Responding to the Under-Utilisation of Necessary Health Care in the Time of COVID-19: A Precision Public Health intervention.

The Veterans' Medicines Advice and Therapeutics Education Services (MATES) program is a national data driven, behaviorally informed, health intervention to improve the use of medicines among Australian veterans. The program, which has been operating since 2004, has led the way in the use of government held data assets to generate evidenced-based health information, which, when provided to clinicians alongside educational materials, can make demonstrable improvements in health and promote practice change.

Comparing time to adverse drug reaction signals in a spontaneous reporting database and a claims database: a case study of rofecoxib-induced myocardial infarction and rosiglitazone-induced heart failure signals in Australia.

INTRODUCTION: The objective of post-marketing surveillance of medicines is to rapidly detect adverse drug reactions (ADRs). Early ADR detection will enable policy makers and health professionals to recognise adverse events that may not have been identified in pre-marketing clinical trials. Multiple methods exist for ADR signal detection. Traditional quantitative methods employed in spontaneous reports data have include reporting odds ratio (ROR), proportional reporting ratio (PRR) and Bayesian techniques. With the development of administrative health claims databases, additional methods such as sequence symmetry analysis (SSA) may be able to be employed routinely to confirm ADR signals. OBJECTIVE AND METHOD: We tested the time to signal detection of quantitative ADR signalling methods in a health claims database (SSA) and in a spontaneous reporting database (ROR, PRR, Bayesian confidence propagation neural network) for rofecoxib-induced myocardial infarction and rosiglitazone-induced heart failure. RESULTS: This study demonstrated that all four signalling methods detected safety signals within 1-3 years of market entry or subsidisation of the medicines, and for both cases the signals were detected before post-marketing clinical trial results. By contrast, the trial results and subsequent warning or withdrawal were published 5-7 years after first marketing of these medicines. CONCLUSION: This case study highlights that a post-marketing quantitative method utilising administrative claims data can be a complementary tool to traditional quantitative methods employed in spontaneous reports that may help to verify safety signals detected in spontaneous reporting data.

The detection of adverse events in randomized clinical trials: can we really say new medicines are safe?

BACKGROUND: While it is well known that randomized controlled trials (RCTs) are usually designed with sufficient sample size and power to detect the efficacy but not safety of a medicine, the extent to which RCTs quantify safety has not been well ascertained. PURPOSE: The aim of this study was to assess the safety data available for five commonly prescribed medicines at the time of marketing. METHODS: Published RCTs for five medicines risperidone, sertraline, donepezil, strontium ranelate and tramadol extended release were identified. All adverse events (AEs) in the trials were independently extracted by two clinical researchers. Using the sample size in the trials, the power to detect the observed difference in AEs rates between the treatment and placebo groups was calculated. A power of 80% or more was deemed adequate to detect AEs; studies with power of < 80% were deemed insufficiently powered to detect AEs. RESULTS: 12 RCTs were identified. Six trials were insufficiently powered to detect any of the potential AEs reported. Of the 150 evaluated AEs, the trials were insufficiently powered to detect 81% (122/150) of the AEs reported. For the adverse events that were detected with adequate powered clinical trials, only 53% (10/19) of potentially very common AEs (≥10%) and 17% (18/106) of potentially common AEs (1%-<10%) were identified. CONCLUSION: Trials are insufficiently powered to detect the majority of adverse events that are reported in clinical trials, even for common adverse events. Observations other than primary efficacy endpoints such as AEs that are not prespecified with adequate power should be treated as hypothesis generating only and not justification of evidence. Claims of safety based on trial evidence not designed for the safety endpoint are often premature.

The validity of sequence symmetry analysis (SSA) for adverse drug reaction signal detection.

PURPOSE: To determine the validity of sequence symmetry analysis (SSA) method to detect adverse drug reactions from an administrative claims database. METHODS: Published randomised controlled trials (RCTs) of 19 medicines were identified through search databases, product information (PI) or the US Food and Drug Administration Web site. All adverse events (AEs) in the RCTs and the PI for the medicines were extracted. AEs were considered 'gold standard positive events' if they were reported as being statistically significant events in adequately powered RCTs. The remaining AEs were considered 'gold standard negative events' if the event was not listed as an AE in the PI for that medicine or any other medicine in its class. Indicators of AEs were identified by consensus from two clinical researchers. SSA was run for each medicine-indicator pair using four different time windows: 3, 6, 9 and 12 months. RESULTS: A total of 120 randomised placebo controlled trials were reviewed for the 19 tested medicines. A total of 165 medicine-indicator pairs (44 positive and 121 negative events) were identified and tested by SSA. At the 12-month time window, the sensitivity, specificity, positive and negative predictive values of SSA were 61% (95%CI 0.46-0.74), 93% (95%CI 0.87-0.96), 77% (95%CI 0.61-0.88) and 87% (95%CI 0.80-0.92), respectively. Using a 3-month time window, the SSA had a lower sensitivity (52%). CONCLUSIONS: The SSA technique was found to have moderate sensitivity and high specificity for detecting ADRs. These results suggest that SSA is a potential tool for detecting ADRs using administrative claims data that could complement existing pharmacosurveillance methods.

