion based program to improve use of medicines and related health services, which implements interventions that include audit and feedback in the form of patient-specific feedback generated from administrative claims records. We aimed to determine changes in medicine use as a result of the program.
The program provides targeted patient-specific feedback to medical practitioners. The feedback is supported with educational material developed by a clinical panel, subject to peer review and overseen by a national editorial committee. Veterans who meet target criteria also receive educational brochures. The program is supported by a national call centre and ongoing national consultation. Segmented regression analyses (interrupted time series) were undertaken to assess changes in medication use in targeted veterans pre and post each intervention.
12 interventions were included; three to increase medicine use, seven which aimed to reduce use, and two which had combination of messages to change use. All programs that aimed to increase medicine use were effective, with relative effect sizes at the time of the intervention ranging from 1% to 8%. Mixed results were seen with programs aiming to reduce inappropriate medicine use. Highly specific programs were effective, with relative effect sizes at the time of the intervention of 10% decline in use of NSAIDs in high risk groups and 14% decline in use of antipsychotics in dementia. Interventions targeting combinations of medicines, including medicine interactions and potentially inappropriate medicines in the elderly did not change practice significantly. Interventions with combinations of messages targeting multiple components of practice had an impact on one component, but not all components targeted.
The Veterans’ MATES program showed positive practice change over time, with interventions increasing use of appropriate medicines where under-use was evident and reduced use of inappropriate medicines when single medicines were targeted. Combinations of messages were less effective, suggesting specific messages focusing on single medicines are required to maximise effect. The program provides a model that could be replicated in other settings.
PMCID: PMC3878826  PMID: 24330781
Health promotion; Quality improvement; Quality use of medicines; Translational research; Clinical audit; Evidence-based practice
15.  Proton pump inhibitors and the risk of pneumonia: a comparison of cohort and self-controlled case series designs 
To compare the results of a new-user cohort study design and the self-controlled case series (SCCS) design using the risk of hospitalisation for pneumonia in those dispensed proton pump inhibitors compared to those unexposed as a case study.
The Australian Government Department of Veterans’ Affairs administrative claims database was used. Exposure to proton pump inhibitors and hospitalisations for pneumonia were identified over a 4 year study period 01 Jul 2007 -30 Jun 2011. The same inclusion and exclusion criteria were applied to both studies, however, the SCCS study included subjects with a least one hospitalisation for pneumonia.
There were 105,467 subjects included in the cohort study and 6775 in the SCCS. Both studies showed an increased risk of hospitalisations for pneumonia in the three defined risk periods following initiation of proton pump inhibitors compared to baseline. With the highest risk in the first 1 to 7 days (Cohort RR, 3.24; 95% CI (2.50, 4.19): SCCS: RR, 3.07; 95% CI (2.69, 3.50)).
This study has shown that the self-controlled case series method produces similar risk estimates to a new-users cohort study design when applied to the association of proton pump inhibitors and pneumonia. Exposure to a proton pump inhibitor increases the likelihood of being admitted to hospital for pneumonia, with the risk highest in the first week of treatment.
PMCID: PMC3699413  PMID: 23800078
16.  Transient ischaemic attack and ischaemic stroke: constructing episodes of care using hospital claims data 
BMC Research Notes  2013;6:128.
Stroke patients may have multiple hospital separations relating to the same stroke. Understanding the pattern of hospitalisations for these patients enables first and recurrent events to be distinguished to better understand care. The aim of this study was to investigate reasons for hospital separations after transient ischaemic attack (TIA) or ischaemic stroke and construct episode of care criteria.
A retrospective observational study was conducted using the Australian Government Department of Veterans’ Affairs administrative claims database. All patients hospitalised for TIA or ischaemic stroke in 2008–2009 were included. Reasons for hospital separations in the 60 days after TIA or ischaemic stroke were classified by a clinical panel as ‘probably’, ‘possibly’ or ‘unlikely’ to be related to the index separation. Based on panel assessment and time between separations, episode of care criteria for TIA and ischaemic stroke were constructed.
