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Intravitreal anti-vascular endothelial growth factor (VEGF) drugs aflibercept and ranibizumab are used in neovascular retinal diseases but may be associated with non-ocular haemorrhage. Our objective was to compare the risk of non-ocular haemorrhage with intravitreal aflibercept versus intravitreal ranibizumab and with individual intravitreal anti-VEGFs versus intravitreal dexamethasone. A retrospective cohort study was conducted using four Italian claims databases, covering 18 million inhabitants from 2011 to 2016. Incident aflibercept users were matched 1:4 to incident ranibizumab users. The outcome was incident non-ocular haemorrhage requiring hospitalisation. Incidence per 1000 person-years (PYs) was estimated. Patients were followed for 180 days using an intention-to-treat (ITT) approach. An as-treated (AT) approach was also employed, using grace periods of 60 or 90 days. Analyses were repeated for aflibercept versus dexamethasone and ranibizumab versus dexamethasone. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. We identified incident users of intravitreal ranibizumab (n = 21,766), aflibercept (n = 3150) and dexamethasone (n = 3900). The incidence of haemorrhage was four events per 1000 PYs for each drug. Aflibercept was not associated with increased risk versus ranibizumab at 180 days (HR 0.97 [95% CI 0.37–2.56]). Results were consistent in the AT analysis (HR 1.19 [95% CI 0.52–2.75]). No increased risk was found for aflibercept and ranibizumab at 180 days versus dexamethasone (HR 0.70 [95% CI 0.30–2.60] and HR 0.67 [95% CI 0.33–1.38], respectively). No association was identified between intravitreal aflibercept and non-ocular haemorrhage versus ranibizumab. A comparable risk for these intravitreal anti-VEGFs and intravitreal dexamethasone was observed.

Background: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. Objectives: To analyse and describe PAS in the EU PAS register, with focus on MDS. Methods: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. Results: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). Conclusions: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Introduction It is generally acknowledged that the ocular safety profile of intravitreal anti-VEGF drugs is acceptable, while the burden of systemic safety of these intravitreal agents is still being debated. The evaluation of the systemic safety of these drugs using real-world data (RWD), such as spontaneous reporting systems (SRS), electronic medical records (EMRs) and claims databases has several advantages, including the capture of outcomes among real-world populations over long observation periods. Nevertheless, there is a relatively small body of research exploring the post-marketing safety of these drugs. Areas covered The aim of this scoping review is to outline and discuss some of the methodological challenges to be faced when investigating the systemic safety of intravitreal anti-VEGF drugs using different sources of RWD. Expert opinion Such challenges include the selection of the most suitable data source, taking into account how well drug utilization is captured and whether the outcomes and covariates of interest can be captured. The strengths and limitations of some analytic methods that can be used to quantify risk, such as the intention-to-treat approach and the as-treated approach, complement each other, and using these together provides a more balanced analysis.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. The prognosis for the neovascular type of advanced AMD improved with the introduction of biological drugs with antiangiogenic properties, beginning with off-label bevacizumab, which was first used intravitreally in 2006. These drugs target newly formed vessels that grow beneath the center of the retina, causing loss of central vision, and they can help to maintain or improve vision. Repeated intravitreal injections are needed to achieve prolonged inhibition of proangiogenic cytokines, primarily vascular endothelial growth factor (VEGF). Major regulatory agencies have approved several molecules for AMD treatment, including ranibizumab, aflibercept, and brolucizumab. The development of further drugs was mainly targeted at prolonging anti-VEGF inhibition-thus reducing the frequency of injections-and expanding the biological targets of proangiogenic cytokine inhibition. Finally, biosimilars are already being marketed in some countries, allowing the containment of costs of AMD treatment, which are growing steadily in many settings because of the need for long-term treatment. This review summarizes the properties and clinical profiles of anti-VEGF biological drugs that are approved to treat neovascular AMD as well as ongoing research on molecules that may be marketed in the near future.

Aim: Primary endpoint was to report polypharmacy distribution in the general population vs ≥65 years old people and to examine the frequency of drug–drug interactions (DDIs) in the Health Local Unit of Palermo, Italy, in relationship with patients’ age. Methods: Drug prescription data for the year 2014 were extracted from the database of the Local Health Unit of Palermo Province, Italy. Patients were divided into five age groups (0–13, 14–64, 65–69, 70–74, and ≥75 year old). The detection of potential DDIs in polypharmacy profiles was performed with NavFarma software (Infologic srl, Padova, Italia), with DDI classification provided by tool Micromedex Drug Reax (Truven Health Analitics, Michigan, USA). Results: We analyzed data of 1,324,641 patients, and 15,801,191 medical prescription were recorded; of these, 11,337,796 regarded chronic conditions. The drug prescriptions reached the highest values in the 65–69 and 70–74 age groups (p = 0.005 and p = 0.008 vs age 14–64 respectively). An overall amount of 6,094,373 DDIs were detected, of which 47,173 were contraindicated. Median number of DDIs was higher in 65–69 and 70–74 age groups (p = 0.008 and p = 0.012 vs age 14–64, respectively). Regarding contraindicated DDIs a significant difference was detected comparing 14–64 vs ≥65 age groups (p = 0.010 vs 65–69 group, p= 0.005 vs 70–74 group and ≥75 group). Conclusions: Polypharmacy is a phenomenon acquiring increasing dimensions also in our province. It interests particularly the older subjects, and assumes a dramatic accent when it is put in relationship with the frequency of DDIs. A proactive vigilance about potential life threatening drug interactions is mandatory.