Prevalence of preventable medication-related hospitalizations in Australia: an opportunity to reduce harm.

OBJECTIVE: To identify the prevalence of potentially preventable medication-related hospitalizations amongst elderly Australian veterans by applying clinical indicators to administrative claims data. DESIGN AND SETTING: Retrospective cohort study in the Australian veteran population from 1 January 2004 to 31 December 2008. PARTICIPANTS: A total of 109 044 veterans with one or more hospitalizations defined by the medication-related clinical indicator set, during the 5-year study period. MAIN OUTCOME MEASURE: The prevalence of potentially preventable medication-related hospitalizations as a proportion of all hospitalizations defined by the clinical indicator set. RESULTS: During the 5-year study period, there were a total of 1 630 008 hospital admissions of which 216 527 (13.3%) were for conditions defined by the medication-related clinical indicator set for 109 044 veterans. The overall proportion of potentially preventable medication-related hospitalizations was 20.3% (n= 43 963). Of the 109 044 veterans included in the study, 28 044 (25.7%) had at least one potentially preventable medication-related hospitalization and 7245 (6.6%) veterans had two or more potentially preventable admissions. Conditions with both a high prevalence of hospitalization and preventability included asthma/chronic obstructive pulmonary disorder, depression and thromboembolic cerebrovascular event (23.3, 18.5 and 18.3%, respectively, were potentially preventable). Other hospitalizations that were less common but had a high level of preventability (at least 20%) included hip fracture, impaction, renal failure, acute confusion, bipolar disorder and hyperkalaemia. CONCLUSIONS: The results of this study highlight those conditions where hospitalizations could potentially be avoided through improved medication management. Strategies to increase the awareness, identification and resolution of these medication-related problems contributing to these hospitalizations are required in Australia.

Managing glaucoma in those with co-morbidity: not as easy as it seems.

PURPOSE: To identify the extent of use of medicines recommended to be used with caution in glaucoma patients with specified comorbidities and to determine evidence of associated harm. Retrospective cohort analysis from administrative claims data and prescription/event sequence symmetry analysis. PARTICIPANTS: Australian Government Department of Veterans' Affairs treatment card holders dispensed glaucoma eye-drops. MAIN OUTCOME MEASURES: Proportion of veterans with glaucoma and diabetes, airways disease, heart failure, ischemic heart disease or depression, dispensed glaucoma eye drops which should be used with caution. For harms, outcome measures were hospitalizations for airways disease and heart disease. RESULTS: The cohort analysis included 25,984 veterans. Of these, 88% with airways disease were dispensed glaucoma eye drops with the potential to aggravate airways disease, 43% with heart failure were dispensed topical beta-blockers and 49% with depression received glaucoma eye drops which should be used cautiously in those with depression. We found increased risk of initiation of inhaled beta-agonist following timolol (adjusted sequence ratio (ASR) 1.48, 99% CI 1.22-1.78) and latanoprost (ASR 1.24, 99% CI 1.11-1.38) initiation. We found increased risk of inhaled corticosteroid initiation following initiation of timolol (ASR 1.43, 99% CI 1.13-1.81). There was increased risk of antidepressant initiation following timolol initiation (ASR 1.24, 99% CI 1.07-1.43), and latanoprost (ASR 1.16, 99% CI 1.03-1.31). There was also increased risk of hospitalization for bradycardia following timolol initiation (ASR 2.22,99% CI 1.15-4.31). CONCLUSION: Use of glaucoma eye drops recommended to be used with caution in co-morbidities is common and was associated with adverse outcomes. Awareness of co-morbidities is required in the selection and prescription of glaucoma eye drops.

