Medication review and deprescribing in different healthcare settings: a position statement from an Italian scientific consortium.

Recent medical advancements have increased life expectancy, leading to a surge in patients affected by multiple chronic diseases and consequent polypharmacy, especially among older adults. This scenario increases the risk of drug interactions and adverse drug reactions, highlighting the need for medication review and deprescribing to reduce inappropriate medications and optimize therapeutic regimens, with the ultimate goal to improving patients' health and quality of life. This position statement from the Italian Scientific Consortium on medication review and deprescribing aims to describe key elements, strategies, tools, timing, and healthcare professionals to be involved, for the implementation of medication review and deprescribing in different healthcare settings (i.e., primary care, hospital, long-term care facilities, and palliative care). Challenges and potential solutions for the implementation of medication review and deprescribing are also discussed.

Myasthenia Gravis Treatment: From Old Drugs to Innovative Therapies with a Glimpse into the Future.

Myasthenia gravis (MG) is a rare autoimmune disease that causes debilitating muscle weakness due to impaired neuromuscular transmission. Since most (about 80-90%) MG patients present autoantibodies against the acetylcholine receptor, standard medical therapy consists of symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine). In addition, considering the autoimmune basis of MG, standard therapy includes immunomodulating agents, such as corticosteroids, azathioprine, cyclosporine A, and cyclophosphamide. New strategies have been proposed for the treatment of MG and include complement blockade (i.e., eculizumab, ravulizumab, and zilucoplan) and neonatal Fc receptor antagonism (i.e., efgartigimod and rozanolixizumab). The aim of this review is to provide a detailed overview of the pre- and post-marketing evidence on the five pharmacological treatments most recently approved for the treatment of MG, by identifying both preclinical and clinical studies registered in clinicaltrials.gov. A description of the molecules currently under evaluation for the treatment of MG is also provided.

The pharmacological treatment of granulomatosis with polyangiitis: a review of clinical trials registered in clinicaltrials.gov and the International Clinical Trials Registry Platform.

To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (GPA), a rare disease. The aim of this study was to identify clinical trials from two study repositories. A review of clinical trials was conducted using publicly available data. Clinicaltrials.gov and International Clinical Trials Registry Platform were searched from inception until 25 September 2022. Only GPA-specific studies were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 (79%) studies were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate pharmacotherapy in this disease (62%). Most studies included all severity types (n = 51; 76%); the scope of almost half of the studies was remission induction (n = 33; 49%). The drug class which was by the most widely investigated in trials was the non-corticosteroid immunosuppressant drug class (46; 68.7%), monoclonal antibodies (32; 47.8%), and corticosteroids (31; 46.3%). There is a need for more GPA trials to generate evidence on effectiveness in terms of severity-specificity and maintenance of remission.

The pharmacological treatment of granulomatosis with polyangiitis: a review of clinical trials To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (referred to in this paper as GPA), a rare disease. The aim of this study was to identify such studies from two study archives. Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) were searched from inception until 25th September 2022. Studies recruiting GPA patients were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate the treatment of this disease through the administration of drugs. Most studies included all severity types (n = 51); the scope of almost half of the studies was to induce remission (n = 33). The drug classes which were the most widely investigated in trials were non-corticosteroid immunosuppressant drugs (n = 46), monoclonal antibodies (n = 32), and corticosteroids (n = 31). There is a need for more GPA clinical trials to generate evidence on effectiveness of drugs in terms of severity-specificity and maintenance of remission.

Effectiveness of homologous/heterologous booster COVID-19 vaccination schedules against severe illness in general population and clinical subgroups in three European countries.