Of the 4520 veterans alive after the index separation, 32% of TIA patients (n=782) and 63% of ischaemic stroke patients (n=1323) had another separation within 60 days. The clinical panel reviewed 460 unique reasons for readmission. Of the 3263 separations, 55% and 85% were classified as related to the index TIA and ischaemic stroke separation, respectively.
Patients hospitalised for ischaemic stroke are likely to have multiple hospital separations for treatment of the same event. Multiple separations for treatment of TIA were less frequent. Consideration of these related separations is recommended when assessing health service utilisation from claims databases.
PMCID: PMC3620927  PMID: 23547772
Ischaemic stroke; Transient ischaemic attack; Hospitalisation; Administrative health claims data
17.  Ascertaining invasive breast cancer cases; the validity of administrative and self-reported data sources in Australia 
Statutory State-based cancer registries are considered the ‘gold standard’ for researchers identifying cancer cases in Australia, but research using self-report or administrative health datasets (e.g. hospital records) may not have linkage to a Cancer Registry and need to identify cases. This study investigated the validity of administrative and self-reported data compared with records in a State-wide Cancer Registry in identifying invasive breast cancer cases.
Cases of invasive breast cancer recorded on the New South Wales (NSW) Cancer Registry between July 2004 and December 2008 (the study period) were identified for women in the 45 and Up Study. Registry cases were separately compared with suspected cases ascertained from: i) administrative hospital separations records; ii) outpatient medical service claims; iii) prescription medicines claims; and iv) the 45 and Up Study baseline survey. Ascertainment flags included diagnosis codes, surgeries (e.g. lumpectomy), services (e.g. radiotherapy), and medicines used for breast cancer, as well as self-reported diagnosis. Positive predictive value (PPV), sensitivity and specificity were calculated for flags within individual datasets, and for combinations of flags across multiple datasets.
Of 143,010 women in the 45 and Up Study, 2039 (1.4%) had an invasive breast tumour recorded on the NSW Cancer Registry during the study period. All of the breast cancer flags examined had high specificity (>97.5%). Of the flags from individual datasets, hospital-derived ‘lumpectomy and diagnosis of invasive breast cancer’ and ‘(lumpectomy or mastectomy) and diagnosis of invasive breast cancer’ had the greatest PPV (89% and 88%, respectively); the later having greater sensitivity (59% and 82%, respectively). The flag with the highest sensitivity and PPV ≥ 85% was 'diagnosis of invasive breast cancer' (both 86%). Self-reported breast cancer diagnosis had a PPV of 50% and sensitivity of 85%, and breast radiotherapy had a PPV of 73% and a sensitivity of 58% compared with Cancer Registry records. The combination of flags with the greatest PPV and sensitivity was ‘(lumpectomy or mastectomy) and (diagnosis of invasive breast cancer or breast radiotherapy)’ (PPV and sensitivity 83%).
In the absence of Cancer Registry data, administrative and self-reported data can be used to accurately identify cases of invasive breast cancer for sample identification, removing cases from a sample, or risk adjustment. Invasive breast cancer can be accurately identified using hospital-derived diagnosis alone or in combination with surgeries and breast radiotherapy.
PMCID: PMC3599953  PMID: 23399047
45 and up study; Sensitivity; Specificity; Positive predictive value; Lumpectomy; Mastectomy; Radiotherapy; Hospital diagnosis; Tamoxifen; Anastrazole; Self-report
18.  Choice of observational study design impacts on measurement of antipsychotic risks in the elderly: a systematic review 
Antipsychotics are frequently and increasingly prescribed to treat the behavioural symptoms associated with dementia despite their modest efficacy. Evidence regarding the potential adverse events of antipsychotics is limited and little is known about the longer-term safety of these medicines in the elderly. The aim of this review was to determine the impact of the choice of observational study design and methods used to control for confounding on the measurement of antipsychotic risks in elderly patients.
