Background: Over the years, several observational studies and case reports have been published hypothesizing a potential association between the use of proton pump inhibitors (PPIs) and sexual dysfunctions in both male and female patients.
Objectives: We aimed to investigate the potential association between PPI use and sexual dysfunction onset using VigiBase, the World Health Organization international pharmacovigilance database.
Methods: All individual case safety reports of sexual dysfunctions containing PPIs (i.e. omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole) as suspected or interacting drugs until 4 September, 2024 were selected from VigiBase using the Standardised MedDRA Query "Sexual dysfunction". A descriptive analysis of the selected individual case safety reports was carried out. Potentially new safety signals were identified through a disproportionality analysis and calculated as a reporting odds ratio (ROR) along with a 95% confidence interval (CI), which were adjusted via Bonferroni correction for multiple testing. To account for age-related effects on sexual functions, a subgroup analysis was carried out by restricting the study population only to patients aged from 18 to 64 years.
Results: A total of 420,598 individual case safety reports concerning PPIs were collected in VigiBase during the study period. Of these, 841 containing at least one Preferred Term included in the "Sexual dysfunction" Standardised MedDRA Query reporting information on sex were retrieved. Overall, disproportionate reporting for omeprazole concerning erectile dysfunction (adjusted ROR, 1.76; 95% CI 1.54-2.01) was observed, while two statistically significant adjusted RORs for esomeprazole, i.e. genital discomfort (ROR, 3.66; 95% CI 1.34-10.04) and oestrogen deficiency (ROR, 3.80; 95% CI 1.03-13.99) in female patients were found. The subgroup analysis confirmed the statistically significant disproportionate reporting of erectile dysfunction for omeprazole (adjusted ROR: 1.80; 95% CI 1.49-2.16), and generated new potential safety signals including an omeprazole-induced libido decrease (adjusted ROR, 1.49; 95% CI 1.05-2.12) and esomeprazole-induced hypogonadism (adjusted ROR, 5.22; 95% CI 1.22-22.34) in male individuals, and omeprazole-induced genital discomfort (adjusted ROR, 3.55; 95% CI 1.13-11.09) in female individuals.
Conclusions: Findings of this study suggest the presence of safety signals of PPI-induced sexual dysfunctions, such as erectile dysfunction, genital discomfort and oestrogen deficiency. However, further observational studies are required to validate and further characterise these potential safety signals.
'Stems', which mark pharmacological relationships between substances, form the backbone of the International Nonproprietary Name (INN) system, developed by the WHO in the 1950s. In this paper, we propose using the INN stems to enhance pharmacovigilance signal detection. After analysis of historical cases and current pharmacovigilance practices, we discuss how stem-based classification could facilitate understanding of the adverse-effects profile of each stem, to be used as a benchmark for early identification of adverse drug reactions that deviate from expected class effects, in other words signals associated with newly marketed medicines or different uses of well-known medicines. We propose a potential framework for integrating stem-based analysis into existing pharmacovigilance databases, supplemented by artificial intelligence approaches, such as machine learning. While acknowledging limitations, such as stem variability and reporting bias, we suggest that this approach offers potential advantages for regulatory authorities and healthcare professionals in post-marketing surveillance. Implementation of stem-based post-marketing surveillance could enhance signal-detection efficiency and contribute to improved patient safety through earlier identification of unexpected adverse effects and adverse reactions.
Background: Incretin-based drugs, namely glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP-4) inhibitors, may have neuroprotective effects. Thus, we assessed whether these drugs are associated with a decreased risk of dementia among patients with type 2 diabetes.
Methods: Using the Clinical Practice Research Datalink from the UK, we formed two new user cohorts of patients at least 50 years of age with type 2 diabetes starting incretin-based drugs or sulfonylureas between 2007 and 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia were estimated separately for GLP-1 RAs and DPP-4 inhibitors using Cox proportional hazards models with propensity score fine-stratification weighting and inverse probability of censoring weights.
Results: Among 275,144 initiators of DPP-4 inhibitors or sulfonylureas, followed for 750,846 person-years, DPP-4 inhibitors were associated with a reduced dementia risk compared with sulfonylureas (4.4 vs. 5.7 events per 1000 person-years; HR 0.77, 95% CI 0.71-0.85). HRs decreased with increasing cumulative duration of use and dose. Similar associations were observed across dementia subtypes and individual DPP-4 inhibitors molecules. Among 181,215 initiators of GLP-1 RAs or sulfonylureas, followed for 530,415 person-years, GLP-1 RAs were associated with a similar reduction in dementia risk compared with sulfonylureas, although with high uncertainty (2.3 vs. 3.1 events per 1000 person-years; HR 0.74, 95% CI 0.46-1.18). The magnitude of the association increased with cumulative duration of use and dose but with high uncertainty.
