Pharmacoepidemiology of inappropriate medications – what’s the problem and how can we address it?

A paper presented at the Ageing medicine: from clinical insight to ageing better, Health Research Board (HRB) Conference, RCSI University of Medicine and Health Sciences in collaboration with the Discipline of Medical Gerontology, School of Medicine, Trinity College Dublin, 25 June 2025.</p

A comparison of contemporary versus older studies of aspirin for primary prevention

Objective: This study compares the benefits and harms of aspirin for primary prevention before and after widespread use of statins and colorectal cancer screening. Methods: We compared studies of aspirin for primary prevention that recruited patients from 2005 onward with previous individual patient meta-analyses that recruited patients from 1978 to 2002. Data for contemporary studies were synthesized using random-effects models. We report vascular (major adverse cardiovascular events [MACE], myocardial infarction [MI], stroke), bleeding, cancer, and mortality outcomes. Results: The IPD analyses of older studies included 95,456 patients for CV prevention and 25,270 for cancer mortality, while the four newer studies had 61,604 patients. Relative risks for vascular outcomes for older vs newer studies follow: MACE: 0.89 (95% CI 0.83-0.95) vs 0.93 (0.86-0.99); fatal hemorrhagic stroke: 1.73 (1.11-2.72) vs 1.06 (0.66-1.70); any ischemic stroke: 0.86 (0.74-1.00) vs 0.86 (0.75-0.98); any MI: 0.84 (0.77-0.92) vs 0.88 (0.77-1.00); and non-fatal MI: 0.79 (0.71-0.88) vs 0.94 (0.83-1.08). Cancer death was not significantly decreased in newer studies (RR 1.11, 0.92-1.34). Major hemorrhage was significantly increased for both older and newer studies (RR 1.48, 95% CI 1.25-1.76 vs 1.37, 95% CI 1.24-1.53). There was no effect in either group on all-cause mortality, cardiovascular mortality, fatal stroke, or fatal MI. Conclusions: In the modern era characterized by widespread statin use and cancer screening, aspirin does not reduce the risk of non-fatal MI or cancer death. There are no mortality benefits and a significant risk of major hemorrhage. Aspirin should no longer be recommended for primary prevention.</div

A comparison of contemporary versus older studies of aspirin for primary prevention

Objective: This study compares the benefits and harms of aspirin for primary prevention before and after widespread use of statins and colorectal cancer screening. Methods: We compared studies of aspirin for primary prevention that recruited patients from 2005 onward with previous individual patient meta-analyses that recruited patients from 1978 to 2002. Data for contemporary studies were synthesized using random-effects models. We report vascular (major adverse cardiovascular events [MACE], myocardial infarction [MI], stroke), bleeding, cancer, and mortality outcomes. Results: The IPD analyses of older studies included 95,456 patients for CV prevention and 25,270 for cancer mortality, while the four newer studies had 61,604 patients. Relative risks for vascular outcomes for older vs newer studies follow: MACE: 0.89 (95% CI 0.83-0.95) vs 0.93 (0.86-0.99); fatal hemorrhagic stroke: 1.73 (1.11-2.72) vs 1.06 (0.66-1.70); any ischemic stroke: 0.86 (0.74-1.00) vs 0.86 (0.75-0.98); any MI: 0.84 (0.77-0.92) vs 0.88 (0.77-1.00); and non-fatal MI: 0.79 (0.71-0.88) vs 0.94 (0.83-1.08). Cancer death was not significantly decreased in newer studies (RR 1.11, 0.92-1.34). Major hemorrhage was significantly increased for both older and newer studies (RR 1.48, 95% CI 1.25-1.76 vs 1.37, 95% CI 1.24-1.53). There was no effect in either group on all-cause mortality, cardiovascular mortality, fatal stroke, or fatal MI. Conclusions: In the modern era characterized by widespread statin use and cancer screening, aspirin does not reduce the risk of non-fatal MI or cancer death. There are no mortality benefits and a significant risk of major hemorrhage. Aspirin should no longer be recommended for primary prevention.</div

Assessing the diagnostic accuracy of multimedia messaging for the diagnosis of scaphoid fractures