We searched PUBMED and the Cochrane controlled trials register for double-blind randomised controlled trials (RCTs), meta-analyses and published observational studies of antipsychotics.
Forty four studies were identified for the endpoints; death, cerebrovascular events, hip fracture and pneumonia. RCTs found a 20% to 30% increased risk of death, or an absolute increase of 1extra death per 100 patients with atypical antipsychotics compared to non-use. Cohort and instrumental variable analyses estimated between 2 to 7 extra deaths per 100 patients with conventional compared to atypical antipsychotics. RCTs found a 2 to 3 times increased risk of all cerebrovascular events with atypical antipsychotics compared to placebo and no association with serious stroke that required hospitalisation. Observational studies using cohort and self-controlled case-series designs reported similar results; no association where the endpoint was stroke causing hospitalisation and a doubling of risk when minor stroke was included. No RCTs were available for the outcome of hip fracture or pneumonia. Observational studies reported a 20% to 40% increased risk of hip fracture with both antipsychotic classes compared to non-use. The risk of pneumonia was a 2 to 3 times greater with both classes compared to non-use while a self-controlled case-series study estimated a 60% increased risk. Conventional antipsychotics were associated with a 50% greater hip fracture risk than atypical antipsychotics, while the risk of pneumonia was similar between the classes.
Choice of observational study design is critical in studying the adverse effects of antispychotics. Cohort and instrumental variable analyses gave more consistent results to clinical studies for mortality outcomes as have self-controlled case-series for the risk of cerebrovascular events and stroke. Observational evidence has highlighted the potential for antipsychotics to be associated with serious adverse events that were not reported in RCTs including hip fracture and pneumonia. Good quality observational studies are required, that employ appropriate study designs that are robust towards unmeasured confounding, to confirm the potential excess risk of hip fracture and pneumonia with antipsychotics.
PMCID: PMC3447663  PMID: 22682666
Antipsychotics; Review; Death; Cerebrovascular events; Stroke; Hip fracture; Pneumonia; Hospitalisation
19.  Prevalence of potentially hazardous drug interactions amongst Australian veterans 
Up to 21% of adverse drug event-related hospital admissions are due to drug interactions. Clinical significance of drug interactions varies, and drug interactions defined ‘potentially hazardous’ are more likely to contribute to morbidity and mortality.
The aim of this study was to assess the prevalence of potentially hazardous drug interactions in an elderly Australian veteran population.
This study assessed the prevalence of potentially hazardous drug interactions, where hazardous was defined in three or more international drug interaction references, using Repatriation Pharmaceutical Benefits Scheme pharmacy claims data. Analysis was limited to patients who received regular concurrent dispensings of potentially hazardous interacting medicines.
Of the 287 074 subjects included in the study, 1.5% were dispensed potentially hazardous interacting drug pairs. For patients dispensed cyclosporin, concomitant use of a statin was common (47%); as was statin use with those dispensed itraconazole (31%). Of those dispensed methotrexate, 24% also received a non-steroidal anti-inflammatory drug; of those on lithium, 18% also received an ACE inhibitor or angiotensin 2 receptor blocker; of those on warfarin, 7.2% and 5.9% were co-dispensed an non-steroidal anti-inflammatory drugs or antiplatelets respectively; for those on verapamil, 5.3% were co-dispensed a beta-blocker, while for those on amiodarone 6.2% were co-dispensed digoxin.
Overall prevalence of potentially serious drug interactions appears to be low in the Australian veteran population. However, patients taking cyclosporine, itraconazole, methotrexate, lithium, warfarin, verapamil and amiodarone appear to be most at risk and their medicine use should be regularly reviewed to prevent potentially hazardous drug interactions.
