Francesco Salvo

Data mining on electronic health record databases for signal detection in pharmacovigilance: which events to monitor?

Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post‐marketing drug safety surveillance. The EU‐ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high‐priority events.

Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies

To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti‐inflammatory drugs (NSAIDs).

Cardiovascular and Gastrointestinal Safety of NSAIDs: A Systematic Review of Meta-Analyses of Randomized Clinical Trials

As part of the Safety of Non‐Steroidal Anti‐Inflammatory Drugs (SOS) Project, we reviewed the incidence of cardiovascular (CV) and gastrointestinal (GI) events associated with the use of this category of drugs. We collected data from published meta‐analyses (MAs) of clinical trials of nonsteroidal anti‐inflammatory drugs (NSAIDs). The Medline, Cochrane, ISI, and SCOPUS databases were systematically searched for MAs of NSAID clinical trials that could potentially contain data on adverse incidents such as myocardial infarction (MI), cerebrovascular events (CeVs), stroke, thromboembolic events (ThEs), heart failure (HF), gastrointestinal bleeding (GIB), and perforation, ulcer, and bleeding (PUB). From 1,733 identified references, 29 MAs were selected for the review. This allowed 109 estimations of incidence rates of CV adverse events and 26 estimations of incidence rates for GI adverse events. No data were found on hemorrhagic stroke or LGIB. Coxibs were studied in more MAs than traditional NSAIDs were (21 MAs for coxibs vs. 7 for traditional NSAIDs; one meta‐analysis studied both). Many NSAIDs were not considered in any of the MAs. Our systematic review of MAs included information on the incidence of CV and GI events and identified important knowledge gaps regarding, in particular, the CV safety of traditional NSAIDs.

A Reference Standard for Evaluation of Methods for Drug Safety Signal Detection Using Electronic Healthcare Record Databases

BackgroundThe growing interest in using electronic healthcare record (EHR) databases for drug safety surveillance has spurred development of new methodologies for signal detection. Although several drugs have been withdrawn postmarketing by regulatory authorities after scientific evaluation of harms and benefits, there is no definitive list of confirmed signals (i.e. list of all known adverse reactions and which drugs can cause them). As there is no true gold standard, prospective evaluation of signal detection methods remains a challenge.ObjectiveWithin the context of methods development and evaluation in the EU-ADR Project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge), we propose a surrogate reference standard of drug-adverse event associations based on existing scientific literature and expert opinion.MethodsThe reference standard was constructed for ten top-ranked events judged as important in pharmacovigilance. A stepwise approach was employed to identify which, among a list of drug-event associations, are well recognized (known positive associations) or highly unlikely (‘negative controls’) based on MEDLINE-indexed publications, drug product labels, spontaneous reports made to the WHO’s pharmacovigilance database, and expert opinion. Only drugs with adequate exposure in the EU-ADR database network (comprising ≈60 million person-years of healthcare data) to allow detection of an association were considered. Manual verification of positive associations and negative controls was independently performed by two experts proficient in clinical medicine, pharmacoepidemiology and pharmacovigilance. A third expert adjudicated equivocal cases and arbitrated any disagreement between evaluators.ResultsOverall, 94 drug-event associations comprised the reference standard, which included 44 positive associations and 50 negative controls for the ten events of interest: bullous eruptions; acute renal failure; anaphylactic shock; acute myocardial infarction; rhabdomyolysis; aplastic anaemia/pancytopenia; neutropenia/agranulocytosis; cardiac valve fibrosis; acute liver injury; and upper gastrointestinal bleeding. For cardiac valve fibrosis, there was no drug with adequate exposure in the database network that satisfied the criteria for a positive association.ConclusionA strategy for the construction of a reference standard to evaluate signal detection methods that use EHR has been proposed. The resulting reference standard is by no means definitive, however, and should be seen as dynamic. As knowledge on drug safety evolves over time and new issues in drug safety arise, this reference standard can be re-evaluated.

Statin-associated psychiatric adverse events: a case/non case evaluation of an Italian database of spontaneous adverse drug reaction reporting

AbstractBackground: The inhibitors of HMG-CoA reductase (‘statins’) are widely prescribed hypolipidaemic drugs, which have been evaluated in several clinical trials involving hundreds of thousands of patients. From a safety perspective, both clinical trials and post-marketing surveillance have demonstrated that statins are generally well tolerated, with rare serious adverse drug reactions (ADRs) that affect mainly muscle, liver and kidney. However, recent interest has been focused on a potential risk of psychiatric ADRs associated with statins, including memory loss, depression, suicidality, aggression and antisocial behaviour. Special attention is currently being paid to the potential for statin-induced sleep disorders. Objective: To investigate the hypothesis that statins may be associated with psychiatric adverse events using quantitative and qualitative signal analysis. Methods: The Interregional Group of Pharmacovigilance database holds reports of suspected ADRs submitted since 1988 from eight Italian regions. In the present analysis, only reports ranked at least ‘possible’, according to WHO causality assessment criteria, were considered. Association between statins and psychiatric events was assessed by the case/non-case methodology, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Cases were defined as patients with at least one reported ADR combined with the system organ class (SOC) ‘psychiatric disorders’. The non-cases comprised all patients who did not experience an ADR related to the SOC ‘psychiatric disorders’. Index reports comprised all ADR reports involving at least one statin, while all ADR reports not involving statins as suspected drugs were used as controls. Results: According to selection criteria, 35 314 reports were included in the analysis. A total of 71 psychiatric preferred terms combined with statins were identified in 60 reports. Among them, 14 reports (23.3%) noted a positive rechallenge. Both the unadjusted (0.8; 95% CI 0.6, 1.1) and adjusted ROR (0.7;95% CI 0.6, 1.0) suggested a lower rate of reports of psychiatric events for statins as a whole class compared with all other drugs, although the difference was not significant. The five most frequently reported psychiatric events combined with statins were insomnia, somnolence, agitation, confusion and hallucination. Only insomnia was reported with higher frequency for statins compared with all other drugs (ROR = 3.3; 95% CI 1.9, 5.7), while confusion was reported with a lower frequency (ROR = 0.4; 95% CI 0.1, 0.9). Amongst statins available in Italy, only simvastatin (ROR = 0.5; 95% CI 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events compared with all other drugs together. Conclusion: A relatively small number of possible statin-associated psychiatric ADRs have been found in our database. No significant risks for a higher overall reporting of psychiatric ADRs associated with statins were identified in comparison with all other drugs combined. However, statin-associated insomnia resulted in a significant ROR that requires further investigation.

