Giada Crescioli

Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis

To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0‐18 years).

Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review

Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb–drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract.

Ticagrelor recommended over clopidogrel, only in clinical trials or also in a real-world practice?

We read with interest the review entitled ‘Ticagrelor recommended over clopidogrel in ST-segment elevation myocardial infarction (STEMI) patients’ by Pappas et al. [1]. This is an expert evaluation of the pharmacological characteristics of ticagrelor vs. clopidogrel in acute coronary syndrome (ACS) patients. Ticagrelor is an oral drug that acts by inhibiting the platelet P2Y12 receptors in a reversible manner [2] and is recommended, 90 mg twice a day, for acute (in-hospital) and post-discharge therapy [3]. Based on the results from the phase 3 trial that led to ticagrelor’s approval, the PLATelet inhibition and patient Outcomes (PLATO) study, the drug shows a clear benefit over clopidogrel in preventing cardiovascular events and death in patients with ACS [4]. Regarding the efficacy profile of ticagrelor vs. clopidogrel in a clinical setting, the authors state that ticagrelor represents the new standard of care for the management of patients with STEMI intended for primary percutaneous coronary intervention (PCI). We agree with the authors’ statement [1] that a clinician deciding whether to use ticagrelor or clopidogrel should carefully consider the contraindications, special warnings, and precautions for these drugs. Clinical data show that ticagrelor treatment is generally well tolerated, and discontinuation rates are comparable to those observed for clopidogrel [5,6]. Nevertheless, few post-marketing studies, i.e., conducted in the real-world setting, evaluated ticagrelor’s safety profile [2,7,8]. An important example is ticagrelor-related dyspnea. In several clinical studies [5], dyspnea incidence in ticagrelor-treated subjects varied between 10%, in the Dose confIrmation Study assessing antiPlatelet Effects of AZD6140 vs. clopidogRel in non– STsegment Elevation myocardial infarction (DISPERSE) study (200 patients with atherosclerosis treated for 4 weeks with 100 or 200 mg/day) [9], and 38.6%, in The ONSET and OFFSet of the Antiplatelet Effects of Ticagrelor (ONSET/OFFSET) study (123 subjects with stable coronary artery disease) [10]. In the PLATO trial, 13.8% of ticagrelor-treated patients reported dyspnea compared with 7.8% of the clopidogrel-treated ones (p < 0.001) [11]. During our activities of intensive pharmacovigilance monitoring in emergency departments (EDs) in Florence (Italy), we encountered several cases of dyspnea, in particular one of them developed in a poststenting ACS 90-year-old man and was associated with the first administration of ticagrelor (90 mg/day plus acetylsalicylic acid 100 mg/day) [12]. In this case, ticagrelor-related dyspnea, often described in clinical studies as mild and moderate [11], was severe, caused an ED admission, and replaced with a well-tolerated clopidogrel therapy. Furthermore, several studies have addressed the safety of ticagrelor with regard to dyspnea and other adverse drug reactions (ADRs). In a single-center study of 100 patients treated with aspirin and ticagrelor 90 mg twice daily following PCI for ACS, ticagrelor was discontinued in nine patients (9%) because of dyspnea within the first 30 days of treatment [13]. Sanchez-Galian et al. conducted a retrospective study on a university hospital registry and identified 113 consecutive patients treated with ticagrelor after ACS [14]. Within the first week of treatment, 15 patients (14%) had dyspnea judged by the investigator to be related to ticagrelor. Gaubert et al. conducted a multicenter, observational prospective study and observed that the rate of ticagrelor withdrawal due to dyspnea was 17% (27 out of 164 patients) [8]. Based on our pharmacovigilance experience, what we observed for dyspnea might happen for other potential ADRs related to ticagrelor use (e.g. bleeding) [15]. Although randomized controlled trials (RCTs) are preferable when evidences of treatment efficacy must be provided, the situation becomes more complex when the risk of adverse effects needs to be assessed. The lack of adverse events data from RCTs is well known; RCTs often do not include large population sample or do not have adequate follow-up to identify rare adverse effects (or adverse effects that happen months/years after the intervention), and the quality of safety data may be poor. Thus, generalizability for RCT results is limited because patients at high risk of adverse effects, medically frail, or with multiple comorbidity are often excluded [16,17]. In some trials, there is a run-in period where those who cannot tolerate the study medication or show adherence to whatever they are assigned to (possibly including placebo) are not randomized. In order to overcome these limitations, data from observational studies should be taken in consideration for the safety profile evaluation of a particular intervention. In our opinion, in order to limit uncertainty and take decisions based on valid evidences, it is necessary to combine the results from both observational and clinical studies when