PMCID: PMC2911555  PMID: 20653678
drug interactions; drug utilization; prescription drugs
20.  A self-controlled case series to assess the effectiveness of beta blockers for heart failure in reducing hospitalisations in the elderly 
To determine the suitability of using the self-controlled case series design to assess improvements in health outcomes using the effectiveness of beta blockers for heart failure in reducing hospitalisations as the example.
The Australian Government Department of Veterans' Affairs administrative claims database was used to undertake a self-controlled case-series in elderly patients aged 65 years or over to compare the risk of a heart failure hospitalisation during periods of being exposed and unexposed to a beta blocker. Two studies, the first using a one year period and the second using a four year period were undertaken to determine if the estimates varied due to changes in severity of heart failure over time.
In the one year period, 3,450 patients and in the four year period, 12, 682 patients had at least one hospitalisation for heart failure. The one year period showed a non-significant decrease in hospitalisations for heart failure 4-8 months after starting beta-blockers, (RR, 0.76; 95% CI (0.57-1.02)) and a significant decrease in the 8-12 months post-initiation of a beta blocker for heart failure (RR, 0.62; 95% CI (0.39, 0.99)). For the four year study there was an increased risk of hospitalisation less than eight months post-initiation and significant but smaller decrease in the 8-12 month window (RR, 0.90; 95% CI (0.82, 0.98)).
The results of the one year observation period are similar to those observed in randomised clinical trials indicating that the self-controlled case-series method can be successfully applied to assess health outcomes. However, the result appears sensitive to the study periods used and further research to understand the appropriate applications of this method in pharmacoepidemiology is still required. The results also illustrate the benefits of extending beta blocker utilisation to the older age group of heart failure patients in which their use is common but the evidence is sparse.
PMCID: PMC3161026  PMID: 21762536
21.  Medicines information provided by pharmaceutical representatives: a comparative study in Australia and Malaysia 
BMC Public Health  2010;10:743.
Pharmaceutical representatives provide medicines information on their promoted products to doctors. However, studies have shown that the quality of this information is often low. No study has assessed the medicines information provided by pharmaceutical representatives to doctors in Malaysia and no recent evidence in Australia is present. We aimed to compare the provision of medicines information by pharmaceutical representatives to doctors in Australia and Malaysia.
Following a pharmaceutical representative's visit, general practitioners in Australia and Malaysia who had agreed to participate, were asked to fill out a questionnaire on the main product and claims discussed during the encounter. The questionnaire focused on provision of product information including indications, adverse effects, precautions, contraindications and the provision of information on the Pharmaceutical Benefit Scheme (PBS) listings and restrictions (in Australia only). Descriptive statistics were produced. Chi-square analysis and clustered linear regression were used to assess differences in Australia and Malaysia.
Significantly more approved product information sheets were provided in Malaysia (78%) than in Australia (53%) (P < 0.001). In both countries, general practitioners reported that indications (Australia, 90%, Malaysia, 93%) and dosages (Australia, 76%, Malaysia, 82%) were frequently provided by pharmaceutical representatives. Contraindications, precautions, drug interactions and adverse effects were often omitted in the presentations (range 25% - 41%). General practitioners in Australia and Malaysia indicated that in more than 90% of presentations, pharmaceutical representatives partly or fully answered their questions on contraindications, precautions, drug interactions and adverse effects. More general practitioners in Malaysia (85%) than in Australia (60%) reported that pharmaceutical representatives should have mentioned contraindications, precautions for use, drug interaction or adverse effects spontaneously (P < 0.001). In 48% of the Australian presentations, general practitioners reported the pharmaceutical representatives failed to mention information on PBS listings to general practitioners.
Information on indications and dosages were usually provided by pharmaceutical representatives in Australia and Malaysia. However, risk and harmful effects of medicines were often missing in their presentations. Effective control of medicines information provided by pharmaceutical representatives is needed.
PMCID: PMC3018442  PMID: 21118551
22.  Influence of Comorbidities on Therapeutic Progression of Diabetes Treatment in Australian Veterans: A Cohort Study 
PLoS ONE  2010;5(11):e14024.