Using 4 data-sources (Spain, Italy, United Kingdom) data and a 1:1 matched cohort study, we aimed to estimate vaccine effectiveness (VE) in preventing SARS-CoV-2 infections with hospitalisations (±30 days) and death (±56 days) in general population and clinical subgroups with homologous/heterologous booster schedules (Comirnaty-BNT and Spikevax-MOD original COVID-19 vaccines) by comparison with unboosted individuals, during Delta and beginning of Omicron variants. Hazard Ratio (HR, by Cox models) and VE ([1-HR]*100) were calculated by inverse probability weights. Between December 2020-February 2022, in adults without prior SARS-CoV-2 infection, we matched 5.5 million people (>1 million with immunodeficiency, 343,727 with cancer) with a booster (3rd) dose by considering doses 1 and 2 vaccine brands and calendar time, age, sex, region, and comorbidities (immunodeficiency, cancer, severe renal disease, transplant recipient, Down Syndrome). We studied booster doses of BNT and MOD administered after doses 1 and 2 with BNT, MOD, or Oxford-AstraZeneca during a median follow-up between 9 and 16 weeks. BNT or MOD showed VE ranging from 70 to 86% across data sources as heterologous 3rd doses, whereas it was 42-88% as homologous 3rd doses. Depending on the severity and available follow-up, 3rd-dose effectiveness lasted between 1 and 5 months. In people with immunodeficiency and cancer, protection across data sources was detected with both heterologous (VE = 54-83%) and homologous (VE = 49-80%) 3rd doses. Overall, both heterologous and homologous 3rd doses with BTN or MOD showed additional protection against the severe effects of SARS-CoV-2 infections for the general population and for patients at potentially high risk of severe COVID-19 (elderly, people with immunodeficiency and cancer) in comparison with two doses schemes during Delta or early Omicron periods. The early VE after vaccination may be due to less testing among vaccinated pairs and unknown confounders, deserving cautious interpretation. The VE wane over time needs further in-depth research to properly envisage when or whether a booster of those vaccines should be administered.

Global incidence and prevalence of differentiated thyroid cancer in childhood: systematic review and meta-analysis.

Objective: Differentiated thyroid cancer (DTC) is rare in childhood and adolescence although it represents the most frequent endocrine malignancy in this population. DTC includes both papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Most pediatric DTCs are PTCs, while FTCs are rare. To date, no systematic reviews on the global epidemiology of pediatric and adolescent DTC have been published. This systematic review and meta-analysis aims to estimate the overall incidence and prevalence of DTCs in patients aged 0-19 years. Methods: The systematic research was conducted from January 2000 to December 2021 through MEDLINE via PubMed, Cochrane Library, and Embase databases. Two separate meta-analyses were performed for PTC and FTC. Results: After the selection phase, a total of 15 studies (3,332 screened) met the inclusion criteria and are reported in the present systematic review. Five studies were conducted in Europe, five in North America, two in South America, one in Asia, one reported data for 49 countries and territories across the five continents, and one from both the USA and Africa. Most of the studies (n = 14) reported data obtained from national registries, and only one provided information collected from hospital medical records. Beyond the actual trend over time, our study reported a pooled global incidence rate (IR) of PTC and FTC in the pediatric age of 0.46 (95% CI: 0.33-0.59) and 0.07 (95% CI: 0.02-0.12) per 100,000 person-years, respectively. The highest IRs were recorded among Caucasian girls, and the lowest in black or other races/ethnicities. Conclusion: Our data confirm that DTC in the pediatric population is a rare condition. The pooled IRs of the studies included in this meta-analysis are ~0.5 for PTC, which is the most common histological type when both genders and all age groups are considered. The implementation of a prospective international registry on pediatric DTC, as part of the wider European Registries for Rare Endocrine Conditions, has been recently proposed. In addition to providing relevant information on the clinical behavior of this rare disease, standardization of data collection will be pivotal to fill current gaps and allow an accurate estimation of the real incidence and risk factors of DTC.

Development and testing of diagnostic algorithms to identify patients with acromegaly in Southern Italian claims databases.

Acromegaly is a rare disease characterized by an excessive production of growth-hormone and insulin-like growth factor 1, typically resulting from a GH-secreting pituitary adenoma. This study was aimed at comparing and measuring accuracy of newly and previously developed coding algorithms for the identification of acromegaly using Italian claims databases. This study was conducted between January 2015 and December 2018, using data from the claims databases of Caserta Local Health Unit (LHU) and Sicily Region in Southern Italy. To detect acromegaly cases from the general target population, four algorithms were developed using combinations of diagnostic, surgical procedure and co-payment exemption codes, pharmacy claims and specialist's visits. Algorithm accuracy was assessed by measuring the Youden Index, sensitivity, specificity, positive and negative predictive values. The percentage of positive cases for each algorithm ranged from 7.9 (95% CI 6.4-9.8) to 13.8 (95% CI 11.7-16.2) per 100,000 inhabitants in Caserta LHU and from 7.8 (95% CI 7.1-8.6) to 16.4 (95% CI 15.3-17.5) in Sicily Region. Sensitivity of the different algorithms ranged from 71.1% (95% CI 54.1-84.6%) to 84.2% (95% CI 68.8-94.0%), while specificity was always higher than 99.9%. The algorithm based on the presence of claims suggestive of acromegaly in ≥ 2 different databases (i.e., hospital discharge records, copayment exemptions registry, pharmacy claims and specialist visits registry) achieved the highest Youden Index (84.2) and the highest positive predictive value (34.8; 95% CI 28.6-41.6). We tested four algorithms to identify acromegaly cases using claims databases with high sensitivity and Youden Index. Despite identifying rare diseases using real-world data is challenging, this study showed that robust validity testing may yield the identification of accurate coding algorithms.