Use of health services and medicines amongst Australian war veterans: a comparison of young elderly, near centenarians and centenarians.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Prevalence of potentially hazardous drug interactions amongst Australian veterans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Up to 21% of adverse drug event related hospital admissions are due to drug interactions. Clinical significance of drug interactions varies. * Studies which only identified drug interactions of potentially major clinical significance found lower prevalence, of between 2 and 16%. * Prevalence of drug interactions defined 'potentially hazardous' has had limited study, with no publications identified for the Australian population. WHAT THIS STUDY ADDS * In the study population of 287 074, 1.5% of subjects were dispensed potentially hazardous interacting drug pairs. * However, limited to populations on specific medicines, it was found that for patients dispensed verapamil, methotrexate, amiodarone, lithium, warfarin, cyclosporin and itraconazole, potentially hazardous interactions occurred at a rate greater than 5%. * These patients should be the focus of medication review programmes to avoid potentially serious adverse drug events. BACKGROUND 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. AIM The aim of this study was to assess the prevalence of potentially hazardous drug interactions in an elderly Australian veteran population. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Improving heart failure outcomes with pharmacist-physician collaboration: how close are we?

Improved management of chronic disease can improve health outcomes and has the potential to reduce health service costs. Heart failure is one of the chronic diseases in which improved management involving multidisciplinary care leads to improved health outcomes. Numerous studies have shown that multidisciplinary teams involving a doctor, pharmacist, nurse, health educator and/or a social worker can improve health outcomes for heart failure patients. Fewer studies have examined the effect of collaborative interventions that specifically involve pharmacists and physicians. This review focuses on the efficacy of pharmacist-physician collaborative medicines reviews in improving health outcomes for heart failure patients. The translation of results from randomized controlled trials to the practice setting is discussed, and barriers to the implementation of collaborative medicines reviews in practice are described.

Brand substitution or multiple switches per patient? An analysis of pharmaceutical brand substitution in Australia.

PURPOSE: To determine the number of times patients have brand and generic products substituted under Australia's Pharmaceutical Benefits Scheme (PBS) brand substitution policy. METHODS: A retrospective cohort study was conducted using Repatriation Pharmaceutical Benefits Scheme (RPBS) pharmacy claims data. Department of Veterans' Affairs (DVA) treatment card holders with at least two dispensings of atenolol, citalopram, enalapril, metformin, omeprazole or ramipril between 1 January 2001 and 28 February 2006 were included. Patients were followed from first dispensing until death, cessation or study end. The main outcome measure was the number of substitutions per patient during follow-up. Based on this, patients were defined as non-switchers, brand substitution or multiple switchers. RESULTS: Data for 160,145 patients were analysed. Overall more than 80% of patients either had no switches or demonstrated brand substitution. For all study drugs, patients were more likely to be non-switchers than have a brand substitution (RR range 2.6-9.4, p < 0.0001) and were more likely to be non-switchers than multiple switchers (RR range 3.2-35.9, p < 0.0001). Patients who switched were more likely to have a brand substitution than multiple switches (RR range 1.2-3.8, p < 0.0001). Multivariate logistic regression showed greater odds of being a multiple switcher with increasing number of prescribers and dispensing pharmacies, and increasing length of follow-up. CONCLUSIONS: Most patients in this study did not substitute products, and those who did were more likely to demonstrate brand substitution than have multiple switches. These results suggest that the brand substitution policy is having its intended effect for most patients.

Pharmaceutical brand substitution in Australia--are there multiple switches per prescription?

BACKGROUND: In Australia, brand substitution by pharmacists has been possible since 1994. There is no limit to the number of substitutions per prescription. Doctors have expressed concern that patients may receive a different product each time their prescription repeats are dispensed, which has the potential to confuse patients. It is unknown how often multiple substitutions per prescription occur. OBJECTIVES: We aimed to identify the number of switches per prescription for a range of medicines and to determine the number of different brand and generic products supplied on each prescription. METHODS: Repatriation Pharmaceutical Benefits Scheme prescription claims between 1 January 2001 and 28 February 2006 were identified for atenolol, citalopram, enalapril, metformin, omeprazole, ramipril, and simvastatin. Original prescriptions with five repeats and all supplies dispensed were included. Switches were identified if a different product was supplied on consecutive repeat dispensings. RESULTS: 533,279 original prescriptions were included. 488,735 (92%) had no switches on repeats and 37,513 (7%) had only one switch. Only 1% of all prescriptions had more than one switch identified on repeats, and in most cases only two different products were supplied. None of the prescriptions had a different product supplied on each dispensing. CONCLUSION AND IMPLICATIONS: Multiple switches per prescription are uncommon and multiple different products are rarely supplied on repeats of the same prescription. The rules of the brand substitution policy appear to be adequate in allowing brand choice for patients, without leading to multiple switches per prescription.