This study assessed whether the number of comorbid conditions unrelated to diabetes was associated with a delay in therapeutic progression of diabetes treatment in Australian veterans.
Methodology/Principal Findings
A retrospective cohort study was undertaken using data from the Australian Department of Veterans' Affairs (DVA) claims database between July 2000 and June 2008. The study included new users of metformin or sulfonylurea medicines. The outcome was the time to addition or switch to another antidiabetic treatment. The total number of comorbid conditions unrelated to diabetes was identified using the pharmaceutical-based comorbidity index, Rx-Risk-V. Competing risk regression analyses were conducted, with adjustments for a number of covariates that included age, gender, residential status, use of endocrinology service, number of hospitalisation episodes and adherence to diabetes medicines. Overall, 20134 veterans were included in the study. At one year, 23.5% of patients with diabetes had a second medicine added or had switched to another medicine, with 41.4% progressing by 4 years. The number of unrelated comorbidities was significantly associated with the time to addition of an antidiabetic medicine or switch to insulin (subhazard ratio [SHR] 0.87 [95% CI 0.84–0.91], P<0.001). Depression, cancer, chronic obstructive pulmonary disease, dementia, and Parkinson's disease were individually associated with a decreased likelihood of therapeutic progression. Age, residential status, number of hospitalisations and adherence to anti-diabetic medicines delayed therapeutic progression.
Increasing numbers of unrelated conditions decreased the likelihood of therapeutic progression in veterans with diabetes. These results have implications for the development of quality measures, clinical guidelines and the construction of models of care for management of diabetes in elderly people with comorbidities.
PMCID: PMC2984440  PMID: 21103337
23.  Use of health services and medicines amongst Australian war veterans: a comparison of young elderly, near centenarians and centenarians 
BMC Geriatrics  2010;10:83.
Age and life expectancy of residents in many developed countries, including Australia, is increasing. Health resource and medicine use in the very old is not well studied. The purpose of this study was to identify annual use of health services and medicines by very old Australian veterans; those aged 95 to 99 years (near centenarians) and those aged 100 years and over (centenarians).
The study population included veterans eligible for all health services subsidised by the Department of Veterans' Affairs (DVA) aged 95 years and over at August 1st 2006. A cohort of veterans aged 65 to 74 years was identified for comparison. Data were sourced from DVA claims databases. We identified all claims between August 1st 2006 and July 31st 2007 for medical consultations, pathology, diagnostic imaging and allied health services, hospital admissions, number of prescriptions and unique medicines. Chi squared tests were used to compare the proportion of centenarians (those aged 100 years and over) and near centenarians (those aged 95 to 99 years) who accessed medicines and health services with the 65 to 74 year age group. For those who accessed health services during follow up, Poisson regression was used to compare differences in the number of times centenarians and near centenarians accessed each health service compared to 65 to 74 year olds.
A similar proportion (98%) of centenarians and near centenarians compared to those aged 65 to 74 consulted a GP and received prescription medicine during follow up. A lower proportion of centenarians and near centenarians had claims for specialist visits (36% and 57% respectively), hospitalisation (19% and 24%), dental (12% and 18%), physiotherapy (13% and 15%), pathology(68% and 78%) and diagnostic imaging services (51% and 68%) (p < 0.0001) and a higher proportion had claims for care plans (19% and 25%), occupational therapy (15% and 17%) and podiatry services (54% and 58%) (p < 0.0001). Compared to those aged 65 to 74, a lower proportion of centenarians and near centenarians received antihypertensives, lipid lowering therapy, antiinflammatories, and antidepressants (p < 0.0001) and a higher proportion received antibiotics, analgesics, diuretics, laxatives, and anti-anaemics (p < 0.0001).