Assessing intravitreal anti-VEGF drug safety using real-world data: methodological challenges in observational research.

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.

Anti-hypertensive drugs deprescribing: an updated systematic review of clinical trials.

BACKGROUND: Polypharmacy is defined as the prescription of at least 5 different medicines for therapeutic or prophylactic effect and is a serious issue among elderly patients, who are frequently affected by multi-morbidity. Deprescribing is one of the proposed approaches to reduce the number of administered drugs, by eliminating those that are inappropriately prescribed. The aim of this systematic review is to provide an updated and systematic assessment of the benefit-risk profile of deprescribing of anti-hypertensive drugs, which are among the most commonly used drugs. METHODS: MEDLINE, EMBASE and The Cochrane Library were searched for studies assessing the efficacy and safety of anti-hypertensive drugs deprescribing in the period between January, 12,016 and December, 312,019. The quality of randomized clinical trials (RCTs) was assessed using the GRADE approach for the evaluation of the main outcomes. The risk of bias assessment was carried out using the Cochrane risk-of-bias tool. RESULTS: Overall, two RCTs were identified. Despite summarized evidence was in favor of anti-hypertensive deprescribing, the overall risk of bias was rated as high for each RCT included. According to the GRADE approach, the overall quality of the RCTs included was moderate regarding the following outcomes: systolic blood pressure < 150 mmHg after 12 weeks of follow-up, quality of life, frailty and cardiovascular risk. CONCLUSIONS: This updated systematic review of the efficacy and safety of anti-hypertensive treatment deprescribing found two recently published RCTs, in addition to the previous guideline of the National Institute for Health and Care Excellence (NICE). Evidence points towards non-inferiority of anti-hypertensive deprescribing as compared to treatment continuation, despite the quality of published studies is not high. High quality experimental studies are urgently needed to further assess the effect of deprescribing for this drug class in specific categories of patients.

Incidence of Skin Cancer in Patients With Chronic Inflammatory Cutaneous Diseases on Targeted Therapies: A Systematic Review and Meta-Analysis of Observational Studies.

Cancer is one of the several comorbidities that have been linked with chronic cutaneous inflammatory diseases namely psoriasis/psoriatic arthritis and hidradenitis suppurativa. Although the chronic inflammatory state, typical of the diseases, may induce pro-tumorigenic effects, the debate whether or not the drugs currently used in clinical practice do in facts increase a patient's risk of malignancy remains largely unsolved. The therapeutic armamentarium has been greatly enhanced at least in the last two decades with the advent of biologics, a heterogeneous group of laboratory-engineered agents with more in the pipeline, and other targeted small molecules. Among the organ systems, skin results as one of the most commonly affected, non-melanoma skin cancers being the main drug-induced manifestations as side effect in course of these treatments. The objective of the study is to systematically review the cutaneous malignancy risk of the newer therapies through an overview of meta-analyses and observational studies on the topic.

Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks.

The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed.

Pharmacokinetics of new oral anticoagulants: implications for use in routine care.

INTRODUCTION: Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant - TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages. In clinical practice, pharmacokinetic aspects of NOACs have to be carefully taken into account to optimize the benefit-risk profile of these drugs. Areas covered: An overview of major issues related to pharmacokinetics of NOACs, such as drug-drug interactions, over- and underdosage in special populations (e.g. elderly, underweight, and chronic kidney disease patients), and impact on adherence and persistence to NOACs therapy and ultimately clinical outcomes in real-world setting, is provided. Expert opinion: NOACs have been proven to be a better option than traditional anticoagulants due to better tolerability and ease of use. However, given specific pharmacokinetic characteristics, NOAC therapy has to be carefully tailored and monitored in relation to patient characteristics with the final goal of maximizing benefits and minimizing risks.