Conclusions: In this population-based study, DPP-4 inhibitors, and possibly GLP-1 RAs, were associated with a reduced dementia risk compared with sulfonylureas.
Post-authorization studies (PAS) are often mandated by regulatory authorities as a condition of marketing authorization of pharmaceutical products. This article explores specific regulations and trends in China, Japan, and South Korea, highlighting the scientific and operational limitations that such PAS pose to the stakeholders in these regions including significant variations in regulatory requirements. Pharmacovigilance guidelines and publications on regional regulatory trends were reviewed. Active surveillance studies are widely adopted to fulfill post-authorization requirements in East Asia countries. These are primary data collection studies, i.e., traditional site-based studies that monitor the frequency of all adverse events (and clinical outcomes when requested) of the newly approved pharmaceutical product during a predefined treatment period. Such studies generally present limitations regarding the product's safety profile characterization, including the absence of a comparator group, selection bias, limited sample size, and considerable resources needed to conduct the studies. These limitations explain the trend toward hypothesis testing studies, conducted with secondary data (e.g., large electronic database studies) as preferred over traditional active surveillance studies. Harmonizing regulatory approaches and enhancing access to comprehensive data sources are critical for generating fit-for-purpose evidence to support regulatory decision making in these regions. Therefore, we propose a decision tool to assist with the planning of PAS in China, Japan, and South Korea. This article is endorsed by the International Society for Pharmacoepidemiology (ISPE).
Background: Medication-related adverse events in primary care are a leading cause of hospital admissions and mortality, commonly resulting from medication errors. Previous reviews have assessed interventions broadly across healthcare settings, but few have focused specifically on interventions targeting medication errors in primary care.
Objective: To evaluate the effectiveness of professional, organisational, and structural interventions in primary care settings in reducing medication-related hospital admissions, emergency department (ED) visits, and mortality.
Methods: We conducted a systematic review using the Cochrane methodology of systematic reviews and PRISMA guidelines for reporting. A comprehensive search of CENTRAL, MEDLINE, Embase, CINAHL, and trial registries up to October 2024 was undertaken. Randomised controlled trials conducted in primary care that assessed the impact of interventions on hospital admissions, ED visits, and mortality were included. Cochrane Risk of bias assessments and random-effects meta-analyses were performed.
Results: Interventions were classified according to the Cochrane Effective Practice and Organisation of Care criteria into Professional, Organisational and Structural. Sixty-two studies met the inclusion criteria. Professional interventions, including educational training and clinical decision tools, showed little to no effect on primary outcomes (risk ratio [RR] 1.01, 95% confidence interval [CI] 0.94-7.00 for hospital admissions; RR 1.00, 95% CI 0.98-1.02 for mortality; very-low to low certainty evidence). Organisational interventions, such as pharmacist-led medication reviews and multidisciplinary care models reduced the number of hospital admissions (RR 0.81, 95% CI 0.70-0.95; low-certainty evidence), but had uncertain effects on ED visits and mortality. Structural interventions, such as system-level support and quality monitoring, showed a reduction in hospital admissions (RR 0.90, 95% CI 0.83-0.97; moderate-certainty evidence), but evidence for other outcomes showed limited or very-low certainty.
Conclusion: Organisational and structural interventions in primary care may reduce medication-related hospital admissions and may help inform clinical practice through implementation of multidisciplinary care models and system-level quality monitoring approaches. However, the overall certainty of evidence is low to very low, highlighting the need for high-quality trials to better inform clinical practice and policy.
Introduction: Medication errors continue to cause inpatient harm in children and can be difficult to both identify and classify. Medication error studies often focus on assessing potential harm and there is little published data on actual harm from medication errors in children.
Objective: Our aim was to use multidisciplinary panels to identify and describe the actual harm resulting from prescribing and administration medication errors occurring at a major paediatric hospital.
Methods: We reviewed medication error data collected from retrospective medication record reviews to identify prescribing errors (26,369 orders, 19,692 errors and 3782 patients) and prospective direct observations (5137 dose administrations, 3663 errors and 1530 patients) to identify administration errors. Errors with the potential to cause serious harm and with evidence that the error reached the patient formed the dataset for our study. Case studies (n = 566) describing the prescribing and administration errors and a brief clinical summary were reviewed by multidisciplinary panels to determine whether there was evidence in patients' records of actual harm and to rate the severity of the harm identified.