STARD 2015 was reproducible in a large set of studies on glaucoma

Aim To investigate the reproducibility of the updated Standards for the Reporting of Diagnostic Accuracy Studies tool (STARD 2015) in a set of 106 studies included in a Cochrane diagnostic test accuracy (DTA) systematic review of imaging tests for diagnosing manifest glaucoma. Methods One senior rater with DTA methodological and clinical expertise used STARD 2015 on all studies, and each of three raters with different training profiles assessed about a third of the studies. Results Raw agreement was very good or almost perfect between the senior rater and an ophthalmology resident with DTA methods training, acceptable with a clinical rater with little DTA methods training, and only moderate with a pharmacology researcher with general, but not DTA, systematic review training and no clinical expertise. The relationship between adherence with STARD 2015 and methodological quality with QUADAS 2 was only partial and difficult to investigate, suggesting that raters used substantial context knowledge in risk of bias assessment. Conclusions STARD 2015 proved to be reproducible in this specific research field, provided that both clinical and DTA methodological expertise are achieved through training of its users.

Prescribing patterns of allopurinol and febuxostat according to directives on the reimbursement criteria and clinical guidelines: analysis of a primary care database

Abstract Objective: According to American clinical guidelines, allopurinol and febuxostat may be prescribed as first-line therapy to treat hyperuricemia. However, the Italian Medicines Agency directive, called Nota 91, allows the reimbursement of second-line febuxostat in the case of failure and/or intolerance of a previous allopurinol therapy, so partially embracing European League Against Rheumatism recommendations and the British Society for Rheumatology Guideline. Such inconsistency might lead to heterogeneity among General Practitioners (GPs) in treatment of hyperuricemia. This study, therefore, aimed to evaluate the prescribing behavior of GPs in terms of compliance with Nota 91 and/or official guidelines. Methods: Using the Health Search Database, a retrospective cohort study was conducted to evaluate the patterns of use of allopurinol and febuxostat between 2011 and 2016. Results: In total, 44,257 and 5837 patients were prescribed with allopurinol and febuxostat, respectively. Among febuxostat users, 4321 (74%) had a previous allopurinol treatment; 92% of switches to febuxostat were related to hyperuricemia, whereas 9% of switchers presented intolerance to allopurinol; 26% of patients were prescribed with febuxostat as first-line therapy. The presence of diabetes and/or moderate/severe renal disease were statistically significant determinants of febuxostat use as first-line therapy. Conclusion: Prescriptions of febuxostat were highly compliant to Nota 91. Only a sub-group of frontline prescriptions of febuxostat were mainly driven by the presence of renal dysfunction, which is able to increase the risk of allopurinol intolerance and/or inefficacy. These findings indicate that GPs’ prescribing behavior for hyperuricemia is highly compliant with both regulatory directives and clinical guidelines.

The use of complementary and alternative medicines during breastfeeding: results from the Herbal supplements in Breastfeeding InvesTigation (HaBIT) study

The use of complementary and alternative medicines (CAMs) during breastfeeding is increasing, mainly because of their presumed greater safety compared with conventional medications. However, CAMs can cause serious adverse effects, and there is limited high‐quality evidence supporting their use during lactation. In Italy, specific investigations on the attitude of lactating women towards CAMs are lacking. The Herbal supplements in Breastfeeding InvesTigation (HaBIT) study aimed to explore attitudes to and knowledge on CAMs among lactating women.

A systematic review of the risk factors for clinical response to opioids for all-age patients with cancer-related pain and presentation of the paediatric STOP pain study

BackgroundInter-patient variability in response to opioids is well known but a comprehensive definition of its pathophysiological mechanism is still lacking and, more importantly, no studies have focused on children. The STOP Pain project aimed to evaluate the risk factors that contribute to clinical response and adverse drug reactions to opioids by means of a systematic review and a clinical investigation on paediatric oncological patients.MethodsWe conducted a systematic literature search in EMBASE and PubMed up to the 24th of November 2016 following Cochrane Handbook and PRISMA guidelines. Two independent reviewers screened titles and abstracts along with full-text papers; disagreements were resolved by discussion with two other independent reviewers. We used a data extraction form to provide details of the included studies, and conducted quality assessment using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.ResultsYoung age, lung or gastrointestinal cancer, neuropathic or breakthrough pain and anxiety or sleep disturbance were associated to a worse response to opioid analgesia. No clear association was identified in literature regarding gender, ethnicity, weight, presence of metastases, biochemical or hematological factors. Studies in children were lacking. Between June 2011 and April 2014, the Italian STOP Pain project enrolled 87 paediatric cancer patients under treatment with opioids (morphine, codeine, oxycodone, fentanyl and tramadol).ConclusionsFuture studies on cancer pain should be designed with consideration for the highlighted factors to enhance our understanding of opioid non-response and safety. Studies in children are mandatory.Trial registrationCRD42017057740.