Introduction: Use of smartphone messaging applications, such as WhatsApp, for communication within clinical teams is widespread. Various studies have shown multiple uses for smartphones and multimedia messaging in orthopedic clinical practice for coordinating clinical duties and diagnosing various injuries but none have assessed scaphoid fractures. Our aims were to: (1) assess diagnostic accuracy (sensitivity, specificity, positive predictive value, and negative predictive value) of viewing scaphoid X-rays on smartphones compared with desktop computers by using radiologist reports on the same X-rays as a reference test and (2) assess the intra-observer reliability of these studies. Methods: This was a prospective cross-sectional study of diagnostic accuracy using paired tests. The standard for reporting diagnostic accuracy (STARD) guidelines were used in its design. We asked orthopedic specialist registrars to interpret whether a scaphoid fracture was present on 20 scaphoid X-rays, obtained from the National Integrated Medical Imaging System (NIMIS). These were viewed on a desktop and on a smartphone. Data were then analyzed by using STATA 14 to run McNemar's test and to compare the sensitivity and specificity of the two index tests. Results: Phone and desktop interpretation had good sensitivity (72.7% and 78.2%) and specificity (75.2% and 77.9%) in assessing scaphoid fractures with no significant difference in sensitivity (p-value = 0.507) or specificity (p-value = 0.547). There was fair to moderate intra-observer reliability (kappa score 0.436; 95% confidence interval 0.295-0.577). Discussion: The fair to moderate scores of intra-observer agreement reflect the difficulty of diagnosing scaphoid fractures on X-rays. This study supports the use of smartphones for the diagnosis of scaphoid fractures.</div

Assessing the diagnostic accuracy of multimedia messaging for the diagnosis of scaphoid fractures

Introduction: Use of smartphone messaging applications, such as WhatsApp, for communication within clinical teams is widespread. Various studies have shown multiple uses for smartphones and multimedia messaging in orthopedic clinical practice for coordinating clinical duties and diagnosing various injuries but none have assessed scaphoid fractures. Our aims were to: (1) assess diagnostic accuracy (sensitivity, specificity, positive predictive value, and negative predictive value) of viewing scaphoid X-rays on smartphones compared with desktop computers by using radiologist reports on the same X-rays as a reference test and (2) assess the intra-observer reliability of these studies. Methods: This was a prospective cross-sectional study of diagnostic accuracy using paired tests. The standard for reporting diagnostic accuracy (STARD) guidelines were used in its design. We asked orthopedic specialist registrars to interpret whether a scaphoid fracture was present on 20 scaphoid X-rays, obtained from the National Integrated Medical Imaging System (NIMIS). These were viewed on a desktop and on a smartphone. Data were then analyzed by using STATA 14 to run McNemar's test and to compare the sensitivity and specificity of the two index tests. Results: Phone and desktop interpretation had good sensitivity (72.7% and 78.2%) and specificity (75.2% and 77.9%) in assessing scaphoid fractures with no significant difference in sensitivity (p-value = 0.507) or specificity (p-value = 0.547). There was fair to moderate intra-observer reliability (kappa score 0.436; 95% confidence interval 0.295-0.577). Discussion: The fair to moderate scores of intra-observer agreement reflect the difficulty of diagnosing scaphoid fractures on X-rays. This study supports the use of smartphones for the diagnosis of scaphoid fractures.</div

A comparison of contemporary versus older studies of aspirin for primary prevention.

Background: Recent aspirin trials have not shown similar benefits for primary prevention as older studies.Objective: To compare benefits and harms of aspirin for primary prevention before and after widespread use of statins and colorectal cancer screening.Methods: We compared studies of aspirin for primary prevention that recruited patients from 2005 onward with previous individual patient data (IPD) meta-analyses that recruited patients from 1978 to 2002. Data for contemporary studies were synthesized using random-effects models. We report vascular [major adverse cardiovascular events (MACE), myocardial infarction (MI) and stroke], bleeding, cancer and mortality outcomes.Results: The IPD analyses of older studies included 95 456 patients for CV prevention and 25 270 for cancer mortality, while the four newer studies had 61 604 patients. Relative risks for vascular outcomes for older versus newer studies follow: MACE: 0.89 [95% confidence interval (CI) 0.83-0.95] versus 0.93 (0.86-0.99); fatal haemorrhagic stroke: 1.73 (1.11-2.72) versus 1.06 (0.66-1.70); any ischaemic stroke: 0.86 (0.74-1.00) versus 0.86 (0.75-0.98); any MI: 0.84 (0.77-0.92) versus 0.88 (0.77-1.00); and non-fatal MI: 0.79 (0.71-0.88) versus 0.94 (0.83-1.08). Cancer death was not significantly decreased in newer studies (1.11, 0.92-1.34). Major haemorrhage was significantly increased (older studies RR 1.48, 95% CI 1.25-1.76 versus newer studies RR 1.37, 1.24-1.53). There was no effect on all-cause mortality, cardiovascular mortality, fatal stroke or fatal MI.Conclusions: Per 1200 persons taking aspirin for primary prevention for 5 years, there will be 4 fewer MACEs, 3 fewer ischaemic strokes, 3 more intracranial haemorrhages and 8 more major bleeding events. Aspirin should no longer be recommended for primary prevention.</p