Medical consultations and medicines are the health services most frequently accessed by Australian veteran centenarians and near centenarians. For most health services, the proportion of very old people who access them is similar to or less than younger elderly. Our results support the findings of other studies which suggest that longevity is not necessarily associated with excessive health service use.
PMCID: PMC2989975  PMID: 21050484
24.  Quality of claims, references and the presentation of risk results in medical journal advertising: a comparative study in Australia, Malaysia and the United States 
BMC Public Health  2010;10:294.
Journal advertising is used by pharmaceutical companies to disseminate medicine information to doctors. The quality of claims, references and the presentation of risk results in Australia and the US has been questioned in several studies. No recent evidence is available on the quality of claims, references and the presentation of risk results in journal advertising in Australia and the US and no Malaysian data have been published. The aim of this study was to compare the quality of claims, references and the presentation of risk results in journal advertising in these three countries.
A consecutive sample of 85 unique advertisements from each country was selected from journal advertising published between January 2004 to December 2006. Claims, references and the presentation of risk results in medical journal advertising were compared between the three countries.
Less than one-third of the claims were unambiguous claims (Australia, 30%, Malaysia 17%, US, 23%). In Malaysia significantly less unambiguous claims were provided than in Australia and the US (P < 0.001). However, the unambiguous claims were supported by more references than other claims (80%). Most evidence was obtained from at least one randomized controlled trial, a systematic review or meta-analysis (Australia, 84%, Malaysia, 81%, US, 76%) with journal articles being the most commonly cited references in all countries. Data on file were significantly more likely to be cited in the US (17%) than in Australia (2%) and Malaysia (4%) (P < 0.001). Advertisements that provided quantitative information reported risk results exclusively as a relative risk reduction
The majority of claims were vague suggesting poor quality of claims in journal advertising in these three countries. Evidence from a randomized controlled trial, systematic review or meta- analysis was commonly cited to support claims. However, the more frequent use of data that have not been published and independently reviewed in the US compared to Australia and Malaysia raises questions on the quality of references in the US. The use of relative rather than absolute benefits may overemphasize the benefit of medicines which may leave doctors susceptible to misinterpreting information.
PMCID: PMC2895591  PMID: 20509953
25.  Medication safety in acute care in Australia: where are we now? Part 2: a review of strategies and activities for improving medication safety 2002-2008 
This paper presents Part 2 of a literature review examining medication safety in the Australian acute care setting. This review was undertaken for the Australian Commission on Safety and Quality in Health Care, updating the 2002 national report on medication safety. Part 2 of the review examined the Australian evidence base for approaches to build safer medication systems in acute care.
A literature search was conducted to identify Australian studies and programs published from 2002 to 2008 which examined strategies and activities for improving medication safety in acute care.
Results and conclusion
Since 2002 there has been significant progress in strategies to improve prescription writing in hospitals with the introduction of a National Inpatient Medication Chart. There are also systems in place to ensure a nationally coordinated approach to the ongoing optimisation of the chart. Progress has been made with Australian research examining the implementation of computerised prescribing systems with clinical decision support. These studies have highlighted barriers and facilitators to the introduction of such systems that can inform wider implementation. However, Australian studies assessing outcomes of this strategy on medication incidents or patient outcomes are still lacking. In studies assessing education for reducing medication errors, academic detailing has been demonstrated to reduce errors in prescriptions for Schedule 8 medicines and a program was shown to be effective in reducing error prone prescribing abbreviations. Published studies continue to support the role of clinical pharmacist services in improving medication safety. Studies on strategies to improve communication between different care settings, such as liaison pharmacist services, have focussed on implementation issues now that funding is available for community-based services. Double checking versus single-checking by nurses and patient self-administration in hospital has been assessed in small studies. No new studies were located assessing the impact of individual patient medication supply, adverse drug event alerts or bar coding. There is still limited research assessing the impact of an integrated systems approach on medication safety in Australian acute care.
PMCID: PMC2754989  PMID: 19772663

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