Gas chromatographic–tandem mass spectrometric identification of phenolic compounds in Sicilian olive oils

Phenolic compounds in Sicilian olive oils were analyzed by GC–MS and GC–MS/MS after extraction with methanol:water 80:20 and derivatization with bis(trimethylsilyl)trifluoracetamide and trimethylchlorosilane (BSTFA:TMCS 99:1). Numerous compounds were detected and 23 were identified. Tyrosol, hydroxytyrosol and the decarbomethoxy ligstroside and oleuropein aglycons in the dialdehydic forms were the most abundant compounds. 4-(Acetoxyethyl)-1-hydroxybenzene, 3,4-dihydroxyphenylacetaldehyde, syringaldehyde and the cis form of ferulic acid were identified: these compounds were not found in olive oils before. The presence of the dialdehydic form of elenolic acid (without carbomethoxy group) linked to 3-methoxy-4-hydroxyphenylethanol was hypothesized. There were quantitative differences in oils from the varieties Nocellara del Belice, Santagatese and Cerasuola; these differences could depend on the olive varieties and ripeness.

Short-term memory loss associated with rosuvastatin

Memory loss and cognitive impairment have been reported in the literature in association with several 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins), but we found no published case reports associated with rosuvastatin. To our knowledge, this is the first reported case of rosuvastatin‐related short‐term memory loss. A 53‐year‐old Caucasian man with hypercholesterolemia experienced memory loss after being treated with rosuvastatin 10 mg/day. He had no other concomitant conditions or drug therapies. After discontinuation of rosuvastatin, the neuropsychiatric adverse reaction resolved gradually, suggesting a probable drug association. During the following year, the patient remained free from neuropsychiatric disturbances. Clinicians should be aware of possible adverse cognitive reactions during statin therapy, including rosuvastatin.

Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies

Introduction: An increased risk of cardiovascular thrombotic events in users of NSAIDs was first demonstrated for rofecoxib. This risk seems to be related to the COX-2 inhibitory potency and has been found with most NSAIDs except naproxen. Two main hypotheses have been advanced: an imbalance between COX-1-dependent platelet production of thromboxane and partly COX-2-dependent endothelial production of prostacyclin, and a COX-2-dependent increase in blood pressure. Areas covered: Clinical trials and observational studies providing information about cardiovascular risk associated with long-term use of NSAIDs were retrieved; 14 clinical trials and 16 observational studies mentioned a follow-up of at least 6 months. Expert opinion: Results are ambiguous: long-term exposure seemed associated with an increased risk of myocardial infarction or stroke with high-dose rofecoxib, and perhaps diclofenac, but less with other NSAIDs. In other studies, little or no increase in risk was associated with exposures shorter than 30 days. Since most NSAIDs are rarely used long term, there is little information on risks associated with long-term use. The relative risks or odds ratios associated with most drugs are mostly well below 2.

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system

AIM We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). METHODS We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. RESULTS DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). CONCLUSIONS The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.

Allergic reactions to oral drugs : A case/non-case study from an Italian spontaneous reporting database (GIF)

Despite the wide number of studies investigating on drug-induced allergy, limited data focused on allergies associated with orally administered drugs are available. The aim of the study is to evaluate allergic drug reactions associated with oral drug use, using an Italian spontaneous reporting database of adverse drug reactions (ADRs). Spontaneous reports associated with oral drugs retrieved from seven Italian regions (GIF research group), collected from 1988 to 2006, were analysed. Association between drugs and allergic adverse reactions was assessed using the case/non-case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Overall, 27,175 reports of adverse reactions related to oral drug use were analysed; of these, 3143 (11.6%) were judged as allergy cases. Paediatric patients (<or=15 years) and inpatients (p<0.001) were more represented in cases than in non-cases. Antibiotics and Non-Steroidal Anti-inflammatory Drugs (NSAIDs) were the only two drug classes associated with a significant increase of ROR. Regarding antibiotics, cinoxacin (6.88; 95%CI 4.19-11.29) and moxifloxacin (4.20; 95% CI 3.19-5.55) were related to the highest ROR values, while propionic acid derivates (ROR 2.75; 95% CI 2.30-3.28), and in particular ibuprofen (4.20; 95% CI 3.13-5.63), have shown the highest ROR values among NSAIDs. The results of the present paper confirm the higher frequency of allergic reactions with oral antibiotics and NSAIDs, although more data are needed. Given the widespread use of these drug classes (some of them being purchased as over the counter drugs), awareness should be raised among patients and prescribers about these risks.