Deprescribing and medicines optimisation, two sides of the same coin? Considerations for design of interventional studies

Interventions to promote deprescribing are an important focus of research. Key decisions for such interventions are whether to target one or multiple medicines, and whether the intervention scope is deprescribing, or also extends to other aspects of medicines optimisation. This article reflects on how these decisions impact on developing interventions and measuring outcomes. Many behavioural strategies are common to deprescribing and medicines optimisation, however operationalisation may differ. Aspects to consider include the burden of multiple simple interventions versus one complex intervention, the extent to which the approach to deprescribing can be specified as part of the intervention, and variability in how the intervention is delivered across patients and providers. Outcomes should be selected based on the intervention target and scope and the audience for whom evidence is being produced. These may include medication changes, and process outcomes to assess intervention delivery. Targeting single medications may allow for a focus on specific clinical or symptom-related outcomes, but a broader perspective may be needed in a generalist setting in the context of multimorbidity and which also considers the patient's priorities. Cost-related outcomes are also important to inform implementation decisions, and modelling approaches may be more feasible for interventions targeting single medications. </p

Efficacy and safety of sacubitril/valsartan in the treatment of heart failure: protocol for a systematic review incorporating unpublished clinical study reports [version 1; peer review: 3 approved]

Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure with reduced ejection fraction. The evidence base for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in the trial design have been highlighted in recent medical literature, necessitating a thorough review of the evidence base for sacubitril/valsartan.Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care with either an active comparator or placebo as a control. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected trials for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the recently updated Cochrane Risk of Bias tool version 2. Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes.Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol has been submitted for registration on PROSPERO.</div

Payments reported by the pharmaceutical industry in Ireland from 2015 to 2019: An observational study.

Background: The pharmaceutical industry makes large numbers of payments to healthcare organisations (HCOs) and healthcare professionals (HCPs). Ireland has a large pharmaceutical industry presence and national debate on legislating for greater industry payment transparency. This study characterises payments in Ireland to HCPs and HCOs during 2015-2019, and the content, consistency and methodology of the data source.Methods: An observational study of TransfersOfValue.ie, the disclosure website for the Irish Pharmaceutical Health Association pharmaceutical companies. We conducted a quantitative analysis, summarising payments to HCOs, HCPs and for research and development (R&D). We quantified disclosure rates of names for HCP and HCO payment recipients. We also conducted a content analysis of the methodology notes and website content.Results: Payments totalling €163 million were reported by 47 companies during 2015-2019, €84.6 million for R&D, with non-R&D payments of €45.1 million to HCOs and €33.6 million to HCPs. HCOs were named for 91.2% of payments, and HCPs for 55.1-62.8% across study years. For 2019, ten companies disclosed >€1 million in payments, and three disclosed >€1 million in HCO and HCP payments. Content analysis of 132 data reports and 46 methodology notes indicated substantial variation in methodologies for reporting between companies.Conclusions: There are substantial payments in Ireland, often the recipient is undisclosed, and companies differ in their reporting. A mandatory disclosure system could enhance transparency.</div

Fixed-dose combination antihypertensives and risk of medication errors

Objective: While fixed-dose combinations (FDC) can improve adherence, they may add complexity to the prescribing/dispensing process, potentially increasing risk of medication errors. This study aimed to determine if prescriptions for antihypertensive FDCs increase the risk of therapeutic duplication and drug-drug interactions (DDI).Methods: This retrospective observational study used administrative pharmacy claims data from the Irish Primary Care Reimbursement Service. Prescriptions dispensed to adults in 2015 were included if they contained an antihypertensive FDC, or the same drugs prescribed separately. The outcomes were therapeutic duplication and potentially serious DDI involving FDC drugs. Relative risk (RR) of these outcomes, adjusted for prescription and patient factors, was determined using generalised linear models with Poisson distributions and propensity score matching.Results: This study included 307 833 FDC prescriptions (67.0%) and 151 632 separate component prescriptions. Half of patients prescribed FDCs were female with a mean age of 67.1 (SD 12.5) years and, compared with separate component prescriptions, FDCs were less often coprescribed with other cardiovascular medications. Therapeutic duplication occurred in 0.8% of prescriptions, most often involving calcium channel blockers, and 10.6% contained a DDI (most often amlodipine and simvastatin). The RR of therapeutic duplication on FDC prescriptions compared with separate component prescriptions was 1.46 (95% CI 1.17 to 1.83) and the adjusted RR was 2.06 (95% CI 1.64 to 2.60). For DDIs, there was no significant difference between FDC and separate component prescriptions after confounder adjustment.Conclusions: This study found FDCs were associated with increased risk of duplication. When considering prescribing FDCs, this safety consideration should be weighed against potential benefits.</p