Diagnostic accuracy research in glaucoma is still incompletely reported: An application of Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015

Background Research has shown a modest adherence of diagnostic test accuracy (DTA) studies in glaucoma to the Standards for Reporting of Diagnostic Accuracy Studies (STARD). We have applied the updated 30-item STARD 2015 checklist to a set of studies included in a Cochrane DTA systematic review of imaging tools for diagnosing manifest glaucoma. Methods Three pairs of reviewers, including one senior reviewer who assessed all studies, independently checked the adherence of each study to STARD 2015. Adherence was analyzed on an individual-item basis. Logistic regression was used to evaluate the effect of publication year and impact factor on adherence. Results We included 106 DTA studies, published between 2003–2014 in journals with a median impact factor of 2.6. Overall adherence was 54.1% for 3,286 individual rating across 31 items, with a mean of 16.8 (SD: 3.1; range 8–23) items per study. Large variability in adherence to reporting standards was detected across individual STARD 2015 items, ranging from 0 to 100%. Nine items (1: identification as diagnostic accuracy study in title/abstract; 6: eligibility criteria; 10: index test (a) and reference standard (b) definition; 12: cut-off definitions for index test (a) and reference standard (b); 14: estimation of diagnostic accuracy measures; 21a: severity spectrum of diseased; 23: cross-tabulation of the index and reference standard results) were adequately reported in more than 90% of the studies. Conversely, 10 items (3: scientific and clinical background of the index test; 11: rationale for the reference standard; 13b: blinding of index test results; 17: analyses of variability; 18; sample size calculation; 19: study flow diagram; 20: baseline characteristics of participants; 28: registration number and registry; 29: availability of study protocol; 30: sources of funding) were adequately reported in less than 30% of the studies. Only four items showed a statistically significant improvement over time: missing data (16), baseline characteristics of participants (20), estimates of diagnostic accuracy (24) and sources of funding (30). Conclusions Adherence to STARD 2015 among DTA studies in glaucoma research is incomplete, and only modestly increasing over time.

Ticagrelor safety profile in real-life setting of acute coronary syndrome patients

We read with great interest the paper by Chen et al, the first of its kind that investigated the efficacy and safety of ticagrelor versus clopidogrel in patients with acute coronary syndrome (ACS) in Asia (including Taiwan) in a real-life clinical setting. In their analysis, the authors reported that a higher number of patients treated with ticagrelor experienced dyspnea as compared with those patients treated with clopidogrel in both overall (25.0% vs. 14.6%, p< 0.001) and propensity-matched (21.0% vs. 11.6%, p1⁄4 0.01) cohorts. Furthermore, they affirmed that the incidence of dyspnearelated discontinuation of P2Y12 antagonist treatment tended to be higher in the ticagrelor group by propensity score matching. In particular, their study showed that when compared with clopidogrel treatment, ticagrelor causes a fourfold increase in the incidence of dyspnea and required discontinuation of a P2Y12 antagonist. During our intensive pharmacovigilance activities in emergency departments (EDs), we encountered several cases of dyspnea associated with ticagrelor treatment. In particular, we observed a case of severe paroxysmal nocturnal dyspnea developed in a poststenting 90-year-old man associated with the first use of ticagrelor. We then conducted a retrospective cohort study in the EDs of the Florence (Italy) metropolitan area to define the occurrence rate of dyspnea leading to ED admission in ACS for patients treated with ticagrelor. Among communitydwelling patients who were prescribed ticagrelor from 2012e2014, the overall dyspnea occurrence was about 2% (1.86%, 20/1073 patients). All cases of outpatient dyspnea were severe and caused an ED admission. The median time between the first prescription of ticagrelor and the onset of dyspnea was 47 days (interquartile range: 10e185). Although the clinical data showed that ticagrelor treatment is generally well-tolerated and discontinuation rates are comparable to those observed for clopidogrel, the Chen et al observational study fits perfectly within this context, since