Results: Actual harm was identified in 89 case studies and rated as minor in 43% (n = 38), moderate in 48% (n = 43) and serious in 9% (n = 8). There were no cases of harm rated as severe resulting in death. Antibacterials were the most common medications in cases with harm (n = 38/89 cases), and dosing errors (n = 32/89) the most common error type associated with harm. Younger patients had a significantly (t = 2.4, df = 198, p = 0.017) greater risk of actual harm from medication errors, and children aged under 12 months formed a higher proportion of those with actual harm (χ2 (1, N = 566) = 10.5, p = 0.001). The most frequent type of administration errors leading to harm were wrong infusion rates of intravenous antibiotics (19/67 cases); 12 of these instances occurred in children under 12 months. Administration errors were more likely to result in actual harm (1.83%; 67 /3663 errors) compared with prescribing errors (0.21%; 42/19,692).
Conclusions: We found higher rates of actual harm associated with medication errors in younger patients, wrong dose prescribing errors and intravenous antibiotic administration errors. These important findings provide opportunities for developing tailored interventions targeting identified high-risk areas to enable the successful reduction of preventable harms in paediatric patients.
Background: Despite ongoing efforts, the prescription of opioids is still common. Long-term opioid use has been associated with an increased risk of adverse cardiovascular outcomes.
Objective: We aimed to evaluate the association between opioid use and the risk of new-onset atrial fibrillation.
Methods: We performed a systematic review and meta-analysis of studies retrieved from MEDLINE and EMBASE databases according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines from inception to 29 January, 2024. The protocol was registered at PROSPERO (CRD42024512500). Two authors independently screened and extracted data from included studies. The quantitative analysis included only observational studies and results were synthesised by a pooled hazard ratio. Risk of bias was performed according to the ROBINS-I Cochrane tool, and the summary of evidence according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations).
Results: Four out of 782 studies met the inclusion criteria for a quantitative analysis with 24,006,367 participants. Overall, 153,734 were opioid users. The proportion of women ranged from 13.2 to 100% and the median age ranged from 34 to 65 years. Studies reported 991,263 cases of new-onset atrial fibrillation. The pooled analysis showed a significant association between use of opioids and new-onset atrial fibrillation (hazard ratio 1.96, 95% confidence interval 1.43-2.69 with high heterogeneity). A sensitivity analysis by removing the study with the largest cohort showed similar results to the main analysis. In the summary of findings, the certainty of the evidence according to GRADE was moderate.
Conclusions: We found a significant association between opioid use and the risk of new-onset atrial fibrillation. When prescribing opioids, the risk of new-onset atrial fibrillation should be considered, especially in the presence of other risk factors for atrial fibrillation.
Background: The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased owing to their favorable cardio-renal-metabolic effects. Some studies have raised concerns about a potential association between GLP-1RA use and malignancy. This study aimed to examine the association between GLP-1RA use and risk of hepatocellular carcinoma (HCC).
Methods: This retrospective propensity score (PS)-matched cohort study used data from the Veterans Health Administration (years 2006-2021). Using a new-user active comparator design, the study included adults who initiated a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP4i) as an active comparator and had no prior history of HCC or liver transplantation. The primary outcome was incident HCC. We developed a PS that included 133 variables encompassing diabetes severity, hepatic conditions, liver disease scores, vital signs, laboratory investigations, comorbidity scores, and use of other medication classes.
Results: Of 147,969 GLP-1RA and 263,664 DPP4i users, 100,248 pairs of GLP-1RA and DPP4i users were PS-matched. Hepatocellular carcinoma occurred in 302 (0.30%) GLP-1RA users and in 230 (0.23%) DPP4i users (odds ratio [OR]: 1.31, 95% confidence interval [95% CI]: 1.11-1.56). Secondary analysis, which stratified patients by duration of medication use, showed an increased risk of HCC in association with GLP-1RA use > 6 months, but similar HCC risk if medication use was < 6 months (OR: 0.96; 95% CI 0.68-1.35).
Conclusions: Glucagon-like peptide-1 receptor agonists use was associated with a modest but statistically significant increase in HCC risk versus DPP4i use. Although the reported benefits of GLP-1RA seem to far exceed this modest increased risk, further studies are warranted due to exponentially increasing GLP-1RA use and their broadening indications.
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